FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Van Buskirk, GA Arsulowicz, D Basu, P Block, L Cai, B Cleary, GW Ghosh, T Gonzalez, MA Kanios, D Marques, M Noonan, PK Ocheltree, T Schwarz, P Shah, V Spencer, TS Tavares, L Ulman, K Uppoor, R Yeoh, T AF Van Buskirk, Glenn A. Arsulowicz, Daniel Basu, Prabir Block, Lawrence Cai, Bing Cleary, Gary W. Ghosh, Tapash Gonzalez, Mario A. Kanios, David Marques, Margareth Noonan, Patrick K. Ocheltree, Terrance Schwarz, Peter Shah, Vinod Spencer, Thomas S. Tavares, Lino Ulman, Katherine Uppoor, Rajendra Yeoh, Thean TI Passive Transdermal Systems Whitepaper Incorporating Current Chemistry, Manufacturing and Controls (CMC) Development Principles SO AAPS PHARMSCITECH LA English DT Article DE CMC; ICH; quality by design (QbD); residual drug; TDS AB In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration's Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro-in vivo correlation considerations for transdermal systems. C1 [Van Buskirk, Glenn A.] Nonclin Drug Dev Consulting Serv LLC, Basking Ridge, NJ 07920 USA. [Arsulowicz, Daniel] Corium Int Inc, Grand Rapids, MI 49512 USA. [Basu, Prabir] Natl Inst Pharmaceut Technol & Engn, Prospect, IL 60056 USA. [Block, Lawrence] Duquesne Univ, Pittsburgh, PA 15282 USA. [Cai, Bing] US FDA, Rockville, MD 20855 USA. [Cleary, Gary W.] Corium Int Inc, Menlo Pk, CA 94025 USA. [Ghosh, Tapash; Ocheltree, Terrance; Uppoor, Rajendra] US FDA, Silver Spring, MD 20993 USA. [Gonzalez, Mario A.] PKinet Int Inc, Pembroke Pines, FL 33027 USA. [Kanios, David] Pharmaceut Res Consultant, Palmetto Bay, FL 33157 USA. [Marques, Margareth] US Pharmacopeia, Rockville, MD 20852 USA. [Noonan, Patrick K.] PK Noonan & Associates LLC, Richmond, VA 23233 USA. [Schwarz, Peter] Lohmann Therapie Syst AG, Andernach, Germany. [Shah, Vinod] Pharmaceut Consultant USP, N Potomac, MD 20878 USA. [Spencer, Thomas S.] Becwar Spencer Associates, Billingham, WA 98226 USA. [Tavares, Lino] Purdue Pharma LP, Stamford, CT 06901 USA. [Ulman, Katherine] Dow Corning Corp, Midland, MI 48686 USA. [Yeoh, Thean] Pfizer Inc, Groton, CT 06340 USA. RP Van Buskirk, GA (reprint author), Nonclin Drug Dev Consulting Serv LLC, Basking Ridge, NJ 07920 USA. EM vanbuskirk@drugdevconsult.com NR 24 TC 12 Z9 12 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD MAR PY 2012 VL 13 IS 1 BP 218 EP 230 DI 10.1208/s12249-011-9740-9 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 949CD UT WOS:000304552300026 PM 22215291 ER PT J AU Anand, O Almoazen, H Mehrotra, N Johnson, J Shukla, A AF Anand, Om Almoazen, Hassan Mehrotra, Nitin Johnson, James Shukla, Atul TI Controlled Release of Modified Insulin Glargine from Novel Biodegradable Injectable Gels SO AAPS PHARMSCITECH LA English DT Article DE diabetes mellitus; insulin glargine; novel biodegradable injectable gels; polylactic-co-glycolic acid (PLGA) ID DIABETES-MELLITUS; PATHOGENESIS; RATS AB The objective of this study was to investigate the duration of biological effects of modified insulin glargine released from a novel biodegradable injectable gel in type II diabetic Zucker diabetic fatty (ZDF) rats. Modified insulin glargine was purified from the marketed formulation by process of dialysis followed by freeze-drying, and the purity was confirmed by the single peak, corresponding to insulin glargine in the HPLC chromatogram. To determine and to compare the biological activity of purified insulin glargine with marketed formulation, it was suspended in isotonic saline solutions and administered subcutaneously to ZDF rats at a dose of 10 IU/kg of insulin and the blood glucose levels were measured. The blood glucose levels of ZDF rats after a subcutaneous injection of a suspension of purified insulin glargine decreased below 200 mg/dL within 2 h and remained at this level up to 6 h, then steadily raised above 400 mg/dL in 12 h. Insulin glargine particles were loaded into a novel biodegradable injectable gel formulation prepared from a blend of polylactic-co-glycolic acid (PLGA) and biocompatible plasticizers. Approximately 0.1 mL of insulin glargine-loaded gel prepared with PLGA was administered subcutaneously to the ZDF rats, and blood glucose levels were measured. The PLGA gel formulations prepared with insulin glargine particles had duration of action of 10 days following a single subcutaneous injection. The addition of zinc sulfate to the formulations prepared with purified insulin glargine particles further slowed down the drop in blood glucose concentrations. C1 [Anand, Om; Almoazen, Hassan; Johnson, James; Shukla, Atul] Univ Tennessee, Dept Pharmaceut Sci, Memphis, TN USA. [Anand, Om] US FDA, Div Bioequivalence 2, Off Gener Drugs, Rockville, MD 20857 USA. [Mehrotra, Nitin] US FDA, Div Pharmacometr, Off Clin Pharmacol, Silver Spring, MD USA. RP Anand, O (reprint author), Univ Tennessee, Dept Pharmaceut Sci, 847 Monroe Ave, Memphis, TN USA. EM omganand@gmail.com OI Almoazen, Hassan/0000-0001-8059-1637 NR 16 TC 0 Z9 0 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD MAR PY 2012 VL 13 IS 1 BP 313 EP 322 DI 10.1208/s12249-011-9744-5 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 949CD UT WOS:000304552300035 PM 22258803 ER PT J AU Yemelyanau, M Amialchuk, A Ali, MM AF Yemelyanau, Maksim Amialchuk, Aliaksandr Ali, Mir M. TI Evidence from the Chernobyl Nuclear Accident: The Effect on Health, Education, and Labor Market Outcomes in Belarus SO JOURNAL OF LABOR RESEARCH LA English DT Article DE Chernobyl; Belarus; Health; Education; Wage; Employment ID RADIOACTIVE FALLOUT; IN-UTERO; CHILDREN; CHILDHOOD; EXPOSURE; ADOLESCENTS; POPULATION; RADIATION; DISEASE AB The Chernobyl nuclear accident of 1986 had deleterious health consequences for the population of Belarus, especially for those who were children at the time of the disaster. Using the 2003-2008 waves of the Belarusian Household Survey of Income and Expenditure (BHSIE), we estimate the effect of radiation exposure on the health, education, and labor market outcomes among cohorts and areas affected by the accident, utilizing the nuclear accident as a natural experiment. We find that young individuals who came from the most contaminated areas had worse health, were less likely to hold university degrees, were less likely to be employed, and had lower wages compared to those who were older at the time of the accident and who came from less contaminated areas. C1 [Amialchuk, Aliaksandr] Univ Toledo, Dept Econ, Toledo, OH 43606 USA. [Yemelyanau, Maksim] CERGE EI, Prague 11121, Czech Republic. [Ali, Mir M.] Univ Toledo, Dept Econ, College Pk, MD 20740 USA. [Ali, Mir M.] US FDA, Off Regulat Policy & Social Sci, College Pk, MD 20740 USA. RP Amialchuk, A (reprint author), Univ Toledo, Dept Econ, Toledo, OH 43606 USA. EM maksim.yemelyanau@gmail.com; aamialc@utnet.utoledo.edu; mir.ali@fda.hhs.gov NR 32 TC 2 Z9 2 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0195-3613 EI 1936-4768 J9 J LABOR RES JI J. Labor Res. PD MAR PY 2012 VL 33 IS 1 BP 1 EP 20 DI 10.1007/s12122-011-9122-9 PG 20 WC Industrial Relations & Labor SC Business & Economics GA 935HV UT WOS:000303510700001 ER PT J AU Rallabhandi, P AF Rallabhandi, Prasad TI Gluten and Celiac Disease-An Immunological Perspective SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID INTESTINAL BARRIER FUNCTION; T-CELL EPITOPES; INTRAEPITHELIAL LYMPHOCYTES; REFRACTORY SPRUE; GUT PERMEABILITY; GLIADIN; DIAGNOSIS; ZONULIN; INTERLEUKIN-15; IDENTIFICATION AB Gluten, a complex protein group in wheat, rye, and barley, causes celiac disease (CD), an autoimmune enteropathy of the small intestine, in genetically susceptible individuals. CD affects about 1% of the general population and causes significant health problems. Adverse inflammatory reactions to gluten are mediated by inappropriate T-cell activation leading to severe damage of the gastrointestinal mucosa, causing atrophy of absorptive surface villi. Gluten peptides bind to the chemokine receptor, CXCR3, and induce release of zonulin, which mediates tight-junction disassembly and subsequent increase in intestinal permeability. Proinflammatory cytokine IL-15 also contributes to the pathology of CD, by driving the expansion of intra-epithelial lymphocytes that damage the epithelium and promote the onset of T-cell lymphomas. There is no cure or treatment for CD, except for avoiding dietary gluten. Current gluten thresholds for food labeling have been established based on the available analytical methods, which show variation in gluten detection and quantification. Also, the clinical heterogeneity of celiac patients poses difficulty in defining clinically acceptable gluten thresholds in gluten-free foods. Presently, there is no bioassay available to measure gluten-induced immunobiological responses. This review focuses on various aspects of CD, and the importance of gluten thresholds and reference material from an immunological perspective. C1 US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Rallabhandi, P (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM Prasad.Rallabhandi@fda.hhs.gov FU FDA Office of Women's Health FX I would like to thank Kristina Williams, Marianne Solomotis, Darcy Hanes, and Karman Balan, FDA, Center for Food Safety and Applied Nutrition, for critical reading of this manuscript. This work was supported by an FDA Office of Women's Health Grant (to Prasad Rallabhandi). NR 59 TC 8 Z9 8 U1 5 U2 39 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD MAR-APR PY 2012 VL 95 IS 2 BP 349 EP 355 DI 10.5740/jaoacint.SGE_Rallabhandi PG 7 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA 929TK UT WOS:000303088400018 PM 22649918 ER PT J AU Sharma, GM AF Sharma, Girdhari M. TI Immunoreactivity and Detection of Wheat Proteins by Commercial ELISA Kits SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID EXERCISE-INDUCED ANAPHYLAXIS; MOLECULAR-WEIGHT GLUTENINS; FOOD ALLERGY; BAKERS ASTHMA; FRACTIONS; GLIADIN; FLOUR; PREVALENCE; EXTRACTION; REACTIVITY AB Wheat proteins are responsible for sensitivities, including baker's asthma, immunoglobulin E (IgE)-mediated allergic reaction, wheat-dependent, exercise-induced anaphylaxis, and celiac disease. The detection of gluten/wheat traces in foods is important to safeguard the health of wheat-sensitive individuals and comply with food labeling. Many immunoanalytical-based commercial kits are available for the quantification of gliadin/gluten/wheat proteins. We compared the immunoreactivity of wheat fractions with wheat-allergic human serum IgE and antibody conjugates used in six commercial immunoassay kits. Moreover, the performance of the kits was tested using corn flour spiked with gluten (5, 10, 25, and 50 ppm) and wheat flour (50, 100, 250, and 500 ppm). The albumin, globulin, gliadin, and glutenin fractions reacted with IgE from nine, eight, two, and eight patients' sera, respectively, out of nine wheat allergic patients tested. Among the antibodies from commercial kits, those from R-Biopharm, Morinaga, and Romer Labs reacted strongly with the gliadin fraction, whereas those from BioKits, ALLER-TEK, and ELISA Systems reacted strongly with the glutenin fraction. All kits showed minimal or no reactivity with albumin and globulin fractions. All kits detected the gluten and wheat flour in a corn flour matrix at the lowest spiked levels of 5 and 50 ppm, respectively. However, there was wide variation among the kits when comparing the recovery of gluten and wheat flour. The recovery was also dependent on the source material (gluten or wheat flour) used for spiking the corn flour matrix. C1 US FDA, Ctr Food Safety & Appl Nutr, Immunobiol Branch, Laurel, MD 20708 USA. RP Sharma, GM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Immunobiol Branch, Laurel, MD 20708 USA. EM Girdhari.Sharma@fda.hhs.gov NR 27 TC 16 Z9 16 U1 1 U2 15 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD MAR-APR PY 2012 VL 95 IS 2 BP 364 EP 371 DI 10.5740/jaoacint.SGE_Sharma PG 8 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA 929TK UT WOS:000303088400020 PM 22649920 ER PT J AU Tallent, SM Kotewicz, KM Strain, EA Bennett, RW AF Tallent, Sandra M. Kotewicz, Kristin M. Strain, Errol A. Bennett, Reginald W. TI Efficient Isolation and Identification of Bacillus cereus Group SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID CULTURE-MEDIA; ENUMERATION; FOODS; STANDARD AB Bacillus cereus is a group of ubiquitous facultative anaerobic sporeforming Gram-positive rods commonly found in soil. The spores frequently contaminate a variety of foods, including produce, meat, eggs, and dairy products. Foodborne illnesses associated with toxins produced by B. cereus can result in self-limiting diarrhea or vomiting. Plate enumeration methods recommended by recognized food authorities to detect the presence of B. cereus in potentially contaminated food products do not inhibit other Gram-positive competitive bacteria. This study evaluated the use of Bacara, a new chromogenic agar, as an efficient method to identify and enumerate B. cereus group from food matrixes, even in the presence of background flora. Inclusivity and exclusivity testing was performed using four different selective and differential media for B. cereus, including Mannitol Egg Yolk Polymyxin (MYP), Polymyxin Pyruvate Egg-Yolk Mannitol Bromothymol Blue Agar, Bacillus Chromogenic Media, Brilliance, and Bacara. MYP and Bacara were also used in plate enumeration studies to isolate B. cereus from artificially contaminated foods. C1 [Tallent, Sandra M.; Strain, Errol A.; Bennett, Reginald W.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Kotewicz, Kristin M.] Oak Ridge Inst Sci & Educ, Oak Ridge, TN 37831 USA. RP Tallent, SM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Sandra.Tallent@fda.hhs.gov NR 12 TC 15 Z9 15 U1 5 U2 37 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 J9 J AOAC INT JI J. AOAC Int. PD MAR-APR PY 2012 VL 95 IS 2 BP 446 EP 451 DI 10.5740/jaoacint.11-251 PG 6 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA 929TK UT WOS:000303088400032 PM 22649932 ER PT J AU Sun, YS Gruber, M Matsumoto, M AF Sun, Yuansheng Gruber, Marion Matsumoto, Mineo TI Overview of global regulatory toxicology requirements for vaccines and adjuvants SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE Vaccine; Adjuvant; Toxicology; Nonclinical; Safety assessment ID RESPONSIVENESS AB This paper provides an overview of the legislations and regulatory approaches currently applied to the nonclinical safety assessment of human preventive vaccine products in three ICH regions, i.e., the EU, USA, and Japan. Perspectives of the three regions with regard to the various types of toxicity studies currently considered to assess the nonclinical safety of preventive vaccines are compared and described in more detail than in published guidelines. In addition, the common issues and current challenges in nonclinical safety assessment of preventive vaccines are discussed. (C) 2012 Elsevier Inc. All rights reserved. C1 [Sun, Yuansheng] Paul Ehrlich Inst, Viral Vaccine Sect, Fed Inst Vaccines & Biomed, D-63225 Langen, Germany. [Gruber, Marion] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Sun, YS (reprint author), Paul Ehrlich Inst, Viral Vaccine Sect, Fed Inst Vaccines & Biomed, Paul Ehrlich Str 51-59, D-63225 Langen, Germany. EM sunyu@pei.de; marion.gruber@FDA.hhs.gov; matsumoto-mineo@pmda.go.jp NR 27 TC 13 Z9 14 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD MAR-APR PY 2012 VL 65 IS 2 BP 49 EP 57 DI 10.1016/j.vascn.2012.01.002 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 925NV UT WOS:000302769000001 PM 22326278 ER PT J AU Cho, S AF Cho, Seungil TI Sample stacking with in-column silylation for less volatile polar compounds using GC-MS SO JOURNAL OF SEPARATION SCIENCE LA English DT Article DE Bisphenol A; In-column silylation; Multiple injections; N; O-bis(trimethylsilyl)trifluoroacetamide (BSTFA); Sample stacking ID GAS-LIQUID CHROMATOGRAPHY; TRIMETHYLSILYL ETHER DERIVATIVES; PEAK-SHIFT TECHNIQUE; BISPHENOL-A; MASS-SPECTROMETRY; DERIVATIZATION; INJECTION; WATER AB This paper presents sample stacking with in-column silylation (SIS) for quantitative analysis of less volatile polar compounds using gas chromatography-mass spectrometry (GC-MS). This was achieved by the combination of sandwiched in-column silylation and multiple injections (up to 100 times or 100 mu L in total). N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) was used as a silylating reagent. For the SIS technique, samples were introduced multiple N times (N = 2 similar to 100) into a capillary column in between BSTFA injections. The quantitative characteristic of SIS technique was studied using bisphenol A (BPA) as a model compound. The sandwiched in-column silylation for the less volatile polar compounds effectively replaced polar hydrogen with trimethylsilyl group to reduce sample adsorption and band broadening. Meanwhile, multiple injections at the SIS technique contributed to increase the sensitivity quantitatively. The capability and limitation of this analytical approach were further investigated with various types of compounds such as hydroxyls, carboxylic acids, and amine. C1 US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. RP Cho, S (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM seungil.cho@fda.hhs.gov NR 21 TC 2 Z9 2 U1 0 U2 10 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9306 J9 J SEP SCI JI J. Sep. Sci. PD MAR PY 2012 VL 35 IS 5-6 BP 661 EP 665 DI 10.1002/jssc.201100920 PG 5 WC Chemistry, Analytical SC Chemistry GA 929DC UT WOS:000303040400006 PM 22331828 ER PT J AU Levi, MS Divine, B Hanig, JP Doerge, DR Vanlandingham, MM George, NI Twaddle, NC Bowyer, JF AF Levi, Mark S. Divine, Becky Hanig, Joseph P. Doerge, Daniel R. Vanlandingham, Michelle M. George, Nysia I. Twaddle, Nathan C. Bowyer, John F. TI A comparison of methylphenidate-, amphetamine-, and methamphetamine-induced hyperthermia and neurotoxicity in male Sprague-Dawley rats during the waking (lights off) cycle SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Amphetamines; Methamphetamine; Methylphenidate; Hyperthermia; Neurotoxicity; Waking cycle ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; BLOOD-BRAIN-BARRIER; NEURONAL DEGENERATION; DOPAMINERGIC INNERVATION; SUBSTITUTED AMPHETAMINES; STRIATAL DOPAMINE; BODY-TEMPERATURE; HYPERTENSIVE-RAT; EXTENDED-RELEASE; C57BL/6J MOUSE AB Previous studies focusing on amphetamine (AMPH), methamphetamine (METH) and methylphenidate (MPH) neurotoxicity have almost exclusively been conducted in rodents during the light cycle, which is when most rodents sleep. There are virtually no studies that have simultaneously compared the effects of these three stimulants on body temperature and also determined serum stimulant levels during exposure. The present study compared the effects of MPH, AMPH and METH treatment on body temperature and neurotoxicity during the waking (dark) cycle of the rat. This was done to more effectively replicate stimulant exposure in waking humans and to evaluate the relative risks of the three stimulants when taken inappropriately or non-therapeutically (e.g., abuse). Four subcutaneous injections (4x), at 2 h intervals, were used to administer each dose of the stimulants tested. Several equimolar doses for the three stimulants were chosen to produce plasma levels ranging from 3 times the highest therapeutic levels (no effect on body temperature) to those only attained by accidental overdose or intentional abuse in humans. Either 4 x 2.0 mg/kg,AMPH or 4 x 2.2 mg/kg METH administered during the waking cycle resulted in peak serum levels of between 1.5 and 2.5 mu M (4 to 5 times over maximum therapeutic levels of METH and AMPH) and produced lethal hyperthermia, 70% striatal dopamine depletions, and neurodegeneration in the cortex and thalamus. These results show that METH and AMPH are equipotent at producing lethal hyperthermia and neurotoxicity in laboratory animals during the wake cycle. Administration of either 4 x 2.2 or 4 x 3.3 mg/kg METH during the sleep cycle produced lower peak body temperatures, minimal dopamine depletions and little neurodegeneration. These findings indicate that administration of the stimulant during the waking cycle compared to sleep cycle may significantly increase the potency of amphetamines to produce hyperthermia, neurotoxicity and lethality. In contrast, body temperature during the waking cycle was only significantly elevated by MPH at 4 x 22 mg/kg, and the serum levels producing this effect were 2-fold (approximately 4.5 mu M) greater on a molar basis than hyperthermic doses of AMPH and METH. Thus, AMPH and METH were equipotent on a mg/kg body weight basis at producing hyperthermia and neurotoxicity while MPH on a mg/kg body weight basis was approximately 10-fold less potent than AMPH and METH. However, the 10-fold lower potency was in large part due to lower plasma levels produced by MPH compared to either AMPH or METH. Published by Elsevier Inc. C1 [Levi, Mark S.; Divine, Becky; Bowyer, John F.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Doerge, Daniel R.; Vanlandingham, Michelle M.; Twaddle, Nathan C.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [George, Nysia I.] US FDA, Div Personalized Nutr & Med, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Hanig, Joseph P.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Bowyer, JF (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 132, Jefferson, AR 72079 USA. EM mark.levi@fda.hhs.gov; becky.divine@fda.hhs.gov; joseph.hanig@fda.hhs.gov; daniel.doerge@fda.hhs.gov; michelle.vanlandingham@fda.hhs.gov; nysia.george@fda.hhs.gov; nathan.twaddle@fda.hhs.gov; john.bowyer@fda.hhs.gov NR 62 TC 13 Z9 13 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAR-APR PY 2012 VL 34 IS 2 BP 253 EP 262 DI 10.1016/j.ntt.2012.01.007 PG 10 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 928YQ UT WOS:000303028800004 PM 22289608 ER PT J AU Paule, MG Green, L Myerson, J Alvarado, M Bachevalier, J Schneider, JS Schantz, SL AF Paule, Merle G. Green, Leonard Myerson, Joel Alvarado, Maria Bachevalier, Jocelyne Schneider, Jay S. Schantz, Susan L. TI Behavioral toxicology of cognition: Extrapolation from experimental animal models to humans Behavioral toxicology symposium overview SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Behavioral toxicology; Nonhuman primate; Monkey; Rodent; Translational neuroscience ID EARLY PARKINSONS-DISEASE; OPERANT TEST BATTERY; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; VISUAL RECOGNITION MEMORY; NMDA RECEPTOR ANTAGONISTS; INFANT RHESUS MACAQUES; MPTP-TREATED MONKEYS; MATCHING-TO-SAMPLE; HIPPOCAMPAL-FORMATION; NONHUMAN-PRIMATES AB A variety of behavioral instruments are available for assessing important aspects of cognition in both animals and humans and, in many cases, the same instruments can be used in both. While nonhuman primates are phylogenetically closest to humans, rodents, pigeons and other animals also offer behaviors worthy of note. Delay Discounting procedures are as useful as any in studies of impulsivity and may have utility in shedding light on processes associated with drug abuse. Specific memory tests such as Visual Paired Comparisons tasks (similar to the Fagan test of infant intelligence) can be modified to allow for assessment of different aspects of memory such as spatial memory. Use of these and other specific memory tasks can be used to directly monitor aspects of cognitive development in infant animals, particularly in nonhuman primates such as monkeys, and children and to draw inferences with respect to possible neuroanatomical substrates sub-serving their functions. Tasks for assessing working memory such as Variable Delayed Response (VDR), modified VDR and Spatial Working Memory tasks are now known to be affected in Parkinson's disease (PD). These and other cognitive function tasks are being used in a monkey model of PD to assess the ability of anti-Parkinson's disease therapies to ameliorate these cognitive deficits without diminishing their therapeutic effects on motor dysfunction. Similarly, in a rat model of the cognitive deficits associated with perinatal exposure to polychlorinated biphenyls (PCBs), clear parallels with children can be seen in at least two areas of executive function: cognitive flexibility and response inhibition. In the rat model, discrimination reversal tasks were utilized to assess cognitive flexibility, a function often assessed in humans using the Wisconsin Card Sorting Task. Response inhibition was assessed using performance in a Differential Reinforcement of Low Response Rates (DRL) task. As the data continue to accumulate, it becomes more clear that our attempts to adapt animal-appropriate tasks for the study of important aspects of human cognition have proven to be very fruitful. Published by Elsevier Inc. C1 [Paule, Merle G.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Green, Leonard; Myerson, Joel] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Alvarado, Maria; Bachevalier, Jocelyne] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Bachevalier, Jocelyne] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Schneider, Jay S.] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Schantz, Susan L.] Univ Illinois, Coll Vet Med, Pharmacol Toxicol Div, Urbana, IL 61801 USA. RP Paule, MG (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM merle.paule@fda.hhs.gov FU NIMH [MH-58846]; NICHD [HD-35471]; NIH [MH-055308, RR-00165] FX Grant sponsor: NIMH; Grant Number: MH-58846; Grant Sponsor: NICHD; Grant Number: HD-35471; Grant Sponsor NIH; Grant Number MH-055308, RR-00165. The findings and conclusions in the report by M.G. Paule are those of the author and do not necessarily represent the views of the FDA and mention of trade names or commercial products does not constitute endorsement or recommendation for use. NR 119 TC 7 Z9 8 U1 7 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAR-APR PY 2012 VL 34 IS 2 BP 263 EP 273 DI 10.1016/j.ntt.2012.01.008 PG 11 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 928YQ UT WOS:000303028800005 PM 22311110 ER PT J AU Morris, JG Greenspan, A Howell, K Gargano, LM Mitchell, J Jones, JL Potter, M Isakov, A Woods, C Hughes, JM AF Morris, J. Glenn, Jr. Greenspan, Allison Howell, Kelly Gargano, Lisa M. Mitchell, Joanne Jones, Jeffrey L. Potter, Morris Isakov, Alexander Woods, Christopher Hughes, James M. TI SOUTHEASTERN CENTER FOR EMERGING BIOLOGIC THREATS TABLETOP EXERCISE: FOODBORNE TOXOPLASMOSIS OUTBREAK ON COLLEGE CAMPUSES SO BIOSECURITY AND BIOTERRORISM-BIODEFENSE STRATEGY PRACTICE AND SCIENCE LA English DT Article ID ACUTE RESPIRATORY SYNDROME; PUBLIC-HEALTH PREPAREDNESS; CORONAVIRUS; IDENTIFICATION; BIOTERRORISM; GONDII AB The use of tabletop exercises as a tool in emergency preparedness and response has proven to be an effective means of assessing readiness for unexpected events. Whereas most exercise developers target a population in a defined space (eg, state, county, metropolitan area, hospital), the Southeastern Center for Emerging Biologic Threats (SECEBT) conducted an innovative tabletop exercise involving an unusual foodborne outbreak pathogen, targeting public health agencies and academic institutions in 7 southeastern states. The exercise tested the ability of participants to respond to a simulated foodborne disease outbreak affecting the region. The attendees represented 4 federal agencies, 9 state agencies, 6 universities, 1 nonprofit organization, and 1 private corporation. The goals were to promote collaborative relationships among the players, identify gaps in plans and policies, and identify the unique contributions of each organization-and notably academic institutions-to outbreak recognition, investigation, and control. Participants discussed issues and roles related to outbreak detection and management, risk communication, and coordination of policies and responsibilities before, during, and after an emergency, with emphasis on assets of universities that could be mobilized during an outbreak response. The exercise generated several lessons and recommendations identified by participants and evaluators. Key recommendations included a need to establish trigger points and protocols for information sharing and alerts among public health, academic, and law enforcement; to establish relationships with local, state, and federal stakeholders to facilitate communications during an emergency; and to catalogue and leverage strengths, assets, and priorities of academic institutions to add value to outbreak responses. C1 [Howell, Kelly; Gargano, Lisa M.] Emory Univ, Dept Med, Res Projects, Atlanta, GA 30322 USA. [Morris, J. Glenn, Jr.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Greenspan, Allison] Emory Global Hlth Inst, IANPHI, Atlanta, GA USA. [Mitchell, Joanne] Bridgewell Solut, Decatur, GA USA. [Jones, Jeffrey L.] Ctr Dis Control & Prevent, Parasit Dis Branch, Div Parasit Dis & Malaria, Ctr Global Hlth, Atlanta, GA USA. [Potter, Morris] Ctr Dis Control & Prevent, US FDA, Atlanta, GA USA. [Potter, Morris] Ctr Dis Control & Prevent, FDA Liaison, Atlanta, GA USA. [Woods, Christopher] Duke Univ, Dept Med, Durham, NC USA. RP Gargano, LM (reprint author), Emory Univ, Dept Med, Res Projects, 1462 Clifton Rd,Room 446, Atlanta, GA 30322 USA. EM lgargan@emory.edu FU NCATS NIH HHS [UL1 TR000064]; NIAID NIH HHS [U54-AI-057157]; OID CDC HHS [H75CH00002]; PHS HHS [U38/CCU423095] NR 25 TC 7 Z9 7 U1 0 U2 10 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1538-7135 EI 1557-850X J9 BIOSECUR BIOTERROR JI Biosecur. Bioterror. PD MAR PY 2012 VL 10 IS 1 BP 89 EP 97 DI 10.1089/bsp.2011.0040 PG 9 WC Public, Environmental & Occupational Health; International Relations SC Public, Environmental & Occupational Health; International Relations GA 917ZU UT WOS:000302219400009 PM 22283568 ER PT J AU Saldanha, LG Dwyer, JT Holden, JM Ireland, JD Andrews, KW Bailey, RL Gahche, JJ Hardy, CJ Moller, A Pilch, SM Roseland, JM AF Saldanha, Leila G. Dwyer, Johanna T. Holden, Joanne M. Ireland, Jayne D. Andrews, Karen W. Bailey, Regan L. Gahche, Jaime J. Hardy, Constance J. Moller, Anders Pilch, Susan M. Roseland, Janet M. TI A structured vocabulary for indexing dietary supplements in databases in the United States SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Article DE LanguaL; Government; Dietary supplements; Databases; Indexing; Structured vocabulary; Thesaurus; Food analysis; Food composition ID INTERNATIONAL INTERFACE STANDARD; FOOD DATABASES AB Food composition databases are critical to assess and plan dietary intakes. Dietary supplement databases are also needed because dietary supplements make significant contributions to total nutrient intakes. However, no uniform system exists for classifying dietary supplement products and indexing their ingredients in such databases. Differing approaches to classifying these products make it difficult to retrieve or link information effectively. A consistent approach to classifying information within food composition databases led to the development of LanguaL (TM), a structured vocabulary. LanguaL (TM) is being adapted as an interface tool for classifying and retrieving product information in dietary supplement databases. This paper outlines proposed changes to the LanguaL (TM) thesaurus for indexing dietary supplement products and ingredients in databases. The choice of 12 of the original 14 LanguaL (TM) facets pertinent to dietary supplements, modifications to their scopes, and applications are described. The 12 chosen facets are: product type; product source; part of source; physical state, shape or form; ingredients; preservation method; packing medium; container or wrapping; contact surface; label claims/consumer group/dietary use; geographic places and regions; and adjunct characteristics of dietary supplements. Published by Elsevier Inc. C1 [Saldanha, Leila G.; Dwyer, Johanna T.; Bailey, Regan L.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Holden, Joanne M.; Andrews, Karen W.; Roseland, Janet M.] ARS, Nutrient Data Lab, USDA, Beltsville, MD 20705 USA. [Ireland, Jayne D.; Moller, Anders] Danish Food Informat, DK-4000 Roskilde, Denmark. [Gahche, Jaime J.] Natl Ctr Hlth Stat CDC, Natl Hlth & Nutr Examinat Survey Planning Branch, Hyattsville, MD 20782 USA. [Hardy, Constance J.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Pilch, Susan M.] Natl Inst Hlth Lib, MEDLINE PubMed Database, Bethesda, MD 20892 USA. RP Saldanha, LG (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd MSC 7517,Room 3B01, Bethesda, MD 20892 USA. EM saldanhl@mail.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769 FU Office of Dietary Supplements, National Institute of Health FX The Office of Dietary Supplements, National Institute of Health funded the development of the LanguaL (TM) Dietary Supplement Structured Vocabulary for use in the United States. NR 10 TC 4 Z9 4 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1575 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD MAR PY 2012 VL 25 IS 2 BP 226 EP 233 DI 10.1016/j.jfca.2011.10.003 PG 8 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA 920QX UT WOS:000302423200017 PM 22611303 ER PT J AU Thorat, C Xu, K Freeman, SN Bonnel, RA Joseph, F Phillips, MI Imoisili, MA AF Thorat, Chandana Xu, Kui Freeman, Scott N. Bonnel, Renan A. Joseph, Francesca Phillips, M. Ian Imoisili, Menfo A. TI What the Orphan Drug Act Has Done Lately for Children With Rare Diseases: A 10-Year Analysis SO PEDIATRICS LA English DT Article DE orphan drugs; rare diseases; Orphan Drug Act; pediatrics AB OBJECTIVES: The 1983 US Orphan Drug Act (ODA) provided incentives to stimulate treatment product development for patients with rare disease. This article highlights a decade of ODA contributions to this goal for children with RDs. METHODS: An internal US Food and Drug Administration database was the information source for orphan designations, marketing approvals, and prevalence numbers for 2000 to 2009. Product categorization was based on the disease age of onset for which they received designation. Category 1 products were for diseases with onset exclusively in Childhood; Category 2 products were for diseases with onset at any age; and Category 3 products were for diseases with adult onset only. Disease prevalence distributions were analyzed by using population intervals of 20 000. RESULTS: From 2000 to 2009, 1138 orphan drugs were designated and 148 received marketing approval, of which 38 (26%) were for pediatric diseases. The proportion of approvals for pediatric products increased from 17.5% (10 of 57) in the first half of the decade, to 30.8% (28 of 91) in the second. More products received designation and marketing approval for pediatric diseases with prevalence numbers fewer than 20 000 than for any other prevalence subgroup. The median disease prevalence for all pediatric orphan designations that received marketing approval was 8972. Among the pediatric orphan drug approvals categorized by therapeutic class, the endocrine/metabolic drugs had the largest representation (39%). CONCLUSIONS: The ODA incentives have led to increased product availability for RDs overall, with an increasing number of marketing approvals for children this past decade. Pediatrics 2012; 129:516-521 C1 [Xu, Kui; Freeman, Scott N.; Joseph, Francesca; Imoisili, Menfo A.] US FDA, Off Orphan Prod Dev, Off Commissioner, Silver Spring, MD 20993 USA. [Thorat, Chandana; Phillips, M. Ian] Keck Grad Inst Appl Life Sci, Ctr Rare Dis Therapies, Claremont, CA USA. [Bonnel, Renan A.] US FDA, Off Pediat Therapeut, Off Commissioner, Silver Spring, MD 20993 USA. RP Imoisili, MA (reprint author), US FDA, Off Orphan Prod Dev, Off Commissioner, 10903 New Hampshire Ave,WO32-5220, Silver Spring, MD 20993 USA. EM menfo.imoisili@fda.hhs.gov NR 8 TC 26 Z9 27 U1 1 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAR PY 2012 VL 129 IS 3 BP 516 EP 521 DI 10.1542/peds.2011-1798 PG 6 WC Pediatrics SC Pediatrics GA 922IQ UT WOS:000302541000050 PM 22371464 ER PT J AU Woo, EJ AF Woo, Emily Jane TI Dural repairs with spinal sealants SO SPINE JOURNAL LA English DT Letter ID BIOGLUE; SURGERY C1 US FDA, Rockville, MD 20857 USA. RP Woo, EJ (reprint author), US FDA, Rockville, MD 20857 USA. NR 7 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1529-9430 J9 SPINE J JI Spine Journal PD MAR PY 2012 VL 12 IS 3 BP 279 EP 279 DI 10.1016/j.spinee.2012.01.017 PG 1 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 919US UT WOS:000302355600018 PM 22469306 ER PT J AU Llorens, A Lloret, E Picouet, PA Trbojevich, R Fernandez, A AF Llorens, Amparo Lloret, Elsa Picouet, Pierre A. Trbojevich, Raul Fernandez, Avelina TI Metallic-based micro and nanocomposites in food contact materials and active food packaging SO TRENDS IN FOOD SCIENCE & TECHNOLOGY LA English DT Review ID SPOILAGE-RELATED MICROFLORA; SILVER NANOPARTICLES; ESCHERICHIA-COLI; ANTIBACTERIAL ACTIVITY; ANTIMICROBIAL ACTIVITY; CELLULOSE FIBERS; STAINLESS-STEEL; ABSORBENT PADS; COMPOSITE FILM; LACTIC-ACID AB Metallic-based micro and nano-structured materials are incorporated into food contact polymers to enhance mechanical and barrier properties, and to prevent the photodegradation of plastics. Additionally heavy metals are effective antimicrobials in the form of salts, oxides, and colloids, complexes such as silver zeolites, or as elemental nanoparticles. They are incorporated for food preservation purposes and to decontaminate surfaces in industrial environments. Other relevant properties in active food packaging, such as the capability for ethylene oxidation or oxygen scavenging, can be used to extend food shelf-life. Silver based nano-engineered materials are currently the most commonly used in commodities due to their antimicrobial capacity. Copper, zinc and titanium nanostructures are also showing promise in food safety and technology. The antimicrobial properties of zinc oxide at the nanoscale will provide affordable and safe innovative strategies. Copper has been shown to be an efficient sensor for humidity, and titanium oxide has resistance to abrasion and UV-blocking performance. The migration of cations from the polymer matrices is the key point to determine their antimicrobial effectiveness; however, this cation migration may affect legal status of the polymer as a food-contact material. C1 [Llorens, Amparo; Fernandez, Avelina] CSIC, Inst Agroquim & Tecnol Alimentos, Valencia 46980, Spain. [Lloret, Elsa; Picouet, Pierre A.] IRTA, Dept Tecnol Aliments, Monells, Girona, Spain. [Trbojevich, Raul] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Fernandez, A (reprint author), CSIC, Inst Agroquim & Tecnol Alimentos, Avda Agustin Escardino 7, Valencia 46980, Spain. EM avelina.fernandez@iata.csic.es RI Fernandez Garcia, Avelina/A-1471-2009 FU Spanish Comision Interministerial de Ciencia y Tecnologia (Ministerio de Ciencia e Innovacion) [AGL07-65936-C02]; Generalitat Valenciana [G Forteza FPA2010/075] FX Authors thank the Spanish Comision Interministerial de Ciencia y Tecnologia (Ministerio de Ciencia e Innovacion) for financial support under contract AGL07-65936-C02. A. Llorens thanks the Generalitat Valenciana for a contract G Forteza FPA2010/075. NR 87 TC 98 Z9 100 U1 25 U2 284 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0924-2244 J9 TRENDS FOOD SCI TECH JI Trends Food Sci. Technol. PD MAR PY 2012 VL 24 IS 1 BP 19 EP 29 DI 10.1016/j.tifs.2011.10.001 PG 11 WC Food Science & Technology SC Food Science & Technology GA 921CI UT WOS:000302455200003 ER PT J AU Archdeacon, P Dixon, C Belen, O Albrecht, R Meyer, J AF Archdeacon, P. Dixon, C. Belen, O. Albrecht, R. Meyer, J. TI Summary of the US FDA Approval of Belatacept SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Belatacept; clinical trials; efficacy; endpoints; safety ID PHASE-III; CYCLOSPORINE; IMMUNOSUPPRESSION; BENEFIT AB Elements of the Food and Drug Administration (FDA) review of the clinical data that supported the approval of the Biologics License Application (BLA) for belatacept for prophylaxis of organ rejection in adult patients receiving a kidney transplant are summarized. The article is not intended as a comprehensive summary of the entire belatacept data submission. Rather, the discussion is meant to illustrate aspects of the FDA's process for evaluating efficacy and safety, using belatacept as an example. C1 [Belen, O.; Albrecht, R.; Meyer, J.] US FDA, Div Transplant & Ophthalmol Prod, Off Antimicrobial Prod, Off New Drugs,Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Dixon, C.] US FDA, Div Biometr 4, Off Biostat, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Archdeacon, P.] US FDA, Off Med Policy, Drug Evaluat & Res, Rockville, MD 20857 USA. RP Meyer, J (reprint author), US FDA, Div Transplant & Ophthalmol Prod, Off Antimicrobial Prod, Off New Drugs,Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. EM Joette.Meyer@fda.hhs.gov NR 13 TC 27 Z9 28 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2012 VL 12 IS 3 BP 554 EP 562 DI 10.1111/j.1600-6143.2011.03976.x PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA 899QZ UT WOS:000300832500012 PM 22335273 ER PT J AU Haynes, LD Jankowska-Gan, E Sheka, A Keller, MR Hernandez-Fuentes, MP Lechler, RI Seyfert-Margolis, V Turka, LA Newell, KA Burlingham, WJ AF Haynes, L. D. Jankowska-Gan, E. Sheka, A. Keller, M. R. Hernandez-Fuentes, M. P. Lechler, R. I. Seyfert-Margolis, V. Turka, L. A. Newell, K. A. Burlingham, W. J. TI Donor-Specific Indirect Pathway Analysis Reveals a B-Cell-Independent Signature which Reflects Outcomes in Kidney Transplant Recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE DTH assay; human; immunological monitoring; indirect pathway; renal transplantation; transplant tolerance ID DELAYED-TYPE HYPERSENSITIVITY; T-REGULATORY-CELLS; ALLOGRAFT ACCEPTANCE; ALLOANTIBODY PRODUCTION; METASTABLE TOLERANCE; ANTIGENS; HUMANS; SUPPRESSION; RELEVANCE; RESPONSES AB To investigate the role of donor-specific indirect pathway T cells in renal transplant tolerance, we analyzed responses in peripheral blood of 45 patients using the trans-vivo delayed-type hypersensitivity assay. Subjects were enrolled into five groupsidentical twin, clinically tolerant (TOL), steroid monotherapy (MONO), standard immunosuppression (SI) and chronic rejection (CR)based on transplant type, posttransplant immunosuppression and graft function. The indirect pathway was active in all groups except twins but distinct intergroup differences were evident, corresponding to clinical status. The antidonor indirect pathway T effector response increased across patient groups (TOL < MONO < SI < CR; p < 0.0001) whereas antidonor indirect pathway T regulatory response decreased (TOL > MONO = SI > CR; p < 0.005). This pattern differed from that seen in circulating naive B-cell numbers and in a cross-platform biomarker analysis, where patients on monotherapy were not ranked closest to TOL patients, but rather were indistinguishable from chronically rejecting patients. Cross-sectional analysis of the indirect pathway revealed a spectrum in T-regulatory:T-effector balance, ranging from TOL patients having predominantly regulatory responses to CR patients having predominantly effector responses. Therefore, the indirect pathway measurements reflect a distinct aspect of tolerance from the recently reported elevation of circulating naive B cells, which was apparent only in recipients off immunosuppression. C1 [Haynes, L. D.; Jankowska-Gan, E.; Sheka, A.; Keller, M. R.; Burlingham, W. J.] Univ Wisconsin, Dept Surg, Transplant Div, Madison, WI 53715 USA. [Seyfert-Margolis, V.; Turka, L. A.] Immune Tolerance Network, Bethesda, MD USA. [Hernandez-Fuentes, M. P.; Lechler, R. I.] Kings Coll London, MRC Ctr Transplantat, London WC2R 2LS, England. [Seyfert-Margolis, V.] US Dept HHS, US FDA, Silver Spring, MD USA. [Turka, L. A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Newell, K. A.] Emory Transplant Ctr, Atlanta, GA USA. [Newell, K. A.] Emory Univ, Dept Surg, Atlanta, GA 30322 USA. RP Burlingham, WJ (reprint author), Univ Wisconsin, Dept Surg, Transplant Div, Madison, WI 53715 USA. EM burlingham@surgery.wisc.edu RI Hernandez-Fuentes, Maria/B-5011-2010 OI Hernandez-Fuentes, Maria/0000-0002-7558-9441 FU NIH [1R01-AI066219]; EU [QLRT-2002-02127]; UK Department of Health by National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre; King's College London and King's College Hospital NHS Foundation Trust; [ITN503ST] FX This work was supported by ITN507ST grant from the NIH-supported Immune Tolerance Network, by NIH grant #1R01-AI066219 (to WJB) and by the EU-sponsored One Study (WJB, LDH and MHF). M.H.F. and R.I.L. acknowledge support from ITN503ST, EU FP6 grant: QLRT-2002-02127 and from the UK Department of Health by National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. The authors wish to thank Glen Leverson for his critical help with statistical analysis. NR 32 TC 27 Z9 28 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2012 VL 12 IS 3 BP 640 EP 648 DI 10.1111/j.1600-6143.2011.03869.x PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA 899QZ UT WOS:000300832500021 PM 22151236 ER PT J AU Huang, SM AF Huang, Shiew-Mei TI PBPK as a tool in regulatory review SO BIOPHARMACEUTICS & DRUG DISPOSITION LA English DT Article C1 US FDA, Off Clin Pharmacol, OTS, CDER, Silver Spring, MD USA. RP Huang, SM (reprint author), US FDA, Off Clin Pharmacol, OTS, CDER, Silver Spring, MD USA. EM ShiewMei.Huang@fda.hhs.gov NR 8 TC 14 Z9 14 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0142-2782 J9 BIOPHARM DRUG DISPOS JI Biopharm. Drug Dispos. PD MAR PY 2012 VL 33 IS 2 SI SI BP 51 EP 52 DI 10.1002/bdd.1777 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 910QK UT WOS:000301655200002 PM 22351604 ER PT J AU Grillo, JA Zhao, P Bullock, J Booth, BP Lu, M Robie-Suh, K Berglund, EG Pang, KS Rahman, A Zhang, L Lesko, LJ Huang, SM AF Grillo, Joseph A. Zhao, Ping Bullock, Julie Booth, Brian P. Lu, Min Robie-Suh, Kathy Berglund, Eva Gil Pang, K. Sandy Rahman, Atiqur Zhang, Lei Lesko, Lawrence J. Huang, Shiew-Mei TI Utility of a physiologically-based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug-drug-disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice SO BIOPHARMACEUTICS & DRUG DISPOSITION LA English DT Article DE Complex drug interactions; renal impairment; physiologically-based pharmacokinetic modeling (PBPK) ID FACTOR-XA INHIBITOR; IN-VITRO; HUMAN-POPULATIONS; LIVER-MICROSOMES; BAY 59-7939; ERYTHROMYCIN; METABOLISM; PHARMACODYNAMICS; TRANSPORT; SAFETY AB Background: Rivaroxaban is an oral Factor Xa inhibitor. The primary objective of this communication was to quantitatively predict changes in rivaroxaban exposure when individuals with varying degrees of renal impairment are co-administered with another drug that is both a P-gp and a moderate CYP3A4 inhibitor. Methods: A physiologically based pharmacokinetic (PBPK) model was developed to simulate rivaroxaban pharmacokinetics in young (20-45 years) or older (55-65 years) subjects with normal renal function, mild, moderate and severe renal impairment, with or without concomitant use of the combined P-gp and moderate CYP3A4 inhibitor, erythromycin. Results: The simulations indicate that combined factors (i.e., renal impairment and the use of erythromycin) have a greater impact on rivaroxaban exposure than expected when the impact of these factors are considered individually. Compared with normal young subjects taking rivaroxaban, concurrent mild, moderate or severe renal impairment plus erythromycin resulted in 1.9-, 2.4- or 2.6-fold increase in exposure, respectively in young subjects; and 2.5-, 2.9-or 3.0-fold increase in exposure in older subjects. Conclusions: These simulations suggest that a drug-drug-disease interaction is possible, which may significantly increase rivaroxaban exposure and increase bleeding risk. These simulations render more mechanistic insights as to the possible outcomes and allow one to reach a decision to add cautionary language to the approved product labeling for rivaroxaban. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Grillo, Joseph A.; Zhao, Ping; Bullock, Julie; Booth, Brian P.; Rahman, Atiqur; Zhang, Lei; Lesko, Lawrence J.; Huang, Shiew-Mei] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Lu, Min; Robie-Suh, Kathy] US FDA, DHP, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Berglund, Eva Gil] Med Prod Agcy, Uppsala, Sweden. [Pang, K. Sandy] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON M5S 1A1, Canada. RP Zhao, P (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM ping.zhao@fda.hhs.gov NR 41 TC 29 Z9 30 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0142-2782 J9 BIOPHARM DRUG DISPOS JI Biopharm. Drug Dispos. PD MAR PY 2012 VL 33 IS 2 SI SI BP 99 EP 110 DI 10.1002/bdd.1771 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 910QK UT WOS:000301655200007 PM 22270945 ER PT J AU Han, J Lynne, AM David, DE Nayak, R Foley, SL AF Han, Jing Lynne, Aaron M. David, Donna E. Nayak, Rajesh Foley, Steven L. TI Sequencing of plasmids from a multi-antimicrobial resistant Salmonella enterica serovar Dublin strain SO FOOD RESEARCH INTERNATIONAL LA English DT Article DE Salmonella enterica serovar Dublin; Plasmid sequencing; Antimicrobial resistance; Virulence ID VIRULENCE PLASMID; ESCHERICHIA-COLI; TYPHIMURIUM; INFECTIONS; SEROTYPE; FOODNET; HOST; RISK AB Salmonella enterica serovar Dublin (S. Dublin) is a host-adapted serotype whose primary host is cattle, which can serve as a potential reservoir for human infections. S. Dublin remains one of the leading causes of severe invasive infections and deaths associated with salmonellosis. Because of their propensity to cause severe infection, antimicrobial therapy is often required, thus antimicrobial resistance is an important concern. Plasmids play a key role in facilitating drug resistance in these pathogens. This study reports the results of DNA sequencing and sequence analysis of plasmids from a highly multidrug resistant strain (resistant to 11/15 drugs tested) of S. Dublin that originated from cattle. The strain was found to contain four plasmids of approximately 8, 77, 89, and 174 kb. The 174 kb plasmid is an incompatibility group (Inc) A/C plasmid containing genes associated with resistance to at least 9 different antimicrobials, as well as disinfectants and metals. The 88.5 kb plasmid is an IncFIB plasmid containing genes associated with resistance to at least 3 antimicrobial agents and mercurial compounds. The 77 kb plasmid is a S. Dublin virulence plasmid containing multiple virulence-associated genes and the 7.9 kb plasmid encodes mobilization and replication genes. Overall, sequencing identified multiple plasmids containing antimicrobial resistance and virulence genes. The resistance genes identified correlated to the observed resistance phenotype, further indicating the importance of plasmids in antimicrobial resistance in many Salmonella. Published by Elsevier Ltd. C1 [Han, Jing; Nayak, Rajesh; Foley, Steven L.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Lynne, Aaron M.] Sam Houston State Univ, Dept Biol Sci, Huntsville, TX 77341 USA. [David, Donna E.] Marshfield Clin Res Fdn, Core Res Lab, Marshfield, WI 54449 USA. RP Foley, SL (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM steven.foley@fda.hhs.gov FU Marshfield Clinic Research Foundation; U.S. Food and Drug Administration; Oak Ridge Institute for Science and Education FX The authors would like to thank Drs. Carl Cerniglia, Bashar Shaheen and Sangeeta Khare for their critical review of the manuscript, and the Marshfield Clinic Research Foundation and U.S. Food and Drug Administration for their support of the research. Dr. Jing Han is supported through the Oak Ridge Institute for Science and Education. NR 21 TC 10 Z9 10 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0963-9969 J9 FOOD RES INT JI Food Res. Int. PD MAR PY 2012 VL 45 IS 2 SI SI BP 931 EP 934 DI 10.1016/j.foodres.2011.04.016 PG 4 WC Food Science & Technology SC Food Science & Technology GA 915MU UT WOS:000302032200051 ER PT J AU Marrero-Ortiz, R Han, J Lynne, AM David, DE Stemper, ME Farmer, D Burkhardt, W Nayak, R Foley, SL AF Marrero-Ortiz, Roberto Han, Jing Lynne, Aaron M. David, Donna E. Stemper, Mary E. Farmer, Doris Burkhardt, William, III Nayak, Rajesh Foley, Steven L. TI Genetic characterization of antimicrobial resistance in Salmonella enterica serovars isolated from dairy cattle in Wisconsin SO FOOD RESEARCH INTERNATIONAL LA English DT Article DE Salmonella enterica; Antimicrobial resistance; Dairy cattle; Plasmid analysis; Pulsed-field gel electrophoresis ID UNITED-STATES; FOOD ANIMALS; PREVALENCE; HERD; COWS; IDENTIFICATION; HEIDELBERG; INTEGRONS; PLASMIDS; HAZARDS AB Salmonella enterica is a pathogen of humans and animals, and is one of the most frequent causes of bacterial foodborne illness worldwide. People consuming contaminated foods or working with infected livestock have the potential to become infected with Salmonella and may require antimicrobial therapy. Antimicrobial resistance in Salmonella has become a problem worldwide due in part to the inappropriate use of antimicrobial agents in human and veterinary medicine. In this study, forty-five Salmonella isolates from diagnostic fecal samples of Wisconsin dairy cattle were serotyped and characterized by antimicrobial susceptibility testing using agar disk diffusion, antimicrobial resistance gene detection by PCR, plasmid analysis and conjugation studies. The predominant serovars detected were Kentucky, Newport, Typhimurium, Cerro, Dublin and Montevideo. Over half (51%) of all isolates were resistant to at least one antimicrobial agent, and 29% were resistant to 8-10 drugs. The most commonly observed resistance phenotypes were to streptomycin (44%), tetracycline (42%), sulfisoxazole (40%), chloramphenicol (35%), ampicillin (33%), and cefoxitin (33%). When resistance was detected phenotypically, a corresponding resistance gene was detected 86.2% of the time. Plasmids ranging in size from <8 to 165 kb were detected in 45% of the isolates. A greater understanding of the factors associated with antimicrobial resistance in Salmonella should provide insights into the factors that contribute to the development of resistant pathogens during dairy production, which in turn can lead to strategies to minimize the spread of antimicrobial resistant Salmonella in the food supply. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Marrero-Ortiz, Roberto; Burkhardt, William, III] US FDA, Ctr Food Safely & Appl Nutr, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. [Marrero-Ortiz, Roberto; Lynne, Aaron M.; David, Donna E.; Stemper, Mary E.; Foley, Steven L.] Marshfield Clin Res Fdn, Natl Farm Med Ctr, Marshfield, WI 54449 USA. [Han, Jing; Nayak, Rajesh; Foley, Steven L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Lynne, Aaron M.] Sam Houston State Univ, Dept Biol Sci, Huntsville, TX 77341 USA. [Farmer, Doris] US FDA, Denver Dist Lab, Denver Fed Ctr, Denver, CO 80225 USA. RP Marrero-Ortiz, R (reprint author), Gulf Coast Seafood Lab Dauphin Isl, 1 Iberville Dr, Dauphin Isl, AL 36528 USA. EM roberto.marrero@fda.hhs.gov FU Marshfield Clinic Research Foundation; Food and Drug Administration; Oak Ridge Institute for Science and Education FX We thank the Marshfield Clinic Research Foundation and the Food and Drug Administration for their support of this work. We would also like to thank Veronica Call and Gwendolyn Anderson for their technical assistance and Drs. Carl Cerniglia, Kuppan Gokulan and Sangeeta Huizhong Chen for their insightful review of the manuscript. Drs. Roberto Marrero-Ortiz and Jing Han are supported through the Oak Ridge Institute for Science and Education Fellowship Program. NR 44 TC 7 Z9 7 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0963-9969 J9 FOOD RES INT JI Food Res. Int. PD MAR PY 2012 VL 45 IS 2 SI SI BP 962 EP 967 DI 10.1016/j.foodres.2011.04.013 PG 6 WC Food Science & Technology SC Food Science & Technology GA 915MU UT WOS:000302032200057 ER PT J AU Louden, BC Haarmann, D Han, J Foley, SL Lynne, AM AF Louden, Brian C. Haarmann, Daniel Han, Jing Foley, Steven L. Lynne, Aaron M. TI Characterization of antimicrobial resistance in Salmonella enterica serovar Typhimurium isolates from food animals in the U.S SO FOOD RESEARCH INTERNATIONAL LA English DT Article DE Salmonella; Antimicrobial resistance; Resistance genes ID ANTIBIOTIC-RESISTANCE; UNITED-STATES; GENES; PATHOGENS AB Salmonella enterica subspecies enteric serovar Typhimurium is the second most common serovar implicated in human diseases in the United States. In this study, 120 S. Typhimurium isolates from animal sources were characterized by antimicrobial susceptibility testing, antimicrobial resistance gene detection and plasmid analysis. Overall, 94 (78%) of the isolates were resistant to one or more antimicrobials and 63 (53%) were resistant to at least five antimicrobials. Resistance was most commonly observed to streptomycin (62%), sulfisoxazole (62%). or tetracycline (61%). When resistance was detected, a corresponding resistance gene was detected in 89% of cases. Class 1 integrons were detected in 51 isolates, all which contained the aadA2 gene. A plasmid Inc group was detected in 68(57%) isolates. Thirty nine (57%) of these isolates were resistant to 5 or more antimicrobials. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Louden, Brian C.; Haarmann, Daniel; Lynne, Aaron M.] Sam Houston State Univ, Dept Biol Sci, Huntsville, TX 77341 USA. [Han, Jing; Foley, Steven L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Lynne, AM (reprint author), Sam Houston State Univ, Dept Biol Sci, Box 2116,1900 Ave 1, Huntsville, TX 77341 USA. EM aml027@shsu.edu FU Sam Houston State University; Oak Ridge Institute for Science and Education FX We appreciate the financial support for this project that was provided by the Sam Houston State University Research Enhancement Fund. Dr. Jing Han is supported through the Oak Ridge Institute for Science and Education. We also thank Joanna Deck for technical assistance with this project and Drs. Rajesh Nayak and John Sutherland for there insightful critique of the manuscript. NR 15 TC 4 Z9 4 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0963-9969 J9 FOOD RES INT JI Food Res. Int. PD MAR PY 2012 VL 45 IS 2 SI SI BP 968 EP 972 DI 10.1016/j.foodres.2011.03.055 PG 5 WC Food Science & Technology SC Food Science & Technology GA 915MU UT WOS:000302032200058 ER PT J AU Hitchins, AD AF Hitchins, Anthony D. TI A meta-analytical estimation of the detection limits of methods for Salmonella in food SO FOOD RESEARCH INTERNATIONAL LA English DT Article DE Foodborne Salmonella; Detection method limits; Meta-analysis; LOD ID RAPPAPORT-VASSILIADIS MEDIUM; UNIVERSAL PREENRICHMENT BROTH; LINKED-IMMUNOSORBENT-ASSAY; HIGHLY CONTAMINATED FOODS; SLM IMMUNOASSAY METHOD; BISMUTH SULFITE; RAW FLESH; SINGLEPATH(R) SALMONELLA; MODIFIED IMMUNODIFFUSION; NONMOTILE SALMONELLA AB The validation of microbial detection methods for foods does not typically state a limit of detection value. Therefore performances of rapid and reference methods for Salmonella detection in foods were compared retrospectively using data from 49 published studies. A total of 576 values for the limit of detection (LOD50) were calculated. The major scientific variables in these independent validation studies were food matrices, Salmonella serovars, and method types (reference, cultural and immunological and nucleic acid based). The basic design feature of the original studies was comparison of the performances of new methods with those of cultural reference methods. A major experimental design variable was the number of laboratories per study. There were 29 single laboratory studies with 20 replicates per level of Salmonella spiked into the food matrix. The 20 multi-laboratory (N >= 10) studies had 5-6 replicates per level of Salmonella. The LOD50 values of the dataset had a mean value of 0.021 MPN g(-1) (standard deviation range (0.013-0.036) and the distribution of their logarithms was symmetrical about the logarithm of the mean if the outlier values were discounted. Eighty-nine percent of the values ranged from 0.01 to 0.04 MPN g(-1). On this basis about 11% of the values were deemed outliers. About three-quarters of them were >0.04 MPN g(-1). The distribution derived in this study can be used as a bench mark against which to evaluate LOD50 data generated in future studies of detection methods for Salmonella in foods and potentially offers a possible way to streamline method validation study experimental design. Published by Elsevier Ltd. C1 US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Hitchins, AD (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM anthony.hitchins@fda.hhs.gov NR 55 TC 1 Z9 1 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0963-9969 J9 FOOD RES INT JI Food Res. Int. PD MAR PY 2012 VL 45 IS 2 SI SI BP 1065 EP 1071 DI 10.1016/j.foodres.2011.02.055 PG 7 WC Food Science & Technology SC Food Science & Technology GA 915MU UT WOS:000302032200074 ER PT J AU Antunes, AMM Sidarus, M Novais, DA Harjivan, SG Santos, PP da Silva, JLF Beland, FA Marques, MM AF Antunes, Alexandra M. M. Sidarus, Muna Novais, David A. Harjivan, Shrika G. Santos, Pedro P. Ferreira da Silva, Joao L. Beland, Frederick A. Matilde Marques, M. TI Oxidation of 2-Hydroxynevirapine, a Phenolic Metabolite of the Anti-HIV Drug Nevirapine: Evidence for an Unusual Pyridine Ring Contraction SO MOLECULES LA English DT Article DE anti-HIV drug; nevirapine; oxidation; pyridine ring contraction ID TO-CHILD TRANSMISSION; REVERSE-TRANSCRIPTASE INHIBITOR; INDUCED SKIN RASH; RANDOMIZED-TRIAL; SINGLE; ZIDOVUDINE; BIOTRANSFORMATION; INTRAPARTUM; PREVENTION; KAMPALA AB Nevirapine (NVP) is an anti-HIV drug associated with severe hepatotoxicity and skin rashes, which raises concerns about its chronic administration. There is increasing evidence that metabolic activation to reactive electrophiles capable of reacting with bionucleophiles is likely to be involved in the initiation of these toxic responses. Phase I NVP metabolism involves oxidation of the 4-methyl substituent and the formation of phenolic derivatives that are conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid species prone to react with bionucleophiles. The covalent adducts thus formed might be at the genesis of toxic responses. As part of a program aimed at evaluating the possible contribution of quinoid derivatives of Phase I phenolic NVP metabolites to the toxic responses elicited by the parent drug, we have investigated the oxidation of 2-hydroxy-NVP with dipotassium nitroso-disulfonate (Fremy's salt), mimicking the one-electron oxidation involved in enzyme-mediated metabolic oxidations. We report herein the isolation and full structural characterization of a 1H-pyrrole-2,5-dione derivative as a major product, stemming from an unusual pyridine ring contraction. C1 [Antunes, Alexandra M. M.; Sidarus, Muna; Novais, David A.; Harjivan, Shrika G.; Santos, Pedro P.; Ferreira da Silva, Joao L.; Matilde Marques, M.] Univ Tecn Lisboa, Inst Super Tecn, Ctr Quim Estrutural, P-1049001 Lisbon, Portugal. [Beland, Frederick A.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Antunes, AMM (reprint author), Univ Tecn Lisboa, Inst Super Tecn, Ctr Quim Estrutural, P-1049001 Lisbon, Portugal. EM alexandra.antunes@ist.utl.pt RI Marques, M. Matilde/E-2535-2012; PTMS, RNEM/C-1589-2014; Antunes, Alexandra/B-7871-2009; Silva, Joao/H-7770-2012; Santos, Pedro Paulo/P-1769-2016; OI Marques, M. Matilde/0000-0002-7526-4962; Antunes, Alexandra/0000-0003-1827-7369; Silva, Joao/0000-0002-9751-9268; Santos, Pedro Paulo/0000-0003-3045-4591; Ferreira da Silva, Joao/0000-0003-2797-5206 FU Fundacao para a Ciencia e a Tecnologia (FCT), Portugal [PEst-OE/QUI/UI0100/2011, PPCDT/QUI/56582/2004, PTDC/QUI-QUI/113910/2009]; National Center for Toxicological Research/Food and Drug Administration [Y1ES1027]; National Institute of Environmental Health Sciences [Y1ES1027] FX We thank the Portuguese NMR Network (IST-UTL Center) and the Portuguese MS Network (IST-UTL Center) for providing access to the facilities. This work was supported in part by Fundacao para a Ciencia e a Tecnologia (FCT), Portugal, through pluriannual funds to Centro de Quimica Estrutural (PEst-OE/QUI/UI0100/2011) and research grants PPCDT/QUI/56582/2004 and PTDC/QUI-QUI/113910/2009, and by Interagency Agreement Y1ES1027 between the National Center for Toxicological Research/Food and Drug Administration and the National Institute of Environmental Health Sciences/National Toxicology Program. The opinions expressed in this paper do not necessarily represent those of the U.S. Food and Drug Administration. NR 35 TC 5 Z9 5 U1 0 U2 14 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD MAR PY 2012 VL 17 IS 3 BP 2616 EP 2627 DI 10.3390/molecules17032616 PG 12 WC Chemistry, Organic SC Chemistry GA 916RJ UT WOS:000302120600025 PM 22391597 ER PT J AU McPhail, B Tie, YF Hong, HX Pearce, BA Schnackenberg, LK Ge, WG Valerio, LG Fuscoe, JC Tong, WD Buzatu, DA Wilkes, JG Fowler, BA Demchuk, E Beger, RD AF McPhail, Brooks Tie, Yunfeng Hong, Huixiao Pearce, Bruce A. Schnackenberg, Laura K. Ge, Weigong Valerio, Luis G., Jr. Fuscoe, James C. Tong, Weida Buzatu, Dan A. Wilkes, Jon G. Fowler, Bruce A. Demchuk, Eugene Beger, Richard D. TI Modeling Chemical Interaction Profiles: I. Spectral Data-Activity Relationship and Structure-Activity Relationship Models for Inhibitors and Non-inhibitors of Cytochrome P450 CYP3A4 and CYP2D6 Isozymes SO MOLECULES LA English DT Article DE structure-activity relationship; SAR; SDAR; classifier; cytochrome P450; inhibitor; CYP3A4; CYP2D6 ID DRUG-DRUG INTERACTIONS; ESTROGEN-RECEPTOR BINDING; VECTOR MACHINE APPROACH; ANALYSIS COSCOSA MODELS; IN-VITRO; DECISION FOREST; C-13 NMR; GENETIC POLYMORPHISMS; MOLECULAR DESCRIPTORS; SPECTROMETRIC DATA AB An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals-drugs, pesticides, and environmental pollutants-interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP) enzymes. In the present work, spectral data-activity relationship (SDAR) and structure- activity relationship (SAR) approaches were used to develop machine-learning classifiers of inhibitors and non-inhibitors of the CYP3A4 and CYP2D6 isozymes. The models were built upon 602 reference pharmaceutical compounds whose interactions have been deduced from clinical data, and 100 additional chemicals that were used to evaluate model performance in an external validation (EV) test. SDAR is an innovative modeling approach that relies on discriminant analysis applied to binned nuclear magnetic resonance (NMR) spectral descriptors. In the present work, both 1D C-13 and 1D N-15-NMR spectra were used together in a novel implementation of the SDAR technique. It was found that increasing the binning size of 1D C-13-NMR and N-15-NMR spectra caused an increase in the tenfold cross-validation (CV) performance in terms of both the rate of correct classification and sensitivity. The results of SDAR modeling were verified using SAR. For SAR modeling, a decision forest approach involving from 6 to 17 Mold(2) descriptors in a tree was used. Average rates of correct classification of SDAR and SAR models in a hundred CV tests were 60% and 61% for CYP3A4, and 62% and 70% for CYP2D6, respectively. The rates of correct classification of SDAR and SAR models in the EV test were 73% and 86% for CYP3A4, and 76% and 90% for CYP2D6, respectively. Thus, both SDAR and SAR methods demonstrated a comparable performance in modeling a large set of structurally diverse data. Based on unique NMR structural descriptors, the new SDAR modeling method complements the existing SAR techniques, providing an independent estimator that can increase confidence in a structure- activity assessment. When modeling was applied to hazardous environmental chemicals, it was found that up to 20% of them may be substrates and up to 10% of them may be inhibitors of the CYP3A4 and CYP2D6 isoforms. The developed models provide a rare opportunity for the environmental health branch of the public health service to extrapolate to hazardous chemicals directly from human clinical data. Therefore, the pharmacological and environmental health branches are both expected to benefit from these reported models. C1 [McPhail, Brooks; Tie, Yunfeng; Fowler, Bruce A.; Demchuk, Eugene] Agcy Tox Subst & Dis Registry, Div Toxicol & Environm Med, Atlanta, GA 30333 USA. [Hong, Huixiao; Pearce, Bruce A.; Schnackenberg, Laura K.; Ge, Weigong; Fuscoe, James C.; Tong, Weida; Buzatu, Dan A.; Wilkes, Jon G.; Beger, Richard D.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Valerio, Luis G., Jr.] US FDA, Sci & Res Staff, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Demchuk, Eugene] W Virginia Univ, Dept Basic Pharmaceut Sci, Morgantown, WV 26506 USA. RP Demchuk, E (reprint author), Agcy Tox Subst & Dis Registry, Div Toxicol & Environm Med, Atlanta, GA 30333 USA. EM BMcPhail@cdc.gov; YTie@cdc.gov; huixiao.hong@fda.hhs.gov; BruceA.Pearce@fda.hhs.gov; Laura.Schnackenberg@fda.hhs.gov; Weigong.Ge@fda.hhs.gov; Luis.Valerio@fda.hhs.gov; James.Fuscoe@fda.hhs.gov; Weida.Tong@fda.hhs.gov; Dan.Buzatu@fda.hhs.gov; Jon.Wilkes@fda.hhs.gov; BFowler@icfi.com; EDemchuk@cdc.gov; Richard.Beger@fda.hhs.gov FU Oak Ridge Institute for Science and Education FX We thank Grazyna Szklarz and Russ Savage for helpful comments. This work was partially supported by the Oak Ridge Institute for Science and Education (B. M. and Y. T.). NR 84 TC 8 Z9 8 U1 0 U2 8 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD MAR PY 2012 VL 17 IS 3 BP 3383 EP 3406 DI 10.3390/molecules17033383 PG 24 WC Chemistry, Organic SC Chemistry GA 916RJ UT WOS:000302120600072 PM 22421792 ER PT J AU Tie, YF McPhail, B Hong, HX Pearce, BA Schnackenberg, LK Ge, WG Buzatu, DA Wilkes, JG Fuscoe, JC Tong, WD Fowler, BA Beger, RD Demchuk, E AF Tie, Yunfeng McPhail, Brooks Hong, Huixiao Pearce, Bruce A. Schnackenberg, Laura K. Ge, Weigong Buzatu, Dan A. Wilkes, Jon G. Fuscoe, James C. Tong, Weida Fowler, Bruce A. Beger, Richard D. Demchuk, Eugene TI Modeling Chemical Interaction Profiles: II. Molecular Docking, Spectral Data-Activity Relationship, and Structure-Activity Relationship Models for Potent and Weak Inhibitors of Cytochrome P450 CYP3A4 Isozyme SO MOLECULES LA English DT Article DE structure-activity relationship; SAR; QSAR; SDAR; docking; molecular modeling; inhibitor; CYP3A4; drug-drug interaction; drug-chemical interaction; DDI; DDCI ID DRUG-DRUG INTERACTIONS; HUMAN LIVER-MICROSOMES; MECHANISM-BASED INACTIVATION; PROTEIN-BINDING SITES; IN-VITRO; ORAL BIOAVAILABILITY; 3A4 INHIBITION; IMIDAZOLE DERIVATIVES; CLINICAL-RELEVANCE; AUTOMATED DOCKING AB Polypharmacy increasingly has become a topic of public health concern, particularly as the U. S. population ages. Drug labels often contain insufficient information to enable the clinician to safely use multiple drugs. Because many of the drugs are bio-transformed by cytochrome P450 (CYP) enzymes, inhibition of CYP activity has long been associated with potentially adverse health effects. In an attempt to reduce the uncertainty pertaining to CYP-mediated drug-drug/chemical interactions, an interagency collaborative group developed a consensus approach to prioritizing information concerning CYP inhibition. The consensus involved computational molecular docking, spectral data-activity relationship (SDAR), and structure-activity relationship (SAR) models that addressed the clinical potency of CYP inhibition. The models were built upon chemicals that were categorized as either potent or weak inhibitors of the CYP3A4 isozyme. The categorization was carried out using information from clinical trials because currently available in vitro high-throughput screening data were not fully representative of the in vivo potency of inhibition. During categorization it was found that compounds, which break the Lipinski rule of five by molecular weight, were about twice more likely to be inhibitors of CYP3A4 compared to those, which obey the rule. Similarly, among inhibitors that break the rule, potent inhibitors were 2-3 times more frequent. The molecular docking classification relied on logistic regression, by which the docking scores from different docking algorithms, CYP3A4 three-dimensional structures, and binding sites on them were combined in a unified probabilistic model. The SDAR models employed a multiple linear regression approach applied to binned 1D C-13-NMR and 1D N-15-NMR spectral descriptors. Structure-based and physical-chemical descriptors were used as the basis for developing SAR models by the decision forest method. Thirty-three potent inhibitors and 88 weak inhibitors of CYP3A4 were used to train the models. Using these models, a synthetic majority rules consensus classifier was implemented, while the confidence of estimation was assigned following the percent agreement strategy. The classifier was applied to a testing set of 120 inhibitors not included in the development of the models. Five compounds of the test set, including known strong inhibitors dalfopristin and tioconazole, were classified as probable potent inhibitors of CYP3A4. Other known strong inhibitors, such as lopinavir, oltipraz, quercetin, raloxifene, and troglitazone, were among 18 compounds classified as plausible potent inhibitors of CYP3A4. The consensus estimation of inhibition potency is expected to aid in the nomination of pharmaceuticals, dietary supplements, environmental pollutants, and occupational and other chemicals for in-depth evaluation of the CYP3A4 inhibitory activity. It may serve also as an estimate of chemical interactions via CYP3A4 metabolic pharmacokinetic pathways occurring through polypharmacy and nutritional and environmental exposures to chemical mixtures. C1 [Tie, Yunfeng; McPhail, Brooks; Fowler, Bruce A.; Demchuk, Eugene] Agcy Tox Subst & Dis Registry, Div Toxicol & Environm Med, Atlanta, GA 30333 USA. [Hong, Huixiao; Pearce, Bruce A.; Schnackenberg, Laura K.; Ge, Weigong; Buzatu, Dan A.; Wilkes, Jon G.; Fuscoe, James C.; Tong, Weida; Beger, Richard D.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Demchuk, Eugene] W Virginia Univ, Dept Basic Pharmaceut Sci, Morgantown, WV 26506 USA. RP Demchuk, E (reprint author), Agcy Tox Subst & Dis Registry, Div Toxicol & Environm Med, Atlanta, GA 30333 USA. EM YTie@cdc.gov; BMcPhail@cdc.gov; Huixiao.Hong@fda.hhs.gov; BruceA.Pearce@fda.hhs.gov; Laura.Schnackenberg@fda.hhs.gov; Weigong.Ge@fda.hhs.gov; Dan.Buzatu@fda.hhs.gov; Jon.Wilkes@fda.hhs.gov; James.Fuscoe@fda.hhs.gov; Weida.Tong@fda.hhs.gov; BFowler@icfi.com; Richard.Beger@fda.hhs.gov; EDemchuk@cdc.gov FU Oak Ridge Institute for Science and Education FX We are grateful to Tingjun Hou for sharing the bioavailability database, Minjun Chen for providing Cmax values, Grazyna Szklarz and Russ Savage for insightful comments, the OpenEye Scientific Software, Inc. for a non-profit software license, and the National Cancer Institute for computer time and technical support at the Advanced Biomedical Computing Center of the Frederick Cancer Research and Development Center. This work was partially supported by the Oak Ridge Institute for Science and Education (B. M. and Y. T.). NR 154 TC 9 Z9 9 U1 1 U2 27 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD MAR PY 2012 VL 17 IS 3 BP 3407 EP 3460 DI 10.3390/molecules17033407 PG 54 WC Chemistry, Organic SC Chemistry GA 916RJ UT WOS:000302120600073 PM 22421793 ER PT J AU Park, EJ Pai, MP Dong, T Zhang, J Ko, CW Lawrence, J Crentsil, V Zhang, L Xu, NN AF Park, Eun Jung Pai, Manjunath P. Dong, Ting Zhang, Jialu Ko, Chia-Wen Lawrence, John Crentsil, Victor Zhang, Lei Xu, Nancy N. TI The Influence of Body Size Descriptors on the Estimation of Kidney Function in Normal Weight, Overweight, Obese, and Morbidly Obese Adults SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE body mass index; Chronic Kidney Disease Epidemiology Collaboration; Cockcroft-Gault equation; creatinine clearance; dosing; glomerular filtration rate; kidney function; Modification of Diet in Renal Disease; obesity; pharmacokinetics ID GLOMERULAR-FILTRATION-RATE; SERUM CREATININE LEVELS; RENAL-FUNCTION; COCKCROFT-GAULT; SURFACE-AREA; MASS INDEX; DISEASE; EQUATION; PHARMACOKINETICS; CLEARANCE AB BACKGROUND: Dosing adjustments for patients with impaired kidney function are often based on estimated creatinine clearance (eCrCl) because measuring kidney function is not always possible for dose adjustment. However, there is no consensus on the body size descriptor that should be used in the estimation equations. OBJECTIVE: To compare the use of alternative body size descriptors (ABSDs) on the performance of kidney function estimation equations compared with measured CrCI (mCrCI). METHODS: We combined 2 data sources with mCrCl: a Food and Drug Administration clinical trial database that includes subjects with body mass index (BMI) less than 40 kg/m(2) and published data from those 40 kg/m(2) or more. The 3 parent equations (Cockcroft-Gault [CG], Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease Epidemiology Collaboration [CKDEPI]), and 14 ABSDmodified equations were compared with mCrCI for accuracy, bias, agreement, goodness of fit (R2), and prediction error. These equations were also compared across mCrCI and BMI strata. RESULTS: Subjects (n = 590) were aged 19-80 years; 33.9% were female and BMI ranged from 17.2 to 95.6 kg/m(2). Compared with mCrCl, the use of total weight in the CG equation yielded low accuracy (12.5%) and significant bias (-107 mUmin) in the morbidly obese group. In contrast, the use of lean body weights (BMI >= 40 kg/m(2)) and total +/- adjusted weights (BMI <40 kg/m(2)) with the CG equation yielded higher accuracy, greater than or equal to 60.7% across all BMI strata, and was unbiased. Transforming the MDRD or CKDEPI equations with body surface area improved accuracy only at mCrCl of 30-80 mUmin and increased the overall prediction error. CONCLUSIONS: No kidney function equation was consistently accurate and unbiased across weight, mCrCl, and estimate ranges. The accuracy and overestimation bias of the CG equation in obese subjects was improved through the selective use of total, adjusted, and lean body weight by BMI strata. C1 [Park, Eun Jung; Dong, Ting; Xu, Nancy N.] Food & Drug Adm, Div Cardiovasc & Renal Products, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Pai, Manjunath P.] Albany Coll Pharm & Hlth Sci, Dept Pharm Practice, Albany, NY USA. [Zhang, Jialu; Ko, Chia-Wen; Lawrence, John] Food & Drug Adm, Ctr Drug Evaluat & Res, Off Biostatist, Silver Spring, MD USA. [Crentsil, Victor] Food & Drug Adm, Ctr Drug Evaluat & Res, Off New Drugs, Div Psychiat Prod, Silver Spring, MD USA. [Zhang, Lei] Food & Drug Adm, Ctr Drug Evaluat & Res, Off Translat Sci, Off Clin Pharmacol, Silver Spring, MD USA. RP Xu, NN (reprint author), Food & Drug Adm, Div Cardiovasc & Renal Products, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. EM nancy.xu@fda.hhs.gov FU Critical Path Initiative at the FDA FX This research was funded by the Critical Path Initiative at the FDA. NR 40 TC 14 Z9 14 U1 1 U2 5 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD MAR PY 2012 VL 46 IS 3 BP 317 EP 328 DI 10.1345/aph.1Q374 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 915CB UT WOS:000301999400001 PM 22395245 ER PT J AU Linet, MS Slovis, TL Miller, DL Kleinerman, R Lee, C Rajaraman, P de Gonzalez, AB AF Linet, Martha S. Slovis, Thomas L. Miller, Donald L. Kleinerman, Ruth Lee, Choonsik Rajaraman, Preetha de Gonzalez, Amy Berrington TI Cancer risks associated with external radiation from diagnostic imaging procedures SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Review ID US RADIOLOGIC TECHNOLOGISTS; ATOMIC-BOMB SURVIVORS; DNA-REPAIR GENES; CARDIAC COMPUTED-TOMOGRAPHY; TECHA RIVER COHORT; X-RAY-EXPOSURE; CARDIOVASCULAR-MAGNETIC-RESONANCE; ACUTE LYMPHOBLASTIC-LEUKEMIA; NORTH-AMERICAN-SOCIETY; LI-FRAUMENI-SYNDROME AB The 600% increase in medical radiation exposure to the US population since 1980 has provided immense benefit, but increased potential future cancer risks to patients. Most of the increase is from diagnostic radiologic procedures. The objectives of this review are to summarize epidemiologic data on cancer risks associated with diagnostic procedures, describe how exposures from recent diagnostic procedures relate to radiation levels linked with cancer occurrence, and propose a framework of strategies to reduce radiation from diagnostic imaging in patients. We briefly review radiation dose definitions, mechanisms of radiation carcinogenesis, key epidemiologic studies of medical and other radiation sources and cancer risks, and dose trends from diagnostic procedures. We describe cancer risks from experimental studies, future projected risks from current imaging procedures, and the potential for higher risks in genetically susceptible populations. To reduce future projected cancers from diagnostic procedures, we advocate the widespread use of evidence-based appropriateness criteria for decisions about imaging procedures; oversight of equipment to deliver reliably the minimum radiation required to attain clinical objectives; development of electronic lifetime records of imaging procedures for patients and their physicians; and commitment by medical training programs, professional societies, and radiation protection organizations to educate all stakeholders in reducing radiation from diagnostic procedures. CA Cancer J Clin 2012. (C) 2012 American Cancer Society. C1 [Linet, Martha S.; Kleinerman, Ruth; Lee, Choonsik; Rajaraman, Preetha; de Gonzalez, Amy Berrington] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Slovis, Thomas L.] Childrens Hosp Michigan, Dept Radiol, Detroit, MI 48201 USA. [Miller, Donald L.] US FDA, Diagnost Devices Branch, Div Mammog Qual, Silver Spring, MD USA. [Miller, Donald L.] US FDA, Radiat Program Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Linet, MS (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7048, Bethesda, MD 20892 USA. EM linetm@mail.nih.gov RI Lee, Choonsik/C-9023-2015; OI Lee, Choonsik/0000-0003-4289-9870; Kleinerman, Ruth/0000-0001-7415-2478 FU National Institutes of Health; National Cancer Institute FX This review was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute. NR 239 TC 70 Z9 72 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 EI 1542-4863 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD MAR-APR PY 2012 VL 62 IS 2 BP 75 EP 100 DI 10.3322/caac.21132 PG 26 WC Oncology SC Oncology GA 904VW UT WOS:000301227600003 PM 22307864 ER PT J AU Ampofo, WK Baylor, N Cobey, S Cox, NJ Daves, S Edwards, S Ferguson, N Grohmann, G Hay, A Katz, J Kullabutr, K Lambert, L Levandowski, R Mishra, AC Monto, A Siqueira, M Tashiro, M Waddell, AL Wairagkar, N Wood, J Zambon, M Zhang, WQ AF Ampofo, William K. Baylor, Norman Cobey, Sarah Cox, Nancy J. Daves, Sharon Edwards, Steven Ferguson, Neil Grohmann, Gary Hay, Alan Katz, Jacqueline Kullabutr, Kornnika Lambert, Linda Levandowski, Roland Mishra, A. C. Monto, Arnold Siqueira, Marilda Tashiro, Masato Waddell, Anthony L. Wairagkar, Niteen Wood, John Zambon, Maria Zhang, Wenqing CA WHO Writing Grp TI Improving influenza vaccine virus selectionReport of a WHO informal consultation held at WHO headquarters, Geneva, Switzerland, 14-16 June 2010 SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE influenza vaccine viruses; vaccine virus selection; WHO recommendations AB For almost 60 years, the WHO Global Influenza Surveillance and Response System (GISRS) has been the key player in monitoring the evolution and spread of influenza viruses and recommending the strains to be used in human influenza vaccines. The GISRS has also worked to continually monitor and assess the risk posed by potential pandemic viruses and to guide appropriate public health responses. The expanded and enhanced role of the GISRS following the adoption of the International Health Regulations (2005), recognition of the continuing threat posed by avian H5N1 and the aftermath of the 2009 H1N1 pandemic provide an opportune time to critically review the process by which influenza vaccine viruses are selected. In addition to identifying potential areas for improvement, such a review will also help to promote greater appreciation by the wider influenza and policy-making community of the complexity of influenza vaccine virus selection. The selection process is highly coordinated and involves continual year-round integration of virological data and epidemiological information by National Influenza Centres (NICs), thorough antigenic and genetic characterization of viruses by WHO Collaborating Centres (WHOCCs) as part of selecting suitable candidate vaccine viruses, and the preparation of suitable reassortants and corresponding reagents for vaccine standardization by WHO Essential Regulatory Laboratories (ERLs). Ensuring the optimal effectiveness of vaccines has been assisted in recent years by advances in molecular diagnosis and the availability of more extensive genetic sequence data. However, there remain a number of challenging constraints including variations in the assays used, the possibility of complications resulting from non-antigenic changes, the limited availability of suitable vaccine viruses and the requirement for recommendations to be made up to a year in advance of the peak of influenza season because of production constraints. Effective collaboration and coordination between human and animal influenza networks is increasingly recognized as an essential requirement for the improved integration of data on animal and human viruses, the identification of unusual influenza A viruses infecting human, the evaluation of pandemic risk and the selection of candidate viruses for pandemic vaccines. Training workshops, assessments and donations have led to significant increases in trained laboratory personnel and equipment with resulting expansion in both geographical surveillance coverage and in the capacities of NICs and other laboratories. This has resulted in a significant increase in the volume of information reported to WHO on the spread, intensity and impact of influenza. In addition, initiatives such as the WHO Shipment Fund Project have facilitated the timely sharing of clinical specimens and virus isolates and contributed to a more comprehensive understanding of the global distribution and temporal circulation of different viruses. It will be important to sustain and build upon the gains made in these and other areas. Although the haemagglutination inhibition (HAI) assay is likely to remain the assay of choice for the antigenic characterization of viruses in the foreseeable future, alternative assays for example based upon advanced recombinant DNA and protein technologies may be more adaptable to automation. Other technologies such as microtitre neuraminidase inhibition assays may also have significant implications for both vaccine virus selection and vaccine development. Microneutralization assays provide an important adjunct to the HAI assay in virus antigenic characterization. Improvements in the use and potential automation of such assays should facilitate large-scale serological studies, while other advanced techniques such as epitope mapping should allow for a more accurate assessment of the quality of a protective immune response and aid the development of additional criteria for measuring immunity. Standardized seroepidemiological surveys to assess the impact of influenza in a population could help to establish well-characterized banks of age-stratified representative sera as a national, regional and global resource, while providing direct evidence of the specific benefits of vaccination. Advances in high-throughput genetic sequencing coupled with advanced bioinformatics tools, together with more X-ray crystallographic data, should accelerate understanding of the genetic and phenotypic changes that underlie virus evolution and more specifically help to predict the influence of amino acid changes on virus antigenicity. Complex mathematical modelling techniques are increasingly being used to gain insights into the evolution and epidemiology of influenza viruses. However, their value in predicting the timing and nature of future antigenic and genetic changes is likely to be limited at present. The application of simpler non-mechanistic statistical algorithms, such as those already used as the basis of antigenic cartography, and phylogenetic modelling are more likely to be useful in facilitating vaccine virus selection and in aiding assessment of the pandemic potential of avian and other animal influenza viruses. The adoption of alternative vaccine technologies such as live-attenuated, quadrivalent or non-HA-based vaccines has significant implications for vaccine virus selection, as well as for vaccine regulatory and manufacturing processes. Recent collaboration between the GISRS and vaccine manufacturers has resulted in the increased availability of egg isolates and high-growth reassortants for vaccine production, the development of qualified cell cultures and the investigation of alternative methods of vaccine potency testing. WHO will continue to support these and other efforts to increase the reliability and timeliness of the global influenza vaccine supply. The WHO GISRS and its partners are continually working to identify improvements, harness new technologies and strengthen and sustain collaboration. WHO will continue in its central role of coordinating worldwide expertise to meet the increasing public health need for influenza vaccines and will support efforts to improve the vaccine virus selection process, including through the convening of periodic international consultations. C1 [Baylor, Norman] US FDA, Rockville, MD 20857 USA. [Ampofo, William K.] Natl Influenza Ctr, Accra, Ghana. [Cobey, Sarah] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Cox, Nancy J.; Katz, Jacqueline] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Daves, Sharon] NAMRU 3, Cairo, Egypt. [Edwards, Steven] Network Expertise Anim Influenzas OFFLU Steering, Hereford, England. [Ferguson, Neil] Univ London Imperial Coll Sci Technol & Med, Sch Med St Marys, London, England. [Grohmann, Gary] Therapeut Goods Adm Labs, Symonston, Australia. [Hay, Alan] Natl Inst Med Res, London NW7 1AA, England. [Kullabutr, Kornnika] Minist Publ Hlth, Nonthaburi, Thailand. [Lambert, Linda] NIH, Bethesda, MD 20892 USA. [Levandowski, Roland] Freelancer, Bethesda, MD USA. [Mishra, A. C.] Natl Influenza Ctr, Pune, Maharashtra, India. [Monto, Arnold] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Siqueira, Marilda] Inst Oswaldo Cruz, BR-20001 Rio De Janeiro, Brazil. [Tashiro, Masato] WHO Collaborating Ctr Reference & Res Influenza, Tokyo, Japan. [Waddell, Anthony L.] Freelancer, Stanley, Hong Kong, Peoples R China. [Wairagkar, Niteen; Zhang, Wenqing] WHO, Zurich, Switzerland. [Wood, John] NIBSC, Potters Bar, Herts, England. [Zambon, Maria] Hlth Protect Agcy, London, England. RP Zhang, WQ (reprint author), WHO HQ Geneva, Geneva, Switzerland. EM zhangw@who.int RI perumal, murugiah/D-1565-2012; Ferguson, Neil/B-8578-2008; HERAUD, Jean-Michel/O-1464-2013; OI Ferguson, Neil/0000-0002-1154-8093; HERAUD, Jean-Michel/0000-0003-1107-0859; Russell, Colin/0000-0002-2113-162X NR 0 TC 28 Z9 28 U1 0 U2 23 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1750-2640 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD MAR PY 2012 VL 6 IS 2 BP 142 EP + DI 10.1111/j.1750-2659.2011.00277.x PG 16 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 897VZ UT WOS:000300689300010 ER PT J AU Zafar, F Choi, M Wang, J Liu, P Badano, A AF Zafar, Fahad Choi, Mina Wang, Joel Liu, Peter Badano, Aldo TI Visual methods for determining ambient illumination conditions when viewing medical images in mobile display devices SO JOURNAL OF THE SOCIETY FOR INFORMATION DISPLAY LA English DT Article DE Mobile displays; medical imaging; ambient illumination ID STAIRCASE-METHOD AB The quality of the displayed image on mobile devices is affected by the varying ambient illumination conditions. Determining appropriate viewing conditions for particular visual tasks requires time and the appropriate instrumentation. To this end, the usefulness of more practical visual tests for use in clinical environments were explored. Experiments to determine the limitations of mobile displays in terms of the visibility of subtle targets for different background luminance and ambient illumination with two mobile devices were conducted. A noise-embedded text detection task and a threshold estimation staircase technique for a range of illuminance between 1 and 80,000 lx encompassing conditions found in dark reading rooms, office spaces, and outdoor scenarios has been compared. It was found that the text detection method holds promise as a surrogate for more complicated tests in the framework of a clinically practical implementation. C1 [Zafar, Fahad] Univ Maryland, Dept Elect & Comp Engn, Baltimore, MD 21201 USA. [Zafar, Fahad; Choi, Mina; Wang, Joel; Liu, Peter; Badano, Aldo] US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Catonsville, MD 21228 USA. [Choi, Mina] George Washington Univ, Dept Elect & Comp Engn, Washington, DC USA. RP Zafar, F (reprint author), Univ Maryland, Dept Elect & Comp Engn, Baltimore, MD 21201 USA. EM fahed.zafar@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 FU Research Participation Program FX The authors acknowledge support from the Research Participation Program administered by ORISE through an interagency agreement between DOE and FDA. The mention of commercial products herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. This is a contribution of the Food and Drug Administration and is not subject to copyright. NR 17 TC 3 Z9 3 U1 0 U2 2 PU SOC INFORMATION DISPLAY PI CAMPBELL PA 1475 S BASCOM AVE, STE 114, CAMPBELL, CA 95008 USA SN 1071-0922 J9 J SOC INF DISPLAY JI J. Soc. Inf. Disp. PD MAR PY 2012 VL 20 IS 3 BP 124 EP 132 DI 10.1889/JSID20.3.124 PN 2 PG 9 WC Engineering, Electrical & Electronic; Materials Science, Multidisciplinary; Optics; Physics, Applied SC Engineering; Materials Science; Optics; Physics GA 914CJ UT WOS:000301926000002 ER PT J AU Simms, KM Kortepeter, C Avigan, M AF Simms, Kelley M. Kortepeter, Cindy Avigan, Mark TI Lamotrigine and aseptic meningitis SO NEUROLOGY LA English DT Article ID FLUID PHARMACOKINETICS; CEREBROSPINAL-FLUID; BRAIN AB Objective: The purpose of this case series is to characterize a recently identified association of the antiepileptic drug (AED) lamotrigine with aseptic meningitis based on cases reported to the Food and Drug Administration (FDA)'s Adverse Event Reporting System (AERS) database. Methods: We performed a data mining analysis of 9 AEDs from the FDA's AERS database. We applied the multi-item gamma Poisson shrinker (MGPS) algorithm to the entire AERS database through November 2, 2009, to generate empirical Bayes geometric mean (EBGM) values with corresponding confidence intervals for 9 AEDs and the adverse event code "meningitis aseptic." The AERS database was also searched for postmarketing reports of aseptic meningitis associated with lamotrigine and a detailed review of each case was performed. Results: Forty AERS cases were identified in this review. Findings from the AERS reports revealed CSF profiles with features of both bacterial as well as viral meningitis. Fifteen cases documented a positive rechallenge; the median time to onset of symptoms upon rechallenge was only 60 minutes. Data mining analysis of several anticonvulsants resulted in disproportionate reporting solely for lamotrigine. Conclusion: There appears to be an association between lamotrigine use and aseptic meningitis. It is notable that nearly 40% of cases in this case series reported a positive rechallenge. Lamotrigine-associated aseptic meningitis should be considered in the differential diagnosis of culture-negative meningitis. This case series highlights the need for continued pharmacovigilance and the importance of systematic monitoring of patients treated with antiepileptic medications. Neurology (R) 2012;78:921-927 C1 [Simms, Kelley M.; Kortepeter, Cindy; Avigan, Mark] US FDA, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD USA. RP Simms, KM (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD USA. EM Kelley.Simms@fda.hhs.gov NR 23 TC 11 Z9 11 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2012 VL 78 IS 12 BP 921 EP 927 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 914GO UT WOS:000301937700016 PM 22357718 ER PT J AU Williams, JR Hirsch, ES Anderson, K Bush, AL Goldstein, SR Grill, S Lehmann, S Little, JT Margolis, RL Palanci, J Pontone, G Weiss, H Rabins, P Marsh, L AF Williams, J. R. Hirsch, E. S. Anderson, K. Bush, A. L. Goldstein, S. R. Grill, S. Lehmann, S. Little, J. T. Margolis, R. L. Palanci, J. Pontone, G. Weiss, H. Rabins, P. Marsh, L. TI A comparison of nine scales to detect depression in Parkinson disease Which scale to use? SO NEUROLOGY LA English DT Article ID RATING-SCALE; VALIDITY; DIAGNOSIS; INVENTORY; DEMENTIA; HAMILTON; RELIABILITY; VALIDATION; ACCURACY; SYMPTOMS AB Objective: The Methods of Optimal Depression Detection in Parkinson's Disease (MOOD-PD) study compared the psychometric properties of 9 depression scales to provide guidance on scale selection in Parkinson disease (PD). Methods: Patients with PD (n = 229) from community-based neurology practices completed 6 self-report scales (Beck Depression Inventory [BDI]-II, Center for Epidemiologic Studies Depression Rating Scale-Revised [CESD-R], 30-item Geriatric Depression Scale [GDS-30], Inventory of Depressive Symptoms-Patient [IDS-SR], Patient Health Questionnaire-9 [PHQ-9], and Unified Parkinson's Disease Rating Scale [UPDRS]-Part I) and were administered 3 clinician-rated scales (17-item Hamilton Depression Rating Scale [HAM-D-17], Inventory of Depressive Symptoms-Clinician [IDS-C], and Montgomery-angstrom sberg Depression Rating Scale [MADRS] and a psychiatric interview. DSM-IV-TR diagnoses were established by an expert panel blinded to the self-reported rating scale data. Receiver operating characteristic curves were used to estimate the area under the curve (AUC) of each scale. Results: All scales performed better than chance (AUC 0.75-0.85). Sensitivity ranged from 0.66 to 0.85 and specificity ranged from 0.60 to 0.88. The UPDRS Depression item had a smaller AUC than the BDI-II, HAM-D-17, IDS-C, and MADRS. The CESD-R also had a smaller AUC than the MADRS. The remaining AUCs were statistically similar. Conclusions: The GDS-30 may be the most efficient depression screening scale to use in PD because of its brevity, favorable psychometric properties, and lack of copyright protection. However, all scales studied, except for the UPDRS Depression, are valid screening tools when PD-specific cutoff scores are used. Neurology (R) 2012;78:998-1006 C1 [Williams, J. R.; Hirsch, E. S.; Lehmann, S.; Little, J. T.; Margolis, R. L.; Palanci, J.; Pontone, G.; Rabins, P.; Marsh, L.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Goldstein, S. R.; Grill, S.; Weiss, H.; Marsh, L.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Williams, J. R.; Goldstein, S. R.] US FDA, Silver Spring, MD USA. [Anderson, K.] Univ Maryland, Med Ctr, Dept Psychiat, Baltimore, MD 21201 USA. [Bush, A. L.; Marsh, L.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Bush, A. L.; Marsh, L.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Bush, A. L.; Marsh, L.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Goldstein, S. R.; Grill, S.] Parkinsons & Movement Disorder Ctr Maryland, Baltimore, MD USA. [Little, J. T.] Georgetown Univ, Med Ctr, Dept Psychiat, Washington, DC 20007 USA. [Little, J. T.] Vet Affairs Med Ctr, Mental Hlth Serv, Washington, DC 20422 USA. RP Marsh, L (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. EM laura.marsh2@va.gov FU NIMH [R01-MH069666]; NINDS [P50-NS58377]; NIA [T32-AG027668]; Department of Veterans Affairs; Donna Jeanne Gault Baumann Fund; Weldon Hall Trust; CHDI Foundation; VA Merit Award; NIH; Neuro Hi Tech; NIH/NIMH; Janssen; Forest Laboratories, Inc.; Amarin Corporation; Medivation, Inc.; NIH (NINDS/NIMH); NARSAD; EMD Serono; ACADIA Pharmaceuticals; Parkinson's Disease Foundation/Parkinson Study Group Mentored Clinical Research; NIH (NIA, NIMH); Eli Lilly and company; Boehringer Ingelheim; Michael J. Fox Foundation; American Psychiatric Association; Dystonia Foundation FX The MOOD-PD study was funded by NIMH grant R01-MH069666. Coauthors were also supported by NINDS grant P50-NS58377 (the Morris K. Udall Parkinson's Disease Research Center of Excellence at Johns Hopkins), NIA grant T32-AG027668, the Department of Veterans Affairs, the Donna Jeanne Gault Baumann Fund, and the Weldon Hall Trust. This article reflects the views of the authors and should not be construed to represent the Food and Drug Administration's views or policies.; Dr. Williams is currently employed by and owns stock in Biogen Idec. E. S. Hirsch reports no disclosures. Dr. Anderson has served on scientific advisory boards for Lundbeck, Inc. and CHDI Foundation; has received funding for travel from CHDI Foundation; serves as a Section Editor for Current Treatment Options in Neurology; serves as a consultant for Guide-point Global; serves on the speakers' bureau for Lundbeck, Inc. and the FDA; and is supported by a VA Merit Award. Dr. Bush and Dr. Goldstein report no disclosures. Dr. Grill has received speaker honoraria from Medtronic, Inc. Dr. Lehmann receives research support from the NIH. Dr. Little has received research support from Neuro Hi Tech and the NIH/NIMH. Dr. Margolis has received research support from Janssen, Forest Laboratories, Inc., Amarin Corporation, Medivation, Inc., the NIH (NINDS/NIMH), and NARSAD; has received payment from AstraZeneca for expert testimony, royalties from Lippincott Williams & Wilkins for a textbook chapter and licensing fees and payments from patents related to stem cells; and payments for the development of educational presentations from Johns Hopkins University. J. Palanci reports no disclosures. Dr. Pontone has received research support from EMD Serono, ACADIA Pharmaceuticals, the NIH, Parkinson's Disease Foundation/Parkinson Study Group Mentored Clinical Research Award, and The Donna Jeanne Gault Baumann Fund. Dr. Weiss reports no disclosures. Dr. Rabins serves on a data safety monitoring board for the VA Health System; serves on the editorial boards of International Journal of Geriatric Psychiatry and International Psychogeriatrics; receives publishing royalties for 36-Hour Day (Johns Hopkins Press 2011); receives research support from the NIH (NIA, NIMH); and has provided legal testimony on behalf of Janssen. Dr. Marsh serves on scientific advisory boards for the National Parkinson Foundation, American Parkinson's Disease Association, and the Parkinson Study Group; receives publishing royalties for Psychiatric Issues in Parkinson's Disease: A Practical Guide (Taylor & Francis, Informa, 2005); served as a consultant for Merck Serono, Boehringer Ingelheim, ACADIA Pharmaceuticals, Lundbeck, Inc., and Ovation Pharmaceuticals; received research support from Forest Laboratories, Inc., Eli Lilly and Company, Boehringer Ingelheim, the Michael J. Fox Foundation, and the NIH; and currently receives research support from the NIH, American Psychiatric Association, and the Dystonia Foundation. NR 40 TC 43 Z9 44 U1 3 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2012 VL 78 IS 13 BP 998 EP 1006 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 916TH UT WOS:000302125600015 PM 22422897 ER PT J AU Cieslak, J Grajkowski, A Ausin, C Gapeev, A Beaucage, SL AF Cieslak, Jacek Grajkowski, Andrzej Ausin, Cristina Gapeev, Alexei Beaucage, Serge L. TI Permanent or reversible conjugation of 2'-O- or 5'-O-aminooxymethylated nucleosides with functional groups as a convenient and efficient approach to the modification of RNA and DNA sequences SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SOLID-PHASE SYNTHESIS; OXIME BOND FORMATION; CHEMOSELECTIVE OXIME; OLIGONUCLEOTIDES; PROTECTION; SUPPORT; OLIGORIBONUCLEOTIDES; DERIVATIZATION AB 2'-O-Aminooxymethyl ribonucleosides are prepared from their 3',5'-disilylated 2'-O-phthalimidooxymethyl derivatives by treatment with NH4F in MeOH. The reaction of these novel ribonucleosides with 1-pyrenecarboxaldehyde results in the efficient formation of stable and yet reversible ribonucleoside 2'-conjugates in yields of 69-82%. Indeed, exposure of these conjugates to 0.5 M tetra-n-butylammonium fluoride (TBAF) in THF results in the cleavage of their iminoether functions to give the native ribonucleosides along with the innocuous nitrile side product. Conversely, the reaction of 5-cholesten-3-one or dansyl chloride with 2'-O-aminooxymethyl uridine provides permanent uridine 2'-conjugates, which are left essentially intact upon treatment with TBAF. Alternatively, 5'-O-aminooxymethyl thymidine is prepared by hydrazinolysis of its 3'-O-levulinyl-5'-O-phthalimidooxymethyl precursor. Pyrenylation of 5'-O-aminooxymethyl thymidine and the sensitivity of the 5'-conjugate to TBAF further exemplify the usefulness of this nucleoside for modifying DNA sequences either permanently or reversibly. Although the versatility and uniqueness of 2'-O-aminooxymethyl ribonucleosides in the preparation of modified RNA sequences is demonstrated by the single or double incorporation of a reversible pyrenylated uridine 2'-conjugate into an RNA sequence, the conjugation of 2'-O-aminooxymethyl ribonucleosides with aldehydes, including those generated from their acetals, provides reversible 2'-O-protected ribonucleosides for potential applications in the solid-phase synthesis of native RNA sequences. The synthesis of a chimeric polyuridylic acid is presented as an exemplary model. C1 [Cieslak, Jacek; Grajkowski, Andrzej; Ausin, Cristina; Beaucage, Serge L.] US FDA, Ctr Drug Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA. [Gapeev, Alexei] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. RP Beaucage, SL (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Therapeut Prot, 8800 Rockville Pike, Bethesda, MD 20892 USA. EM serge.beaucage@fda.hhs.gov NR 36 TC 5 Z9 5 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR PY 2012 VL 40 IS 5 BP 2312 EP 2329 DI 10.1093/nar/gkr896 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 915JG UT WOS:000302019900042 PM 22067450 ER PT J AU Nguyen, TB Wang, SJ Anugu, V Rose, N McKenna, M Petrick, N Burns, JE Summers, RM AF Nguyen, Tan B. Wang, Shijun Anugu, Vishal Rose, Natalie McKenna, Matthew Petrick, Nicholas Burns, Joseph E. Summers, Ronald M. TI Distributed Human Intelligence for Colonic Polyp Classification in Computer-aided Detection for CT Colonography SO RADIOLOGY LA English DT Article ID TOMOGRAPHIC VIRTUAL COLONOSCOPY; OBSERVER PERFORMANCE; FEASIBILITY; POPULATION; CURVES; READER AB Purpose: To assess the diagnostic performance of distributed human intelligence for the classification of polyp candidates identified with computer-aided detection (CAD) for computed tomographic (CT) colonography. Materials and Methods: This study was approved by the institutional Office of Human Subjects Research. The requirement for informed consent was waived for this HIPAA-compliant study. CT images from 24 patients, each with at least one polyp of 6 mm or larger, were analyzed by using CAD software to identify 268 polyp candidates. Twenty knowledge workers (KWs) from a crowdsourcing platform labeled each polyp candidate as a true or false polyp. Two trials involving 228 KWs were conducted to assess reproducibility. Performance was assessed by comparing the area under the receiver operating characteristic curve (AUC) of KWs with the AUC of CAD for polyp classification. Results: The detection-level AUC for KWs was 0.845 +/- 0.045 (standard error) in trial 1 and 0.855 +/- 0.044 in trial 2. These were not significantly different from the AUC for CAD, which was 0.859 +/- 0.043. When polyp candidates were stratified by difficulty, KWs performed better than CAD on easy detections; AUCs were 0.951 +/- 0.032 in trial 1, 0.966 +/- 0.027 in trial 2, and 0.877 +/- 0.048 for CAD (P = .039 for trial 2). KWs who participated in both trials showed a significant improvement in performance going from trial 1 to trial 2; AUCs were 0.759 +/- 0.052 in trial 1 and 0.839 +/- 0.046 in trial 2 (P = .041). Conclusion: The performance of distributed human intelligence is not significantly different from that of CAD for colonic polyp classification. C1 [Nguyen, Tan B.; Wang, Shijun; Anugu, Vishal; Rose, Natalie; McKenna, Matthew; Burns, Joseph E.; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. [Petrick, Nicholas] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Burns, Joseph E.] Univ Calif Irvine, Irvine Med Ctr, Dept Radiol Sci, Orange, CA 92668 USA. RP Summers, RM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C224D,MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov FU National Institutes of Health, Clinical Center; Clinical Research Training Program; National Institutes of Health; Pfizer; iCAD Medical; iCAD FX J.E.B., and R.M.S. supported by the Intramural Research Programs of the National Institutes of Health, Clinical Center. T.B.N. supported in part through the Clinical Research Training Program, a public-private partnership supported jointly by the National Institutes of Health and Pfizer (via a grant to the Foundation for the National Institutes of Health from Pfizer).; T.B.N. Financial activities related to the present article: received grant through the Clinical Research Training Program, a public-private partnership supported jointly by the National Institutes of Health and Pfizer (via a grant to the Foundation for the National Institutes of Health from Pfizer). Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. S. W. No potential conflicts of interest to disclose. V. A. No potential conflicts of interest to disclose. N.R. No potential conflicts of interest to disclose. M. M. No potential conflicts of interest to disclose. N.P. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: author and institution have patent applications submitted in related areas for the National Institutes of Health and the Food and Drug Administration. Other relationships: none to disclose. J.E.B. No potential conflicts of interest to disclose. R. M. S. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received grant from iCAD Medical; author and institution receive royalties for a patent license from iCAD Medical and software license from Translational Sciences Corporation and have patents issued and pending in related areas. Other relationships: Viatronix provided the V3D-Colon software free of charge to author's laboratory, and software was used in the submitted work; author's laboratory is supported in part by a Cooperative Research and Development Agreement with iCAD; is a stockholder of Johnson & Johnson. NR 31 TC 25 Z9 26 U1 2 U2 9 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAR PY 2012 VL 262 IS 3 BP 824 EP 833 DI 10.1148/radiol.11110938 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 916RR UT WOS:000302121400011 PM 22274839 ER PT J AU Seidel, SE Tilley, BC Huang, P Palesch, YY Bergmann, KJ Goetz, CG Swearingen, CJ AF Seidel, Sydney E. Tilley, Barbara C. Huang, Peng Palesch, Yuko Y. Bergmann, Kenneth J. Goetz, Christopher G. Swearingen, Christopher J. TI Subject-investigator reproducibility of the Unified Parkinson's Disease Rating Scale SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE UPDRS; Parkinson's disease; Concordance correlation; Kappa; NET-PD ID SOCIETY-SPONSORED REVISION; CLINICAL-TRIAL; CAREGIVER RATINGS; MOTOR EXAMINATION; MDS-UPDRS; RELIABILITY; PATIENT; SECTION; DISABILITY; AGREEMENT AB Objective: To evaluate the subject-investigator agreement on the Unified Parkinson's Disease Rating Scale (UPDRS) subsections I and II. Methods: Subject-investigator agreement was estimated at baseline and endpoint by Kappa statistics for individual items and concordance correlations for subscale totals using data from two NIH Exploratory Trials in Parkinson's Disease studies. Results: All but two questions had moderate subject-investigator agreement at baseline and endpoint. Participants consistently rated their disease activity worse that investigators. Conclusion: UPDRS self-administration produces similar results to investigator-administration. Although slightly elevated, UPDRS self-administration can be accommodated in a clinical trial setting. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Swearingen, Christopher J.] Univ Arkansas Med Sci, Dept Pediat, Biostat Program, Little Rock, AR 72202 USA. [Seidel, Sydney E.; Palesch, Yuko Y.] Med Univ S Carolina, Div Biostat & Epidemiol, Charleston, SC 29425 USA. [Tilley, Barbara C.] Univ Texas Houston, Hlth Sci Ctr, Sch Publ Hlth, Houston, TX 77030 USA. [Huang, Peng] Johns Hopkins Univ, Oncol Biostat Div, Baltimore, MD 21205 USA. [Bergmann, Kenneth J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Goetz, Christopher G.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. RP Swearingen, CJ (reprint author), Univ Arkansas Med Sci, Dept Pediat, Biostat Program, Slot 512-43,1 Childrens Way, Little Rock, AR 72202 USA. EM cswearingen@uams.edu OI Swearingen, Christopher/0000-0003-4262-4906 FU NINDS [T32 RR023258-01, T32 NS48007-01A1, U01NS043127, U10-NS053372]; Parkinson's Disease Foundation (PDF) of Rush PDF Parkinson's Disease Research Center FX Support for Ms. Seidel was received from NINDS T32 RR023258-01. Dr. Swearingen received support from NINDS T32 NS48007-01A1. Drs. Huang, Palesch, Goetz and Tilley received funding from NINDS U01NS043127. Dr. Goetz is supported by the Parkinson's Disease Foundation (PDF) as part of the Rush PDF Parkinson's Disease Research Center. Dr. Bergmann received funding from NINDS U10-NS053372. NR 23 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD MAR PY 2012 VL 18 IS 3 BP 230 EP 233 DI 10.1016/j.parkreldis.2011.10.006 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 912PX UT WOS:000301813200004 PM 22018910 ER PT J AU Rothmann, MD Zhang, JJ Lu, L Fleming, TR AF Rothmann, Mark D. Zhang, Jenny J. Lu, Laura Fleming, Thomas R. TI Testing in a Prespecified Subgroup and the Intent-to-Treat Population SO DRUG INFORMATION JOURNAL LA English DT Article DE biomarker; subgroup analysis; intent-to-treat ID CLINICAL-TRIALS; DESIGN; SUBSET AB In many settings, testing has been proposed to assess the effect of an experimental regimen within a biomarker-positive subgroup where it is biologically plausible that benefit is stronger in such patients, and in the overall population that also includes biomarker-negative subjects less likely to benefit from that regimen. A statistically favorable result in the biomarker-positive subgroup would lead to a claim for that subgroup. whereas a statistically favorable result for the overall population would lead to a claim that includes both biomarker subgroups. The latter setting is problematic when biomarker-negative patients truly do not benefit from the experimental regimen. When it is prespecified that biomarker-negative patients should not be included in the primary analysis of treatment effect in biomarker-positive patients because of the likelihood that treatment effects would differ between the 2 subgroups, it is logically inconsistent to include biomarker-positive patients in the primary analysis of treatment effect in biomarker-negative patients. C1 [Rothmann, Mark D.; Zhang, Jenny J.; Lu, Laura] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Fleming, Thomas R.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Rothmann, MD (reprint author), US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 21,Room 3528, Silver Spring, MD 20993 USA. EM mark.rothmann@fda.hhs.gov FU NIH/NIAID [R37 AI 29168] FX For Thomas R. Fleming, the source of financial support for research described in this article is NIH/NIAID grant entitled "Statistical Issues in AIDS Research" (R37 AI 29168). NR 5 TC 10 Z9 10 U1 0 U2 2 PU DRUG INFORMATION ASSOC PI HORSHAM PA 800 ENTERPRISE ROAD, SUITE 200, HORSHAM, PA 19044-3595 USA SN 0092-8615 J9 DRUG INF J JI Drug Inf. J. PD MAR PY 2012 VL 46 IS 2 BP 175 EP 179 DI 10.1177/0092861512436579 PG 5 WC Health Care Sciences & Services; Pharmacology & Pharmacy SC Health Care Sciences & Services; Pharmacology & Pharmacy GA 907DO UT WOS:000301398200004 PM 22723719 ER PT J AU Lando, AM Chen, CC AF Lando, Amy M. Chen, Cary C. TI Trends in Ownership and Usage of Food Thermometers in the United States, 1998 through 2010 SO JOURNAL OF FOOD PROTECTION LA English DT Article ID HANDLING BEHAVIORS; SAMPLE SELECTION; SAFETY EDUCATION; TELEPHONE SURVEY; BEEF PATTIES; CONSUMER; HEALTH; HOME; NONRESPONSE AB Food safety research has shown that the use of a food thermometer is the best way to ensure that meat, poultry, and other foods reach an internal temperature sufficient to destroy foodborne pathogens. The 1998, 2001, 2006, and 2010 Food Safety Surveys were used to analyze changes in food thermometer ownership and usage for roasts, chicken parts, and hamburgers in the United States. A probit regression model was used to evaluate differing trends in ownership across demographic subgroups, and probit models with sample selection were used to evaluate differing trends in food thermometer usage for roasts, chicken parts, and hamburgers. The Food Safety Surveys are nationally representative telephone surveys tracking consumers' food safety attitudes and behaviors. Findings from these surveys indicate that the percentage of consumers who own food thermometers has increased from 49% in 1998 to 70% in 2010 (P < 0.05). The use of food thermometers has also increased over this time period but varies by food type. Of those who own food thermometers, a higher percentage reported using thermometers for roasts (76% in 1998 and 82% in 2010, P < 0.05) than for chicken parts (33% in 1998 and 53% in 2(110, P < 0.05) and hamburgers (14% in 1998 and 23% in 2010, P < 0.05). The results also show that men, non-Hispanic whites, those with some college education or higher, those with higher incomes, and those 65 years and older were more likely to own food thermometers. After controlling for food thermometer ownership, those aged 18 to 29 years were more likely to use a food thermometer for roasts and chicken parts than those aged 65 to 101 years. The results suggest that educational programs encouraging food thermometer usage should focus first on food thermometer ownership. C1 [Lando, Amy M.; Chen, Cary C.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Lando, AM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM amy.lando@fda.hhs.gov FU U.S. Food and Drug Administration; U.S. Department of Agriculture Food Safety and Inspection Service FX We thank Dr. Chung-Tung (Jordan) Lin for his helpful suggestions and advice. We thank Dr. Andrew Bershadker for his help with our discussion of probit models, and we thank two anonymous reviewers for helpful comments. Support was provided by the U.S. Food and Drug Administration and the U.S. Department of Agriculture Food Safety and Inspection Service. NR 33 TC 7 Z9 7 U1 2 U2 7 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X J9 J FOOD PROTECT JI J. Food Prot. PD MAR PY 2012 VL 75 IS 3 BP 556 EP 562 DI 10.4315/0362-028X.JFP-11-314 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 907GS UT WOS:000301406400018 PM 22410231 ER PT J AU Zhu, L Stewart, D Reineke, K Ravishankar, S Palumbo, S Cirigliano, M Tortorello, M AF Zhu, L. Stewart, D. Reineke, K. Ravishankar, S. Palumbo, S. Cirigliano, M. Tortorello, M. TI Comparison of Swab Transport Media for Recovery of Listeria monocytogenes from Environmental Samples SO JOURNAL OF FOOD PROTECTION LA English DT Article AB Environmental monitoring is recognized as an important strategy for controlling Listeria monocytogenes in food processing facilities. Samples are taken by swabbing environmental surfaces, and the swabs are immersed in a medium for transport to the laboratory. In this study, buffered peptone water (BPW), Dey-Engley neutralizing broth (DE), neutralizing buffer (NB), Letheen broth (LE), and newly described MCC buffer (MCC) were evaluated as transport media for recovery of sanitizer-stressed L. monocytogenes from inoculated swabs. After storage at 4 degrees C, the media performed similarly, but at 25 degrees C relative recovery efficiency from the inoculated sponges was DE > LE > BPW > MCC > NB. Recoveries from stainless steel surfaces followed similar trends. MCC, DE, and NB were compared for L. monocytogenes recovery in the presence of Escherichia coli, Enterococcus faecalis, Lactobacillus plantarum, Pseudomonas fluorescens, and Listeria innocua. After 4 C storage, all population levels changed little; after 25 degrees C storage, DE allowed the best growth of L. monocytogenes regardless of other species present. MCC, DE, and NB performed similarly for recovery of L. monocytogenes from an artificial milk biofilm and for recovery of Listeria spp. from swabs obtained from a meat processing facility. Transport medium formulation, time and temperature of swab storage, and coexistence of other species affect recovery of sanitizer-stressed L. monocytogenes from environmental swabs. The study confirms the need to maintain 4 degrees C storage conditions during swab transport. C1 [Stewart, D.; Reineke, K.; Tortorello, M.] US FDA, Bedford Pk, IL 60501 USA. [Zhu, L.; Ravishankar, S.; Palumbo, S.] IIT, Natl Ctr Food Safety & Technol, Bedford Pk, IL 60501 USA. [Cirigliano, M.] Unilever, Englewood Cliffs, NJ 07632 USA. RP Tortorello, M (reprint author), US FDA, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. EM mary.tortorello@fda.hhs.gov RI Robertson, Simon/D-1549-2012 FU U.S. Food and Drug Administration to the National Center for Food Safety and Technology at Illinois Institute of Technology FX This article is dedicated to the memory of our colleague and friend, Sam Palumbo. The authors thank Cindy Dohm for providing environmental swabs and Dennis Ruggles (U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Biostatistics Branch) for the statistical analysis of the data from the meat processing facility. This work was supported by a grant from the U.S. Food and Drug Administration to the National Center for Food Safety and Technology at Illinois Institute of Technology. NR 13 TC 0 Z9 0 U1 2 U2 11 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X J9 J FOOD PROTECT JI J. Food Prot. PD MAR PY 2012 VL 75 IS 3 BP 580 EP 584 DI 10.4315/0362-028X.JFP-11-386 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 907GS UT WOS:000301406400023 PM 22410235 ER PT J AU Ruan, JQ Li, N Xia, QS Fu, PP Peng, SY Ye, Y Lin, G AF Ruan, Jianqing Li, Na Xia, Qingsu Fu, Peter P. Peng, Shuying Ye, Yang Lin, Ge TI Characteristic ion clusters as determinants for the identification of pyrrolizidine alkaloid N-oxides in pyrrolizidine alkaloid-containing natural products using HPLC-MS analysis SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE pyrrolizidine alkaloid N-oxides; pyrrolizidine alkaloid; HPLC-MS analysis; characteristic fragment ions; fragmentation pathway ID METABOLIC-ACTIVATION; MASS-SPECTROMETRY; SENECIO-SCANDENS; DNA-ADDUCTS; CLIVORINE; QIANLIGUANG; TOXICITY; EXTRACT; SAFETY; RAT AB Pyrrolizidine alkaloid (PA)containing plants are widely distributed in the world. PAs are hepatotoxic, affecting livestock and humans. PA N-oxides are often present together with PAs in plants and also exhibit hepatotoxicity but with less potency. HPLCMS is generally used to analyze PA-containing herbs, although PA references are unavailable in most cases. However, to date, without reference standards, HPLCMS methodology cannot distinguish PA N-oxides from PAs because they both produce the same characteristic ions in mass spectra. In the present study, the mass spectra of 10 PA N-oxides and the corresponding PAs were systemically investigated using HPLCMS to define the characteristic mass fragment ions specific to PAs and PA N-oxides. Mass spectra of toxic retronecine-type PA N-oxides exhibited two characteristic ion clusters at m/z 118120 and 136138. These ion clusters were produced by three unique fragmentation pathways of PA N-oxides and were not found in their corresponding PAs. Similarly, the nontoxic platynecine-type PA N-oxides also fragmented via three similar pathways to form two characteristic ion clusters at m/z 120122 and 138140. Further application of using these characteristic ion clusters allowed successful and rapid identification of PAs and PA N-oxides in two PA-containing herbal plants. Our results demonstrated, for the first time, that these characteristic ion clusters are unique determinants to discriminate PA N-oxides from PAs even without the availability of reference samples. Our findings provide a novel and specific method to differentiate PA N-oxides from PAs in PA-containing natural products, which is crucial for the assessment of their intoxication. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Ruan, Jianqing; Li, Na; Lin, Ge] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Ruan, Jianqing; Li, Na; Ye, Yang; Lin, Ge] Chinese Acad Sci, Shanghai Inst Mat Med, Joint Res Lab Promoting Globalizat Tradit Chinese, Beijing 100864, Peoples R China. [Xia, Qingsu; Fu, Peter P.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Peng, Shuying; Ye, Yang] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China. RP Lin, G (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. EM peter.fu@fda.hhs.gov; linge@cuhk.edu.hk FU Research Grant Council of Hong Kong Special Administrative Region, China (GRF) [CUHK2140690]; National Natural Science Funds for Distinguished Young Scholar [30925043] FX The authors greatly acknowledge the funding support from Research Grant Council of Hong Kong Special Administrative Region, China (GRF Grant Project no. CUHK2140690) to the present study. The financial support from the National Natural Science Funds for Distinguished Young Scholar (No. 30925043) is also greatly acknowledged. They thank Dr Po-Chuen Chan of NTP for supplying riddelliine, Dr John A. Edgar of CSIRO for supplying lasiocarpine, and Prof. Hai Shen Chen of Secondary Military Medical University for supplying Platyphylline. This article is not an official guidance or policy statement of the US Food and Drug Administration (FDA). No official support or endorsement by the US FDA is intended or should be inferred. NR 28 TC 12 Z9 12 U1 3 U2 33 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1076-5174 J9 J MASS SPECTROM JI J. Mass Spectrom. PD MAR PY 2012 VL 47 IS 3 BP 331 EP 337 DI 10.1002/jms.2969 PG 7 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 909OX UT WOS:000301575200008 PM 22431459 ER PT J AU Statler, JD Miller, DL Dixon, RG AF Statler, John D. Miller, Donald L. Dixon, Robert G. TI Leave No Sponge Uncounted Response SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter C1 [Statler, John D.] Virginia Intervent & Vasc Associates, Fredericksburg, VA USA. [Statler, John D.] Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, Bethesda, MD USA. [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Dixon, Robert G.] Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. RP Statler, JD (reprint author), Virginia Intervent & Vasc Associates, Fredericksburg, VA USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD MAR PY 2012 VL 23 IS 3 BP 434 EP 434 DI 10.1016/j.jvir.2011.12.006 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 906EQ UT WOS:000301328100032 ER PT J AU Akiyama, T Khan, AA Nawaz, MS West, CS AF Akiyama, Tatsuya Khan, Ashraf A. Nawaz, M. S. West, Christine S. TI Molecular characterisation of high-level ciprofloxacin-resistant Salmonella enterica with multiple antibiotic resistance and class 1 integrons isolated from imported foods SO INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS LA English DT Letter C1 [Akiyama, Tatsuya; Khan, Ashraf A.; Nawaz, M. S.; West, Christine S.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Khan, AA (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Ashraf.khan@fda.hhs.gov RI Khan, Ashraf/E-8133-2013 NR 5 TC 2 Z9 2 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-8579 J9 INT J ANTIMICROB AG JI Int. J. Antimicrob. Agents PD MAR PY 2012 VL 39 IS 3 BP 263 EP 264 DI 10.1016/j.ijantimicag.2011.10.003 PG 2 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 896RE UT WOS:000300587100015 PM 22100280 ER PT J AU Sahin, O Fitzgerald, C Stroika, S Zhao, SH Sippy, RJ Kwan, P Plummer, PJ Han, J Yaeger, MJ Zhang, QJ AF Sahin, Orhan Fitzgerald, Collette Stroika, Steven Zhao, Shaohua Sippy, Rachel J. Kwan, Patrick Plummer, Paul J. Han, Jing Yaeger, Michael J. Zhang, Qijing TI Molecular Evidence for Zoonotic Transmission of an Emergent, Highly Pathogenic Campylobacter jejuni Clone in the United States SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID FIELD GEL-ELECTROPHORESIS; GUILLAIN-BARRE-SYNDROME; POPULATION-STRUCTURE; COLI INFECTIONS; RISK-FACTORS; ABORTION; DISEASES; EPIDEMIOLOGY; EVOLUTIONARY; ATTRIBUTION AB Campylobacter jejuni is a major zoonotic pathogen. A highly virulent, tetracycline-resistant C. jejuni clone (clone SA) has recently emerged in ruminant reservoirs and has become the predominant cause of sheep abortion in the United States. To determine whether clone SA is associated with human disease, we compared the clinical isolates of clone SA from sheep abortions with the human isolates of the PulseNet National Campylobacter databases at the CDC and the FDA using pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and serotyping. The combined SmaI and KpnI PFGE pattern designations of clone SA from sheep were indistinguishable from those of 123 (9.03%) human C. jejuni isolates (total, 1,361) in the CDC database, among which 56 were associated with sporadic infections and 67 were associated with outbreaks that occurred in multiple states from 2003 to 2010. Most of the outbreaks were attributed to raw milk, while the sources for most of the sporadic cases were unknown. All clone SA isolates examined, including PFGE-matched human isolates, belong to sequence type 8 (ST-8) by MLST and serotype HS:1,8, further indicating the clonality of the related isolates from different host species. Additionally, C. jejuni clone SA was identified in raw milk, cattle feces, the feces and bile of healthy sheep, and abortion cases of cattle and goats, indicating the broad distribution of this pathogenic clone in ruminants. These results provide strong molecular and epidemiological evidence for zoonotic transmission of this emergent clone from ruminants to humans and indicate that C. jejuni clone SA is an important threat to public health. C1 [Sahin, Orhan; Sippy, Rachel J.; Plummer, Paul J.; Han, Jing; Zhang, Qijing] Iowa State Univ, Dept Vet Microbiol & Prevent Med, Ames, IA 50011 USA. [Plummer, Paul J.] Iowa State Univ, Dept Vet Diagnost & Prod Anim Med, Ames, IA USA. [Yaeger, Michael J.] Iowa State Univ, Dept Vet Pathol, Ames, IA USA. [Fitzgerald, Collette; Stroika, Steven; Kwan, Patrick] Ctr Dis Control & Prevent, Enter Dis Lab Branch, Atlanta, GA USA. [Zhao, Shaohua] US FDA, Ctr Vet Med, Laurel, MD USA. RP Zhang, QJ (reprint author), Iowa State Univ, Dept Vet Microbiol & Prevent Med, Ames, IA 50011 USA. EM zhang123@iastate.edu RI Zhang, Qijing/B-7530-2012; Plummer, Paul/B-2817-2011 OI Plummer, Paul/0000-0002-5784-8382 FU National Institute of Food and Agriculture at the USDA [2010-65110-20419]; Iowa Livestock Health Advisory Council [109-05-14] FX This work was supported by the National Research Initiative Competitive Grants Program of the National Institute of Food and Agriculture at the USDA (grant no. 2010-65110-20419) and the Iowa Livestock Health Advisory Council (grant no. 109-05-14). NR 59 TC 32 Z9 32 U1 2 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2012 VL 50 IS 3 BP 680 EP 687 DI 10.1128/JCM.06167-11 PG 8 WC Microbiology SC Microbiology GA 901WB UT WOS:000300997800023 PM 22189122 ER PT J AU Sillo, P Pinter, D Ostorhazi, E Mazan, M Wikonkal, N Ponyai, K Volokhov, DV Chizhikov, VE Szathmary, S Stipkovits, L Karpati, S AF Sillo, Palma Pinter, Dora Ostorhazi, Eszter Mazan, Mercedes Wikonkal, Norbert Ponyai, Katinka Volokhov, Dmitriy V. Chizhikov, Vladimir E. Szathmary, Susan Stipkovits, Laszlo Karpati, Sarolta TI Eosinophilic Fasciitis Associated with Mycoplasma arginini Infection SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID POLYMERASE-CHAIN-REACTION; PNEUMONIAE INFECTION; MYALGIA-SYNDROME; HEMOLYTIC-ANEMIA; IGM ANTIBODIES; PATIENT; IDENTIFICATION; HEMOPLASMA; DISEASE; SAMPLES AB Eosinophilic fasciitis (EF) with generalized sclerodermiform skin lesions developed over a 19-month period in a previously healthy 23-year-old man. Although we confirmed EF by skin histology and laboratory tests, the recurrent fevers and the clinical observation of sclerotic prepuce with urethritis indicated further bacteriological analysis by conventional microbiological and DNA-based tests. Urethra cultures were positive for an arginine-hydrolyzing mycoplasma and Ureaplasma urealyticum. The patient also had serum IgM antibodies to Mycoplasma pneumoniae using enzyme-linked immunosorbent assay (ELISA)-based qualitative detection. Mycoplasma arginini was isolated from two independent venous blood serum samples and was identified by conventional microbiological tests and sequencing of the 16S rRNA and rpoB genes (GenBank sequence accession numbers HM179555 and HM179556, respectively). M. arginini genomic DNA also was detected by species-specific PCR in the skin lesion biopsy sample. Treatment with corticosteroids and long-term courses of selected antibiotics led to remission of skin symptoms and normalization of laboratory values. This report provides the first evidence of EF associated with mycoplasma infection and the second report of human infection with M. arginini and therefore suggests that this mycoplasma infection might have contributed to the pathogenesis of the disease. C1 [Sillo, Palma; Pinter, Dora; Ostorhazi, Eszter; Wikonkal, Norbert; Ponyai, Katinka; Karpati, Sarolta] Semmelweis Univ Hungary, Dept Dermatol Venereol & Dermatooncol, Budapest, Hungary. [Mazan, Mercedes; Karpati, Sarolta] Hungarian Acad Sci, Mol Med Res Grp, Budapest, Hungary. [Volokhov, Dmitriy V.; Chizhikov, Vladimir E.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Szathmary, Susan] GalenBio Inc, Carlsbad, CA USA. [Szathmary, Susan; Stipkovits, Laszlo] RT Europe Res Ctr 9200, Mosonmagyarovar, Hungary. RP Karpati, S (reprint author), Semmelweis Univ Hungary, Dept Dermatol Venereol & Dermatooncol, Maria Utca 41, Budapest, Hungary. EM skarpati@t-online.hu RI Sillo, Palma/O-9495-2014 OI Sillo, Palma/0000-0002-6940-8368 FU Hungarian Scientific Research Fund OTKA [73296] FX This work was supported by the Hungarian Scientific Research Fund OTKA, ID 73296. NR 39 TC 11 Z9 11 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2012 VL 50 IS 3 BP 1113 EP 1117 DI 10.1128/JCM.05568-11 PG 5 WC Microbiology SC Microbiology GA 901WB UT WOS:000300997800096 PM 22189109 ER PT J AU Dobrovolskaia, MA Patri, AK Simak, J Hall, JB Semberova, J Lacerda, SHDP McNeil, SE AF Dobrovolskaia, Marina A. Patri, Anil K. Simak, Jan Hall, Jennifer B. Semberova, Jana Lacerda, Silvia H. De Paoli McNeil, Scott E. TI Nanoparticle Size and Surface Charge Determine Effects of PAMAM Dendrimers on Human Platelets in Vitro SO MOLECULAR PHARMACEUTICS LA English DT Article DE PAMAM dendrimers; platelets; aggregation; activation; nanomaterials; thrombogenicity; coagulation; nanoparticles; thrombocyte; dendrimers; blood; nanomedicine ID SUPPORTED LIPID-BILAYERS; COARSE-GRAINED MODEL; POLY(AMIDOAMINE) DENDRIMERS; THROMBUS FORMATION; LATEX-PARTICLES; PROTEIN CORONA; HOLE FORMATION; AGGREGATION; CELLS; MICROPARTICLES AB Blood platelets are essential in maintaining hemostasis. Various materials can activate platelets and cause them to aggregate. Platelet aggregation in vitro is often used as a marker for materials thrombogenic properties, and studying nanomaterial interaction with platelets is an important step toward understanding their hematocompatibility. Here we report evaluation of 12 formulations of PAMAM dendrimers varying in size and surface charge. Using a cell counter based method, light transmission aggregometry and scanning electron microscopy, we show that only large cationic dendrimers, but not anionic, neutral or small cationic dendrimers, induce aggregation of human platelets in plasma in vitro. The aggregation caused by large cationic dendrimers was proportional to the number of surface amines. The observed aggregation was not associated with membrane microparticle release, and was insensitive to a variety of chemical and biological inhibitors known to interfere with various pathways of platelet activation. Taken in context with previously reported studies, our data suggest that large cationic PAMAM dendrimers induce platelet aggregation through disruption of membrane integrity. C1 [Dobrovolskaia, Marina A.; Patri, Anil K.; Hall, Jennifer B.; McNeil, Scott E.] SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, Frederick, MD 21702 USA. [Simak, Jan; Semberova, Jana; Lacerda, Silvia H. De Paoli] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Dobrovolskaia, MA (reprint author), Lab SAIC Frederick Inc, Nanotechnol Characterizat, NCI Frederick, 1050 Boyles St,Bldg 469, Frederick, MD 21702 USA. EM marina@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute, National Institutes of Health [N01-CO-12400, HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400 and HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. We thank Nader Ayub, Kent Worthington, Barry Neun, David Parmiter and Jamie Rodriguez for excellent technical support. NR 45 TC 74 Z9 74 U1 4 U2 47 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD MAR PY 2012 VL 9 IS 3 BP 382 EP 393 DI 10.1021/mp200463e PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 902DG UT WOS:000301018200005 PM 22026635 ER PT J AU Akkoyunlu, M AF Akkoyunlu, M. TI TACI Expression is Low Both in Human and Mouse Newborns SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Letter ID SECRETION; APRIL; BAFF C1 US FDA, Lab Bacterial Polysaccharides, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Akkoyunlu, M (reprint author), US FDA, Lab Bacterial Polysaccharides, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, 29 Lincoln Dr,HFM-428, Bethesda, MD 20892 USA. EM mustafa.akkoyunlu@fda.hhs.gov RI Akkoyunlu, Mustafa/I-5712-2012 NR 4 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD MAR PY 2012 VL 75 IS 3 BP 368 EP 368 DI 10.1111/j.1365-3083.2011.02651.x PG 1 WC Immunology SC Immunology GA 895MB UT WOS:000300499200015 PM 21988533 ER PT J AU Peterson, TA Nehrt, NL Park, D Kann, MG AF Peterson, Thomas A. Nehrt, Nathan L. Park, DoHwan Kann, Maricel G. TI Incorporating molecular and functional context into the analysis and prioritization of human variants associated with cancer SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID SINGLE NUCLEOTIDE POLYMORPHISMS; MISSENSE MUTATIONS; SOMATIC MUTATIONS; PROTEIN FUNCTION; POINT MUTATIONS; DATABASE; SUBSTITUTIONS; SEQUENCE; DOMAIN; TOOL AB Background and objective With recent breakthroughs in high-throughput sequencing, identifying deleterious mutations is one of the key challenges for personalized medicine. At the gene and protein level, it has proven difficult to determine the impact of previously unknown variants. A statistical method has been developed to assess the significance of disease mutation clusters on protein domains by incorporating domain functional annotations to assist in the functional characterization of novel variants. Methods Disease mutations aggregated from multiple databases were mapped to domains, and were classified as either cancer-or non-cancer-related. The statistical method for identifying significantly disease-associated domain positions was applied to both sets of mutations and to randomly generated mutation sets for comparison. To leverage the known function of protein domain regions, the method optionally distributes significant scores to associated functional feature positions. Results Most disease mutations are localized within protein domains and display a tendency to cluster at individual domain positions. The method identified significant disease mutation hotspots in both the cancer and non-cancer datasets. The domain significance scores (DS-scores) for cancer form a bimodal distribution with hotspots in oncogenes forming a second peak at higher DS-scores than non-cancer, and hotspots in tumor suppressors have scores more similar to non-cancers. In addition, on an independent mutation benchmarking set, the DS-score method identified mutations known to alter protein function with very high precision. Conclusion By aggregating mutations with known disease association at the domain level, the method was able to discover domain positions enriched with multiple occurrences of deleterious mutations while incorporating relevant functional annotations. The method can be incorporated into translational bioinformatics tools to characterize rare and novel variants within large-scale sequencing studies. C1 [Kann, Maricel G.] Univ Maryland Baltimore Cty, Dept Biol Sci, Baltimore, MD 21250 USA. [Nehrt, Nathan L.] US FDA, Div Imaging & Appl Math, OSEL, CDRH, Silver Spring, MD USA. RP Kann, MG (reprint author), Univ Maryland Baltimore Cty, Dept Biol Sci, 1000 Hilltop Circle, Baltimore, MD 21250 USA. EM mkann@umbc.edu RI Kann, Maricel/E-5701-2012 FU National Institutes of Health (NIH) [1K22CA143148]; ORISE; DOE; FDA FX This work was supported by the National Institutes of Health (NIH) 1K22CA143148 to MGK (PI). NLN is funded by the Research Participation Program administered by ORISE through an interagency agreement between DOE and FDA. NR 52 TC 9 Z9 9 U1 0 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAR PY 2012 VL 19 IS 2 BP 275 EP 283 DI 10.1136/amiajnl-2011-000655 PG 9 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 898UP UT WOS:000300768100022 PM 22319177 ER PT J AU Ururahy, MAG Loureiro, MB Freire-Neto, FP de Souza, KSC Zuhl, I Brandao-Neto, J Hirata, RDC Doi, SD Arrais, RF Hirata, MH Almeida, MD de Rezende, AA AF Galvao Ururahy, Marcela Abbott Loureiro, Melina Bezerra Freire-Neto, Francisco Paulo Costa de Souza, Karla Simone Zuhl, Irina Brandao-Neto, Jose Crespo Hirata, Rosario Dominguez Doi, Sonia de Quateli Arrais, Ricardo Fernando Hirata, Mario Hiroyuki Almeida, Maria das Gracas de Rezende, Adriana Augusto TI Increased TLR2 expression in patients with type 1 diabetes: evidenced risk of microalbuminuria SO PEDIATRIC DIABETES LA English DT Article DE inflammation; microalbuminuria; toll-like receptors; type 1 diabetes ID TOLL-LIKE RECEPTORS; PATHOGEN RECOGNITION; GENE-EXPRESSION; INNATE IMMUNITY; CHILDREN; NEPHROPATHY; MACROPHAGES; MONOCYTES; EXERCISE; DISEASE AB Objective: To study the activation of an inflammatory cascade through leukocyte mRNA expression of TLR2, TLR4, MyD88, and pro-inflammatory cytokines in individuals with childhood onset type 1 diabetes. Design and methods: Seventy-six type 1 diabetic patients and 100 normoglycemic subjects (NG) 6 to 20 years old were recruited. Type 1 diabetic patients (DM1) were considered to have good (DM1G) or poor (DM1P) glycemic control according to the values of glycated hemoglobin. TLR2, TLR4, MyD88, interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) mRNA expressions were measured in peripheral blood leukocytes (PBL) by real-time polymerase chain reaction (PCR). Urea, creatinine, albumin, and total protein serum levels were determined. Urinary albumin-to-creatinine ratio (ACR) was calculated. Results: DM1 and DM1P patients showed higher glycated hemoglobin (10 and 11%, respectively) and serum glucose concentrations (208 and 226 mg/ dL, respectively) compared to NG (Glycated hemoglobin: 7% and glucose: 76 mg/ dL) (p < 0.05). PBL mRNA expressions of TLR2, MyD88, IL-1 beta, IL-6, and TNF-alpha were higher in DM1 and TLR2, IL-1 beta, and IL-6 expressions were higher in DMP1 compared to NG (p < 0.05). In DM1, serum albumin and total protein were lower, while serum urea and ACR were higher in comparison to NG (p < 0.05). However, these differences compared to NG were more pronounced in DM1P, which included nine individuals with microalbuminuria. Conclusions: Increased mRNA expression of TLR2, MyD88, and pro-inflammatory cytokines in leukocytes of patients with childhood onset type 1 diabetes indicates the development of a TLR2-mediated pro-inflammatory process, which may also be associated with an early inflammatory process in the kidney and the occurrence of microalbuminuria. C1 [Galvao Ururahy, Marcela Abbott; Loureiro, Melina Bezerra; Freire-Neto, Francisco Paulo; Costa de Souza, Karla Simone; Almeida, Maria das Gracas; de Rezende, Adriana Augusto] Univ Fed Rio Grande do Norte, Dept Clin & Toxicol Anal, BR-59012570 Natal, RN, Brazil. [Zuhl, Irina] US FDA, Ctr Biol Res & Evaluat, Rockville, MD 20852 USA. [Brandao-Neto, Jose] Univ Fed Rio Grande do Norte, Dept Clin Med, BR-59012570 Natal, RN, Brazil. [Crespo Hirata, Rosario Dominguez; Hirata, Mario Hiroyuki] Univ Sao Paulo, Dept Clin & Toxicol Anal, BR-05508900 Sao Paulo, Brazil. [Doi, Sonia de Quateli] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Arrais, Ricardo Fernando] Univ Fed Rio Grande do Norte, Dept Pediat, BR-59012570 Natal, RN, Brazil. RP de Rezende, AA (reprint author), Rua Pastor Gabino Brelaz 1401,Bl A,Apto 101, BR-59082010 Natal, RN, Brazil. EM adrirezende@ufrnet.br RI Hirata, Mario/D-3593-2012; Inov Farmaceutica, Inct/K-2313-2013; Hirata, Mario/C-9718-2013 FU CNPq [476351/2006-5, 564248/2008-8, 620099/2008-9]; CNPq, Brazil; Center for Biologics Research and Evaluation, Food and Drug Administration, Bethesda, MD, USA FX This study was supported by a grant from CNPq (project grants: 476351/2006-5, 564248/2008-8 and 620099/2008-9). M. H. H., R. D. C. H., and J. B. N. are recipients of fellowships from CNPq, Brazil. We thank Nga N. Nguyen from Center for Biologics Research and Evaluation, Food and Drug Administration, Bethesda, MD, USA, by the support in the synthesis of primers and probes. We thank the Albalab Com. Prods Lab. e Hosp. Limitada for the donation of BioSystems Reagents and Instruments kits for biochemical analyses. We are grateful to the technical support provided by students and technicians from LABMULT/UFRN/RN, in special to Joao Felipe Bezerra, and LABMAD/USP/SP, in special to Lidio Gonc, alves Lima Neto. We also thank all the physicians, nurses, and hospital staff at HOSPED/UFRN who were involved in this study. All authors have declared no conflict of interest. NR 26 TC 7 Z9 7 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1399-543X J9 PEDIATR DIABETES JI Pediatr. Diabetes PD MAR PY 2012 VL 13 IS 2 BP 147 EP 154 DI 10.1111/j.1399-5448.2011.00794.x PG 8 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 898ER UT WOS:000300719500003 PM 21848584 ER PT J AU Stankowski, RV Cole, JG Jerse, AE AF Stankowski, Rachel Vonck Cole, Jessica G. Jerse, Ann E. TI The Natural History of Incident Gonococcal Infection in Adolescent Women: Similar Observations in a Female Mouse Model of Gonococcal and Chlamydial Coinfection SO SEXUALLY TRANSMITTED DISEASES LA English DT Letter ID GENITAL-TRACT C1 [Stankowski, Rachel Vonck] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI 54449 USA. [Cole, Jessica G.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Jerse, Ann E.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. RP Stankowski, RV (reprint author), Marshfield Clin Fdn Med Res & Educ, Marshfield, WI 54449 USA. NR 5 TC 1 Z9 1 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD MAR PY 2012 VL 39 IS 3 BP 238 EP 238 PG 1 WC Infectious Diseases SC Infectious Diseases GA 900VS UT WOS:000300920400015 ER PT J AU Liu, Q Davit, BM Cherstniakova, SA Dandamudi, S Walters, JF Lee, CH Raines, KW Ren, K Williamson, LN Conner, DP AF Liu, Qing Davit, Barbara M. Cherstniakova, Svetlana A. Dandamudi, Suman Walters, Johnetta F. Lee, Christina H. Raines, Kimberly W. Ren, Ke Williamson, Leeh N. Conner, Dale P. TI Common Deficiencies with Bioequivalence Submissions in Abbreviated New Drug Applications Assessed by FDA SO AAPS JOURNAL LA English DT Article DE ANDA; bioequivalence; common deficiency; FDA AB A generic product must meet the standards established by the Food and Drug Administration (FDA) to be approved for marketing in the USA. FDA approves a generic product for marketing if it is proved to be therapeutically equivalent to the reference product. Bioequivalence (BE) between a proposed generic product and its corresponding reference product is one of the major components of therapeutic equivalence. These approvals may be delayed if the BE portion of the submission is determined to be deficient. Many of these BE deficiencies recur commonly and can be avoided. We conducted a survey of the BE submissions to abbreviated new drug applications (ANDAs) over years 2001 to 2008 to identify the most commonly occurring BE deficiencies. Recurring deficiencies are found in a majority of the ANDAs reviewed by FDA's Division of Bioequivalence. The most common deficiencies were the two deficiencies related to dissolution (method and specifications) found in 23.3% of the applications and analytical method validation and/or report found in 16.5% of the applications. The approval of generic drugs would be greatly accelerated if these deficiencies could be avoided. C1 [Liu, Qing; Davit, Barbara M.; Cherstniakova, Svetlana A.; Dandamudi, Suman; Walters, Johnetta F.; Lee, Christina H.; Raines, Kimberly W.; Ren, Ke; Williamson, Leeh N.; Conner, Dale P.] US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, Rockville, MD 20855 USA. RP Liu, Q (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, 7520 Standish Pl, Rockville, MD 20855 USA. EM qing.liu@fda.hhs.gov NR 4 TC 3 Z9 3 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD MAR PY 2012 VL 14 IS 1 BP 19 EP 22 DI 10.1208/s12248-011-9312-7 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 896GP UT WOS:000300554000002 PM 22130775 ER PT J AU Jackson, SA Kotewicz, ML Patel, IR Lacher, DW Gangiredla, J Elkins, CA AF Jackson, Scott A. Kotewicz, Michael L. Patel, Isha R. Lacher, David W. Gangiredla, Jayanthi Elkins, Christopher A. TI Rapid Genomic-Scale Analysis of Escherichia coli O104:H4 by Using High-Resolution Alternative Methods to Next-Generation Sequencing SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; HEMORRHAGIC COLITIS; OUTBREAK; VIRULENCE; GERMANY AB Two technologies, involving DNA microarray and optical mapping, were used to quickly assess gene content and genomic architecture of recent emergent Escherichia coli O104:H4 and related strains. In real-time outbreak investigations, these technologies can provide congruent perspectives on strain, serotype, and pathotype relationships. Our data demonstrated clear discrimination between clinically, temporally, and geographically distinct O104:H4 isolates and rapid characterization of strain differences. C1 [Jackson, Scott A.; Kotewicz, Michael L.; Patel, Isha R.; Lacher, David W.; Gangiredla, Jayanthi; Elkins, Christopher A.] US FDA, Ctr Food Safety & Appl Nutr, Div Mol Biol, Laurel, MD USA. RP Elkins, CA (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Mol Biol, Laurel, MD USA. EM chris.elkins@fda.hhs.gov FU National Bioforensics Analysis Center; Department of Homeland Security; Center for Food Safety and Applied Nutrition FX Seminal funding and support were received from the National Bioforensics Analysis Center and the Department of Homeland Security for microarray and optical mapping program development; we acknowledge Joseph E. LeClerc (FDA-CFSAN) for contributions to this work. This study was funded by the Center for Food Safety and Applied Nutrition. NR 18 TC 8 Z9 9 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD MAR PY 2012 VL 78 IS 5 BP 1601 EP 1605 DI 10.1128/AEM.07464-11 PG 5 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 896AI UT WOS:000300537400034 PM 22210216 ER PT J AU Rump, LV Bodeis-Jones, S Abbott, J Zhao, SH Kase, J Lorenz, S Fischer, M Brown, E Meng, JH AF Rump, Lydia V. Bodeis-Jones, Sonya Abbott, Jason Zhao, Shaohua Kase, Julie Lorenz, Sandra Fischer, Markus Brown, Eric Meng, Jianghong TI Genetic Characterization of Escherichia coli O104 Isolates from Different Sources in the United States SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID NON-O157 SHIGA TOXIN; MULTIPLEX PCR; STRAINS; IDENTIFICATION; PREVALENCE; ISLAND AB Escherichia coli O104 isolates collected from different sources in the United States were examined for virulence genes typical of enterohemorrhagic E. coli and those identified in the O104:H4 isolate associated with the 2011 German outbreak. The unexpected presence of virulence markers in these isolates highlights the importance of screening unusual and potentially pathogenic Shiga toxin-producing E. coli serotypes. C1 [Rump, Lydia V.; Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Rump, Lydia V.; Meng, Jianghong] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. [Bodeis-Jones, Sonya; Abbott, Jason; Zhao, Shaohua] Ctr Vet Med, Res Off, Div Anim & Food Microbiol, Laurel, MD USA. [Kase, Julie; Lorenz, Sandra; Brown, Eric] US FDA, Ctr Food Safety & Appl Nutr, Div Microbiol, College Pk, MD USA. [Lorenz, Sandra; Fischer, Markus] Univ Hamburg, Inst Food Chem, Hamburg, Germany. RP Meng, JH (reprint author), Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. EM jmeng@umd.edu RI Fischer, Markus/G-9477-2012 FU Joint Institute for Food Safety & Applied Nutrition (JIFSAN), University of Maryland, College Park, MD FX The study was supported in part by the Joint Institute for Food Safety & Applied Nutrition (JIFSAN), University of Maryland, College Park, MD. NR 18 TC 8 Z9 9 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD MAR PY 2012 VL 78 IS 5 BP 1615 EP 1618 DI 10.1128/AEM.07533-11 PG 4 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 896AI UT WOS:000300537400037 PM 22210209 ER PT J AU DaSilva, L Parveen, S DePaola, A Bowers, J Brohawn, K Tamplin, ML AF DaSilva, Ligia Parveen, Salina DePaola, Angelo Bowers, John Brohawn, Kathy Tamplin, Mark L. TI Development and Validation of a Predictive Model for the Growth of Vibrio vulnificus in Postharvest Shellstock Oysters SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID UNITED-STATES; GULF-COAST; BACTERIAL-GROWTH; TEMPERATURE; SALINITY; PARAHAEMOLYTICUS; MULTIPLICATION; PATHOGENS; SHELLFISH; SURVIVAL AB Postharvest growth of Vibrio vulnificus in oysters can increase risk of human infection. Unfortunately, limited information is available regarding V. vulnificus growth and survival patterns over a wide range of storage temperatures in oysters harvested from different estuaries and in different oyster species. In this study, we developed a predictive model for V. vulnificus growth in Eastern oysters (Crassostrea virginica) harvested from Chesapeake Bay, MD, over a temperature range of 5 to 30 degrees C and then validated the model against V. vulnificus growth rates (GRs) in Eastern and Asian oysters (Crassostrea ariakensis) harvested from Mobile Bay, AL, and Chesapeake Bay, VA, respectively. In the model development studies, V. vulnificus was slowly inactivated at 5 and 10 degrees C with average GRs of -0.0045 and -0.0043 log most probable number (MPN)/h, respectively. Estimated average growth rates at 15, 20, 25, and 30 degrees C were 0.022, 0.042, 0.087, and 0.093 log MPN/h, respectively. With respect to Eastern oysters, bias (B-f) and accuracy (A(f)) factors for model-dependent and -independent data were 1.02 and 1.25 and 1.67 and 1.98, respectively. For Asian oysters, B-f and A(f) were 0.29 and 3.40. Residual variations in growth rate about the fitted model were not explained by season, region, water temperature, or salinity at harvest. Growth rate estimates for Chesapeake Bay and Mobile Bay oysters stored at 25 and 30 degrees C showed relatively high variability and were lower than Food and Agricultural Organization (FAO)/WHO V. vulnificus quantitative risk assessment model predictions. The model provides an improved tool for designing and implementing food safety plans that minimize the risk associated with V. vulnificus in oysters. C1 [DaSilva, Ligia; Parveen, Salina] Univ Maryland Eastern Shore, Food Sci & Technol Phd Program, Dept Agr Food & Resource Sci, Princess Anne, MD USA. [DePaola, Angelo] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL USA. [Bowers, John] US FDA, Div Publ Hlth & Biostat, College Pk, MD USA. [Brohawn, Kathy] Maryland Dept Environm, Baltimore, MD 21224 USA. [Tamplin, Mark L.] Univ Tasmania, Food Safety Ctr, Tasmanian Inst Agr Res, Hobart, Tas, Australia. RP Parveen, S (reprint author), Univ Maryland Eastern Shore, Food Sci & Technol Phd Program, Dept Agr Food & Resource Sci, Princess Anne, MD USA. EM sparveen@umes.edu FU National Research Initiative of the United States Department of Agriculture, Cooperative State Research, Education and Extension Service [2006-35201-16644]; University of Maryland Eastern Shore Advanced Curriculum Technology-Based Instructional Opportunities Network (ACTION) FX This project was supported by the National Research Initiative of the United States Department of Agriculture, Cooperative State Research, Education and Extension Service, grant 2006-35201-16644 and University of Maryland Eastern Shore Advanced Curriculum Technology-Based Instructional Opportunities Network (ACTION). NR 39 TC 12 Z9 13 U1 1 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD MAR PY 2012 VL 78 IS 6 BP 1675 EP 1681 DI 10.1128/AEM.07304-11 PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 897EX UT WOS:000300629800007 PM 22247136 ER PT J AU Zhao, S Blickenstaff, K Bodeis-Jones, S Gaines, SA Tong, E McDermott, PF AF Zhao, S. Blickenstaff, K. Bodeis-Jones, S. Gaines, S. A. Tong, E. McDermott, P. F. TI Comparison of the Prevalences and Antimicrobial Resistances of Escherichia coli Isolates from Different Retail Meats in the United States, 2002 to 2008 SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID MOBILE GENE CASSETTES; FOOD ANIMALS; SALMONELLA-ENTERICA; CHLORAMPHENICOL RESISTANCE; GREATER WASHINGTON; MONITORING-SYSTEM; BETA-LACTAMASES; ANTIBIOTIC USE; HUMANS; HEALTH AB Escherichia coli isolates were recovered from the National Antimicrobial Resistance Monitoring System retail meat program and examined for antimicrobial susceptibility. Retail meat samples (n = 11,921) from four U. S. states collected during 2002 to 2008, consisting of 2,988 chicken breast, 2,942 ground turkey, 2,991 ground beef, and 3,000 pork chop samples, were analyzed. A total of 8,286 E. coli isolates were recovered. The greatest numbers of samples contaminated with the organism were chicken (83.5%) and turkey (82.0%), followed by beef (68.9%) and pork (44.0%). Resistance was most common to tetracycline (50.3%), followed by streptomycin (34.6%), sulfamethoxazole-sulfisoxazole (31.6%), ampicillin (22.5%), gentamicin (18.6%), kanamycin (8.4%), amoxicillin-clavulanic acid (6.4%), and cefoxitin (5.2%). Less than 5% of the isolates had resistance to trimethoprim, ceftriax-one, ceftiofur, nalidixic acid, chloramphenicol, and ciprofloxacin. All isolates were susceptible to amikacin. Compared to beef and pork isolates, the poultry meat isolates had a greater percentage of resistance to all tested drugs, with the exception of chloramphenicol, to which pork isolates had the most resistance. More than half of the turkey isolates (56%) were resistant to multidrugs (>= 3 classes) compared to 38.9% of chicken, 17.3% of pork, and 9.3% of beef isolates. The blaCMY gene was present in all ceftriaxone- and ceftiofur-resistant isolates. The cmlA, flo, and catI genes were present in 45%, 43%, and 40% of chloramphenicol-resistant isolates, respectively. Most nalidixic acid-resistant isolates (98.5%) had a gyrA mutation in S83 or D87 or both, whereas only 6.7% had a parC mutation in either S80 or E84. The results showed that E. coli was commonly present in the retail meats, and antimicrobial resistance profiles differed according to the animal origin of the isolates. C1 [Zhao, S.; Blickenstaff, K.; Bodeis-Jones, S.; Gaines, S. A.; Tong, E.; McDermott, P. F.] US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD USA. RP Zhao, S (reprint author), US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD USA. EM shaohua.zhao@fda.hhs.gov NR 46 TC 30 Z9 31 U1 0 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD MAR PY 2012 VL 78 IS 6 BP 1701 EP 1707 DI 10.1128/AEM.07522-11 PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 897EX UT WOS:000300629800010 PM 22247155 ER PT J AU Lanzarotta, A Marcott, C Story, GM Dowrey, AE Sommer, AJ AF Lanzarotta, Adam Marcott, Curtis Story, Gloria M. Dowrey, Anthony E. Sommer, Andre J. TI Infrared Microspectroscopy Using Prism-Based Spectrographs and Focal Plane Array Detection SO APPLIED SPECTROSCOPY LA English DT Article DE Infrared microspectroscopy; Infrared spectrographs; Array detection ID REGION; PERFORMANCE AB Several prism-based spectrographs employing a mercury cadmium telluride (MCI) focal plane array detector have been interfaced to an infrared microscope. In the combined system, the area-defining aperture of the microscope also served as the entrance slit to the spectrograph. This investigation considered the fundamental limits of diffraction for both the spectrograph and microscope in order to determine both the spatial and spectral resolution of the system as a whole. Experimental results for spectral resolution, spectral range, and peak-to-peak noise have been presented. Finally, the dynamic capabilities of one spectrograph/microscope combination were investigated. C1 [Lanzarotta, Adam; Sommer, Andre J.] Miami Univ, Mol Microspect Lab, Dept Chem & Biochem, Oxford, OH 45056 USA. [Marcott, Curtis] Light Light Solut LLC, Athens, GA 30608 USA. [Story, Gloria M.; Dowrey, Anthony E.] Procter & Gamble Co, Miami Valley Innovat Ctr, Cincinnati, OH 45253 USA. [Lanzarotta, Adam] US FDA, Trace Examinat Sect, Forens Chem Ctr, Cincinnati, OH 45237 USA. RP Sommer, AJ (reprint author), Miami Univ, Mol Microspect Lab, Dept Chem & Biochem, Oxford, OH 45056 USA. EM sommeraj@muohio.edu FU Procter and Gamble Company; Kodak FX The authors would like to thank the Procter and Gamble Company and Kodak for financial support. The cross-sectioned photographic film provided by Sharon Markel and Lola Darmon of Kodak is greatly appreciated. The mentioning of specific products/instruments in this manuscript is for information purposes' only and does not constitute an endorsement by either the Food and Drug Administration and/or the Forensic Chemistry Center. NR 28 TC 1 Z9 1 U1 0 U2 4 PU SOC APPLIED SPECTROSCOPY PI FREDERICK PA 5320 SPECTRUM DRIVE SUITE C, FREDERICK, MD 21703 USA SN 0003-7028 J9 APPL SPECTROSC JI Appl. Spectrosc. PD MAR PY 2012 VL 66 IS 3 BP 304 EP 311 DI 10.1366/11-06412 PG 8 WC Instruments & Instrumentation; Spectroscopy SC Instruments & Instrumentation; Spectroscopy GA 896VK UT WOS:000300599300010 PM 22449308 ER PT J AU Yu, BB Tiwari, RC AF Yu, Binbing Tiwari, Ram C. TI A Bayesian approach to mixture cure models with spatial frailties for population-based cancer relative survival data SO CANADIAN JOURNAL OF STATISTICS-REVUE CANADIENNE DE STATISTIQUE LA English DT Article DE Colon cancer; cure fraction; finite mixture models; random effects; relative survival; SEER ID FAILURE TIME MODEL; REGRESSION-MODELS; FRACTION; CHILDHOOD; DEATHS AB As the treatments of cancer progress, a certain number of cancers are curable if diagnosed early. In population-based cancer survival studies, cure is said to occur when mortality rate of the cancer patients returns to the same level as that expected for the general cancer-free population. The estimates of cure fraction are of interest to both cancer patients and health policy makers. Mixture cure models have been widely used because the model is easy to interpret by separating the patients into two distinct groups. Usually parametric models are assumed for the latent distribution for the uncured patients. The estimation of cure fraction from the mixture cure model may be sensitive to misspecification of latent distribution. We propose a Bayesian approach to mixture cure model for population-based cancer survival data, which can be extended to county-level cancer survival data. Instead of modeling the latent distribution by a fixed parametric distribution, we use a finite mixture of the union of the lognormal, loglogistic, and Weibull distributions. The parameters are estimated using the Markov chain Monte Carlo method. Simulation study shows that the Bayesian method using a finite mixture latent distribution provides robust inference of parameter estimates. The proposed Bayesian method is applied to relative survival data for colon cancer patients from the Surveillance, Epidemiology, and End Results (SEER) Program to estimate the cure fractions. The Canadian Journal of Statistics 40: 4054; 2012 (C) 2012 Statistical Society of Canada C1 [Yu, Binbing] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Tiwari, Ram C.] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Yu, BB (reprint author), NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. EM yubi@mail.nih.gov FU National Institute on Aging, National Institutes of Health FX The authors wish to thank two anonymous reviewers and the Associate Editor for their helpful comments. The views expressed in this article by the author, Dr. Tiwari, are solely his own and do necessarily reflect that of the FDA. Dr. Yu was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. This research utilised the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, Maryland, USA (http://biowulf.nih.gov). NR 36 TC 3 Z9 3 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0319-5724 J9 CAN J STAT JI Can. J. Stat.-Rev. Can. Stat. PD MAR PY 2012 VL 40 IS 1 BP 40 EP 54 DI 10.1002/cjs.10135 PG 15 WC Statistics & Probability SC Mathematics GA 897PY UT WOS:000300667000003 ER PT J AU Honig, PK Huang, SM AF Honig, P. K. Huang, S-M TI Regulatory Science and the Role of the Regulator in Biomedical Innovation SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material C1 [Huang, S-M] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM honigpk@hotmail.com NR 26 TC 2 Z9 2 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 IS 3 BP 347 EP 352 DI 10.1038/clpt.2011.352 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VG UT WOS:000300524200001 PM 22343804 ER PT J AU Goodman, JL AF Goodman, J. L. TI Transforming Regulatory Science 2012: Making a Difference SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB The world is in the midst of scientific revolutions that can transform medicine and public health. Yet translation to needed products remains slow and expensive. There are major opportunities for new regulatory science to help transform product development and evaluation. A plan by the US Food and Drug Administration (FDA), Advancing Regulatory Science," identifies eight priorities and numerous actions to help catalyze transformation. Scientific excellence and collaboration, including public and private sectors, are essential for change that benefits health and economies globally. C1 US Dept HHS, US FDA, Silver Spring, MD USA. RP Goodman, JL (reprint author), US Dept HHS, US FDA, Silver Spring, MD USA. EM jesse.goodman@fda.hhs.gov NR 7 TC 3 Z9 3 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 IS 3 BP 375 EP 377 DI 10.1038/clpt.2011.329 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VG UT WOS:000300524200011 PM 22343811 ER PT J AU Woodcock, J AF Woodcock, J. TI Evidence vs. Access: Can Twenty-First-Century Drug Regulation Refine the Tradeoffs? SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB As the pharmaceutical industry productivity crisis worsens, there are calls for regulatory changes to support innovation. At the same time, prescribers and payers desire more information about drugs at the time they are released to the market. Will new regulatory schemes be able to accommodate these disparate needs? C1 US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Woodcock, J (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM janet.woodcock@fda.hhs.gov NR 7 TC 25 Z9 25 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 IS 3 BP 378 EP 380 DI 10.1038/clpt.2011.337 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VG UT WOS:000300524200012 PM 22343812 ER PT J AU Barratt, RA Bowens, SL McCune, SK Johannessen, JN Buckman, SY AF Barratt, R. A. Bowens, S. L. McCune, S. K. Johannessen, J. N. Buckman, S. Y. TI The Critical Path Initiative: Leveraging Collaborations to Enhance Regulatory Science SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID DRUG DEVELOPMENT; TRANSPORTERS; CONSORTIUM; FDA AB Since 2004, the Critical Path Initiative has prompted industry, academia, and government agencies to work together to share the information, technology, and expertise critical to modernize and transform our approach to drug development and review. Various collaborations have been sharing data in a precompetitive space, establishing data standards, and facilitating collective tool development. As a result, the organization is making progress toward developing knowledge and tools that can reduce uncertainty in medical product development. C1 [Barratt, R. A.; Bowens, S. L.; McCune, S. K.; Johannessen, J. N.; Buckman, S. Y.] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Buckman, SY (reprint author), US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM shaavhree.buckman@fda.hhs.gov NR 11 TC 11 Z9 11 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 IS 3 BP 380 EP 383 DI 10.1038/clpt.2011.318 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VG UT WOS:000300524200013 PM 22343813 ER PT J AU Eichler, HG Oye, K Baird, LG Abadie, E Brown, J Drum, CL Ferguson, J Garner, S Honig, P Hukkelhoven, M Limn, JCW Lim, R Lumpkin, MM Neil, G O'Rourke, B Pezalla, E Shoda, D Seyfert-Margolis, V Sigal, EV Sobotka, J Tan, D Unger, TF Hirsch, G AF Eichler, H-G Oye, K. Baird, L. G. Abadie, E. Brown, J. Drum, C. L. Ferguson, J. Garner, S. Honig, P. Hukkelhoven, M. Limn, J. C. W. Lim, R. Lumpkin, M. M. Neil, G. O'Rourke, B. Pezalla, E. Shoda, D. Seyfert-Margolis, V. Sigal, E. V. Sobotka, J. Tan, D. Unger, T. F. Hirsch, G. TI Adaptive Licensing: Taking the Next Step in the Evolution of Drug Approval SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID RARE DISEASES; MEDICINES; ACCESS; AUTHORIZATION; DILEMMA; TRIALS; EUROPE AB Traditional drug licensing approaches are based on binary decisions. At the moment of licensing, an experimental therapy is presumptively transformed into a fully vetted, safe, efficacious therapy. By contrast, adaptive licensing (AL) approaches are based on stepwise learning under conditions of acknowledged uncertainty, with iterative phases of data gathering and regulatory evaluation. This approach allows approval to align more closely with patient needs for timely access to new technologies and for data to inform medical decisions. The concept of AL embraces a range of perspectives. Some see AL as an evolutionary step, extending elements that are now in place. Others envision a transformative framework that may require legislative action before implementation. This article summarizes recent AL proposals; discusses how proposals might be translated into practice, with illustrations in different therapeutic areas; and identifies unresolved issues to inform decisions on the design and implementation of AL. C1 [Eichler, H-G; Oye, K.; Baird, L. G.; Drum, C. L.; Hirsch, G.] MIT, Ctr Biomed Innovat, Cambridge, MA 02139 USA. [Eichler, H-G] European Med Agcy, London, England. [Oye, K.] MIT, Dept Polit Sci, Cambridge, MA 02139 USA. [Oye, K.] MIT, Div Engn Syst, Cambridge, MA 02139 USA. [Abadie, E.] Agence Francais Securite Sanit Prod Sante, St Denis, France. [Brown, J.] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Ferguson, J.] Novartis Vaccines & Diagnost, Cambridge, MA USA. [Garner, S.] Natl Inst Hlth & Clin Excellence, London, England. [Garner, S.] Commonwealth Fund, New York, NY USA. [Honig, P.] AstraZeneca, London, England. [Hukkelhoven, M.] Bristol Myers Squibb Co, New York, NY 10154 USA. [Limn, J. C. W.; Tan, D.] Singapore Hlth Sci Author, Singapore, Singapore. [Lim, R.] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Lumpkin, M. M.; Seyfert-Margolis, V.] US FDA, Silver Spring, MD USA. [Neil, G.] Johnson & Johnson, New Brunswick, NJ USA. [O'Rourke, B.] Canadian Agcy Drugs & Technol Hlth, Ottawa, ON, Canada. [Pezalla, E.] Aetna, Hartford, CT USA. [Shoda, D.; Unger, T. F.] Pfizer, New York, NY USA. [Sigal, E. V.] Friends Canc Res, Washington, DC USA. [Sobotka, J.] Ohio No Univ, Raabe Coll Pharm, Ada, OH 45810 USA. RP Oye, K (reprint author), MIT, Ctr Biomed Innovat, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM oye@mit.edu RI Drum, Chester/A-6089-2015 OI Drum, Chester/0000-0001-6327-4584 FU Sloan Foundation; Kauffman Foundation; Merck Company Foundation; Massachusetts Technology Collaborative; Sanofi; Alnylam; Amgen; Biogen-Idec; Biomarin; Bristol-Myers Squibb; Genentech; GlaxoSmithKline; Inno Biologics; Johnson Johnson; LFB Biotechnologies; Merrimack Pharmaceuticals; Metabolix; Millipore; Novartis; Pfizer; Quintiles; Sanofi Pasteur; Burroughs Wellcome Foundation FX All the authors have institutional affiliations, corporate affiliations, and/or financial interests in the subject matter discussed in this work as noted in the author list. H.-G.E. is an affiliate of the MIT Center for Biomedical, Innovation but does not receive financial support. The Center for Biomedical Innovation currently receives or has received financial support from the Sloan Foundation, Kauffman Foundation, Merck Company Foundation, Massachusetts Technology Collaborative, and Sanofi, as well as consortium members Alnylam, Amgen, Biogen-Idec, Biomarin, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Inno Biologics, Johnson & Johnson, LFB Biotechnologies, Merrimack Pharmaceuticals, Metabolix, Millipore, Novartis, Pfizer, Quintiles, and Sanofi Pasteur. C.L.D. received support from the Burroughs Wellcome Foundation. NR 33 TC 109 Z9 111 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 IS 3 BP 426 EP 437 DI 10.1038/clpt.2011.345 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VG UT WOS:000300524200021 PM 22336591 ER PT J AU Gnjidic, D Hilmer, SN Blyth, FM Naganathan, V Cumming, RG Handelsman, DJ McLachlan, AJ Abernethy, DR Banks, E Le Couteur, DG AF Gnjidic, D. Hilmer, S. N. Blyth, F. M. Naganathan, V. Cumming, R. G. Handelsman, D. J. McLachlan, A. J. Abernethy, D. R. Banks, E. Le Couteur, D. G. TI High-Risk Prescribing and Incidence of Frailty Among Older Community-Dwelling Men SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID DRUG BURDEN INDEX; RESIDENTIAL AGED CARE; CLINICAL-PHARMACOLOGY; CONCORD HEALTH; PHYSICAL FUNCTION; SHORT-FORM; PEOPLE; IMPACT; ADULTS; PROJECT AB Evidence about the association between treatment with high-risk medicines and frailty in older individuals is limited. We investigated the relationship between high-risk prescribing and frailty at baseline, as well as 2-year incident frailty, in 1,662 men >= 70 years of age. High-risk prescribing was defined as polypharmacy (>= 5 medicines), hyperpolypharmacy (>= 10 medicines), and by the Drug Burden Index (DBI), a dose-normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, Cl: 1.69-3.84) for polypharmacy, 5.80 (95% Cl: 2.90-11.61) for hyperpolypharmacy, and 2.33 (95% Cl: 1.58-3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% Cl: 1.42-4.23) for polypharmacy, 2.50 (95% Cl: 0.76-8.26) for hyperpolypharmacy, and 2.14 (95% Cl: 1.25-3.64) for DBI exposure. High-risk prescribing may contribute to frailty in community-dwelling older men. C1 [Gnjidic, D.; Hilmer, S. N.] Royal N Shore Hosp, Dept Clin Pharmacol, Sydney, NSW, Australia. [Gnjidic, D.; Hilmer, S. N.] Royal N Shore Hosp, Dept Aged Care, Sydney, NSW, Australia. [Gnjidic, D.; Hilmer, S. N.; Blyth, F. M.; Naganathan, V.; Cumming, R. G.; Handelsman, D. J.; Le Couteur, D. G.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Gnjidic, D.; Blyth, F. M.; Naganathan, V.; Cumming, R. G.; McLachlan, A. J.; Le Couteur, D. G.] Concord Hosp, Ctr Educ & Res Ageing, Concord, Australia. [Cumming, R. G.] Univ Sydney, Sch Publ Hlth, Sydney, NSW 2006, Australia. [Handelsman, D. J.; Le Couteur, D. G.] Concord Hosp, ANZAC Med Inst, Concord, Australia. [McLachlan, A. J.] Univ Sydney, Fac Pharm, Sydney, NSW 2006, Australia. [Abernethy, D. R.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Banks, E.] Australian Natl Univ, Natl Ctr Epidemiol & Populat Hlth, Canberra, ACT, Australia. RP Gnjidic, D (reprint author), Royal N Shore Hosp, Dept Clin Pharmacol, Sydney, NSW, Australia. EM danijela.gnjidic@sydney.edu.au OI Hilmer, Sarah/0000-0002-5970-1501; McLachlan, Andrew/0000-0003-4674-0242 FU Australian National Health and Medical Research Council (NHMRC) [301916]; Sydney Medical School Foundation; Ageing and Alzheimer's Research Foundation; Geoff and Elaine Penney Ageing Research Unit FX The CHAMP study is funded by the Australian National Health and Medical Research Council (NHMRC Project grant 301916), the Sydney Medical School Foundation, and the Ageing and Alzheimer's Research Foundation. The authors gratefully acknowledge the funding support from the Geoff and Elaine Penney Ageing Research Unit. NR 44 TC 83 Z9 85 U1 5 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 IS 3 BP 521 EP 528 DI 10.1038/clpt.2011.258 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VG UT WOS:000300524200033 PM 22297385 ER PT J AU Kruhlak, NL Benz, RD Zhou, H Colatsky, TJ AF Kruhlak, N. L. Benz, R. D. Zhou, H. Colatsky, T. J. TI (Q)SAR Modelling and Safety Assessment in Regulatory Review SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID URINARY-TRACT TOXICITIES; DRUG-INDUCED HEPATOBILIARY; E-STATE INDEXES; DEVELOPMENTAL TOXICITY; GENETIC TOXICITY; MDL-QSAR; HAZARD IDENTIFICATION; CARCINOGENICITY DATA; COMPREHENSIVE MODEL; END-POINTS AB The ability to predict clinical safety based on chemical structures is becoming an increasingly important part of regulatory decision making. (Quantitative) structure-activity relationship ((Q)SAR) models are currently used to evaluate late-arising safety concerns and possible nonclinical effects of a drug and its related compounds when adequate safety data are absent or equivocal. Regulatory use will likely increase with the standardization of analytical approaches, more complete and reliable data collection methods, and a better understanding of toxicity mechanisms. C1 [Kruhlak, N. L.; Benz, R. D.; Zhou, H.; Colatsky, T. J.] US FDA, Div Drug Safety Res, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Colatsky, TJ (reprint author), US FDA, Div Drug Safety Res, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM Thomas.Colatsky@fda.hhs.gov NR 36 TC 31 Z9 31 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 IS 3 BP 529 EP 534 DI 10.1038/clpt.2011.300 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VG UT WOS:000300524200034 PM 22258468 ER PT J AU Huang, SM Rowland, M AF Huang, S-M Rowland, M. TI The Role of Physiologically Based Pharmacokinetic Modeling in Regulatory Review SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID DRUG DEVELOPMENT; TRANSPORTERS; VARIANTS AB During regulatory review of clinical pharmacology data in new drug applications and biologics license applications, questions are routinely asked about how intrinsic factors (e.g., organ dysfunction, age, and genetics) and extrinsic factors (e.g., drug-drug interactions) might influence dose-response and exposure-response and about the impact of these individual factors on the efficacy and safety of the candidate compound. Physiologically based pharmacokinetic (PBPK) modeling and simulation is one of the tools that can be used to address these critical questions. C1 [Huang, S-M; Rowland, M.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Huang, SM (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM ShiewMei.Huang@fda.hhs.gov NR 41 TC 52 Z9 54 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 IS 3 BP 542 EP 549 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VG UT WOS:000300524200036 PM 22318616 ER PT J AU O'Neill, RT Temple, R AF O'Neill, R. T. Temple, R. TI The Prevention and Treatment of Missing Data in Clinical Trials: An FDA Perspective on the Importance of Dealing With It SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article AB At the request of the Food and Drug Administration (FDA) and with its funding, the Panel on the Handling of Missing Data in Clinical Trials was created by the National Research Council's Committee on National Statistics. This panel recently published a report(1) with recommendations that will be of use not only to the FDA but also to the entire clinical trial community so that the latter can take measures to improve the conduct and analysis of clinical trials. C1 [O'Neill, R. T.] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP O'Neill, RT (reprint author), US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM Robert.ONeill@fda.hhs.gov; Robert.Temple@fda.hhs.gov NR 6 TC 44 Z9 47 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 IS 3 BP 550 EP 554 DI 10.1038/clpt.2011.340 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VG UT WOS:000300524200037 PM 22318615 ER PT J AU Staffa, JA Dal Pan, GJ AF Staffa, J. A. Dal Pan, G. J. TI Regulatory Innovation in Postmarketing Risk Assessment and Management SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID EMERGENCY-DEPARTMENT VISITS; UNITED-STATES; RHABDOMYOLYSIS; PATTERNS; THERAPY; DRUGS; SURVEILLANCE; EVENTS; FDA; US AB The contemporary science of drug safety seeks not only to identify the risks associated with the use of medicines but also to quantify these risks, identify their risk factors, and assess strategies to minimize them. It monitors the use of medicines in actual practice to understand how the medical care system interacts with the intrinsic pharmacologic properties of medicines to produce the observed effects. To the extent possible, these analyses use a population-based approach that at times requires creativity and innovation. The key to effective safety management of drugs in the postmarketing setting is the ability to access sufficient good-quality data, interpret the data appropriately, challenge old assumptions, and define best practices in contemporary drug safety approaches. C1 [Staffa, J. A.; Dal Pan, G. J.] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. RP Staffa, JA (reprint author), US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. EM judy.staffa@fda.hhs.gov NR 21 TC 13 Z9 14 U1 3 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 IS 3 BP 555 EP 557 DI 10.1038/clpt.2011.289 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VG UT WOS:000300524200038 PM 22297386 ER PT J AU Agarwal, S Arya, V Zhang, L AF Agarwal, S. Arya, V. Zhang, L. TI EXPLORING ADDITIONAL CUT-OFF CRITERIA IN THE P-GP DECISION TREE: THE I-GUT CONCEPT SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Agarwal, S.; Arya, V.; Zhang, L.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S97 EP S97 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900255 ER PT J AU Borders-Hemphill, V Mosholder, AD AF Borders-Hemphill, V. Mosholder, A. D. TI US UTILIZATION PATTERNS OF INFLUENZA ANTIVIRAL MEDICATIONS DURING THE 2009 H1N1 INFLUENZA PANDEMIC SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Borders-Hemphill, V.; Mosholder, A. D.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S103 EP S104 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900271 ER PT J AU Burkhart, K AF Burkhart, K. TI MANY DRUGS HIGHLY ASSOCIATED WITH ANGIOEDEMA ENHANCE NITRIC OXIDE SIGNALING SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Burkhart, K.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S101 EP S101 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900265 ER PT J AU Chinn, LW Poon, R Fadiran, EO Parekh, A Huang, S Zhang, L AF Chinn, L. W. Poon, R. Fadiran, E. O. Parekh, A. Huang, S. Zhang, L. TI COMPARISON OF INCLUSION OF WOMEN IN EARLY VERSUS LATE PHASE CLINICAL TRIALS IN NEW DRUG AND BIOLOGICS APPLICATIONS RECENTLY APPROVED BY THE US FDA SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Chinn, L. W.; Poon, R.; Fadiran, E. O.; Parekh, A.; Huang, S.; Zhang, L.] US FDA, Silver Spring, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S97 EP S97 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900254 ER PT J AU Crentsil, V Lee, J Jackson, A AF Crentsil, V. Lee, J. Jackson, A. TI USING MODELING AND SIMULATION TO OPTIMIZE DRUG RISK-BENEFIT IN OLDER ADULTS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Crentsil, V.; Lee, J.; Jackson, A.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S47 EP S47 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900122 ER PT J AU Gnjidic, D Hilmer, SN Le Couteur, DG Abernethy, DR AF Gnjidic, D. Hilmer, S. N. Le Couteur, D. G. Abernethy, D. R. TI HIGH RISK PRESCRIBING AND INCIDENCE OF FRAILTY AMONG OLDER COMMUNITY-DWELLING MEN. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Gnjidic, D.; Hilmer, S. N.] Royal N Shore Hosp, Sydney, NSW, Australia. [Gnjidic, D.; Hilmer, S. N.; Le Couteur, D. G.] Univ Sydney, Sydney, NSW 2006, Australia. [Le Couteur, D. G.] Ctr Educ & Res Ageing CERA, Sydney, NSW, Australia. [Abernethy, D. R.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S14 EP S14 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900033 ER PT J AU Ke, B Nallani, SC Zhao, P Rostami-Hodjegan, A Unadkat, JD AF Ke, B. Nallani, S. C. Zhao, P. Rostami-Hodjegan, A. Unadkat, J. D. TI USING PBPK MODEL TO GAIN INSIGHT INTO CHANGES IN DISPOSITION OF CYP3A-METABOLIZED DRUGS IN PREGNANT WOMEN: DISCERNING CYP3A INDUCTION IN THE GUT VS. THE LIVER. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Ke, B.; Nallani, S. C.; Zhao, P.] US FDA, Silver Spring, MD USA. [Rostami-Hodjegan, A.] Univ Manchester, Manchester, Lancs, England. [Unadkat, J. D.] Univ Washington, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S50 EP S51 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900132 ER PT J AU Lee, J Crentsil, V AF Lee, J. Crentsil, V. TI THE UTILITY OF PROBABILISTIC SIMULATION IN DRUG RISK-BENEFIT ASSESSMENT IN OLDER ADULTS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Lee, J.; Crentsil, V.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S46 EP S46 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900121 ER PT J AU Otugo, O Poon, R Copeland, V Khanijow, K Umarjee, S Chinn, L Fadiran, EO Zhang, L Parekh, A AF Otugo, O. Poon, R. Copeland, V. Khanijow, K. Umarjee, S. Chinn, L. Fadiran, E. O. Zhang, L. Parekh, A. TI SURVEY OF THE PRESENTATION OF SEX ANALYSIS IN THE FDA REVIEW OF EFFICACY AND SAFETY CLINICAL DATA OF NEW MOLECULAR ENTITY DRUGS AND BIOLOGICS APPROVED FROM 2007 TO 2009 SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Otugo, O.; Poon, R.; Copeland, V.; Khanijow, K.; Umarjee, S.; Chinn, L.; Fadiran, E. O.; Zhang, L.; Parekh, A.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S97 EP S98 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900256 ER PT J AU Park, E Dong, T Crentsil, V Zhang, J Xu, NN AF Park, E. Dong, T. Crentsil, V. Zhang, J. Xu, N. N. TI A COMPARISON OF THE COCKCROFT-GAULT AND THE MODIFICATION OF DIET IN RENAL DISEASE STUDY EQUATIONS AS PREDICTIVE MODELS OF CLINICAL OUTCOMES WITH EPTIFIBATIDE. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Park, E.; Dong, T.; Crentsil, V.; Zhang, J.; Xu, N. N.] FDA CDER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S89 EP S90 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900233 ER PT J AU Shord, SS Mummaneni, P Vaidyanathan, J Gieser, G Amur, S Adebowale, A AF Shord, S. S. Mummaneni, P. Vaidyanathan, J. Gieser, G. Amur, S. Adebowale, A. TI SYSTEMATIC EVALUATION OF PHARMACOGENETIC ASSOCIATED ADVERSE EVENTS IN THE LITERATURE AND THE LABELING. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Shord, S. S.; Mummaneni, P.; Vaidyanathan, J.; Gieser, G.; Amur, S.; Adebowale, A.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S18 EP S18 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900045 ER PT J AU Singh, RP Sahre, MD Derendorf, H Schmith, VD AF Singh, R. P. Sahre, M. D. Derendorf, H. Schmith, V. D. TI MODELING OF INVESTIGATIVE STATIC GLOBAL ASSESSMENT SCORE (ISGA) IN ACNE VULGARIS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Singh, R. P.; Derendorf, H.] Univ Florida, Gainesville, FL USA. [Sahre, M. D.] Food & Drug Adm, Silver Spring, MD USA. [Schmith, V. D.] GlaxoSmithKline Inc, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S83 EP S83 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900216 ER PT J AU Singh, RP Sahre, D Derendorf, H Schmith, VD AF Singh, R. P. Sahre, D. Derendorf, H. Schmith, V. D. TI DISEASE PROGRESSION MODELING OF INFLAMMATORY LESION COUNTS (LES) IN ACNE VULGARIS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Singh, R. P.; Derendorf, H.] Univ Florida, Gainesville, FL USA. [Sahre, D.] Food & Drug Adm, Silver Spring, MD USA. [Schmith, V. D.] GlaxoSmithKline Inc, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S83 EP S83 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900215 ER PT J AU Vaidyanathan, J Arya, V Agarwal, S Vieira, MDT Zhao, P Huang, S Zhang, L AF Vaidyanathan, J. Arya, V. Agarwal, S. Vieira, M. de L. T. Zhao, P. Huang, S. Zhang, L. TI WHAT CRITERIA MAY BE APPROPRIATE IN DETERMINING THE NEED FOR IN VIVO EVALUATION OF A NEW MOLECULAR ENTITY'S (NME'S) POTENTIAL TO INHIBIT OATP1B1 (ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B1). SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Vaidyanathan, J.; Arya, V.; Agarwal, S.; Vieira, M. de L. T.; Zhao, P.; Huang, S.; Zhang, L.] US FDA, Silver Spring, MD USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S53 EP S53 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900140 ER PT J AU Vieira, ML Zhao, P Kim, M Apparaju, S Huang, S AF Vieira, M. L. Zhao, P. Kim, M. Apparaju, S. Huang, S. TI PREDICTING CYP3A4 INHIBITION IN CYP2D6 POOR METABOLIZERS USING PBPK MODELING AND SIMULATION: FESOTERODINE AS AN EXAMPLE. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Vieira, M. L.; Zhao, P.; Kim, M.; Apparaju, S.; Huang, S.] US FDA, Silver Spring, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S53 EP S53 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900139 ER PT J AU Vieira, ML Kirby, B Ragueneau-Majlessi, I Chien, JY Fischer, V Fretland, A Galetin, A Grime, K Hall, SD Plowchalk, DR Riley, R Seibert, E Skordos, K Snoeys, J Venkatakrishnan, K Einolf, HJ Obach, RS Berglund, EG Zhao, P Zhang, L Reynolds, KS Huang, S AF Vieira, M. L. Kirby, B. Ragueneau-Majlessi, I. Chien, J. Y. Fischer, V. Fretland, A. Galetin, A. Grime, K. Hall, S. D. Plowchalk, D. R. Riley, R. Seibert, E. Skordos, K. Snoeys, J. Venkatakrishnan, K. Einolf, H. J. Obach, R. S. Berglund, E. G. Zhao, P. Zhang, L. Reynolds, K. S. Huang, S. TI EVALUATION OF FDA AND EMA MODELS' CUT-OFF VALUES FOR CYP3A INHIBITION PREDICTION: A COLLABORATIVE EFFORT AMONG ACADEMIC, REGULATORY AGENCIES, AND INNOVATION AND QUALITY CONSORTIUM (IQC) PHARMACEUTICAL SCIENTISTS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Vieira, M. L.; Zhao, P.; Zhang, L.; Reynolds, K. S.; Huang, S.] US FDA, Silver Spring, MD USA. [Kirby, B.] Univ Washington, Seattle, WA 98195 USA. [Ragueneau-Majlessi, I.] Univ Washington, Silver Spring, MD USA. [Chien, J. Y.; Hall, S. D.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Fischer, V.] Abbott, Abbott Pk, IL USA. [Fretland, A.] Hoffmann LaRoche, Nutley, NJ USA. [Galetin, A.] Univ Manchester, Manchester, Lancs, England. [Grime, K.] AstraZeneca, Mindal, Sweden. [Plowchalk, D. R.; Obach, R. S.] Pfizer, Groton, CT USA. [Riley, R.] AstraZeneca, London, England. [Seibert, E.] Boehringer Ingelheim GmbH & Co KG, Ridgefield, CT USA. [Skordos, K.] GlaxoSmithKline Inc, King Of Prussia, PA USA. [Snoeys, J.] Janssen Pharmaceut Co Johnson & Johnson, Beerse, Belgium. [Venkatakrishnan, K.] Millennium, Cambridge, MA USA. [Einolf, H. J.] Novartis, E Hanover, NJ USA. [Berglund, E. G.] MPA, Uppsala, Sweden. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S48 EP S48 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900125 ER PT J AU Vieira, ML Kirby, B Ragueneau-Majlessi, I Chien, JY Fischer, V Fretland, A Galetin, A Grime, K Hall, SD Plowchalk, DR Riley, R Seibert, E Skordos, K Snoeys, J Venkatakrishnan, K Einolf, HJ Obach, RS Berglund, EG Zhao, P Zhang, L Reynolds, KS Huang, S AF Vieira, M. L. Kirby, B. Ragueneau-Majlessi, I. Chien, J. Y. Fischer, V. Fretland, A. Galetin, A. Grime, K. Hall, S. D. Plowchalk, D. R. Riley, R. Seibert, E. Skordos, K. Snoeys, J. Venkatakrishnan, K. Einolf, H. J. Obach, R. S. Berglund, E. G. Zhao, P. Zhang, L. Reynolds, K. S. Huang, S. TI EVALUATION OF FDA AND EMA MODELS' CUT-OFF VALUES FOR CYP3A INHIBITION PREDICTION: A COLLABORATIVE EFFORT AMONG ACADEMIC, REGULATORY AGENCIES, AND INNOVATION AND QUALITY CONSORTIUM (IQC) PHARMACEUTICAL SCIENTISTS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Vieira, M. L.; Zhao, P.; Zhang, L.; Reynolds, K. S.; Huang, S.] US FDA, Silver Spring, MD USA. [Kirby, B.] Univ Washington, Seattle, WA 98195 USA. [Ragueneau-Majlessi, I.] Univ Washington, Silver Spring, WA USA. [Chien, J. Y.; Hall, S. D.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Fischer, V.] Abbott, Abbott Pk, IL USA. [Fretland, A.] Hoffmann LaRoche, Nutley, NJ USA. [Galetin, A.] Univ Manchester, Manchester, Lancs, England. [Grime, K.] AstraZeneca, Mindal, Sweden. [Plowchalk, D. R.; Obach, R. S.] Pfizer, Groton, CT USA. [Riley, R.] AstraZeneca, London, England. [Seibert, E.] Boehringer Ingelheim GmbH & Co KG, Ridgefield, CT USA. [Skordos, K.] GlaxoSmithKline Inc, King Of Prussia, PA USA. [Snoeys, J.] Johnson & Johnson, Janssen Pharmaceut Co, Beerse, Belgium. [Venkatakrishnan, K.] Millennium, Cambridge, MA USA. [Einolf, H. J.] Novartis, E Hanover, NJ USA. [Berglund, E. G.] MPA, Uppsala, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S3 EP S3 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900007 ER PT J AU Younis, IR Laughren, TP Wang, Y Mathis, M Gobburu, JV AF Younis, I. R. Laughren, T. P. Wang, Y. Mathis, M. Gobburu, J. V. TI LEARN-APPLY APPROACH FOR ESTABLISHING DOSING RECOMMENDATIONS: PALIPERIDONE FOR THE TREATMENT OF ADOLESCENT SCHIZOPHRENIA. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Younis, I. R.; Laughren, T. P.; Wang, Y.; Mathis, M.; Gobburu, J. V.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S54 EP S55 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900143 ER PT J AU Yu, C Choi, S Li, L Dave, D Kim, M AF Yu, C. Choi, S. Li, L. Dave, D. Kim, M. TI POINTS TO CONSIDER IN A DRUG-DRUG INTERACTION (DDI) STUDY WITH ORAL CONTRACEPTIVES (OC) SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Yu, C.; Li, L.; Kim, M.] US FDA, Off Clin Pharmacol, OTS, CDER, Silver Spring, MD USA. [Choi, S.] Univ Illinois, Coll Pharm, Chicago, IL USA. [Dave, D.] US FDA, Off Womens Hlth, OC, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S99 EP S99 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900259 ER PT J AU Degheidy, HA Venzon, DJ Farooqui, MZH Abbasi, F Arthur, DC Wilson, WH Wiestner, A Stetler-Stevenson, MA Marti, GE AF Degheidy, Heba A. Venzon, David J. Farooqui, Mohammed Z. H. Abbasi, Fatima Arthur, Diane C. Wilson, Wyndham H. Wiestner, Adrian Stetler-Stevenson, M. A. Marti, Gerald E. TI Combined normal donor and CLL: Single tube ZAP-70 analysis SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE chronic lymphocytic leukemia; ZAP-70; flow cytometry; one tube assay; IGHV; cytogenetics ID CHRONIC LYMPHOCYTIC-LEUKEMIA; GENE MUTATION STATUS; GENOMIC ABERRATIONS; PROGNOSTIC-FACTORS; CD38 EXPRESSION; DIAGNOSIS; SURVIVAL; RATIO AB Introduction: Zeta-chain-associated protein kinase 70 (ZAP-70) has been identified as an independent prognostic marker in chronic lymphocytic leukemia (CLL). Based on our previous studies, we have developed a combined one-tube technology with multiple internal controls to optimize ZAP-70 assessment. Methods: Forty-eight untreated CLL cases were examined for ZAP-70 expression using a modified 7-color one-tube assay. Normal donor (ND) whole blood is stained with CD3 APC-Cy7 and CD19 APC. In a second tube, patient whole blood is stained with CD5 PE-Cy7, CD19 PerCP-Cy5.5, and CD20 eFluor450. After surface staining and fixation, these two tubes are combined. After saponin permeabilization, the cells were stained with two anti-ZAP-70 clones (1E7.2/AF488 and SBZAP/PE). The results obtained from this modified tube were compared with those obtained concurrently using the non-mixed single sample tubes. Five different methods of ZAP-70 expression analysis were evaluated: percentage positive cells using ND T-cells as a reference; the internal patient T-cell/clone ratio; ND T-cell/clone ratio; clone/ND B-cell ratio; and modified Z-index. Result: Overall, the combined patient and ND mix tube performed better than the non-mixed single sample tube. The strongest correlations between ZAP-70 expression and immunoglobulin heavy chain variable (IGHV) mutational status were seen with percentage positive ND T-cell, ND T-cell/clone ratio, and clone/ND B-cell ratio for both 1E7.2 and SBZAP clone (P < 0.0001). Conclusion: The modified one tube method combining the ND and patient sample provides highly reliable results that correlate with the IGHV mutational status. This method should be considered as part of the next step in standardization of the ZAP-70 assay in CLL. Published 2011 Wiley Periodicals, Inc.(dagger) C1 [Farooqui, Mohammed Z. H.; Wiestner, Adrian] NHLBI, NIH, Bethesda, MD 20892 USA. [Arthur, Diane C.; Stetler-Stevenson, M. A.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Metab Branch, Bethesda, MD 20892 USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Degheidy, Heba A.; Abbasi, Fatima; Marti, Gerald E.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Marti, GE (reprint author), OIVD DIHD CDRH, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM gemarti@mac.com FU NHLBI; NIH; CBER/FDA FX Grant sponsor: Intramural Research Program of the NHLBI, NIH and CBER/FDA. NR 21 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD MAR PY 2012 VL 82B IS 2 BP 67 EP 77 DI 10.1002/cyto.b.20622 PG 11 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 897WT UT WOS:000300692000003 PM 22031337 ER PT J AU Nicholson, TL Brockmeier, SL Loving, CL Register, KB Kehrli, ME Stibitz, SE Shore, SM AF Nicholson, Tracy L. Brockmeier, Susan L. Loving, Crystal L. Register, Karen B. Kehrli, Marcus E., Jr. Stibitz, Scott E. Shore, Sarah M. TI Phenotypic Modulation of the Virulent Bvg Phase Is Not Required for Pathogenesis and Transmission of Bordetella bronchiseptica in Swine SO INFECTION AND IMMUNITY LA English DT Article ID III SECRETION SYSTEM; RESPIRATORY SYNDROME VIRUS; ENTEROPATHOGENIC ESCHERICHIA-COLI; TOXIGENIC PASTEURELLA-MULTOCIDA; GERM-FREE PIGS; INTRANASAL INOCULATION; DERMONECROTIC TOXIN; GENE-EXPRESSION; INFECTION; REGULON AB The majority of virulence gene expression in Bordetella is regulated by a two-component sensory transduction system encoded by the bvg locus. In response to environmental cues, the BvgAS regulatory system controls expression of a spectrum of phenotypic phases, transitioning between a virulent (Bvg(+)) phase and a nonvirulent (Bvg(-)) phase, a process referred to as phenotypic modulation. We hypothesized that the ability of Bordetella bronchiseptica to undergo phenotypic modulation is required at one or more points during the infectious cycle in swine. To investigate the Bvg phase-dependent contribution to pathogenesis of B. bronchiseptica in swine, we constructed a series of isogenic mutants in a virulent B. bronchiseptica swine isolate and compared each mutant to the wild-type isolate for its ability to colonize and cause disease. We additionally tested whether a BvgAS system capable of modulation is required for direct or indirect transmission. The Bvg(-) phase-locked mutant was never recovered from any respiratory tract site at any time point examined. An intermediate phase-locked mutant (Bvg(i)) was found in numbers lower than the wild type at all respiratory tract sites and time points examined and caused limited to no disease. In contrast, colonization of the respiratory tract and disease caused by the Bvg(+) phase-locked mutant and the wild-type strain were indistinguishable. The Bvg(+) phase-locked mutant transmitted to naive pigs by both direct and indirect contact with efficiency equal to that of the wild-type isolate. These results indicate that while full activation of the BvgAS regulatory system is required for colonization and severe disease, it is not deleterious to direct and indirect transmission. Overall, our results demonstrate that the Bvg(+) phase is sufficient for respiratory infection and host-to-host transmission of B. bronchiseptica in swine. C1 [Nicholson, Tracy L.; Brockmeier, Susan L.; Loving, Crystal L.; Register, Karen B.; Kehrli, Marcus E., Jr.; Shore, Sarah M.] Agr Res Serv, Natl Anim Dis Ctr, USDA, Ames, IA USA. [Stibitz, Scott E.] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Nicholson, TL (reprint author), Agr Res Serv, Natl Anim Dis Ctr, USDA, Ames, IA USA. EM tracy.nicholson@ars.usda.gov NR 39 TC 12 Z9 12 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2012 VL 80 IS 3 BP 1025 EP 1036 DI 10.1128/IAI.06016-11 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 897DA UT WOS:000300621600015 PM 22158743 ER PT J AU Santercole, V Delmonte, P Kramer, JKG AF Santercole, Viviana Delmonte, Pierluigi Kramer, John K. G. TI Comparison of Separations of Fatty Acids from Fish Products Using a 30-m Supelcowax-10 and a 100-m SP-2560 Column SO LIPIDS LA English DT Article DE Supelcowax-10; SP-2560; GC; Fish oil; Fish muscle; Fatty acid determination; Silver-ion SPE columns; Equivalent chain length (ECL) ID GAS-LIQUID-CHROMATOGRAPHY; THIN-LAYER-CHROMATOGRAPHY; EQUIVALENT CHAIN-LENGTHS; HUMAN-MILK LIPIDS; DOCOSAHEXAENOIC ACID; TRANS ISOMERS; METHYL-ESTERS; OIL DEODORIZATION; FOOD-PRODUCTS; LINOLEIC-ACID AB Commercial fish oils and foods containing fish may contain trans and/or isomerized fatty acids (FA) produced during processing or as part of prepared foods. The current American Oil Chemists' Society (AOCS) official method for marine oils (method Ce 1i-07) is based on separation by use of poly(ethylene glycol) (PEG) columns, for example Supelcowax-10 or equivalent, which do not resolve most unsaturated FA geometric isomers. Highly polar 100-m cyanopropyl siloxane (CPS) columns, for example SP-2560 and CP Sil 88 are recommended for separation of geometric FA isomers. Complementary separations were achieved by use of two different elution temperature programs with the same CPS column. This study is the first direct comparison of the separations achieved by use of 30-m Supelcowax-10 and 100-m SP-2560 columns for fatty acid methyl esters (FAME) prepared from the same fish oil and fish muscle sample. To simplify the identification of the FA in these fish samples, FA were fractionated on the basis of the number and type of double bonds by silver-ion solid-phase extraction (Ag+-SPE) before GC analysis. The results showed that a combination of the three GC separations was necessary to resolve and identify most of the unsaturated FA, FA isomers, and other components of fish products, for example phytanic and phytenic acids. Equivalent chain length (ECL) values of most FAME in fish were calculated from the separations achieved by use of both GC columns; the values obtained were shown to be consistent with previously reported values for the Supelcowax-10 column. ECL values were also calculated for the FA separated on the SP-2560 column. The calculated ECL values were equally valid under isothermal and temperature-programmed elution GC conditions, and were valuable for confirmation of the identity of several unsaturated FAME in the fish samples. When analyzing commercially prepared fish foods, deodorized marine oils, or foods fortified with marine oils it is strongly recommended that quantitative data acquired by use of PEG columns is complemented with data obtained from separations using highly polar CPS columns. C1 [Santercole, Viviana] Porto Conte Ric Srl, I-07040 Santa Maria La Palma, Italy. [Delmonte, Pierluigi] US FDA, College Pk, MD 20740 USA. [Kramer, John K. G.] Agr & Agri Food Canada, Guelph Food Res Ctr, Guelph, ON N1G5C9, Canada. RP Santercole, V (reprint author), Porto Conte Ric Srl, SP 55 Porto Conte Capo Caccia,Km 8-4, I-07040 Santa Maria La Palma, Italy. EM vivianas@uniss.it; Pierluigi.delmonte@fda.hhs.gov; jkgkramer@rogers.com NR 39 TC 18 Z9 18 U1 2 U2 48 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0024-4201 J9 LIPIDS JI Lipids PD MAR PY 2012 VL 47 IS 3 BP 329 EP 344 DI 10.1007/s11745-011-3645-y PG 16 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 896RT UT WOS:000300588900010 PM 22246430 ER PT J AU Gannavaram, S Debrabant, A AF Gannavaram, Sreenivas Debrabant, Alain TI Involvement of TatD nuclease during programmed cell death in the protozoan parasite Trypanosoma brucei SO MOLECULAR MICROBIOLOGY LA English DT Article ID LEISHMANIA-MAJOR METACASPASE; APOPTOTIC DNA-DEGRADATION; BLOOD-STREAM FORM; RNA-INTERFERENCE; ENDONUCLEASE-I; YEAST; REPLICATION; EXPRESSION AB In this report, we describe the involvement of TatD nuclease during programmed cell death (PCD) in the human protozoan parasite Trypanosoma brucei. T. brucei TatD nuclease showed intrinsic DNase activity, was localized in the cytoplasm and translocated to the nucleus when cells were treated with inducers previously demonstrated to cause PCD in T. brucei. Overexpression of TatD nuclease resulted in elevated PCD and conversely, loss of TatD expression by RNAi conferred significant resistance to the induction of PCD in T. brucei. Co-immunoprecipitation studies revealed that TatD nuclease interacts with endonucleaseG suggesting that these two nucleases could form a DNA degradation complex in the nucleus. Together, biochemical activity, RNAi and subcellular localization results demonstrate the role of TatD nuclease activity in DNA degradation during PCD in these evolutionarily ancient eukaryotic organisms. Further, in conjunction with endonucleaseG, TatD may represent a critical nuclease in a caspase-independent PCD pathway in trypanosomatid parasites since caspases have not been identified in these organisms. C1 [Gannavaram, Sreenivas; Debrabant, Alain] US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Debrabant, A (reprint author), US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM alain.debrabant@fda.hhs.gov NR 26 TC 11 Z9 12 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAR PY 2012 VL 83 IS 5 BP 926 EP 935 DI 10.1111/j.1365-2958.2012.07978.x PG 10 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 897VV UT WOS:000300688800005 PM 22288397 ER PT J AU Lucas, AD AF Lucas, Anne D. TI Environmental Fate of Polyhexamethylene Biguanide SO BULLETIN OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY LA English DT Article DE Polyhexamethylene biguanide (PHMB); Environmental fate ID WATER AB Polyhexamethylene biguanide (PHMB) is used as a bacteriocidal agent in a variety of applications from medical devices to pools, but is highly toxic to some aquatic species. The stability of PHMB in various environmental matrices was examined. 80% of PHMB was present in fortified creek samples after 20 days, but bound immediately to soils with the exception of sandy soil. PHMB was absorbed to below detectable levels by weathered concrete within 12 h. In addition, one over the counter wound care product containing PHMB was evaluated to assess environmental leaching; detectable levels (20 mu g/mL) were still present after 1 week. C1 US FDA, Ctr Devices & Radiol Hlth, OSEL DB, Silver Spring, MD 20993 USA. RP Lucas, AD (reprint author), US FDA, Ctr Devices & Radiol Hlth, OSEL DB, 10903 New Hampshire Ave,Bldg 64,Room 4011, Silver Spring, MD 20993 USA. EM anne.lucas@fda.hhs.gov NR 13 TC 5 Z9 5 U1 4 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0007-4861 J9 B ENVIRON CONTAM TOX JI Bull. Environ. Contam. Toxicol. PD MAR PY 2012 VL 88 IS 3 BP 322 EP 325 DI 10.1007/s00128-011-0436-3 PG 4 WC Environmental Sciences; Toxicology SC Environmental Sciences & Ecology; Toxicology GA 890PX UT WOS:000300158000004 PM 22037631 ER PT J AU Norris, SE Landstrom, J Weintraub, A Bull, TE Widmalm, G Freedberg, DI AF Norris, Scott E. Landstrom, Jens Weintraub, Andrej Bull, Thomas E. Widmalm, Goran Freedberg, Daron I. TI Transient hydrogen bonding in uniformly 13C,15N-Labeled Carbohydrates in Water SO BIOPOLYMERS LA English DT Article DE polysaccharides; carbohydrate NMR; oligosaccharide; isotopic labeling; molecular dynamics simulations; radial distribution function; hydrogen bonding ID MOLECULAR-DYNAMICS SIMULATIONS; ESCHERICHIA-COLI O142; NMR-SPECTROSCOPY; FORCE-FIELD; AQUEOUS-SOLUTION; RESONANCE-SPECTROSCOPY; MAGNETIC-RESONANCE; CHEMICAL-SHIFTS; PROTEIN NMR; POLYSACCHARIDE AB We report NMR studies of transient hydrogen bonding in a polysaccharide (PS) dissolved in water without cosolvent at ambient temperature. The PS portion of the Escherichia coli O142 lipopolysaccharide is comprised of repeating pentasaccharide units of GalNAc (N-acetyl galactosamine), GlcNAc (N-acetyl glucosamine), and rhamnose in a 3:1:1 ratio, respectively. A 105-ns molecular dynamics (MD) simulation on one pentasaccharide repeat unit predicts transient inter-residue hydrogen bonds from the GalNAc NH groups in the PS. To investigate these predictions experimentally, the PS was uniformly 13C,15N enriched and the NH, carbonyl, C2, C4, and methyl resonances of the GalNAc and GlcNAc residues assigned using through-bond triple-resonance NMR experiments. Temperature dependence of amide NH chemical shifts and one-bond NH J couplings support that NH groups on two of the GalNAc residues are donors in transient hydrogen bonds. The remaining GalNAc and GlcNAc NHs do not appear to be donors from either temperature-dependent chemical shifts or one-bond NH J couplings. These results substantiate the presence of weak or partial hydrogen bonds in carbohydrates, and that MD simulations of repeating units in PSs provide insight into overall PS structure and dynamics. Published 2011 Wiley Periodicals, Inc. Biopolymers 97: 145154, 2012. C1 [Landstrom, Jens; Widmalm, Goran] Stockholm Univ, Arrhenius Lab, Dept Organ Chem, S-10691 Stockholm, Sweden. [Norris, Scott E.; Bull, Thomas E.; Freedberg, Daron I.] US FDA, Ctr Biol Evaluat & Res, Lab Bacterial Polysaccharides, Rockville, MD 20852 USA. [Weintraub, Andrej] Karolinska Univ Hosp, Karolinska Inst, Div Clin Microbiol, Dept Lab Med, S-14186 Huddinge, Sweden. RP Widmalm, G (reprint author), Stockholm Univ, Arrhenius Lab, Dept Organ Chem, S-10691 Stockholm, Sweden. EM gw@organ.su.se; daron_freedberg@nih.gov OI Weintraub, Andrej/0000-0003-3646-247X FU Swedish Research Council; Knut and Alice Wallenberg Foundation; Carl Tryggers Stiftelse for Vetenskaplig Forskning FX Contract grant sponsors: Swedish Research Council, The Knut and Alice Wallenberg Foundation, Carl Tryggers Stiftelse for Vetenskaplig Forskning NR 49 TC 9 Z9 9 U1 2 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 J9 BIOPOLYMERS JI Biopolymers PD MAR PY 2012 VL 97 IS 3 BP 145 EP 154 DI 10.1002/bip.21710 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 867UN UT WOS:000298480400001 PM 21858784 ER PT J AU McCarthy, S Burkhardt, W AF McCarthy, Susan Burkhardt, William, III TI Efficacy of electrolyzed oxidizing water against Listeria monocytogenes and Morganella morganii on conveyor belt and raw fish surfaces SO FOOD CONTROL LA English DT Article DE EO water; L. monocytogenes; M. morganii; Conveyor belt; Raw fish ID ESCHERICHIA-COLI O157-H7; SALMON PROCESSING PLANTS; KITCHEN CUTTING BOARDS; SMOKED SALMON; SMALL OUTBREAK; TYPING METHODS; RAINBOW-TROUT; CONTAMINATION; PREVALENCE; BACTERIA AB Listeria monocytogenes and Morganella morganii have been implicated in listeriosis outbreaks and histamine fish poisoning, respectively. Possible sources of contamination of food products include processing equipment, food handlers, and fish smokehouses. Treatment of food preparation surfaces and of whole fish during handling with agents such as, electrolyzed oxidizing (EO) water, could reduce biofilm formation on seafood products and in seafood processing plants. We examined the efficacy of EO water against L. monocytogenes and M. morganii biofilms using the MBEC (TM) Assay System (Innovotech Inc.), conveyor belt coupons, and raw fish surfaces. The MBEC (TM) Assay System was used to assess the activity of EO water against 24-h biofilms of 90 L. monocytogenes strains and five M. morganii strains. Biofilms were exposed to PBS or EO water for 0 (control), 5, 15, and 30 min. All bacterial isolates were susceptible (reduction of 7 log(10)CFU) to treatment with EO water for 5 min based on results obtained using this assay system. EO water was used to treat four L monocytogenes strains and one M. morganii strain attached to conveyor belt coupons and fish surfaces. Three L monocytogenes strains and one M. morganii strain on belt coupons were reduced by 1-2.5 log(10)CFU/cm(2) by exposure (5 min) to EO water compared to exposure to sterile distilled water. Strain to strain variability in susceptibility to EO water was evidenced by the fact that numbers of one L. monocytogenes strain were not reduced by EO water treatment of belt surfaces. EO water was not effective against L. monocytogenes and M. morganii on fish surfaces as growth occurred during cold storage. These results suggest that exposure of conveyor belts to EO water for a minimum of 5 min could assist in the removal of some biofilms. Removal of food residue with continuous or intermittent spraying of food processing equipment (e.g., conveyor belts, slicers) could reduce or prevent further biofilm formation. Additional sanitizers must be investigated for activity against bacteria associated with raw fish. Published by Elsevier Ltd. C1 [McCarthy, Susan; Burkhardt, William, III] US FDA, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP McCarthy, S (reprint author), US FDA, Gulf Coast Seafood Lab, 1 Iberville Dr, Dauphin Isl, AL 36528 USA. EM susan.mccarthy@fda.hhs.gov; william.burkhardt@fda.hhs.gov NR 45 TC 14 Z9 17 U1 2 U2 25 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-7135 J9 FOOD CONTROL JI Food Control PD MAR-APR PY 2012 VL 24 IS 1-2 BP 214 EP 219 DI 10.1016/j.foodcont.2011.09.030 PG 6 WC Food Science & Technology SC Food Science & Technology GA 856QS UT WOS:000297659100033 ER PT J AU Abraham, A Jester, ELE Granade, HR Plakas, SM Dickey, RW AF Abraham, Ann Jester, Edward L. E. Granade, Hudson R. Plakas, Steven M. Dickey, Robert W. TI Caribbean ciguatoxin profile in raw and cooked fish implicated in ciguatera SO FOOD CHEMISTRY LA English DT Article DE Ciguatoxins; Ciguatera fish poisoning; Toxin profile; Caribbean ID JACK CARANX-LATUS; TOXINS; JAVANICUS AB A cooked meal remnant and uncooked portion of a Caribbean barracuda suspected in ciguatera fish poisoning were examined for the presence of ciguatoxins (CTX). Samples were analysed using a tiered method of CTX analysis consisting of in vitro cell (N2a) assay to assess composite toxicity and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for structural confirmation. Meal remnant and uncooked fish extracts were cytotoxic by N2a cell assay and Caribbean ciguatoxin congener C-CTX-1 was structurally confirmed. Sample extracts were fractionated by LC and fractions analysed by the cell assay. The cytotoxicity profiles of cooked meal remnant and uncooked fish were similar. Cytotoxicity-guided LC-MS/MS analyses identified several CTX congeners contributing to the composite toxicity of the samples. C-CTX-1 was a major contributor, supporting its utility as a biomarker of Caribbean ciguatoxic fish. Published by Elsevier Ltd. C1 [Abraham, Ann; Jester, Edward L. E.; Granade, Hudson R.; Plakas, Steven M.; Dickey, Robert W.] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP Abraham, A (reprint author), US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. EM ann.abraham@fda.hhs.gov NR 22 TC 11 Z9 11 U1 1 U2 27 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0308-8146 J9 FOOD CHEM JI Food Chem. PD MAR 1 PY 2012 VL 131 IS 1 BP 192 EP 198 DI 10.1016/j.foodchem.2011.08.059 PG 7 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA 845MI UT WOS:000296826400025 ER PT J AU Bentayeb, K Ackerman, LK Begley, TH AF Bentayeb, Karim Ackerman, Luke K. Begley, Timothy H. TI Ambient Ionization-Accurate Mass Spectrometry (AMI-AMS) for the Identification of Nonvisible Set-off in Food-Contact Materials SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE set-off; food-contact materials; printing inks; AMI-AMS; DART ID RAPID IDENTIFICATION; POLY(VINYL CHLORIDE); MIGRATION; ADDITIVES; INKS AB Set-off is the unintentional transfer of substances used in printing from the external printed surface of food packaging to the inner, food-contact surface. Ambient ionization-accurate mass spectrometry (AMI-AMS) detected and identified compounds from print set-off not visible to the human eye. AMI mass spectra from inner and outer surfaces of printed and nonprinted food packaging were compared to detect and identify nonvisible set-off components. A protocol to identify unknowns was developed using a custom open-source database of printing inks and food-packaging compounds. The protocol matched print-related food-contact surface ions with the molecular formulas of common ions, isotopes, and fragments of compounds from the database. AMI-AMS was able to detect print set-off and identify seven different compounds. Set-off on the packaging samples was confirmed using gas chromatographic-mass spectrometric (GC-MS) analysis of single-sided solvent extracts. N-Ethyl-2(and 4)-methylbenzenesulfonamide, 2,4-diphenyl-4-methyl-1(and 2)-pentene, and 2,4,7,9-tetramethyl-5-decyne-4,7-diol were present on the food-contact layer at concentrations from 0.21 to 2.7 +/- 1.6 mu g dm(-2), corresponding to nearly milligram per kilogram concentrations in the packaged food. Other minor set-off compounds were detected only by AMI-AMS, a fast, simple, and thorough technique to detect and identify set-off in food packaging. C1 [Bentayeb, Karim; Ackerman, Luke K.; Begley, Timothy H.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Ackerman, LK (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM Luke.Ackerman@fda.hhs.gov RI Ackerman, Luke/E-4597-2011 OI Ackerman, Luke/0000-0001-6626-3039 FU Departamento de Ciencia, Tecnologia y Universidad of the Gobierno de Aragon (Spain) FX K.B. acknowledges the Departamento de Ciencia, Tecnologia y Universidad of the Gobierno de Aragon (Spain), for the fellowship provided by the program "Fomento de la Movilidad de los Investigadores" in 2011. NR 15 TC 12 Z9 12 U1 4 U2 34 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD FEB 29 PY 2012 VL 60 IS 8 BP 1914 EP 1920 DI 10.1021/jf204456z PG 7 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 899ZI UT WOS:000300854900004 PM 22250944 ER PT J AU Charoo, NA Shamsher, AAA Zidan, AS Rahman, Z AF Charoo, Naseem A. Shamsher, Areeg A. A. Zidan, Ahmed S. Rahman, Ziyaur TI Quality by design approach for formulation development: A case study of dispersible tablets SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Quality by design; Dispersible tablets; Critical quality attributes; Risk assessment; Design space; Control strategy ID SODIUM; SPACE AB The focus of the current investigations was to apply quality by design (QbD) approach to the development of dispersible tablets. Critical material and process parameters are linked to the critical quality attributes of the product. Variability is reduced by product and process understanding which translates into quality improvement, risk reduction and productivity enhancement. The risk management approach further leads to better understanding of the risks, ways to mitigate them and control strategy is proposed commensurate with the level of the risk. Design space in combination with pharmaceutical quality management system provide for flexible regulatory approaches with opportunity for continuous improvement that benefit patient and manufacturer alike. The development of dispersible tablet was proposed in the current study through a QbD paradigm for a better patient compliance and product quality. The quality target product profile of a model biopharmaceutical class II drug was identified. Initial risk analysis led to the identification of the critical quality attributes. Physicochemical characterization and compatibility studies of the drug with commonly used excipients were performed. Experiments were designed with focus on critical material and process attributes. Design space was identified and risk factors for all the possible failure modes were below critical levels after the implementation of control strategy. Compliance to the design space provides an opportunity to release batches in a real time. In conclusion, QbD tools together with risk and quality management tools provided an effective and efficient paradigm to build the quality into dispersible tablet. Published by Elsevier B.V. C1 [Zidan, Ahmed S.; Rahman, Ziyaur] US FDA, CDER, DPQR, Silver Spring, MD 20993 USA. [Charoo, Naseem A.] Blue Nile Pharmaceut Co, Khartoum, Sudan. [Shamsher, Areeg A. A.] RAK Med & Hlth Sci Univ, Ras Al Khaima, U Arab Emirates. [Zidan, Ahmed S.] Zagazig Univ, Fac Pharm, Zagazig, Egypt. RP Rahman, Z (reprint author), US FDA, CDER, DPQR, LS Bldg 64,Room 1076,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM rahman.ziyaur@gmail.com RI Zidan, Ahmed/I-1147-2012; OI Rahman, Ziyaur/0000-0002-0402-825X NR 38 TC 37 Z9 39 U1 3 U2 36 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARMACEUT JI Int. J. Pharm. PD FEB 28 PY 2012 VL 423 IS 2 BP 167 EP 178 DI 10.1016/j.ijpharm.2011.12.024 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 903XT UT WOS:000301157000003 PM 22209997 ER PT J AU Liu, XF Doub, WH Guo, CN AF Liu, Xiaofei Doub, William H. Guo, Changning TI Evaluation of metered dose inhaler spray velocities using Phase Doppler Anemometry (PDA) SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Metered dose inhaler; MDI; Droplet velocity; Droplet size; Phase Doppler Anemometry ID AEROSOLS AB Droplet velocity is an important parameter which can significantly influence inhalation drug delivery performance. Together with the droplet size, this parameter determines the efficiency of the deposition of MDI products at different sites within the lungs. In this study, Phase Doppler Anemometry (PDA) was used to investigate the instantaneous droplet velocity emitted from MDIs as well as the corresponding droplet size distribution. The nine commercial MDI products surveyed showed significantly different droplet velocities, indicating that droplet velocity could be used as a discriminating parameter for in vitro testing of MDI products. The droplet velocity for all tested MDI products decreased when the testing distance was increased from 3 cm to 6 cm from the front of mouthpiece, with CFC formulations showing a larger decrease than HFA formulations. The mean droplet diameters of the nine MDIs were also significantly different from one-another. Droplet size measurements made using PDA (a number-based technique) could not be directly compared to results obtained using laser light scattering measurements (a volume-based technique). This work demonstrates that PDA can provide unique information useful for characterizing MDI aerosol plumes and evaluating MDI drug delivery efficiency. PDA could also aid the evaluation of in vitro equivalence in support of formulation or manufacturing changes and in evaluation of abbreviated new drug applications (ANDAs) for MDIs. Published by Elsevier B.V. C1 [Liu, Xiaofei; Doub, William H.; Guo, Changning] US FDA, Div Pharmaceut Anal, St Louis, MO 63101 USA. RP Guo, CN (reprint author), US FDA, Div Pharmaceut Anal, 1114 Market St,Room 1002, St Louis, MO 63101 USA. EM changning.guo@fda.hhs.gov FU US Food and Drugs Administration [1165] FX This work was supported by US Food and Drugs Administration through its Critical Path Initiative fund (Project #1165). NR 11 TC 7 Z9 7 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARMACEUT JI Int. J. Pharm. PD FEB 28 PY 2012 VL 423 IS 2 BP 235 EP 239 DI 10.1016/j.ijpharm.2011.12.006 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 903XT UT WOS:000301157000010 PM 22183132 ER PT J AU Zidan, AS Rahman, Z Sayeed, V Raw, A Yu, L Khan, MA AF Zidan, Ahmed S. Rahman, Ziyaur Sayeed, Vilayat Raw, Andre Yu, Lawrence Khan, Mansoor A. TI Crystallinity evaluation of tacrolimus solid dispersions by chemometric analysis SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Tacrolimus; Solid dispersions; Crystallinity; Near-infrared Raman ID NEAR-INFRARED SPECTROSCOPY; PHARMACEUTICAL APPLICATIONS; RAMAN-SPECTROSCOPY; AMORPHOUS STATE; STABILITY; NIFEDIPINE; SYSTEMS; CRYSTALLIZATION; FORMULATION; TECHNOLOGY AB Different destructive and nondestructive analytical methods, namely powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), Raman and near-infrared (NIR) spectroscopy and imaging, to detect and characterize tacrolimus trace crystallinity in an amorphous solid dispersion (SD) using chemometric analysis were developed. The SD was spiked with different percentages of the crystalline drug to construct an array of SDs with different crystallinity percentages. Partial least square (PLS) regression analysis was employed to compare the performance of the calibration models created using these analytical methods. The obtained results indicated a significant interaction between tacrolimus and the employed polymer and a drug dissolution dependency on the crystalline fraction within the SDs. Using two PLS factors, these analytical methods were ranked according to its specificity to detect the trace crystallinity of SDs as NIR > PXRD > Raman > DSC. Through the application of PLS, root-mean-squared error of calibration values of 2.91%, 5.36%, 7.07% and 11.58% were calculated for the calibration models constructed by NIR, PXRD, Raman and DSC, respectively. Having a prediction error of 2.1% and a correlation coefficient of 0.99, it is demonstrated that combined NIR imaging and chemometric analysis outperformed the other methods in detecting trace crystallinity in tacrolimus amorphous systems. The spatial distributions of amorphous and crystalline drug were also obtained in order to allow for studying the crystallization dissemination in the solid dispersions. Consequently, NIR and NIR imaging coupled with chemometry was shown to be a powerful tool for the prediction of drug crystallinity within SDs. (C) 2011 Elsevier B.V. All rights reserved. C1 [Khan, Mansoor A.] US FDA, Div Prod Qual Res, CDER, OPS,OTR, Silver Spring, MD 20993 USA. [Zidan, Ahmed S.] Zagazig Univ, Fac Pharm, Dept Pharmaceut & Ind Pharm, Zagazig, Egypt. RP Khan, MA (reprint author), US FDA, Div Prod Qual Res, CDER, OPS,OTR, LS Bldg 64,Room 1070,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mansoor.Khan@fda.hhs.gov RI Zidan, Ahmed/I-1147-2012; OI Rahman, Ziyaur/0000-0002-0402-825X FU Oak Ridge Institute for Science and Education (ORISE) FX The authors would like to thank the Oak Ridge Institute for Science and Education (ORISE) for supporting the post doctoral research program. NR 42 TC 32 Z9 33 U1 2 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARMACEUT JI Int. J. Pharm. PD FEB 28 PY 2012 VL 423 IS 2 BP 341 EP 350 DI 10.1016/j.ijpharm.2011.11.003 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 903XT UT WOS:000301157000023 PM 22100517 ER PT J AU Xu, XM Khan, MA Burgess, DJ AF Xu, Xiaoming Khan, Mansoor A. Burgess, Diane J. TI Predicting hydrophilic drug encapsulation inside unilamellar liposomes SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Liposome; Encapsulation efficiency; Lipid molecular area; Mathematical model; Langmuir balance; Log-Normal distribution ID REVERSE-PHASE EVAPORATION; LIPID-BILAYERS; METAL-IONS; SIZE; VESICLES; MULTILAMELLAR; EXTRUSION; PHOSPHATIDYLCHOLINE; PHOSPHOLIPIDS; GENERATION AB A mathematical model has been developed to predict the encapsulation efficiency of hydrophilic drugs in unilamellar liposomes, and will be useful in formulation development to rapidly achieve optimized formulations. This model can also be used to compare drug encapsulation efficiencies of liposomes prepared via different methods, and will assist in the development of suitable process analytical technologies to achieve real-time monitoring and control of drug encapsulation during liposome manufacturing for hydrophilic molecules. Liposome particle size as well as size distribution, lipid concentration, lipid molecular surface area, and bilayer thickness were used in constructing the model. Most notably, a Log-Normal probability function was utilized to account for sample particle size distribution. This is important to avoid significant estimation error. The model-generated predictions were validated using experimental results as well as literature data, and excellent correlations were obtained in both cases. A Langmuir balance study provided insight regarding the effect of media on the liposome drug encapsulation process. The results revealed an inverse correlation between media ionic strength and lipid average molecular area, which helps to explain the phenomenon of inverse correlation between media ionic strength and drug encapsulation efficiency. Finally, a web application has been written to facilitate use of the model allowing calculations to be easily performed. This model will be useful in formulation development to rapidly achieve optimized formulation. (C) 2011 Elsevier B.V. All rights reserved. C1 [Xu, Xiaoming; Burgess, Diane J.] Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT 06269 USA. [Khan, Mansoor A.] FDA CDER DPQR, Silver Spring, MD 20993 USA. RP Burgess, DJ (reprint author), Univ Connecticut, Dept Pharmaceut Sci, 69 N Eagleville Rd,U3092, Storrs, CT 06269 USA. EM xiaoming.xu@me.com; mansoor.khan@fda.hhs.gov; d.burgess@uconn.edu OI Xu, Xiaoming/0000-0003-1672-0830 FU FDA [HHSF223201010484P] FX This research was supported by FDA funding (HHSF223201010484P). NR 32 TC 32 Z9 33 U1 1 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARMACEUT JI Int. J. Pharm. PD FEB 28 PY 2012 VL 423 IS 2 BP 410 EP 418 DI 10.1016/j.ijpharm.2011.12.019 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 903XT UT WOS:000301157000031 PM 22207162 ER PT J AU Xu, XM Khan, MA Burgess, DJ AF Xu, Xiaoming Khan, Mansoor A. Burgess, Diane J. TI A quality by design (QbD) case study on liposomes containing hydrophilic API: II. Screening of critical variables, and establishment of design space at laboratory scale SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Liposome; QbD; Tenofovir; Encapsulation efficiency; Plackett-Burman; Central composite design; Response surface method (RSM); Design space AB Two statistical designs were used in this case study as part of an investigation into the feasibility and the advantages of applying QbD concepts to liposome-based complex parenteral controlled release systems containing a hydrophilic active pharmaceutical ingredient (API). The anti-viral drug Tenofovir was used as a model compound. First design (Plackett-Burman) was used to screen eight high-risk variables obtained from risk analysis and assess their impact on liposome characteristics (drug encapsulation efficiency, particle size, and physical stability). It was discovered that out of eight high-risk variables only lipid and drug concentration had significant effects on the drug encapsulation efficiency. This allowed the use of a central composite design (CCD) (with more predictive capability) to fully elucidate the relationship between lipid concentration, drug concentration and encapsulation efficiency. On comparing the CCD model generated response surface with additional data points, the accuracy and robustness of the model was confirmed. Using this developed model, the design space for Tenofovir liposomes preparation has been established in a laboratory setting, within which the preparation variability is minimized. With regard to sample storage stability, it was shown that at 4 degrees C the prepared Tenofovir liposomes, dispersed in aqueous phase, achieved stability for at least 2 years. These principles can be applied to liposomes containing other hydrophilic APIs, and can provide time and cost saving to industrial formulation scientists, and result in a more robust liposome preparation process. (C) 2011 Elsevier B.V. All rights reserved. C1 [Xu, Xiaoming; Burgess, Diane J.] Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT 06269 USA. [Khan, Mansoor A.] FDA CDER DPQR, Silver Spring, MD 20993 USA. RP Burgess, DJ (reprint author), Univ Connecticut, Dept Pharmaceut Sci, 69 N Eagleville Rd,U3092, Storrs, CT 06269 USA. EM xiaoming.xu@me.com; mansoor.khan@fda.hhs.gov; d.burgess@uconn.edu OI Xu, Xiaoming/0000-0003-1672-0830 FU FDA [REQ1044477] FX This research was supported by FDA critical path funding (Solicitation No.: REQ1044477). NR 15 TC 38 Z9 39 U1 1 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARMACEUT JI Int. J. Pharm. PD FEB 28 PY 2012 VL 423 IS 2 BP 543 EP 553 DI 10.1016/j.ijpharm.2011.11.036 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 903XT UT WOS:000301157000046 PM 22155413 ER PT J AU Zichel, R Chearwae, W Pandey, GS Golding, B Sauna, ZE AF Zichel, Ran Chearwae, Wanida Pandey, Gouri Shankar Golding, Basil Sauna, Zuben E. TI Aptamers as a Sensitive Tool to Detect Subtle Modifications in Therapeutic Proteins SO PLOS ONE LA English DT Article ID FACTOR-VIII CONCENTRATE; HUMAN THROMBIN; MONOCLONAL-ANTIBODIES; TOPICAL THROMBINS; BIOSIMILARS; COMPARABILITY; INHIBITORS; SURFACES; EPITOPES; SURGERY AB Therapeutic proteins are derived from complex expression/production systems, which can result in minor conformational changes due to preferential codon usage in different organisms, post-translational modifications, etc. Subtle conformational differences are often undetectable by bioanalytical methods but can sometimes profoundly impact the safety, efficacy and stability of products. Numerous bioanalytical methods exist to characterize the primary structure of proteins, post translational modifications; protein-substrate/protein/protein interactions and functional bioassays are available for most proteins that are developed as products. There are however few analytical techniques to detect changes in the tertiary structure of proteins suitable for use during drug development and quality control. For example, x-ray crystallography and NMR are impractical for routine use and do not capture the heterogeneity of the product. Conformation-sensitive antibodies can be used to map proteins. However the development of antibodies to represent sufficient epitopes can be challenging. Other limitations of antibodies include limited supply, high costs, heterogeneity and batch to batch variations in titer. Here we provide proof-of-principle that DNA aptamers to thrombin can be used as surrogate antibodies to characterize conformational changes. We show that aptamers can be used in assays using either an ELISA or a label-free platform to characterize different thrombin products. In addition we replicated a heat-treatment procedure that has previously been shown to not affect protein activity but can result in conformational changes that have serious adverse consequences. We demonstrate that a panel of aptamers (but not an antibody) can detect changes in the proteins even when specific activity is unaffected. Our results indicate a novel approach to monitor even small changes in the conformation of proteins which can be used in a routine drug-development and quality control setting. The technique can provide an early warning of structural changes during the manufacturing process that could have consequential outcomes downstream. C1 [Zichel, Ran; Chearwae, Wanida; Pandey, Gouri Shankar; Sauna, Zuben E.] US FDA, Ctr Biol Evaluat & Res, Div Hematol, Lab Hemostasis, Bethesda, MD 20014 USA. [Golding, Basil] US FDA, Ctr Biol Evaluat & Res, Div Hematol, Lab Plasma Derivat, Bethesda, MD 20014 USA. RP Zichel, R (reprint author), Israel Inst Biol Res, Dept Biotechnol, IL-70450 Ness Ziona, Israel. EM zuben.sauna@fda.hhs.gov FU Laboratory of Hemostasis; Center for Biologics Evaluation and Research, Food and Drug Administration's Modernization of Science FX This work was supported by funds from the Laboratory of Hemostasis and the Center for Biologics Evaluation and Research, Food and Drug Administration's Modernization of Science program (ZES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 13 Z9 13 U1 3 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 27 PY 2012 VL 7 IS 2 AR e31948 DI 10.1371/journal.pone.0031948 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 927OV UT WOS:000302918500050 PM 22384109 ER PT J AU Monaco, S Fiorini, M Farinazzo, A Ferrari, S Gelati, M Piccardo, P Zanusso, G Ghetti, B AF Monaco, Salvatore Fiorini, Michele Farinazzo, Alessia Ferrari, Sergio Gelati, Matteo Piccardo, Pedro Zanusso, Gianluigi Ghetti, Bernardino TI Allelic Origin of Protease-Sensitive and Protease-Resistant Prion Protein Isoforms in Gerstmann-Straussler-Scheinker Disease with the P102L Mutation SO PLOS ONE LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; TRANSGENIC MICE; PHENOTYPIC HETEROGENEITY; SYNTHETIC PEPTIDE; TRUNCATED FORMS; WILD-TYPE; PRP; NEURODEGENERATION; IDENTIFICATION; VARIABILITY AB Gerstmann-Straussler-Scheinker (GSS) disease is a dominantly inherited prion disease associated with point mutations in the Prion Protein gene. The most frequent mutation associated with GSS involves a proline-to-leucine substitution at residue 102 of the prion protein, and is characterized by marked variability at clinical, pathological and molecular levels. Previous investigations of GSS P102L have shown that disease-associated pathological prion protein, or PrPSc, consists of two main conformers, which under exogenous proteolysis generates a core fragment of 21 kDa and an internal fragment of 8 kDa. Both conformers are detected in subjects with spongiform degeneration, whereas only the 8 kDa fragment is recovered in cases lacking spongiosis. Several studies have reported an exclusive derivation of protease-resistant PrPSc isoforms from the mutated allele; however, more recently, the propagation of protease-resistant wild-type PrPSc has been described. Here we analyze the molecular and pathological phenotype of six GSS P102L cases characterized by the presence of 21 and 8 kDa PrP fragments and two subjects with only the 8 kDa PrP fragment. Using sensitive protein separation techniques and Western blots with antibodies differentially recognizing wild-type and mutant PrP we observed a range of PrPSc allelic conformers, either resistant or sensitive to protease treatment in all investigated subjects. Additionally, tissue deposition of protease-sensitive wild-type PrPSc molecules was seen by conventional PrP immunohistochemistry and paraffin-embedded tissue blot. Our findings enlarge the spectrum of conformational allelic PrPSc quasispecies propagating in GSS P102L thus providing a molecular support to the spectrum of disease phenotypes, and, in addition, impact the diagnostic role of PrP immunohistochemistry in prion diseases. C1 [Monaco, Salvatore; Fiorini, Michele; Farinazzo, Alessia; Ferrari, Sergio; Gelati, Matteo; Zanusso, Gianluigi] Univ Verona, Dept Neurol Neuropsychol Morphol & Motor Sci, I-37100 Verona, Italy. [Piccardo, Pedro] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Piccardo, Pedro; Ghetti, Bernardino] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN USA. RP Monaco, S (reprint author), Univ Verona, Dept Neurol Neuropsychol Morphol & Motor Sci, I-37100 Verona, Italy. EM salvatore.monaco@univr.it OI ZANUSSO, Gianluigi/0000-0001-5199-6264; Monaco, Salvatore/0000-0003-3191-8597 FU National Institute of Neurological Disease and Stroke (NINDS), National Institutes of Health [R01 NS029822]; National Institute on Aging (NIA), National Institutes of Health [P30 AG010133]; Fondazione Cariverona FX This work was supported by grants R01 NS029822 to BG from National Institute of Neurological Disease and Stroke (NINDS), P30 AG010133 from National Institute on Aging (NIA) to BG (both Institutes are part of the National Institutes of Health) and by the grant "Disabilita cognitiva e comportamentale nelle demenze e nelle psicosi" from Fondazione Cariverona to SM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 11 Z9 11 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 23 PY 2012 VL 7 IS 2 AR e32382 DI 10.1371/journal.pone.0032382 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 927NZ UT WOS:000302916100076 PM 22384235 ER PT J AU Erdemira, A Guess, TM Halloran, J Tadepalli, SC Morrison, TM AF Erdemira, Ahmet Guess, Trent M. Halloran, Jason Tadepalli, Srinivas C. Morrison, Tina M. TI Considerations for reporting finite element analysis studies in biomechanics SO JOURNAL OF BIOMECHANICS LA English DT Article DE Standards in modeling; Tissue mechanics; Joint biomechanics; Musculoskeletal system; Device mechanics; Device evaluation ID GROUP RANDOMIZED-TRIALS; COMPUTATIONAL BIOMECHANICS; UPDATED GUIDELINES; VALIDATION; ENVIRONMENT; MECHANICS; MODELS AB Simulation-based medicine and the development of complex computer models of biological structures is becoming ubiquitous for advancing biomedical engineering and clinical research. Finite element analysis (FEA) has been widely used in the last few decades to understand and predict biomechanical phenomena. Modeling and simulation approaches in biomechanics are highly interdisciplinary, involving novice and skilled developers in all areas of biomedical engineering and biology. While recent advances in model development and simulation platforms offer a wide range of tools to investigators, the decision making process during modeling and simulation has become more opaque. Hence, reliability of such models used for medical decision making and for driving multiscale analysis comes into question. Establishing guidelines for model development and dissemination is a daunting task, particularly with the complex and convoluted models used in FEA. Nonetheless, if better reporting can be established, researchers will have a better understanding of a model's value and the potential for reusability through sharing will be bolstered. Thus, the goal of this document is to identify resources and considerate reporting parameters for FEA studies in biomechanics. These entail various levels of reporting parameters for model identification, model structure, simulation structure, verification, validation, and availability. While we recognize that it may not be possible to provide and detail all of the reporting considerations presented, it is possible to establish a level of confidence with selective use of these parameters. More detailed reporting, however, can establish an explicit outline of the decision-making process in simulation-based analysis for enhanced reproducibility, reusability, and sharing. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Erdemira, Ahmet] Cleveland Clin, Lerner Res Inst, Dept Biomed Engn ND20, Cleveland, OH 44195 USA. [Guess, Trent M.; Halloran, Jason] Cleveland Clin, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44195 USA. [Guess, Trent M.] Univ Missouri Kansas City, Dept Civil & Mech Engn, Kansas City, MO 64110 USA. [Tadepalli, Srinivas C.] Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA. [Morrison, Tina M.] Food & Drug Adm, Ctr Devices & Radiol Hlth, Silver Spring, MD 20933 USA. RP Erdemira, A (reprint author), Cleveland Clin, Lerner Res Inst, Dept Biomed Engn ND20, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM erdemira@ccf.org FU National Institutes of Health [R01 EB009643, R01EB006735, R01HD037433]; National Science Foundation [CMMI-1039524, CBET-0821459, CMS-0506297]; Missouri Life Sciences Research Board [09-1078]; FDA/CDRH FX This manuscript was a product of discussions within the Working Group 6, Tissue Mechanics, of the Interagency Modeling and Analysis Group (IMAG), of which all the authors were members. The authors are thankful for the input from Working Group 10, Model Sharing and Standards, of the IMAG for inspiring this work with their significant efforts to draft a proposal for modeling standards. The authors appreciate discussions with fellow members of the Working Group 6 and its successor, the Biomechanics Working Group of the IMAG, as well as other IMAG members, and investigators in the biomechanics community. The authors would also like to acknowledge Ganesh Thiagarajan and Andrew McCulloch for their feedback on the early versions of this document. Additionally, the authors appreciate the input and support from scientists in the Regulatory Review of Computational Modeling working group at the Center for Devices and Radiological Health at the US Food and Drug Administration. Funding to support contributions of individual authors were: Ahmet Erdemir and Jason Halloran (National Institutes of Health, R01 EB009643, R01EB006735); Srinivas C. Tadepalli (National Institutes of Health, R01HD037433); Trent Guess (National Science Foundation, CMMI-1039524, CBET-0821459, CMS-0506297; Missouri Life Sciences Research Board, 09-1078); Tina Morrison (FDA/CDRH Critical Path Initiative Project). An online development version of this article for prospective editing, comments and feedback is available in the IMAG wiki (hap://www.imagwiki.nibib.nih.gov/mediawiki/index.php?title=Reporting_in _FEA). NR 25 TC 36 Z9 38 U1 3 U2 28 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD FEB 23 PY 2012 VL 45 IS 4 BP 625 EP 633 DI 10.1016/j.jbiomech.2011.11.038 PG 9 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 911VR UT WOS:000301748800001 PM 22236526 ER PT J AU Young, WM South, P Begley, TH Diachenko, GW Noonan, GO AF Young, Wendy M. South, Paul Begley, Timothy H. Diachenko, Gregory W. Noonan, Gregory O. TI Determination of Perfluorochemicals in Cow's Milk Using Liquid Chromatography-Tandem Mass Spectrometry SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE perfluorochemicals; milk; method development; PFOA; PFOS ID SOLID-PHASE EXTRACTION; PERFLUORINATED COMPOUNDS; HUMAN EXPOSURE; POLYFLUOROALKYL CHEMICALS; PERFLUOROOCTANE SULFONATE; FLUOROTELOMER ALCOHOLS; FOOD; WATER; POPULATION; FISH AB This study describes a new method developed for detection of 10 different perfluorochemicals (PFCs) in cow's milk, seven perfluorinated carboxylates and three perfluorinated sulfonate salts. After attempting multiple methods employing both acidic and basic extractions, a basic extraction using 10 mM sodium hydroxide in methanol digestion along with weak anion-exchange solid-phase extraction was employed. Vortex mixing and varying sonication times were compared as part of sample processing. Results show that sonication during sample processing yield decreased recovery of longer chain perfluorinated carboxylates. The final method developed was used to determine the concentration of PFCs in 12 raw and 49 retail milk samples from across the United States. With the exception of a single raw milk sample obtained from a dairy farm that had applied PFC containing biosolids to its fields, there were no milk samples containing PFCs. C1 [Young, Wendy M.; South, Paul; Begley, Timothy H.; Diachenko, Gregory W.; Noonan, Gregory O.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Young, WM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM wendy.young@fda.hhs.gov NR 41 TC 10 Z9 11 U1 4 U2 38 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD FEB 22 PY 2012 VL 60 IS 7 BP 1652 EP 1658 DI 10.1021/jf204565x PG 7 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 897IT UT WOS:000300644100008 PM 22243628 ER PT J AU Chen, C Liu, Y Maruvada, S Myers, M Khismatullin, D AF Chen, C. Liu, Y. Maruvada, S. Myers, M. Khismatullin, D. TI Effect of ethanol injection on cavitation and heating of tissues exposed to high-intensity focused ultrasound SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID HEPATOCELLULAR-CARCINOMA; RADIOFREQUENCY ABLATION; INERTIAL CAVITATION; MIMICKING MATERIAL; HEPATIC-TUMORS; HIFU EXPOSURE; IN-VIVO; SUSPENSIONS; METASTASES; DELIVERY AB Cavitation activity and temperature rise have been investigated in a tissue-mimicking material and excised bovine liver treated with ethanol and insonated with a 0.825 MHz focused acoustic transducer. The acoustic power was varied from 1.3 to 26.8 W to find the threshold leading to the onset of inertial cavitation. Cavitation events were quantified by three independent techniques: B-mode ultrasound imaging, needle hydrophone measurements and passive cavitation detection. Temperature in or near the focal zone was measured by thermocouples embedded in the samples. The results of this study indicate that the treatment of tissue phantoms and bovine liver samples with ethanol reduces their threshold power for inertial cavitation. This in turn leads to a sudden rise in temperature in ethanol-treated samples at a lower acoustic power than that in untreated ones. The analysis of passive cavitation detection data shows that once the threshold acoustic power is reached, inertial cavitation becomes a major contributor to acoustic scattering in ethanol-treated phantoms and bovine liver samples as compared to control. This study opens up the possibility of improved tumor ablation therapy via a combination of percutaneous ethanol injection and high-intensity focused ultrasound. C1 [Chen, C.; Khismatullin, D.] Tulane Univ, Dept Biomed Engn, New Orleans, LA 70118 USA. [Liu, Y.; Maruvada, S.; Myers, M.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Khismatullin, D (reprint author), Tulane Univ, Dept Biomed Engn, New Orleans, LA 70118 USA. EM damir@tulane.edu RI Khismatullin, Damir/A-2104-2012 FU ORISE; Louisiana Board of Regents [(2007-12)-ENH-PKSFI-PRS-01] FX The authors gratefully acknowledge the financial support via the ORISE Fellowship to CC. The work of DK was supported in part by Louisiana Board of Regents grant LEQSF (2007-12)-ENH-PKSFI-PRS-01. The authors thank Ronald Roy for helpful discussions and Joshua Soneson for providing HIFU simulator v1.2 for the calculation of the pressure and temperature fields. NR 49 TC 8 Z9 9 U1 0 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD FEB 21 PY 2012 VL 57 IS 4 BP 937 EP 961 DI 10.1088/0031-9155/57/4/937 PG 25 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 895IV UT WOS:000300490700008 PM 22290554 ER PT J AU Arinaminpathy, N Ratmann, O Koelle, K Epstein, SL Price, GE Viboud, C Miller, MA Grenfell, BT AF Arinaminpathy, Nimalan Ratmann, Oliver Koelle, Katia Epstein, Suzanne L. Price, Graeme E. Viboud, Cecile Miller, Mark A. Grenfell, Bryan T. TI Impact of cross-protective vaccines on epidemiological and evolutionary dynamics of influenza SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PANDEMIC INFLUENZA; HERD-IMMUNITY; A H3N2; VACCINATION; VIRUSES; TRANSMISSIBILITY; SCHOOLCHILDREN; CHALLENGE; CONTACTS; CHILDREN AB Large-scale immunization has profoundly impacted control of many infectious diseases such as measles and smallpox because of the ability of vaccination campaigns to maintain long-term herd immunity and, hence, indirect protection of the unvaccinated. In the case of human influenza, such potential benefits of mass vaccination have so far proved elusive. The central difficulty is a considerable viral capacity for immune escape; new pandemic variants, as well as viral escape mutants in seasonal influenza, compromise the buildup of herd immunity from natural infection or deployment of current vaccines. Consequently, most current influenza vaccination programs focus mainly on protection of specific risk groups, rather than mass prophylactic protection. Here, we use epidemiological models to show that emerging vaccine technologies, aimed at broad-spectrum protection, could qualitatively alter this picture. We demonstrate that sustained immunization with such vaccines could-through potentially lowering transmission rates and improving herd immunity-significantly moderate both influenza pandemic and seasonal epidemics. More subtly, phylodynamic models indicate that widespread cross-protective immunization could slow the antigenic evolution of seasonal influenza; these effects have profound implications for a transition to mass vaccination strategies against human influenza, and for the management of antigenically variable viruses in general. C1 [Arinaminpathy, Nimalan; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Ratmann, Oliver; Koelle, Katia] Duke Univ, Dept Biol, Durham, NC 27708 USA. [Ratmann, Oliver] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, London W2 1NY, England. [Koelle, Katia; Viboud, Cecile; Miller, Mark A.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Epstein, Suzanne L.; Price, Graeme E.] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Arinaminpathy, N (reprint author), Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. EM nimpathy@princeton.edu OI Ratmann, Oliver/0000-0001-8667-4118 FU National Institutes of Health [R01 GM083983-01]; Bill and Melinda Gates Foundation; National Science Foundation [EF-0742373, EF-08-27416]; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; James S. McDonnell Foundation; Sir Henry Wellcome Fellowship [WT092311MF]; Center for Biologics Evaluation and Research, Food and Drug Administration FX We thank Prof. Adrian Hill and Dr. Julia Gog for helpful discussion. This research was supported by National Institutes of Health Grant R01 GM083983-01. B. T. G. was also supported by the Bill and Melinda Gates Foundation; National Science Foundation Grant EF-0742373; the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security; and the Fogarty International Center, National Institutes of Health. K. K. and O.R. were supported by National Science Foundation Grant EF-08-27416; K. K. was further supported by the James S. McDonnell Foundation and the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security; and O.R. was further supported by Sir Henry Wellcome Fellowship Grant WT092311MF. S. L. E. and G. E. P. were supported by funds from the Center for Biologics Evaluation and Research, Food and Drug Administration. NR 36 TC 22 Z9 23 U1 0 U2 19 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 21 PY 2012 VL 109 IS 8 BP 3173 EP 3177 DI 10.1073/pnas.1113342109 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KM UT WOS:000300495100096 PM 22323589 ER PT J AU McDaniel, LP Ding, W Dobrovolsky, VN Shaddock, JG Mittelstaedt, RA Doerge, DR Heflich, RH AF McDaniel, L. Patrice Ding, Wei Dobrovolsky, Vasily N. Shaddock, Joseph G., Jr. Mittelstaedt, Roberta A. Doerge, Daniel R. Heflich, Robert H. TI Genotoxicity of furan in Big Blue rats SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Pig-a mutation; Hprt mutation; Comet assay; Micronucleus assay; Cancer mode of action ID ETHYL-N-NITROSOUREA; RED-BLOOD-CELLS; IN-VIVO GENOTOXICITY; REACTIVE METABOLITE; RISK-ASSESSMENT; BONE-MARROW; MOUSE-LIVER; DNA-DAMAGE; MICE; ASSAY AB Furan is a multispecies liver carcinogen whose cancer mode of action (MOA) is unclear. A major metabolite of furan is a direct acting mutagen; however, it is not known if genotoxicity is a key step in the tumors that result from exposure to furan. In order to address this question, transgenic Big Blue rats were treated by gavage five times a week for 8 weeks with two concentrations of furan used in cancer bioassays (2 and 8 mg/kg), and with two higher concentrations (16 and 30 mg/kg). Peripheral blood samples taken 24 h after the 5th dose (1 week of dosing) were used to assay for micronucleus (MN) frequency in normochromatic erythrocytes (NCEs) and reticulocytes (RETs), and Pig-a gene mutation in total red blood cells (RBCs). 2411 after the last dose of the 8-week treatment schedule, the rats were euthanized, and their tissues were used to perform NCE and RET MN assays, the Pig-a RBC assay, Pig-a and Hprt lymphocyte gene mutation assays, the liver cll transgene mutation assay, and the liver Comet assay. The responses in the MN assays conducted at both sampling times, and all the gene mutation assays, were uniformly negative; however, the Comet assay was positive for the induction of liver DNA damage. As the positive responses in the Comet assay were seen only with doses in excess of the cancer bioassay doses, and at least one of these closes (30 mg/kg) produced toxicity in the liver, the overall findings from the study are consistent with furan having a predominantly nongenotoxic MOA for cancer. Published by Elsevier B.V. C1 [McDaniel, L. Patrice; Ding, Wei; Dobrovolsky, Vasily N.; Shaddock, Joseph G., Jr.; Mittelstaedt, Roberta A.; Heflich, Robert H.] US FDA, Div Genet & Mol Toxicol, NCTR, Jefferson, AR 72079 USA. [Doerge, Daniel R.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Heflich, RH (reprint author), US FDA, Div Genet & Mol Toxicol, NCTR, HFT 120,3900 NCTR Rd, Jefferson, AR 72079 USA. EM robert.heflich@FDA.hhs.gov RI Ding, Wei/L-1503-2014 FU National Institute for Environmental Health Sciences; U.S. Food and Drug Administration/National Center for Toxicological Research; Oak Ridge Institute for Science and Education FX This study was supported by Interagency Agreements 224-07-007 and Y1ES1027 between the National Institute for Environmental Health Sciences/National Toxicology Program and the U.S. Food and Drug Administration/National Center for Toxicological Research. WD was supported by a postdoctoral appointment from the Oak Ridge Institute for Science and Education. The authors are grateful for the help provided by Michelle Bishop, Lascelles Lyn-Cook, Mason Pearce, Lynda McGarrity, and Drs. Ben Aidoo and Manju Manjanatha. The views presented in this communication are not necessarily those of the U.S. Food and Drug Administration. NR 53 TC 22 Z9 22 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD FEB 18 PY 2012 VL 742 IS 1-2 BP 72 EP 78 DI 10.1016/j.mrgentox.2011.12.011 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 900AB UT WOS:000300857900012 PM 22200623 ER PT J AU Gatti, JC AF Gatti, Jasmine C. TI The Importance of Physicians Identifying and Reporting Adverse Drug Events SO AMERICAN FAMILY PHYSICIAN LA English DT Editorial Material C1 US FDA, Silver Spring, MD USA. RP Gatti, JC (reprint author), US FDA, Silver Spring, MD USA. EM Jasmine.Gatti@fda.hhs.gov NR 4 TC 0 Z9 1 U1 0 U2 0 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD FEB 15 PY 2012 VL 85 IS 4 BP 318 EP 318 PG 1 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 980AZ UT WOS:000306867300006 PM 22335311 ER PT J AU Neil, KP Biggerstaff, G MacDonald, JK Trees, E Medus, C Musser, KA Stroika, SG Zink, D Sotir, MJ AF Neil, Karen P. Biggerstaff, Gwen MacDonald, J. Kathryn Trees, Eija Medus, Carlota Musser, Kimberlee A. Stroika, Steven G. Zink, Don Sotir, Mark J. TI A Novel Vehicle for Transmission of Escherichia coli O157:H7 to Humans: Multistate Outbreak of E. coli O157:H7 Infections Associated With Consumption of Ready-to-Bake Commercial Prepackaged Cookie Dough-United States, 2009 SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HEMOLYTIC-UREMIC-SYNDROME; O157-H7 INFECTIONS; CONTAMINATED CHOCOLATE; SALMONELLA-TYPHIMURIUM; SHIGELLA; EXPOSURE; DIARRHEA; SPINACH; LETTUCE; BARS AB Background. Escherichia coli O157:H7 is a Shiga toxin-producing E. coli (STEC) associated with numerous foodborne outbreaks in the United States and is an important cause of bacterial gastrointestinal illness. In May 2009, we investigated a multistate outbreak of E. coli O157: H7 infections. Methods. Outbreak-associated cases were identified using serotyping and molecular subtyping procedures. Traceback investigation and product testing were performed. A matched case-control study was conducted to identify exposures associated with illness using age-, sex-, and state-matched controls. Results. Seventy-seven patients with illnesses during the period 16 March-8 July 2009 were identified from 30 states; 35 were hospitalized, 10 developed hemolytic-uremic syndrome, and none died. Sixty-six percent of patients were <19 years; 71% were female. In the case-control study, 33 of 35 case patients (94%) consumed ready-to-bake commercial prepackaged cookie dough, compared with 4 of 36 controls (11%) (matched odds ratio = 41.3; P<.001); no other reported exposures were significantly associated with illness. Among case patients consuming cookie dough, 94% reported brand A. Three nonoutbreak STEC strains were isolated from brand A cookie dough. The investigation led to a recall of 3.6 million packages of brand A cookie dough and a product reformulation. Conclusions. This is the first reported STEC outbreak associated with consuming ready-to-bake commercial prepackaged cookie dough. Despite instructions to bake brand A cookie dough before eating, case patients consumed the product uncooked. Manufacturers should consider formulating ready-to-bake commercial prepackaged cookie dough to be as safe as a ready-to-eat product. More effective consumer education about the risks of eating unbaked cookie dough is needed. C1 [Neil, Karen P.; Biggerstaff, Gwen; Trees, Eija; Stroika, Steven G.; Sotir, Mark J.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Neil, Karen P.] Ctr Dis Control & Prevent, Epidem Intelligence Serv, Off Workforce & Career Dev, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [MacDonald, J. Kathryn] Washington State Dept Hlth, Shoreline, WA USA. [Medus, Carlota] Minnesota Dept Hlth, St Paul, MN USA. [Musser, Kimberlee A.] New York State Dept Hlth, Bacteriol Lab, Wadsworth Ctr, Albany, NY 12237 USA. [Zink, Don] US FDA, Off Ctr Director, Ctr Food Safety & Appl Nutr, Silver Spring, MD USA. RP Neil, KP (reprint author), Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, 1600 Clifton Rd NE,MS-A38, Atlanta, GA 30333 USA. EM kneil@cdc.gov NR 40 TC 31 Z9 33 U1 3 U2 23 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 15 PY 2012 VL 54 IS 4 BP 511 EP 518 DI 10.1093/cid/cir831 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 888YM UT WOS:000300040600010 PM 22157169 ER PT J AU Lacana, E Yao, LP Pariser, AR Rosenberg, AS AF Lacana, Emanuela Yao, Lynne P. Pariser, Anne R. Rosenberg, Amy S. TI The role of immune tolerance induction in restoration of the efficacy of ERT in Pompe disease SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE Pompe disease; glycogen storage disease type II; lysosomal storage diseases; enzyme replacement therapy; cross-reactive immunologic material; antibody ID ACID ALPHA-GLUCOSIDASE; ENZYME REPLACEMENT THERAPY; ALGLUCOSIDASE ALPHA; MALTASE DEFICIENCY; NEPHROTIC SYNDROME; CLINICAL-OUTCOMES; NATURAL COURSE; HEMOPHILIA-B; GENE-THERAPY; RECEPTORS AB Pompe disease is a lysosomal storage disorder caused by deficiency in the enzyme acid alpha-glucosidase (GAA). Pompe disease is characterized by the accumulation of glycogen, predominantly in muscle tissue, leading to progressive muscle weakness, loss of motor, respiratory, and, in the infantile-onset form, cardiac function. Disease progression is highly variable depending on phenotype, but premature death due to respiratory complications occurs in most patients. Beginning in 2006, approved alglucosidase alfa enzyme replacement therapies [recombinant human (rh) GAA] have been available to treat Pompe patients. Treatment of classic infantile-onset patients, who manifest the severest form of the disease, with alglucosidase alfa (Myozyme (R)) has led to extended survival and an evolving understanding of the pathophysiology and course of the disease. Moreover, such treatment has brought to light the role of the immune response in abrogating the efficacy of rhGAA in classic infantile-onset patients with severe genetic mutations. Thus, optimization of treatment for such patients includes development and utilization of strategies to prevent or eliminate immune responses, including modulating the immune system (prophylactic and therapeutic immune tolerance induction regimens) and engineering the enzyme to be less immunogenic and more effective. Future research is also critical for evaluating and mitigating novel disease-associated pathologies uncovered by prolonged survival of infantile-onset patients including development of novel therapeutics, and for protein design strategies to increase delivery of enzyme replacement therapy to critical target tissues. Such efforts would be greatly bolstered by further development of predictive animal models and biomarkers to facilitate clinical trials and patient management. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. C1 [Rosenberg, Amy S.] US FDA, Off Pharmaceut Sci, Off Biotechnol Prod, Div Therapeut Prot,Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Pariser, Anne R.] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Rosenberg, AS (reprint author), US FDA, Off Pharmaceut Sci, Off Biotechnol Prod, Div Therapeut Prot,Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. EM amy.rosenberg@fda.hhs.gov RI 李, 涵/B-4995-2012 NR 59 TC 16 Z9 16 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4868 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD FEB 15 PY 2012 VL 160C IS 1 SI SI BP 30 EP 39 DI 10.1002/ajmc.31316 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 879ZG UT WOS:000299372700005 PM 22253234 ER PT J AU Khurana, S Verma, N Talaat, KR Karron, RA Golding, H AF Khurana, Surender Verma, Nitin Talaat, Kawsar R. Karron, Ruth A. Golding, Hana TI Immune Response Following H1N1pdm09 Vaccination: Differences in Antibody Repertoire and Avidity in Young Adults and Elderly Populations Stratified by Age and Gender SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID INACTIVATED INFLUENZA VACCINE; A H1N1 VIRUS; CELL RESPONSES; NEUTRALIZING ANTIBODIES; B-CELLS; INFECTION; DYNAMICS; CHILDREN; DISEASE; HUMANS AB Background. The H1N1 2009 influenza (H1N1pdm09) pandemic had unexpected features, including lower morbidity and mortality in elderly populations. Methods. We performed in-depth elucidation of antibody responses generated post-H1N1pdm09 vaccination in elderly (aged 66-83 years) and younger (aged 18-45 or 46-65 years) adults using H1N1pdm09 whole-genome-fragment phage display library and measured antibody isotype and affinity to antigenic domains within hemagglutinin (HA). Results. H1N1pdm09 vaccination induced 10-fold higher antibody levels in elderly compared with younger adults. These antibodies primarily targeted the HA1 globular domain, including neutralizing epitopes in the receptor-binding domain. Antibody epitope repertoire, isotype, and affinity maturation after H1N1pdm09 vaccination evolved independently for HA2, HA1, and HA1 N-terminus antigenic regions. Postvaccination serum samples from elderly subjects demonstrated substantially higher avidity than from younger subjects (> 60% vs < 30% resistance to 7 mol/L urea) and slower antibody dissociation rates using surface plasmon resonance. We also identified a gender difference in postvaccination antibody avidity (female < male subjects) in adults < 65 years old. Conclusions. This is the first study in humans that provides evidence for a qualitatively superior antibody response in elderly adults after H1N1pdm09 vaccination. These findings may help explain the age-related mortality observed during the H1N1pdm09 pandemic. The difference in gender specific avidity merits further exploration. C1 [Khurana, Surender; Verma, Nitin; Golding, Hana] US FDA, Div Viral Prod, CBER, Bethesda, MD 20892 USA. [Talaat, Kawsar R.; Karron, Ruth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. RP Golding, H (reprint author), US FDA, Div Viral Prod, CBER, Bethesda, MD 20892 USA. EM hana.golding@fda.hhs.gov FU Food and Drug Administration; CSL Limited; National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX Financial support. This work was supported by Food and Drug Administration Pandemic Flu Preparedness funds (H. G).; Potential conflicts of interest. The original clinical trial from which serum specimens were obtained was sponsored by CSL Limited. R. A. K. has received research support from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); has served as a consultant to or member of a scientific advisory board for Novartis, Novavax, and GlaxoSmithKline; and has served as a member of a data and safety monitoring board for GlaxoSmithKline. K. R. T. has received research support from NIAID, NIH. All other authors report no potential conflicts. NR 37 TC 33 Z9 34 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2012 VL 205 IS 4 BP 610 EP 620 DI 10.1093/infdis/jir791 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 885QU UT WOS:000299795000013 PM 22207649 ER PT J AU Adesunloye, B Huang, X Ning, YMM Madan, RA Gulley, JL Beatson, M Kluetz, PG Adelberg, D Arlen, PM Parnes, HL Mulquin, M Steinberg, SM Wright, JJ Trepel, JB Dawson, NA Chen, C Apolo, AB Figg, WD Dahut, WL AF Adesunloye, Bamidele Huang, Xuan Ning, Yangmin M. Madan, Ravi A. Gulley, James L. Beatson, Melony Kluetz, Paul Gustav Adelberg, David Arlen, Philip M. Parnes, Howard L. Mulquin, Marcia Steinberg, Seth M. Wright, John Joseph Trepel, Jane B. Dawson, Nancy Ann Chen, Clara Apolo, Andrea Borghese Figg, William Douglas Dahut, William L. TI Phase II trial of bevacizumab and lenalidomide with docetaxel and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, US FDA, Silver Spring, MD USA. NCI, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 207 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400208 PM 28143000 ER PT J AU Tran, DT Banerjee, S Alayash, AI Crumbliss, AL Fitzgerald, MC AF Tran, Duc T. Banerjee, Sambuddha Alayash, Abdu I. Crumbliss, Alvin L. Fitzgerald, Michael C. TI Slow Histidine H/D Exchange Protocol for Thermodynamic Analysis of Protein Folding and Stability Using Mass Spectrometry SO ANALYTICAL CHEMISTRY LA English DT Article ID LIGAND-BINDING INTERACTIONS; GUANIDINE-HYDROCHLORIDE; ASSOCIATION CONSTANTS; CARBONIC-ANHYDRASE; HEMOGLOBIN; DENATURATION; DISSOCIATION; COMPLEXES; FLUORESCENCE; HAPTOGLOBIN AB Described here is a mass spectrometry-based protocol to study the thermodynamic stability of proteins and protein ligand complexes using the chemical denaturant dependence of the slow HID exchange reaction of the imidazole C-2 proton in histidine side chains. The protocol is developed using several model protein systems including: ribonuclease (Rnase) A, myoglobin, bovine carbonic anhydrase (BCA) H, hemoglobin (Hb), and the hemoglobin haptoglobin (Hb Hp) protein complex. Folding free energies consistent with those previously determined by other more conventional techniques were obtained for the two-state folding proteins, Rnase A and myoglobin. The protocol successfully detected a previously observed partially unfolded intermediate stabilized in the BCA II folding/unfolding reaction, and it could be used to generate a K-d value of 0.24 nM for the Hb Hp complex. The compatibility of the protocol with conventional mass spectrometry-based proteomic sample preparation and analysis methods was also demonstrated in an experiment in which the protocol was used to detect the binding of zinc to superoxide dismutase in the yeast cell lysate sample. The yeast cell sample analyses also helped define the scope of the technique, which requires the presence of globally protected histidine residues in a protein's three-dimensional structure for successful application. C1 [Banerjee, Sambuddha; Crumbliss, Alvin L.; Fitzgerald, Michael C.] Duke Univ, Dept Chem, Durham, NC 27708 USA. [Tran, Duc T.; Fitzgerald, Michael C.] Duke Univ, Dept Biochem, Durham, NC 27708 USA. [Alayash, Abdu I.] US FDA, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, Bethesda, MD 20892 USA. RP Fitzgerald, MC (reprint author), Duke Univ, Dept Chem, Box 90346, Durham, NC 27708 USA. EM michael.c.fitzgerald@duke.edu FU National Institutes of Health [GM084174, S10RR027746]; National Science Foundation [CHE 0809466] FX This work was supported in part by National Institutes of Health Grants GM084174 and S10RR027746 (to M.C.F.) and in part by a National Science Foundation Grant CHE 0809466 (to A.L.C.). NR 31 TC 15 Z9 15 U1 0 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD FEB 7 PY 2012 VL 84 IS 3 BP 1653 EP 1660 DI 10.1021/ac202927p PG 8 WC Chemistry, Analytical SC Chemistry GA 886OH UT WOS:000299863200066 PM 22185579 ER PT J AU Toomey, VM Litzau, JJ Flurer, CL AF Toomey, Valerie M. Litzau, Jonathan J. Flurer, Cheryl L. TI Isolation and structural characterization of two tadalafil analogs found in dietary supplements SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Tadalafil analog; PDE-5 inhibitors; Dietary supplement; LC-MS; NMR ID SYNTHETIC PHOSPHODIESTERASE-5 INHIBITORS; PERFORMANCE LIQUID-CHROMATOGRAPHY; MASS-SPECTROMETRY; STRUCTURE ELUCIDATION; SILDENAFIL; VARDENAFIL; MATRICES; PRODUCT AB During routine screenings of two "libido enhancer" dietary supplements using LC-MS(n), two compounds were detected that displayed structural similarities to tadalafil. These compounds were isolated from the supplements using high-performance liquid chromatography with fraction collection, and were characterized further using accurate mass determination and NMR. "Compound 1" had an m/z of 434 for the [M+H](+) ion, with a corresponding chemical formula of C(24)H(24)N(3)O(5). "Compound 2" had an m/z of 432 for the [M+H](+) ion, with a corresponding chemical formula of C(25)H(26)N(3)O(4). Although mass spectrometry indicated that these modifications occurred in place of the -CH(3) found on the pyrazinopyridoindole-1,4-dione of tadalafil, NMR was required to elucidate the correct configurations of these substitutions. The data obtained using NMR indicated that the structure of the -C(3)H(7)O moiety found in Compound 1 was 2-hydroxypropyl, and the -C(4)H(9) in Compound 2 was n-butyl. These new analogs were given the names 2-hydroxypropylnortadalafil and n-butylnortadalafil, respectively. Published by Elsevier B.V. C1 [Toomey, Valerie M.; Litzau, Jonathan J.; Flurer, Cheryl L.] US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. RP Flurer, CL (reprint author), US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA. EM cheryl.flurer@fda.hhs.gov NR 14 TC 23 Z9 23 U1 0 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD FEB 5 PY 2012 VL 59 BP 50 EP 57 DI 10.1016/j.jpba.2011.09.038 PG 8 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 857KD UT WOS:000297716500007 PM 22055930 ER PT J AU Burckart, GJ AF Burckart, Gilbert J. TI Clinical pharmacology and clinical pharmacy: a marriage of necessity SO EUROPEAN JOURNAL OF HOSPITAL PHARMACY-SCIENCE AND PRACTICE LA English DT Editorial Material ID FUTURE RP Burckart, GJ (reprint author), US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3184, Silver Spring, MD 20993 USA. EM gilbert.burckart@fda.hhs.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2047-9956 J9 EUR J HOSP PHARM-S P JI Eur. J. Hosp. Pharm.-Sci. Pract. PD FEB PY 2012 VL 19 IS 1 BP 19 EP U41 DI 10.1136/ejhpharm-2011-000002 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 017HB UT WOS:000309579700007 ER PT J AU Weaver, JL AF Weaver, James L. TI Establishing the Carcinogenic Risk of Immunomodulatory Drugs SO TOXICOLOGIC PATHOLOGY LA English DT Article DE carcinogenicity; immunomodulatory; drugs ID EPSTEIN-BARR-VIRUS; TRANSPLANT RECIPIENTS; CYNOMOLGUS MONKEYS; LYMPHOPROLIFERATIVE DISORDER; RENAL-TRANSPLANTATION; RHEUMATOID-ARTHRITIS; MACACA-FASCICULARIS; IMMUNE-RESPONSES; KAPOSIS-SARCOMA; MALIGNANCY AB The first effective immunosuppressive drug (ISD) was azathioprine, approved in 1968. Early experience with this drug suggested that patients might have an excess risk of tumors including lymphoma and skin tumors. Comparison among various registries has shown that the cumulative risk of tumors increases over time. The risk is additionally increased by the more intense immunosuppressive regimens needed for lung or heart-lung transplants. The link between immunosuppression and tumorigenesis was further reinforced by the high concordance of tumor types between transplant and HIV patients. The role of the immune system in tumor defense includes both direct tumor surveillance and immunity against oncogenic viruses. In transplant patients, at least two-thirds of the lymphomas are Epstein-Barr virus (EBV)-positive. Existing methods of testing for carcinogenicity are not considered adequate to identify the hazard of tumorigenesis due to these drugs. Research is ongoing in Food and Drug Administration laboratories and at collaborators' laboratories to evaluate experimental systems that may have the ability to adequately identify this class of hazard. Initial work is on various model systems similar to EBV. These include the MHV-68 mouse model, lymphocryptovirus (LCV-1) in the cynomolgus monkey, and preliminary work with mice with humanized immune systems using EBV directly. C1 FDA, Div Drug Safety Res, Off Testing & Res, CDER, Silver Spring, MD 20993 USA. RP Weaver, JL (reprint author), FDA, Div Drug Safety Res, Off Testing & Res, CDER, Life Sci Bldg 64,Room 2064,10903 New Hampshire Av, Silver Spring, MD 20993 USA. EM james.weaver@fda.hhs.gov NR 33 TC 5 Z9 5 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD FEB PY 2012 VL 40 IS 2 BP 267 EP 271 DI 10.1177/0192623311427711 PG 5 WC Pathology; Toxicology SC Pathology; Toxicology GA 961JL UT WOS:000305460600016 PM 22105649 ER PT J AU Badano, A AF Badano, Aldo TI PREDICTING PERCEIVED IMAGE QUALITY: A CRITIQUE OF LIN AND KUO (2011) SO PERCEPTUAL AND MOTOR SKILLS LA English DT Article ID MOBILE DISPLAY AB A recent study by Lin and Kuo reported on the image quality of a small mobile display under different ambient illumination levels. In this commentary, the present author discusses the limitations of their approach with respect to the rigorous quantification of image quality and the caveats associated with preference studies of new display technologies. Quantitatively predicting image quality using preference-based methods can be useful for initial decisions in early phases of product development, but provides limited value for the rigorous quantification of image quality of display devices. C1 US FDA, Ctr Devices & Radiol Hlth, Div Imaging & Appl Math, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. RP Badano, A (reprint author), US FDA, Ctr Devices & Radiol Hlth, Div Imaging & Appl Math, Off Sci & Engn Labs, 10993 New Hampshire Ave, Silver Spring, MD 20993 USA. EM aldo.badano@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 NR 4 TC 2 Z9 2 U1 0 U2 3 PU AMMONS SCIENTIFIC, LTD PI MISSOULA PA PO BOX 9229, MISSOULA, MT 59807-9229 USA SN 0031-5125 J9 PERCEPT MOTOR SKILL JI Percept. Mot. Skills PD FEB PY 2012 VL 114 IS 1 BP 236 EP 238 DI 10.2466/22.27.PMS.114.1.236-238 PG 3 WC Psychology, Experimental SC Psychology GA 919LV UT WOS:000302330100022 PM 22582691 ER PT J AU Liang, XY Pfeiffer, RM Wheeler, W Maeder, D Burdette, L Meredith, Y Chanock, S Margaret, TA Goldstein, AM Yang, XHR AF Liang, Xueying Pfeiffer, Ruth M. Wheeler, William Maeder, Dennis Burdette, Laurie Meredith, Yeager Chanock, Stephen Margaret, Tucker A. Goldstein, Alisa M. Yang, Xiaohong R. TI Association Of Genetic Variants With The Risk Of Dysplastic Nevi In Melanoma-Prone Families With And Without CDKN2A/CDK4 Mutations SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 20th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY SEP 18-20, 2011 CL Heidelberg, GERMANY SP Int Genet Epidemiol Soc (IGES) C1 [Liang, Xueying] US FDA, Div Epidemiol, CDRH, Rockville, MD 20857 USA. [Pfeiffer, Ruth M.; Margaret, Tucker A.; Goldstein, Alisa M.; Yang, Xiaohong R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wheeler, William] Informat Management Serv Inc, Washington, DC USA. [Maeder, Dennis; Burdette, Laurie; Meredith, Yeager; Chanock, Stephen] SAIC Frederick Inc, Core Genotyping Facil, Frederick, MD USA. RI Bianchi Scarra, Giovanna/G-8933-2014 OI Bianchi Scarra, Giovanna/0000-0002-6127-1192 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2012 VL 36 IS 2 MA 36 BP 128 EP 128 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 918JG UT WOS:000302244900041 ER PT J AU Stangl, D Inoue, LYT Irony, TZ AF Stangl, Dalene Inoue, Lurdes Y. T. Irony, Telba Z. TI Celebrating 70: An Interview with Don Berry SO STATISTICAL SCIENCE LA English DT Article DE Bayesian inference; adaptive design; clinical trials; mammography ID CANCER-SUSCEPTIBILITY GENES; BAYESIAN CLINICAL-TRIALS; BREAST-CANCER; MAMMOGRAPHY; PROBABILITY; BENEFITS; BRCA1 AB Donald (Don) Arthur Berry, born May 26, 1940 in Southbridge, Massachusetts, earned his A.B. degree in mathematics from Dartmouth College and his M.A. and Ph.D. in statistics from Yale University. He served first on the faculty at the University of Minnesota and subsequently held endowed chair positions at Duke University and The University of Texas M.D. Anderson Center. At the time of the interview he served as Head of the Division of Quantitative Sciences, and Chairman and Professor of the Department of Biostatistics at UT M.D. Anderson Center. Don's research deals with the theory and applications of statistics, especially Bayesian methods for sequential design of experiments. His work challenges the status quo, always striving to improve design and analysis of clinical trials, genetic modeling and the process of health-related decision making. His research impacts health research broadly, but has achieved the greatest influence in cancer research. As of 2010, he has published over 200 articles and 10 books and has mentored 24 Ph.D. and 16 M.S. students. Don's honors include fellowship election to the International Statistical Institute, the American Statistical Association and the Institute of Mathematical Statistics. He gave Presidential invited addresses to the Western North American Region of the International Biometric Society (New Mexico, 2004), the Canadian Statistical Society (Ottawa, 2006) and the Eastern North American Region of the International Biometric Society (Washington, 2008). Don married Donna Berry in 1960. Together they raised six children, Don, Mike, Tim, Scott, Jennifer and Erin. Celebrating Don's 70th birthday, the authors co-organized two invited sessions and a dinner reception at the ENAR 2010 in New Orleans. This interview occurred while his family, friends, colleagues and students gathered to celebrate his birthday and his contributions to statistics. C1 [Stangl, Dalene] Duke Univ, Durham, NC 27708 USA. [Inoue, Lurdes Y. T.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Irony, Telba Z.] US FDA, Gen & Surg Devices Branch, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Stangl, D (reprint author), Duke Univ, Durham, NC 27708 USA. EM dalene@stat.duke.edu; linoue@uw.edu; telba.irony@fda.hhs.gov NR 27 TC 2 Z9 2 U1 2 U2 2 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 0883-4237 J9 STAT SCI JI Stat. Sci. PD FEB PY 2012 VL 27 IS 1 BP 144 EP 159 DI 10.1214/11-STS366 PG 16 WC Statistics & Probability SC Mathematics GA 917SV UT WOS:000302199800012 ER PT J AU Uhlenhaut, C Cohen, JI Pavletic, S Illei, G Gea-Banacloche, JC Abu-Asab, M Krogmann, T Gubareva, L McClenahan, S Krause, PR AF Uhlenhaut, C. Cohen, J. I. Pavletic, S. Illei, G. Gea-Banacloche, J. C. Abu-Asab, M. Krogmann, T. Gubareva, L. McClenahan, S. Krause, P. R. TI Use of a novel virus detection assay to identify coronavirus HKU1 in the lungs of a hematopoietic stem cell transplant recipient with fatal pneumonia SO TRANSPLANT INFECTIOUS DISEASE LA English DT Article DE viral infections; generic virus detection; virus discovery; immunocompromised; coronavirus; HKU1 ID COMMUNITY-ACQUIRED PNEUMONIA; INFLUENZA-A VIRUS; INFECTION; CHILDREN; OLD AB A 38-year-old female patient with systemic lupus erythematosus presented with pulmonary infiltrates and hypoxemia for several months following immunodepleting autologous hematopoietic stem cell transplantation. She was treated for influenza, which was isolated repeatedly from oropharynx and bronchoalveolar lavage (BAL) fluids, and later empirically for lupus pneumonitis, but died 6 months after transplant. Autopsy findings failed to show influenza in the lungs or lupus pneumonitis. A novel generic polymerase chain reaction (PCR)-based assay using degenerate primers identified human coronavirus (CoV) HKU1 RNA in BAL fluid at autopsy. CoVwas confirmed by virus-specific PCRs of lung tissue at autopsy. Electron microscopy showed viral particles consistent with CoV HKU1 in lung tissue both at autopsy and from aprevious biopsy. Although human CoV HKU1 infection is not usually severe, in highly immunocompromised patients, it can be associated with fatal pneumonia. C1 [Uhlenhaut, C.; McClenahan, S.; Krause, P. R.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20892 USA. [Cohen, J. I.; Krogmann, T.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Pavletic, S.; Gea-Banacloche, J. C.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Illei, G.] NIAMSD, Mol Physiol & Therapeut Branch, Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. [Illei, G.] NIAMSD, Off Clin Director, Bethesda, MD 20892 USA. [Abu-Asab, M.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Gubareva, L.] Ctr Dis Control & Prevent, Virus Surveillance & Diag Branch, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. RP Krause, PR (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20892 USA. EM philip.krause@fda.hhs.gov OI Krause, Philip/0000-0002-1045-7536; Abu-Asab, Mones/0000-0002-4047-1232 FU Center for Biologics Evaluation and Research; National Institute of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Cancer Institute, and the Centers for Disease Control and Prevention FX This work was supported by the intramural research programs of the Center for Biologics Evaluation and Research, the National Institute of Allergy and Infectious Diseases, the National Institute of Dental and Craniofacial Research, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Cancer Institute, and the Centers for Disease Control and Prevention. NR 21 TC 5 Z9 6 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-2273 J9 TRANSPL INFECT DIS JI Transpl. Infect. Dis. PD FEB PY 2012 VL 14 IS 1 BP 79 EP 85 DI 10.1111/j.1399-3062.2011.00657.x PG 7 WC Immunology; Infectious Diseases; Transplantation SC Immunology; Infectious Diseases; Transplantation GA 895MW UT WOS:000300501300012 PM 21749586 ER PT J AU Lev, D Thorat, C Phillips, I Thomas, M Imoisili, MA AF Lev, Daniel Thorat, Chandana Phillips, Ian Thomas, Mathew Imoisili, Menfo A. TI The routes to orphan drug designation - our recent experience at the FDA SO DRUG DISCOVERY TODAY LA English DT Editorial Material C1 [Thomas, Mathew; Imoisili, Menfo A.] US FDA, Off Orphan Prod Dev, Silver Spring, MD USA. [Lev, Daniel; Thorat, Chandana; Phillips, Ian] Keck Grad Inst Appl Life Sci, Ctr Rare Dis Therapies, Claremont, CA USA. RP Imoisili, MA (reprint author), US FDA, Off Orphan Prod Dev, Silver Spring, MD USA. EM menfo.imoisili@fda.hhs.gov NR 3 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD FEB PY 2012 VL 17 IS 3-4 BP 97 EP 99 DI 10.1016/j.drudis.2011.12.014 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 905YT UT WOS:000301312800001 PM 22210120 ER PT J AU Place, AR Bowers, HA Bachvaroff, TR Adolf, JE Deeds, JR Sheng, J AF Place, Allen R. Bowers, Holly A. Bachvaroff, Tsetvan R. Adolf, Jason E. Deeds, Jonathan R. Sheng, Jian TI Karlodinium veneficum-The little dinoflagellate with a big bite SO HARMFUL ALGAE LA English DT Review DE Blooms; Fish gills; Karlotoxin; Mixotrophy; Parasitism ID MEMBRANE-PERMEABILIZING ACTIVITIES; GYRODINIUM-CORSICUM PAULMIER; MARINE DINOFLAGELLATE; CHESAPEAKE-BAY; GYMNODINIUM-GALATHEANUM; AMPHIDINIUM-KLEBSII; MICRUM DINOPHYCEAE; AMOEBOPHRYA SP; ABSOLUTE-CONFIGURATION; CRASSOSTREA-VIRGINICA AB For decades, high densities of the dinoflagellate Karlodinium veneficurn have been associated with aquatic faunal mortalities worldwide. This small (<8-12 mu m) athecate phytoplankton, common in coastal aquatic ecosystems, has a mixed nutritional mode, relying on both photosynthesis and phagotrophy for growth (mixotrophy). It is frequently present in relatively low cell abundance (10(2)-10(3) cells mL(-1)), but is capable of forming intense blooms of 10(4)-10(5) cells mL-1 that are often associated with fish kills. A suite of toxic compounds (karlotoxins) have been characterized, both in the laboratory and in the field, with hemolytic, ichthyotoxic, and cytotoxic properties. These toxins have been shown to generate pores in membranes with desmethyl sterols and increase the ionic permeability resulting in membrane depolarization, disruption of motor functions, osmotic cell swelling and lysis. The biological raison d'etre for karlotoxin production appears to be prey capture but grazing deterrence is an additional advantage. Strain variation in types of karlotoxins and toxin cell quotas is extensive. Since its initial description in 1956 by Dorothy Ballentine toxic and nontoxic strains are common. Despite numerous name changes it is now clearly recognized as a cosmopolitan species with extensive ecosystem impacts. (C) 2011 Elsevier B.V. All rights reserved. C1 [Place, Allen R.; Bowers, Holly A.; Bachvaroff, Tsetvan R.; Adolf, Jason E.] Univ Maryland, Environm Res Ctr, Inst Marine & Environm Technol, Baltimore, MD 21202 USA. [Deeds, Jonathan R.] US FDA, Washington Seafood Lab, Laurel, MD 20708 USA. [Sheng, Jian] Univ Minnesota, Minneapolis, MN 55455 USA. RP Place, AR (reprint author), Univ Maryland, Environm Res Ctr, Inst Marine & Environm Technol, 701 E Pratt St, Baltimore, MD 21202 USA. EM place@umces.edu RI Place, Allen/F-9267-2013 FU National Oceanic and Atmospheric Administration [NA04NOS4780276, U50/CCU 323376]; Centers for Disease Control and Prevention; Maryland Department of Health and Mental Hygiene; University of Maryland Center for Environmental Sciences [4580]; Institute of Marine and Environmental Technology [11-227]; ECOHAB [ECO672] FX This paper is partially a result of research funded by the National Oceanic and Atmospheric Administration Coastal Ocean Program under award #NA04NOS4780276 to University of Maryland Biotechnology Institute and Grant #U50/CCU 323376, Centers for Disease Control and Prevention and the Maryland Department of Health and Mental Hygiene. This is contribution #4580 from the University of Maryland Center for Environmental Sciences, contribution#11-227 from the Institute of Marine and Environmental Technology and contribution #ECO672 from the ECOHAB program.[SS] NR 119 TC 33 Z9 37 U1 8 U2 71 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9883 J9 HARMFUL ALGAE JI Harmful Algae PD FEB PY 2012 VL 14 SI SI BP 179 EP 195 DI 10.1016/j.hal.2011.10.021 PG 17 WC Marine & Freshwater Biology SC Marine & Freshwater Biology GA 899LS UT WOS:000300818000012 ER PT J AU Farb, A Zuckerman, B AF Farb, Andrew Zuckerman, Bram TI Live Case Demonstration of Interventional Cardiology Procedures A Regulatory Perspective SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material DE complications; interventional cardiology procedures; live case demonstrations C1 [Farb, Andrew; Zuckerman, Bram] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Farb, A (reprint author), US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,WO66-1116, Silver Spring, MD 20993 USA. EM andrew.farb@fda.hhs.gov NR 5 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD FEB PY 2012 VL 5 IS 2 BP 225 EP 227 DI 10.1016/j.jcin.2011.11.006 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 904XO UT WOS:000301232400015 PM 22361608 ER PT J AU El Fiky, A Perreault, R Rabin, RL AF El Fiky, A. Perreault, R. Rabin, R. L. TI Type I And III IFN Expression Attenuated In Human Alternatively Activated Macrophages SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [El Fiky, A.; Perreault, R.; Rabin, R. L.] FDA CBER, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB163 EP AB163 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400616 ER PT J AU Huynh, S Menzies, S Khurana, T Lin, T Yan, L deVore, N Slater, JE Rabin, RL AF Huynh, S. Menzies, S. Khurana, T. Lin, T. Yan, L. deVore, N. Slater, J. E. Rabin, R. L. TI Radial Immunodiffusion (RID) to Sandwich ELISA for the Quantitation of Fel d 1 and Amb a 1 in Cat and Short Ragweed Pollen Allergenic Extracts SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Huynh, S.; Menzies, S.; Khurana, T.; Lin, T.; Yan, L.; deVore, N.; Slater, J. E.; Rabin, R. L.] US FDA, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB88 EP AB88 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400333 ER PT J AU Khurana, T Collison, M Chew, F Jeong, K Slater, J AF Khurana, T. Collison, M. Chew, F. Jeong, K. Slater, J. TI Allergen Specificity Of 3 Scfv Antibodies Developed For A Multiplex Assay Of Blattella Germanica Extract Potency SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Khurana, T.; Collison, M.; Slater, J.] US FDA, Bethesda, MD 20014 USA. [Chew, F.] Natl Univ Singapore, Singapore 117548, Singapore. [Jeong, K.] Inst Trop Med, Seoul, South Korea. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB89 EP AB89 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400336 ER PT J AU Kwegyir-Afful, EK Foye, OT Williams, K Luccioli, S AF Kwegyir-Afful, E. K. Foye, O. T. Williams, K. Luccioli, S. TI A Bioassay For Assessing Dose-Response Relationships In A Food Allergic Mouse Model SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Kwegyir-Afful, E. K.; Luccioli, S.] FDA, Off Food Addit Safety, CFSAN, College Pk, MD USA. [Kwegyir-Afful, E. K.] Off Sci & Innovat, Off Commissioner, Silver Spring, MD USA. [Foye, O. T.; Williams, K.] FDA, Off Appl Res & Safety Assessment, CFSAN, Beltsville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB175 EP AB175 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400662 ER PT J AU Malyukova, I Gendel, SM Luccioli, S AF Malyukova, I. Gendel, S. M. Luccioli, S. TI Milk Is The Predominant Undeclared Allergen In Us Food Product Recalls SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Malyukova, I.; Gendel, S. M.; Luccioli, S.] US FDA, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, College Pk, MD USA. NR 0 TC 6 Z9 6 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB234 EP AB234 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133401050 ER PT J AU Slater, JE Khurana, T Collison, M Haynes, B Cambareri, E AF Slater, J. E. Khurana, T. Collison, M. Haynes, B. Cambareri, E. TI Using Human Single Chain Variable Fragment (scFv) Antibodies for Identification of Potential Allergens of Neurospora crassa SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 02-06, 2012 CL Orlando, FL SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Slater, J. E.; Khurana, T.; Collison, M.] FDA CBER OVRR DBPAP, Rockville, MD USA. [Haynes, B.; Cambareri, E.] Neugenesis Corp, Burlingame, CA USA. NR 0 TC 0 Z9 0 U1 3 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2012 VL 129 IS 2 SU S BP AB106 EP AB106 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 903QL UT WOS:000301133400402 ER PT J AU Yu, BW van Ingen, H Vivekanandan, S Rademacher, C Norris, SE Freedberg, DI AF Yu, Bingwu van Ingen, Hugo Vivekanandan, Subramanian Rademacher, Christoph Norris, Scott E. Freedberg, Daron I. TI More accurate (1)J(CH) coupling measurement in the presence of (3)J(HH) strong coupling in natural abundance SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Heteronuclear coupling; Strong coupling; One-bond CH coupling; HSQC ID RESIDUAL DIPOLAR COUPLINGS; 2-DIMENSIONAL NMR-SPECTRA; BOND VECTOR ORIENTATIONS; TWO-DIMENSIONAL NMR; SHIFT CORRELATION; QUANTITATIVE-J; SPIN SYSTEMS; CONSTANTS; RELAXATION; PROTEINS AB J couplings are essential for measuring RDCs (residual dipolar couplings), now routinely used to deduce molecular structure and dynamics of glycans and proteins. Accurate measurement of (1)J(CH) is critical for RDCs to reflect the true structure and dynamics in the molecule of interest. We report noticeable discrepancies between (1)J(CH) values measured with HSQC type pulse sequences in the H-1 dimension from those measured in the C-13 dimension for 17 sugars and show that these discrepancies arise from strong scalar coupling. In order to determine how to minimize errors in measuring (1)J(CH), we analyze the strong coupling effects in detail using the product operator-formalism and spectral simulations based on the solution of the Liouville equation (not considering relaxation effects) in the presence of strong coupling. We report that the apparent (1)J(CH) measured with 2D HSQC-based sequences in either dimension can be in error by up to 4 Hz and that the values measured in the H-1 dimension can disagree with those in the C-13 dimension by up to 7 Hz. We demonstrate that spectral simulations can reproduce the errors induced by strong coupling and that these can be used to extract true (1)J(CH) values. We find that the (1)J(CH) values measured using a modified Z-filtered coupled HSQC are still affected by strong coupling. We conclude that spectral simulation yields accurate (1)J(CH) with errors as low as 1% in the presence of strong coupling. Published by Elsevier Inc. C1 [Yu, Bingwu; Vivekanandan, Subramanian; Norris, Scott E.; Freedberg, Daron I.] US FDA, Lab Bacterial Polysaccharides, CBER, Bethesda, MD 20892 USA. [van Ingen, Hugo] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [van Ingen, Hugo] Univ Toronto, Dept Biochem & Chem, Toronto, ON M5S 1A8, Canada. [Rademacher, Christoph] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. [Rademacher, Christoph] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. RP Freedberg, DI (reprint author), US FDA, Lab Bacterial Polysaccharides, CBER, Bethesda, MD 20892 USA. EM daron_freedberg@nih.gov RI Subramanian, Vivekanandan/F-5865-2012; S, Vivekanandan/E-5197-2011; Rademacher, Christoph/H-3101-2012; van Ingen, Hugo/Q-2883-2016 OI Rademacher, Christoph/0000-0001-7082-7239; van Ingen, Hugo/0000-0002-0808-3811 FU Niels Stensen Foundation; Dutch Science Foundation; EMBO FX We gratefully acknowledge helpful discussions with Dr. Dennis Torchia (NIDCR/NIH), Prof. A.J. Shaka (UC Irvine) and Drs. Clemens Anklin, Pavel Kessler and Amy Freund (Bruker Biospin). HvI acknowledges financial support from the Niels Stensen Foundation and a Veni fellowship from the Dutch Science Foundation. CR gratefully acknowledges EMBO for a long-term fellowship. NR 36 TC 18 Z9 18 U1 0 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD FEB PY 2012 VL 215 BP 10 EP 22 DI 10.1016/j.jmr.2011.09.037 PG 13 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 903CC UT WOS:000301092500002 PM 22227287 ER PT J AU Wear, KA Nagaraja, S Dreher, ML Gibson, SL AF Wear, Keith A. Nagaraja, Srinidhi Dreher, Maureen L. Gibson, Sheng L. TI Relationships of quantitative ultrasound parameters with cancellous bone microstructure in human calcaneus in vitro SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID HUMAN TRABECULAR BONE; ACOUSTIC-WAVE PROPAGATION; BIOT-ATTENBOROUGH MODEL; WEAK SCATTERING MODEL; FREQUENCY-DEPENDENCE; BACKSCATTER MEASUREMENTS; MECHANICAL-PROPERTIES; PHASE-VELOCITY; MIMICKING PHANTOMS; MINERAL DENSITY AB Ultrasound parameters (attenuation, phase velocity, and backscatter), bone mineral density (BMD), and microarchitectural features were measured on 29 human cancellous calcaneus samples in vitro. Regression analysis was performed to predict ultrasound parameters from BMD and microarchitectural features. The best univariate predictors of the ultrasound parameters were the indexes of bone quantity: BMD and bone volume fraction (BV/TV). The most predictive univariate models for attenuation, phase velocity, and backscatter coefficient yielded adjusted squared correlation coefficients of 0.69-0.73. Multiple regression models yielded adjusted correlation coefficients of 0.74-0.83. Therefore attenuation, phase velocity, and backscatter are primarily determined by bone quantity, but multiple regression models based on bone quantity plus microarchitectural features achieve slightly better predictive performance than models based on bone quantity alone. [DOI: 10.1121/1.3672701] C1 [Wear, Keith A.; Nagaraja, Srinidhi; Dreher, Maureen L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Gibson, Sheng L.] Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA. RP Wear, KA (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Blvd, Silver Spring, MD 20993 USA. EM keith.wear@fda.hhs.gov FU FDA Office of Women's Health FX The authors are grateful to (1) the FDA Office of Women's Health for funding, (2) Dr. James Reynolds and Angela Stuber, NIH Clinical Center, who helped with DXA measurements, and (3) Dr. Andres Laib, Scanco Medical AG, Bruttisellen, Switzerland for producing a microCT image. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. Certain equipment, instruments or materials are identified in this paper to adequately specify the experimental details. Such identification does not imply recommendation by the National Institute of Standards and Technology nor does it imply the materials are necessarily the best available for the purpose. NR 87 TC 23 Z9 25 U1 0 U2 6 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD FEB PY 2012 VL 131 IS 2 BP 1605 EP 1612 DI 10.1121/1.3672701 PN 1 PG 8 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA 895ID UT WOS:000300488800075 PM 22352530 ER PT J AU Shields, JM Lee, MM Murphy, HR AF Shields, Joan M. Lee, Michelle Minjung Murphy, Helen R. TI Use of a common laboratory glassware detergent improves recovery of Cryptosporidium parvum and Cyclospora cayetanensis from lettuce, herbs and raspberries SO INTERNATIONAL JOURNAL OF FOOD MICROBIOLOGY LA English DT Article DE Cryptosporidium; Cyclospora cayetanensis; Wash; Recovery rates; Leafy greens; Raspberries ID STANDARD METHODS; SALAD PRODUCTS; GIARDIA CYSTS; WATER; OOCYSTS; INFECTIVITY; PARASITE; OUTBREAK; SAMPLES AB The success of any protocol designed to detect parasitic protozoa on produce must begin with an efficient initial wash step. Cryptosporidium parvum and Cyclospora cayetanensis oocysts were seeded onto herbs, lettuces and raspberries, eluted with one of four wash solutions and the recovered number of oocysts determined via fluorescent microscopy. Recovery rates for fluorescein thiosemicarbazide labeled C. parvum oocysts seeded onto spinach and raspberries and washed with de-ionized water were 38.4 +/- 10.1% and 34.9 +/- 6.2%, respectively. Two alternative wash solutions viz. 1 M glycine, pH 5.5 and a detachment solution were tested also using labeled C. parvum seeded spinach and raspberries. No statistically significant difference was noted in the recovery rates. However, a wash solution containing 0.1% Alconox (R), a laboratory glassware detergent, resulted in a significant improvement in oocyst recovery. 72.6 +/- 6.6% C parvum oocysts were recovered from basil when washed with 0.1% Alconox (R) compared to 47.9 +/- 5.8% using detachment solution. Also, C cayetanensis oocysts were seeded onto lettuces, herbs and raspberries and the recovery using de-ionized water were compared to 0.1% Alconox wash: basil 17.5 +/- 5.0% to 76.1 +/- 14.0%, lollo rosso lettuce 38.3 +/- 5.5% to 72.5 +/- 8.1%. Tango leaf lettuce 45.9 +/- 5.4% to 71.1 +/- 7.8% and spring mix (mesclun) 39.8 +/- 0.7% to 80.2 +/- 11.3%, respectively. These results suggest that the use of Alconox in a wash solution significantly improves recovery resulting in the detection of these parasitic protozoa on high risk foods. Published by Elsevier B.V. C1 [Shields, Joan M.; Murphy, Helen R.] Ctr Food Safety & Appl Nutr, Div Virulence Assessment, Off Appl Res & Safety Assessment, US FDA, Rockville, MD 20857 USA. [Lee, Michelle Minjung] Kyungpook Natl Univ, Taegu, South Korea. RP Shields, JM (reprint author), 8301 Muirkirk Rd,MOD-1,HFS-025, Laurel, MD 20708 USA. EM jan.Shields@hhs.fda.gov NR 35 TC 8 Z9 9 U1 1 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1605 J9 INT J FOOD MICROBIOL JI Int. J. Food Microbiol. PD FEB 1 PY 2012 VL 153 IS 1-2 BP 123 EP 128 DI 10.1016/j.ijfoodmicro.2011.10.025 PG 6 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA 898NZ UT WOS:000300750400018 PM 22094179 ER PT J AU Fuchs-Schundeln, N Izem, R AF Fuchs-Schuendeln, Nicola Izem, Rima TI Explaining the low labor productivity in East Germany - A spatial analysis SO JOURNAL OF COMPARATIVE ECONOMICS LA English DT Article DE Transferability of human capital; Spatial allocation of labor ID REUNIFICATION; MIGRATION; DETERMINANTS; MARKET AB Fuchs-Schundeln, Nicola, and Izem, Rima-Explaining the low labor productivity in East Germany - A spatial analysis This paper sheds light on the transferability of human capital in periods of dramatic structural change by analyzing the unique event of German reunification. We explore whether the comparatively low labor productivity in East Germany after reunification is caused by the depreciation of human capital at reunification, or by unfavorable job characteristics. East German workers should have been hit harder by reunification the more specific human capital was. Treating both human capital and job characteristics as unobservables, we derive their relative importance in explaining the low labor productivity by estimating a spatial structural model that predicts commuting behavior across the former East-West border and the resulting regional unemployment rates. The identification of the model is based on the slope of the unemployment rate across the former border. The results indicate that East and West German skills are very similar, while job characteristics differ significantly between East and West in the sample period 1998-2004. Hence, they suggest that a significant part of the human capital accumulated in the East before 1990 was transferable. Journal of Comparative Economics 40 (1) (2012) 1-21. Goethe University Frankfurt, Germany; Food and Drug Administration, United States. (C) 2011 Association for Comparative Economic Studies All rights reserved. C1 [Fuchs-Schuendeln, Nicola] Goethe Univ Frankfurt, D-6000 Frankfurt, Germany. [Izem, Rima] US FDA, Rockville, MD 20857 USA. RP Fuchs-Schundeln, N (reprint author), Goethe Univ Frankfurt, D-6000 Frankfurt, Germany. EM fuchs@wiwi.uni-frankfurt.de; rima_izem@yahoo.fr NR 42 TC 7 Z9 8 U1 2 U2 25 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0147-5967 J9 J COMP ECON JI J. Comp. Econ. PD FEB PY 2012 VL 40 IS 1 BP 1 EP 21 DI 10.1016/j.jce.2011.09.001 PG 21 WC Economics SC Business & Economics GA 900BY UT WOS:000300862800001 ER PT J AU Beger, RD Colatsky, T AF Beger, Richard D. Colatsky, Thomas TI Metabolomics data and the biomarker qualification process SO METABOLOMICS LA English DT Article DE Biomarkers; Metabolomics; Metabonomics; Personalized medicine; Drug safety ID MINIMUM REPORTING STANDARDS; INDUCED HEPATOTOXICITY; SAFETY BIOMARKERS; DRUG DEVELOPMENT; METABONOMICS; CANCER; ACID; LIVER; PHENOTYPES; PROTEOMICS AB Since its initial applications in healthcare research over a decade ago, metabolomics has matured into a technology that can now reliably detect and quantify hundreds of metabolites in biofluids and tissue samples. With substantial improvements in analytical capabilities in recent years, metabolomics now has the potential to provide sensitive and specific biomarkers of health and disease status, drug toxicity and therapeutic efficacy. Although many of the clinical biomarkers currently in use are metabolites such as glucose, cholesterol, and creatinine, few, if any, new metabolites (or panel of metabolites) derived from metabolomic analyses have been submitted to the FDA as biomarker candidates. Under a recent FDA draft Guidance for Industry from the Center for Drug Evaluation and Research (CDER), biomarkers discovered using metabolomics, like those derived from genetic, transcriptomic, and proteomic studies, may be submitted to CDER for consideration as new drug development tools and entered into a formal biomarker qualification process. The qualification process begins with a letter of intent from the submitter, followed by discussions with FDA and then the submission of data supporting the performance of the biomarker within a specific context of use. CDER forms a Biomarker Qualification Review Team at the start of the interactive process to advise the biomarker developer on the type of information important to support the proposed context of use, and review the data that evaluates the biomarker for the proposed context of use when the biomarker development appears complete and the full supporting data are submitted. Once qualified, a biomarker can be used in drug development within the qualified context of use without requesting additional regulatory review concerning its suitability. C1 [Beger, Richard D.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Colatsky, Thomas] US FDA, Div Drug Safety Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Beger, RD (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Richard.Beger@fda.hhs.gov NR 63 TC 5 Z9 5 U1 3 U2 32 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1573-3882 J9 METABOLOMICS JI Metabolomics PD FEB PY 2012 VL 8 IS 1 BP 2 EP 7 DI 10.1007/s11306-011-0342-z PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 902ME UT WOS:000301041600002 ER PT J AU Abdul-Sater, AA Grajkowski, A Erdjument-Bromage, H Plumlee, C Levi, A Schreiber, MT Lee, C Shuman, H Beaucage, SL Schindler, C AF Abdul-Sater, Ali A. Grajkowski, Andrzej Erdjument-Bromage, Hediye Plumlee, Courtney Levi, Assaf Schreiber, Michael T. Lee, Carolyn Shuman, Howard Beaucage, Serge L. Schindler, Christian TI The overlapping host responses to bacterial cyclic dinucleotides SO MICROBES AND INFECTION LA English DT Article DE L. pneumophila; Cyclic dinucleotides; PAMPs; Interferons (ifns); Cytokines and signal transduction ID I INTERFERON RESPONSE; INNATE IMMUNE-SYSTEM; C-DI-GMP; LEGIONELLA-PNEUMOPHILA; EFFECTOR PROTEINS; CYTOSOLIC DNA; RNA; MACROPHAGES; CRYOPYRIN/NALP3; RECOGNITION AB Macrophages respond to infection with Legionella pneumophila by the induction of inflammatory mediators, including type I Interferons (IFN-Is). To explore whether the bacterial second messenger cyclic 3'-5' diguanylate (c-diGMP) activates some of these mediators, macrophages were infected with L. pneumophila strains in which the levels of bacterial c-diGMP had been altered. Intriguingly, there was a positive correlation between c-diGMP levels and IFN-I expression. Subsequent studies with synthetic derivatives of c-diGMP, and newly described cyclic 3'-5' diadenylate (c-diAMP), determined that these molecules activate overlapping inflammatory responses in human and murine macrophages. Moreover, UV crosslinking studies determined that both dinucleotides physically associate with a shared set of host proteins. Fractionation of macrophage extracts on a biotin-c-diGMP affinity matrix led to the identification of a set of candidate host binding proteins. These studies suggest that mammalian macrophages can sense and mount a specific inflammatory response to bacterial dinucleotides. (C) 2011 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. C1 [Abdul-Sater, Ali A.; Levi, Assaf; Schreiber, Michael T.; Lee, Carolyn; Shuman, Howard; Schindler, Christian] Columbia Univ, Dept Microbiol & Immunol, New York, NY 10032 USA. [Schindler, Christian] Columbia Univ, Dept Med, New York, NY 10032 USA. [Grajkowski, Andrzej; Beaucage, Serge L.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Erdjument-Bromage, Hediye] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Rockefeller Res Labs, New York, NY 10065 USA. [Plumlee, Courtney] Univ Connecticut, Ctr Hlth, Dept Immunol, Farmington, CT 06030 USA. [Levi, Assaf; Shuman, Howard] Univ Chicago, Dept Microbiol, Cummings Life Sci Ctr, Chicago, IL 60637 USA. RP Schindler, C (reprint author), Columbia Univ, Dept Microbiol & Immunol, HHSC 1208,701 W 168th St, New York, NY 10032 USA. EM cws4@columbia.edu RI Schreiber, Michael/B-8476-2013 OI Schreiber, Michael/0000-0002-8948-857X FU NIH [AI096088, AI058211, AI23549] FX These studies were supported by the NIH grants, AI096088 (CS) & AI058211 (CS) and AI23549 (HS). NR 32 TC 11 Z9 12 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD FEB PY 2012 VL 14 IS 2 BP 188 EP 197 DI 10.1016/j.micinf.2011.09.002 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 899MD UT WOS:000300819100010 PM 21933720 ER PT J AU Banugaria, S Prater, S Bali, D Rehder, C Rosenberg, A Kishnani, P AF Banugaria, Suhrad Prater, Sean Bali, Deeksha Rehder, Catherine Rosenberg, Amy Kishnani, Priya TI Long Term Outcome and Clinical Experience on Immune Tolerance Induction Therapies in Infantile Pompe Disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 8th Anuual Research Meeting of the WORLD Symposium on Lysosomal Disease Networks CY FEB 07-10, 2012 CL San Diego, CA C1 [Rehder, Catherine] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Rosenberg, Amy] US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2012 VL 105 IS 2 BP S20 EP S20 DI 10.1016/j.ymgme.2011.11.026 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 885DI UT WOS:000299758300037 ER PT J AU Pariser, A AF Pariser, Ann TI Clinical Development of Products to Treat Rare Diseases SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 8th Anuual Research Meeting of the WORLD Symposium on Lysosomal Disease Networks CY FEB 07-10, 2012 CL San Diego, CA C1 [Pariser, Ann] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2012 VL 105 IS 2 BP S50 EP S50 DI 10.1016/j.ymgme.2011.11.125 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 885DI UT WOS:000299758300136 ER PT J AU Garofolo, F Michon, J Leclaire, V Booth, B Lowes, S Viswanathan, CT Welink, J Haidar, S Teixeira, LD Tang, D Desilva, B AF Garofolo, Fabio Michon, Josee Leclaire, Virginie Booth, Brian Lowes, Stephen Viswanathan, C. T. Welink, Jan Haidar, Sam Teixeira, Leonardo de Souza Tang, Daniel Desilva, Binodh TI US FDA/EMA harmonization of their bioanalytical guidance/guideline and activities of the Global Bioanalytical Consortium SO BIOANALYSIS LA English DT Editorial Material ID METHOD VALIDATION; RECENT ISSUES; GUIDANCE AB The 2011 annual conference of the American Association of Pharmaceutical Scientists, held in Washington DC, USA, hosted a roundtable entitled: 'Update of the US FDA/European Medicines Agency (EMA) harmonization of their bioanalytical guidance - Global Bioanalytical Consortium activity and impact on small and large molecules.' The roundtable was initiated with a presentation from CT Viswanathan on the history of the revision of the FDA guideline on bioanalytical method validation. It was followed by a presentation by Jan Welink who presented an update on the final European Medicines Agency guideline on bioanalytical method validation with relevance to ongoing harmonization efforts. The final presentation was by Fabio Garofolo on the progress of the Global Bioanalytical Consortium harmonization teams for small and large molecules. Brian Booth and Sam Haidar of the FDA updated the audience on the status of the revision of the FDA bioanalytical guidance. The roundtable was moderated by Stephen Lowes. C1 [Garofolo, Fabio; Michon, Josee; Leclaire, Virginie] Algorithme Pharma Inc, Montreal, PQ, Canada. [Booth, Brian; Haidar, Sam] US FDA, CDER, Silver Spring, MD USA. [Lowes, Stephen] Adv BioServ, Ithaca, NY USA. [Welink, Jan] Med Evaluat Board, The Hague, Netherlands. [Teixeira, Leonardo de Souza] ICF, Goiania, Go, Brazil. [Tang, Daniel] ICON APAC, Shanghai, Peoples R China. [Desilva, Binodh] Bristol Myers Squibb Co, Princeton, NJ USA. RP Garofolo, F (reprint author), Algorithme Pharma Inc, Montreal, PQ, Canada. EM fgarofolo@algopharm.com NR 8 TC 14 Z9 14 U1 1 U2 6 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1757-6180 J9 BIOANALYSIS JI Bioanalysis PD FEB PY 2012 VL 4 IS 3 BP 231 EP 236 DI 10.4155/BIO.12.1 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 897KM UT WOS:000300649600007 PM 22303826 ER PT J AU Dang, Y Moore, J Huang, G Lipp, M Jones, B Griffiths, JC AF Dang, Yi Moore, Jeffrey Huang, Gloria Lipp, Markus Jones, Barbara Griffiths, James C. TI Establishing USP Rebaudioside A and Stevioside Reference Standards for the Food Chemicals Codex SO LC GC NORTH AMERICA LA English DT Article AB The United States Pharmacopeial Convention (USP) publishes the Food Chemicals Codex (FCC), which is a compendium of food ingredient documentary standards (monographs) that provide tests, procedures, and acceptance criteria to indicate the safety and quality of a food ingredient. Physical reference standards can be associated with the procedures of an FCC monograph and the reference standards are needed for conducting the procedures. This article describes characterization and collaborative testing of new USP rebaudioside A and stevioside reference standards and their suitability for intended uses in the FCC rebaudioside A monograph. C1 [Dang, Yi; Moore, Jeffrey; Jones, Barbara; Griffiths, James C.] US Pharmacopeial Convent Inc, Rockville, MD USA. [Huang, Gloria] US FDA, Rockville, MD 20857 USA. RP Dang, Y (reprint author), US Pharmacopeial Convent Inc, Rockville, MD USA. EM yd@usp.org; andjm@usp.org NR 2 TC 0 Z9 0 U1 0 U2 2 PU ADVANSTAR COMMUNICATIONS INC PI DULUTH PA 131 W 1ST STREET, DULUTH, MN 55802 USA SN 1527-5949 J9 LC GC N AM JI LC GC N. AM. PD FEB PY 2012 SU S BP 55 EP 58 PG 4 WC Chemistry, Analytical SC Chemistry GA 896DE UT WOS:000300544800035 ER PT J AU O'Leary, ST Glanz, JM McClure, DL Akhtar, A Daley, MF Nakasato, C Baxter, R Davis, RL Izurieta, HS Lieu, TA Ball, R AF O'Leary, Sean T. Glanz, Jason M. McClure, David L. Akhtar, Aysha Daley, Matthew F. Nakasato, Cynthia Baxter, Roger Davis, Robert L. Izurieta, Hector S. Lieu, Tracy A. Ball, Robert TI The Risk of Immune Thrombocytopenic Purpura After Vaccination in Children and Adolescents SO PEDIATRICS LA English DT Article DE immune thrombocytopenia purpura; children; vaccines; adverse reactions; thrombocytopenia ID HEPATITIS-B-VACCINE; INTRA-CRANICAL HEMORRHAGE; RUBELLA VACCINATION; ADVERSE EVENTS; MMR VACCINE; MEASLES; MUMPS; CHILDHOOD; IMMUNIZATION; SURVEILLANCE AB BACKGROUND: The risk of immune thrombocytopenic purpura (ITP) after childhood vaccines other than measles-mumps-rubella vaccine (MMR) is unknown. METHODS: Using data from 5 managed care organizations for 2000 to 2009, we identified a cohort of 1.8 million children ages 6 weeks to 17 years. Potential ITP cases were identified by using diagnostic codes and platelet counts. All cases were verified by chart review. Incidence rate ratios were calculated comparing the risk of ITP in risk (1 to 42 days after vaccination) and control periods. RESULTS: There were 197 chart-confirmed ITP cases out of 1.8 million children in the cohort. There was no elevated risk of ITP after any vaccine in early childhood other than MMR in the 12- to 19-month age group. There was a significantly elevated risk of ITP after hepatitis A vaccine at 7 to 17 years of age, and for varicella vaccine and tetanus-diphtheria-acellular pertussis vaccine at 11 to 17 years of age. For hepatitis A, varicella, and tetanus-diphtheria-acellular pertussis vaccines, elevated risks were based on one to two vaccine-exposed cases. Most cases were acute and mild with no long-term sequelae. CONCLUSIONS: ITP is unlikely after early childhood vaccines other than MMR. Because of the small number of exposed cases and potential confounding, the possible association of ITP with hepatitis A, varicella, and tetanus-diphtheria-acellular pertussis vaccines in older children requires further investigation. Pediatrics 2012;129:248-255 C1 [O'Leary, Sean T.; Daley, Matthew F.] Univ Colorado, Dept Pediat, Aurora, CO USA. [O'Leary, Sean T.] Childrens Hosp Colorado, Sect Pediat Infect Dis, Childrens Outcomes Res Program, Aurora, CO 80045 USA. [O'Leary, Sean T.; Glanz, Jason M.; McClure, David L.; Daley, Matthew F.; Nakasato, Cynthia] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Akhtar, Aysha; Izurieta, Hector S.; Ball, Robert] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. Kaiser Permanente Hawaii, Ctr Hlth Res Hawaii, Honolulu, HI USA. [Baxter, Roger] Kaiser Permanente Vaccine Study Ctr, Oakland, CA USA. [Davis, Robert L.] Kaiser Permanente Georgia, Ctr Hlth Res SE, Atlanta, GA USA. [Lieu, Tracy A.] Harvard Pilgrim Hlth Care Inst, Dept Ambulatory Care & Prevent, Ctr Child Hlth Care Studies, Boston, MA USA. [Lieu, Tracy A.] Childrens Hosp Boston, Div Gen Pediat, Boston, MA USA. RP O'Leary, ST (reprint author), Childrens Hosp Colorado, Sect Pediat Infect Dis, Childrens Outcomes Res Program, Mail Stop F443,13199 E Montview Blvd,Suite 300, Aurora, CO 80045 USA. EM sean.o'leary@childrenscolorado.org FU Sanofi Pasteur; GlaxoSmithKline; Novartis; Merck; Pfizer; Kaiser Permanente; Food and Drug Administration FX Dr Baxter receives research support from Sanofi Pasteur, GlaxoSmithKline, Novartis, Merck, and Pfizer. None of the other authors have any relevant disclosures.; This publication was supported by a subcontract from Kaiser Permanente with funds provided by the Food and Drug Administration. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of Kaiser Permanente or the Food and Drug Administration. NR 44 TC 27 Z9 27 U1 0 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2012 VL 129 IS 2 BP 248 EP 255 DI 10.1542/peds.2011-1111 PG 8 WC Pediatrics SC Pediatrics GA 893YZ UT WOS:000300395100046 PM 22232308 ER PT J AU Ribeiro-Gomes, FL Peters, NC Debrabant, A Sacks, DL AF Ribeiro-Gomes, Flavia L. Peters, Nathan C. Debrabant, Alain Sacks, David L. TI Efficient Capture of Infected Neutrophils by Dendritic Cells in the Skin Inhibits the Early Anti-Leishmania Response SO PLOS PATHOGENS LA English DT Article ID APOPTOSIS FOLLOWING INGESTION; MAJOR INFECTION; STREPTOCOCCUS-PNEUMONIAE; CUTANEOUS LEISHMANIASIS; MICROBIAL INFECTION; SUPPRESSOR-CELLS; IMMUNE-RESPONSE; SAND FLIES; T-CELLS; GRANULOCYTES AB Neutrophils and dendritic cells (DCs) converge at localized sites of acute inflammation in the skin following pathogen deposition by the bites of arthropod vectors or by needle injection. Prior studies in mice have shown that neutrophils are the predominant recruited and infected cells during the earliest stage of Leishmania major infection in the skin, and that neutrophil depletion promotes host resistance to sand fly transmitted infection. How the massive influx of neutrophils aimed at wound repair and sterilization might modulate the function of DCs in the skin has not been previously addressed. The infected neutrophils recovered from the skin expressed elevated apoptotic markers compared to uninfected neutrophils, and were preferentially captured by dermal DCs when injected back into the mouse ear dermis. Following challenge with L. major directly, the majority of the infected DCs recovered from the skin at 24 hr stained positive for neutrophil markers, indicating that they acquired their parasites via uptake of infected neutrophils. When infected, dermal DCs were recovered from neutrophil depleted mice, their expression of activation markers was markedly enhanced, as was their capacity to present Leishmania antigens ex vivo. Neutrophil depletion also enhanced the priming of L. major specific CD4(+) T cells in vivo. The findings suggest that following their rapid uptake by neutrophils in the skin, L. major exploits the immunosuppressive effects associated with the apoptotic cell clearance function of DCs to inhibit the development of acquired resistance until the acute neutrophilic response is resolved. C1 [Ribeiro-Gomes, Flavia L.; Peters, Nathan C.; Sacks, David L.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Debrabant, Alain] US FDA, Div Emerging & Transfus Transmitted Dis, OBRR, CBER, Bethesda, MD 20014 USA. RP Ribeiro-Gomes, FL (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM dsacks@nih.gov RI Ribeiro-Gomes, Flavia/F-7609-2015 FU NIH, NIAID FX This research was supported in part by the Intramural Research program of the NIH, NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 62 Z9 62 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2012 VL 8 IS 2 AR e1002536 DI 10.1371/journal.ppat.1002536 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 898GQ UT WOS:000300728100038 PM 22359507 ER PT J AU Ahn, Y Linder, SW Veach, BT Yan, SS Fernandez, AH Pineiro, SA Cerniglia, CE AF Ahn, Youngbeom Linder, Sean W. Veach, Brian T. Yan, S. Steve Fernandez, A. Haydee Pineiro, Silvia A. Cerniglia, Carl E. TI In vitro enrofloxacin binding in human fecal slurries SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Enrofloxacin; Binding; Human fecal slurries ID HUMAN INTESTINAL MICROBIOTA; ANTIMICROBIAL AGENTS; SELECTIVE DECONTAMINATION; LIQUID-CHROMATOGRAPHY; MODIFYING ENZYME; METAGENOMICS ERA; HUMAN FECES; CIPROFLOXACIN; ANTIBIOTICS; COMMUNITIES AB Most antibiotic inactivation studies have been conducted through in vitro incubations of human use aminoglycosides, beta-lactams, and fluoroquinolones, usually at fecal concentrations expected with therapeutic dose regimens in humans and animals. Less is known about the inactivation of these molecules when ingested at concentrations consistent with residue levels present in animal-derived foods from antibiotic treated animals. In this investigation, we used the fluoroquinolone, enrofloxacin which is specifically marketed for veterinary medicine as test compound. Fecal suspensions at 10%, 25%, and 50% (w/v) were subjected to physicochemical and molecular characterization and used in the drug binding studies. The fecal binding of enrofloxacin added at concentrations of 0.06, 0.1, 1, 5, 15, 50, and 150 mg/L was determined in various fecal slurry suspensions using analytical chemistry and microbiological assay methods. There was consistent correlation between both assay methods. By the analytical chemistry assay, the 10%, 25% and 50% diluted autoclaved fecal samples dosed with enrofloxacin showed binding of 50 +/- 4.6%, 54 +/- 6.5% and 56 +/- 6.8% of the enrofloxacin, respectively. Binding of enrofloxacin to fecal contents occurred rapidly within 10 min and remained constant over the incubation period. Denaturing gradient gel electrophoreses and pyrosequencing analysis showed varied profiles of the bacterial composition of the human intestinal microbiota for fecal samples from different individuals. This study provided information on methodological questions that have concerned regulatory authorities on in vitro testing to determine if concentrations of veterinary antimicrobial agent residues entering the human colon remain microbiologically active. Published by Elsevier Inc. C1 [Ahn, Youngbeom; Cerniglia, Carl E.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Linder, Sean W.; Veach, Brian T.] US FDA, Arkansas Reg Lab, Off Regulatory Affairs, Jefferson Labs, Jefferson, AR 72079 USA. [Yan, S. Steve; Fernandez, A. Haydee; Pineiro, Silvia A.] US FDA, Ctr Vet Med, Rockville, MD 20855 USA. RP Cerniglia, CE (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM young.ahn@fda.hhs.gov; sean.linder@fda.hhs.gov; veach@fda.hhs.gov; steve.yan@fda.hhs.gov; fernandez@fda.hhs.gov; pineiro@fda.hhs.gov; carl.cerniglia@fda.hhs.gov NR 60 TC 7 Z9 7 U1 0 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD FEB PY 2012 VL 62 IS 1 BP 74 EP 84 DI 10.1016/j.yrtph.2011.11.013 PG 11 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA 887XN UT WOS:000299965400009 PM 22178170 ER PT J AU Temple, R AF Temple, Robert TI A regulator's view of comparative effectiveness research SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT University-of-Pennsylvania Annual Conference on Statistical Issues in Clinical Trials CY APR 13-13, 2011 CL Philadelphia, PA ID PLACEBO-CONTROLLED TRIALS; CALCIUM-CHANNEL BLOCKERS; ACTIVE-CONTROL TRIALS; RISK; HYPERTENSION; DISEASE; ISSUES; DRUGS AB Background 'Comparative effectiveness' is the current enthusiasm, and for good reason. After knowing a treatment works, the most critical question is how it compares with alternatives. Comparative studies are not commonly conducted by drug companies and they represent a significant methodological challenge. Comparative data could include evidence of overall superiority to an alternative or advantages in identifiable subsets, for example, people who do not respond to or tolerate alternatives, or members of a genetic subset and could also include convincing evidence that there is little difference between two treatments. Purpose To describe regulations, guidance, and Food and Drug Administration experience related to studies of comparative effectiveness, including approaches to showing superiority and problems encountered in showing similarity. Methods Review of Food and Drug Administration regulations and guidance and experience with showing superiority and similarity, particularly related to randomized trials and epidemiologic studies. Results Methods exist, and they have been successful for showing overall superiority of one drug over another, advantages in specific population subsets. Efforts to show true equivalence face problems of definition and very large sample sizes needed to rule out small differences. Limitations There is need for further discussion of what is meant by similarity or equivalence of two treatments. Conclusion Comparative studies are challenging because differences between effective therapies are likely to be small and can be detected reliably only in randomized trials, often large ones. Despite the difficulties, comparative trials have been successful and we clearly would like to see more of them. Clinical Trials 2012; 9: 56-65. http://ctj.sagepub.com C1 US FDA, Ctr Drug Evaluat & Res, Washington, DC 20204 USA. RP Temple, R (reprint author), US FDA, Ctr Drug Evaluat & Res, Washington, DC 20204 USA. EM robert.temple@fda.hhs.gov NR 28 TC 14 Z9 14 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2012 VL 9 IS 1 BP 56 EP 65 DI 10.1177/1740774511422548 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 893UA UT WOS:000300380200009 PM 21975523 ER PT J AU Keene, AM Peters, D Rouse, R Stewart, S Rosen, ET Tyner, KM AF Keene, Athena M. Peters, David Rouse, Rodney Stewart, Sharron Rosen, Elliot T. Tyner, Katherine M. TI Tissue and cellular distribution of gold nanoparticles varies based on aggregation/agglomeration status SO NANOMEDICINE LA English DT Article DE agglomeration; aggregation; biodistribution; gold nanoparticles ID PARTICLE-SIZE; TITANIUM-DIOXIDE; LASER-ABLATION; QUANTUM DOTS; IN-VITRO; BIODISTRIBUTION; NANOTECHNOLOGY; AGGREGATION; CLEARANCE; STABILITY AB Aim: The ability of nanoparticles to form larger superstructures of aggregates and agglomerates has been extensively noted in the literature. The in vivo biological impact of these structures, however, has not been assessed. This knowledge gap is especially critical in the safety assessment of nanoparticles to be used for therapeutic purposes. Method/results: Here we show that when administered intravenously into a mouse model, gold nanoparticle superstructures of reversible agglomerates and irreversible aggregates demonstrate significant differences in organ and cellular distribution compared with the primary particle building blocks. In addition, different structures produced different blood serum chemistry data. Conclusion: These findings raise the possibility for different mechanisms of toxicity between the structures. Such a possibility necessitates complete characterization and stability assessment of nanomaterials prior to their in vivo administration. C1 [Keene, Athena M.; Peters, David; Rouse, Rodney; Stewart, Sharron; Rosen, Elliot T.; Tyner, Katherine M.] US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Drug Saftey Res, Silver Spring, MD 20993 USA. RP Tyner, KM (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Drug Saftey Res, Bldg 64,Room 2086 HFD 910,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM katherine.tyner@fda.hhs.gov FU Center for Drug Evaluation and Research FX This project was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US FDA. The findings and conclusions in this article have not been formally disseminated by the FDA and should not be construed to represent any Agency determination or policy. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 32 TC 15 Z9 15 U1 0 U2 21 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1743-5889 J9 NANOMEDICINE-UK JI Nanomedicine PD FEB PY 2012 VL 7 IS 2 BP 199 EP 209 DI 10.2217/NNM.11.125 PG 11 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA 893DM UT WOS:000300335800011 PM 22339133 ER PT J AU Woo, EJ AF Woo, Emily Jane TI Re: Williams BJ, Smith JS, Fu KM, et al. Does bone morphogenetic protein increase the incidence of perioperative complications in spinal fusion? Spine 2011; 36: 1685-91. SO SPINE LA English DT Letter C1 US FDA, Rockville, MD 20857 USA. RP Woo, EJ (reprint author), US FDA, Rockville, MD 20857 USA. NR 3 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD FEB 1 PY 2012 VL 37 IS 3 BP 259 EP 259 DI 10.1097/BRS.0b013e31823fcf42 PG 1 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 891OU UT WOS:000300227300028 PM 22108375 ER PT J AU Burall, LS Laksanalamai, P Datta, AR AF Burall, Laurel S. Laksanalamai, Pongpan Datta, Atin R. TI Listeria monocytogenes Mutants with Altered Growth Phenotypes at Refrigeration Temperature and High Salt Concentrations SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID OSMOLYTE TRANSPORTERS BETL; TRANSPOSON INSERTION; STRESS TOLERANCE; VIRULENCE; GENE; IDENTIFICATION; PROTEIN; SYSTEM; TRANSCRIPTION; DISRUPTION AB Listeria monocytogenes can survive and grow in refrigerated temperatures and high-salt environments. In an effort to better understand the associated mechanisms, a library of similar to 5,200 transposon mutants of LS411, a food isolate from the Jalisco cheese outbreak, were screened for their ability to grow in brain heart infusion (BHI) broth at 5 degrees C or in the presence of 7% NaCl and two mutants with altered growth profiles were identified. The LS522 mutant has a transposon insertion between secA2 and iap and showed a significant reduction in growth in BHI broth at 5 degrees C and in the presence of 7% NaCl. Reverse transcriptase quantitative PCR (RT-qPCR) revealed a substantial reduction in the expression of iap. Additionally, a hypothetical gene (met), containing a putative S-adenosylmethionine-dependent methyltransferase domain, downstream of iap had downregulated expression. In-frame deletion mutants of iap and met were created in LS411. The LS560 (LS411 Delta iap) mutant showed reduced growth at 5 degrees C and in the presence of 7% salt, confirming its role in cold and salt growth attenuation. Surprisingly, the LS655 (LS411 Delta met) mutant showed slightly increased growth during refrigeration, though no alteration was seen in salt growth relative to the wild-type strain. The LS527 mutant, containing an insertion 36 bp upstream of the gbu operon, showed reduced expression of the gbu transcript by RT-qPCR and also showed growth reduction at 5 degrees C and in the presence of 7% salt. This attenuation was severely exacerbated when the mutant was grown under the combined stresses. Analysis of the gbu operon deletion mutant showed decreased growth in 7% salt and refrigeration, supporting the previously characterized role for this gene in cold and salt adaptation. These studies indicate the potential for an intricate relationship between environmental stress regulation and virulence in L. monocytogenes. C1 [Burall, Laurel S.; Laksanalamai, Pongpan; Datta, Atin R.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. RP Datta, AR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. EM atin.datta@fda.hhs.gov NR 40 TC 10 Z9 10 U1 2 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD FEB PY 2012 VL 78 IS 4 BP 1265 EP 1272 DI 10.1128/AEM.06576-11 PG 8 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 887HX UT WOS:000299918600042 PM 22179239 ER PT J AU Dickey, RW AF Dickey, Robert W. TI FDA Risk Assessment of Seafood Contamination after the BP Oil Spill SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter C1 US FDA, Gulf Coast Seafood Lab, Dauphin Isl, AL USA. RP Dickey, RW (reprint author), US FDA, Gulf Coast Seafood Lab, Dauphin Isl, AL USA. EM Robert.Dickey@fda.hhs.gov NR 14 TC 5 Z9 5 U1 1 U2 18 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2012 VL 120 IS 2 BP A54 EP A55 DI 10.1289/ehp.1104539 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 887GR UT WOS:000299915400001 PM 22297092 ER PT J AU Xia, XD Luo, YG Yang, Y Vinyard, B Schneider, K Meng, JH AF Xia, Xiaodong Luo, Yaguang Yang, Yang Vinyard, Bryan Schneider, Keith Meng, Jianghong TI Effects of Tomato Variety, Temperature Differential, and Post-Stem Removal Time on Internalization of Salmonella enterica Serovar Thompson in Tomatoes SO JOURNAL OF FOOD PROTECTION LA English DT Article ID UNITED-STATES; ERWINIA-CAROTOVORA; FOODBORNE ILLNESS; HEALTHY TOMATOES; FRESH PRODUCE; INFILTRATION; OUTBREAKS; CONTAMINATION; SUSPENSIONS; PATHOGENS AB Tomatoes have been implicated in salmonellosis outbreaks due to possible contamination through bacterial internalization during postharvest handling. This study was conducted to determine the effects of tomato variety, temperature differential between tomato pulp and bacterial suspension, and the time delay between stem removal and immersion in bacterial suspension on internalization of Salmonella enterica serovar Thompson in tomato fruit. Mature green tomatoes at 32.2 degrees C were immersed in water containing approximately 10(6) CFU/ml S. enterica bacteria. Different tomato varieties (Mountain Spring, Applause, and BHN961), temperature differentials (-10, 0, and 10 degrees F, or -5.6, 0, and 5.6 degrees C, respectively), and post stem removal times (0, 2, and 16 h) were evaluated for their effects on S. enterica internalization. The incidence and density of internalized cells were determined by culture enrichment and most-probable-number methods, respectively. Overall, variety and post stem removal time by variety interaction significantly affected the incidence of S. enterica internalization (P < 0.0001), while temperature differential had no significant effect (P = 0.36). Mountain Spring tomatoes were less susceptible to S. enterica internalization than were Applause and BHN961. Increasing the time interval between stem removal and immersion greatly reduced pathogen internalization in BHN961 and Applause, while it had no effect in Mountain Spring tomatoes. The variety and interactions between varieties and post stem removal times (P = 0.0363) and between temperature differentials and post stem removal times (P = 0.0257) had significant effects on the populations of internalized S. enterica. Furthermore, all internalized S. enterica cells were found within the core tissue segments immediately underneath the stem scars. C1 [Xia, Xiaodong; Luo, Yaguang; Yang, Yang] ARS, USDA, Beltsville Agr Res Ctr, Environm Microbiol & Food Safety Lab, Beltsville, MD 20705 USA. [Xia, Xiaodong] NW A&F Univ, Sch Food Sci & Engn, Yangling 712100, Shaanxi, Peoples R China. [Vinyard, Bryan] ARS, USDA, Beltsville Agr Res Ctr, Biometr Consulting Serv, Beltsville, MD 20705 USA. [Schneider, Keith] Univ Florida, Dept Food Sci & Human Nutr, Gainesville, FL 32611 USA. [Meng, Jianghong] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. [Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. RP Luo, YG (reprint author), ARS, USDA, Beltsville Agr Res Ctr, Environm Microbiol & Food Safety Lab, 10300 Baltimore Ave, Beltsville, MD 20705 USA. EM Yaguang.Luo@ars.usda.gov FU Center for Produce Safety [2009-51] FX This study was partially supported by a research grant from the Center for Produce Safety (project identification no. 2009-51). We would like to thank Dr. Mike Mahovic for critical reading of the manuscript, Dr. Bin Thou, Ruth Oni, Ellen Turner. and Yitzy Paul for their technical assistance, and Dr. Xiangwu Nou for providing an S. enterica strain. NR 25 TC 8 Z9 9 U1 0 U2 25 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X J9 J FOOD PROTECT JI J. Food Prot. PD FEB PY 2012 VL 75 IS 2 BP 297 EP 303 DI 10.4315/0362-028X.JFP-11-078 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 887YB UT WOS:000299969900011 PM 22289590 ER PT J AU Hoelzer, K Pouillot, R Egan, K Dennis, S AF Hoelzer, K. Pouillot, R. Egan, K. Dennis, S. TI Produce Consumption in the United States: An Analysis of Consumption Frequencies, Serving Sizes, Processing Forms, and High-Consuming Population Subgroups for Microbial Risk Assessments SO JOURNAL OF FOOD PROTECTION LA English DT Article ID FRESH PRODUCE; VEGETABLE CONSUMPTION; FRUIT; CHILDREN; OUTBREAKS; CYCLOSPORIASIS; AVAILABILITY; PATHOGENS; STANDARDS; SPROUTS AB A great variety of fruits and vegetables are available in the United States. These items are produced in various geographic regions by a diverse industry. Produce has been increasingly identified as a vehicle for disease outbreaks. Changes in consumption may explain this increase, but analyses of produce consumption are limited. Comprehensive assessments of the public health risks associated with produce depend on quantitative consumption data, including the population fractions and subgroups of consumers, the quantities consumed by these individuals, and the processing that occurs before consumption. Here, we provide an analysis of nationally representative consumption estimates by estimating consumption frequencies, serving sizes, and processing forms for a variety of produce commodities based on 1999 through 2006 data from "What We Eat in America," the dietary interview component of the National Health and Nutrition Examination Survey performed by the National Center for Health Statistics. Consumption patterns for fresh and heat-treated produce were assessed, compared with U.S. food availability estimates from the U.S. Department of Agriculture Economic Research Service (ERS), and combined with ERS data on temporal trends in food availability and nondomestic produce origins. To identify high-consuming population subgroups, we explored consumer habits and demographic predictors of fresh produce consumption (data available at www.foodrisk.org). Our analysis of common outbreak vehicles revealed limited temporal changes in food availability but frequent consumption as fresh commodities. In addition to providing quantitative consumption estimates for risk assessments, our data clearly show that produce consumption differs among fruits and vegetables, fresh and heat-treated foods, and demographic subgroups. These results are valuable for risk assessments and outbreak investigations and allow targeting of risk communication or interventions to those individuals at greatest risk. C1 [Hoelzer, K.; Pouillot, R.; Egan, K.; Dennis, S.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Hoelzer, K (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM karin.hoelzer@fda.hhs.gov RI Pouillot, Regis/E-8103-2010 OI Pouillot, Regis/0000-0002-6107-5212 FU Center for Food Safety and Applied Nutrition FX This work was supported in part by appointments to the Research Participation Program at the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 54 TC 9 Z9 9 U1 2 U2 18 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X J9 J FOOD PROTECT JI J. Food Prot. PD FEB PY 2012 VL 75 IS 2 BP 328 EP 340 DI 10.4315/0362-028X.JFP-11-313 PG 13 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 887YB UT WOS:000299969900015 PM 22289594 ER PT J AU Jacobson, AP Gill, VS Irvin, KA Wang, H Hammack, TS AF Jacobson, Andrew Patrick Gill, Vikas Singh Irvin, Kari Anne Wang, Hua Hammack, Thomas Seyliard TI Evaluation of Methods To Prepare Samples of Leafy Green Vegetables for Preenrichment with the Bacteriological Analytical Manual Salmonella Culture Method SO JOURNAL OF FOOD PROTECTION LA English DT Article ID ESCHERICHIA-COLI O157-H7; FRESH PRODUCE; MICROBIOLOGICAL QUALITY; RELATIVE EFFECTIVENESS; UNITED-STATES; RECOVERY; OUTBREAKS; PREVALENCE; ENTERICA; LETTUCE AB Three sample preparation procedures, soak, stomach, and blend, were evaluated using the Bacteriological Analytical Manual Salmonella culture method with eight types of leafy green produce. In the soak method, test portions were added to lactose broth without homogenization; in the stomach method, test portions were stomached with lactose broth; and in the blend method, test portions were blended with lactose broth. Twenty artificially contaminated test portions were analyzed with each procedure in individual experimental trials. The number of test portions identified as positive were compared among the procedures. Statistically significant differences were identified with Fisher's exact two-tailed F test (P < 0.05). Where differences did occur (P < 0.05), the soak procedure was the most effective or was at least as effective as homogenization by either blending or stomaching. Statistically significant differences most frequently occurred with romaine lettuce and cabbage; for these items, blending was significantly less effective than the soak procedure. Overall, for all of the produce types examined, results showed that the soak procedure was more effective than either of the homogenization procedures in recovering Salmonella from leafy green produce. Of the 540 test portions examined by each sample preparation method, 344 were positive for the presence of Salmonella by soaking, 293 by stomaching, and 232 by blending. We recommend that the soak procedure replace homogenization for the analysis of leafy green produce because the soak procedure is more productive than homogenization by either blending or stomaching of the leafy green produce types as reported herein. C1 [Jacobson, Andrew Patrick; Gill, Vikas Singh; Irvin, Kari Anne; Wang, Hua; Hammack, Thomas Seyliard] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Jacobson, AP (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Andrew.jacobson@cfsan.fda.gov NR 33 TC 5 Z9 5 U1 0 U2 14 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X J9 J FOOD PROTECT JI J. Food Prot. PD FEB PY 2012 VL 75 IS 2 BP 400 EP 404 DI 10.4315/0362-028X.JFP-11-196 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 887YB UT WOS:000299969900026 PM 22289605 ER PT J AU Kyriakou, A Neufeld, E Szczerba, D Kainz, W Luechinger, R Kozerke, S McGregor, R Kuster, N AF Kyriakou, Adamos Neufeld, Esra Szczerba, Dominik Kainz, Wolfgang Luechinger, Roger Kozerke, Sebastian McGregor, Robert Kuster, Niels TI Patient-specific simulations and measurements of the magneto-hemodynamic effect in human primary vessels SO PHYSIOLOGICAL MEASUREMENT LA English DT Article DE MRI; MHD; simulation; measurement; EM; flow ID BLOOD-FLOW; MODELS AB This paper investigates the main characteristics of the magneto-hemodynamic (MHD) response for application as a biomarker of vascular blood flow. The induced surface potential changes of a volunteer exposed to a 3 T static B0 field of a magnetic resonance imaging (MRI) magnet were measured over time at multiple locations by an electrocardiogram device and compared to simulation results. The flow simulations were based on boundary conditions derived from MRI flow measurements restricted to the aorta and vena cava. A dedicated and validated low-frequency electromagnetic solver was applied to determine the induced temporal surface potential change from the obtained 4D flow distribution using a detailed whole-body model of the volunteer. The simulated MHD signal agreed with major characteristics of the measured signal (temporal location of main peak, magnitude, variation across chest and along torso) except in the vicinity of the heart. The MHD signal is mostly influenced by the aorta; however, more vessels and better boundary conditions are needed to analyze the finer details of the response. The results show that the MHD signal is strongly position dependent with highly variable but reproducibly measurable distinguished characteristics. Additional investigations are necessary before determining whether the MHD effect is a reliable reference for location-specific information on blood flow. C1 [Kyriakou, Adamos; Neufeld, Esra; Szczerba, Dominik; Kuster, Niels] Fdn Res Informat Technol Soc ITIS, CH-8004 Zurich, Switzerland. [Kyriakou, Adamos; Luechinger, Roger; Kozerke, Sebastian; McGregor, Robert; Kuster, Niels] ETH, Swiss Fed Inst Technol, CH-8092 Zurich, Switzerland. [Kainz, Wolfgang] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Kyriakou, A (reprint author), Fdn Res Informat Technol Soc ITIS, Zeughausstr 43, CH-8004 Zurich, Switzerland. EM neufeld@itis.ethz.ch RI Kozerke, Sebastian/J-3209-2015 OI Kozerke, Sebastian/0000-0003-3725-8884 FU CTI [11604.1]; FDA's Critical Path Initiative FX This study was supported by the CTI (11604.1) project Sim4Life and by FDA's Critical Path Initiative. NR 14 TC 9 Z9 9 U1 1 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0967-3334 J9 PHYSIOL MEAS JI Physiol. Meas. PD FEB PY 2012 VL 33 IS 2 BP 117 EP 130 DI 10.1088/0967-3334/33/2/117 PG 14 WC Biophysics; Engineering, Biomedical; Physiology SC Biophysics; Engineering; Physiology GA 887VY UT WOS:000299960700003 PM 22227810 ER PT J AU Mack, J Rabins, P Anderson, K Goldstein, S Grill, S Hirsch, ES Lehmann, S Little, JT Margolis, RL Palanci, J Pontone, G Weiss, H Williams, JR Marsh, L AF Mack, Joel Rabins, Peter Anderson, Karen Goldstein, Susanne Grill, Stephen Hirsch, Elaina S. Lehmann, Susan Little, John T. Margolis, Russell L. Palanci, Justin Pontone, Gregory Weiss, Howard Williams, James R. Marsh, Laura TI Prevalence of Psychotic Symptoms in a Community-Based Parkinson Disease Sample SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE delusions; hallucinations; psychosis; Parkinson disease ID VISUAL HALLUCINATIONS; RISK-FACTORS; DEPRESSION; DIAGNOSIS; DEMENTIA; QUESTIONNAIRE; COMPLICATIONS; DELUSIONS; MORTALITY AB Objectives: To determine the prevalence of psychotic phenomena, including minor symptoms, in a Parkinson disease (PD) sample and compare the clinical correlates associated with the various psychotic phenomena. To evaluate the extent to which cases met National Institute of Neurological Diseases and Stroke (NINDS)/National Institute of Mental Health (NIMH)-proposed criteria for PD-associated psychosis. Methods: A total of 250 patients with idiopathic PD and Mini Mental State Exam scores greater than 23 from three community-based movement disorder clinics underwent comprehensive research diagnostic evaluations by a geriatric psychiatrist as part of a study on mood disorders in PD. Psychotic symptoms were categorized using a checklist, which included a breakdown of hallucinations, delusions, and minor symptoms. Clinical characteristics of groups with minor and other psychotic symptoms were compared. The NINDS/NIMH criteria for PD-psychosis were retrospectively applied. Results: Of the total sample, 26% of patients were found to have any current psychotic symptoms, with 47.7% of those having isolated minor symptoms, and 52.3% having hallucinations and/or delusions. Compared to those with no current psychiatric symptoms, minor symptoms were associated with more depressive symptoms and worse quality of life, and 90.8% of those with psychotic symptoms fulfilled the NINDS/NIMH proposed criteria. Conclusions: Psychotic symptoms are common in PD patients, with minor psychotic phenomena present in nearly half of affected patients in a community-based sample. Psychotic symptoms, including minor phenomena, were clinically significant. The NINDS/NIMH PD-psychosis criteria captured the clinical characteristics of psychosis as it relates to PD. Longitudinal studies are needed to determine whether minor psychotic symptoms represent a precursor to hallucinations and delusions, and to further validate diagnostic criteria. (Am J Geriatr Psychiatry 2012; 20:123-132) C1 [Marsh, Laura] Michael E DeBakey VA Med Ctr, Houston, TX 77030 USA. [Marsh, Laura] Baylor Coll Med, Houston, TX 77030 USA. [Mack, Joel; Rabins, Peter; Goldstein, Susanne; Grill, Stephen; Hirsch, Elaina S.; Lehmann, Susan; Little, John T.; Margolis, Russell L.; Palanci, Justin; Pontone, Gregory; Weiss, Howard; Marsh, Laura] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Anderson, Karen] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. [Goldstein, Susanne; Grill, Stephen] Parkinsons & Movement Disorder Ctr Maryland, Baltimore, MD USA. [Little, John T.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Goldstein, Susanne; Williams, James R.] US FDA, Silver Spring, MD USA. RP Marsh, L (reprint author), Michael E DeBakey VA Med Ctr, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM laura.marsh2@va.gov FU NIH [RO1-MH069666]; Morris K. Udall Parkinson's Disease Research Center of Excellence at Johns Hopkins [P50-NS-038377, T32-AG-027668]; Department of Veterans Affairs; Donna Jeanne Gault Baumann Fund; Weldon Hall Trust; Boeringer-Ingelheim; Forest Research Institute; Eli Lilly; Michael J. Fox Foundation FX Supported by grants from the NIH [RO1-MH069666 (MOOD-PD Study), P50-NS-038377 (the Morris K. Udall Parkinson's Disease Research Center of Excellence at Johns Hopkins) and #T32-AG-027668], the Department of Veterans Affairs, the Donna Jeanne Gault Baumann Fund, and the Weldon Hall Trust.; Disclosure of competing interests: Dr. Margolis: Consultant to Astrazeneca ($3000); Dr. Marsh: Grant/Research funding from Boeringer-Ingelheim ($155,480, 4/07-8/09), Forest Research Institute ($154,029, 8/04-12/09), Eli Lilly ($93,727, 11/04-10/08), Michael J. Fox Foundation ($32,352, 1/09-12/09), and NIH ($2,394,225, 7/04 present). NR 42 TC 33 Z9 35 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD FEB PY 2012 VL 20 IS 2 BP 123 EP 132 DI 10.1097/JGP.0b013e31821f1b41 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 883TT UT WOS:000299658500003 PM 21617521 ER PT J AU Speranza, G Gutierrez, ME Kummar, S Strong, JM Parker, RJ Collins, J Yu, YK Cao, L Murgo, AJ Doroshow, JH Chen, A AF Speranza, Giovanna Gutierrez, Martin E. Kummar, Shivaani Strong, John M. Parker, Robert J. Collins, Jerry Yu, Yunkai Cao, Liang Murgo, Anthony J. Doroshow, James H. Chen, Alice TI Phase I study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Triterpenoid; CDDO; Adverse event; Thromboembolism ID ACTIVATED RECEPTOR-GAMMA; ACUTE MYELOGENOUS LEUKEMIA; VENOUS THROMBOSIS; CANCER CELLS; APOPTOSIS; PATHWAY; GROWTH; AGGREGATION; TRAIL; FLIP AB The triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic Acid (CDDO, previously RTA 401) is a multifunctional molecule that controls cellular growth and differentiation. While CDDO is capable of activating the transcription factor peroxisome proliferator activator receptor-gamma (PPAR gamma), its apoptotic effects in malignant cells have been shown to occur independently of PPAR gamma. A phase I dose-escalation study was conducted to determine the toxicity, the maximum tolerated dose, and the pharmacokinetics and pharmacodynamics of CDDO, administered as a 5-day continuous infusion every 28 days in patients with advanced cancers. An accelerated titration design was followed, with one patient per cohort entered, and doses ranging from 0.6 to 38.4 mg/m(2)/h. Pharmacokinetics of CDDO was assessed and cleaved poly (ADP-ribose) polymerase (c-PARP), as a marker of apoptosis, was measured in peripheral blood mononuclear cells to assess drug effect. Seven patients, one patient per dose level up to dose level 7 (38.4 mg/m(2)/h), were enrolled and received a total of 11 courses of treatment. Cmax increased proportionally with dose. Preclinically determined efficacious blood level (1 mu M) of drug was attained at the highest dose level. One patient, at dose level 6, experienced grade 2 mucositis, nausea, vomiting, and anorexia. Four patients developed thromboembolic events subsequently considered as dose-limiting toxicity. No antitumor activity was noted. A causal relationship of observed thromboembolic events to CDDO was considered possible but could not be established. C1 [Speranza, Giovanna; Kummar, Shivaani; Collins, Jerry; Murgo, Anthony J.; Doroshow, James H.; Chen, Alice] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Gutierrez, Martin E.; Kummar, Shivaani; Yu, Yunkai; Cao, Liang; Doroshow, James H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Strong, John M.; Parker, Robert J.] Food & Drug Adm, Ctr Drug Evaluat & Res, Lab Clin Pharmacol, Silver Spring, MD USA. RP Chen, A (reprint author), 6301 Execut Blvd,Suite 7130, Rockville, MD 20852 USA. EM chenali@mail.nih.gov FU NCI NIH HHS [HHSN261200800001E] NR 33 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD FEB PY 2012 VL 69 IS 2 BP 431 EP 438 DI 10.1007/s00280-011-1712-y PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 881UW UT WOS:000299516700016 PM 21805353 ER PT J AU Miksys, SL Uhl, K Tyndale, RF AF Miksys, S. L. Uhl, K. Tyndale, R. F. TI Twenty-First-Century Neuroscience: The Potential for Innovative Therapies for Brain Disorders SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID ALZHEIMERS-DISEASE; CLINICAL-PRACTICE; NERVOUS-SYSTEM; RARE DISEASES C1 [Miksys, S. L.; Tyndale, R. F.] Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Miksys, S. L.; Tyndale, R. F.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Miksys, S. L.; Tyndale, R. F.] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada. [Miksys, S. L.; Tyndale, R. F.] Univ Toronto, Dept Toxicol, Toronto, ON, Canada. [Uhl, K.] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Tyndale, RF (reprint author), Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON, Canada. EM r.tyndale@utoronto.ca FU Canadian Institutes of Health Research [86471, MOP 97751]; NIDA NIH HHS [DA 029160] NR 23 TC 0 Z9 0 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2012 VL 91 IS 2 BP 153 EP 157 DI 10.1038/clpt.2011.310 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 883SC UT WOS:000299654000001 PM 22261679 ER PT J AU Sastalla, I Tang, SX Crown, D Liu, SH Eckhaus, MA Hewlett, IK Leppla, SH Moayeri, M AF Sastalla, Inka Tang, Shixing Crown, Devorah Liu, Shihui Eckhaus, Michael A. Hewlett, Indira K. Leppla, Stephen H. Moayeri, Mahtab TI Anthrax Edema Toxin Impairs Clearance in Mice SO INFECTION AND IMMUNITY LA English DT Article ID BACILLUS-ANTHRACIS; DIPHTHERIA-TOXIN; PROTECTIVE ANTIGEN; WATER CHANNEL; LETHAL TOXIN; ADENYLATE-CYCLASE; CELL CHEMOTAXIS; AQUAPORIN-2; RECEPTOR; PHOSPHORYLATION AB The anthrax edema toxin (ET) of Bacillus anthracis is composed of the receptor-binding component protective antigen (PA) and of the adenylyl cyclase catalytic moiety, edema factor (EF). Uptake of ET into cells raises intracellular concentrations of the secondary messenger cyclic AMP, thereby impairing or activating host cell functions. We report here on a new consequence of ET action in vivo. We show that in mouse models of toxemia and infection, serum PA concentrations were significantly higher in the presence of enzymatically active EF. These higher concentrations were not caused by ET-induced inhibition of PA endocytosis; on the contrary, ET induced increased PA binding and uptake of the PA oligomer in vitro and in vivo through upregulation of the PA receptors TEM8 and CMG2 in both myeloid and nonmyeloid cells. ET effects on protein clearance from circulation appeared to be global and were not limited to PA. ET also impaired the clearance of ovalbumin, green fluorescent protein, and EF itself, as well as the small molecule biotin when these molecules were coinjected with the toxin. Effects on injected protein levels were not a result of general increase in protein concentrations due to fluid loss. Functional markers for liver and kidney were altered in response to ET. Concomitantly, ET caused phosphorylation and activation of the aquaporin-2 water channel present in the principal cells of the collecting ducts of the kidneys that are responsible for fluid homeostasis. Our data suggest that in vivo, ET alters circulatory protein and small molecule pharmacokinetics by an as-yet-undefined mechanism, thereby potentially allowing a prolonged circulation of anthrax virulence factors such as EF during infection. C1 [Sastalla, Inka; Crown, Devorah; Liu, Shihui; Leppla, Stephen H.; Moayeri, Mahtab] NIAID, Bacterial Toxins & Therapeut Sect, NIH, Bethesda, MD 20892 USA. [Tang, Shixing; Hewlett, Indira K.] US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Eckhaus, Michael A.] NIH, Diagnost & Res Serv Branch, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Moayeri, M (reprint author), NIAID, Bacterial Toxins & Therapeut Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mmoayeri@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases; Biodefense Advanced Research and Development Agency, U.S. Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases and Biodefense Advanced Research and Development Agency, U.S. Department of Health and Human Services. NR 54 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD FEB PY 2012 VL 80 IS 2 BP 529 EP 538 DI 10.1128/IAI.05947-11 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 883UU UT WOS:000299661200006 PM 22104108 ER PT J AU Gnjidic, D Le Couteur, DG Abernethy, DR Hilmer, SN AF Gnjidic, Darujela Le Couteur, David G. Abernethy, Darrell R. Hilmer, Sarah N. TI Drug Burden Index and Beers Criteria: Impact on Functional Outcomes in Older People Living in Self-Care Retirement Villages SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE Drug Burden Index; Beers criteria; self-care retirement villages; function; geriatrics ID INAPPROPRIATE MEDICATION USE; LOWER-EXTREMITY FUNCTION; PHYSICAL FUNCTION; BENZODIAZEPINE USE; ELDERLY PERSONS; GRIP STRENGTH; COMMUNITY; PERFORMANCE; ADULTS; DISABILITY AB The objectives of this study were to determine whether Drug Burden Index (DBI), a measure of individuals' exposure to anticholinergic and sedative drugs, and Beers criteria, an explicit measure of potentially inappropriate drug use, are associated with function in older adults living in low-level care facilities; and to compare DBI with Beers criteria as a predictor of function in older people. The study population consisted of 115 residents living in low-level care facilities in Sydney, Australia. Data on demographics, drugs, and comorbidities were collected. Outcomes included objective measures of physical function Short Performance Physical Battery (SPPB) and grip strength. In total, 50 (44%) participants were exposed to DBI drugs, 51 (44%) participants received at least 1 Beers criteria drug, and 30 (26%) were exposed to both. After adjusting for confounders, for every unit increase in DBI, the SPPB score decreased by 1.3 (P = .04). DBI was not associated with weaker grip strength. Beers criteria were not associated with any of the outcomes. In older adults living in self-care retirement villages, DBI was associated with impairments in physical functioning. Exposure to Beers criteria drugs was common; however, Beers criteria did not predict functional outcomes in this population of older adults. C1 [Gnjidic, Darujela] Univ Sydney, Sydney Med Sch, Dept Clin Pharmacol, St Leonards, NSW 2065, Australia. [Gnjidic, Darujela; Hilmer, Sarah N.] Royal N Shore Hosp, Dept Clin Pharmacol, St Leonards, NSW 2065, Australia. [Gnjidic, Darujela; Hilmer, Sarah N.] Royal N Shore Hosp, Dept Aged Care, St Leonards, NSW 2065, Australia. [Le Couteur, David G.] Concord Hosp, Ctr Educ & Res Ageing, Concord, NSW, Australia. [Abernethy, Darrell R.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. RP Gnjidic, D (reprint author), Univ Sydney, Sydney Med Sch, Dept Clin Pharmacol, 11C Main Bldg RNSH, St Leonards, NSW 2065, Australia. EM dgnjidic@med.usyd.edu.au OI Hilmer, Sarah/0000-0002-5970-1501 FU Geoff and Elaine Penney Ageing Research Unit FX The authors gratefully acknowledge the funding support from the Geoff and Elaine Penney Ageing Research Unit, and thank the participating sites and residents who took part in the study. NR 48 TC 17 Z9 18 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD FEB PY 2012 VL 52 IS 2 BP 258 EP 265 DI 10.1177/0091270010395591 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 883TK UT WOS:000299657600012 PM 21292625 ER PT J AU Banda, NK Hyatt, S Antonioli, AH White, JT Glogowska, M Takahashi, K Merkel, TJ Stahl, GL Mueller-Ortiz, S Wetsel, R Arend, WP Holers, VM AF Banda, Nirmal K. Hyatt, Stephanie Antonioli, Alexandra H. White, Jason T. Glogowska, Magdalena Takahashi, Kazue Merkel, Tod J. Stahl, Gregory L. Mueller-Ortiz, Stacey Wetsel, Rick Arend, William P. Holers, V. Michael TI Role of C3a Receptors, C5a Receptors, and Complement Protein C6 Deficiency in Collagen Antibody-Induced Arthritis in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MEMBRANE ATTACK COMPLEX; EFFECTOR PHASE; RHEUMATOID-ARTHRITIS; PASSIVE TRANSFER; ANAPHYLATOXIN RECEPTOR; JOINT DESTRUCTION; DENDRITIC CELLS; ACTIVATION; C5L2; EXPRESSION AB The complement system, especially the alternative pathway, plays essential roles in the induction of injury in collagen Ab-induced arthritis (CAIA) in mice. The goal of the current study was to directly compare the roles of receptors for C3a and C5a, as well as the membrane attack complex, as effector mechanisms in the pathogenesis of CAIA. Clinical disease activity in C3aR(-/-), C5aR(-/-), and C6-deficient (C6-def) mice was decreased by 52, 94, and 65%, respectively, as compared with wild-type mice. Decreases in histopathologic injury as well as in IgG and C3 deposition paralleled the clinical disease activity. A decrease in the percentage of synovial neutrophils was observed in C3aR(-/-), C5aR(-/-), and C6-def mice, and a decrease in macrophages was observed in C3aR(-/-) and C5aR(-/-), but not in C6-def, mice. Synovial mRNA obtained by laser capture microdissection exhibited a decrease in TNF-alpha in C5aR(-/-) mice and in IL-1 beta in both C5aR(-/-) and C6-def mice, whereas C3aR(-/-) mice demonstrated no change in either cytokine. Our findings show that absent C3aR-, C5aR-, or membrane attack complex-initiated effector mechanisms each decrease susceptibility to CAIA, with clinical effects most pronounced in C5aR-deficient mice. Although the absence of C3aR, C5aR, or C6 led to differential deficiencies in effector mechanisms, decreased proximal joint IgG and C3 deposition was common to all three genotypes in comparison with wild-type mice. These data suggest the existence of positive-feedback amplification pathways downstream of all three effectors that promote additional IgG deposition and C3 activation in the joint. The Journal of Immunology, 2012, 188: 1469-1478. C1 [Holers, V. Michael] Univ Colorado, Sch Med, Div Rheumatol, BDC,Dept Med, Aurora, CO 80045 USA. [Banda, Nirmal K.; Hyatt, Stephanie; Antonioli, Alexandra H.; White, Jason T.; Glogowska, Magdalena; Arend, William P.; Holers, V. Michael] Univ Colorado, Sch Med, Dept Immunol, Aurora, CO 80045 USA. [Takahashi, Kazue] Massachusetts Gen Hosp Children, Boston, MA 02114 USA. [Merkel, Tod J.] US FDA, Div Bacterial Prod, Lab Resp Pathogens, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Stahl, Gregory L.] Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Boston, MA 02115 USA. [Mueller-Ortiz, Stacey; Wetsel, Rick] Univ Texas Houston, Inst Mol Med, Houston, TX 77030 USA. RP Holers, VM (reprint author), Univ Colorado, Sch Med, Div Rheumatol, BDC,Dept Med, 1775 Aurora Court,Mail Stop B115,Room M-20-3104, Aurora, CO 80045 USA. EM Michael.Holers@UCDenver.edu FU National Institutes of Health [AR051749] FX This work was supported by National Institutes of Health Grant AR051749 (to V.M.H.). NR 49 TC 41 Z9 43 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2012 VL 188 IS 3 BP 1469 EP 1478 DI 10.4049/jimmunol.1102310 PG 10 WC Immunology SC Immunology GA 884FL UT WOS:000299690200062 PM 22205026 ER PT J AU Hilmer, SN Gnjidic, D Abernethy, DR AF Hilmer, Sarah N. Gnjidic, Danijela Abernethy, Darrell R. TI Pharmacoepidemiology in the Postmarketing Assessment of the Safety and Efficacy of Drugs in Older Adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Pharmacoepidemiology; Drug safety and efficacy; Older adults ID SERUM ANTICHOLINERGIC ACTIVITY; ATYPICAL ANTIPSYCHOTIC MEDICATIONS; TERM-CARE FACILITIES; BURDEN INDEX; PROSPECTIVE COHORT; PHYSICAL FUNCTION; COGNITIVE PERFORMANCE; ELDERLY-PATIENTS; CLINICAL-TRIAL; HIP FRACTURE AB Much of the information on safety and efficacy of drugs in older people is obtained after marketing. Pharmacoepidemiologic studies play an increasing role in obtaining this information. Pharmacoepidemiologic studies contribute significantly to knowledge of risks associated with medicines in older people and less so to that of benefits. Recent improvements in methodology in both pharmacoepidemiology and geriatric medicine have improved the validity and reduced the bias of these studies. Pharmacoepidemiologic studies are a critical component of assessing the risks of medicines in older people. Where possible, findings of pharmacoepidemiologic studies should be tested with well-conducted interventional randomized trials in relevant populations of older people. C1 [Hilmer, Sarah N.; Gnjidic, Danijela] Royal N Shore Hosp, Dept Clin Pharmacol, St Leonards, NSW 2065, Australia. [Hilmer, Sarah N.; Gnjidic, Danijela] Royal N Shore Hosp, Dept Aged Care, St Leonards, NSW 2065, Australia. [Hilmer, Sarah N.; Gnjidic, Danijela] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Gnjidic, Danijela] Concord RG Hosp, CERA, Sydney, NSW, Australia. [Abernethy, Darrell R.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. RP Hilmer, SN (reprint author), Royal N Shore Hosp, Dept Clin Pharmacol, St Leonards, NSW 2065, Australia. EM shilmer@med.usyd.edu.au OI Hilmer, Sarah/0000-0002-5970-1501 FU Geoff and Elaine Penney Ageing Research Unit FX This work was supported by the Geoff and Elaine Penney Ageing Research Unit. NR 95 TC 23 Z9 23 U1 2 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2012 VL 67 IS 2 BP 181 EP 188 DI 10.1093/gerona/glr066 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 885RT UT WOS:000299799200010 PM 21653991 ER PT J AU Sansone, SA Rocca-Serra, P Field, D Maguire, E Taylor, C Hofmann, O Fang, H Neumann, S Tong, WD Amaral-Zettler, L Begley, K Booth, T Bougueleret, L Burns, G Chapman, B Clark, T Coleman, LA Copeland, J Das, S de Daruvar, A de Matos, P Dix, I Edmunds, S Evelo, CT Forster, MJ Gaudet, P Gilbert, J Goble, C Griffin, JL Jacob, D Kleinjans, J Harland, L Haug, K Hermjakob, H Sui, SJH Laederach, A Liang, SG Marshall, S McGrath, A Merrill, E Reilly, D Roux, M Shamu, CE Shang, CA Steinbeck, C Trefethen, A Williams-Jones, B Wolstencroft, K Xenarios, I Hide, W AF Sansone, Susanna-Assunta Rocca-Serra, Philippe Field, Dawn Maguire, Eamonn Taylor, Chris Hofmann, Oliver Fang, Hong Neumann, Steffen Tong, Weida Amaral-Zettler, Linda Begley, Kimberly Booth, Tim Bougueleret, Lydie Burns, Gully Chapman, Brad Clark, Tim Coleman, Lee-Ann Copeland, Jay Das, Sudeshna de Daruvar, Antoine de Matos, Paula Dix, Ian Edmunds, Scott Evelo, Chris T. Forster, Mark J. Gaudet, Pascale Gilbert, Jack Goble, Carole Griffin, Julian L. Jacob, Daniel Kleinjans, Jos Harland, Lee Haug, Kenneth Hermjakob, Henning Sui, Shannan J. Ho Laederach, Alain Liang, Shaoguang Marshall, Stephen McGrath, Annette Merrill, Emily Reilly, Dorothy Roux, Magali Shamu, Caroline E. Shang, Catherine A. Steinbeck, Christoph Trefethen, Anne Williams-Jones, Bryn Wolstencroft, Katherine Xenarios, Ioannis Hide, Winston TI Toward interoperable bioscience data SO NATURE GENETICS LA English DT Editorial Material AB To make full use of research data, the bioscience community needs to adopt technologies and reward mechanisms that support interoperability and promote the growth of an open 'data commoning' culture. Here we describe the prerequisites for data commoning and present an established and growing ecosystem of solutions using the shared 'Investigation-Study-Assay' framework to support that vision. C1 [Sansone, Susanna-Assunta; Rocca-Serra, Philippe; Maguire, Eamonn; Trefethen, Anne] Univ Oxford, Oxford E Res Ctr, Oxford, England. [Field, Dawn; Taylor, Chris; Booth, Tim] Wallingford Ctr Ecol & Hydrol CEH, Environm Bioinformat Ctr, Nat Environm Res Council, Oxford, England. [Taylor, Chris; de Matos, Paula; Haug, Kenneth; Hermjakob, Henning; Steinbeck, Christoph] European Bioinformat Inst, European Mol Biol Lab EMBL Outstn, Cambridge, England. [Hofmann, Oliver; Begley, Kimberly; Chapman, Brad; Sui, Shannan J. Ho; Hide, Winston] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Fang, Hong] US FDA, ICF Int, Natl Ctr Toxicol Res, Jefferson, AR USA. [Neumann, Steffen] Leibniz Inst Plant Biochem, Dept Stress & Dev Biol, Halle, Germany. [Tong, Weida] US FDA, Ctr Bioinformat, Natl Ctr Toxicol Res, Jefferson, AR USA. [Amaral-Zettler, Linda] Marine Biol Lab, Josephine Bay Paul Ctr Comparat Mol Biol & Evolut, Woods Hole, MA 02543 USA. [Begley, Kimberly] Ontario Inst Canc Res Informat & Biocomp, Toronto, ON, Canada. [Bougueleret, Lydie; Xenarios, Ioannis] Swiss Prot Grp, Swiss Inst Bioinformat, Geneva, Switzerland. [Burns, Gully] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. [Clark, Tim; Das, Sudeshna] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Clark, Tim; Das, Sudeshna; Merrill, Emily] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Coleman, Lee-Ann] British Lib, London, England. [Copeland, Jay; Shamu, Caroline E.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [de Daruvar, Antoine] Univ Bordeaux, Lab Bordelais Rech lnformat LaBRI, CNRS, UMR 5800, Talence, France. [de Daruvar, Antoine; Jacob, Daniel] Univ Bordeaux, Ctr Bioinformat Bordeaux CBiB, Bordeaux, France. [Dix, Ian] AstraZeneca Plc, Knowledge Engn & Informat Sci, Discovery Informat, Macclesfield, Cheshire, England. [Edmunds, Scott; Liang, Shaoguang] BGI Shenzhen, Yantian, Peoples R China. [Evelo, Chris T.] Maastricht Univ, Dept Bioinformat BiGCaT, Maastricht, Netherlands. [Evelo, Chris T.] Netherlands Bioinformat Ctr, NBIC Fac, Nijmegen, Netherlands. [Forster, Mark J.] Syngenta RDIS, Bracknell, Berks, England. [Gaudet, Pascale] Northwestern Univ, Ctr Genet Med, Chicago, IL 60611 USA. [Gaudet, Pascale] Swiss Inst Bioinformat Computat Anal & Lab Invest, Geneva, Switzerland. [Gilbert, Jack] Argonne Natl Lab, Argonne, IL 60439 USA. [Goble, Carole; Wolstencroft, Katherine] Univ Manchester, Sch Comp Sci, Manchester, Lancs, England. [Griffin, Julian L.] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England. [Griffin, Julian L.] Univ Cambridge, Cambridge Syst Biol Ctr, Cambridge, England. [Griffin, Julian L.] Med Res Council MRC Human Nutr Res, Elsie Widdowson Lab, Cambridge, England. [Jacob, Daniel] INRA, Fruit Biol & Pathol Ctr, UMR 1332, Villenave Dornon, France. [Kleinjans, Jos] PA Maastricht Univ, Dept Toxicogenom, Netherlands Toxicogenom Ctr, Maastricht, Netherlands. [Harland, Lee; Williams-Jones, Bryn] ConnectedDiscovery, London, England. [Laederach, Alain] Univ N Carolina, Dept Biol, Chapel Hill, NC USA. [Marshall, Stephen; Reilly, Dorothy] Novartis Inst BioMed Res, Quantitat Biol Unit, Cambridge, MA USA. [McGrath, Annette] CSIRO Math Informat & Stat, Canberra, ACT, Australia. [Roux, Magali] CNRS UPS76, Inst Sci & Technol Informat, Vandoeuvre Les Nancy, France. [Roux, Magali] Univ Paris 06, CNRS UMR 7606, Paris, France. [Shang, Catherine A.] Macquarie Univ, Sydney, NSW 2109, Australia. [Xenarios, Ioannis] Vital IT, Swiss Inst Bioinformat, Lausanne, Switzerland. RP Sansone, SA (reprint author), Univ Oxford, Oxford E Res Ctr, Oxford, England. EM susanna-assunta.sansone@oerc.ox.ac.uk RI Steinbeck, Christoph/B-4131-2008; Neumann, Steffen/K-5554-2012; Kleinjans, Jos/E-7241-2015; Trivedi, Kruti/E-7558-2015; Evelo, Chris/D-2914-2009; Haug, Ove Kenneth/D-8694-2017; OI Neumann, Steffen/0000-0002-7899-7192; Evelo, Chris/0000-0002-5301-3142; Haug, Ove Kenneth/0000-0003-3168-4145; Coleman, Lee-Ann/0000-0001-5313-8394; Goble, Carole/0000-0003-1219-2137; Burns, Gully/0000-0003-1493-865X; Hide, Winston/0000-0002-8621-3271; Sansone, Susanna-Assunta/0000-0001-5306-5690; Chapman, Brad/0000-0002-3026-1856; Edmunds, Scott/0000-0001-6444-1436; Laederach, Alain/0000-0002-5088-9907; Hofmann, Oliver/0000-0002-7738-1513; Xenarios, Ioannis/0000-0002-3413-6841 FU Biotechnology and Biological Sciences Research Council [BB/I025840/1, BB/D006422/1, BB/E025080/1, BB/G010218/1, BB/H024921/1, BB/I000771/1, BB/I000860/1, BB/I000917/1, BB/I000933/1, BB/I004637/1, BBG0102181]; Medical Research Council [MC_UP_A090_1006, UD99999906]; NCI NIH HHS [1RC2CA148222-01, RC2 CA148222]; NCRR NIH HHS [S10 RR031865, U24 RR025736, U24-RR025736]; NHGRI NIH HHS [U54 HG006097]; NHLBI NIH HHS [R01 HL111527]; NIGMS NIH HHS [R00 GM079953, R01 GM083871, R01 GM101237, R01-GM083871, U24 GM104203]; NIMH NIH HHS [R21 MH087336] NR 29 TC 109 Z9 110 U1 2 U2 32 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD FEB PY 2012 VL 44 IS 2 BP 121 EP 126 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 883WA UT WOS:000299664400006 PM 22281772 ER PT J AU Triant, VA Josephson, F Rochester, CG Althoff, KN Marcus, K Munk, R Cooper, C D'Agostino, RB Costagliola, D Sabin, CA Williams, PL Hughes, S Post, WS Chandra-Strobos, N Guaraldi, G Young, SS Obenchain, R Bedimo, R Miller, V Strobos, J AF Triant, V. A. Josephson, F. Rochester, C. G. Althoff, K. N. Marcus, K. Munk, R. Cooper, C. D'Agostino, R. B. Costagliola, D. Sabin, C. A. Williams, P. L. Hughes, S. Post, W. S. Chandra-Strobos, N. Guaraldi, G. Young, S. S. Obenchain, R. Bedimo, R. Miller, V. Strobos, J. TI Adverse Outcome Analyses of Observational Data: Assessing Cardiovascular Risk in HIV Disease SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; REVERSE-TRANSCRIPTASE INHIBITORS; INDIVIDUAL ANTIRETROVIRAL DRUGS; CORONARY-HEART-DISEASE; INFECTED PATIENTS; CLINICAL-TRIALS; ABACAVIR USE; THERAPY; EVENTS; COHORT AB Clinical decisions are ideally based on randomized trials but must often rely on observational data analyses, which are less straightforward and more influenced by methodology. The authors, from a series of expert roundtables convened by the Forum for Collaborative HIV Research on the use of observational studies to assess cardiovascular disease risk in human immunodeficiency virus infection, recommend that clinicians who review or interpret epidemiological publications consider 7 key statistical issues: (1) clear explanation of confounding and adjustment; (2) handling and impact of missing data; (3) consistency and clinical relevance of outcome measurements and covariate risk factors; (4) multivariate modeling techniques including timedependent variables; (5) how multiple testing is addressed; (6) distinction between statistical and clinical significance; and (7) need for confirmation from independent databases. Recommendations to permit better understanding of potential methodological limitations include both responsible public access to de-identified source data, where permitted, and exploration of novel statistical methods. C1 [Miller, V.; Strobos, J.] Univ Calif Berkeley, Berkeley Sch Publ Hlth, Washington, DC 20036 USA. [Triant, V. A.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Josephson, F.] Med Prod Agcy, Uppsala, Sweden. [Rochester, C. G.; Marcus, K.; Cooper, C.] US FDA, Silver Spring, MD USA. [Althoff, K. N.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Munk, R.] Univ New Mexico, Sch Med, Dept Internal Med, Div Infect Dis, Albuquerque, NM 87131 USA. [D'Agostino, R. B.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Costagliola, D.] Univ Paris 06, UMR S 943, Paris, France. [Costagliola, D.] INSERM, UMR S 943, Paris, France. [Costagliola, D.] AP HP, Paris, France. [Costagliola, D.] Hop La Pitie Salpetriere, Serv Malad Infect & Trop, Paris, France. [Sabin, C. A.] UCL, Res Dept Infect & Populat Hlth, Sch Med, London WC1E 6BT, England. [Williams, P. L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Hughes, S.] GlaxoSmithKline Inc, Dept Stat, Brentford, Middx, England. [Post, W. S.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Chandra-Strobos, N.] Johns Hopkins Bayview Med Ctr, Dept Med, Div Cardiol, Baltimore, MD USA. [Guaraldi, G.] Univ Modena & Reggio Emilia, Dept Med & Med Specialties, Modena, Italy. [Young, S. S.] Natl Inst Stat Sci, Res Triangle Pk, NC USA. [Obenchain, R.] Risk Benefit Stat LLC, Carmel, IA USA. [Bedimo, R.] Univ Texas SW Med Ctr Dallas, VA N Texas Healthcare Syst, Dallas, TX 75390 USA. [Bedimo, R.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Infect Dis, Dallas, TX 75390 USA. [Strobos, J.] Forum Collaborat HIV Res, Washington, DC USA. RP Strobos, J (reprint author), Univ Calif Berkeley, Berkeley Sch Publ Hlth, 1608 Rhode Isl Ave NW, Washington, DC 20036 USA. EM jur@berkeley.edu RI Costagliola, Dominique/H-5849-2011; OI Costagliola, Dominique/0000-0003-0765-0869; Obenchain, Robert/0000-0002-8395-1666; Guaraldi, Giovanni/0000-0002-5724-3914 FU Forum for Collaborative HIV Research; HAART Oversight Committee; Gilead Sciences; Abbott Laboratories; ViiV Healthcare; Tibotec Therapeutics; Bill and Melinda Gates Foundation; AmfAR; National Institutes of Health; Centers for Disease Control and Prevention; Bristol-Myers Squibb; BD Bio-sciences; bioMerieux; Boehringer Ingelheim Pharmaceuticals; Idenix Pharmaceuticals; Merck Research Laboratories; Monogram Biosciences; Roche Molecular Diagnostics; EMD Serono; Centocor Ortho Biotech; Merck Co.; Abbott; Boehringer-Ingelheim; GlaxoSmithKline; Janssen-Cilag; Merck Sharp Dohme-Chibret; Roche Pharmaceuticals; Janssen Pharmaceuticals FX Support for the series of expert roundtable discussions, at which the need for this article was identified, was graciously provided by the Forum for Collaborative HIV Research, the HAART Oversight Committee, Gilead Sciences, Abbott Laboratories, ViiV Healthcare, and Tibotec Therapeutics. The Forum's HIV activities are supported by the Bill and Melinda Gates Foundation, AmfAR, the National Institutes of Health, the Centers for Disease Control and Prevention, Gilead Sciences, Abbott Laboratories, ViiV Healthcare, Bristol-Myers Squibb, BD Bio-sciences, bioMerieux, Boehringer Ingelheim Pharmaceuticals, Idenix Pharmaceuticals, Merck Research Laboratories, Monogram Biosciences, Roche Molecular Diagnostics, EMD Serono, and Centocor Ortho Biotech.; R. B. receives financial support to provide scientific advice to Merck and Co, Tibotec Therapeutics, Gilead Sciences, EMD Serono, and Abbott and receives research funding from Merck & Co. D. C. receives financial support to provide scientific advice to, and receives grants from, Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme-Chibret, and Roche Pharmaceuticals. S. H. is an employee of GlaxoSmithKline and holds stock options in GlaxoSmithKline. C. A. S. receives financial support for providing scientific advice to Janssen Pharmaceuticals, ViiV Healthcare, Gilead Sciences, and Bristol-Myers Squibb. V. A. T. and K. N. A. are supported by National Institutes of Health grants. C. G. R., K. M., and C. C. are employees of the US government. The views expressed in this article are their individual views and not those of the US government. F. J. is an employee of the Swedish Medical Products Agency (MPA). The views expressed in this article are his individual views, not those of the MPA. J. S. and V. M. are employees of the Forum for Collaborative HIV Research, an administrative unit in the School of Public Health of the University of California, Berkeley. All other authors report no potential conflicts of interest. NR 41 TC 8 Z9 8 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 1 PY 2012 VL 54 IS 3 BP 408 EP 413 DI 10.1093/cid/cir829 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 876SM UT WOS:000299128000022 PM 22095570 ER PT J AU Dreher, MR Sharma, KV Woods, DL Reddy, G Tang, YQ Pritchard, WF Chiesa, OA Karanian, JW Esparza, JA Donahue, D Levy, EB Willis, SL Lewis, AL Wood, BJ AF Dreher, Matthew R. Sharma, Karun V. Woods, David L. Reddy, Goutham Tang, Yiqing Pritchard, William F. Chiesa, Oscar A. Karanian, John W. Esparza, Juan A. Donahue, Danielle Levy, Elliot B. Willis, Sean L. Lewis, Andrew L. Wood, Bradford J. TI Radiopaque Drug-Eluting Beads for Transcatheter Embolotherapy: Experimental Study of Drug Penetration and Coverage in Swine SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID UNRESECTABLE HEPATOCELLULAR-CARCINOMA; RANDOMIZED CONTROLLED TRIAL; ARTERIAL EMBOLIZATION; TRANSARTERIAL CHEMOEMBOLIZATION; LIVER-TUMORS; HEPATIC MALIGNANCIES; RABBIT LIVER; IN-VITRO; MICROSPHERES; DOXORUBICIN AB Purpose: To determine local doxorubicin levels surrounding radiopaque drug-eluting beads (DEBs) in normal swine liver and kidney following transcatheter arterial chemoembolization. The influence of bead size (70-150 mu m or 100-300 mu m) was compared with regard to tissue penetration and spatial distribution of the bead, as well as eventual drug coverage (ie, amount of tissue exposed to drug). Materials and Methods: Radiopaque DEBs were synthesized by suspension polymerization followed by incorporation of iodized oil and doxorubicin. Chemoembolization of swine liver and kidney was performed under fluoroscopic guidance. Three-dimensional tissue penetration of "imageable" DEBs was investigated ex vivo with micro computed tomography (microCT). Drug penetration from the bead surface and drug coverage was evaluated with epifluorescence microscopy, and cellular localization of doxorubicin was evaluated with confocal microscopy. Necrosis was evaluated with hematoxylin and eosin staining. Results: MicroCT demonstrated that 70-150-mu m DEBs were present in more distal arteries and located in a more frequent and homogeneous spatial distribution. Tissue penetration of doxorubicin from the bead appeared similar (similar to 300 mu m) for both DEBs, with a maximum tissue drug concentration at 1 hour coinciding with nuclear localization of doxorubicin. The greater spatial frequency of the 70-150-mu m DEBs resulted in approximately twofold improved drug coverage in kidney. Cellular death is predominantly observed around the DEBs beginning at 8 hours, but increased at 24 and 168 hours. Conclusions: Smaller DEBs penetrated further into targeted tissue (ie, macroscopic) with a higher spatial density, resulting in greater and more uniform drug coverage (ie, microscopic) in swine. C1 [Dreher, Matthew R.; Sharma, Karun V.; Woods, David L.; Reddy, Goutham; Donahue, Danielle; Levy, Elliot B.; Wood, Bradford J.] NCI, Ctr Intervent Oncol, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Pritchard, William F.; Chiesa, Oscar A.; Karanian, John W.; Esparza, Juan A.] US FDA, Ctr Devices & Radiol Hlth, Laurel, MD USA. [Sharma, Karun V.] Georgetown Univ Hosp, Dept Radiol, Washington, DC 20007 USA. [Tang, Yiqing; Willis, Sean L.; Lewis, Andrew L.] Biocompatibles, Farnham, Surrey, England. RP Wood, BJ (reprint author), NCI, Ctr Intervent Oncol, Ctr Clin, NIH, 9000 Rockville Pike,Bldg 10,Room 1C341,MSC 1182, Bethesda, MD 20892 USA. EM bwood@nih.gov OI Lewis, Andrew/0000-0001-5779-5631 FU Biocompatibles (Farnham, UK); National Institutes of Health (NIH); Society of Interventional Radiology Foundation; United States Food and Drug Administration FX B.J.W. and M.R.D. received research support from Biocompatibles (Farnham, UK). ALL., S.L.W., and Y.T. are paid employees of Biocompatibles. None of the other authors have identified a conflict of interest.; This study was conducted in the Center for Interventional Oncology and is supported in part by the Intramural Research Program of the National Institutes of Health (NIH), the Society of Interventional Radiology Foundation Ring Grant, and an Interagency Agreement between the NIH and the United States Food and Drug Administration. NIH and Biocompatibles UK have a Cooperative Research and Development Agreement. NR 39 TC 26 Z9 27 U1 3 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD FEB PY 2012 VL 23 IS 2 BP 257 EP 264 DI 10.1016/j.jvir.2011.10.019 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 883TA UT WOS:000299656600017 PM 22178039 ER PT J AU Xu, P Luthra, P Li, Z Fuentes, S D'Andrea, JA Wu, JG Rubin, S Rota, PA He, BA AF Xu, Pei Luthra, Priya Li, Zhuo Fuentes, Sandra D'Andrea, James Alexander Wu, Jianguo Rubin, Steven Rota, Paul A. He, Biao TI The V Protein of Mumps Virus Plays a Critical Role in Pathogenesis SO JOURNAL OF VIROLOGY LA English DT Article ID CYSTEINE-RICH DOMAIN; MESSENGER-RNA; PARAMYXOVIRUS SIMIAN-VIRUS-5; INTERFERON-BETA; OUTBREAK; GENE; DEGRADATION; ACTIVATION; EXPRESSION; INDUCTION AB Mumps virus (MuV) causes an acute infection in humans characterized by a wide array of symptoms ranging from relatively mild manifestations, such as parotitis, to more-severe complications, such as meningitis and encephalitis. Widespread mumps vaccination has reduced mumps incidence dramatically; however, outbreaks still occur in vaccinated populations. The V protein of MuV, when expressed in cell culture, blocks interferon (IFN) expression and signaling and interleukin-6 (IL-6) signaling. In this work, we generated a recombinant MuV incapable of expressing the V protein (rMuV Delta V). The rescued MuV was derived from a clinical wild-type isolate from a recent outbreak in the United States (MuV(Iowa/US/06), G genotype). Analysis of the virus confirmed the roles of V protein in blocking IFN expression and signaling and IL-6 signaling. We also found that the rMuV(Iowa/US/06)Delta V virus induced high levels of IL-6 expression in vitro, suggesting that V plays a role in reducing IL-6 expression. In vivo, the rMuV(Iowa/US/06)Delta V virus was highly attenuated, indicating that the V protein plays an essential role in viral virulence. C1 [Xu, Pei; Luthra, Priya; Li, Zhuo; Fuentes, Sandra; D'Andrea, James Alexander; He, Biao] Univ Georgia, Coll Vet Med, Dept Infect Dis, Athens, GA 30602 USA. [Xu, Pei; Luthra, Priya] Penn State Univ, Intercoll Grad, Program Cell & Dev Biol, University Pk, PA 16802 USA. [Wu, Jianguo; He, Biao] Wuhan Univ, State Key Lab Virol, Coll Life Sci, Wuhan 430072, Peoples R China. [Wu, Jianguo; He, Biao] Wuhan Univ, Chinese French Liver Dis Res Inst, Zhongnan Hosp, Wuhan 430072, Peoples R China. [Rubin, Steven] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Rota, Paul A.] Ctr Dis Control & Prevent, Atlanta, GA USA. RP He, BA (reprint author), Univ Georgia, Coll Vet Med, Dept Infect Dis, Athens, GA 30602 USA. EM bhe@uga.edu FU NIH [K02 065795]; National Natural Science Foundation of China [30928001] FX This work has been supported by grants from NIH (K02 065795) and National Natural Science Foundation of China Funds for Distinguished Young Scholar-B Plan (No. 30928001 to B.H. and J.W.) NR 44 TC 14 Z9 14 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2012 VL 86 IS 3 BP 1768 EP 1776 DI 10.1128/JVI.06019-11 PG 9 WC Virology SC Virology GA 879CT UT WOS:000299308000043 PM 22090137 ER PT J AU Hoffmann, M Monday, SR Fischer, M Brown, EW AF Hoffmann, M. Monday, S. R. Fischer, M. Brown, E. W. TI Genetic and phylogenetic evidence for misidentification of Vibrio species within the Harveyi clade SO LETTERS IN APPLIED MICROBIOLOGY LA English DT Article DE identification; Harveyi clade; MLSA; molecular genetic; vibrios ID MULTILOCUS SEQUENCE-ANALYSIS; CAMPBELLII AB Aim: This report describes the use of a six-gene multi-locus sequence analysis (MLSA) to correctly identify Vibrio strains of the Harveyi clade. Methods and Results: Vibrio isolates were characterized using a six housekeeping gene MLSA. The study provided evidence supporting: (i) a substantial number of reference strains maintained within commercial culture collections are misidentified taxonomically at the species level; (ii) two V. alginolyticus subclades retain species-level divergence; and (iii) V. communis and V. owensii likely are the same species. Conclusion: A significant number (n = 10) of Harveyi clade Vibrio strains have been inaccurately identified, including evidence that V. communis and V. owensii strains, two recently discovered species assigned to the Harveyi clade, comprise a single species. Significance and Impact of the study: As Harveyi clade vibrios have an enormous impact on human and aquatic animal health, it is of paramount importance to identify members of the Harveyi clade correctly. C1 [Hoffmann, M.] US FDA, Div Microbiol, Off Regulatory Sci, College Pk, MD 20740 USA. [Hoffmann, M.; Fischer, M.] Univ Hamburg, Dept Chem, Inst Food Chem, Hamburg, Germany. RP Hoffmann, M (reprint author), US FDA, Div Microbiol, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM maria.hoffman@fda.hhs.gov RI Fischer, Markus/G-9477-2012 FU Oak Ridge Associated Universities FX This project was supported by an appointment of M. H. to the Research Fellowship Program for the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Associated Universities. NR 13 TC 14 Z9 14 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0266-8254 J9 LETT APPL MICROBIOL JI Lett. Appl. Microbiol. PD FEB PY 2012 VL 54 IS 2 BP 160 EP 165 DI 10.1111/j.1472-765X.2011.03183.x PG 6 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 874WH UT WOS:000298988300013 PM 22118600 ER PT J AU Gnanashanmugam, D Troy, SB Musingwini, G Huang, CH Halpern, MS Stranix-Chibanda, L Shetty, AK Kouiavskaia, D Nathoo, K Chumakov, K Maldonado, YA AF Gnanashanmugam, Devasena Troy, Stephanie B. Musingwini, Georgina Huang, ChunHong Halpern, Meira S. Stranix-Chibanda, Lynda Shetty, Avinash K. Kouiavskaia, Diana Nathoo, Kusum Chumakov, Konstantin Maldonado, Yvonne A. TI Immunologic Response to Oral Polio Vaccine in Human Immunodeficiency Virus-infected and Uninfected Zimbabwean Children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE OPV; polio; HIV; Africa; children ID ANTIBODY-RESPONSE; MUCOSAL IMMUNITY; HIV; IMMUNIZATION; TETANUS; AFRICA; BORN; IMMUNOGENICITY; LYMPHOCYTES; ERADICATION AB Background: Poliovirus eradication is dependent on maintaining adequate community-wide levels of serologic protection. Many African countries with conditions that favor continued wild poliovirus propagation also have a high prevalence of pediatric human immunodeficiency virus (HIV) infection. Data are limited regarding the degree of serologic immunity conferred on HIV-infected children after immunization with oral polio vaccine (OPV). Methods: This was a cross-sectional study correlating HIV infection and neutralizing antibodies against poliovirus serotypes 1, 2, and 3 in 95 Zimbabwean children 2 months to 2 years of age, born to HIV-infected mothers, who received OPV according to the national schedule. Results: HIV-infected children had significantly lower rates of seroconversion to all 3 poliovirus serotypes than HIV-uninfected children (60%, 67%, and 47% vs. 96%, 100%, and 82%, P = 0.001, 0.0003, and 0.015 for serotypes 1, 2, and 3 in HIV-infected and uninfected children, respectively, after >= 3 OPV doses). Among poliovirus seroconverters, HIV-infected children also had significantly lower geometric mean titers against serotypes 1 and 2 than HIV-uninfected children (geometric mean titers: 198 and 317 vs. 1193 and 1056, P = 0.032 and 0.050, for serotypes 1 and 2, respectively, after >= 3 OPV doses). In addition, HIV-infected children had significantly higher levels of total IgG and significantly lower CD4% and mean weight than HIV-uninfected children. Of note, none of the HIV-infected children were receiving antiretroviral therapy, and 71% had a CD4% indicating severe immunodeficiency. Conclusions: Pediatric HIV infection is associated with a poor serologic response to OPV, which could pose an obstacle to global polio eradication. C1 [Troy, Stephanie B.] Eastern Virginia Med Sch, Div Infect Dis, Dept Internal Med, Norfolk, VA 23507 USA. [Gnanashanmugam, Devasena; Troy, Stephanie B.; Huang, ChunHong; Halpern, Meira S.; Maldonado, Yvonne A.] Stanford Univ, Sch Med, Div Pediat Infect Dis, Stanford, CA 94305 USA. [Gnanashanmugam, Devasena] Pharmaceutical Prod Dev Inc PPD, Wilmington, NC USA. [Musingwini, Georgina; Stranix-Chibanda, Lynda; Shetty, Avinash K.; Maldonado, Yvonne A.] Univ Zimbabwe, Dept Community Med ZAPP UZ, Zimbabwe AIDS Prevent Project, Harare, Zimbabwe. [Stranix-Chibanda, Lynda; Nathoo, Kusum] Univ Zimbabwe, Coll Hlth Sci, Dept Paediat & Child Hlth, Harare, Zimbabwe. [Shetty, Avinash K.] Wake Forest Univ, Bowman Gray Sch Med, Div Pediat Infect Dis, Winston Salem, NC USA. [Kouiavskaia, Diana; Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Troy, SB (reprint author), Eastern Virginia Med Sch, Div Infect Dis, Dept Internal Med, 825 Fairfax Ave,Suite 572, Norfolk, VA 23507 USA. EM amadapaah@gmail.com FU Howard G. Buffett Foundation FX This work was supported by a grant from the Howard G. Buffett Foundation, Principal Investigator: Yvonne Maldonado, title: "Eliminating Polio through Safe Vaccination." Y.M. and A.S. have worked on the vaccine advisory board for Merck and Novartis. The authors have no other funding or conflicts of interest to disclose. NR 34 TC 8 Z9 8 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD FEB PY 2012 VL 31 IS 2 BP 176 EP 180 DI 10.1097/INF.0b013e31823faa5f PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 879GA UT WOS:000299316500016 PM 22146742 ER PT J AU Yang, X Greenhaw, J Shi, Q Su, ZQ Qian, F Davis, K Mendrick, DL Salminen, WF AF Yang, Xi Greenhaw, James Shi, Qiang Su, Zhenqiang Qian, Feng Davis, Kelly Mendrick, Donna L. Salminen, William F. TI Identification of Urinary microRNA Profiles in Rats That May Diagnose Hepatotoxicity SO TOXICOLOGICAL SCIENCES LA English DT Article DE microRNA; urinary; hepatotoxicity; biomarkers ID INDUCED LIVER-INJURY; TETRACHLORIDE-INDUCED NEPHROTOXICITY; GENE-EXPRESSION; CARBON-TETRACHLORIDE; ALANINE AMINOTRANSFERASE; BIOMARKERS; DISEASE; CANCER; ACETAMINOPHEN; RNA AB Circulating microRNAs (miRNAs) have emerged as novel noninvasive biomarkers for several diseases and other types of tissue injury. This study tested the hypothesis that changes in the levels of urinary miRNAs correlate with liver injury induced by hepatotoxicants. Sprague-Dawley rats were administered acetaminophen (APAP) or carbon tetrachloride (CCl4) and one nonhepatotoxicant (penicillin/PCN). Urine samples were collected over a 24 h period after a single oral dose of APAP (1250 mg/kg), CCl4 (2000 mg/kg), or PCN (2400 mg/kg). APAP and CCl4 induced liver injury based upon increased serum alanine and aspartate aminotransferase levels and histopathological findings, including liver necrosis. APAP and CCl4 both significantly increased the urinary levels of 44 and 28 miRNAs, respectively. In addition, 10 of the increased miRNAs were in common between APAP and CCl4. In contrast, PCN caused a slight decrease of a different nonoverlapping set of urinary miRNAs. Cluster analysis revealed a distinct urinary miRNA pattern from the hepatotoxicant-treated groups when compared with vehicle controls and PCN. Analysis of hepatic miRNA levels suggested that the liver was the source of the increased urinary miRNAs after APAP exposure; however, the results from CCl4 were equivocal. Computational analysis was used to predict target genes of the 10 shared hepatotoxicant-induced miRNAs. Liver gene expression profiling using whole genome microarrays identified eight putative miRNA target genes that were significantly altered in the liver of APAP- and CCl4-treated animals. In conclusion, the patterns of urinary miRNA may hold promise as biomarkers of hepatotoxicant-induced liver injury. C1 [Yang, Xi; Greenhaw, James; Shi, Qiang; Mendrick, Donna L.; Salminen, William F.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Davis, Kelly] Toxicol Pathol Associates, Frederick, MD USA. [Su, Zhenqiang; Qian, Feng] ICF Int, Fairfax, VA USA. RP Salminen, WF (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM william.salminen@fda.hhs.gov RI Su, Zhenqiang/H-3914-2012; Qiang, Shi/E-6266-2012 FU NCTR; U.S. Department of Energy; U.S. FDA FX X.Y. is supported by the Research Participation Program at the NCTR administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. NR 44 TC 43 Z9 46 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2012 VL 125 IS 2 BP 335 EP 344 DI 10.1093/toxsci/kfr321 PG 10 WC Toxicology SC Toxicology GA 879QD UT WOS:000299346000003 PM 22112502 ER PT J AU Schwartzkopff, F Petersen, F Grimm, TA Brandt, E AF Schwartzkopff, Franziska Petersen, Frank Grimm, Tobias Alexander Brandt, Ernst TI CXC chemokine ligand 4 (CXCL4) down-regulates CC chemokine receptor expression on human monocytes SO INNATE IMMUNITY LA English DT Article DE CCR1; -2; -5; CXCL4; chemokine release; human monocytes; heterologous receptor down-regulation ID ENDOTHELIAL-CELL; TRANSENDOTHELIAL MIGRATION; CHEMOTACTIC CYTOKINES; PLATELET CHEMOKINES; PLATELET-FACTOR-4; PROTEIN; DESENSITIZATION; MACROPHAGES; RANTES; ALPHA AB During acute inflammation, monocytes are essential in abolishing invading micro-organisms and encouraging wound healing. Recruitment by CC chemokines is an important step in targeting monocytes to the inflamed tissue. However, cell surface expression of the corresponding chemokine receptors is subject to regulation by various endogenous stimuli which so far have not been comprehensively identified. We report that the platelet-derived CXC chemokine ligand 4 (CXCL4), a known activator of human monocytes, induces down-regulation of CC chemokine receptors (CCR) 1, -2, and -5, resulting in drastic impairment of monocyte chemotactic migration towards cognate CC chemokine ligands (CCL) for these receptors. Interestingly, CXCL4-mediated down-regulation of CCR1, CCR2 and CCR5 was strongly dependent on the chemokine's ability to stimulate autocrine/paracrine release of TNF-alpha. In turn, TNF-alpha induced the secretion CCL3 and CCL4, two chemokines selective for CCR1 and CCR5, while the secretion of CCR2-ligand CCL2 was TNF-alpha-independent. Culture supernatants of CXCL4-stimulated monocytes as well as chemokine-enriched preparations thereof reproduced CXCL4-induced CCR down-regulation. In conclusion, CXCL4 may act as a selective regulator of monocyte migration by stimulating the release of autocrine, receptor-desensitizing chemokine ligands. Our results stress a co-ordinating role for CXCL4 in the cross-talk between platelets and monocytes during early inflammation. C1 [Brandt, Ernst] Res Ctr Borstel, Dept Immunol & Cell Biol, D-23845 Borstel, Germany. [Grimm, Tobias Alexander] US FDA, Rockville, MD 20857 USA. RP Brandt, E (reprint author), Res Ctr Borstel, Dept Immunol & Cell Biol, Parkallee 22, D-23845 Borstel, Germany. EM ebrandt@fz-borstel.de FU Deutsche Forschungsgemeinschaft [Sonderforschungsbereich 367, C4] FX The authors gratefully acknowledge the supply of platelet concentrates by Dr Gesa Washington and Sonja Schottstaedt (Department of Transfusions Medicine, Universtatsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany). The authors thank Dr Kathleen A. Clouse (FDA, CDER/OBP/DMA, Maryland, USA) for technical support by her laboratory and Dr Holger Heine and Dr Oliver Umland (Immunology and Cell Biology, Research Center Borstel, Borstel, Germany) for their introduction to the light cycler technique. We thank Christine Engellenner, Gabriele Huss, Erika Kaltenhauser and Renate Bergmann for perfect technical assistance. This work was supported, in part, by Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 367, Projekt C4. NR 49 TC 9 Z9 9 U1 0 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1753-4259 J9 INNATE IMMUN-LONDON JI Innate Immun. PD FEB PY 2012 VL 18 IS 1 BP 124 EP 139 DI 10.1177/1753425910388833 PG 16 WC Biochemistry & Molecular Biology; Immunology; Medicine, Research & Experimental; Microbiology SC Biochemistry & Molecular Biology; Immunology; Research & Experimental Medicine; Microbiology GA 877FL UT WOS:000299162600012 PM 21088050 ER PT J AU Yang, X Greenhaw, J Ali, A Shi, Q Roberts, DW Hinson, JA Muskhelishvili, L Beger, R Pence, LM Ando, Y Sun, JC Davis, K Salminen, WF AF Yang, Xi Greenhaw, James Ali, Akhtar Shi, Qiang Roberts, Dean W. Hinson, Jack A. Muskhelishvili, Levan Beger, Richard Pence, Lisa M. Ando, Yosuke Sun, Jinchun Davis, Kelly Salminen, William F. TI Changes in Mouse Liver Protein Glutathionylation after Acetaminophen Exposure SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID S-GLUTATHIONYLATION; REDOX REGULATION; NONHEPATOTOXIC REGIOISOMER; IN-VIVO; MICE; TOXICITY; DISULFIDE; HEPATOTOXICITY; STRESS; INJURY AB The role of protein glutathionylation in acetaminophen (APAP)induced liver injury was investigated in this study. A single oral gavage dose of 150 or 300 mg/kg APAP in B6C3F1 mice produced increased serum alanine aminotransferase and aspartate aminotransferase levels and liver necrosis in a dosedependent manner. The ratio of GSH to GSSG was decreased in a dose-dependent manner, suggesting that APAP produced a more oxidizing environment within the liver. Despite the increased oxidation state, the level of global protein glutathionylation was decreased at 1 h and continued to decline through 24 h. Immunohistochemical localization of glutathionylated proteins showed a complex dynamic change in the lobule zonation of glutathionylated proteins. At 1 h after APAP exposure, the level of glutathionylation decreased in the single layer of hepa-tocytes around the central veins but increased mildly in the remaining centrilobular hepatocytes. This increase correlated with the immunohistochemical localization of APAP covalently bound to protein. Thereafter, the level of glutathionylation decreased dramatically over time in the centrilobular regions with major decreases observed at 6 and 24 h. Despite the overall decreased glutathionylation, a layer of cells lying between the undamaged periportal region and the damaged centrilobular hepatocytes exhibited high levels of glutathionylation at 3 and 6 h in all samples and in some 24-h samples that had milder injury. These temporal and zonal pattern changes in protein glutathionylation after APAP exposure indicate that protein glutathionylation may play a role in protein homeostasis during APAP-induced hepatocellular injury. C1 [Yang, Xi; Greenhaw, James; Ali, Akhtar; Shi, Qiang; Beger, Richard; Pence, Lisa M.; Ando, Yosuke; Sun, Jinchun; Salminen, William F.] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. [Muskhelishvili, Levan; Davis, Kelly] Natl Ctr Toxicol Res, Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Roberts, Dean W.] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Hinson, Jack A.] Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA. RP Salminen, WF (reprint author), US FDA, Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM william.salminen@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [DK081406, R01-DK079008]; Arkansas Children's Hospital Research Institute; Arkansas Biosciences Institute FX X. Y. was supported by the Research Participation Program at the National Center for Toxicological Research, which is administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. D. W. R. was supported, in part, by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK081406], the Arkansas Children's Hospital Research Institute, and the Arkansas Biosciences Institute, the major research component of the Tobacco Settlement Proceeds Act of 2000. J.A.H. was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK079008]. NR 39 TC 10 Z9 11 U1 1 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2012 VL 340 IS 2 BP 360 EP 368 DI 10.1124/jpet.111.187948 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 879IT UT WOS:000299323600014 PM 22045778 ER PT J AU Giri, CP Shima, K Tall, BD Curtis, S Sathyamoorthy, V Hanisch, B Kim, KS Kopecko, DJ AF Giri, Chandrakant P. Shima, Kensuke Tall, Ben D. Curtis, Sherill Sathyamoorthy, Venugopal Hanisch, Brock Kim, Kwang S. Kopecko, Dennis J. TI Cronobacter spp. (previously Enterobacter sakazakii) invade and translocate across both cultured human intestinal epithelial cells and human brain microvascular endothelial cells SO MICROBIAL PATHOGENESIS LA English DT Article DE Transcytosis; Meningitis; Cronobacter sakazakii; Blood-brain barrier; CNS ID INFANT MILK FORMULA; DUBLINENSIS SP-NOV; NECROTIZING ENTEROCOLITIS; RAT MODEL; INVASION; MENINGITIS; VIRULENCE; OMPA; IDENTIFICATION; CYTOSKELETON AB The mechanism of Cronobacter pathogenesis in neonatal meningitis and potential virulence factors (aside from host cell invasion ability) remain largely unknown. To ascertain whether Cronobacter can invade and transcytose across intestinal epithelial cells, enter into the blood stream and then transcytose across the blood-brain-barrier, we have utilized human intestinal INT407 and Caco-2 cells and brain microvascular endothelial cell (HBMEC) monolayers on Transwell filters as experimental model systems. Our data indicate a wide range of heterogeneity with respect to invasion efficiency among twenty-three Cronobacter isolates screened. For selected isolates, we observed significant levels of transcytosis for Cronobacter sakazakii across tight monolayers of both Caco-2 and HBMEC, mimicking in vivo ability to cross the intestine as well as the blood brain barrier, and at a frequency equivalent to that of a control meningitis-causing Escherichia coli K1 strain. Finally, EM analysis demonstrated intracellular Cronobacter bacteria within host vacuoles in HBMEC; as well as transcytosed bacteria at the basolateral surface. These data reveal that certain Cronobacter isolates can invade and translocate across both cultured human intestinal epithelial cells and HBMEC, thus demonstrating a potential path for neonatal infections of the central nervous system (CNS) following oral ingestion. Published by Elsevier Ltd. C1 [Giri, Chandrakant P.; Shima, Kensuke; Hanisch, Brock; Kopecko, Dennis J.] US FDA, Ctr Biol Evaluat & Res, Lab Enter & Sexually Transmitted Dis, DBPAP,OVRR, Bethesda, MD 20892 USA. [Tall, Ben D.; Curtis, Sherill; Sathyamoorthy, Venugopal] US FDA, Ctr Food Safety & Appl Nutr, Div Virulence Assessment, Laurel, MD 20708 USA. [Kim, Kwang S.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Kopecko, DJ (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Enter & Sexually Transmitted Dis, DBPAP,OVRR, HFM-440,29 Lincoln Dr,NIH Campus Bldg 29-420, Bethesda, MD 20892 USA. EM chandrakant.giri@fda.hhs.gov; kensuke.shima@uk-sh.de; ben.tall@fda.hhs.gov; sherill.curtis@fda.hhs.gov; venugopal.sathyamoorthy@fda.hhs.gov; brock.hanisch@fda.hhs.gov; kwangkim@jhmi.edu; dennis.kopecko@fda.hhs.gov OI Tall, Ben/0000-0003-0399-3629 NR 43 TC 14 Z9 17 U1 2 U2 17 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0882-4010 J9 MICROB PATHOGENESIS JI Microb. Pathog. PD FEB PY 2012 VL 52 IS 2 BP 140 EP 147 DI 10.1016/j.micpath.2011.10.003 PG 8 WC Immunology; Microbiology SC Immunology; Microbiology GA 876WY UT WOS:000299139700006 PM 22023990 ER PT J AU Thompson, J Pikis, A AF Thompson, J. Pikis, A. TI Metabolism of sugars by genetically diverse species of oral Leptotrichia SO MOLECULAR ORAL MICROBIOLOGY LA English DT Article DE dental caries; glycosyl hydrolase family 4; Leptotrichia; oral microbiology; phospho-a-glucosidase; sucrose isomers ID PHOSPHO-ALPHA-GLUCOSIDASE; GLUCOSYL-D-FRUCTOSES; STREPTOCOCCUS-MUTANS; BACILLUS-SUBTILIS; FUSOBACTERIUM-MORTIFERUM; KLEBSIELLA-PNEUMONIAE; SUCROSE ISOMERS; ACID PRODUCTION; DENTAL-CARIES; BUCCALIS AB Leptotrichia buccalis ATCC 14201 is a gram-negative, anaerobic rod-shaped bacterium resident in oral biofilm at the tooth surface. The sequenced genome of this organism reveals three contiguous genes at loci: Lebu_1525, Lebu_1526 and Lebu_1527. The translation products of these genes exhibit significant homology with phospho-a-glucosidase (Pagl), a regulatory protein (GntR) and a phosphoenol pyruvate-dependent sugar transport protein (EIICB), respectively. In non-oral bacterial species, these genes comprise the sim operon that facilitates sucrose isomer metabolism. Growth studies showed that L.buccalis fermented a wide variety of carbohydrates, including four of the five isomers of sucrose. Growth on the isomeric disaccharides elicited expression of a 50-kDa polypeptide comparable in size to that encoded by Lebu_1525. The latter gene was cloned, and the expressed protein was purified to homogeneity from Escherichia coli TOP10 cells. In the presence of two cofactors, NAD+ and Mn2+ ions, the enzyme readily hydrolyzed p-nitrophenyl-a-glucopyranoside 6-phosphate (pNPaG6P), a chromogenic analogue of the phosphorylated isomers of sucrose. By comparative sequence alignment, immunoreactivity and signature motifs, the enzyme can be assigned to the phospho-a-glucosidase (Pagl) clade of Family 4 of the glycosyl hydrolase super family. We suggest that the products of Lebu_1527 and Lebu_1525, catalyze the phosphorylative translocation and hydrolysis of sucrose isomers in L.buccalis, respectively. Four genetically diverse, but 16S rDNA-related, species of Leptotrichia have recently been described: L.goodfellowii, L.hofstadii, L.shahii and L.wadei. The phenotypic traits of these new species, with respect to carbohydrate utilization, have also been determined. C1 [Thompson, J.; Pikis, A.] NIDCR, Microbial Biochem & Genet Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Pikis, A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Thompson, J (reprint author), NIDCR, Microbial Biochem & Genet Unit, Oral Infect & Immun Branch, NIH, Bldg 30,Rm 325,Convent Dr,MSC-4350, Bethesda, MD 20892 USA. EM jthompson@dir.nidcr.nih.gov FU NIDCR, National Institutes of Health, Bethesda, MD FX We thank Rick Dreyfuss for assistance with photography and computer graphics and Nga Nguyen for microsequence analyses. This work was supported by the Intramural Research Program of the NIDCR, National Institutes of Health, Bethesda, MD. NR 42 TC 2 Z9 5 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2041-1006 J9 MOL ORAL MICROBIOL JI Mol. Oral Microbiol. PD FEB PY 2012 VL 27 IS 1 BP 34 EP 44 DI 10.1111/j.2041-1014.2011.00627.x PG 11 WC Dentistry, Oral Surgery & Medicine; Microbiology SC Dentistry, Oral Surgery & Medicine; Microbiology GA 874II UT WOS:000298948900004 PM 22230464 ER PT J AU Lee, HY Inselman, AL Kanungo, J Hansen, DK AF Lee, Hyung-yul Inselman, Amy L. Kanungo, Jyotshnabala Hansen, Deborah K. TI Alternative models in developmental toxicology SO SYSTEMS BIOLOGY IN REPRODUCTIVE MEDICINE LA English DT Article; Proceedings Paper CT Symposium on Current Trends in Developmental and Reproductive Toxicology - Biomarkers, Animal Models, Alternative Testing, Risk Assessment, and Regulatory Aspects CY AUG 21-23, 2011 CL Kalamazoo, MI DE alternative models; developmental toxicology; embryonic stem cells; in vitro; whole embryo culture; zebrafish ID STEM-CELL TEST; WHOLE-EMBRYO CULTURE; NEURAL-TUBE DEFECTS; MORPHOLOGICAL SCORING SYSTEM; VITRO EMBRYOTOXICITY TESTS; IN-VITRO; RAT EMBRYOS; MOUSE EMBRYOS; GENE-EXPRESSION; QUANTITATIVE PREDICTION AB In light of various pressures, toxicologists have been searching for alternative methods for safety testing of chemicals. According to a recent policy in the European Union (Regulation, Evaluation Authorisation and Restriction of Chemicals, REACH), it has been estimated that over the next twelve to fifteen years, approximately 30,000 chemicals may need to be tested for safety, and under current guidelines such testing would require the use of approximately 7.2 million laboratory animals [Hofer et al. 2004]. It has also been estimated that over 80% of all animals used for safety testing under REACH legislation would be used for examining reproductive and developmental toxicity [Hofer et al., 2004]. In addition to REACH initiatives, it has been estimated that out of 5,000 to 10,000 new drug entities that a pharmaceutical company may start with, only one is finally approved by the Food and Drug Administration at a cost of over one billion dollars [Garg et al. 2011]. A large portion of this cost is due to animal testing. Therefore, both the pharmaceutical and chemical industries are interested in using alternative models and in vitro tests for safety testing. This review will examine the current state of three alternative models - whole embryo culture (WEC), the mouse embryonic stem cell test (mEST), and zebrafish. Each of these alternatives will be reviewed, and advantages and disadvantages of each model will be discussed. These models were chosen because they are the models most commonly used and would appear to have the greatest potential for future applications in developmental toxicity screening and testing. C1 [Lee, Hyung-yul; Inselman, Amy L.; Hansen, Deborah K.] US FDA, Div Personalized Nutr & Med, NCTR, Jefferson, AR 72079 USA. [Kanungo, Jyotshnabala] US FDA, Div Neurotoxicol, NCTR, Jefferson, AR 72079 USA. RP Hansen, DK (reprint author), US FDA, Div Personalized Nutr & Med, NCTR, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM deborah.hansen@fda.hhs.gov NR 80 TC 14 Z9 14 U1 0 U2 18 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1939-6368 J9 SYST BIOL REPROD MED JI Syst. Biol. Reprod. Med. PD FEB PY 2012 VL 58 IS 1 SI SI BP 10 EP 22 DI 10.3109/19396368.2011.648302 PG 13 WC Andrology; Reproductive Biology SC Endocrinology & Metabolism; Reproductive Biology GA 875TS UT WOS:000299058600003 PM 22239077 ER PT J AU Taylor, JL De Silva, RS Kovacikova, G Lin, W Taylor, RK Skorupski, K Kull, FJ AF Taylor, Jennifer L. De Silva, Rukman S. Kovacikova, Gabriela Lin, Wei Taylor, Ronald K. Skorupski, Karen Kull, F. Jon TI The Crystal Structure of AphB, a Virulence Gene Activator from Vibrio Cholerae, Reveals Residues that Influence its Response to Oxygen and pH SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 56th Annual Meeting of the Biophysical-Society CY FEB 25-29, 2012 CL San Diego, CA SP Biophys Soc C1 [Taylor, Jennifer L.; Kull, F. Jon] Dartmouth Coll, Dept Chem, Hanover, NH 03755 USA. [De Silva, Rukman S.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [Kovacikova, Gabriela; Lin, Wei; Taylor, Ronald K.; Skorupski, Karen] Dartmouth Coll, Dept Microbiol, Hanover, NH 03755 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JAN 31 PY 2012 VL 102 IS 3 SU 1 BP 75A EP 75A PG 1 WC Biophysics SC Biophysics GA 179ZF UT WOS:000321561200379 ER PT J AU Blinova, K Gray, RA AF Blinova, Ksenia Gray, Richard A. TI Optical Screening of Electrical, Mechanical, and Signaling Function on Adult Cardiac Myocytes as Alternative QT-Screen SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 56th Annual Meeting of the Biophysical-Society CY FEB 25-29, 2012 CL San Diego, CA SP Biophys Soc C1 [Blinova, Ksenia; Gray, Richard A.] FDA, Silver Spring, MD USA. RI Gray, Richard/F-3916-2015 OI Gray, Richard/0000-0003-2798-6378 NR 0 TC 0 Z9 0 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JAN 31 PY 2012 VL 102 IS 3 SU 1 BP 543A EP 543A PG 1 WC Biophysics SC Biophysics GA 179ZF UT WOS:000321561203632 ER PT J AU Osmulski, PA Gaczynska, M Karpowicz, P Madabhushi, S Tokmina-Lukaszewska, M Stuart, C Jong, W Mikolajczyk, M Anderson, MC Marszal, E AF Osmulski, Pawel A. Gaczynska, Maria Karpowicz, Przemek Madabhushi, Srividya Tokmina-Lukaszewska, Monika Stuart, Christine Jong, Wesley Mikolajczyk, Malgosia Anderson, Martha C. Marszal, Ewa TI Scanning Probe Microscopy of Serpin Polymers SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 56th Annual Meeting of the Biophysical-Society CY FEB 25-29, 2012 CL San Diego, CA SP Biophys Soc C1 [Osmulski, Pawel A.; Gaczynska, Maria; Karpowicz, Przemek; Madabhushi, Srividya; Tokmina-Lukaszewska, Monika] UTHSCSA, San Antonio, TX USA. [Stuart, Christine; Jong, Wesley; Mikolajczyk, Malgosia; Anderson, Martha C.; Marszal, Ewa] US FDA, Bethesda, DC USA. RI Anderson, Martha/C-1720-2015 OI Anderson, Martha/0000-0003-0748-5525 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JAN 31 PY 2012 VL 102 IS 3 SU 1 BP 589A EP 589A PG 1 WC Biophysics SC Biophysics GA 179ZF UT WOS:000321561204157 ER PT J AU Bhatnagar, J Sim, HM Georgieva, E Kapoor, K Chufan, E Ohnuma, S Borbat, PP Freed, JH Sauna, ZE Ambudkar, SV AF Bhatnagar, Jaya Sim, Hong-May Georgieva, Elka Kapoor, Khyati Chufan, Eduardo Ohnuma, Shinobu Borbat, Peter P. Freed, Jack H. Sauna, Zuben E. Ambudkar, Suresh V. TI Mapping Conformational Changes Associated with the Catalytic Cycle of Human P-Glycoprotein (ABCB1) SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 56th Annual Meeting of the Biophysical-Society CY FEB 25-29, 2012 CL San Diego, CA SP Biophys Soc C1 [Bhatnagar, Jaya; Sim, Hong-May; Kapoor, Khyati; Chufan, Eduardo; Ohnuma, Shinobu; Ambudkar, Suresh V.] NCI, NIH, Bethesda, MD 20892 USA. [Georgieva, Elka; Borbat, Peter P.; Freed, Jack H.] Cornell Univ, Natl Biomed Ctr Adv ESR Technol, ACERT, Ithaca, NY USA. [Sauna, Zuben E.] US FDA, Div Hematol, CBER, Bethesda, MD 20014 USA. RI Borbat, Petr/A-8658-2014; borbat, peter/B-1616-2016 NR 0 TC 0 Z9 0 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JAN 31 PY 2012 VL 102 IS 3 SU 1 BP 606A EP 607A PG 2 WC Biophysics SC Biophysics GA 179ZF UT WOS:000321561204245 ER PT J AU Ou, W Delisle, J Jacques, J Shih, J Price, G Kuhn, JH Wang, V Verthelyi, D Kaplan, G Wilson, CA AF Ou, Wu Delisle, Josie Jacques, Jerome Shih, Joanna Price, Graeme Kuhn, Jens H. Wang, Vivian Verthelyi, Daniela Kaplan, Gerardo Wilson, Carolyn A. TI Induction of ebolavirus cross-species immunity using retrovirus-like particles bearing the Ebola virus glycoprotein lacking the mucin-like domain SO VIROLOGY JOURNAL LA English DT Article DE Ebola; Ebolavirus; Envelope glycoprotein; Filovirus; Mucin-like domain; Retrovirus; Virus-like particles; DNA vaccine ID DNA VACCINES; PROTECTIVE EFFICACY; NONHUMAN-PRIMATES; PROTEINS CD55; INSECT CELLS; INFECTION; EPITOPES; IMMUNOGENICITY; IMMUNIZATION; RESPONSES AB Background: The genus Ebolavirus includes five distinct viruses. Four of these viruses cause hemorrhagic fever in humans. Currently there are no licensed vaccines for any of them; however, several vaccines are under development. Ebola virus envelope glycoprotein (GP(1,2)) is highly immunogenic, but antibodies frequently arise against its least conserved mucin-like domain (MLD). We hypothesized that immunization with MLD-deleted GP(1,2) (GP Delta MLD) would induce cross-species immunity by making more conserved regions accessible to the immune system. Methods: To test this hypothesis, mice were immunized with retrovirus-like particles (retroVLPs) bearing Ebola virus GP Delta MLD, DNA plasmids (plasmo-retroVLP) that can produce such retroVLPs in vivo, or plasmo-retroVLP followed by retroVLPs. Results: Cross-species neutralizing antibody and GP(1,2)-specific cellular immune responses were successfully induced. Conclusion: Our findings suggest that GP Delta MLD presented through retroVLPs may provide a strategy for development of a vaccine against multiple ebolaviruses. Similar vaccination strategies may be adopted for other viruses whose envelope proteins contain highly variable regions that may mask more conserved domains from the immune system. C1 [Ou, Wu; Delisle, Josie; Price, Graeme; Wilson, Carolyn A.] US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. [Jacques, Jerome; Kaplan, Gerardo] US FDA, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Bethesda, MD 20892 USA. [Shih, Joanna] NCI, Biometr Res Branch, Rockville, MD USA. [Kuhn, Jens H.] NIAID, NIH, Integrated Res Facil Ft Detrick, Frederick, MD USA. [Wang, Vivian; Verthelyi, Daniela] US FDA, Ctr Drug Evaluat & Review, Div Therapeut Prot, Off Biotechnol Prod, Bethesda, MD 20892 USA. RP Wilson, CA (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Bldg 29B,Room 5NN22,8800 Rockville Pike, Bethesda, MD 20892 USA. EM carolyn.wilson@fda.hhs.gov RI Kuhn, Jens H./B-7615-2011 OI Kuhn, Jens H./0000-0002-7800-6045 FU Biomedical Advanced Research and Development Authority (BARDA); NIAID [HHSN272200200016I] FX We thank Julia Misplon and Chia-Yun Lo for their advice and input into the design of some of the immunologic evaluations performed in these studies. This research was partially supported by an inter-agency agreement with the Biomedical Advanced Research and Development Authority (BARDA). In addition, we thank Ronald Rabin and Andrew Byrnes for their critical review of the manuscript.; JHK performed this work as an employee of Tunnell Consulting, Inc., a subcontractor to Battelle Memorial Institute under its prime contract with NIAID, under Contract No. HHSN272200200016I. NR 55 TC 6 Z9 7 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD JAN 25 PY 2012 VL 9 AR 32 DI 10.1186/1743-422X-9-32 PG 13 WC Virology SC Virology GA 950NE UT WOS:000304655200001 PM 22273269 ER PT J AU Shao, L Fan, XH Cheng, NT Wu, LH Xiong, HS Fang, H Ding, D Shi, LM Cheng, YY Tong, WD AF Shao, Li Fan, Xiaohui Cheng, Ningtao Wu, Leihong Xiong, Haoshu Fang, Hong Ding, Don Shi, Leming Cheng, Yiyu Tong, Weida TI Shifting from Population-wide to Personalized Cancer Prognosis with Microarrays SO PLOS ONE LA English DT Article ID GENE-EXPRESSION PROFILES; BREAST-CANCER; CLASSIFICATION; PREDICTION; CYCLOPHOSPHAMIDE; FLUOROURACIL; CHEMOTHERAPY; DOXORUBICIN; CARCINOMAS; PACLITAXEL AB The era of personalized medicine for cancer therapeutics has taken an important step forward in making accurate prognoses for individual patients with the adoption of high-throughput microarray technology. However, microarray technology in cancer diagnosis or prognosis has been primarily used for the statistical evaluation of patient populations, and thus excludes inter-individual variability and patient-specific predictions. Here we propose a metric called clinical confidence that serves as a measure of prognostic reliability to facilitate the shift from population-wide to personalized cancer prognosis using microarray-based predictive models. The performance of sample-based models predicted with different clinical confidences was evaluated and compared systematically using three large clinical datasets studying the following cancers: breast cancer, multiple myeloma, and neuroblastoma. Survival curves for patients, with different confidences, were also delineated. The results show that the clinical confidence metric separates patients with different prediction accuracies and survival times. Samples with high clinical confidence were likely to have accurate prognoses from predictive models. Moreover, patients with high clinical confidence would be expected to live for a notably longer or shorter time if their prognosis was good or grim based on the models, respectively. We conclude that clinical confidence could serve as a beneficial metric for personalized cancer prognosis prediction utilizing microarrays. Ascribing a confidence level to prognosis with the clinical confidence metric provides the clinician an objective, personalized basis for decisions, such as choosing the severity of the treatment. C1 [Shao, Li; Fan, Xiaohui; Wu, Leihong; Xiong, Haoshu; Cheng, Yiyu] Zhejiang Univ, Coll Pharmaceut Sci, Pharmaceut Informat Inst, Hangzhou 310003, Zhejiang, Peoples R China. [Cheng, Ningtao] Emory Univ, Atlanta, GA 30322 USA. [Cheng, Ningtao] Georgia Inst Technol, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. [Fang, Hong; Ding, Don] ICF Int NCTR FDA, Jefferson, AR USA. [Shi, Leming; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Shao, L (reprint author), Zhejiang Univ, Coll Pharmaceut Sci, Pharmaceut Informat Inst, Hangzhou 310003, Zhejiang, Peoples R China. EM chengyy@zju.edu.cn; weida.tong@fda.hhs.gov OI Wu, Leihong/0000-0002-4093-3708 FU National Science Foundation of China [30801556, 30830121]; National ST Major Project [2008ZX09312-001]; Science Foundation of Chinese University [2009QNA7031]; Zhejiang Provincial Natural Science Foundation of China [R2080693] FX This work was supported by the National Science Foundation of China (No. 30801556 and 30830121), National S&T Major Project (No. 2008ZX09312-001), Science Foundation of Chinese University (No. 2009QNA7031), and the Zhejiang Provincial Natural Science Foundation of China (No. R2080693). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 4 Z9 4 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 25 PY 2012 VL 7 IS 1 AR e29534 DI 10.1371/journal.pone.0029534 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 910ME UT WOS:000301640600005 PM 22295060 ER PT J AU Allard, MW Luo, Y Strain, E Li, C Keys, CE Son, I Stones, R Musser, SM Brown, EW AF Allard, Marc W. Luo, Yan Strain, Errol Li, Cong Keys, Christine E. Son, Insook Stones, Robert Musser, Steven M. Brown, Eric W. TI High resolution clustering of Salmonella enterica serovar Montevideo strains using a next-generation sequencing approach SO BMC GENOMICS LA English DT Article ID FIELD GEL-ELECTROPHORESIS; ESCHERICHIA-COLI O157-H7; VARIABLE NUMBER; HIGH-THROUGHPUT; SEROTYPES; DNA; PHYLOGENY; EVOLUTION; ALIGNMENT; ACCURACY AB Background: Next-Generation Sequencing (NGS) is increasingly being used as a molecular epidemiologic tool for discerning ancestry and traceback of the most complicated, difficult to resolve bacterial pathogens. Making a linkage between possible food sources and clinical isolates requires distinguishing the suspected pathogen from an environmental background and placing the variation observed into the wider context of variation occurring within a serovar and among other closely related foodborne pathogens. Equally important is the need to validate these high resolution molecular tools for use in molecular epidemiologic traceback. Such efforts include the examination of strain cluster stability as well as the cumulative genetic effects of sub-culturing on these clusters. Numerous isolates of S. Montevideo were shot-gun sequenced including diverse lineage representatives as well as numerous replicate clones to determine how much variability is due to bias, sequencing error, and or the culturing of isolates. All new draft genomes were compared to 34 S. Montevideo isolates previously published during an NGS-based molecular epidemiological case study. Results: Intraserovar lineages of S. Montevideo differ by thousands of SNPs, that are only slightly less than the number of SNPs observed between S. Montevideo and other distinct serovars. Much less variability was discovered within an individual S. Montevideo clade implicated in a recent foodborne outbreak as well as among individual NGS replicates. These findings were similar to previous reports documenting homopolymeric and deletion error rates with the Roche 454 GS Titanium technology. In no case, however, did variability associated with sequencing methods or sample preparations create inconsistencies with our current phylogenetic results or the subsequent molecular epidemiological evidence gleaned from these data. Conclusions: Implementation of a validated pipeline for NGS data acquisition and analysis provides highly reproducible results that are stable and predictable for molecular epidemiological applications. When draft genomes are collected at 15x-20x coverage and passed through a quality filter as part of a data analysis pipeline, including sub-passaged replicates defined by a few SNPs, they can be accurately placed in a phylogenetic context. This reproducibility applies to all levels within and between serovars of Salmonella suggesting that investigators using these methods can have confidence in their conclusions. C1 [Allard, Marc W.; Li, Cong; Keys, Christine E.; Son, Insook; Musser, Steven M.; Brown, Eric W.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Luo, Yan; Strain, Errol] US FDA, Off Food Def Commun & Emergency Response, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Stones, Robert] Food & Environm Res Agcy, York YO41 1LZ, N Yorkshire, England. RP Allard, MW (reprint author), US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Marc.Allard@fda.hhs.gov FU CFSAN-FDA FX We thank the NCBI rapid annotation pipeline team, Bill Klimke, Dmitry Dernovoy, Stacy Ciufo, Ruth Timme, Kathleen O'Neill, Azat Badretdin and Tatiana Tatusova, for key genome annotation services, and Charlie Wang and Guojie Cao for expert data collection. We acknowledge David Weingaertner for excellent graphical support, and would also like to thank Donald Zink, John Guzewich, Sherri McGarry, Mickey Parrish, Kathy Gombas, Roberta Wagner, Donald Kraemer, and Michael Landa from CFSAN-FDA for program support and for important epidemiological and investigatory insights as well as important discussion of our manuscript. We would also like to acknowledge our FDA-ORA regional field laboratories in Denver, Arkansas, and Atlanta for providing key outbreak and historical isolates along with the Iowa, Connecticut, North Carolina, Maryland, Ohio, California, and Rhode Island State Departments of Public Health for generous contributions of additional clinical S. Montevideo isolates. In particular, we would like to acknowledge Stacey Kinney (Connecticut Department of Health) and Mary DiMartino (Iowa Department of Health) for providing key human-food matching pairs of S. Montevideo. Mark Wilson, Peter Evans, Stephanie Defibaugh-Chavez, Kurt Lienau, Peter Gerner-Smidt, and several anonymous people also provided helpful reviews. No human subjects or animals were used in this study. All authors have read the manuscript and agree to its content, subject matter, and author line order. These data are novel and have not been previously published elsewhere. Disclosure forms provided by the authors will be available with the full text of this article. NR 39 TC 50 Z9 51 U1 4 U2 24 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JAN 19 PY 2012 VL 13 AR 32 DI 10.1186/1471-2164-13-32 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 954CG UT WOS:000304923100001 PM 22260654 ER PT J AU Cheng, YZ Kwon, DY Arai, AL Mucci, D Kassis, JA AF Cheng, Yuzhong Kwon, Deborah Y. Arai, Allison L. Mucci, Diane Kassis, Judith A. TI P-Element Homing Is Facilitated by engrailed Polycomb-Group Response Elements in Drosophila melanogaster SO PLOS ONE LA English DT Article ID ENHANCER-PROMOTER COMMUNICATION; GENE DISRUPTION PROJECT; TRANSPOSABLE ELEMENT; BITHORAX COMPLEX; EXPRESSION; REGION; TRANSCRIPTION; CHROMOSOME; CHROMATIN; PROTEINS AB P-element vectors are commonly used to make transgenic Drosophila and generally insert in the genome in a nonselective manner. However, when specific fragments of regulatory DNA from a few Drosophila genes are incorporated into P-transposons, they cause the vectors to be inserted near the gene from which the DNA fragment was derived. This is called P-element homing. We mapped the minimal DNA fragment that could mediate homing to the engrailed/invected region of the genome. A 1.6 kb fragment of engrailed regulatory DNA that contains two Polycomb-group response elements (PREs) was sufficient for homing. We made flies that contain a 1.5kb deletion of engrailed DNA (en(Delta 1.5)) in situ, including the PREs and the majority of the fragment that mediates homing. Remarkably, homing still occurs onto the en(Delta 1.5) chromosome. In addition to homing to en, P[en] inserts near Polycomb group target genes at an increased frequency compared to P[EPgy2], a vector used to generate 18,214 insertions for the Drosophila gene disruption project. We suggest that homing is mediated by interactions between multiple proteins bound to the homing fragment and proteins bound to multiple areas of the engrailed/invected chromatin domain. Chromatin structure may also play a role in homing. C1 [Cheng, Yuzhong; Kwon, Deborah Y.; Arai, Allison L.; Kassis, Judith A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Mucci, Diane] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Cheng, YZ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM jkassis@mail.nih.gov OI Kassis, Judith/0000-0001-9268-3213 FU National Institutes of Health, National Institute of Child Health and Human Development (NIH, NICHD); Cystic Fibrosis Foundation FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Child Health and Human Development (NIH, NICHD). Diane Mucci was supported by a grant from the Cystic Fibrosis Foundation. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 35 TC 9 Z9 9 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 19 PY 2012 VL 7 IS 1 AR e30437 DI 10.1371/journal.pone.0030437 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 907YS UT WOS:000301457200062 PM 22276200 ER PT J AU Rahman, Z Zidan, AS Berendt, RT Khan, MA AF Rahman, Ziyaur Zidan, Ahmed S. Berendt, Robert T. Khan, Mansoor A. TI Tannate complexes of antihistaminic drug: Sustained release and taste masking approaches SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Brompheniramine maleate; Tannic acid; Complex; Solid-state NMR; Electronic tongue; Bitter taste ID TANNIC-ACID; NMR; FORMULATION; DELIVERY; SOLIDS; PRINCIPLE; CHITOSAN; TABLET; SALTS AB The aim of this investigation was to evaluate the complexation potential of brompheniramine maleate (BPM) and tannic acid (TA) for sustained release and taste masking effects. The complexes (1:1-1:7 TA to BPM ratio) were prepared by the solvent evaporation method using methanol, phosphate buffer pH 6.8 or 0.1 N HCl as common solvents. The complexes were characterized microscopically by scanning electron microscopy (SEM), chemically by Fourier transform infrared (FTIR) and solid-state NMR (SSNMR), thermally by differential scanning calorimetry (DSC), for crystallinity by powder X-ray powder diffraction (PXRD), for organoleptic evaluation by electronic tongue (e-tongue), and for solubility in 0.1 N HCl and phosphate buffer pH 6.8. The dissolution studies were carried out using the USP II method at 50 rpm in 500 ml of dissolution media (0.1 N HCl or phosphate buffer pH 6.8). SEM images revealed that the morphology of complexes were completely different from the individual components, and all complexes had the same morphological characteristics, irrespective of the solvent used for their preparation, pH or ratio of BPM and TA. The FTIR spectra showed the presence of chemical interactions between the TA and BPM. DSC, PXRD and SSNMR indicated that the drug lost its crystalline nature by formation of the complex. Complexation has significantly reduced the solubility of BPM and sustained the drug release up to 24 h in phosphate buffer pH 6.8 media. The bitter taste of the BPM was completely masked which was indicated by Euclidean distance values which was far from the drug but near to its placebo in the complexes in all ratios studied. The taste masked complexes can be potentially developed as suitable dosage forms for pediatric use. In summary, complexation of BPM and TA effectively sustained the dissolution and masked the bitter taste of drug for the development of suitable dosage forms for pediatric use. Published by Elsevier B.V. C1 [Rahman, Ziyaur; Zidan, Ahmed S.; Berendt, Robert T.; Khan, Mansoor A.] US FDA, CDER, DPQR, Silver Spring, MD 20993 USA. [Zidan, Ahmed S.] Zagazig Univ, Fac Pharm, Zagazig, Egypt. RP Khan, MA (reprint author), US FDA, CDER, DPQR, LS Bldg 64,Room 1070,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mansoor.Khan@fda.hhs.gov RI Zidan, Ahmed/I-1147-2012; OI Rahman, Ziyaur/0000-0002-0402-825X FU National Institute of Health (IAA) [Y1-HD-0052-01]; Oak Ridge Institute for Science and Education (ORISE) FX The authors would like to thank the Oak Ridge Institute for Science and Education (ORISE) for supporting the post doctoral research program and Dr. Samy Raghu for assisting in running solution NMR experiment. This work was supported in part by a funding from National Institute of Health (IAA, Y1-HD-0052-01). NR 51 TC 10 Z9 11 U1 0 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARMACEUT JI Int. J. Pharm. PD JAN 17 PY 2012 VL 422 IS 1-2 BP 91 EP 100 DI 10.1016/j.ijpharm.2011.10.033 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 920IV UT WOS:000302398700013 PM 22037447 ER PT J AU Tang, XB Tian, LJ Esteso, G Choi, SC Barrow, AD Colonna, M Borrego, F Coligan, JE AF Tang, Xiaobin Tian, Linjie Esteso, Gloria Choi, Seung-Chul Barrow, Alexander D. Colonna, Marco Borrego, Francisco Coligan, John E. TI Leukocyte-Associated Ig-like Receptor-1-Deficient Mice Have an Altered Immune Cell Phenotype SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; DISCOIDIN DOMAIN RECEPTOR-1; ZONE B-CELLS; T-CELLS; INHIBITORY RECEPTOR; DENDRITIC CELLS; TYROSINE-PHOSPHATASE; COLLAGEN INTERACTION; AUTOIMMUNE-DISEASES; ACTIVATION AB Cross-linking of the collagen binding receptor leukocyte-associated Ig-like receptor-1 (LAIR-1) in vitro delivers an inhibitory signal that is able to downregulate activation-mediated signals. To study the in vivo function of LAIR-1, we generated LAIR-1(-/-) mice. They are healthy and fertile and have normal longevity; however, they show certain phenotypic characteristics distinct from wildtype mice, including increased numbers of splenic B, regulatory T, and dendritic cells. As LAIR-1(-/-) mice age, the splenic T cell population shows a higher frequency of activated and memory T cells. Because LAIR-1(+/+) and LAIR-1(-/-) T cells traffic with equal proficiency to peripheral lymphoid organs, this is not likely due to abnormal T lymphocyte trafficking. LAIR-1(-/-) mice have lower serum levels of IgG1 and, in response to T-dependent immunization with trinitrophenyl-OVA, switch less efficiently to Ag specific IgG2a and IgG2b, whereas switching to IgG1 is not affected. Several mouse disease models, including experimental autoimmune encephalitis and colitis, were used to examine the effect of LAIR-1 deficiency, and no differences in the responses of LAIR-1(-/-) and LAIR-1(+/+) mice were observed. Taken together, these observations indicate that LAIR-1 plays a role in regulating immune cells and suggest that any adverse effects of its absence may be balanced in vivo by other inhibitory receptors. The Journal of Immunology, 2012, 188: 548-558. C1 [Tang, Xiaobin; Tian, Linjie; Esteso, Gloria; Choi, Seung-Chul; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Barrow, Alexander D.; Colonna, Marco] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Borrego, Francisco] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. RP Coligan, JE (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Twinbrook 2,Room 205,12441 Parklawn Dr, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov RI Tian, Linjie/E-6878-2014; OI Colonna, Marco/0000-0001-5222-4987 FU National Institute of Allergy and Infectious Diseases; European Commission FX This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases. A. D. B. is the recipient of a Marie Curie International Outgoing fellowship from the European Commission Framework Programme (FP)7. NR 58 TC 16 Z9 19 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2012 VL 188 IS 2 BP 548 EP 558 DI 10.4049/jimmunol.1102044 PG 11 WC Immunology SC Immunology GA 879IU UT WOS:000299323700007 PM 22156345 ER PT J AU Mac Mahon, S Begley, TH Diachenko, GW Stromgren, SA AF Mac Mahon, Shaun Begley, Timothy H. Diachenko, Gregory W. Stromgren, Selen A. TI A liquid chromatography-tandem mass spectrometry method for the detection of economically motivated adulteration in protein-containing foods SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Melamine; Economic adulteration; Mass spectrometry; Protein ID MELAMINE; MILK; CATS; DOGS; UREA AB A new analytical method was developed to determine the presence of six (6) compounds with the potential to be used in economic adulteration to enhance the nitrogen content in milk products and bulk proteins. Residues were extracted from the matrix with 2% formic acid, after which acetonitrile (ACN) was added to induce precipitation of the proteins. Extracts were analyzed by liquid chromatography using a ZIC-HILIC column with tandem mass spectrometry (LC-MS/MS) using electrospray ionization (ESI). Single-laboratory method validation data was collected in six matrices fortified at concentrations down to 1.0 mu g/g (ppm). Average recoveries and average relative standard deviations (RSD) using spiked matrix calibration standard curves were the following: cyromazine (CY) 95.9% (7.5% RSD), dicyandiamide (DC) 98.1% (5.6% RSD), urea 102.5% (8.6% RSD), biuret (BU) 97.2% (6.6% RSD), triuret (TU) 97.7% (5.7% RSD), and amidinourea (AU) 93.4% (7.4% RSD). This method provides a rapid and effective approach to proactively combat economically motivated adulteration in protein-containing products. Published by Elsevier B.V. C1 [Mac Mahon, Shaun; Begley, Timothy H.; Diachenko, Gregory W.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Stromgren, Selen A.] US FDA, Off Reg Operat, Div Field Sci, Rockville, MD 20857 USA. RP Mac Mahon, S (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM shaun.macmahon@fda.hhs.gov NR 17 TC 48 Z9 51 U1 5 U2 60 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD JAN 13 PY 2012 VL 1220 BP 101 EP 107 DI 10.1016/j.chroma.2011.11.066 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 882TE UT WOS:000299586000014 PM 22197251 ER PT J AU Dal Pan, GJ Temple, R AF Dal Pan, Gerald J. Temple, Robert TI Balancing Transparency and Uncertainty SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Dal Pan, Gerald J.] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Dal Pan, GJ (reprint author), US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22,Room 4304, Silver Spring, MD 20993 USA. EM gerald.dalpan@fda.hhs.gov NR 9 TC 5 Z9 5 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JAN 9 PY 2012 VL 172 IS 1 BP 74 EP 75 DI 10.1001/archinternmed.2011.546 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 874LM UT WOS:000298958900020 PM 22082709 ER PT J AU Maruvada, S Liu, Y Pritchard, WF Herman, BA Harris, GR AF Maruvada, S. Liu, Y. Pritchard, W. F. Herman, B. A. Harris, G. R. TI Comparative study of temperature measurements in ex vivo swine muscle and a tissue-mimicking material during high intensity focused ultrasound exposures SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID EXPERIMENTAL VALIDATION; HIFU; CAVITATION; MODEL AB Tissue-mimicking materials (TMMs) can provide a convenient, stable, and reproducible means for testing high intensity focused ultrasound (HIFU) devices. When TMMs containing thermal sensors are used to measure ultrasound-induced temperature rise, it is important that measurement results reasonably represent those that occur in biological tissue. Therefore the aim of this paper is to compare the thermal behavior of the TMM under HIFU exposure to that of ex vivo tissue. This was accomplished using both a previously developed TMM and fresh ex vivo swine muscle that were instrumented with bare 50 mu m thin wire thermocouples. HIFU at 825 kHz was focused at the thermocouple junction. 30 s exposures of increasing peak negative pressure (1 to 5 MPa) were applied and the temperature profile during and after sonication was recorded. B-mode imaging was used to monitor bubble activity during sonication. If bubble formation was noted during the sonication, the sonication was repeated at the same pressure levels two more times at 20 min intervals. Temperature traces obtained at various pressure levels demonstrated similar types of heating profiles in both the tissue and TMM, the exact nature of which depended on whether bubbles formed during the HIFU exposure. The onset of bubble activity occurred at lower ultrasonic pressures in the TMM, but the basic temperature rise features due to HIFU exposure were essentially the same for both materials. C1 [Maruvada, S.; Liu, Y.; Pritchard, W. F.; Herman, B. A.; Harris, G. R.] US FDA, Ctr Device & Radiol Hlth, Silver Spring, MD 20993 USA. RP Maruvada, S (reprint author), US FDA, Ctr Device & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM subha.maruvada@fda.hhs.gov NR 30 TC 9 Z9 9 U1 0 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JAN 7 PY 2012 VL 57 IS 1 BP 1 EP 19 DI 10.1088/0031-9155/57/1/1 PG 19 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 863FH UT WOS:000298147700002 PM 22127191 ER PT J AU Modi, BG Neustadter, J Binda, E Lewis, J Filler, RB Roberts, SJ Kwong, BY Reddy, S Overton, JD Galan, A Tigelaar, R Cai, LN Fu, P Shlomchik, M Kaplan, DH Hayday, A Girardi, M AF Modi, Badri G. Neustadter, Jason Binda, Elisa Lewis, Julia Filler, Renata B. Roberts, Scott J. Kwong, Bernice Y. Reddy, Swapna Overton, John D. Galan, Anjela Tigelaar, Robert Cai, Lining Fu, Peter Shlomchik, Mark Kaplan, Daniel H. Hayday, Adrian Girardi, Michael TI Langerhans Cells Facilitate Epithelial DNA Damage and Squamous Cell Carcinoma SO SCIENCE LA English DT Article ID ARYL-HYDROCARBON RECEPTOR; CONTACT HYPERSENSITIVITY; MOUSE SKIN; T-CELLS; RAS GENE; H-RAS; MICE; CARCINOGENESIS; 7,12-DIMETHYLBENZ(A)ANTHRACENE; EXPRESSION AB Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12-dimethylbenz[a]anthracene (DMBA) is a model PAH widely used to study tumorigenesis. Mice lacking Langerhans cells (LCs), a signatory epidermal dendritic cell (DC), are protected from cutaneous chemical carcinogenesis, independent of T cell immunity. Investigation of the underlying mechanism revealed that LC-deficient skin was relatively resistant to DMBA-induced DNA damage. LCs efficiently metabolized DMBA to DMBA-trans-3,4-diol, an intermediate proximal to oncogenic Hras mutation, and DMBA-treated LC-deficient skin contained significantly fewer Hras mutations. Moreover, DMBA-trans-3,4-diol application bypassed tumor resistance in LC-deficient mice. Additionally, the genotoxic impact of DMBA on human keratinocytes was significantly increased by prior incubation with human-derived LC. Thus, tissue-associated DC can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between immune cells and carcinogenesis. C1 [Modi, Badri G.; Neustadter, Jason; Lewis, Julia; Filler, Renata B.; Roberts, Scott J.; Kwong, Bernice Y.; Reddy, Swapna; Galan, Anjela; Tigelaar, Robert; Girardi, Michael] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA. [Shlomchik, Mark] Yale Univ, Sch Med, Dept Lab Med & Immunobiol, New Haven, CT 06520 USA. [Overton, John D.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Overton, John D.] Yale Univ, Sch Med, Yale Ctr Genome Anal, New Haven, CT 06520 USA. [Cai, Lining] Biotranex, Monmouth Jct, NJ 08852 USA. [Fu, Peter] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Kaplan, Daniel H.] Univ Minnesota, Dept Dermatol, Minneapolis, MN 55455 USA. [Kaplan, Daniel H.] Univ Minnesota, Dept Immunobiol, Minneapolis, MN 55455 USA. [Binda, Elisa; Hayday, Adrian] Kings Coll London, Guys & St Thomas Hosp, Peter Gorer Dept Immunobiol, Comprehens Biomed Res Ctr, London SE1 9RT, England. [Binda, Elisa; Hayday, Adrian] Canc Res UK CRUK, London Res Inst, London WC2 A, England. RP Girardi, M (reprint author), Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA. EM girardi@yale.edu RI Kaplan, Daniel/N-2779-2013 OI Kaplan, Daniel/0000-0002-7851-7320 FU NIH [R01CA102703, T32, RO1-AR044077, RO1-AR056632]; Richard K. Gershon Research Fellowship; National Cancer Institute of the Yale Comprehensive Cancer Center [P30 CA016359]; Wellcome Trust; Cancer Research UK; Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre; St. Thomas' NHS Foundation Trust FX Funding for this work was provided by the NIH grants R01CA102703 (to M. G.), T32 (to J.N.), RO1-AR044077 (to M. S.), and RO1-AR056632 (to D. H. K.) and the Richard K. Gershon Research Fellowship (to B. G. M.). This work was supported by resources of the National Cancer Institute (grant P30 CA016359) of the Yale Comprehensive Cancer Center, the Wellcome Trust (to A. H.), Cancer Research UK (to A. H.), and the Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to Guy's and St. Thomas' NHS Foundation Trust in partnership with King's College London (KCL) and King's College Hospital NHS Foundation Trust (to A. H. and E. B.). This paper is not an official guidance or policy statement of the U. S. FDA, and no official support or endorsement by the FDA is intended or should be inferred. We thank E. Gulcicek for HPLC support and M. Choi for sequence analysis support; M. Udey (NIH), A. Balmain [Univ. of California San Francisco (UCSF)], A. Behrens (CRUK), F. Nestle (KCL), and R. Groves (KCL) for protocol advice; O. Sobolev (KCL), J. Strid (KCL), F. Geissmann (KCL), K. Golubets (Yale), D. Smith (Yale), and G. Tokmoulina (Yale) for assistance; and A. Takashima (Univ. of Toledo) for XS106 cells and A. Balmain (UCSF) for CarC cells. The data tabulated in this paper are reported in the main text and in the supporting online material. Illumina sequence data are available from the National Center for Biotechnology Information Sequence Read Archive, accession no. SRA048406. Sites of experiments: New Haven, CT, USA, and London, UK. NR 33 TC 48 Z9 50 U1 2 U2 23 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 6 PY 2012 VL 335 IS 6064 BP 104 EP 108 DI 10.1126/science.1211600 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 872YA UT WOS:000298846200061 PM 22223807 ER PT J AU Song, FH El-Demerdash, A Lee, SJSH Smith, RE AF Song, Fenhong El-Demerdash, Aref Lee, Shwn-Ji Susie H. Smith, Robert E. TI Fast screening of lovastatin in red yeast rice products by flow injection tandem mass spectrometry SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Red yeast rice; Lovastatin; Flow injection LC-MS/MS ID DIETARY-SUPPLEMENTS; ELECTROSPRAY-IONIZATION; AMBIENT CONDITIONS; VARDENAFIL ANALOG; IDENTIFICATION; QUANTIFICATION; MEDICINES AB Drug adulteration in dietary supplement materials is a world-wide problem and poses a regulatory challenge. Red yeast rice is a product used by consumers to lower blood levels of cholesterol. While most current methods to analyze red yeast rice are based on HPLC separation with a photo-diode array detector and/or a mass spectrometry detector, which takes 20-40 min analysis time per sample, we developed a method to do fast screening of the active compound lovastatin by direct infusion into a mass spectrometer. This method takes under 1 min per analysis on the instrument. By using multiple reaction monitoring with five product ions, all the ion ratios of the analyte in the samples are compared with those from the standards for qualitative analysis. The results from this method were compared to the result from the liquid chromatography tandem mass spectrometry, which uses retention time and one ion ratio as the confirmation criteria. No false positives or false negatives were found among the 12 samples tested. The method also seems to be effective in measuring the lovastatin in red yeast rice semi-quantitatively. This kind of method could be adapted to the screening of other dietary supplement products. Published by Elsevier B.V. C1 [Song, Fenhong; El-Demerdash, Aref; Lee, Shwn-Ji Susie H.; Smith, Robert E.] US FDA, Total Diet & Pesticide Res Ctr, Lenexa, KS 66214 USA. RP Song, FH (reprint author), US FDA, Total Diet & Pesticide Res Ctr, 11510 W 80th St, Lenexa, KS 66214 USA. EM fenhong.Song@fda.hhs.gov NR 17 TC 14 Z9 14 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JAN 5 PY 2012 VL 57 BP 76 EP 81 DI 10.1016/j.jpba.2011.08.039 PG 6 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 855BW UT WOS:000297539500011 PM 21943718 ER PT J AU Gago-Martinez, A Hungerford, JM AF Gago-Martinez, Ana Hungerford, James M. TI Comment on "The Effect of Uncontrolled Factors in a Validated Liquid Chromatography-Tandem Mass Spectrometry Method Question Its Use As Reference Method for Marine Toxins: Major Causes for Concern" SO ANALYTICAL CHEMISTRY LA English DT Article C1 [Gago-Martinez, Ana] Univ Vigo, Vigo 36310, Spain. [Gago-Martinez, Ana] EU RLMB, Vigo, Spain. [Hungerford, James M.] US FDA, Bothell, WA USA. [Hungerford, James M.] AOAC Marine & Freshwater Toxins Task Force, Bothell, WA USA. RP Gago-Martinez, A (reprint author), Univ Vigo, Vigo 36310, Spain. EM anagago@uvigo.es NR 2 TC 1 Z9 1 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD JAN 3 PY 2012 VL 84 IS 1 BP 475 EP 475 DI 10.1021/ac2020933 PG 1 WC Chemistry, Analytical SC Chemistry GA 871UT UT WOS:000298763900068 PM 22011329 ER PT S AU Brown, RP AF Brown, R. P. BE Boutrand, JP TI Allowable limits for toxic leachables: practical use of ISO 10993-17 standard SO BIOCOMPATIBILITY AND PERFORMANCE OF MEDICAL DEVICES SE Woodhead Publishing Series in Biomaterials LA English DT Article; Book Chapter DE tolerable intake; allowable limit; risk assessment; route-to-route extrapolation; mixtures; LD50; ISO 10993-17; leachables ID HEALTH-EFFECTS CLASSIFICATION; MINIMAL RISK LEVELS; TOXICOLOGICAL CONCERN TTC; CHEMICAL-MIXTURES; INTERNATIONAL PERSPECTIVE; DERIVATION; SAFETY; 21ST-CENTURY; PLASTICIZER; THRESHOLDS AB This chapter describes an approach for setting tolerable intake (TI) values for chemical compounds released from medical device materials based on the method described in the ISO 10993-17 standard (Biological evaluation of medical devices - Part 17: Establishment of allowable limits for leachable substances). Practical advice is provided on how to derive both non-cancer and cancer-based TI values and recommendations are offered on how to account for potential toxicological interactions among the chemical constituents of an extract, how to derive a TI from an LD50 value (i.e., a dose associated with 50% death in exposed animals), and how to conduct route-to-route extrapolation of dose. The chapter also explores how the approach outlined in the ISO 10993-17 standard for derivation of TI values compares with methods developed by other groups for the establishment of safe exposure levels for environmental pollutants and impurities in drug substances and how to identify a key toxicity study to serve as the basis for the TI value. C1 US FDA, Lab Biocompatibil & Toxicol, Div Biol, Off Sci & Engn Labs,Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Brown, RP (reprint author), US FDA, Lab Biocompatibil & Toxicol, Div Biol, Off Sci & Engn Labs,Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Ronald.Brown@fda.hhs.gov NR 62 TC 0 Z9 0 U1 0 U2 0 PU WOODHEAD PUBL LTD PI CAMBRIDGE PA ABINGTON HALL ABINGTON, CAMBRIDGE CB1 6AH, CAMBS, ENGLAND SN 2049-9485 BN 978-0-85709-645-6; 978-0-85709-070-6 J9 WOODH PUBL SER BIOM PY 2012 VL 50 BP 95 EP 119 D2 10.1533/9780857096456 PG 25 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA BGV58 UT WOS:000324305700008 ER PT J AU Zornberg, GL AF Zornberg, Gwen L. BE Kalali, A Preskorn, S Kwentus, J Stahl, SM TI Regulatory issues SO ESSENTIAL CNS DRUG DEVELOPMENT LA English DT Article; Book Chapter ID FDA C1 [Zornberg, Gwen L.] Epidemiol Res Contracts, Silver Spring, MD USA. [Zornberg, Gwen L.] FDA CDER Off Surveillance & Epidemiol, Silver Spring, MD USA. RP Zornberg, GL (reprint author), Epidemiol Res Contracts, Silver Spring, MD USA. NR 4 TC 1 Z9 1 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-0-521-76606-7 PY 2012 BP 14 EP 30 D2 10.1017/CBO9780511977640 PG 17 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA BFZ90 UT WOS:000322009100003 ER PT S AU Alterman, MA Hunziker, P AF Alterman, Michail A. Hunziker, Peter BE Alterman, MA Hunziker, P TI Amino Acid Analysis Methods and Protocols Preface SO AMINO ACID ANALYSIS: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Editorial Material; Book Chapter C1 [Alterman, Michail A.] US FDA, Ctr Biol Evaluat & Res, Tumor Vaccines & Biotechnol Branch, Bethesda, MD USA. RP Alterman, MA (reprint author), US FDA, Ctr Biol Evaluat & Res, Tumor Vaccines & Biotechnol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-444-5 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 828 BP V EP V D2 10.1007/978-1-61779-445-2 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA BFY24 UT WOS:000321876500001 ER PT S AU Gogichaeva, NV Alterman, MA AF Gogichaeva, Natalia V. Alterman, Michail A. BE Alterman, MA Hunziker, P TI Amino Acid Analysis by Means of MALDI TOF Mass Spectrometry or MALDI TOF/TOF Tandem Mass Spectrometry SO AMINO ACID ANALYSIS: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Amino acid analysis; Mass spectrometry; Absolute protein quantitation; Quantitative mass spectrometry; MALDI TOF; MALDI TOF/TOF; Metabolomics ID CAPILLARY-ELECTROPHORESIS; QUANTITATIVE-ANALYSIS; GAS-CHROMATOGRAPHY; PERFORMANCE; PROTEINS; QUANTIFICATION; DERIVATIZATION; METABOLISM; DISORDERS; MOLECULES AB Here, we describe two different amino acid analysis protocols based on the application of matrix-assisted laser desorption ionization time-of-flight (MALDI TOF) mass spectrometry (MS). First protocol describes a MALDI TOF MS-based method for a routine simultaneous qualitative and quantitative analysis of free amino acids and protein hydrolysates (Alterman et al. Anal Biochem 335: 184-191, 2004). Linear responses between the amino acid concentration and the peak intensity ratio of corresponding amino acid to internal standard were observed for all amino acids analyzed in the range of concentrations from 20 to 300 mu M. Limit of quantitation varied from 0.03 mu M for arginine to 3.7 mu M for histidine and homocysteine. This method has one inherent limitation: the analysis of isomeric and isobaric amino acids. To solve this problem, a second protocol based on the use of MALDI TOF/TOF MS/MS for qualitative analysis of amino and organic acids was developed. This technique is capable of distinguishing isobaric and isomeric compounds (Gogichayeva et al. J Am Soc Mass Spectrom 18: 279-284,2007). Both methods do not require amino acid derivatization or chromatographic separation, and the data acquisition time is decreased to several seconds for a single sample. C1 [Gogichaeva, Natalia V.] Univ Kansas, Analyt Prote Lab, Lawrence, KS 66045 USA. [Alterman, Michail A.] US FDA, Ctr Biol Evaluat & Res, Tumor Vaccines & Biotechnol Branch, Bethesda, MD USA. RP Gogichaeva, NV (reprint author), Univ Kansas, Analyt Prote Lab, Lawrence, KS 66045 USA. NR 23 TC 5 Z9 5 U1 2 U2 20 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-444-5 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 828 BP 121 EP 135 DI 10.1007/978-1-61779-445-2_12 D2 10.1007/978-1-61779-445-2 PG 15 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA BFY24 UT WOS:000321876500013 PM 22125142 ER PT J AU Reaman, G O'Leary, M AF Reaman, Gregory O'Leary, Maura BE Cairo, MS Perkins, SL TI Special Considerations in Infants and Adolescents with Hematological Malignancies SO HEMATOLOGICAL MALIGNANCIES IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS LA English DT Article; Book Chapter ID ACUTE-LYMPHOBLASTIC-LEUKEMIA; CHILDRENS-ONCOLOGY-GROUP; NON-HODGKINS-LYMPHOMA; CHRONIC MYELOID-LEUKEMIA; DNA TOPOISOMERASE-II; MANTLE-CELL LYMPHOMA; CANCER-GROUP; UNITED-STATES; YOUNG-ADULTS; RISK-FACTORS C1 [Reaman, Gregory] US FDA, Off Hematol & Oncol Prod, OND Ctr Drug Evaluat & Res, Silver Spring, MD USA. [O'Leary, Maura] US FDA, CBER, Rockville, MD 20857 USA. RP Reaman, G (reprint author), US FDA, Off Hematol & Oncol Prod, OND Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 50 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4299-60-2 PY 2012 BP 29 EP 40 PG 12 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA BFP07 UT WOS:000320848700003 ER PT B AU Burkhardt, B Waxman, I AF Burkhardt, Burgit Waxman, Ian BE Cairo, MS Perkins, SL TI Adolescent Non-Hodgkin Lymphoma SO HEMATOLOGICAL MALIGNANCIES IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS LA English DT Article; Book Chapter ID ACUTE-LYMPHOBLASTIC-LEUKEMIA; LARGE-CELL LYMPHOMA; CHILDRENS CANCER GROUP; PEDIATRIC-ONCOLOGY-GROUP; YOUNG-ADULTS; PROGNOSTIC-SIGNIFICANCE; CLINICAL-FEATURES; DOSE METHOTREXATE; CHILDHOOD; CHEMOTHERAPY C1 [Burkhardt, Burgit] Univ Hosp Munster, Munster, Germany. [Waxman, Ian] US FDA, Off Oncol Drug Prod, Bethesda, MD 20014 USA. RP Burkhardt, B (reprint author), Univ Hosp Munster, Munster, Germany. NR 50 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4299-60-2; 978-981-4299-61-9 PY 2012 BP 329 EP 347 PG 19 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA BFP07 UT WOS:000320848700017 ER PT J AU Graham, J Peck, J AF Graham, Jove Peck, Jonathan BE Kurtz, SM TI FDA Regulation of Polyaryletheretherketone Implants SO PEEK BIOMATERIALS HANDBOOK SE PDL Handbook Series LA English DT Article; Book Chapter C1 [Graham, Jove; Peck, Jonathan] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Graham, J (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. NR 11 TC 2 Z9 2 U1 0 U2 0 PU WILLIAM ANDREW INC PI NORWICH PA 13 EATON AVE, NORWICH, NY 13815 USA BN 978-1-4377-4464-4 J9 PDL HANDB SER PY 2012 BP 277 EP 292 DI 10.1016/B978-1-4377-4463-7.10017-X PG 16 WC Materials Science, Biomaterials; Polymer Science SC Materials Science; Polymer Science GA BFO18 UT WOS:000320709100018 ER PT J AU Goldberg, RL AF Goldberg, Rebecca L. TI Administering Real Food: How the Eat-Food Movement Should-and Should Not-Approach Government Regulation SO ECOLOGY LAW QUARTERLY LA English DT Article ID ENVIRONMENTAL-LAW; AGENCIES; CAPTURE; SCIENCE; TRUTH; STATE AB Led by Michael Pollan, the fast-growing food movement has changed the way many Americans think about what they eat. Increasingly, the movement is focusing on issues of national policy, which makes sense in such a highly regulated field. Yet, to date, legal scholarship has done little to explore how the goals of this nascent movement relate to the current system of food regulation in the United States. This Article begins to fill that void. The Article focuses on one aspect of the greater food movement: the "eat-food movement," which encourages the consumption of "real," unprocessed food. Upon juxtaposing the philosophy of the eat-food movement with the structure and mission of FDA and USDA, the Article concludes that certain types of command-and-control regulation pose unique threats to the movement's integrity. On the other hand, disclosure-based regulation, used in combination with twenty-first century information and communication technologies, holds particular promise for this movement. The idea that the relative merits of different types of regulation should be assessed in light of a given movement's specific goals and a given agency's specific structure has implications for administrative law more broadly. C1 US FDA, Off Chief Counsel, Rockville, MD 20857 USA. RP Goldberg, RL (reprint author), US FDA, Off Chief Counsel, Rockville, MD 20857 USA. NR 165 TC 1 Z9 1 U1 1 U2 3 PU UNIV CALIFORNIA BERKELEY SCH LAW PI BERKELEY PA BOAT HALL, 588 SIMON HALL, BERKELEY, CA 94720-7200 USA SN 0046-1121 J9 ECOL LAW QUART JI Ecol. Law Q. PY 2012 VL 39 IS 3 BP 773 EP 829 PG 57 WC Environmental Studies; Law SC Environmental Sciences & Ecology; Government & Law GA 171XF UT WOS:000320962700002 ER PT B AU Choudhuri, S Arvidson, K Chanderbhan, R AF Choudhuri, Supratim Arvidson, Kirk Chanderbhan, Ronald BE Gupta, RC TI Carcinogenesis: mechanisms and moclels SO VETERINARY TOXICOLOGY: BASIC AND CLINICAL PRINCIPLES, 2ND EDITION LA English DT Article; Book Chapter ID NATIONAL TOXICOLOGY PROGRAM; K-RAS ONCOGENE; TRANSGENIC MICE; MISMATCH-REPAIR; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; MAMMALIAN-CELLS; AFLATOXIN B-1; MGMT PROTECTS; CANCER; MUTATIONS C1 [Choudhuri, Supratim; Chanderbhan, Ronald] US FDA, Div Biotechnol & GRAS Notice Review, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Arvidson, Kirk] US FDA, Div Food Contact Notificat, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Choudhuri, S (reprint author), US FDA, Div Biotechnol & GRAS Notice Review, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, College Pk, MD USA. NR 43 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-385927-3 PY 2012 BP 406 EP 425 DI 10.1016/B978-0-12-385926-6.00026-0 PG 20 WC Toxicology; Veterinary Sciences SC Toxicology; Veterinary Sciences GA BER41 UT WOS:000317854000027 ER PT J AU Tubaro, A Sosa, S Hungerford, J AF Tubaro, Aurelia Sosa, Silvio Hungerford, James BE Gupta, RC TI Toxicology and diversity of marine toxins SO VETERINARY TOXICOLOGY: BASIC AND CLINICAL PRINCIPLES, 2ND EDITION LA English DT Article; Book Chapter ID BLOOD COLLECTION CARDS; DINOFLAGELLATE ALEXANDRIUM-OSTENFELDII; SINGLE-LABORATORY VALIDATION; PARALYTIC SHELLFISH TOXINS; HUMAN HEALTH IMPLICATIONS; FEMALE NMRI MICE; OKADAIC ACID; DOMOIC ACID; LIQUID-CHROMATOGRAPHY; BREVETOXIN PBTX-3 C1 [Tubaro, Aurelia; Sosa, Silvio] Univ Trieste, Trieste, Italy. [Hungerford, James] US FDA, AOAC Task Force & GR Marine & Freshwater Toxins A, Bothell, WA USA. RP Tubaro, A (reprint author), Univ Trieste, Trieste, Italy. NR 219 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-385927-3 PY 2012 BP 896 EP 934 DI 10.1016/B978-0-12-385926-6.00080-6 PG 39 WC Toxicology; Veterinary Sciences SC Toxicology; Veterinary Sciences GA BER41 UT WOS:000317854000070 ER PT S AU Martinez, MN Khan, MA AF Martinez, Marilyn N. Khan, Mansoor A. BE Wright, JC Burgess, DJ TI Regulatory Issues and Challenges Associated with the Development of Performance Specifications for Modified Release Parenteral Products SO LONG ACTING INJECTIONS AND IMPLANTS SE Advances in Delivery Science and Technology LA English DT Article; Book Chapter ID HUMAN OSTEOSARCOMA XENOGRAFTS; INTERSTITIAL FLUID PRESSURE; DRUGS FOLLOWING INJECTION; IN-VITRO; RAT PLASMA; SUBCUTANEOUS ABSORPTION; EXTRACELLULAR-MATRIX; LYMPHATIC TRANSPORT; BIOLOGICAL-ACTIVITY; SPECIES-DIFFERENCE AB Once a parenteral product has been shown to be safe and effective, specifications need to be developed to ensure consistent product performance across batches and throughout the shelf life of that product. This in turn necessitates an appreciation of the physiological variables and critical quality attributes that influence product performance. The assessment of the critical quality attributes and manufacturing processes of new drugs provides the basis for establishing these important quality standards. This chapter provides an overview of the questions and background information that regulators of human or veterinary parenteral dosage forms may consider when establishing the criteria that will ensure repeatable product quality and performance. C1 [Martinez, Marilyn N.] US FDA, Off New Anim Drug Evaluat, Ctr Vet Med, Rockville, MD 20855 USA. [Khan, Mansoor A.] US FDA, Div Prod Qual Res, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Martinez, MN (reprint author), US FDA, Off New Anim Drug Evaluat, Ctr Vet Med, Rockville, MD 20855 USA. EM Marilyn.Martinez@fda.hhs.gov NR 63 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 2192-6204 BN 978-1-4614-0553-5 J9 ADV DEL SCI TECHNOL PY 2012 BP 505 EP 535 DI 10.1007/978-1-4614-0554-2_24 D2 10.1007/978-1-4614-0553-5 PG 31 WC Engineering, Biomedical; Pharmacology & Pharmacy SC Engineering; Pharmacology & Pharmacy GA BFM67 UT WOS:000320563100024 ER PT S AU Liu, Y Shen, JX Kainz, WG Qian, SS Wu, W Chen, J AF Liu, Yan Shen, Jianxiang Kainz, Wolfgang Qian, Songsong Wu, Wen Chen, Ji GP IEEE TI Computational Study of External Fixation Devices Surface Heating in MRI RF Environment SO 2012 IEEE INTERNATIONAL SYMPOSIUM ON ELECTROMAGNETIC COMPATIBILITY (EMC) SE IEEE International Symposium on Electromagnetic Compatibility LA English DT Proceedings Paper CT IEEE International Symposium on Electromagnetic Compatibility (EMC) CY AUG 05-10, 2012 CL Pittsburgh, PA SP IEEE, Electromagnet Compatibil Soc, China Electrotechn Soc, Evaluat Engn (EE), ENR, Microwave Digest, Microwave Journal, RF Globalnet, SAFETY & EMC Magazine, In Compliance Magazine, ITEM Media, ETS LINDGREN, Keystone Compliance, Retlif Testing Labs, Andro Computat Solutions, LLC, MIDCOM, Wurth Elekt, Gauss Instruments GmbH AB Heating effect by external fixation devices under MRI RF field was studied numerically for both 1.5-T and 3-T MRI systems. It is found that changing insertion depth and pin spacing could largely affect the surface heating level. In 1.5-T MRI, smaller insertion depth and larger pin spacing will produce larger temperature rise. However, for 3T system, the relation is not very clear when insertion depth became larger than 5cm or when pin spacing became larger than 20cm. Effect of connection bar material on external fixator is also studied and the heating mechanism of the device is analysed. C1 [Liu, Yan; Shen, Jianxiang; Chen, Ji] Univ Houston, Houston, TX 77204 USA. [Shen, Jianxiang; Kainz, Wolfgang] US FDA, Rockville, MD 20852 USA. [Qian, Songsong; Wu, Wen] Nanjing Univ Sci & Technol, Nanjing 210094, Peoples R China. RP Liu, Y (reprint author), Univ Houston, Houston, TX 77204 USA. EM yliu32@mail.uh.edu; jshen5@mail.uh.edu; wolfgang.kainz@fda.hhs.gov; songtsien@163.com; wuwen@mail.njust.edu.cn; jchen18@.uh.edu NR 7 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2158-110X BN 978-1-4673-2060-3 J9 IEEE INT SYMP ELEC PY 2012 BP 602 EP 606 PG 5 WC Engineering, Electrical & Electronic SC Engineering GA BEJ75 UT WOS:000316991700110 ER PT J AU Dal Pan, GJ AF Dal Pan, Gerald J. BE Ravina, B Cummings, J McDermott, MP Poole, RM TI Clinical approaches to post-marketing drug safety assessment SO CLINICAL TRIALS IN NEUROLOGY: DESIGN, CONDUCT, ANALYSIS LA English DT Article; Book Chapter ID PLACEBO-CONTROLLED TRIALS; ACTIVE-CONTROL TRIALS; APLASTIC-ANEMIA; PHARMACOVIGILANCE; RHABDOMYOLYSIS; FELBAMATE; IBUPROFEN; EVENTS; ISSUES C1 US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Dal Pan, GJ (reprint author), US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 28 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-0-521-76259-5 PY 2012 BP 160 EP 172 D2 10.1017/CBO9781139032445 PG 13 WC Medicine, Research & Experimental; Clinical Neurology SC Research & Experimental Medicine; Neurosciences & Neurology GA BDY84 UT WOS:000315680000016 ER PT B AU Katz, R AF Katz, Russell BE Ravina, B Cummings, J McDermott, MP Poole, RM TI Evidentiary standards for neurological drugs and biologics approval SO CLINICAL TRIALS IN NEUROLOGY: DESIGN, CONDUCT, ANALYSIS LA English DT Article; Book Chapter ID PLACEBO-CONTROLLED TRIALS; ACTIVE-CONTROL TRIALS; CLINICAL-TRIALS; ISSUES C1 US FDA, Div Neurol Prod, Silver Spring, MD 20993 USA. RP Katz, R (reprint author), US FDA, Div Neurol Prod, Silver Spring, MD 20993 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-0-521-76259-5 PY 2012 BP 197 EP 205 D2 10.1017/CBO9781139032445 PG 9 WC Medicine, Research & Experimental; Clinical Neurology SC Research & Experimental Medicine; Neurosciences & Neurology GA BDY84 UT WOS:000315680000019 ER PT B AU Mann, EA Como, PG AF Mann, Eric A. Como, Peter G. BE Ravina, B Cummings, J McDermott, MP Poole, RM TI Premarket review of neurological devices SO CLINICAL TRIALS IN NEUROLOGY: DESIGN, CONDUCT, ANALYSIS LA English DT Article; Book Chapter C1 [Mann, Eric A.; Como, Peter G.] US FDA, Div Ophthalm Neurol & ENT Devices, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Mann, EA (reprint author), US FDA, Div Ophthalm Neurol & ENT Devices, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-0-521-76259-5 PY 2012 BP 206 EP 214 D2 10.1017/CBO9781139032445 PG 9 WC Medicine, Research & Experimental; Clinical Neurology SC Research & Experimental Medicine; Neurosciences & Neurology GA BDY84 UT WOS:000315680000020 ER PT J AU Neyarapally, GA Hammad, TA Pinheiro, SP Iyasu, S AF Neyarapally, George A. Hammad, Tarek A. Pinheiro, Simone P. Iyasu, Solomon TI Review of quality assessment tools for the evaluation of pharmacoepidemiological safety studies SO BMJ OPEN LA English DT Review ID RANDOMIZED CONTROLLED-TRIALS; HEALTH-CARE; CRITICAL-APPRAISAL; SYSTEMATIC REVIEWS; MEDICAL LITERATURE; RISK-FACTORS; ALCOHOL-CONSUMPTION; PRACTICE GUIDELINES; PROGNOSTIC-FACTORS; PUBLISHED REPORTS AB Objectives: Pharmacoepidemiological studies are an important hypothesis-testing tool in the evaluation of postmarketing drug safety. Despite the potential to produce robust value-added data, interpretation of findings can be hindered due to well-recognised methodological limitations of these studies. Therefore, assessment of their quality is essential to evaluating their credibility. The objective of this review was to evaluate the suitability and relevance of available tools for the assessment of pharmacoepidemiological safety studies. Design: We created an a priori assessment framework consisting of reporting elements (REs) and quality assessment attributes (QAAs). A comprehensive literature search identified distinct assessment tools and the prespecified elements and attributes were evaluated. Primary and secondary outcome measures: The primary outcome measure was the percentage representation of each domain, RE and QAA for the quality assessment tools. Results: A total of 61 tools were reviewed. Most tools were not designed to evaluate pharmacoepidemiological safety studies. More than 50% of the reviewed tools considered REs under the research aims, analytical approach, outcome definition and ascertainment, study population and exposure definition and ascertainment domains. REs under the discussion and interpretation, results and study team domains were considered in less than 40% of the tools. Except for the data source domain, quality attributes were considered in less than 50% of the tools. Conclusions: Many tools failed to include critical assessment elements relevant to observational pharmacoepidemiological safety studies and did not distinguish between REs and QAAs. Further, there is a lack of considerations on the relative weights of different domains and elements. The development of a quality assessment tool would facilitate consistent, objective and evidence-based assessments of pharmacoepidemiological safety studies. C1 [Neyarapally, George A.; Hammad, Tarek A.; Pinheiro, Simone P.; Iyasu, Solomon] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Neyarapally, GA (reprint author), US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM george.neyarapally@fda.hhs.gov NR 98 TC 3 Z9 3 U1 1 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-6055 J9 BMJ OPEN JI BMJ Open PY 2012 VL 2 IS 5 AR e001362 DI 10.1136/bmjopen-2012-001362 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 091MN UT WOS:000315053900059 ER PT J AU Ahn, Y Jung, JY Chung, YH Chae, M Jeon, CO Cerniglia, CE AF Ahn, Youngbeom Jung, Ji Young Chung, Yong Hyun Chae, Minho Jeon, Che Ok Cerniglia, Carl E. TI In vitro Analysis of the Impact of Enrofloxacin Residues on the Human Intestinal Microbiota Using H-1-NMR Spectroscopy SO JOURNAL OF MOLECULAR MICROBIOLOGY AND BIOTECHNOLOGY LA English DT Article DE Enrofloxacin residues; Human intestinal microbiota; Nuclear magnetic resonance spectroscopy ID HUMAN COLONIC MICROFLORA; ESCHERICHIA-COLI; ANTIMICROBIAL AGENTS; FECAL WATER; GASTROINTESTINAL-TRACT; CHEMOSTAT MODEL; GUT MICROBIOTA; FATTY-ACIDS; CIPROFLOXACIN; EXTRACTS AB Exposure of humans to antimicrobial residues in food-producing animals may alter the intestinal microbiota which could result in a potential risk to human health. To determine the effect of enrofloxacin on the human intestinal microbiota, fecal suspensions (25%) were cultured in the presence of 0.06-5 mu g/ml enrofloxacin. The bacterial community was analyzed by plating on selective culture media, pyrosequencing and nuclear magnetic resonance (NMR) spectroscopy. Pyrosequencing analysis of 16S rRNA genes and viable counts on Bacteroides sp., Enterococcus sp., and Bifidobacterium sp. selection medium indicated that there were no significant changes in the bacteria numbers at the selected enrofloxacin concentrations ( 0.06, 0.1, and 1 mu g/ml) relative to the control samples after a 48 h incubation. NMR analysis showed remarkably similar spectra in cultures treated with 0.06, 0.1, and 1 mu g/ml enrofloxacin, with some slight differences in peak heights. However, hierarchical clustering analysis indicated significant differences in metabolite concentrations between the control and those samples treated with 1 mu g/ml enrofloxacin. Leucine, phenylalanine, proline, and 2-oxovalerate were positively correlated with the concentration of enrofloxacin. NMR analysis is a potentially useful tool to monitor changes of the human intestinal microbiota, in addition to traditional culture methods and pyrosequencing. Copyright (c) 2012 S. Karger AG, Basel C1 [Ahn, Youngbeom; Cerniglia, Carl E.] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. [Chae, Minho] Univ Texas SW Med Ctr Dallas, Cecil H & Ida Green Ctr Reprod Biol Sci, Dallas, TX 75390 USA. [Jung, Ji Young; Jeon, Che Ok] Chung Ang Univ, Dept Life Sci, Seoul 156756, South Korea. [Chung, Yong Hyun] Korea Occupat Safety & Hlth Agcy, Toxicol Res Team, Taejon, South Korea. RP Ahn, Y (reprint author), US FDA, Natl Ctr Toxicol Res, Div Microbiol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM young.ahn@fda.hhs.gov NR 45 TC 0 Z9 0 U1 0 U2 6 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1464-1801 J9 J MOL MICROB BIOTECH JI J. Mol. Microbiol. Biotechnol. PY 2012 VL 22 IS 5 BP 317 EP 325 DI 10.1159/000345147 PG 9 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 084CU UT WOS:000314514900005 PM 23221505 ER PT S AU Danyluk, MD Parish, ME Goodrich-Schneider, RM Worobo, RW AF Danyluk, M. D. Parish, M. E. Goodrich-Schneider, R. M. Worobo, R. W. BE Demirci, A Ngadi, MO TI Microbial decontamination of juices SO MICROBIAL DECONTAMINATION IN THE FOOD INDUSTRY: NOVEL METHODS AND APPLICATIONS SE Woodhead Publishing in Food Science Technology and Nutrition LA English DT Article; Book Chapter DE apple; orange; Salmonella; E. coli; Cryptosporidium; HACCP ID ESCHERICHIA-COLI O157-H7; UNPASTEURIZED ORANGE JUICE; PULSED ELECTRIC-FIELDS; HEMOLYTIC UREMIC SYNDROME; PRESSED APPLE CIDER; LISTERIA-MONOCYTOGENES; FRUIT JUICES; CARBON-DIOXIDE; UV-IRRADIATION; TYPHOID-FEVER AB The microbiological concerns of juice decontamination historically involved prevention of spoilage. A number of Salmonella, Escherichia coli O157:H7, and Cryptosporidium parvum outbreaks associated with raw (unpasteurized) juices in the 1990s led to the introduction of regulation requiring 100% juice products be produced under a Hazard Analysis Critical Control Point (HACCP) program by the US Food and Drug Administration. This regulation requires that juice processors obtain at least a 5-log reduction of the 'pertinent microorganism' as a decontamination step. As a result of juice HACCP, most decontamination methods are measured to the 5-log reduction of the pertinent pathogen performance standard this regulation requires. In this chapter, outbreaks associated with juices will be summarized and we will discuss means by which microorganisms are eliminated in juices through both classical processing and novel methods for juice decontamination, what future trends in juice decontamination may be and provide further sources of information. C1 [Danyluk, M. D.] Univ Florida, Citrus Res & Educ Ctr, Inst Food & Agr Sci, Lake Alfred, FL 33850 USA. [Danyluk, M. D.; Goodrich-Schneider, R. M.] Univ Florida, Dept Food Sci & Human Nutr, Inst Food & Agr Sci, Gainesville, FL 32611 USA. [Parish, M. E.] FDA CFSAN Off Food Safety, College Pk, MD 20740 USA. [Worobo, R. W.] Cornell Univ, Dept Food Sci & Technol, Geneva, NY 14456 USA. RP Danyluk, MD (reprint author), Univ Florida, Citrus Res & Educ Ctr, Inst Food & Agr Sci, 700 Expt Stn Rd, Lake Alfred, FL 33850 USA. EM mddanyluk@ufl.edu; Michey.Parish@fda.hhs.gov; goodrich@ufl.edu; rww8@cornell.edu RI Worobo, Randy/D-8779-2014 NR 143 TC 1 Z9 1 U1 0 U2 4 PU WOODHEAD PUBL LTD PI CAMBRIDGE PA ABINGTON HALL ABINGTON, CAMBRIDGE CB1 6AH, CAMBS, ENGLAND SN 2042-8049 BN 978-0-85709-575-6 J9 WOODHEAD PUBL FOOD S JI Woodhead Publ. Food Sci. Technol. Nutr. PY 2012 IS 234 BP 163 EP 189 D2 10.1533/9780857095756 PG 27 WC Food Science & Technology SC Food Science & Technology GA BDP47 UT WOS:000314306900007 ER PT J AU Badal, A Badano, A AF Badal, Andreu Badano, Aldo GP IEEE TI A GPU-OPTIMIZED BINARY SPACE PARTITION STRUCTURE TO ACCELERATE THE MONTE CARLO SIMULATION OF CT PROJECTIONS OF VOXELIZED PATIENT MODELS WITH METAL IMPLANTS SO 2012 9TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING (ISBI) LA English DT Proceedings Paper CT 9th IEEE International Symposium on Biomedical Imaging (ISBI) - From Nano to Macro CY MAY 02-05, 2012 CL Barcelona, SPAIN SP IEEE, IEEE Engn Med & Biol Soc (EMBS), IEEE Signal Proc Soc DE CT; Monte Carlo; GPU; metal artifact ID PHOTON AB Monte Carlo x-ray transport simulation codes can generate radiographic images that are equivalent to images produced by clinical systems. Most codes optimized for medical imaging use voxels to represent the patient anatomy and employ delta scattering (Woodcock algorithm) as an essential acceleration technique. With delta scattering all voxels have the same attenuation and x rays cross multiple voxels in each step reducing the time spent accessing memory and computing voxel interfaces. A drawback of this approach is that it is inefficient in phantoms with highly attenuating voxels. We present a binary space partition structure, bitree, that improves the performance of delta scattering by selecting an optimum attenuation within different regions while minimizing the interfaces to be crossed. The described bitree and its traversal algorithm are optimized for GPU-computing and have been implemented in the PENELOPE-based MC-GPU code. The bitree approach reduced the execution time by 88.6% for the simulation of a head CT scan with a metallic implant. C1 [Badal, Andreu; Badano, Aldo] US FDA, Div Imaging & Appl Math, CDRH, OSEL, Silver Spring, MD 20993 USA. RP Badal, A (reprint author), US FDA, Div Imaging & Appl Math, CDRH, OSEL, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. OI badano, aldo/0000-0003-3712-6670 NR 12 TC 0 Z9 0 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1858-8 PY 2012 BP 634 EP 637 PG 4 WC Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BDA85 UT WOS:000312384100160 ER PT J AU Wei, ZS Wang, SJ Petrick, N Yao, JH Periaswamy, S Summers, RM AF Wei, Zhuoshi Wang, Shijun Petrick, Nicholas Yao, Jianhua Periaswamy, Senthil Summers, Ronald M. GP IEEE TI SUPINE AND PRONE CT COLONOGRAPHY REGISTRATION BY MATCHING GRAPHS OF TENIAE COLI SO 2012 9TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING (ISBI) LA English DT Proceedings Paper CT 9th IEEE International Symposium on Biomedical Imaging (ISBI) - From Nano to Macro CY MAY 02-05, 2012 CL Barcelona, SPAIN SP IEEE, IEEE Engn Med & Biol Soc (EMBS), IEEE Signal Proc Soc DE CTC; registration; graph; teniae coli ID COLONOSCOPY; TRIAL AB This paper proposes a registration method for supine and prone CTC scans. The method matches graphs built using the teniae coli, three muscles that run the length of the colon. The teniae are visible on CTC and were detected using fully-automatically software. Then key points of the teniae were obtained by non-uniformed sampling of the teniae. Graphs were built using these key points. The colon registration was formulated as a graph matching problem. Mean field theory was applied to match the graphs. The proposed method was tested on 10 pairs of supine and prone CTC scans. The average registration error was 2.5cm (+/- 0.7 cm, 95% C.I. [2.1 2.9]), significantly improving the baseline graph matching method for CTC registration. C1 [Wei, Zhuoshi; Wang, Shijun; Yao, Jianhua; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab Radiol &, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Petrick, Nicholas] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Periaswamy, Senthil] ICAD Inc, Nashua, NH 03062 USA. RP Wei, ZS (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab Radiol &, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. FU Intramural Research Programs of the NIH Clinical Center; Food and Drug Administration; CRADA with iCAD FX This research was supported by the Intramural Research Programs of the NIH Clinical Center and the Food and Drug Administration. We thank Drs. Perry Pickhardt, J. Richard Choi and William Schindler for providing CTC data and Viatronix Inc. for providing V3D Colon software. Support also provided in part by a CRADA with iCAD. NR 12 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1858-8 PY 2012 BP 712 EP 715 PG 4 WC Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BDA85 UT WOS:000312384100179 ER PT S AU Le, HND Kim, MS Kim, DH AF Le, Hanh N. D. Kim, Moon S. Kim, Do-Hyun GP IEEE TI Comparison of Singular Value Decomposition and Principal Component Analysis applied to Hyperspectral Imaging of Biofilm SO 2012 IEEE PHOTONICS CONFERENCE (IPC) SE IEEE Photonics Conference LA English DT Proceedings Paper CT 25th IEEE Photonics Conference (IPC) CY SEP 23-27, 2012 CL Burlingame, CA SP IEEE, Kotura, Rockley Grp, Intel, Cisco, Oracle Labs, Corning, Google, Luxtera, Fiber Chip, Rambus, Analog Devices, PMC, Sinoora, Soitec, Photon Design, Nat Photon, Commun Technol Roadmap, Simgui AB Different degrees of bacterial attachment to various surface morphologies observed by Hyperspectral Imaging Method are studied. Fore-ground and back-ground distinction performed by Singular Value Decomposition and Principal Component Analysis is also discussed. C1 [Le, Hanh N. D.; Kim, Do-Hyun] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Kim, Moon S.] US Dept Agr, Agr Res Serv, Beltsville, MD 20705 USA. RP Le, HND (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Do-Hyun.Kim@fda.hhs.gov NR 4 TC 1 Z9 1 U1 0 U2 4 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2374-0140 BN 978-1-4577-0733-9 J9 IEEE PHOTON CONF PY 2012 BP 6 EP + PG 2 WC Engineering, Electrical & Electronic; Optics SC Engineering; Optics GA BDD75 UT WOS:000312865000004 ER PT S AU Guldenring, D Finlay, DD Strauss, DG Galeotti, L Nugent, CD Donnelly, MP Bond, RR AF Guldenring, Daniel Finlay, Dewar D. Strauss, David G. Galeotti, Loriano Nugent, Chris D. Donnelly, Mark P. Bond, Raymond R. GP IEEE TI Transformation of the Mason-Likar 12-Lead Electrocardiogram to the Frank Vectorcardiogram SO 2012 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 34th Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBS) CY AUG 28-SEP 01, 2012 CL San Diego, CA SP IEEE, Engn Med & Biol Soc (EMBS), CAS, SMC, PubMed, MEDLINE ID SURFACE POTENTIAL MAPS; RECONSTRUCTION; INTERPOLATION; SYSTEM; ECG AB Vectorcardiograpic (VCG) parameters can supplement the diagnostic information of the 12-lead electrocardiogram (ECG). Nevertheless, the VCG is seldom recorded in modern-day practice. A common approach today is to derive the Frank VCG from the standard 12-lead ECG (distal limb electrode positions). There is, to date no direct method that allows for a transformation from 12-lead ECGs with proximal limb electrode positions (Mason-Likar (ML) 12-lead ECG), to Frank VCGs. In this research, we develop such a transformation (ML2VCG) by means of multivariate linear regression on a training data set of 545 ML 12-lead ECGs and corresponding Frank VCGs that were both extracted surface potential maps (BSPMs). We compare the performance of the ML2VCG method against an alternative approach (2step method) that utilizes two existing transformations that are applied consecutively (ML 12-lead ECG to standard 12-lead ECG and subsequently to Frank VCG). We quantify the performance of ML2VCG and 2step on an unseen test dataset (181 ML 12-lead ECGs and corresponding Frank VCGs again extracted from BSPMs) through root mean squared error (RMSE) values, calculated over the QRST, between actual and transformed Frank leads. The ML2VCG transformation achieved a reduction of the median RMSE values for leads X (13.9 mu V; p<.001), Y (15.1 mu V; p<.001) and Z (2.6 mu V; p=.001) when compared to the 2step transformation. Our results show that the 2step method may not be optimal when transforming ML 12-lead ECGs to Frank VCGs. The utilization of the herein developed ML2VCG transformation should thus be considered when transforming ML 12-lead ECGs to Frank VCGs. C1 [Guldenring, Daniel; Finlay, Dewar D.; Nugent, Chris D.; Donnelly, Mark P.] Univ Ulster, Sch Comp & Math, Comp Sci Res Inst, Jordanstown Campus, Newtownabbey BT37 0QB, North Ireland. [Strauss, David G.; Galeotti, Loriano] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. RP Guldenring, D (reprint author), Univ Ulster, Sch Comp & Math, Comp Sci Res Inst, Jordanstown Campus, Newtownabbey BT37 0QB, North Ireland. EM guldenring-d2@email.ulster.ac.uk RI Guldenring, Daniel/E-5039-2015; GALEOTTI, LORIANO/N-4240-2014; OI Guldenring, Daniel/0000-0002-8847-2744; GALEOTTI, LORIANO/0000-0002-3200-9080; Nugent, Chris/0000-0003-0882-7902 FU Department for Employment and Learning, Northern Ireland; Healthcare Informatics Society of Ireland; U. S. Department of Energy; U. S. Food and Drug Administration; U. S. Department of Health and Human Services FX This work has been supported in parts by the Centre for Intelligent Point of Care Sensors, funded by the Department for Employment and Learning, Northern Ireland and the Healthcare Informatics Society of Ireland. This project was supported in part and by an appointment to the Research Participation Program at the Centers for Devices and Radiological Health and administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U. S. Department of Energy and the U. S. Food and Drug Administration. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the U. S. Department of Health and Human Services. NR 19 TC 8 Z9 8 U1 0 U2 4 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4577-1787-1 J9 IEEE ENG MED BIO PY 2012 BP 677 EP 680 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BDH78 UT WOS:000313296500165 ER PT S AU Liu, YB Maruvada, S Herman, BA Harris, GR AF Liu, Yunbo Maruvada, Subha Herman, Bruce A. Harris, Gerald R. BE Muratore, R Konofagou, EE TI Temperature-dependent Physical Properties of Egg White for HIFU Applications SO 11TH INTERNATIONAL SYMPOSIUM ON THERAPEUTIC ULTRASOUND SE AIP Conference Proceedings LA English DT Proceedings Paper CT 11th International Symposium on Therapeutic Ultrasound (ISTU) CY APR 11-13, 2011 CL New York, NY SP Int Soc Therapeut Ultrasound, Amer Inst Ultrasound Med, Focused Ultrasound Fdn, Philips, Imason SAS, Verason Inc, InSightec Ltd, EyeTechCare, SuperSon Imagine SA, Image Guided Therapy, Elect & Innovat Ltd, Onda Corp, Son Concepts Inc, GE DE Blood coagulation surrogate; HIFU ablation; Temperature dependency ID INTENSITY FOCUSED ULTRASOUND AB Because egg white denatures at elevated temperature due to its protein content, it has the potential for use as a blood coagulation surrogate in pre-clinical evaluations of thermal therapy procedures such as high intensity focused ultrasound (HIFU) surgery. We therefore have measured the relevant physical properties of egg white, including coagulation temperature, frequency-dependent attenuation, sound speed, viscosity, and thermal properties, as a function of temperature (20 - 95 degrees C). Thermal coagulation and attenuation (5-12 MHz) of cow blood, pig blood, and human blood also were assessed and compared with egg white. For a 30 s thermal exposure, both egg white and blood samples started to denature at 65 degrees C and coagulate into an elastic gel at 85 degrees C. The temperature-dependent parameters were found to be similar to that of the blood samples. For example, the attenuation of egg white ranged from 0.23f(1.09) to 2.7f(0.5) dB/cm over the 20 degrees C - 95 degrees C range. These results suggest that egg white would make a useful blood mimic for bench testing of therapeutic ultrasound devices. C1 [Liu, Yunbo; Maruvada, Subha; Herman, Bruce A.; Harris, Gerald R.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Liu, YB (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. NR 5 TC 0 Z9 0 U1 1 U2 4 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 978-0-7354-1093-0 J9 AIP CONF PROC PY 2012 VL 1481 BP 216 EP 220 DI 10.1063/1.4757337 PG 5 WC Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Physics; Radiology, Nuclear Medicine & Medical Imaging GA BDG90 UT WOS:000313182200037 ER PT S AU Soneson, JE AF Soneson, Joshua E. BE Muratore, R Konofagou, EE TI Practical Limits of the Parabolic Approximation for Focused Ultrasound Beams SO 11TH INTERNATIONAL SYMPOSIUM ON THERAPEUTIC ULTRASOUND SE AIP Conference Proceedings LA English DT Proceedings Paper CT 11th International Symposium on Therapeutic Ultrasound (ISTU) CY APR 11-13, 2011 CL New York, NY SP Int Soc Therapeut Ultrasound, Amer Inst Ultrasound Med, Focused Ultrasound Fdn, Philips, Imason SAS, Verason Inc, InSightec Ltd, EyeTechCare, SuperSon Imagine SA, Image Guided Therapy, Elect & Innovat Ltd, Onda Corp, Son Concepts Inc, GE DE Linear ultrasound; Approximation methods ID NONLINEAR ACOUSTICS AB Applying the parabolic approximation to the wave equation results in a far simpler and more tractable model for ultrasound propagation. The approximate (Kuznetsov) model assumes that sound propagates predominantly in the axial direction and that the pressure amplitude is a slowly varying function of the axial coordinate. Since the terms "predominantly" and "slowly" ar far from quantitative descriptors, and since recent work shows excellent agreement between simulation and experiment at surprisingly low F-numbers, the present work seeks to more firmly establish the region of validity of this approximation for focused ultrasound sources. To this end, the focused beam of a flat panel transducer is modeled using both the full wave equation and its parabolic approximation. The simulation results are compared as a function of focusing depth and beam steering angle. C1 US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Soneson, JE (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 978-0-7354-1093-0 J9 AIP CONF PROC PY 2012 VL 1481 BP 357 EP 361 DI 10.1063/1.4757361 PG 5 WC Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Physics; Radiology, Nuclear Medicine & Medical Imaging GA BDG90 UT WOS:000313182200061 ER PT S AU Wear, KA Gammell, PM Maruvada, S Liu, YB Harris, GR AF Wear, Keith A. Gammell, Paul M. Maruvada, Subha Liu, Yunbo Harris, Gerald R. BE Muratore, R Konofagou, EE TI Comparison of Hydrophone Phase Response Obtained via Time Delay Spectrometry Measurement and Hilbert Transformation SO 11TH INTERNATIONAL SYMPOSIUM ON THERAPEUTIC ULTRASOUND SE AIP Conference Proceedings LA English DT Proceedings Paper CT 11th International Symposium on Therapeutic Ultrasound (ISTU) CY APR 11-13, 2011 CL New York, NY SP Int Soc Therapeut Ultrasound, Amer Inst Ultrasound Med, Focused Ultrasound Fdn, Philips, Imason SAS, Verason Inc, InSightec Ltd, EyeTechCare, SuperSon Imagine SA, Image Guided Therapy, Elect & Innovat Ltd, Onda Corp, Son Concepts Inc, GE DE Time Delay Spectrometry; Hydrophone; Phase measurement ID CALIBRATION; AMPLITUDE; MHZ AB If a hydrophone's sensitivity varies appreciably with frequency, its response must be deconvolved with the measured hydrophone signal for accurate pressure measurements. For deconvolution, the phase response of the hydrophone must be known. We examine the hypothesis that hydrophones behave as minimum phase systems, in which case the phase response can be calculated from the amplitude response via Hilbert transformation. The relative amplitude and phase responses of several types of hydrophones were measured via time delay spectrometry. One hydrophone was a piezo-ceramic needle designed for high-intensity focused ultrasound (HIFU) applications. The phase response of one of the hydrophones was calibrated independently by a national standards laboratory. This reference hydrophone was used to compute the absolute amplitude and phase responses of the other hydrophones. Over the 5-18 MHz frequency range studied, there was no significant difference between the measured and Hilbert-transform-calculated phase responses for the several hydrophone types considered. Thus, this data supports the hypothesis that many types of hydrophones behave as minimum phase systems, permitting the phase response to be obtained directly from a measurement of the amplitude response. C1 [Wear, Keith A.; Maruvada, Subha; Liu, Yunbo; Harris, Gerald R.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Gammell, Paul M.] Gammell Appl Technol, LLC, Exmore, VA 23350 USA. RP Wear, KA (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 978-0-7354-1093-0 J9 AIP CONF PROC PY 2012 VL 1481 BP 450 EP 456 DI 10.1063/1.4757376 PG 7 WC Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Physics; Radiology, Nuclear Medicine & Medical Imaging GA BDG90 UT WOS:000313182200076 ER PT J AU Xia, QS Chiang, HM Zhou, YT Yin, JJ Liu, F Wang, C Guo, L Fu, PP AF Xia, Qingsu Chiang, Hsiu-Mei Zhou, Yu-Ting Yin, Jun-Jie Liu, Fang Wang, Cheng Guo, Lei Fu, Peter P. TI Phototoxicity of Kava - Formation of Reactive Oxygen Species Leading to Lipid Peroxidation and DNA Damage SO AMERICAN JOURNAL OF CHINESE MEDICINE LA English DT Article DE Kava Extract; Photosensitivity; UVA Light; Reactive Oxygen Species; Lipid Peroxidation; HaCaT Keratinocytes; 8-OHdG ID SINGLET OXYGEN; FREE-RADICALS; UVA; INDUCTION; PHOTOIRRADIATION; FIBROBLASTS; SUPPLEMENTS; SUPEROXIDE; DERMOPATHY; CHEMISTRY AB Kava is one of the most widely sold herbal dietary supplements in the United States. It has been reported that, besides exhibiting hepatotoxicity, kava also possesses photosensitivity and induces dermopathy in humans. In this study, we determined that UVA irradiation of kava in the presence of a lipid, methyl linoleate, generated lipid peroxidation which was mediated by singlet oxygen generated during photoirradiation. The six major kavalactones (yangonin, 7,8-dihydrokawa in, kawain, 7,8-dihydromethysticin, methysticin, and 5,6-dehydrokawain) were also studied in parallel; only 5,6-dehydrokawain and yangonin-induced a low level of lipid peroxidation. UVA irradiation of kava in human HaCaT skin keratinocytes induced cytotoxicity which was mediated by oxidative stress, led to DNA strand cleavage, and produced 8-hydroxy-2'-deoxyguanosine (8-OHdG) adduct. Study by the electron spin resonance (ESR) method revealed that UVA irradiation of kava produced singlet oxygen and carbon-centered radicals. The overall results suggest that kava is photocytotoxic and photo-genotoxic, both mediated by free radicals generated during photoirradiation. C1 [Xia, Qingsu; Liu, Fang; Wang, Cheng; Guo, Lei; Fu, Peter P.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chiang, Hsiu-Mei] China Med Univ, Dept Cosmeceut, Taichung, Taiwan. [Zhou, Yu-Ting; Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Fu, PP (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov RI Chiang, Hsiu-Mei/L-8150-2013; Yin, Jun Jie /E-5619-2014 NR 34 TC 6 Z9 6 U1 0 U2 5 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA 5 TOH TUCK LINK, SINGAPORE 596224, SINGAPORE SN 0192-415X J9 AM J CHINESE MED JI Am. J. Chin. Med. PY 2012 VL 40 IS 6 BP 1271 EP 1288 DI 10.1142/S0192415X12500942 PG 18 WC Integrative & Complementary Medicine; Medicine, General & Internal SC Integrative & Complementary Medicine; General & Internal Medicine GA 052PN UT WOS:000312210400014 PM 23227797 ER PT J AU Pfister, M Nolin, TD Arya, V AF Pfister, Marc Nolin, Thomas D. Arya, Vikram TI Optimizing Drug Development and Use in Patients With Kidney Disease: Opportunities, Innovations, and Challenges SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Editorial Material C1 [Pfister, Marc] Quantitat Solut Inc, Bridgewater, NJ 08807 USA. [Nolin, Thomas D.] Univ Pittsburgh, Sch Med, Dept Med, Renal Electrolyte Div, Pittsburgh, PA USA. [Nolin, Thomas D.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA. [Arya, Vikram] US FDA, Div Clin Pharmacol 4, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Pfister, M (reprint author), Quantitat Solut Inc, Bridgewater, NJ 08807 USA. NR 15 TC 1 Z9 1 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JAN PY 2012 VL 52 SU 1 BP 4S EP 6S DI 10.1177/0091270011415414 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 055QB UT WOS:000312430400001 PM 22232753 ER PT J AU Zhang, L Xu, N Xiao, S Arya, V Zhao, P Lesko, LJ Huang, SM AF Zhang, Lei Xu, Nancy Xiao, Shen Arya, Vikrain Zhao, Ping Lesko, Lawrence J. Huang, Shiew-Mei TI Regulatory Perspectives on Designing Pharmacokinetic Studies and Optimizing Labeling Recommendations for Patients With Chronic Kidney Disease SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE Chronic kidney disease; renal impairment; pharmacokinetics; guidance; regulatory; labeling; Cockcroft-Gault; modification of diet in renal disease; hemodialysis ID GLOMERULAR-FILTRATION-RATE; SERUM CREATININE VALUES; RENAL-DISEASE; COCKCROFT-GAULT; ESTIMATING EQUATIONS; DRUG; DIET; CLEARANCE; IMPAIRMENT; METABOLISM AB To optimize drug closing, it is critical to understand how various intrinsic and extrinsic factors affect systemic exposure of the drug and the response. Chronic kidney disease (or renal impairment) can affect pharmacokinetic characteristics of a therapeutic drug and its metabolites and therefore is one of the most important intrinsic factors that can affect a patient's response to drugs. During drug development, it is critical to understand how renal impairment can affect a drug's pharmacokinetics so that appropriate dosing recommendations can be included in the label, The US Food and Drug Administration (FDA) has published various guidance documents and opinion papers to address scientific and regulatory issues in the study design, data analysis, and labeling recommendations related to closing in patients with impaired renal function. The 2010 FDA draft guidance on renal impairment provides several updated recommendations that include criteria or principles for evaluating the pharmacokinetics of drugs that are either principally renally cleared or nonrenally cleared in subjects with renal impairment and for categorizing renal function by equations estimating glomerular filtration rate using the Modification of Diet in Pencil Disease equations or creatinine clearance using the Cockcroft-Gault equation. The objective of this article is to discuss the FDA's current recommendations and provide examples that illustrate the importance of and challenges in studying effect of renal impairment during drug development. C1 [Zhang, Lei; Arya, Vikrain; Zhao, Ping; Lesko, Lawrence J.; Huang, Shiew-Mei] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Xu, Nancy; Xiao, Shen] US FDA, Ctr Drug Evaluat & Res, Off Drug Evaluat 1, Off New Drugs, Silver Spring, MD 20993 USA. RP Zhang, L (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Bldg 51,Room 3106,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM leik.zhang@fda.hhs.gov NR 51 TC 10 Z9 10 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JAN PY 2012 VL 52 SU 1 BP 79S EP 90S DI 10.1177/0091270011415410 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 055QB UT WOS:000312430400010 PM 22232757 ER PT J AU Zhao, P Vieira, MDT Grillo, JA Song, PF Wu, TC Zheng, JH Arya, V Berglund, EG Atkinson, AJ Sugiyama, Y Pang, KS Reynolds, KS Abernethy, DR Zhang, L Lesko, LJ Huang, SM AF Zhao, Ping Vieira, Manuela de L. T. Grillo, Joseph A. Song, Pengfei Wu, Ta-Chen Zheng, Jenny H. Arya, Vikram Berglund, Eva Gil Atkinson, Arthur J., Jr. Sugiyama, Yuichi Pang, K. Sandy Reynolds, Kellie S. Abernethy, Darrell R. Zhang, Lei Lesko, Lawrence J. Huang, Shiew-Mei TI Evaluation of Exposure Change of Nonrenally Eliminated Drugs in Patients With Chronic Kidney Disease Using Physiologically Based Pharmacokinetic Modeling and Simulation SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE renal impairment; drug-drug interaction; PBPK; combined intrinsic and extrinsic factors ID RENAL IMPAIRMENT; TISSUE DISTRIBUTION; SILDENAFIL CITRATE; HUMAN-POPULATIONS; LIVER-CIRRHOSIS; METABOLISM; TELITHROMYCIN; REPAGLINIDE; PREDICTION; TRANSPORT AB Chronic kidney disease, or renal impairment (RI) can increase plasma levels for drugs that are primarily venally cleared and for some drugs whose renal elimination is not a major pathway. We constructed physiologically based pharmacokinetic (PBPK) models for 3 nonrenally eliminated drugs (sildenafil, repaglinide, and telithromycin). These models integrate drug-dependent parameters derived from in vitro, in silico, and in vivo data, and system-dependent parameters that are independent of the test drugs. Plasma pharmacokinetic profiles of test drugs were simulated in subjects with severe RI and normal renal function. respectively. The simulated versus observed areas under the concentration versus time curve changes (AUCR, severe RI/normal/were comparable for slidenafil (2.2 vs 2.0) and telithromycin (1.6 vs 1.9). For repaglinide. the initial, simulated AUCR was lower than that observed (1.2 vs 3.0). The underestimation was corrected once the estimated changes in transporter activity were incorporated into the model. The simulated AUCR values were confirmed using a static, clearance concept model. The PBPK models were further used to evaluate the changes in pharmacokinetic profiles of sildenefil metabolite by RI and of telithromycin by RI and co-administration with ketoconazole. The simulations demonstrate the utility and challenges of the PBPK approach in evaluating the pharmocokinetics of nonrenally cleared drugs in subjects with RI. C1 [Zhao, Ping; Vieira, Manuela de L. T.; Grillo, Joseph A.; Song, Pengfei; Wu, Ta-Chen; Zheng, Jenny H.; Arya, Vikram; Reynolds, Kellie S.; Abernethy, Darrell R.; Zhang, Lei; Lesko, Lawrence J.; Huang, Shiew-Mei] US FDA, Off Clin Pharmacol, Off Translat Sci, Silver Spring, MD 20993 USA. [Vieira, Manuela de L. T.] Univ Florida, Dept Pharmaceut, Gainesville, FL USA. [Berglund, Eva Gil] Med Prod Agcy, Uppsala, Sweden. [Atkinson, Arthur J., Jr.] Northwestern Univ, Chicago, IL 60611 USA. [Sugiyama, Yuichi] Univ Tokyo, Dept Mol Pharmacol, Tokyo 1138654, Japan. [Pang, K. Sandy] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON M5S 1A1, Canada. RP Zhao, P (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, WO Bldg 51 Room 3195,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM ping.zhao@fda.hhs.gov FU Center for Drug Evaluation and Research FX Dr Vieira was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and US Food and Drug Administration. NR 50 TC 41 Z9 43 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JAN PY 2012 VL 52 SU 1 BP 91S EP 108S DI 10.1177/0091270011415528 PG 18 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 055QB UT WOS:000312430400011 PM 22232759 ER PT J AU Tortorici, MA Cutler, D Zhang, L Pfister, M AF Tortorici, Michael A. Cutler, David Zhang, Lei Pfister, Marc TI Design, Conduct, Analysis, and Interpretation of Clinical Studies in Patients With Impaired Kidney Function SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE Chronic kidney disease; pharmacokinetics; pharmacometrics; impaired kidney function; efficacy; safety; dosing ID NONRENAL DRUG CLEARANCE; RENAL IMPAIRMENT; PHARMACOKINETICS; HEMODIALYSIS; DISEASE; METABOLISM; TRANSPORT; IMPACT AB Chronic kidney disease has been shown to alter the pharmacokinetics of drugs that are eliminated not only via the renal pathway but also by metabolism or nonrenal transport. Guidance documents from regulatory agencies on the pharmacokinetics of drugs in patients with impaired kidney function provide a framework for facilitating study design, conduct, data analysis, and the generation of dosing recommendations. Design considerations include establishment of appropriate enrollment criteria, selection of appropriate matched control group(s). and staging of impaired kidney function by estimated glomerular filtration rate or creatinine clearance. When studies in hemodialysis patients ore conducted, optimizing the timing of characterization of the pharmacokinetics profile based on the schedule of hemodialysis sessions will allow for a robust assessment in these patients. In addition to traditional noncompartmental approaches. the use of pharmacometric approaches can integrate data from multiple clinical studies and provide a quantitative rationale for dose selection in patients Wit 17 impaired kidney function. This article addresses the challenges and opportunities associated with the design, conduct. analysis, and interpretation of clinical studies to allow for their future facilitation and for the establishment of safe and efficacious dosing in patients with impaired kidney function. C1 [Tortorici, Michael A.] Pfizer, Collegeville, PA 19426 USA. [Cutler, David] Merck & Co Inc, N Wales, PA USA. [Zhang, Lei] US FDA, Silver Spring, MD USA. [Pfister, Marc] Quantitat Solut, Bridgewater, NJ USA. RP Tortorici, MA (reprint author), Pfizer, 500 Arcola Rd,F3316, Collegeville, PA 19426 USA. EM Michal.Tortorici@pfizer.com NR 34 TC 6 Z9 6 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JAN PY 2012 VL 52 SU 1 BP 109S EP 118S DI 10.1177/0091270011416364 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 055QB UT WOS:000312430400012 PM 22232746 ER PT J AU Hariharan, S Madabushi, R AF Hariharan, Sudharshan Madabushi, Rajanikanth TI Clinical Pharmacology Basis of Deriving Dosing Recommendations for Dabigatran in Patients With Severe Renal Impairment SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE Dabigatran; Randomized Evaluation of Long-term Anti-coagulant Therapy (RE-LY); renal impairment ID CHRONIC KIDNEY-DISEASE; PLATELET DYSFUNCTION; ATRIAL-FIBRILLATION; INSUFFICIENCY; MANAGEMENT; PEDIATRICS AB The objective of this work was to derive a dosing regimen for dabigatran in patients with severe renal impairment by modeling and simulation. Data from a dedicated renal impairment study were used to model the pharmacokinetics of dabigatran in normal and renal-impaired subjects. Model parameters were used to simulate the average concentration time-course of dabigatran following various dosing regimens. Pharmacokinetics of dabigatran in normal and renal-impaired subjects were best described by a 2-compartment open model with first-order absorption and elimination. Simulations were performed to select an appropriate regimen that reasonably matched the exposures on an average with those observed in subjects with moderate renal impairment who did not require a dose adjustment because of a favorable benefit-risk. Dabigatran 150 mg given once daily resulted in 35% higher average C-max,C-ss, whereas a 75 mg once daily regimen resulted in 42% lower average C-tau relative to that observed with 150 117,14 administered twice daily in subjects with moderate renal impairment. A twice daily regimen of dabigatran 75 mg resulted in a reasonable matching of exposures and was selected as on appropriate dosing regimen in patients with severe renal impairment. This recommendation was incorporated in the dosing and recommendation section of dabigatran product insert. C1 [Hariharan, Sudharshan; Madabushi, Rajanikanth] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Madabushi, R (reprint author), US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Rajnikanth.Madabushi@fda.hhs.gov NR 16 TC 31 Z9 31 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JAN PY 2012 VL 52 SU 1 BP 119S EP 125S DI 10.1177/0091270011415527 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 055QB UT WOS:000312430400013 PM 21956605 ER PT J AU Jin, K Stockbridge, N AF Jin, Kun Stockbridge, Norman TI Predicting acute hypotensive episodes from ambulatory blood pressure telemetry SO STATISTICS AND ITS INTERFACE LA English DT Article DE B-spline smoothing; Rank analysis; Cross validation; Acute hypertensive episode; Ambulatory blood pressure telemetry ID SELECTION AB The biological data collected from intensive care units contain signal and noise. To extract information that will be useful for predicting or discriminating the cases likely to develop an acute hypotensive episode (AHE), we begin by applying a spline-based smoothing method to the observed mean arterial pressure (MAP) curves. The coefficients of the fitted spline model form a discretization matrix of the continuous MAP curves. A rank-based discriminant analysis and a cross-validation method are developed to find the best prediction subset in the training set. The selected best subsets are used to predict AHE in the test sets. This work is from participation of PhysioNet/Computers in Cardiology Challenge 2009: Predicting Acute Hypotensive Episodes. C1 [Jin, Kun] US FDA, CDER, Div Biometr 1, Silver Spring, MD 20993 USA. [Stockbridge, Norman] US FDA, CDER, Div Cardiovasc & Renal Prod, Silver Spring, MD 20993 USA. RP Jin, K (reprint author), US FDA, CDER, Div Biometr 1, WO21,Rm 4622,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM kun.jin@fda.hhs.gov; norman.stockbridge@fda.hhs.gov NR 6 TC 0 Z9 0 U1 0 U2 0 PU INT PRESS BOSTON, INC PI SOMERVILLE PA PO BOX 43502, SOMERVILLE, MA 02143 USA SN 1938-7989 J9 STAT INTERFACE JI Stat. Interface PY 2012 VL 5 IS 4 BP 425 EP 429 PG 5 WC Mathematical & Computational Biology; Mathematics, Interdisciplinary Applications SC Mathematical & Computational Biology; Mathematics GA 054TF UT WOS:000312365700006 ER PT B AU Shilpakala, SR Atreya, CD Ketha, KMV AF Shilpakala, Sainath Rao Atreya, Chintamani D. Ketha, Krishna Mohan V. BE AbelSantos, E TI Detection of Bacterial Spores: Prospects and Challenges SO BACTERIAL SPORES: CURRENT RESEARCH AND APPLICATIONS LA English DT Article; Book Chapter ID BACILLUS-ANTHRACIS SPORES; REAL-TIME PCR; POLYMERASE-CHAIN-REACTION; INVASIVE STREPTOMYCES INFECTIONS; CLOSTRIDIUM-DIFFICILE INFECTION; AMINO-ACID SUBSTITUTIONS; COLLAGEN-LIKE REGION; MYXOCOCCUS-XANTHUS; CEREUS GROUP; RAPID-DETECTION AB Bacteria of several genera are able to form endospores when subjected to certain starvation conditions. The endospores are dormant forms that are structurally and biochemically different from the corresponding growing or vegetative cells. These bacterial endospores resist antibiotics, desiccation, and ordinary boiling than the vegetative cells. The detection of bacterial endospores can be important for a wide variety of purposes. In the sanitation and hygiene fields, detection of bacterial spores can be critical to monitor indoor environments, water quality and food quality. Similarly, in the public health perspective detection of bacterial spores is very important in ensuring regulation of safer transfusion and other therapeutic products, administered either orally or intravenously. Monitoring of bacterial spores is gaining importance even in other areas such as agriculture wherein soil or plant samples are periodically monitored for bacterial spores to ensure high levels of the bacterial population/toxin to be effective against insect pests. More recently, with the possibility of bacterial spores being used as bio-threat agents there has been an augmented effort in developing much more sensitive, specific and rapid detection systems for bacterial spores. The review discusses about current methods of bacterial spore detection and the challenges involved. C1 [Shilpakala, Sainath Rao; Atreya, Chintamani D.; Ketha, Krishna Mohan V.] US FDA, Sect Cell Biol, Lab Cellular Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Shilpakala, SR (reprint author), US FDA, Sect Cell Biol, Lab Cellular Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. EM shilpakala.sainathrao@fda.hhs.gov; chintamani.atreya@fda.hhs.gov; krishna.ketha@fda.hhs.gov NR 165 TC 0 Z9 0 U1 1 U2 4 PU CAISTER ACADEMIC PRESS PI WYMONDHAM PA 32 HEWITTS LANE, WYMONDHAM NR 18 0JA, ENGLAND BN 978-1-908230-00-3 PY 2012 BP 215 EP 236 PG 22 WC Microbiology SC Microbiology GA BCZ84 UT WOS:000312233000013 ER PT J AU Volpe, D Tobin, GA Tavakkoli, F Dowling, TC Parker, RJ AF Volpe, Donna Tobin, Grainne A. Tavakkoli, Fatemeh Dowling, Thomas C. Parker, Robert J. TI EFFECT OF UREMIC SERUM AND UREMIC TOXIN ON IN VITRO MICROSOMAL METABOLISM SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 18th North American Regional International-Society-for-the-Study-of-Xenobiotics (ISSX) Meeting CY OCT 14-18, 2012 CL Dallas, TX SP Int Soc Study Xenobiot (ISSX) C1 [Volpe, Donna; Tobin, Grainne A.; Parker, Robert J.] US FDA, Rockville, MD 20857 USA. [Tavakkoli, Fatemeh; Dowling, Thomas C.] Univ Maryland, College Pk, MD 20742 USA. RI Dowling, Thomas/D-2147-2013 OI Dowling, Thomas/0000-0003-3214-9283 NR 0 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2012 VL 44 SU 1 BP 57 EP 58 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 045EC UT WOS:000311676800111 ER PT J AU Lumen, A Mattie, DR Fisher, JW AF Lumen, Annie Mattie, David R. Fisher, Jeffrey W. TI AN IN SILICO APPROACH FOR ASSESSING THE RISK OF THYROID HORMONE DISRUPTION DURING PREGNANCY DUE TO PERCHLORATE, A SODIUM IODIDE SYMPORTER INHIBITOR SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 18th North American Regional International-Society-for-the-Study-of-Xenobiotics (ISSX) Meeting CY OCT 14-18, 2012 CL Dallas, TX SP Int Soc Study Xenobiot (ISSX) C1 [Lumen, Annie] US FDA, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. [Fisher, Jeffrey W.] FDA NCTR, Jefferson, AR USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2012 VL 44 SU 1 BP 102 EP 102 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 045EC UT WOS:000311676800201 ER PT S AU Smith, MA Hoorfar, J AF Smith, M. A. Hoorfar, J. BE Hoorfar, J TI Investigating a large outbreak of salmonellosis in the US involving fresh produce SO CASE STUDIES IN FOOD SAFETY AND AUTHENTICITY: LESSONS FROM REAL-LIFE SITUATIONS SE Woodhead Publishing in Food Science Technology and Nutrition LA English DT Article; Book Chapter DE fresh produce; tracing; recall; pathogen; outbreak ID UNITED-STATES; ILLNESS AB Fresh produce is an important part of a healthy diet. However, produce is susceptible to contamination with pathogens. Identifying the food vehicle responsible for an outbreak is critical to minimizing the public health and economic impacts of an outbreak. Identifying the food vehicle and its source may also help prevent future outbreaks. The case study describes an especially challenging investigation of an outbreak of salmonellosis that occurred in the US in 2008. C1 [Smith, M. A.] US FDA, Ctr Food Safety & Allied Nutr, Off Food Safety HFS 317, College Pk, MD 20740 USA. [Hoorfar, J.] Tech Univ Denmark, Natl Food Inst, DK-2860 Soborg, Denmark. RP Smith, MA (reprint author), US FDA, Ctr Food Safety & Allied Nutr, Off Food Safety HFS 317, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM michelle.smith@fda.hhs.gov; jhoo@food.dtu.dk NR 11 TC 0 Z9 0 U1 0 U2 1 PU WOODHEAD PUBL LTD PI CAMBRIDGE PA ABINGTON HALL ABINGTON, CAMBRIDGE CB1 6AH, CAMBS, ENGLAND SN 2042-8049 BN 978-0-85709-693-7 J9 WOODHEAD PUBL FOOD S JI Woodhead Publ. Food Sci. Technol. Nutr. PY 2012 IS 240 BP 33 EP 42 D2 10.1533/9780857096937 PG 10 WC Food Science & Technology; Public, Environmental & Occupational Health SC Food Science & Technology; Public, Environmental & Occupational Health GA BCU96 UT WOS:000311550100007 ER PT S AU Feng, P AF Feng, P. BE Hoorfar, J TI Learning from outbreaks of Escherichia coli O157:H7 caused by low pH foods SO CASE STUDIES IN FOOD SAFETY AND AUTHENTICITY: LESSONS FROM REAL-LIFE SITUATIONS SE Woodhead Publishing in Food Science Technology and Nutrition LA English DT Article; Book Chapter DE acidity; foodborne illness; Escherichia coli O157:H7 ID HEMOLYTIC-UREMIC SYNDROME; APPLE CIDER; O157-H7 INFECTION; ACID ADAPTATION; CHEDDAR CHEESE; SURVIVAL; CONSUMPTION; SAUSAGE; CONTAMINATION; MANUFACTURE AB Most bacteria cannot grow or survive in low pH environments; hence, increasing the acidity of foods, either through fermentation such as in making sausage, cheese and other dairy products or by the addition of weak acids, such as in pickling, has been used as a method of food preservation since ancient times. Accordingly, foods that have low pH have often been regarded as being low-risk in terms of food safety. This chapter examines the safety of acidic foods and the effectiveness of low pH in controlling enterohemorrhagic Escherichia coli (EHEC) serotype O157:H7, a pathogen that has caused foodborne illnesses worldwide. C1 US FDA, Div Microbiol, College Pk, MD 20740 USA. RP Feng, P (reprint author), US FDA, Div Microbiol, HFS 711,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM peter.feng@fda.hhs.gov NR 28 TC 0 Z9 0 U1 0 U2 2 PU WOODHEAD PUBL LTD PI CAMBRIDGE PA ABINGTON HALL ABINGTON, CAMBRIDGE CB1 6AH, CAMBS, ENGLAND SN 2042-8049 BN 978-0-85709-693-7 J9 WOODHEAD PUBL FOOD S JI Woodhead Publ. Food Sci. Technol. Nutr. PY 2012 IS 240 BP 244 EP 253 D2 10.1533/9780857096937 PG 10 WC Food Science & Technology; Public, Environmental & Occupational Health SC Food Science & Technology; Public, Environmental & Occupational Health GA BCU96 UT WOS:000311550100030 ER PT B AU Chong, GT Lee, RK AF Chong, Gabriel T. Lee, Richard K. BE Kahook, MY TI LOCATION OF GLAUCOMA DRAINAGE IMPLANTS AND TUBES SO ESSENTIALS OF GLAUCOMA SURGERY LA English DT Article; Book Chapter ID RANDOMIZED CLINICAL-TRIAL; REFRACTORY GLAUCOMA; OPTIC-NERVE; INSERTION; SURGERY; PLACEMENT; DEVICES; VALVE C1 [Chong, Gabriel T.] Raleigh Ophthalmol, Raleigh, NC USA. [Lee, Richard K.] US FDA, Div Ophthalm Neurol & ENT Devices, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Chong, GT (reprint author), Raleigh Ophthalmol, Raleigh, NC USA. NR 23 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE ROAD, THOROFARE, NJ 08086-9447 USA BN 978-1-61711-012-2 PY 2012 BP 95 EP 104 PG 10 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA BCO13 UT WOS:000310814200010 ER PT B AU Radcliffe, NM Kahook, MY AF Radcliffe, Nathan M. Kahook, Malik Y. BE Kahook, MY TI ENDOCYCLOPHOTOCOAGULATION SO ESSENTIALS OF GLAUCOMA SURGERY LA English DT Article; Book Chapter ID ENDOSCOPIC CYCLOPHOTOCOAGULATION; GLAUCOMA C1 [Radcliffe, Nathan M.] Weill Cornell Med Coll, Glaucoma Serv, New York, NY USA. [Radcliffe, Nathan M.] New York Hosp, New York, NY 10021 USA. [Radcliffe, Nathan M.] NYU, New York, NY 10003 USA. [Kahook, Malik Y.] Univ Colorado, Dept Ophthalmol, Boulder, CO 80309 USA. [Kahook, Malik Y.] Univ Colorado, Dept Bioengn, Glaucoma Serv, Boulder, CO 80309 USA. [Kahook, Malik Y.] US FDA, Ophthalm Device Div, Rockville, MD 20857 USA. RP Radcliffe, NM (reprint author), Weill Cornell Med Coll, Glaucoma Serv, New York, NY USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE ROAD, THOROFARE, NJ 08086-9447 USA BN 978-1-61711-012-2 PY 2012 BP 221 EP 225 PG 5 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA BCO13 UT WOS:000310814200027 ER PT B AU Khaimi, MA Kahook, MY AF Khaimi, Mahmoud A. Kahook, Malik Y. BE Kahook, MY TI EX-PRESS GLAUCOMA FILTRATION DEVICE SO ESSENTIALS OF GLAUCOMA SURGERY LA English DT Article; Book Chapter ID DRAINAGE IMPLANT; SCLERAL FLAP; SURGERY; PHACOEMULSIFICATION; TRABECULECTOMY; EXTRUSION C1 [Khaimi, Mahmoud A.] Univ Oklahoma, Dean A McGee Eye Inst, Oklahoma City, OK USA. [Khaimi, Mahmoud A.] NBA Oklahoma City Thunder Basketball Team, Oklahoma City, OK USA. [Kahook, Malik Y.] Univ Colorado, Dept Ophthalmol, Boulder, CO 80309 USA. [Kahook, Malik Y.] Univ Colorado, Dept Bioengn, Glaucoma Serv, Boulder, CO 80309 USA. [Kahook, Malik Y.] US FDA, Ophthalm Device Div, Rockville, MD 20857 USA. RP Khaimi, MA (reprint author), Oklahoma City VA Med Ctr, Glaucoma Serv, Oklahoma City, OK USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE ROAD, THOROFARE, NJ 08086-9447 USA BN 978-1-61711-012-2 PY 2012 BP 325 EP 330 PG 6 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA BCO13 UT WOS:000310814200040 ER PT B AU Pantcheva, M Kahook, MY AF Pantcheva, Mina Kahook, Malik Y. BE Kahook, MY TI TRABECTOME SO ESSENTIALS OF GLAUCOMA SURGERY LA English DT Article; Book Chapter C1 [Pantcheva, Mina] Univ Colorado, Sch Med, Dept Ophthalmol, Aurora, CO 80045 USA. [Kahook, Malik Y.] Univ Colorado, Dept Bioengn, Glaucoma Serv, Aurora, CO USA. [Kahook, Malik Y.] US FDA, Ophthalm Device Div, Rockville, MD 20857 USA. RP Pantcheva, M (reprint author), Univ Colorado, Sch Med, Dept Ophthalmol, Aurora, CO 80045 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE ROAD, THOROFARE, NJ 08086-9447 USA BN 978-1-61711-012-2 PY 2012 BP 337 EP 341 PG 5 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA BCO13 UT WOS:000310814200042 ER PT B AU Kramm, RL Eydelman, MB AF Kramm, R. Lee Eydelman, Malvina B. BE Kahook, MY TI UNITED STATES FOOD AND DRUG ADMINISTRATION REGULATION OF OPHTHALMIC DEVICES SO ESSENTIALS OF GLAUCOMA SURGERY LA English DT Article; Book Chapter C1 [Kramm, R. Lee; Eydelman, Malvina B.] US FDA, Ctr Devices & Radiol Hlth, Div Ophthalm Neurol & ENT Devices, Off Device Evaluat, Silver Spring, MD USA. RP Kramm, RL (reprint author), US FDA, Ctr Devices & Radiol Hlth, Div Ophthalm Neurol & ENT Devices, Off Device Evaluat, Silver Spring, MD USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE ROAD, THOROFARE, NJ 08086-9447 USA BN 978-1-61711-012-2 PY 2012 BP 373 EP 376 PG 4 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA BCO13 UT WOS:000310814200045 ER PT B AU Parekh, A AF Parekh, Ameeta BE SchenckGustafsson, K DeCola, PR Pfaff, DW Pisetsky, DS TI Women in Clinical Drug Trials: United States Food and Drug Administration Update on Policies and Practices SO HANDBOOK OF CLINICAL GENDER MEDICINE LA English DT Article; Book Chapter ID PROLONGATION; INTERVAL AB It is now well established that subgroup populations deserve a careful assessment of their response differences in order to derive maximum benefit from medical products, and that the concept of 'one size fits all' is an antiquated approach to drug development. These concepts are integrated into the United States Food and Drug Administration's (FDA) drug development, regulatory review, and approval paradigm, and form the essence of personalized medicine. Factors affecting drug exposure and response, such as patient age, sex, race, and genetic makeup, have gained heightened attention due to emerging evidence of their outcome differences and scientific investigators now routinely examine these demographic features during clinical research. This chapter discusses the historical context of women's participation in clinical drug trials and how FDA regulatory policies and practices for addressing sex differences in treatment response have evolved over the years. An overview of this topic was discussed at the Gender Medicine Conference held in October 2010 in Stockholm, Sweden to commemorate the 200th anniversary of the Karolinska Institutet. Copyright (C) 2012 S. Karger AG, Basel C1 US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Parekh, A (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM ameeta.parekh@fda.hhs.gov NR 23 TC 0 Z9 0 U1 0 U2 2 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND BN 978-3-8055-9929-0 PY 2012 BP 466 EP 472 PG 7 WC Primary Health Care SC General & Internal Medicine GA BCO36 UT WOS:000310829000048 ER PT S AU Stokes, WS Kulpa-Eddy, J Brown, K Srinivas, G McFarlands, R AF Stokes, W. S. Kulpa-Eddy, J. Brown, K. Srinivas, G. McFarlands, R. BE Jungback, C TI Recent Progress and Future Directions for Reduction, Refinement, and Replacement of Animal Use in Veterinary Vaccine Potency and Safety Testing: A report from the 2010 NICEATM-ICCVAM International Vaccine Workshop SO POTENCY TESTING OF VETERINARY VACCINES FOR ANIMALS: THE WAY FROM IN VIVO TO IN VITRO SE Developments in Biologicals LA English DT Proceedings Paper CT International Scientific Workshop on Potency Testing of Veterinary Vaccines - Way from in Vivo to in Vitro CY DEC 01-03, 2010 CL Paul Ehrlich Inst, Langen, GERMANY SP Paul Ehrlich Inst, European Directorate Qual Med & Healthcare, Int Alliance Biol Standardizat HO Paul Ehrlich Inst DE Veterinary vaccines; potency; safety; ICCVAM; recommendations; workshop ID HUMANE END-POINTS; RABIES VACCINES AB Veterinary vaccines contribute to improved animal and human health and welfare by preventing infectious diseases. However, testing necessary to ensure vaccine effectiveness and safety can involve large numbers of animals and significant pain and distress. NICEATM and ICCVAM recently convened an international workshop to review the state of the science of human and veterinary vaccine potency and safety testing, and to identify priority activities to advance new and improved methods that can further reduce, refine and replace animal use. Rabies, Clostridium sp., and Leptospira sp. vaccines were identified as the highest priorities, while tests requiring live viruses and bacteria hazardous to laboratory workers, livestock, pets, and wildlife were also considered high priorities. Priority research, development and validation activities to address critical knowledge and data gaps were identified, including opportunities to apply new science and technology. Enhanced international harmonization and cooperation and closer collaborations between human and veterinary researchers were recommended to expedite progress. Implementation of the workshop recommendations is expected to advance new methods for vaccine testing that will benefit animal welfare and ensure continued and improved protection of human and animal health. C1 [Stokes, W. S.] NIEHS, Natl Toxicol Program Interagency Ctr Evaluat Alte, POB 12233,Mail Stop K2-16, Res Triangle Pk, NC 27709 USA. [Kulpa-Eddy, J.; Srinivas, G.] US Dept Agr, Riverdale, MD USA. [Brown, K.] Pair O Docs Enterprises, Parkville, Vic, Australia. [McFarlands, R.] United States Food & Drug Adm, Rockville, MD USA. RP Stokes, WS (reprint author), NIEHS, Natl Toxicol Program Interagency Ctr Evaluat Alte, POB 12233,Mail Stop K2-16, Res Triangle Pk, NC 27709 USA. EM stokes@niehs.nih.gov NR 14 TC 4 Z9 4 U1 0 U2 5 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 1424-6074 BN 978-3-8055-9892-7 J9 DEV BIOLOGICALS JI Dev. Biols PY 2012 VL 134 BP 9 EP + PG 3 WC Pharmacology & Pharmacy; Veterinary Sciences SC Pharmacology & Pharmacy; Veterinary Sciences GA BCP26 UT WOS:000310938700002 PM 22888590 ER PT S AU Arciniega, J Sirota, LA AF Arciniega, J. Sirota, L. A. BE Jungback, C TI Potential Application of the Consistency Approach for Vaccine Potency Testing SO POTENCY TESTING OF VETERINARY VACCINES FOR ANIMALS: THE WAY FROM IN VIVO TO IN VITRO SE Developments in Biologicals LA English DT Proceedings Paper CT International Scientific Workshop on Potency Testing of Veterinary Vaccines - Way from in Vivo to in Vitro CY DEC 01-03, 2010 CL Paul Ehrlich Inst, Langen, GERMANY SP Paul Ehrlich Inst, European Directorate Qual Med & Healthcare, Int Alliance Biol Standardizat HO Paul Ehrlich Inst DE consistency approach; vaccine; potency ID QUALITY-CONTROL AB The Consistency Approach offers the possibility of reducing the number of animals used for a potency test. However, it is critical to assess the effect that such reduction may have on assay performance. Consistency of production, sometimes referred to as consistency of manufacture or manufacturing, is an old concept implicit in regulation, which aims to ensure the uninterrupted release of safe and effective products. Consistency of manufacture can be described in terms of process capability, or the ability of a process to produce output within specification limits. For example, the standard method for potency testing of inactivated rabies vaccines is a multiple-dilution vaccination challenge test in mice that gives a quantitative, although highly variable estimate. On the other hand, a single-dilution test that does not give a quantitative estimate, but rather shows if the vaccine meets the specification has been proposed. This simplified test can lead to a considerable reduction in the number of animals used. However, traditional indices of process capability assume that the output population (potency values) is normally distributed, which clearly is not the case for the simplified approach. Appropriate computation of capability indices for the latter case will require special statistical considerations. C1 [Arciniega, J.; Sirota, L. A.] USFDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Arciniega, J (reprint author), USFDA, Ctr Biol Evaluat & Res, 1401 Rockville Pike, Rockville, MD 20852 USA. EM juan.arciniega@fda.hhs.gov NR 14 TC 1 Z9 1 U1 0 U2 2 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 1424-6074 BN 978-3-8055-9892-7 J9 DEV BIOLOGICALS JI Dev. Biols PY 2012 VL 134 BP 135 EP 139 PG 5 WC Pharmacology & Pharmacy; Veterinary Sciences SC Pharmacology & Pharmacy; Veterinary Sciences GA BCP26 UT WOS:000310938700018 PM 22888606 ER PT J AU Ogunsola, OA Kraeling, ME Zhong, S Pochan, DJ Bronaugh, RL Raghavan, SR AF Ogunsola, Oluwatosin A. Kraeling, Margaret E. Zhong, Sheng Pochan, Darrin J. Bronaugh, Robert L. Raghavan, Srinivasa R. TI Structural analysis of "flexible" liposome formulations: new insights into the skin-penetrating ability of soft nanostructures SO SOFT MATTER LA English DT Article ID TRANSMISSION ELECTRON-MICROSCOPY; SODIUM DODECYL-SULFATE; VESICLE MICELLE TRANSITION; ANGLE SCATTERING DATA; LIPID VESICLES; PERCUTANEOUS-ABSORPTION; INTERMEDIATE STRUCTURES; DRUG CARRIERS; SURFACTANT; MIXTURES AB Self-assembled nanocontainers that can penetrate the protective barrier of skin could prove useful for the needle-free delivery of chemicals, drugs or vaccines into the skin. The main examples of these are the so-called "flexible liposomes", which are mixtures of lipids and detergents. In vitro experiments by numerous researchers have confirmed the skin-penetrating ability of these structures, which is believed to involve the squeezing of flexible bilayers through the pores in the stratum corneum. Here, we reexamine the structure of "flexible" liposome formulations and show that these are actually mixtures of liposomes and micelles. These findings are reinforced through a combination of small-angle neutron scattering (SANS) and cryo-transmission electron microscopy (cryo-TEM). We believe that our new findings necessitate a new mechanism for the penetration of soft assemblies into the skin. Several possibilities in this regard are considered, including one in which micelles facilitate the dynamic exchange of amphiphiles between liposomes and/or lipid bilayers. C1 [Ogunsola, Oluwatosin A.; Raghavan, Srinivasa R.] Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. [Ogunsola, Oluwatosin A.; Kraeling, Margaret E.; Bronaugh, Robert L.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20742 USA. [Zhong, Sheng; Pochan, Darrin J.] Univ Delaware, Dept Mat Sci & Engn, Newark, DE 19716 USA. RP Raghavan, SR (reprint author), Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. EM sraghava@umd.edu FU JIFSAN; ORISE FX This work was funded by a grant from JIFSAN and an ORISE fellowship to OAO. We acknowledge NIST for facilitating the SANS experiments performed as part of this work. We also acknowledge Dr Hee-Young Lee and Dr Matthew Dowling for assistance with the formulation studies and modeling, Dr Li Komatsu and Dr Li Mu for assistance with the skin penetration studies, and Amy Beaven for guidance in using the confocal microscope. NR 35 TC 12 Z9 12 U1 1 U2 40 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1744-683X J9 SOFT MATTER JI Soft Matter PY 2012 VL 8 IS 40 BP 10226 EP 10232 DI 10.1039/c2sm26614h PG 7 WC Chemistry, Physical; Materials Science, Multidisciplinary; Physics, Multidisciplinary; Polymer Science SC Chemistry; Materials Science; Physics; Polymer Science GA 033VJ UT WOS:000310829200003 ER PT S AU Okelo, PO AF Okelo, P. O. BE FinkGremmels, J TI Detection and enumeration of microbiological hazards in animal feed SO ANIMAL FEED CONTAMINATION: EFFECTS ON LIVESTOCK AND FOOD SAFETY SE Woodhead Publishing in Food Science Technology and Nutrition LA English DT Article; Book Chapter DE microbiological; detection; enumeration; analysis; hazards; pathogens; contamination; animal feed; feedstuffs; fodder ID ESCHERICHIA-COLI; BETA-GLUCURONIDASE; CATTLE FEEDS; IDENTIFICATION; ENTEROBACTERIACEAE; CONTAMINATION; POULTRY; SAMPLES; BACTERIOPHAGES; BACTERIA AB This chapter provides an overview of methods for pathogen detection and microbiological enumeration that are relevant to implementation of control measures to improve safety to animals and humans that may be applied during the production, storage, distribution and use of animal feed. It does not discuss in detail the procedures that need to be followed to properly apply the methods used to detect and enumerate microbiological hazards in feed and fodder. Instead, readers are encouraged to consult separate texts for further reading on specific methods in common use for detailed descriptions of sampling and analytical procedures. C1 US FDA, Ctr Vet Med, Rockville, MD 20855 USA. RP Okelo, PO (reprint author), US FDA, Ctr Vet Med, Rockville, MD 20855 USA. EM phares.okelo@fda.hhs.gov NR 35 TC 0 Z9 0 U1 0 U2 0 PU WOODHEAD PUBL LTD PI CAMBRIDGE PA ABINGTON HALL ABINGTON, CAMBRIDGE CB1 6AH, CAMBS, ENGLAND SN 2042-8049 BN 978-0-85709-361-5 J9 WOODHEAD PUBL FOOD S JI Woodhead Publ. Food Sci. Technol. Nutr. PY 2012 IS 215 BP 56 EP 65 D2 10.1533/9780857093615 PG 10 WC Agriculture, Dairy & Animal Science; Food Science & Technology SC Agriculture; Food Science & Technology GA BCH69 UT WOS:000310214700005 ER PT S AU Scheid, JF AF Scheid, J. F. BE FinkGremmels, J TI Management of animal feed safety in the USA SO ANIMAL FEED CONTAMINATION: EFFECTS ON LIVESTOCK AND FOOD SAFETY SE Woodhead Publishing in Food Science Technology and Nutrition LA English DT Article; Book Chapter DE animal feed and pet food safety; regulation of animal feeds; pet foods; ingredients; animal feed safety system; current Good Manufacturing Practice regulations (cGMP); FDA-licensed and non-licensed feed mills; Food Safety Modernization Act (FSMA) AB The US regulatory system for animal feed and pet food safety is made up of programs and policies addressing specific, identified hazards. In general, the system has worked well, but challenges have come from unexpected sources. The Food and Drug Administration has established the Animal Feed Safety System (AFSS) Initiative to analyze the feed safety regulatory system and developed recommendations to address 'gaps' in the current system. Meanwhile, the melamine contamination crisis highlighted the evolving nature of international commerce in food and animal feed, and the need for a review of the policies used to protect animals and humans against feed-borne risks. And, in 2011, the Food Safety Modernization Act became law, bringing additional changes to the rules applying to feed safety. C1 US FDA, Ctr Vet Med, Rockville, MD 20855 USA. RP Scheid, JF (reprint author), US FDA, Ctr Vet Med, 7519 Standish Pl, Rockville, MD 20855 USA. EM jon.scheid@fda.hhs.gov NR 6 TC 1 Z9 1 U1 1 U2 4 PU WOODHEAD PUBL LTD PI CAMBRIDGE PA ABINGTON HALL ABINGTON, CAMBRIDGE CB1 6AH, CAMBS, ENGLAND SN 2042-8049 BN 978-0-85709-361-5 J9 WOODHEAD PUBL FOOD S JI Woodhead Publ. Food Sci. Technol. Nutr. PY 2012 IS 215 BP 608 EP 624 D2 10.1533/9780857093615 PG 17 WC Agriculture, Dairy & Animal Science; Food Science & Technology SC Agriculture; Food Science & Technology GA BCH69 UT WOS:000310214700026 ER PT J AU Shah, R De Jager, LS Begley, TH AF Shah, Romina De Jager, Lowri S. Begley, Timothy H. TI Simultaneous determination of steviol and steviol glycosides by liquid chromatography-mass spectrometry SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE rebaudioside A; stevioside; steviol glycosides ID REBAUDIANA EXTRACTS; REBAUDIOSIDE-A; SWEETENER AB A direct, versatile method for the determination of steviol and nine steviol glycosides in food products has been developed by using electrospray ionisation liquid chromatography-mass spectrometry in the negative-ion mode. Ten stevia compounds were readily separated on an amino column by using a gradient separation. Data for analyte quantification were collected in the selected ion monitoring mode, giving the method limit of detection of 0.01-0.34 mu g g(-1) and repeatability at the limit of quantitation of 2%-15% relative standard deviation. Thirty-four commercially available food products were tested by using the optimised method, and in these products rebaudioside A and stevioside comprised 52%-100% of the total steviol glycosides. Multiple reaction monitoring data were collected to provide analyte confirmation. Stability data for rebaudioside A stored at room temperature, 40 degrees C and 60 degrees C over a period of 1-14 days are shown. C1 [Shah, Romina; De Jager, Lowri S.; Begley, Timothy H.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Shah, R (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM romina.shah@fda.hhs.gov NR 16 TC 8 Z9 9 U1 1 U2 20 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2012 VL 29 IS 12 BP 1861 EP 1871 DI 10.1080/19440049.2012.725946 PG 11 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 030VM UT WOS:000310598200005 PM 23050630 ER PT J AU Yue, LQ AF Yue, Lilly Q. TI REGULATORY CONSIDERATIONS IN THE DESIGN OF COMPARATIVE OBSERVATIONAL STUDIES USING PROPENSITY SCORES SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Causal inference; Observational study; Propensity scores; Regulatory perspective ID BIAS AB In the evaluation of medical products, including drugs, biological products, and medical devices, comparative observational studies could play an important role when properly conducted randomized, well-controlled clinical trials are infeasible due to ethical or practical reasons. However, various biases could be introduced at every stage and into every aspect of the observational study, and consequently the interpretation of the resulting statistical inference would be of concern. While there do exist statistical techniques for addressing some of the challenging issues, often based on propensity score methodology, these statistical tools probably have not been as widely employed in prospectively designing observational studies as they should be. There are also times when they are implemented in an unscientific manner, such as performing propensity score model selection for a dataset involving outcome data in the same dataset, so that the integrity of observational study design and the interpretability of outcome analysis results could be compromised. In this paper, regulatory considerations on prospective study design using propensity scores are shared and illustrated with hypothetical examples. C1 US FDA, CDRH, Silver Spring, MD 20993 USA. RP Yue, LQ (reprint author), US FDA, CDRH, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM lilly.yue@fda.hhs.gov NR 16 TC 3 Z9 3 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 6 BP 1272 EP 1279 DI 10.1080/10543406.2012.715111 PG 8 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 024UG UT WOS:000310133900013 PM 23075022 ER PT J AU Naum, M Lampel, KA AF Naum, Marianna Lampel, Keith A. BE Yan, X Juneja, VK Fratamico, PM Smith, JL TI Shigella Species SO OMICS, MICROBIAL MODELING AND TECHNOLOGIES FOR FOODBORNE PATHOGENS LA English DT Article; Book Chapter ID ENTEROINVASIVE ESCHERICHIA-COLI; PATHOGENICITY ISLAND; BLACK-HOLES; FLEXNERI; EVOLUTION; GENES; SPP. C1 [Naum, Marianna; Lampel, Keith A.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Lampel, KA (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM marianna.naum@fda.hhs.gov; keith.lampel@fda.hhs.gov NR 10 TC 0 Z9 0 U1 0 U2 2 PU DESTECH PUBLICATIONS, INC PI LANCASTER PA 439 DUKE STREET, LANCASTER, PA 17602-4967 USA BN 978-1-60595-047-1 PY 2012 BP 135 EP 152 PG 18 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA BCG73 UT WOS:000310166100007 ER PT J AU Wang, SL Chen, HF AF Wang, Shiliang Chen, Haifeng BE Yan, X Juneja, VK Fratamico, PM Smith, JL TI Pathogenic Vibrio SO OMICS, MICROBIAL MODELING AND TECHNOLOGIES FOR FOODBORNE PATHOGENS LA English DT Article; Book Chapter ID MANNOSE-SENSITIVE HEMAGGLUTININ; FRAGMENT-LENGTH-POLYMORPHISM; MULTILOCUS SEQUENCE-ANALYSIS; COMPARATIVE GENOMIC ANALYSIS; CHOLERA-TOXIN PROPHAGE; CLASSICAL CTX PROPHAGE; O1 EL-TOR; PANDEMIC STRAINS; GENE-EXPRESSION; FUNCTIONAL-CHARACTERIZATION C1 [Wang, Shiliang] J Craig Venter Inst, Rockville, MD 20850 USA. [Chen, Haifeng] USDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Washington, DC USA. RP Wang, SL (reprint author), J Craig Venter Inst, 9704 Med Ctr Dr, Rockville, MD 20850 USA. EM shiliang@jcvi.org; haifeng.chen@fda.hhs.gov NR 142 TC 0 Z9 0 U1 0 U2 2 PU DESTECH PUBLICATIONS, INC PI LANCASTER PA 439 DUKE STREET, LANCASTER, PA 17602-4967 USA BN 978-1-60595-047-1 PY 2012 BP 233 EP 268 PG 36 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA BCG73 UT WOS:000310166100010 ER PT J AU Chen, YH Danyluk, MD Schaffner, DW AF Chen, Yuhuan Danyluk, Michelle D. Schaffner, Donald W. BE Yan, X Juneja, VK Fratamico, PM Smith, JL TI Microbial Quantitative Risk Assessment SO OMICS, MICROBIAL MODELING AND TECHNOLOGIES FOR FOODBORNE PATHOGENS LA English DT Article; Book Chapter ID ESCHERICHIA-COLI O157-H7; TO-EAT FOODS; LISTERIA-MONOCYTOGENES; DOSE-RESPONSE; VIRULENCE; CAMPYLOBACTER; MODEL; INLA; SALMONELLA; MUTATIONS C1 [Schaffner, Donald W.] Rutgers State Univ, New Brunswick, NJ 08901 USA. [Danyluk, Michelle D.] Univ Florida, Ctr Agr Res & Educ, IFAS, Lake Alfred, FL 33850 USA. [Chen, Yuhuan] US FDA, College Pk, MD 20740 USA. RP Schaffner, DW (reprint author), Rutgers State Univ, 65 Dudley Rd, New Brunswick, NJ 08901 USA. EM yuhuan.chen@fda.hhs.gov; mddanyluk@crec.ifas.ufl.edu; schaffner@aesop.rutgers.edu NR 64 TC 0 Z9 0 U1 2 U2 5 PU DESTECH PUBLICATIONS, INC PI LANCASTER PA 439 DUKE STREET, LANCASTER, PA 17602-4967 USA BN 978-1-60595-047-1 PY 2012 BP 423 EP 446 PG 24 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA BCG73 UT WOS:000310166100016 ER PT J AU Chen, HF Wang, SL AF Chen, Haifeng Wang, Shiliang BE Yan, X Juneja, VK Fratamico, PM Smith, JL TI DNA Microarray Technology for the Detection of Foodborne Viral Pathogens SO OMICS, MICROBIAL MODELING AND TECHNOLOGIES FOR FOODBORNE PATHOGENS LA English DT Article; Book Chapter ID REVERSE TRANSCRIPTION-PCR; PADLOCK PROBES; OLIGONUCLEOTIDE MICROARRAYS; EXPRESSION ANALYSIS; MESSENGER-RNA; RVP ASSAY; AMPLIFICATION; VIRUSES; NASBA; CDNA C1 [Chen, Haifeng] US FDA, Div Mol Biol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. [Wang, Shiliang] J Craig Venter Inst, Rockville, MD 20850 USA. RP Chen, HF (reprint author), US FDA, Div Mol Biol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. EM Chen@fda.hhs.gov; shiliang@jcvi.org NR 93 TC 2 Z9 2 U1 0 U2 1 PU DESTECH PUBLICATIONS, INC PI LANCASTER PA 439 DUKE STREET, LANCASTER, PA 17602-4967 USA BN 978-1-60595-047-1 PY 2012 BP 579 EP 602 PG 24 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA BCG73 UT WOS:000310166100021 ER PT S AU Fink, DW Bauer, SR Au, P Haudenschild, CC Lee, MH McCright, BK AF Fink, D. W. Bauer, S. R. Au, P. Haudenschild, C. C. Lee, M. H. McCright, B. K. BE Atala, A TI Regulatory considerations of stem and progenitor cell-based products: US Food and Drug Administration SO PROGENITOR AND STEM CELL TECHNOLOGIES AND THERAPIES SE Woodhead Publishing Series in Biomaterials LA English DT Article; Book Chapter DE Food and Drug Administration; cellular product manufacturing; preclinical testing; clinical trials; combination products AB This chapter focuses on US Food and Drug Administration (FDA) regulatory considerations for stem/progenitor cell-based products (S/PCPs) intended to treat, mitigate or cure disease. Information critical to the regulatory decision-making process for determining the safety and efficacy of investigational S/PCPs is described. Included are sections that cover cellular product manufacturing and characterization, preclinical testing and clinical trial design. Increased regulatory complexity associated with stem/progenitor cell-based combination products is also discussed. C1 [Fink, D. W.; Bauer, S. R.; Au, P.; Haudenschild, C. C.; Lee, M. H.; McCright, B. K.] US FDA, Off Cellular Tissue & Gene Therapies, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Fink, DW (reprint author), US FDA, Off Cellular Tissue & Gene Therapies, Ctr Biol Evaluat & Res, 1401 Rockville Pike,Suite 200N,Mail Code HFM 715, Rockville, MD 20852 USA. EM donald.fink@fda.hhs.gov NR 19 TC 0 Z9 0 U1 0 U2 0 PU WOODHEAD PUBL LTD PI CAMBRIDGE PA ABINGTON HALL ABINGTON, CAMBRIDGE CB1 6AH, CAMBS, ENGLAND SN 2049-9485 BN 978-0-85709-607-4; 978-1-84569-984-0 J9 WOODH PUBL SER BIOM PY 2012 VL 38 BP 147 EP 168 D2 10.1533/9780857096074 PG 22 WC Cell & Tissue Engineering; Cell Biology; Engineering, Biomedical SC Cell Biology; Engineering GA BCI09 UT WOS:000310233400009 ER PT J AU Balsam, J Ossandon, M Bruck, HA Rasooly, A AF Balsam, Joshua Ossandon, Miguel Bruck, Hugh Alan Rasooly, Avraham TI Modeling and design of micromachined optical Soller collimators for lensless CCD-based fluorometry SO ANALYST LA English DT Article ID OPTOFLUIDIC MICROSCOPY; CAENORHABDITIS-ELEGANS; CHIP; IMMUNODETECTION; SYSTEM AB To address the needs of medical diagnostics in resource-poor settings, it is necessary to develop low cost, simple and portable Point of Care detectors for integrated medical diagnostics. Previously, we have described a simple lensless fluorometer with sensitivity in the range of current ELISA plate readers. The key to the lensfree fluorometer is the uniform spatial distribution of light, which we achieved using a simple optical collimator based on a "stack of pinholes'' (a stack of black PMMA plates with arrays of pinholes machined via laser) enabling the light to be collimated from the LED light source through the necessary wavelength filters and the assay's microfluidics directly onto the CCD without a lens. In this paper, we describe the optical principle for designing these Soller collimators for lensfree CCD-based fluorometry. The illuminating surface was modeled as a collection of differential areas emitting uniformly and spherically, and the intensity contribution of each emitting area was summed over the detector surface. To compute the final light intensity distribution from such a differential model we derived an integral equation to sum the individual intensity contributions from the two-dimensional emitting surface. The equation is for a single-hole collimator. Light intensity measurements were taken by placing a collimator with a particular aspect ratio (the ratio of hole length to diameter (L/d)) over the CCD image sensor and capturing an image. The resulting image is the 2D light intensity profile generated by the collimator. As the aspect ratio is increased the slope of the light intensity profile increases, corresponding to an increased degree of collimation. To test the model, the measured maximum and mean light intensities were compared with the theoretical predictions generated from the model. There was an agreement between the variation of the mean (R-2 = 0.990) and maximum (R-2 = 0.938) values of light intensities with aspect ratios based modeling. These profile measurements suggest an excellent agreement with the theoretical predictions. The integral equation presented here can be used to perfect the design of the optical Soller collimator. These results may lead to the development of more effective Soller collimators for lensfree CCD-based fluorometry for use in simple low cost lensfree optical detectors with the potential to enhance the accessibility and the quality of health care for underserved populations. C1 [Balsam, Joshua; Bruck, Hugh Alan; Rasooly, Avraham] US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Ossandon, Miguel; Rasooly, Avraham] NCI, NIH, Bethesda, MD USA. [Balsam, Joshua] UMCP, College Pk, MD 20742 USA. RP Rasooly, A (reprint author), US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. EM rasoolya@mail.nih.gov NR 22 TC 9 Z9 9 U1 1 U2 8 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0003-2654 J9 ANALYST JI Analyst PY 2012 VL 137 IS 21 BP 5011 EP 5017 DI 10.1039/c2an35729a PG 7 WC Chemistry, Analytical SC Chemistry GA 015EF UT WOS:000309427600018 PM 22973572 ER PT J AU Tsong, Y Wang, W AF Tsong, Yi Wang, William TI GUEST EDITORS' NOTE FOR THE SPECIAL ISSUE ON THE STATISTICAL CONSIDERATIONS FOR THE DESIGN AND ANALYSIS OF BRIDGING AND MULTIREGIONAL CLINICAL TRIALS SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Editorial Material C1 [Tsong, Yi] US FDA, Div Biometr 6, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Wang, William] Merck & Co Inc, Merck Res Labs, Beijing, Peoples R China. RP Tsong, Y (reprint author), US FDA, Div Biometr 6, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, Bldg 21,Room 4628,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM yi.tsong@fda.hhs.gov NR 4 TC 0 Z9 0 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 5 SI SI BP 875 EP 878 DI 10.1080/10543406.2012.702650 PG 4 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 008UX UT WOS:000308983200001 PM 22946936 ER PT J AU Wang, SJ Hung, HMJ AF Wang, Sue-Jane Hung, H. M. James TI ETHNIC SENSITIVE OR MOLECULAR SENSITIVE BEYOND ALL REGIONS BEING EQUAL IN MULTIREGIONAL CLINICAL TRIALS SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Bayesian credible interval; Ethnic sensitive; Molecular sensitive; Region driven ID DESIGN; NEPHROPATHY; CLOPIDOGREL; TAMOXIFEN; GENOTYPE; OUTCOMES AB For decades, clinical trials have been the primary mechanism for medical products to enter the marketplace. Over more than a decade, globalization of medical product development via a multiregional clinical trial (MRCT) approach has generated greater enthusiasm because of tangible benefits in terms of cost and time for drug development. There are, however, many challenges including and not limited to design issues, statistical analysis methods, interpretation of extreme region performance, and in-process quality assurance issues. This article presents a number of examples to exemplify regional variability expected versus precision of treatment effect estimates that are generally impacted by the type of primary efficacy endpoint evaluated. We explore region-driven intrinsic and extrinsic ethnic factors for potential explanation of regional heterogeneity caused by differences in medical practice and/or disease etiology. Bayesian credible interval may be considered as a viable approach to assess the robustness of region-specific treatment effect. Ethnic-sensitive or molecular-sensitive region-driven designs may be explored to prospectively address the potential regional heterogeneity versus the potential predictiveness of causal genetic variants or molecular target biomarkers on treatment effect. C1 [Wang, Sue-Jane; Hung, H. M. James] US FDA, Div Biometr 1, OB, OTS,CDER, Silver Spring, MD 20993 USA. RP Wang, SJ (reprint author), US FDA, Div Biometr 1, OB, OTS,CDER, 10903 New Hampshire Ave,Bldg 21,HFD 710,Mail Stop, Silver Spring, MD 20993 USA. EM suejane.wang@fda.hhs.gov FU RSR funds [05-02, 05-14] FX The regulatory research work presented here was supported by the RSR funds, number 05-02, 05-14. This article reflects the views of the authors and should not be construed to represent the views or policies of the U. S. Food and Drug Administration. NR 30 TC 3 Z9 3 U1 1 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 5 SI SI BP 879 EP 893 DI 10.1080/10543406.2012.701576 PG 15 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 008UX UT WOS:000308983200002 PM 22946937 ER PT J AU Tsou, HH Tsong, Y Liu, JT Dong, XY Wu, YT AF Tsou, Hsiao-Hui Tsong, Yi Liu, Jung-Tzu Dong, Xiaoyu Wu, Yute TI WEIGHTED EVIDENCE APPROACH OF BRIDGING STUDY SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Bridging study; Noninferiority; Simultaneous test; Weighted evidence approach ID CLINICAL-TRIALS; RATIO AB The ICH E5 Guidance facilitates the registration of medicine among ICH regions by recommending a framework for evaluating the impact of ethnic factors upon a medicine's effect. It further describes the use of bridging studies, when necessary, to allow extrapolation of foreign clinical data to a new region. Bridging studies are performed in a new region for medicines already approved in the original region. The conventional noninferiority criterion requires the treatment effect (adjusted for placebo) attained in the new region preserves a prespecified proportion of the treatment effect attained in the original region. Such a bridging criterion, however, is often impractical. Hsiao et al. (2007) proposed a Bayesian approach that borrows the strength of the original trial to establish the treatment effect in the bridging region through using a weighted prior distribution. The weight, however, is often difficult to prespecify. In this presentation, we consider the overall treatment effect by combining the weighted effects attained in the original and bridging regions. The maximum weight allowed to be placed on the estimate of bridging region in order to show a significant overall treatment effect represents the strength of the treatment effect in the bridging region. Regional approval will be evaluated either by comparing the weight estimate with the prespecified limit or by benefit-risk evaluation of the medicine. Sample size requirements for the approaches are derived. The simulation results of type I error rate and power for the proposed methods are given. An example illustrates the application of the proposed procedures. C1 [Tsou, Hsiao-Hui; Liu, Jung-Tzu] Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, Zhunan 350, Miaoli County, Taiwan. [Tsong, Yi; Wu, Yute] US FDA, Off Biostat, CDER, Silver Spring, MD USA. [Liu, Jung-Tzu] Natl Tsing Hua Univ, Inst Bioinformat & Struct Biol, Hsinchu, Taiwan. [Dong, Xiaoyu] Univ Maryland Baltimore Cty, Dept Math & Stat, Baltimore, MD 21228 USA. RP Tsou, HH (reprint author), Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, 35 Keyan Rd, Zhunan 350, Miaoli County, Taiwan. EM tsouhh@nhri.org.tw RI Tsou, Hsiao-Hui /E-3837-2010 OI Tsou, Hsiao-Hui /0000-0001-6773-4111 NR 16 TC 2 Z9 5 U1 0 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 5 SI SI BP 952 EP 965 DI 10.1080/10543406.2012.701580 PG 14 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 008UX UT WOS:000308983200007 PM 22946942 ER PT J AU Dong, XY Guo, Y Tsong, Y AF Dong, Xiaoyu Guo, Yu Tsong, Yi TI A NOTE ON TWO APPROACHES OF TESTING BRIDGING EVIDENCE TO A NEW REGION SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Rejection rate; Type I error rate; Weighted evidence test; Weighted z-test ID TRIALS AB Bridging studies are performed in a new region for medicines already approved in the original region. In order to borrow the strength of the original trial to establish the treatment effect in the bridging region, Lan et al. (2005) proposed to use a weighted z-test approach to combine the test statistics of the same hypothesis for both the original and bridging regions for bridging study. Based on a similar concept, Tsou et al. (2012) proposed instead to test a hypothesis of the weighted treatment effects of the original and bridging regions. In this article, we explore the differences of the concept in hypothesis testing and perform a simulation study to examine the type I error rate and power of the two approaches. C1 [Dong, Xiaoyu; Tsong, Yi] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Guo, Yu] Univ Maryland, Dept Math, College Pk, MD 20742 USA. RP Tsong, Y (reprint author), 4628,Bldg 21,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM yi.tsong@fda.hhs.gov FU CDER Office of Biostatistics ORISE Fund FX This project was supported by the 2010 CDER Office of Biostatistics ORISE Fund. This article does not represent the Food and Drug Administration's official position. NR 5 TC 1 Z9 3 U1 0 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 5 SI SI BP 966 EP 976 DI 10.1080/10543406.2012.702651 PG 11 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 008UX UT WOS:000308983200008 PM 22946943 ER PT J AU Chen, XY Lu, N Nair, R Xu, YL Kang, CL Huang, Q Li, N Chen, HZ AF Chen, Xiaoyuan Lu, Nelson Nair, Rajesh Xu, Yunling Kang, Cailian Huang, Qin Li, Ning Chen, Hongzhuan TI DECISION RULES AND ASSOCIATED SAMPLE SIZE PLANNING FOR REGIONAL APPROVAL UTILIZING MULTIREGIONAL CLINICAL TRIALS SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Decision rule; Multiregional clinical trial; Sample size planning AB Multiregional clinical trials provide the potential to make safe and effective medical products simultaneously available to patients globally. As regulatory decisions are always made in a local context, this poses huge regulatory challenges. In this article we propose two conditional decision rules that can be used for medical product approval by local regulatory agencies based on the results of a multiregional clinical trial. We also illustrate sample size planning for such trials. C1 [Chen, Xiaoyuan; Chen, Hongzhuan] Shanghai Jiao Tong Univ, Sch Med, Dept Pharmacol & Biostat, Shanghai 200030, Peoples R China. [Lu, Nelson; Nair, Rajesh; Xu, Yunling] US FDA, Off Surveillance & Biometr, CDRH, Silver Spring, MD USA. [Chen, Xiaoyuan; Kang, Cailian; Huang, Qin] China State Food & Drug Adm, Ctr Drug Evaluat, Beijing, Peoples R China. [Li, Ning] US FDA, Alumni Assoc, Gaithersburg, MD USA. RP Li, N (reprint author), 520 Skidmore Blvd, Gaithersburg, MD 20877 USA. EM ericylee1@gmail.com NR 9 TC 2 Z9 4 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 5 SI SI BP 1001 EP 1018 DI 10.1080/10543406.2012.701582 PG 18 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 008UX UT WOS:000308983200011 PM 22946946 ER PT J AU Tsong, Y Chang, WJ Dong, XY Tsou, HH AF Tsong, Yi Chang, Wan-Jung Dong, Xiaoyu Tsou, Hsiao-Hui TI ASSESSMENT OF REGIONAL TREATMENT EFFECT IN A MULTIREGIONAL CLINICAL TRIAL SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Bridging study; Consistent trend; Multiregional trial ID SAMPLE-SIZE AB The 11th question-and-answer document (Q&A) for ICH E5 (1998) was published in 2006. This Q&A describes points to consider for evaluating the possibility of bridging among regions by a multiregional trial. The primary objective of a multiregional bridging trial is to show the overall efficacy of a drug in all participating regions while also evaluating the possibility of applying the overall trial results to each region. To apply the overall results to a specific region, it suggested that the results in that region should be consistent with the overall results. The Japanese Ministry of Health, Labor, and Welfare (MHLW) published the "Basic Principles on Global Clinical Trials" guidance document (2007) and proposed two methods to support the bridging claims. Due to the limited sample sizes allocated to the region, the regular interaction test for treatment by region is not practical. On the other hand, the sample size requirement for the Japanese region as described in Uyama et al. (2005) and Uesaka (2009) is to satisfy an 80% or greater power for the Japanese region, conditioning on the effect of the overall global trial. Quan et al. (2010) further extended the results to trials with various endpoints. Ko, Tsou, Liu and Hsiao (2010) focused on a specific region and established statistical criteria for consistency between the region of interest and overall results. The proposed method was based on the assumption that true effect size is uniform across regions. In this article, we propose to analyze a completed multiregional trial for any specific regional effect by controlling the type I error rate adjusted for the regional sample size and the planned power of the global trial. Accordingly, in order to attain the approval for a specific region, we propose to determine the sample size requirement for the specific regions using the overall power planned and a regional acceptable type I error rate. C1 [Chang, Wan-Jung; Tsou, Hsiao-Hui] Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, Zhunan Town 350, Miaoli County, Taiwan. [Tsong, Yi] US FDA, Off Biostat, CDER, Silver Spring, MD USA. [Dong, Xiaoyu] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. RP Tsou, HH (reprint author), Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, 35 Keyan Rd, Zhunan Town 350, Miaoli County, Taiwan. EM tsouhh@nhri.org.tw RI Tsou, Hsiao-Hui /E-3837-2010 OI Tsou, Hsiao-Hui /0000-0001-6773-4111 NR 9 TC 5 Z9 5 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 5 SI SI BP 1019 EP 1036 DI 10.1080/10543406.2012.701583 PG 18 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 008UX UT WOS:000308983200012 PM 22946947 ER PT J AU Chen, CT Hung, HMJ Hsiao, CF AF Chen, Chi-Tian Hung, H. M. James Hsiao, Chin-Fu TI DESIGN AND EVALUATION OF MULTIREGIONAL TRIALS WITH HETEROGENEOUS TREATMENT EFFECT ACROSS REGIONS SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Bridging study; Ethnic effect; Multiregional trials ID SAMPLE-SIZE; METAANALYSIS AB To speed up drug development to allow faster access to medicines for patients globally, conducting multiregional trials incorporating subjects from many countries around the world under the same protocol may be desired. Several statistical methods have been proposed for the design and evaluation of multiregional trials. However, in most of the recent approaches for sample size determination in multiregional trials, a common treatment effect of the primary endpoint across regions is usually assumed. In practice, it might be expected that there is a difference in treatment effect due to regional difference (e. g., ethnic difference). In this article, a random effect model for heterogeneous treatment effect across regions is proposed for the design and evaluation of multiregional trials. We also address consideration of the determination of the number of subjects in a specific region to establish the consistency of treatment effects between the specific region and the entire group. C1 [Hsiao, Chin-Fu] Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, Zhunan 350, Miaoli County, Taiwan. [Chen, Chi-Tian] Natl Taiwan Univ, Div Biometry, Grad Inst Agron, Coll Bioresource & Agr, Taipei 10764, Taiwan. [Hung, H. M. James] US FDA, Div Biometr 1, OB OTS CDER DB1, Silver Spring, MD USA. [Hsiao, Chin-Fu] Natl Hlth Res Inst, Div Clin Trial Stat, Inst Populat Hlth Sci, Zhunan 350, Miaoli County, Taiwan. RP Hsiao, CF (reprint author), Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, 35 Keyan Rd, Zhunan 350, Miaoli County, Taiwan. EM chinfu@nhri.org.tw RI Hsiao, Chin-Fu/E-3993-2010 FU National Science Council, Taiwan [WSC 100-2118-M-400-001] FX The work in this article contributed by Chi-Tian Chen and Chin-Fu Hsiao was supported by the grant WSC 100-2118-M-400-001 from the National Science Council, Taiwan. The views expressed in this article do not necessarily represent those of the U. S. Food and Drug Administration. NR 15 TC 2 Z9 2 U1 0 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 5 SI SI BP 1037 EP 1050 DI 10.1080/10543406.2012.701585 PG 14 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 008UX UT WOS:000308983200013 PM 22946948 ER PT J AU Tsou, HH Tsong, Y Chang, WJ Dong, XY Hsiao, CF AF Tsou, Hsiao-Hui Tsong, Yi Chang, Wan-Jung Dong, Xiaoyu Hsiao, Chin-Fu TI DESIGN AND ANALYSIS ISSUES OF MULTIREGIONAL CLINICAL TRIALS WITH DIFFERENT REGIONAL PRIMARY ENDPOINTS SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Adjustment of type I error rate; Adjustment of type II error rate; Multiregional clinical trial; Primary endpoints AB One of the challenges of multiregional drug development program is to design and analyze a multiple regional clinical trial with the objective being to satisfy different regional requirements on primary endpoints. Considered in this article is a multiregional clinical trial (MRCT) designed to test for two primary endpoints. Data of a regular fixed-size well-controlled parallel arm trial are used to test for two null hypotheses in terms of two distinct yet correlated endpoints. The two hypotheses may be tested sequentially or simultaneously. Depending on the structure of the hypotheses to be tested and the understanding of type I error rate control, various scenarios of type I error rate adjustments may be applied. Furthermore, for the objective of getting approval from regional authorities for different primary endpoints, various sample size and power determinations may be applied. In this article, comparisons of different approaches are discussed systematically. C1 [Tsou, Hsiao-Hui; Chang, Wan-Jung; Hsiao, Chin-Fu] Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, Zhunan 350, Miaoli County, Taiwan. [Tsong, Yi] US FDA, Off Biostat, CDER, Silver Spring, MD USA. [Dong, Xiaoyu] Univ Maryland Baltimore Cty, Dept Math & Stat, Baltimore, MD 21228 USA. RP Tsou, HH (reprint author), Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, 35 Keyan Rd, Zhunan 350, Miaoli County, Taiwan. EM tsouhh@nhri.org.tw RI Tsou, Hsiao-Hui /E-3837-2010; Hsiao, Chin-Fu/E-3993-2010 OI Tsou, Hsiao-Hui /0000-0001-6773-4111; NR 2 TC 1 Z9 1 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 5 SI SI BP 1051 EP 1059 DI 10.1080/10543406.2012.701586 PG 9 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 008UX UT WOS:000308983200014 PM 22946949 ER PT J AU Tsong, Y AF Tsong, Yi TI STATISTICAL CONSIDERATIONS ON DESIGN AND ANALYSIS OF BRIDGING AND MULTIREGIONAL CLINICAL TRIALS SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Editorial Material DE Bridging trial; Extrapolation; Multiregional trial C1 US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Tsong, Y (reprint author), US FDA, Off Biostat, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22,Room 4628, Silver Spring, MD 20993 USA. EM yi.tsong@fda.hhs.gov NR 9 TC 0 Z9 0 U1 0 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 5 SI SI BP 1078 EP 1080 DI 10.1080/10543406.2012.702652 PG 3 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 008UX UT WOS:000308983200017 PM 22946952 ER PT J AU Hardbower, DM Dolman, JL Glasner, DR Kendra, JA Williamson, KE AF Hardbower, Dana M. Dolman, Jessica L. Glasner, Dustin R. Kendra, Joseph A. Williamson, Kurt E. TI Optimization of viral profiling approaches reveals strong links between viral and bacterial communities in a eutrophic freshwater lake SO AQUATIC MICROBIAL ECOLOGY LA English DT Article DE Virioplankton; Bacterioplankton; RAPD-PCR; tRFLP; Eutrophic lake; Community dynamics ID FIELD GEL-ELECTROPHORESIS; POLYMORPHIC DNA PCR; 16S RIBOSOMAL-RNA; SEASONAL DYNAMICS; POPULATION-DYNAMICS; TROPHIC STATUS; ENVIRONMENTAL VARIABLES; AQUATIC ECOSYSTEMS; TEMPERATE LAKES; MARINE VIRUSES AB The goals of this 18 mo field study were to examine temporal changes in viral community composition in a temperate eutrophic freshwater lake (Lake Matoaka) and to identify potential drivers of seasonal changes in microbial community composition. We show that analyses of aquatic viral community composition can be streamlined by concentrating viruses from small water samples without compromising the resolution of the community profile data. The use of small-volume viral concentrates paired with randomly amplified polymorphic DNA (RAPD) polmerase chain reaction (PCR) generated significantly richer and more complex banding patterns than the use of pulsed-field gel electrophoresis (PFGE) and the large-volume concentrates that PFGE requires. Thus, the small-volume RAPD-PCR approach was used in the subsequent analyses. Viral and bacterial communities in Lake Matoaka were highly dynamic, exhibiting strong seasonal shifts. However, repeating annual patterns were not detected among the bacterial or viral communities. Temperature was the most important factor explaining changes in viral and bacterial abundance. Viral and bacterial abundance were also significantly correlated to each other. Multivariate analysis indicated weak relationships between temperature and bacterial community composition and between temperature and viral community composition. Mantel tests revealed a strong and significant correlation between viral and bacterial community composition. Taken together with the correlation between viral and bacterial abundance, these data suggest that phages dominate the virioplankton of Lake Matoaka and indicate tightly linked phage-host dynamics. C1 [Hardbower, Dana M.; Dolman, Jessica L.; Glasner, Dustin R.; Kendra, Joseph A.; Williamson, Kurt E.] Coll William & Mary, Dept Biol, Williamsburg, VA 23185 USA. [Hardbower, Dana M.] Vanderbilt Univ, Interdisciplinary Grad Program Biol & Biomed Sci, Nashville, TN 37212 USA. [Glasner, Dustin R.] US FDA, Lab Retroviruses, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Williamson, KE (reprint author), Coll William & Mary, Dept Biol, 3035 Integrated Sci Ctr, Williamsburg, VA 23185 USA. EM kewilliamson@wm.edu FU Jeffress Memorial Trust [J-988] FX We thank L. Epp for running capillary electrophoresis and assistance with tRFLP analysis. We thank E. Orlova and D. Kiernan for assistance with field sampling and recording environmental data. Thanks to R. Chambers and the staff of the Keck Environmental Field Laboratory for water chemical analysis. Thanks also to M. Saxton and S. Williamson for reading the manuscript. This work was supported by a grant to K.E.W. from the Jeffress Memorial Trust (J-988). NR 81 TC 3 Z9 3 U1 1 U2 20 PU INTER-RESEARCH PI OLDENDORF LUHE PA NORDBUNTE 23, D-21385 OLDENDORF LUHE, GERMANY SN 0948-3055 J9 AQUAT MICROB ECOL JI Aquat. Microb. Ecol. PY 2012 VL 67 IS 1 BP 59 EP 76 DI 10.3354/ame01582 PG 18 WC Ecology; Marine & Freshwater Biology; Microbiology SC Environmental Sciences & Ecology; Marine & Freshwater Biology; Microbiology GA 004AF UT WOS:000308651800006 ER PT J AU Struble, EB Ma, L Zhong, LL Lesher, A Beren, J Zhang, P AF Struble, Evi Budo Ma, Li Zhong, Lilin Lesher, A. Beren, Joel Zhang, Pei TI Human Antibodies Can Cross Guinea Pig Placenta and Bind Its Neonatal Fc Receptor: Implications for Studying Immune Prophylaxis and Therapy during Pregnancy SO CLINICAL & DEVELOPMENTAL IMMUNOLOGY LA English DT Article ID I-RELATED RECEPTOR; IMMUNOGLOBULIN-G; AMINO-ACIDS; MOTHER; TRANSMISSION; HEPATITIS; INFECTION; YOUNG; IGG; IMMUNIZATION AB Despite increased use of monoclonal and polyclonal antibody therapies, including during pregnancy, there is little data on appropriate animal models that could humanely be used to understand determinants of protection and to evaluate safety of these biologics in the mother and the developing fetus. Here, we demonstrate that pregnant guinea pigs can transport human IgG transplacentally at the end of pregnancy. We also observe that human IgG binds to an engineered soluble variant of the guinea pig neonatal Fc receptor in vitro in a manner similar to that demonstrated for the human variant, suggesting that this transplacental transport mirrors the receptor-based mechanism seen in humans. Using an intravenous antihepatitis B-specific immune globulin preparation as an example, we show that this transport results in neutralizing activity in the mother and the newborn that would potentially be prophylactic against hepatitis B viral infection. These preliminary data lay the groundwork for introducing pregnant guinea pigs as an appropriate model for the evaluation of antibody therapies and advancing the health of women and neonates. C1 [Struble, Evi Budo; Ma, Li; Zhong, Lilin; Zhang, Pei] US FDA, Lab Plasma Derivat, Div Hematol, OBRR, Bethesda, MD 20892 USA. [Lesher, A.; Beren, Joel] US FDA, Div Vet Serv, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Struble, EB (reprint author), US FDA, Lab Plasma Derivat, Div Hematol, OBRR, Bethesda, MD 20892 USA. EM evi.struble@fda.hhs.gov FU Office of Women's Health, FDA FX The authors thank Drs. John Finlayson and Mei-ying Yu for helpful discussions and reading the paper. This work was partially supported by a grant by the Office of Women's Health, FDA to E. B. Struble and P. Zhang. NR 48 TC 2 Z9 2 U1 1 U2 2 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1740-2522 J9 CLIN DEV IMMUNOL JI Clin. Dev. Immunol. PY 2012 AR 538701 DI 10.1155/2012/538701 PG 9 WC Immunology SC Immunology GA 005OJ UT WOS:000308759400001 ER PT J AU Tsai, CA Huang, CH Chang, CW Chen, CH AF Tsai, Chen-An Huang, Chien-Hsun Chang, Ching-Wei Chen, Chun-Houh TI Recursive Feature Selection with Significant Variables of Support Vectors SO COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE LA English DT Article ID GENE-EXPRESSION PROFILES; CANCER CLASSIFICATION; MACHINES AB The development of DNA microarray makes researchers screen thousands of genes simultaneously and it also helps determine high-and low-expression level genes in normal and disease tissues. Selecting relevant genes for cancer classification is an important issue. Most of the gene selection methods use univariate ranking criteria and arbitrarily choose a threshold to choose genes. However, the parameter setting may not be compatible to the selected classification algorithms. In this paper, we propose a new gene selection method (SVM-t) based on the use of t-statistics embedded in support vector machine. We compared the performance to two similar SVM-based methods: SVM recursive feature elimination (SVMRFE) and recursive support vector machine (RSVM). The three methods were compared based on extensive simulation experiments and analyses of two published microarray datasets. In the simulation experiments, we found that the proposed method is more robust in selecting informative genes than SVMRFE and RSVM and capable to attain good classification performance when the variations of informative and noninformative genes are different. In the analysis of two microarray datasets, the proposed method yields better performance in identifying fewer genes with good prediction accuracy, compared to SVMRFE and RSVM. C1 [Tsai, Chen-An] Natl Taiwan Univ, Dept Agron, Taipei 106, Taiwan. [Huang, Chien-Hsun] Columbia Univ, Dept Stat, New York, NY 10027 USA. [Chang, Ching-Wei] US FDA, Div Personalized Nutr & Med, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chen, Chun-Houh] Acad Sinica, Inst Stat Sci, Taipei 115, Taiwan. RP Tsai, CA (reprint author), Natl Taiwan Univ, Dept Agron, Taipei 106, Taiwan. EM catsai@ntu.edu.tw OI Tsai, Chen-An/0000-0002-7490-4331 FU NRPGM from the National Science Council [NSC94-3112-B-001-012-Y, NSC95-3112-B-001-018, NSC 96-3112-B-001-017] FX The authors thank Dr. Chen-Hsin Chen for helpful discussion and edits to the paper. This project was initiated when all the authors were with the Genomic Statistics Unit (stationed at the Academia Sinica), Advanced Bioinformatics Core of the National Research Program for Genomic Medicine (NRPGM) in Taiwan. The work was partially supported by the NRPGM Grants (NSC94-3112-B-001-012-Y, NSC95-3112-B-001-018, and NSC 96-3112-B-001-017) from the National Science Council. NR 19 TC 1 Z9 1 U1 0 U2 4 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1748-670X J9 COMPUT MATH METHOD M JI Comput. Math. Method Med. PY 2012 AR 712542 DI 10.1155/2012/712542 PG 12 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 997ZU UT WOS:000308207800001 ER PT J AU Miller, RA Pelsor, FR Kane, AS Reimschuessel, R AF Miller, Ron A. Pelsor, Francis R. Kane, Andrew S. Reimschuessel, Renate TI Oxytetracycline Pharmacokinetics in Rainbow Trout during and after an Orally Administered Medicated Feed Regimen SO JOURNAL OF AQUATIC ANIMAL HEALTH LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; AEROMONAS-SALMONICIDA; OXOLINIC ACID; CUTOFF VALUES; BIOAVAILABILITY; PLASMA; SUSCEPTIBILITY; ANTIBIOTICS; LIVER; SERUM AB The pharmacokinetic-pharmacodynamic predictor of antimicrobial activity for tetracyclines is reported to be the area under the concentration-time curve at steady state (AUC(ss)) divided by the minimal inhibitory concentration of the targeted pathogen. Here, we estimate AUC(ss) values for oxytetracycline (OTC) in serum of rainbow trout Oncorhynchus mykiss by using a destructive sampling study design. Seventy-two rainbow trout were fed OTC-medicated feed at 74.7 +/- 1.5 mg/kg (mean +/- SD) body weight (BW) by oral gavage for 10 consecutive days. Serum was collected from nine fish at 1, 3, 6, 8, 10, 12, 15, and 22 d after dosing began. Serum OTC concentrations were measured by high-performance liquid chromatography with a 0.01-mu g/mL limit of detection. The average OTC AUC(ss) was 29.2 mu g x h/mL and was estimated using nonlinear mixed-effects modeling and bootstrap resampling techniques. The elimination half-life was estimated as 85.0 h, and the fraction of steady state achieved was estimated as 0.85. The calculated AUC(ss) (24.8 mu g x h/mL) following 10 d of oral dosing with 75 mg OTC/kg BW was less than the estimated AUC(ss). Results suggest that the pharmacokinetics of OTC exposure, including the AUC(ss), is better evaluated by using multiday dosimetry than by using a standard single-dose protocol. C1 [Miller, Ron A.; Pelsor, Francis R.] US FDA, Ctr Vet Med, Off New Anim Drug Evaluat, Rockville, MD 20855 USA. [Kane, Andrew S.] Univ Florida, Dept Environm & Global Hlth, Coll Publ Hlth & Hlth Profess, Gainesville, FL 32611 USA. [Reimschuessel, Renate] US FDA, Ctr Vet Med, Res Off, Laurel, MD 20708 USA. RP Miller, RA (reprint author), US FDA, Ctr Vet Med, Off New Anim Drug Evaluat, 7500 Standish Pl, Rockville, MD 20855 USA. EM ron.miller@fda.hhs.gov FU Oak Ridge Associated Universities; FDA FX This work was supported in part by the Oak Ridge Associated Universities through a grant sponsored by the FDA. We would like to thank Christie Decker, Mark McDonald, and Sam Howard for maintaining the animals used in this work. Reference to trade names does not imply endorsement by the U.S. Government. NR 33 TC 5 Z9 5 U1 2 U2 23 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0899-7659 J9 J AQUAT ANIM HEALTH JI J. Aquat. Anim. Health PY 2012 VL 24 IS 2 BP 121 EP 128 DI 10.1080/08997659.2012.675933 PG 8 WC Fisheries; Veterinary Sciences SC Fisheries; Veterinary Sciences GA 996YL UT WOS:000308130700008 PM 22838083 ER PT J AU Lanier, WA Wagstaff, RS DeMill, JH Friedrichs, MD Metos, J AF Lanier, William A. Wagstaff, Rachelle S. DeMill, Jessica H. Friedrichs, Michael D. Metos, Julie TI Teacher Awareness and Implementation of Food and Physical Activity Policies in Utah Elementary Schools, 2010 SO PREVENTING CHRONIC DISEASE LA English DT Article ID CORONARY-HEART-DISEASE; WELLNESS POLICY; HEALTH POLICIES; PUBLIC-SCHOOLS; NUTRITION; IMPACT; OVERWEIGHT; EDUCATION; PROGRAMS; OBESITY AB Introduction Schools are a key venue for childhood obesity prevention policies. The objective of this study was to examine factors associated with elementary school teacher awareness and implementation of their schools' food and physical activity policies. Methods We collected data through an online survey of teachers at Utah elementary schools with food and physical activity policies. We used bivariate analysis and logistic regression to assess association of variables with teacher awareness and implementation. Results Of 1,243 teacher respondents, 546 (44%) were aware of the food policy and 550 (44%) were aware of the physical activity policy. Food policy awareness was associated with knowing where written policies were located (odds ratio [OR], 2.7; 95% confidence interval [CI], 2.0-3.5), knowing the school health program coordinator (OR, 1.9; 95% CI, 1.4-2.7), and being reminded of policies at least once per semester (OR, 2.3; 95% CI, 1.7-2.9). Policy awareness was associated with both food (OR, 4.6; 95% CI, 3.6-6.0) and physical activity (OR, 1.6, 95% CI, 1.2-2.3) policy implementation. Helping develop the physical activity policy was associated with its implementation (OR, 2.4; 95% CI, 1.2-4.7). Thinking that students were more overweight than in the past was associated with food policy implementation (OR, 1.6; 95% CI, 1.1-2.5). Conclusion Establishing food and physical activity policies at schools does not ensure teacher awareness or implementation. To promote policy awareness and implementation, school leaders should involve teachers in policy development, remind teachers of policies at least once per semester, and continue to educate teachers about childhood obesity. C1 [Lanier, William A.] Utah Dept Hlth, EIS, Salt Lake City, UT 84116 USA. [Lanier, William A.; Metos, Julie] Univ Utah, Salt Lake City, UT USA. [Lanier, William A.] Ctr Dis Control & Prevent, EIS Field Assignments Branch, Atlanta, GA USA. RP Lanier, WA (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM william.lanier@fda.hhs.gov FU Utah Department of Health; CDC, Division of Nutrition and Physical Activity [U58/DP001386] FX This study was funded through a Utah Department of Health Cooperative Agreement with CDC, Division of Nutrition and Physical Activity (no. U58/DP001386). We thank Sarah Rigby, Lynda Blades, MPH, Nicole Bissonette, MPH, Heather R. Borski, MPH, and Kathryn Clark at the Utah Department of Health for their assistance with the study. NR 28 TC 1 Z9 1 U1 3 U2 10 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD JAN PY 2012 VL 9 AR 110091 DI 10.5888/pcd9.110091 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 977GI UT WOS:000306644300018 ER PT J AU Yang, HHW Weisz, A AF Yang, H. -H. W. Weisz, A. TI Determination of synthetic by-products and an intermediate in the colour additive D&C Orange No. 5 using high-performance liquid chromatography SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE D&C Orange No. 5; 2,4,6-tribromoresorcinol; 2-(3,5-dibromo-2,4-dihydroxybenzoyl)benzoic acid; phthalic acid; high-performance liquid chromatography (HPLC) AB Specifications in the US Code of Federal Regulations for the colour additive D&C Orange No. 5 (Colour Index No. 45370: 1) limit the levels of the synthetic by-products 2-(3,5-dibromo-2,4-dihydroxybenzoyl)benzoic acid (Br2BBA) and brominated resorcinol (Br3R) as well as the level of the intermediate phthalic acid (PhthAc). The present work reports the development and application of a high-performance liquid chromatography (HPLC) method for the quantitative determination of these impurities in D&C Orange No. 5 and its lakes. Br2BBA, Br3R and PhthAc were quantified by using five-point calibration curves with data points that ranged from 0.010% to 0.700%, from 0.012% to 0.706% and from 0.006% to 1.383% by weight, respectively. The HPLC method was applied to the analysis of test portions from 11 lots of D&C Orange No. 5 and one lot of D&C Orange No. 5 lake submitted to the US Food and Drug Administration (USFDA) for certification. C1 [Yang, H. -H. W.; Weisz, A.] US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Weisz, A (reprint author), US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM adrian.weisz@fda.hhs.gov NR 4 TC 3 Z9 3 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2012 VL 29 IS 9 BP 1386 EP 1390 DI 10.1080/19440049.2012.696216 PG 5 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 990OK UT WOS:000307640100006 PM 22779771 ER PT J AU Nazari, ZE Banoee, M Sepahi, AA Rafii, F Shahverdi, AR AF Nazari, Zeinab Esmail Banoee, Maryam Sepahi, Abbas Akhavan Rafii, Fatemeh Shahverdi, Ahmad Reza TI The combination effects of trivalent gold ions and gold nanoparticles with different antibiotics against resistant Pseudomonas aeruginosa SO GOLD BULLETIN LA English DT Article DE Au3+; Au NPs; Antibiotic resistance; Combination effect; Pseudomonas aeruginosa ID ENHANCED ANTIBACTERIAL ACTIVITY; SILVER COLLOIDAL PARTICLES; GRAM-NEGATIVE BACTERIA; ANTIMICROBIAL ACTIVITIES; TRIPHENYLPHOSPHINE LIGANDS; STAPHYLOCOCCUS-AUREUS; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; EFFLUX; COMPLEXES AB Despite much success in drug design and development, Pseudomonas aeruginosa is still considered as one of the most problematic bacteria due to its ability to develop mutational resistance against a variety of antibiotics. In search for new strategies to enhance antibacterial activity of antibiotics, in this work, the combination effect of gold materials including trivalent gold ions (Au3+) and gold nanoparticles (Au NPs) with 14 different antibiotics was investigated against the clinical isolates of P. aeruginosa, Staphylococcus aureus and Escherichia coli. Disk diffusion assay was carried out, and test strains were treated with the sub-inhibitory contents of gold nanomaterial. Results showed that Au NPs did not increase the antibacterial effect of antibiotics at tested concentration (40 mu g/disc). However, the susceptibility of resistant P. aeruginosa increased in the presence of Au3+ and methicillin, erythromycin, vancomycin, penicillin G, clindamycin and nalidixic acid, up to 147 %. As an individual experiment, the same group of antibiotics was tested for their activity against clinical isolates of S. aureus, E. coli and a different resistant strain of P. aeruginosa in the presence of sub-inhibitory contents of Au3+, where Au3+ increased the susceptibility of test strains to methicillin, erythromycin, vancomycin, penicillin G, clindamycin and nalidixic acid. Our finding suggested that using the combination of sub-inhibitory concentrations of Au3+ and methicillin, erythromycin, nalidixic acid or vancomycin may be a promising new strategy for the treatment of highly resistant P. aeruginosa infections. C1 [Shahverdi, Ahmad Reza] Univ Tehran Med Sci, Fac Pharm, Dept Pharmaceut Biotechnol & Biotechnol, Res Ctr, Tehran, Iran. [Nazari, Zeinab Esmail] Aalborg Univ, Inst Phys & Nanotechnol, Aalborg, Denmark. [Banoee, Maryam; Sepahi, Abbas Akhavan] Azad Univ, N Tehran Branch, Tehran, Iran. [Rafii, Fatemeh] Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Shahverdi, AR (reprint author), Univ Tehran Med Sci, Fac Pharm, Dept Pharmaceut Biotechnol & Biotechnol, Res Ctr, Tehran, Iran. EM shahverd@sina.tums.ac.ir FU Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran FX This work was supported by the Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. NR 36 TC 5 Z9 5 U1 4 U2 20 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0017-1557 J9 GOLD BULL JI Gold Bull. PY 2012 VL 45 IS 2 BP 53 EP 59 DI 10.1007/s13404-012-0048-7 PG 7 WC Chemistry, Inorganic & Nuclear; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 981EV UT WOS:000306950600002 ER PT J AU Kuselman, I Pennecchi, F Burns, C Fajgelj, A de Zorzi, P AF Kuselman, Ilya Pennecchi, Francesca Burns, Cathy Fajgelj, Ales de Zorzi, Paolo TI IUPAC/CITAC Guide: Investigating out-of-specification test results of chemical composition based on metrological concepts (IUPAC Technical Report) SO PURE AND APPLIED CHEMISTRY LA English DT Article; Proceedings Paper CT 43rd IUPAC Congress CY JUL 30-AUG 07, 2011 CL San Juan, PR SP IUPAC DE acceptance limits; IUPAC Analytical Chemistry Division; measurement uncertainty; out-of-specification test results; producer's and consumer's risks; warning and action lines ID LONG-TERM STABILITY AB A metrological background for investigating out-of-specification (OOS) test results of chemical composition is discussed. When an OOS test result is identified, it is important to determine its root causes and to avoid reoccurrence of such results. An investigation of the causes based on metrological concepts is proposed. It includes assessment of validation data of the measurement process and its metrological traceability chains, evaluation of measurement uncertainty, and related producer's and consumer's risks. This approach allows distinguishing between OOS test results that indicate an actual change in chemical composition of an analyzed object, and OOS test results that are metrologically related with a certain confidence probability, i.e., caused by measurement problems, while the analyzed object still meets the specification requirements at the time of testing. Practical examples illustrating applications of the described approach in environmental and food analysis, as well in drug analysis and stability study of drug products, are described. Acceptance limits, warning and action lines for the test results, and corresponding producer's and consumer's risks are discussed. C1 [Kuselman, Ilya] Natl Phys Lab Israel, IL-91904 Jerusalem, Israel. [Pennecchi, Francesca] Ist Nazl Ric Metrol, I-10135 Turin, Italy. [Burns, Cathy] US FDA, Denver, CO 80225 USA. [Fajgelj, Ales] IAEA, Vienna Int Ctr, A-1400 Vienna, Austria. [de Zorzi, Paolo] Ist Super Protez & Ric Ambientale, I-00128 Rome, Italy. RP Kuselman, I (reprint author), Natl Phys Lab Israel, IL-91904 Jerusalem, Israel. EM ilya.kuselman@moital.gov.il RI Pennecchi, Francesca/G-9812-2015 OI Pennecchi, Francesca/0000-0003-1328-3858 NR 44 TC 6 Z9 6 U1 1 U2 4 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0033-4545 EI 1365-3075 J9 PURE APPL CHEM JI Pure Appl. Chem. PY 2012 VL 84 IS 9 BP 1939 EP 1971 DI 10.1351/PAC-REP-11-10-04 PG 33 WC Chemistry, Multidisciplinary SC Chemistry GA 992YK UT WOS:000307817300011 ER PT S AU Gammell, PM Liu, YB Maruvada, S Harris, GR AF Gammell, Paul M. Liu, Yunbo Maruvada, Subha Harris, Gerald R. BE Thompson, DO Chimenti, DE TI DETECTOR MODULE FOR A SIMPLIFIED ULTRASONIC TIME DELAY SPECTROMETRY SYSTEM SO REVIEW OF PROGRESS IN QUANTITATIVE NONDESTRUCTIVE EVALUATION, VOLS 31A AND 31B SE AIP Conference Proceedings LA English DT Proceedings Paper CT 38th Annual Review of Progress in Quantitative Nondestructive Evaluation (QNDE) CY JUL 17-22, 2011 CL Univ Vermont, Burlington, VT SP QNDE Programs, AF Res Lab, Army Res Lab, Amer Soc Nondestruct Testing (ASNT), Dept Energy, AMES Lab, Fed Aviat Adm (FAA), Natl Aeronaut & Space Adm (NASA), Natl Sci Fdn (NSF), Ind/Univ Cooperat Res Ctr, Iowa State Univ, Ctr Nondestruct Evaluat HO Univ Vermont DE Ultrasonics; Time Delay Spectrometry; Envelope Detector AB When setting up a water-tank based ultrasonic system, aligning the transmitting and receiving transducers to maximize the received signal is required. With a digital time delay spectrometry (TDS) system the "dechirped" signal is observed while positional adjustments are being made. Observation is easier if only the envelope, rather than the modulated signal, is displayed. A module is described that provides an envelope (rectified signal) that, when displayed on an oscilloscope, is suitable as an alignment aid for use with the TDS system described elsewhere in these Proceedings. C1 [Gammell, Paul M.] Gammell Appl Technol LLC, 6139 Pleasant Cove Dr, Exmore, VA 23350 USA. [Liu, Yunbo; Maruvada, Subha; Harris, Gerald R.] Ctr Devices & Radiol Hlth, US FDA, Silver Spring, MD 20993 USA. RP Gammell, PM (reprint author), Gammell Appl Technol LLC, 6139 Pleasant Cove Dr, Exmore, VA 23350 USA. EM pgammell@ieee.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 978-0-7354-1013-8 J9 AIP CONF PROC PY 2012 VL 1430 BP 1861 EP 1864 DI 10.1063/1.4716437 PG 4 WC Physics, Applied SC Physics GA BBH82 UT WOS:000306913600227 ER PT S AU Gammell, PM Liu, YB Maruvada, S Wear, KA Harris, GR AF Gammell, Paul M. Liu, Yunbo Maruvada, Subha Wear, Keith A. Harris, Gerald R. BE Thompson, DO Chimenti, DE TI PHASE MEASUREMENT WITH A SIMPLIFIED ULTRASONIC TIME DELAY SPECTROMETRY SYSTEM SO REVIEW OF PROGRESS IN QUANTITATIVE NONDESTRUCTIVE EVALUATION, VOLS 31A AND 31B SE AIP Conference Proceedings LA English DT Proceedings Paper CT 38th Annual Review of Progress in Quantitative Nondestructive Evaluation (QNDE) CY JUL 17-22, 2011 CL Univ Vermont, Burlington, VT SP QNDE Programs, AF Res Lab, Army Res Lab, Amer Soc Nondestruct Testing (ASNT), Dept Energy, AMES Lab, Fed Aviat Adm (FAA), Natl Aeronaut & Space Adm (NASA), Natl Sci Fdn (NSF), Ind/Univ Cooperat Res Ctr, Iowa State Univ, Ctr Nondestruct Evaluat HO Univ Vermont DE Ultrasonics; Time Delay Spectrometry; Phase Measurement AB Time delay spectrometry (TDS) is a swept-frequency technique that has proven useful in several ultrasonic applications. We previously have described a system that is easy to replicate with equipment available in most acoustics laboratories. By incorporating quadrature demodulation into the software processing phase data can be obtained as well as the amplitude data. C1 [Gammell, Paul M.] Gammell Appl Technol LLC, 6139 Pleasant Cove Dr, Exmore, VA 23350 USA. [Liu, Yunbo; Maruvada, Subha; Wear, Keith A.; Harris, Gerald R.] Food & Drug Adm, Ctr Dev & Radiol Hlth, Silver Spring, MD 20993 USA. RP Gammell, PM (reprint author), Gammell Appl Technol LLC, 6139 Pleasant Cove Dr, Exmore, VA 23350 USA. EM pgammell@ieee.org NR 6 TC 1 Z9 1 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 978-0-7354-1013-8 J9 AIP CONF PROC PY 2012 VL 1430 BP 2013 EP 2020 DI 10.1063/1.4716456 PG 8 WC Physics, Applied SC Physics GA BBH82 UT WOS:000306913600247 ER PT J AU Rashid, MM McKean, JW Kloke, JD AF Rashid, M. Mushfiqur McKean, Joseph W. Kloke, John D. TI R Estimates and Associated Inferences for Mixed Models With Covariates in a Multicenter Clinical Trial SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Exchangeable; Dispersion function; Nonparametric; Robustness; Variance components; Wilcoxon ID REGRESSION COEFFICIENTS; LINEAR-MODELS; RANK; HYPOTHESES; DESIGNS; TESTS AB Robust rank-based methods are proposed for the analysis of data from multicenter clinical trials using a mixed model (including covariates) in which the treatment effects are assumed to be fixed and the center effects are assumed to be random. These rank-based methods are developed under the usual mixed-model structure but without the normality assumption of the random components in the model. For this mixed model, our proposed estimation includes R estimation of the fixed effects, robust estimation of the variance components, and studentized residuals. Our accompanying inference includes estimates of the standard errors of the fixed-effects estimators and tests of general linear hypotheses concerning fixed effects. While the development is for general scores function, the Wilcoxon linear scores are emphasized. A discussion of the relative efficiency results shows that the R estimates are highly efficient compared to the traditional maximum likelihood (ML) estimates. A small Monte Carlo study confirms the validity of the analysis and its gain in power over the ML analysis for heavy-tailed distributions. We further develop a rank-based test for center by treatment interactions. We discuss the results of our analysis for an example of a multicenter clinical trial which shows the robustness of our procedure. C1 [Rashid, M. Mushfiqur] US FDA, Ctr Drug Evaluat & Res, Sliver Spring, MD 20993 USA. [McKean, Joseph W.] Western Michigan Univ, Dept Stat, Kalamazoo, MI 49008 USA. [Kloke, John D.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53792 USA. RP Rashid, MM (reprint author), US FDA, Ctr Drug Evaluat & Res, Sliver Spring, MD 20993 USA. EM mushfiqur.rashid@fda.hhs.gov; joseph.mckean@wmich.edu; kloke@biostat.wisc.edu NR 31 TC 2 Z9 2 U1 0 U2 4 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PY 2012 VL 4 IS 1 BP 37 EP 49 DI 10.1080/19466315.2011.636293 PG 13 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 990WP UT WOS:000307662900004 ER PT J AU Zaslavsky, BG AF Zaslavsky, Boris G. TI Bayesian Sample Size Estimates for One Sample Test in Clinical Trials With Dichotomous and Countable Outcomes SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Beta distribution; Gamma distribution; Hypothesis; Posterior distribution; Power; Prior distribution; Type I and II errors ID FREQUENTIST EVIDENCE; HYPOTHESIS; OPINION; LIMITS AB This article presents a Bayesian approach to sample size determination in binomial and Poisson clinical trials. It uses exact methods and Bayesian methodology. Our sample size estimations are based on power calculations under the one-sided alternative hypothesis that a new treatment is better than a control by a clinically important margin. The method resembles a standard frequentist problem formulation and, in the case of conjugate prior distributions with integer parameters, is similar to the frequentist approach. We evaluate Type I and II errors through the use of credible limits in Bayesian models and through the use of confidence limits in frequentist models. Particularly, for conjugate priors with integer parameters, credible limits are identical to frequentist confidence limits with adjusted numbers of events and sample sizes. We consider conditions under which the minimal Bayesian sample size is less than the frequentist one and vice versa. C1 US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Zaslavsky, BG (reprint author), US FDA, Ctr Biol Evaluat & Res, 1401 Rockville Pike,HFM 219, Rockville, MD 20852 USA. EM boris.zaslavsky@fda.hhs.gov FU FDA/CBER Critical Path initiative grant FX This research was partially supported by the FDA/CBER Critical Path initiative grant. NR 32 TC 5 Z9 5 U1 0 U2 4 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PY 2012 VL 4 IS 1 BP 76 EP 85 DI 10.1080/19466315.2011.633872 PG 10 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 990WP UT WOS:000307662900008 ER PT J AU Brown, CK Friedel, HD Barker, AR Buhse, LF Keitel, S Cecil, TL Kraemer, J Morris, JM Reppas, C Stickelmeyer, MP Yomota, C Shah, VP AF Brown, Cynthia K. Friedel, Horst Dieter Barker, Amy R. Buhse, Lucinda F. Keitel, Susanne Cecil, Todd L. Kraemer, Johannes Morris, J. Michael Reppas, Christos Stickelmeyer, Mary P. Yomota, Chikako Shah, Vinod P. TI FIP/AAPS Joint Workshop Report: Dissolution/In Vitro Release Testing of Novel/Special Dosage Forms SO PHARMAZEUTISCHE INDUSTRIE LA English DT Article ID IN-VITRO; DISINTEGRATION TIME; INHALER PRODUCTS; TEXTURE ANALYZER; DRUG-RELEASE; TABLETS; SUPPOSITORIES; SUSPENSIONS; SYSTEMS; PROFILE C1 [Brown, Cynthia K.; Barker, Amy R.; Stickelmeyer, Mary P.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Friedel, Horst Dieter] Bayer HealthCare, Berlin, Germany. [Buhse, Lucinda F.] US FDA, CDER OPS, St Louis, MO USA. [Keitel, Susanne] Council Europe, EDQM, Strasbourg, France. [Cecil, Todd L.] US Pharmacopeia, Rockville, MD USA. [Kraemer, Johannes] PHAST, Homburg, Germany. [Morris, J. Michael] Irish Med Board, Dublin, Ireland. [Reppas, Christos] Univ Athens, Panepistimiopolis, Greece. [Yomota, Chikako] Natl Inst Hlth Sci, Tokyo, Japan. [Shah, Vinod P.] FIP Sci Secretary, The Hague, Netherlands. RP Brown, CK (reprint author), Eli Lilly & Co, Indianapolis, IN 46285 USA. EM browrick@lilly.com FU International Pharmaceutical Federation (FIP); Royal Pharmaceutical Society of Great Britain (RPSGB); American Association of Pharmaceutical Sciences (AAPS); US Food and Drug Administration (FDA) FX This revision of this publication represents the scientific opinion of many experts and in particular, is derived from two key workshops (London, 2008 and Los Angeles, 2009) held under the auspices of the International Pharmaceutical Federation (FIP) with cosponsorship from the Royal Pharmaceutical Society of Great Britain (RPSGB), American Association of Pharmaceutical Sciences (AAPS), and the US Food and Drug Administration (FDA). The authors would like to acknowledge the following workshop presenters for their technical contributions to the workshops which were fundamental to the revision of this publication. NR 63 TC 0 Z9 0 U1 1 U2 5 PU ECV-EDITIO CANTOR VERLAG MEDIZIN NATURWISSENSCHAFTEN PI AULENDORF PA BANDELSTOCKWEG 20, POSTFACH 1255, D-88322 AULENDORF, GERMANY SN 0031-711X J9 PHARM IND JI Pharm. Ind. PY 2012 VL 74 IS 7 BP 1147 EP + PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 983UF UT WOS:000307143500003 ER PT S AU Guenther, JC McCormick, KJ Bryant, CM AF Guenther, Julia C. McCormick, Kelly J. Bryant, Cory M. BE Alpas, H Smith, M Kulmyrzaev, A TI US Government Efforts to Build Global Food Defense Capacity SO STRATEGIES FOR ACHIEVING FOOD SECURITY IN CENTRAL ASIA SE NATO Science for Peace and Security Series C-Environmental Security LA English DT Proceedings Paper CT NATO Advanced Training Course on Strategies for Achieving Food Security in Central Asia CY MAR 31-APR 02, 2011 CL Bishkek, KYRGYZSTAN SP NATO DE Food defense; Intentional contamination; Capacity building AB Today's world is smaller and everything, including food, is shared amongst people in many countries. With the increase of international trade and the growing food import and export industry, it is even more important that we all take measures to ensure that the food we consume is safe from contamination - both unintentional and intentional. The chapter summarizes the U.S. Government's efforts to build global food defense capacity through cooperation and collaboration with international partners. C1 [Guenther, Julia C.; Bryant, Cory M.] US FDA, Ctr Food Safety & Appl Nutr, Off Food Def Commun & Emergency Response, Food Def Oversight Team, College Pk, MD USA. [McCormick, Kelly J.] USDA, Food Safety Team, Off Capac Bldg & Dev, Foreign Agr Serv, Washington, DC 20250 USA. RP Guenther, JC (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Food Def Commun & Emergency Response, Food Def Oversight Team, College Pk, MD USA. EM julia.guenther@fda.hhs.gov; kelly.mccormick@fas.usda.gov; cory.bryant@fda.hhs.gov NR 1 TC 0 Z9 0 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 1871-4668 BN 978-94-007-2501-0 J9 NATO SCI PEACE SECUR JI NATO Sci. Peace Secur. Ser. C- Environ. Secur. PY 2012 BP 109 EP + DI 10.1007/978-94-007-2502-7_10 PG 4 WC Agricultural Engineering; Food Science & Technology; Public, Environmental & Occupational Health SC Agriculture; Food Science & Technology; Public, Environmental & Occupational Health GA BBK45 UT WOS:000307196600010 ER PT J AU Conklin, SD Chen, PE AF Conklin, Sean D. Chen, Peter E. TI Quantification of four arsenic species in fruit juices by ion-chromatography-inductively coupled plasma-mass spectrometry SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE ICP/MS; HPLC; trace elements (toxic); heavy metals; arsenic; metals speciation; toxic elements; fruit juices ID PERFORMANCE LIQUID-CHROMATOGRAPHY; TERRESTRIAL ORGANISMS; AMANITA-MUSCARIA; MARINE ORGANISMS; ACUTE TOXICITY; UNITED-STATES; TOTAL DIET; SPECIATION; EXTRACTION; SEPARATION AB A method using ion chromatography-inductively coupled plasma-mass spectrometry (IC-ICP-MS) for the quantification of arsenic species in fruit juices has been developed and validated. The method is capable of quantifying four anionic arsenic species - arsenite (As(III)), arsenate (As(V)), dimethylarsinic acid (DMA) and monomethylarsonic acid (MMA) - in the presence of unretained species such as arsenobetaine (AsB). Method validation was based on repeatability, analysis of reference materials, recovery of fortified samples, and determination of detection and quantification limits. The method was tested for use with apple, pear, cranberry, grape (red, white and purple) juices, as well as several juice blends. Limits of detection were 0.35, 0.41, 0.45 and 0.70 mu g kg(-1) for As(III), DMA, MMA and As(V), respectively. Chromatographic recovery was good for most samples (90-107% compared to total arsenic), though recovery for some grape juice samples was lower (67-78%). C1 [Conklin, Sean D.; Chen, Peter E.] US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Conklin, SD (reprint author), US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD USA. EM sean.conklin@fda.hhs.gov NR 38 TC 13 Z9 14 U1 4 U2 59 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2012 VL 29 IS 8 BP 1272 EP 1279 DI 10.1080/19440049.2012.687775 PG 8 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 976AN UT WOS:000306553000012 PM 22639850 ER PT J AU Zhang, K Wong, JW Begley, TH Hayward, DG Limm, W AF Zhang, Kai Wong, Jon W. Begley, Timothy H. Hayward, Douglas G. Limm, William TI Determination of siloxanes in silicone products and potential migration to milk, formula and liquid simulants SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE siloxanes; migration; silicone nipples; silicone baking products; milk/infant formula ID MASS-SPECTROMETRY; LINEAR SILOXANES; BAKING MOLDS; EXTRACTION; FOODSTUFFS; WATER; FISH; MICE; FOOD AB A pressurised solvent extraction procedure coupled with a gas chromatography-mass spectrometry-selective ion monitoring (GC-MS-SIM) method was developed to determine three cyclic siloxanes, octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), dodecamethylcyclohexasiloxane (D6) and three linear siloxanes, octamethyltrisiloxane (L3), decamethyltetrasiloxane (L4), dodecamethylpentasiloxane (L5), in silicone products. Additionally, two different extraction methods were developed to measure these siloxanes migrating into milk, infant formula and liquid simulants (50 and 95% ethanol in water). The limits of quantification (LOQs) of the six siloxanes ranged from 6 ng/g (L3) to 15 ng/g (D6). Silicone nipples and silicone bakewares were extracted using pressurised solvent extraction (PSE) and analysed using the GC-MS-SIM method. No linear siloxanes were detected in the silicone nipple samples analysed. The three cyclic siloxanes (D4, D5 and D6) were detected in all silicone nipple samples with concentrations ranging from 0.5 to 269 mu g/g. In the bakeware samples, except for L3, the other five siloxanes were detected with concentrations ranging from 0.2 mu g/g (L4) to 7030 mu g/g (D6). To investigate the potential migration of the six siloxanes from silicone nipples to milk and infant formula, a liquid extraction and dispersive clean-up procedure was developed for the two matrices. The procedure used a mix of hexane and ethyl acetate (1 : 1, v/v) as extraction solvent and C-18 powder as the dispersive clean-up sorbent. For the liquid simulants, extraction of the siloxanes was achieved using hexane without any salting out or clean-up procedures. The recoveries of the six siloxanes from the milk, infant formula and simulants fortified at 50, 100, 200, 500 and 1000 mu g/l ranged from 70 to 120% with a relative standard derivation (RSD) of less than 15% (n=4). Migration tests were performed by exposing milk, infant formula and the liquid simulants to silicone baking sheets with known concentrations of the six siloxanes at 40 degrees C. No siloxanes were detected in milk or infant formula after 6 h of direct contact with the silicone baking sheet plaques, indicating insignificant migration of the siloxanes to milk or infant formula. Migration tests in the two simulants lasted up to 72 h and the three cyclic siloxanes were detected in 50% ethanol after an 8-h exposure and after 2 h in 95% ethanol. The highest detected concentrations of D4, D5 and D6 were 42, 36 and 155 ng/ml, respectively, indicating very limited migration of D4, D5 or D6 into the two simulants. C1 [Zhang, Kai; Wong, Jon W.; Begley, Timothy H.; Hayward, Douglas G.; Limm, William] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. RP Zhang, K (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy,HFS 706, College Pk, MD 20740 USA. EM kai.zhang@fda.hhs.gov NR 23 TC 5 Z9 5 U1 3 U2 27 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2012 VL 29 IS 8 BP 1311 EP 1321 DI 10.1080/19440049.2012.684891 PG 11 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 976AN UT WOS:000306553000017 PM 22575024 ER PT J AU Mahmood, I AF Mahmood, Iftekhar TI Prediction of Clearance and Volume of Distribution in the Obese from Normal Weight Subjects An Allometric Approach SO CLINICAL PHARMACOKINETICS LA English DT Article ID UNIVERSAL METABOLIC ALLOMETRY; DRUG CLEARANCE; PHARMACOKINETICS; PROPOFOL; CHILDREN; DISPOSITION; VOLUNTEERS; VANCOMYCIN; CIMETIDINE; EXPONENT AB Background and Objective: The principles of allometry can be applied within a given species (intra-species scaling), for example extrapolation of pharmacokinetic parameters from adults to adolescents and older children (>5 years of age). Similarly, allometric scaling may also be used to predict pharmacokinetic parameters from normal weight subjects to the obese. The objective of this investigation was to evaluate the predictive performance of several allometric methods for the prediction of drug clearance (CL) and volume of distribution (Y-d) in the obese from normal weight subjects. Methods: CL and V-d values for 12 drugs for obese and normal weight subjects were obtained from the literature. Three methods (simple allometry and fixed exponents of 0.75 and 1.0) and two methods (simple allometry and a fixed exponent of 1.0) were used to predict CL and V-d, respectively, using total body weight in the obese from normal weight subjects. When data were available, ideal body weight, percentage ideal body weight and body mass index were also used for prediction purposes. Results: The results of the study indicated that CL could be predicted with accuracy in the obese from normal weight subjects using total body weight and simple allometry as well as fixed exponent of 0.75. The prediction of V-d in the obese from normal weight subjects was less accurate than the prediction of CL in this population. For the prediction of CL and V-d in the obese, simple allometry performed better than the fixed exponent of 0.75 or 1.0, respectively. Conclusions: The study indicated that allometric scaling can be applied to predict CL in the obese from normal weight subjects with high accuracy. The predicted CL can then be used to select a dose to initiate a clinical trial (pharmacokinetics, safety and efficacy). C1 US FDA, OBRR, Ctr Biol Evaluat & Res, Rockville, MD 20862 USA. RP Mahmood, I (reprint author), US FDA, OBRR, Ctr Biol Evaluat & Res, 1401 Rockville Pike, Rockville, MD 20862 USA. EM Iftekhar.mahmood@fda.hhs.gov NR 49 TC 6 Z9 6 U1 0 U2 5 PU ADIS INT LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND SN 0312-5963 J9 CLIN PHARMACOKINET JI Clin. Pharmacokinet. PY 2012 VL 51 IS 8 BP 527 EP 542 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 977CO UT WOS:000306634200004 PM 22671778 ER PT J AU Hamburg, MA AF Hamburg, Margaret A. TI Remarks at the Annual Conference of the Food and Drug Law Institute SO FOOD AND DRUG LAW JOURNAL LA English DT Article C1 US FDA, Rockville, MD 20857 USA. RP Hamburg, MA (reprint author), US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FOOD DRUG LAW INST PI WASHINGTON PA 1000 VERMONT AVE NW, SUITE 1200, WASHINGTON, DC 20005-4903 USA SN 1064-590X J9 FOOD DRUG LAW J JI Food Drug Law J. PY 2012 VL 67 IS 2 BP 123 EP 129 PG 7 WC Food Science & Technology; Law; Nutrition & Dietetics; Pharmacology & Pharmacy SC Food Science & Technology; Government & Law; Nutrition & Dietetics; Pharmacology & Pharmacy GA 972HO UT WOS:000306268100001 PM 24620415 ER PT J AU Brown, CK Friedel, HD Barker, AR Buhse, LF Keitel, S Cecil, TL Kraemer, J Morris, JM Reppas, C Stickelmeyer, MP Yomota, C Shah, VP AF Brown, Cynthia K. Friedel, Horst Dieter Barker, Amy R. Buhse, Lucinda F. Keitel, Susanne Cecil, Todd L. Kraemer, Johannes Morris, J. Michael Reppas, Christos Stickelmeyer, Mary P. Yomota, Chikako Shah, Vinod P. TI FIP/AAPS Joint Workshop Report: Dissolution/In Vitro Release Testing of Novel/Special Dosage Forms SO PHARMAZEUTISCHE INDUSTRIE LA English DT Article C1 [Brown, Cynthia K.; Barker, Amy R.; Stickelmeyer, Mary P.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Friedel, Horst Dieter] Bayer HealthCare, Berlin, Germany. [Buhse, Lucinda F.] US FDA, CDER, OPS, St Louis, MO USA. [Keitel, Susanne] Council Europe, EDQM, Strasbourg, France. [Cecil, Todd L.] Pharmacopeia, Rockville, MD USA. [Kraemer, Johannes] PHAST, Homburg, Germany. [Morris, J. Michael] Irish Med Board, Dublin, Ireland. [Reppas, Christos] Univ Athens, Panepistimiopolis, Greece. [Yomota, Chikako] Natl Inst Hlth Sci, Tokyo, Japan. [Shah, Vinod P.] FIP Sci Secretary, The Hague, Netherlands. RP Brown, CK (reprint author), Eli Lilly & Co, Indianapolis, IN 46285 USA. EM brownck@lilly.com NR 0 TC 0 Z9 0 U1 1 U2 3 PU ECV-EDITIO CANTOR VERLAG MEDIZIN NATURWISSENSCHAFTEN PI AULENDORF PA BANDELSTOCKWEG 20, POSTFACH 1255, D-88322 AULENDORF, GERMANY SN 0031-711X J9 PHARM IND JI Pharm. Ind. PY 2012 VL 74 IS 6 BP 988 EP + DI 10.1208/s12249-011-9634 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 969XP UT WOS:000306093000003 ER PT S AU Le, D Wang, QZ Ramella-Roman, J Pfefer, J AF Le, Du Wang, Quanzeng Ramella-Roman, Jessica Pfefer, Joshua BE Cullum, BM McLamore, ES TI Quantitative Evaluation of Mucosal Vascular Contrast in Narrow Band Imaging Using Monte Carlo Modeling SO SMART BIOMEDICAL AND PHYSIOLOGICAL SENSOR TECHNOLOGY IX SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Smart Biomedical and Physiological Sensor Technology IX CY APR 26, 2012 CL Baltimore, MD SP SPIE DE Narrow band imaging; Monte Carlo modeling; reflectance; light-tissue interaction; mucosal cancer ID MAGNIFYING ENDOSCOPY; FLUORESCENCE-SPECTRA; BARRETTS-ESOPHAGUS; TISSUE; DIAGNOSIS; CANCER; SYSTEM; LESIONS; NEOPLASIA AB Narrow-band imaging (NBI) is a spectrally-selective reflectance imaging technique for enhanced visualization of superficial vasculature. Prior clinical studies have indicated NBI's potential for detection of vasculature abnormalities associated with gastrointestinal mucosal neoplasia. While the basic mechanisms behind the increased vessel contrast - hemoglobin absorption and tissue scattering - are known, a quantitative understanding of the effect of tissue and device parameters has not been achieved. In this investigation, we developed and implemented a numerical model of light propagation that simulates NBI reflectance distributions. This was accomplished by incorporating mucosal tissue layers and vessel-like structures in a voxel-based Monte Carlo algorithm. Epithelial and mucosal layers as well as blood vessels were defined using wavelength-specific optical properties. The model was implemented to calculate reflectance distributions and vessel contrast values as a function of vessel depth (0.05 to 0.50 mm) and diameter (0.01 to 0.10 mm). These relationships were determined for NBI wavelengths of 410 nm and 540 nm, as well as broadband illumination common to standard endoscopic imaging. The effects of illumination bandwidth on vessel contrast were also simulated. Our results provide a quantitative analysis of the effect of absorption and scattering on vessel contrast. Additional insights and potential approaches for improving NBI system contrast are discussed. C1 [Le, Du; Wang, Quanzeng; Pfefer, Joshua] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Le, D (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM du.le@fda.hhs.gov NR 30 TC 0 Z9 0 U1 0 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-9045-2 J9 PROC SPIE PY 2012 VL 8367 AR 836709 DI 10.1117/12.918375 PG 10 WC Engineering, Biomedical; Instruments & Instrumentation; Optics; Physics, Applied SC Engineering; Instruments & Instrumentation; Optics; Physics GA BAY34 UT WOS:000306053200005 ER PT S AU Hughes, JP Chessell, I Malamut, R Perkins, M Backonja, M Baron, R Farrar, JT Field, MJ Gereau, RW Gilron, I McMahon, SB Porreca, F Rappaport, BA Rice, F Richman, LK Segerdahl, M Seminowicz, DA Watkins, LR Waxman, SG Wiech, K Woolf, C AF Hughes, Jane P. Chessell, Iain Malamut, Richard Perkins, Martin Backonja, Miroslav Baron, Ralf Farrar, John T. Field, Mark J. Gereau, Robert W. Gilron, Ian McMahon, Stephen B. Porreca, Frank Rappaport, Bob A. Rice, Frank Richman, Laura K. Segerdahl, Marta Seminowicz, David A. Watkins, Linda R. Waxman, Stephen G. Wiech, Katja Woolf, Clifford GP Annals NY Acad Sci TI Understanding chronic inflammatory and neuropathic pain SO ANNALS MEETING REPORTS SE Annals of the New York Academy of Sciences LA English DT Article ID ANALGESIC-DRUG-DEVELOPMENT; CLINICAL-TRIALS; IMMPACT RECOMMENDATIONS; POSTHERPETIC NEURALGIA; ALZHEIMERS-DISEASE; DOUBLE-BLIND; MECHANISMS; ANTIBODY; ERYTHROMELALGIA; MULTICENTER AB This meeting report highlights the main topics presented at the conference "Chronic Inflammatory and Neuropathic Pain," convened jointly by the New York Academy of Sciences, MedImmune, and Grunenthal GmbH, on June 2-3, 2011, with the goal of providing a conducive environment for lively, informed, and synergistic conversation among participants from academia, industry, clinical practice, and government to explore new frontiers in our understanding and treatment of chronic and neuropathic pain. The program included leading and emerging investigators studying the pathophysiological mechanisms underlying neuropathic and chronic pain, and experts in the clinical development of pain therapies. Discussion included novel issues, current challenges, and future directions of basic research in pain and preclinical and clinical development of new therapies for chronic pain. C1 [Hughes, Jane P.; Chessell, Iain] MedImmune, Cambridge, England. [Malamut, Richard; Perkins, Martin] AstraZeneca R&D, Montreal, PQ, Canada. [Backonja, Miroslav] LifeTree Res, Salt Lake City, UT USA. [Backonja, Miroslav] Univ Wisconsin, Madison, WI USA. [Baron, Ralf] Univ Kiel, Kiel, Germany. [Farrar, John T.] Univ Penn, Philadelphia, PA 19104 USA. [Field, Mark J.] Grunenthal GmbH, Aachen, Germany. [Gereau, Robert W.] Washington Univ, Sch Med, St Louis, MO USA. [Gilron, Ian] Queens Univ, Dept Anesthesiol & Perioperat Med, Kingston, ON, Canada. [McMahon, Stephen B.] Kings Coll London, London WC2R 2LS, England. [Porreca, Frank] Univ Arizona, Phoenix, AZ USA. [Rappaport, Bob A.] US FDA, Ctr Drug Evaluat & Res, Div Anesthesia Analgesia & Addict Prod, White Oak, MD USA. [Rice, Frank] Integrated Tissue Dynam LLC, Rensselaer, NY USA. [Rice, Frank] Albany Med Coll, Albany, NY 12208 USA. [Richman, Laura K.] MedImmune, Gaithersburg, MD USA. [Segerdahl, Marta] AstraZeneca, Sodertalje, Sweden. [Seminowicz, David A.] Univ Maryland, Sch Dent, Baltimore, MD 21201 USA. [Watkins, Linda R.] Univ Colorado, Boulder, CO 80309 USA. [Waxman, Stephen G.] Yale Univ, Sch Med, New Haven, CT USA. [Waxman, Stephen G.] Vet Affairs Connecticut Healthcare Syst, West Haven, CT USA. [Wiech, Katja] Univ Oxford, Oxford, England. [Woolf, Clifford] Childrens Hosp, Boston, MA 02115 USA. RP Hughes, JP (reprint author), MedImmune, Cambridge, England. RI Seminowicz, David/F-8732-2015 OI Seminowicz, David/0000-0003-3111-3756 FU NYAS Bronze Sponsor Depomed, Inc.; NYAS Academy Friend Sponsors Bristol-Myers Squibb Research and Development; Regeneron Pharmaceuticals, Inc. FX The conference "Chronic Inflammatory and Neuropathic Pain," jointly presented by the New York Academy of Sciences, MedImmune, and Grunenthal GmbH, was supported in part by NYAS Bronze Sponsor Depomed, Inc., and by NYAS Academy Friend Sponsors Bristol-Myers Squibb Research and Development, and Regeneron Pharmaceuticals, Inc. NR 54 TC 11 Z9 11 U1 1 U2 15 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 BN 978-1-57331-886-0 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1255 BP 30 EP 44 DI 10.1111/j.1749-6632.2012.06561.x PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA BAV38 UT WOS:000305606100003 PM 22564068 ER PT J AU Fu, PP Xia, QS Sun, X Yu, HT AF Fu, Peter P. Xia, Qingsu Sun, Xin Yu, Hongtao TI Phototoxicity and Environmental Transformation of Polycyclic Aromatic Hydrocarbons (PAHs)-Light-Induced Reactive Oxygen Species, Lipid Peroxidation, and DNA Damage SO JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH PART C-ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS LA English DT Review DE phototoxicity; polycyclic aromatic hydrocarbons; cancer; DNA damage ID SALMONELLA MICROSOME MUTAGENICITY; ATMOSPHERIC PARTICULATE MATTER; ACTIVITY-RELATIONSHIP MODEL; DIRECT-ACTING MUTAGENICITY; TUMOR-INITIATING ACTIVITY; STEADY-STATE PHOTOLYSIS; NITRO-GROUP ORIENTATION; SINGLE-STRAND CLEAVAGE; VISIBLE-LIGHT; UVA LIGHT AB Polycyclic aromatic hydrocarbons (PAHs) are a class of mutagenic and tumorigenic environmental contaminants. Although the mechanisms by which PAHs induce cancer in experimental animals have been extensively studied and the metabolic activation pathways have been determined, the environmental fate of PAHs and the phototoxicity exerted by PAHs, as well as their photoreaction products formed in the environment, have received much less attention. In this review, the formation of oxygenated PAHs, PAH quinones, nitro-PAHs, and halogenated PAHs from photoreaction of environmental PAHs are addressed. Upon light irradiation, PAHs and all PAH photoreaction products can absorb light energy to reach photo-excited states, which react with molecular oxygen, medium, and coexisting chemicals to produce reactive oxygen species (ROS) and other reactive intermediates, such as oxygenated PAHs and free radicals. These intermediates, including ROS, induce lipid peroxidation, and DNA damage including DNA strand breakage, oxidation to 8-oxo-2'-deoxyguanosine, and DNA-adducts. Since these toxicological endpoints are associated with age-related diseases, including cancer, environmental PAHs concomitantly exposed to sunlight may potentially promote human skin damage, leading to ageing and skin cancers. Thus, we suggest that (i) in addition to the widely recognized metabolic pathways, more attention must be paid to photoreaction as an important activation pathway for PAHs, (ii) risk assessment of environmental PAHs should take into consideration the complex photochemical reactions leading to mixtures of products that are also phototoxic; and (iii) the study of structure-toxicity relationships should be expanded to cover the complex photoreactions and extrinsic factors that affect phototoxicity endpoints. C1 [Fu, Peter P.; Xia, Qingsu] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Sun, Xin] Chinese Ctr Dis Control & Prevent, Natl Inst Occupat Hlth & Poisoning Control, Beijing, Peoples R China. [Yu, Hongtao] Jackson State Univ, Dept Chem & Biochem, Jackson, MS USA. RP Fu, PP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov NR 201 TC 48 Z9 49 U1 8 U2 112 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1059-0501 J9 J ENVIRON SCI HEAL C JI J. Environ. Sci. Health Pt. C-Environ. Carcinog. Ecotoxicol. Rev. PY 2012 VL 30 IS 1 BP 1 EP 41 DI 10.1080/10590501.2012.653887 PG 41 WC Oncology; Environmental Sciences; Toxicology SC Oncology; Environmental Sciences & Ecology; Toxicology GA 958DE UT WOS:000305215800001 PM 22458855 ER PT J AU Fisher, J Lumen, A Latendresse, J Mattie, D AF Fisher, Jeffrey Lumen, Annie Latendresse, John Mattie, David TI Extrapolation of Hypothalamic-Pituitary-Thyroid Axis Perturbations and Associated Toxicity in Rodents to Humans: Case Study with Perchlorate SO JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH PART C-ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS LA English DT Review DE thyroid gland; rat; human; perchlorate; BBDR models; HPT axis ID LOW-DOSE PERCHLORATE; SPRAGUE-DAWLEY RATS; SCHOOL-AGE-CHILDREN; IN-UTERO EXPOSURE; AMMONIUM-PERCHLORATE; DRINKING-WATER; UNITED-STATES; POLYCHLORINATED-BIPHENYLS; IODIDE UPTAKE; CONGENITAL HYPOTHYROIDISM AB Functional aspects of the Hypothalamic-Pituitary-Thyroid (HPT) axis in rats and humans are compared, exposing why extrapolation of toxicant-induced perturbations in the rat HPT axis to the human HPT axis cannot be accomplished using default risk assessment methodology. Computational tools, such as biologically based dose response models for the HPT axis, are recommended to perform complex animal to human extrapolations involving the HPT axis. Experimental and computational evidence are presented that suggest perchlorate acts directly on the thyroid gland in rats. The apparent escape from perchlorate-induced inhibition of thyroidal uptake of radioactive iodide in humans is discussed along with "rebound" or increased thyroidal uptake of radioactive iodide observed after discontinued clinical treatment with perchlorate. C1 [Fisher, Jeffrey; Lumen, Annie] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Latendresse, John] Natl Ctr Toxicol Res, Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Mattie, David] Mol Bioeffects Branch, Wright Patterson AFB, OH USA. RP Fisher, J (reprint author), US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM jeffrey.fisher@fda.hhs.gov FU USAF (AFCEE); USAF (711 HPW/RHDJ); Henry M. Jackson Foundation for the Advancement of Military Medicine at Wright-Patterson AFB, OH FX We thank Drs. Fred Beland and Luisa Camacho for their editorial review and suggestions to improve this manuscript. Funding for A. Lumen was provided by the USAF (AFCEE and 711 HPW/RHDJ) through a cooperative agreement with the Henry M. Jackson Foundation for the Advancement of Military Medicine at Wright-Patterson AFB, OH. NR 93 TC 7 Z9 8 U1 3 U2 18 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1059-0501 J9 J ENVIRON SCI HEAL C JI J. Environ. Sci. Health Pt. C-Environ. Carcinog. Ecotoxicol. Rev. PY 2012 VL 30 IS 1 BP 81 EP 105 DI 10.1080/10590501.2012.653889 PG 25 WC Oncology; Environmental Sciences; Toxicology SC Oncology; Environmental Sciences & Ecology; Toxicology GA 958DE UT WOS:000305215800003 PM 22458857 ER PT J AU Zou, P Zheng, N Yu, YK Yu, SH Sun, W McEachern, D Yang, YS Yu, LX Wang, SM Sun, DX AF Zou, Peng Zheng, Nan Yu, Yanke Yu, Shanghai Sun, Wei McEachern, Donna Yang, Yongsheng Yu, Lawrence X. Wang, Shaomeng Sun, Duxin TI Preclinical Pharmacokinetics of MI-219, a Novel Human Double Minute 2 (HDM2) Inhibitor and Prediction of Human Pharmacokinetics SO JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES LA English DT Article ID INVARIANT TIME METHODS; HUMAN DRUG CLEARANCE; PARAMETERS; METABOLISM; ACCURACY; VOLUME; RATS AB Purpose. The two purposes of this study were evaluating preclinical pharmacokinetics of MI-219 and predicting clearance (CL) and volume of distribution at steady-state (Vd(ss)) of MI-219 in humans. Methods. Pharmacokinetic studies were conducted on mice, rats, dogs, and monkeys. Human CL of MI-219 was predicted using allometric scaling (SA), multi-exponential allometric scaling (ME), rule of exponents (RoE), single species scaling, two-term power equation (TTPE), physiologically based in vitro-in vivo extrapolation (IVIVE), and f(u) corrected intercept method (FCIM). In vitro assays were conducted to determine in vitro intrinsic CL, protein binding, and blood-plasma partition coefficients. To estimate half-life of MI-219, plasma concentration-time profile in humans was predicted using kallynochron and apolysichron time transformation (Dedrick plots) and normalization with MRT and Vd(ss) (Wajima's method). In addition, simultaneous interspecies scaling of CL, Vd(ss) and concentration-time profile were performed by using Nonlinear Mixed Effects Modeling (NONMEM). Results. Preclinical studies showed that the elimination of MI-219 was mainly through metabolism. The validation using observed monkey CL and Vd(ss) showed that MA, IVIVE and Oie-Tozer methods were accurately than the other methods. Human CL of MI-219 predicted by ME and IVIVE was between 0.237-0.342 L*h(-1)*kg(-1). Human Vd(ss) predicted by Oie-Tozer method and allometric scaling of unbound volume of distribution of tissues (VT/fu(T)) method was between 0.93-1.40 L*kg(-1). Superimposition of rat, monkey and dog data was observed in Dedrick plots and Wajima's transformations. Conclusions. The predicted human pharmacokinetics is useful for the design of first-in-human study. C1 [Sun, Duxin] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA. [Yu, Shanghai; Sun, Wei; McEachern, Donna; Wang, Shaomeng] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Yu, Shanghai; Sun, Wei; McEachern, Donna; Wang, Shaomeng] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA. [Yu, Shanghai; Sun, Wei; McEachern, Donna; Wang, Shaomeng] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Yang, Yongsheng] US FDA, Off Testing & Res, Rockville, MD 20857 USA. [Yu, Lawrence X.] US FDA, Off Gener Drugs, Rockville, MD 20857 USA. RP Sun, DX (reprint author), Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA. EM shaomeng@umich.edu; duxins@umich.edu RI Zou, Peng/J-9300-2015; SUN, Wei/M-1180-2015; Yu, Lawrence/L-6280-2016 FU National Institutes of Health [RO1 CA120023, R21 CA143474]; University of Michigan Cancer Center Research Grant (Munn); University of Michigan Cancer Center Core Grant FX This work was partially supported by the National Institutes of Health (RO1 CA120023 and R21 CA143474); University of Michigan Cancer Center Research Grant (Munn); and University of Michigan Cancer Center Core Grant to DS. NR 28 TC 7 Z9 7 U1 0 U2 11 PU CANADIAN SOC PHARMACEUTICAL SCIENCES PI EDMONTON PA 3118 DENTISTRY-PHARMACY CENTRE UNIV ALBERTA CAMPUS, EDMONTON, ALBERTA T6G2N8, CANADA SN 1482-1826 J9 J PHARM PHARM SCI JI J. Pharm. Pharm. Sci. PY 2012 VL 15 IS 2 BP 265 EP 280 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 961HG UT WOS:000305454300001 PM 22579006 ER PT S AU Brunner, CC Tischenko, O de las Heras, H Renger, B Schlattl, H Hoeschen, C AF Brunner, Claudia C. Tischenko, Oleg de las Heras, Hugo Renger, Bernhard Schlattl, Helmut Hoeschen, Christoph BE Pelc, NJ Nishikawa, RM Whiting, BR TI The CTDOR geometry: An optimized data treatment to demonstrate its potential SO MEDICAL IMAGING 2012: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 05-08, 2012 CL San Diego, CA SP SPIE, Agilent Technol, Diamond SA, DQE Instruments Inc, eMagin, Isuzu Glass Co Ltd, Medtron Inc, Ocean Thin Films Inc DE Computed tomography; CTDOR; OPED ID RECONSTRUCTION AB In order to decrease the patient's radiation exposure from Computed Tomography, the new CT geometry CTDOR has been invented. It consists of two data sets: A conventional arc or flat panel detector and a mask ring with shieldings on the outside and detectors on the inside separated by windows. Combined with the reconstruction algorithm OPED, it has the theoretical potential to decrease the dose about 50% while providing the same image quality as conventional systems. First steps to evaluate this theory were done with a mask ring demonstrator combined with a conventional C-arm device. Although the quality of the demonstrator is limited, this set-up was supposed to demonstrate how the combination of the two data sets works in principle. Preliminary results from earlier studies, however, provided images of rather poor quality. This work presents better images obtained with an optimized data treatment. We showed that most artifacts are eliminated and that we get sharper images with higher contrast compared to the images reconstructed from the single data sets and compared to the earlier study. Regarding the limitations of the set-up, the resulting images were remarkably good. CTDOR is therefore a promising method, which is worth to perform further studies. C1 [Brunner, Claudia C.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Brunner, CC (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM claudia.brunner@fda.hhs.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8962-3 J9 PROC SPIE PY 2012 VL 8313 AR 83132M DI 10.1117/12.908231 PG 13 WC Optics; Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BAM70 UT WOS:000304768000089 ER PT S AU Castellanos, IMS Kaczmarek, R Brunner, CC Heras, HDL Liu, H Chakrabarti, K AF Castellanos, Ivan M. Suarez Kaczmarek, Richard Brunner, Claudia C. Heras, Hugo De las Liu, Haimo Chakrabarti, Kish BE Pelc, NJ Nishikawa, RM Whiting, BR TI Evaluation of Automatic Exposure Control Performance in Full-Field Digital Mammography Systems using Contrast-Detail Analysis SO MEDICAL IMAGING 2012: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 05-08, 2012 CL San Diego, CA SP SPIE, Agilent Technol, Diamond SA, DQE Instruments Inc, eMagin, Isuzu Glass Co Ltd, Medtronic, Inc., Ocean Thin Films Inc DE Digital Mammography; FFDM; AEC; CDMAM; Contrast-Detail Analysis AB Full Field Digital Mammography (FFDM) is increasingly replacing screen-film systems for screening and diagnosis of breast abnormalities. All FFDM systems are equipped with an Automatic Exposure Control (AEC) which automatically selects technique factors to optimize dose and image quality. It is therefore crucial that AEC performance is properly adjusted and optimized to different breast thicknesses. In this work, we studied the AEC performance of three widely used FFDM systems using the CDMAM and QUART mam/digi phantoms. We used the CDMAM phantom to generate Contrast-Detail (C-D) curves for each AEC mode available in the FFDM systems under study for phantoms with equivalent X-Ray attenuation properties as 3.2 cm, 6 cm and 7.5 cm thick breasts. Generated C-D curves were compared with ideal C-D curves constructed using a metric referred to as the k-factor which is the product of the thickness and the diameter of the smallest correctly identified disks in the CDMAM phantom. Previous observer studies have indicated that k-factor values of 60 to 80 mu m(2) are particularly useful in demonstrating the threshold for object detectability for detectors used in digital mammography systems. The QUART mam/digi phantom was used to calculate contrast-to-noise ratio (CNR) values at different phantom thicknesses. The results of the C-D analysis and CNR measurements were used to determine limiting CNR values intended to provide a threshold for proper image quality assessment. The results of the Contrast-Detail analysis show that for two of the three evaluated FFDM systems, at higher phantom thicknesses, low contrast signal detectability gets worse. This agrees with the results obtained with the QUART mam/digi phantom, where CNR decreases below determined limiting CNR values. C1 [Castellanos, Ivan M. Suarez] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Chakrabarti, K (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM kish.chakrabarti@fda.hhs.gov NR 7 TC 1 Z9 1 U1 0 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8962-3 J9 PROC SPIE PY 2012 VL 8313 AR 83134I DI 10.1117/12.912167 PG 13 WC Optics; Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BAM70 UT WOS:000304768000155 ER PT S AU Fang, Y Badal, A Karim, KS Badano, A AF Fang, Yuan Badal, Andreu Karim, Karim S. Badano, Aldo BE Pelc, NJ Nishikawa, RM Whiting, BR TI Spatio-temporal Monte Carlo modeling of a-Se detectors for breast imaging: Energy-weighted Swank noise and detective quantum efficiency SO MEDICAL IMAGING 2012: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 05-08, 2012 CL San Diego, CA SP SPIE, Agilent Technol, Diamond SA, DQE Instruments Inc, eMagin, Isuzu Glass Co Ltd, Medtronic, Inc., Ocean Thin Films Inc DE Monte Carlo; ARTEMIS; detective quantum efficiency; Swank factor; amorphous selenium ID AMORPHOUS SELENIUM; DIGITAL RADIOLOGY; RAY; MAMMOGRAPHY; ABSORPTION; SCREENS; DQE AB We study the effect of energy weighting in Swank noise and Detective Quantum Efficiency (DQE) at zero spatial frequency with a detailed Monte Carlo (MC) transport code that includes the three-dimensional spatial and temporal transport of electron-hole pairs in semiconductor x-ray detectors. The transport model takes into account recombination and trapping of carriers including effects of Coulomb forces and external applied electric field. We report pulse-height spectra (PHS) for mono-energetic x rays from 6 to 28 keV photon energy with 0.5 keV step size, and for clinical mammography spectra. A first-approximation electronic noise model is included in the simulations. The Swank calculations take into account the entire PHS distribution while the DQE(0) is calculated from the simulated Swank factor, and quantum efficiency values from the PENELOPE database of attenuation coefficients. The simulated DQE(0) is based on the entire clinical x-ray spectrum and takes into account the energy distribution following Tapiovaara and Wagner's (Phys. Med. Biol. 30, 1985) description for the weighting of carrier transport processes. Swank and DQE simulations for semiconductor detectors can provide insight into the fundamental limitations and possible optimization of breast imaging systems. C1 [Fang, Yuan; Badal, Andreu; Badano, Aldo] OSEL CDRH FDA, Div Imaging & Appl Math, Silver Spring, MD 20993 USA. RP Fang, Y (reprint author), OSEL CDRH FDA, Div Imaging & Appl Math, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM yuan.fang@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 NR 19 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8962-3 J9 PROC SPIE PY 2012 VL 8313 AR 83135S DI 10.1117/12.912012 PG 6 WC Optics; Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BAM70 UT WOS:000304768000198 ER PT S AU Dong, ZD Patel, H AF Dong, Zedong Patel, Hasmukh BE Williams, RO Watts, AB Miller, DA TI Scientific and Regulatory Considerations for Development and Commercialization of Poorly Water-Soluble Drugs SO FORMULATING POORLY WATER SOLUBLE DRUGS SE AAPS Advances in the Pharmaceutical Sciences Series LA English DT Article; Book Chapter ID CARBAMAZEPINE POLYMORPHS; IN-VITRO; DISCOVERY; BIOAVAILABILITY; CLASSIFICATION; NANOPARTICLES; DISSOLUTION; FORMULATION; DIHYDRATE; STABILITY AB This chapter focuses on the Chemistry, Manufacturing, and Controls (CMC) from the scientific and regulatory perspective of the development of poorly water-soluble drugs to provide insights into regulatory filing from Investigational New Drug Application (IND) to New Drug Application (NDA) submission. The chapter includes two primary sections to cover the two regulatory stages for CMC module of filing, IND and NDA. The IND section of the chapter includes the following contents: ( I) brief description of general filing requirements as outlined in the Code of Federal Regulations (CFR) and relevant guidances; (2) discussion of potential regulatory issues for developing poorly water-soluble drugs using various pharmaceutical technologies in the IND stage, i.e., solid-form selection, particle-size reduction, lipid formulation, and amorphous solid dispersion. The NDA section of the chapter includes the following: (I) general regulatory filing requirements of an NDA application; (2) potential regulatory issues associated with poorly water-soluble drugs; detailed discussions are carried out on topics including solid-form selection of the drug substance, drug product development using novel pharmaceutical technologies, development of control strategies, etc.; (3) case studies of marketed drug products of poorly water-soluble drugs in various dosage forms; this part uses the public information of the approved products as examples to support the discussions as outlined in part (2); and (4) brief discussion on the concept of Biopharmaceutics Classification System (BCS) in the development of poorly soluble drugs. The book chapter concludes with a brief summary which emphasizes on the link between regulation and science. C1 [Dong, Zedong; Patel, Hasmukh] US FDA, Off New Drug Qual Assessment, Silver Spring, MD 20993 USA. RP Dong, ZD (reprint author), US FDA, Off New Drug Qual Assessment, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zedong.dong@fda.hhs.gov NR 79 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 2210-7371 BN 978-1-4614-1143-7 J9 AAPS ADV PHARM SCI PY 2012 VL 3 BP 603 EP 629 DI 10.1007/978-1-4614-1144-4_14 D2 10.1007/978-1-14614-1144-4 PG 27 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BYP68 UT WOS:000299651700014 ER PT S AU Kim, DH Ryu, SH Shin, DH Song, CG AF Kim, Do-Hyun Ryu, Sang Hun Shin, Dong-Ho Song, Chul-Gyu BE Oraevsky, AA Wang, LV TI Image quality assessment using different types of optical diffusers for photoacoustic tomography SO PHOTONS PLUS ULTRASOUND: IMAGING AND SENSING 2012 SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Photons Plus Ultrasound - Imaging and Sensing/Photonics West BiOS Symposium CY JAN 22-24, 2012 CL San Francisco, CA SP SPIE DE photoacoustic tomography; phantom; image quality AB We have investigated different types of optical diffusers for the image quality assessment of photoacoustic tomography (PAT). PAT has been adapted in many biomedical research efforts over the past decade, however, studies on image quality of PAT have not been performed as much as that for photoacoustic microscopy. We developed a simple imaging phantom using strings of red plastic embedded in gelatinous base. Using a 532 nm Nd:YAG laser and focused/unfocused transducers, we reconstructed PAT images of the phantom with various types of optical diffusers placed on top of phantoms. Our initial results showed that the uniformity of the diffuser did not affect the PAT image quality, while the degree of light scattering contributed relatively more to the image quality. Image quality of biological samples will be presented and discussed. C1 [Kim, Do-Hyun] US FDA, Silver Spring, MD 20993 USA. RP Song, CG (reprint author), Chonbuk Natl Univ, Jeonju 561756, Jeonbuk, South Korea. EM song133436g@gmail.com FU National Research Foundation of Korea (NRF)-Korea government [MEST 2011-0030781] FX This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST 2011-0030781) for SHR, DHS, and CGS. NR 6 TC 0 Z9 0 U1 0 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8866-4 J9 PROC SPIE PY 2012 VL 8223 AR 82233B DI 10.1117/12.918721 PG 7 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BAP68 UT WOS:000305073300093 ER PT J AU Kim, PW Sorbello, AF Wassel, RT Pham, TM Tonning, JM Nambiar, S AF Kim, Peter W. Sorbello, Alfred F. Wassel, Ronald T. Pham, Tracy M. Tonning, Joseph M. Nambiar, Sumathi TI Eosinophilic Pneumonia in Patients Treated with Daptomycin Review of the Literature and US FDA Adverse Event Reporting System Reports SO DRUG SAFETY LA English DT Article ID THERAPY AB Background: Eosinophilic pneumonia (EP) has been noted in association with daptomycin use. The product labelling was recently updated to include EP in the Warnings and Precautions and Post-Marketing Experience sections. Objective: The objective of this study was to analyse adverse event (AE) reports submitted to the US FDA as well as published cases to characterize the clinical features and course of EP in daptomycin-treated patients. Methods: We searched for EP cases associated with daptomycin administration in the FDA Adverse Event Reporting System (AERS) submitted from 2004 to 2010, and the published literature. Cases were defined as definite, probable, possible and unlikely in terms of the diagnosis of EP and the potential association with daptomycin exposure. Definite cases had concurrent exposure to daptomycin, fever, dyspnoea with increased oxygen requirement or required mechanical ventilation, new infiltrates on chest imaging, bronchoalveolar lavage with >25% eosinophils and clinical improvement following daptomycin withdrawal. Additionally, we assessed inpatient daptomycin utilization. Results: We identified 7 definite, 13 probable, 38 possible cases of daptomycin-induced EP, and 23 unlikely cases. The seven definite EP cases had resolution after daptomycin was stopped, including two with EP recurrence following daptomycin rechallenge. Regarding the definite cases: (i) ages ranged from 60 to 87 years; (ii) dosing ranged from 4.4 to 8.0 mg/kg/day; and (iii) EP developed 10 days to 4 weeks after starting daptomycin. There was a gradual increase in the number of patients with an inpatient hospital discharge billing for daptomycin from the year 2004 to 2010. Conclusions: We report 7 definite, 13 probable and 38 possible EP cases associated with daptomycin administration. As AERS is based on voluntary reporting, the incidence of EP cannot be assessed. Healthcare providers should have heightened awareness of this serious AE associated with daptomycin use. C1 [Kim, Peter W.; Nambiar, Sumathi] US FDA, Ctr Drug Evaluat & Res, Off Antimicrobial Prod, Silver Spring, MD 20993 USA. [Sorbello, Alfred F.; Wassel, Ronald T.; Pham, Tracy M.; Tonning, Joseph M.] US FDA, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD 20993 USA. RP Kim, PW (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Antimicrobial Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM peter.kim@fda.hhs.gov NR 18 TC 19 Z9 22 U1 0 U2 3 PU ADIS INT LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND SN 0114-5916 J9 DRUG SAFETY JI Drug Saf. PY 2012 VL 35 IS 6 BP 447 EP 457 PG 11 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA 955TF UT WOS:000305043100003 PM 22612850 ER PT J AU Hung, HMJ Wang, SJ AF Hung, H. M. James Wang, Sue-Jane TI SAMPLE SIZE ADAPTATION IN FIXED-DOSE COMBINATION DRUG TRIAL SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Interim analysis; Min test; Nuisance parameter; Sample size reallocation AB Statistical testing in clinical trials can be complex when the statistical distribution of the test statistic involves a nuisance parameter. Some type of nuisance parameters such as standard deviation of a continuous response variable can be handled without too much difficulty. Other type of nuisance parameters, specifically associated with the main parameter under testing, can be difficult to handle. Without knowledge of the possible value of such a nuisance parameter, the maximum type I error associated with testing the main parameter may occur at an extreme value of the nuisance parameter. A well known example is the intersection-union test for comparing a combination drug with its two component drugs where the nuisance parameter is the mean difference between the two components. Knowledge of the possible range of value of this mean difference may help enhance the clinical trial design. For instance, if the interim internal data suggest that this mean difference falls into a possible range of value, then the sample size may be reallocated after the interim look to possibly improve the efficiency of statistical testing. This research sheds some light into possible power advantage from such a sample size reallocation at the interim look. C1 [Hung, H. M. James] US FDA, Div Biometr 1, OB OTS CDER, Silver Spring, MD USA. [Wang, Sue-Jane] US FDA, Off Biostat, OTS CDER, Silver Spring, MD USA. RP Hung, HMJ (reprint author), US Food & Drug Adm FDA, Div Biometr 1, OB OTS CDER, 10903 New Hampshire Ave,Bldg 21,Room 4616, Silver Spring, MD 20993 USA. EM hsienming.hung@fda.hhs.gov FU RSR [05-02]; Center for Drug Evaluation and Research of the U.S. Food and Drug Administration FX The research work presented in this paper was supported by the RSR fund 05-02, provided by Center for Drug Evaluation and Research of the U.S. Food and Drug Administration. The authors thank Dr. Qing Liu for providing many constructive comments to enhance this paper. The views expressed in this paper are not necessarily those of the U.S. Food and Drug Administration. NR 8 TC 2 Z9 2 U1 0 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 4 SI SI BP 679 EP 686 DI 10.1080/10543406.2012.676533 PG 8 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 950VU UT WOS:000304679600005 ER PT J AU Zaslavsky, BG Scott, J AF Zaslavsky, Boris G. Scott, John TI SAMPLE SIZE ESTIMATION IN SINGLE-ARM CLINICAL TRIALS WITH MULTIPLE TESTING UNDER FREQUENTIST AND BAYESIAN APPROACHES SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Bonferroni adjustment; Confidence limits; Credible limits; Multiple testing; Order statistics ID INCOMPLETE BETA-FUNCTION; ASYMPTOTIC-EXPANSION; END-POINTS; DISCRETE-DISTRIBUTIONS; TOLERANCE LIMITS; ADJUSTMENT; STRATEGIES AB In this paper, we study one-sided multiple testing problems for normal and binomial distributions. We use order statistics to test the null hypothesis {all H-i0 are true}. This approach allows us to uniformly address frequentist and Bayesian multiple testing models. To calculate order statistics, we use confidence limits. In frequentist models, we apply an adjustment to the confidence limits that is equivalent to the Bonferroni adjustment of p-values. In the Bayesian case, we adjust the credible limits following a concept of reconciliation between the Bayesian posterior probability and the frequentist p-value. We also study the quantitative relationship between the number of tests and the sample size of a clinical trial. If the number of tests is very large, we suggest using asymptotic order statistics. We study the performance of these statistics. The asymptotic order statistics for the normal distribution are used to extend the results for independent observations to dependent observations. C1 [Zaslavsky, Boris G.; Scott, John] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Zaslavsky, BG (reprint author), US FDA, Ctr Biol Evaluat & Res, HFM 219,1401 Rockville Pike, Rockville, MD 20852 USA. EM Boris.Zaslavsky@FDA.HHS.gov OI Scott, John/0000-0002-9116-948X NR 31 TC 0 Z9 0 U1 1 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 4 SI SI BP 819 EP 835 DI 10.1080/10543406.2012.676585 PG 17 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 950VU UT WOS:000304679600014 PM 22651117 ER PT S AU Cheng, WC Tannous, W Badano, A AF Cheng, Wei-Chung Tannous, Widad Badano, Aldo BE Abbey, CK MelloThoms, CR TI Impact of solid-state lighting on observer performance of color discrimination SO MEDICAL IMAGING 2012: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY FEB 08-09, 2012 CL San Diego, CA SP SPIE, Agilent Technol, Diamond SA, DQE Instruments, Inc, eMagin, Isuzu Glass Co Ltd, Medtron, Inc, Ocean Thin Films, Inc DE Solid-state lighting; color discrimination; illuminant metamerism; color perception ID VISION AB We studied the impact of the microscope light source on reader's performance using a microscopic version of the Farnsworth-Munsell 100 hue test for photographic slide film. Each pair of two adjacent color caps in the original test kit was reproduced on the film with random order and a 5X objective was used to examine the microscopic color patterns. The subject's visual task was to determine whether the color pair was in the correct hue order or not. The test was repeated for both a light-emitting diode lamp and a conventional halogen lamp. In this paper, we discuss the methodology using preliminary results. C1 [Cheng, Wei-Chung; Tannous, Widad; Badano, Aldo] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20093 USA. RP Cheng, WC (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20093 USA. NR 7 TC 0 Z9 0 U1 0 U2 3 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8967-8 J9 PROC SPIE PY 2012 VL 8318 AR 83181T DI 10.1117/12.912436 PG 5 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BAO45 UT WOS:000304905600062 ER PT S AU Choi, M Albani, L Badano, A AF Choi, Mina Albani, Luigi Badano, Aldo BE Abbey, CK MelloThoms, CR TI An image-dependent model of veiling glare effects on detection performance in large-luminance-range displays SO MEDICAL IMAGING 2012: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY FEB 08-09, 2012 CL San Diego, CA SP SPIE, Agilent Technol, Diamond SA, DQE Instruments, Inc, eMagin, Isuzu Glass Co Ltd, Medtron, Inc, Ocean Thin Films, Inc ID SCATTERING AB One limitation of visual detection tasks in complex scenes with a large range of luminance values is the decrease in sensitivity due to veiling glare in the display device and in the human eye caused by unwanted light scattering. We used our previously measured results regarding the increase in detection thresholds due to veiling glare to formulate an empirical model for this phenomenon. Our results are based on a ring glare source and a Gaussian target on white noise using a dual-layer, high-dynamic-range liquid-crystal display prototype. The thresholds, measured using a double-random staircase technique with added signal-absent images, are modeled as a function of illuminance at the eyes and angular distance between the veiling glare source and the detection target. In this work, we model increases in detection contrast thresholds due to veiling glare for any image by calculating the contribution of each display pixel. We validate our model by determining threshold increases for the set of experimental results previously obtained with human subjects. Our image-dependent model predicts how the contrast threshold is affected by veiling glare for any target location. Finally, we discuss the range of validity of our model and show predictions for sample mammography, chest CT, and chest radiography images displayed on large-luminance-range devices. C1 [Badano, Aldo] US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Badano, A (reprint author), US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 62,Room 3116, Silver Spring, MD 20993 USA. EM aldo.badano@fda.hhs.gov NR 10 TC 0 Z9 0 U1 1 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8967-8 J9 PROC SPIE PY 2012 VL 8318 AR 831804 DI 10.1117/12.913649 PG 10 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BAO45 UT WOS:000304905600003 ER PT S AU Kumcu, A Platisa, L Platisa, M Vansteenkiste, E Deblaere, K Badano, A Philips, W AF Kumcu, Asli Platisa, Ljiljana Platisa, Milan Vansteenkiste, Ewout Deblaere, Karel Badano, Aldo Philips, Wilfried BE Abbey, CK MelloThoms, CR TI Reader behavior in a detection task using single- and multi-slice image datasets SO MEDICAL IMAGING 2012: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY FEB 08-09, 2012 CL San Diego, CA SP SPIE, Agilent Technol, Diamond SA, DQE Instruments, Inc, eMagin, Isuzu Glass Co Ltd, Medtron, Inc, Ocean Thin Films, Inc DE Observer study; multi-slice; reader behavior; browsing patterns; visual search AB We assess human reader behavior such as reading times and browsing trends in a signal detection experiment with synthetic single-slice (ss) and multi-slice (ms) image datasets of varying task complexity, defined in this study as the ratio of the background lump size to the signal width. Three dataset types were generated by inserting one 3D Gaussian target of fixed size into the center of 3D volumes of correlated Gaussian noise with three different kernel sizes. Corresponding signal intensities were determined separately for the three background types using the staircase method targeting an AUC of 0.7 for ss datasets. Non-expert human readers were presented with ss (central slice of the volume) and ms datasets (slice-by-slice viewing in a stack-browsing mode). Readers were aware of the target's approximate location within the slice or volume. Readers could scroll freely through the ms datasets at arbitrary speed and direction with no time limit. Experiments were conducted in a controlled viewing environment on a 5MP digital mammography display. AUCs were 0.68-0.73 for ss; 0.82-0.98 for ms datasets. Reading time (ms, ss), the number of repetitions through the stack (ms), and the average number of slices per repetition (ms) were assessed. Browsing speeds were in the range of 1-7 slices per second. Results show that readers spent the shortest time and fewest repetitions reading TP cases, with FP and FN cases requiring the most attention. The reported trends concur with earlier chest x-ray and mammography studies which report that readers fixate longer on regions subsequently rated incorrectly. C1 [Kumcu, Asli; Platisa, Ljiljana; Vansteenkiste, Ewout; Philips, Wilfried] Univ Ghent, TELIN IPI IBBT, B-9000 Ghent, Belgium. [Platisa, Milan] TASS NV, Leuven, Belgium. [Deblaere, Karel] Ghent Univ Hosp, Dept Neuroradiol, Ghent, Belgium. [Badano, Aldo] CDRH FDA, Silver Spring, MD USA. RP Kumcu, A (reprint author), Univ Ghent, TELIN IPI IBBT, B-9000 Ghent, Belgium. EM asli.kumcu@telin.ugent.be OI Kumcu, Asli/0000-0002-5144-1258 NR 17 TC 0 Z9 0 U1 0 U2 2 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8967-8 J9 PROC SPIE PY 2012 VL 8318 AR 831803 DI 10.1117/12.912387 PG 13 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BAO45 UT WOS:000304905600002 ER PT S AU Platisa, L Kumcu, A Platisa, M Vansteenkiste, E Deblaere, K Badano, A Philips, W AF Platisa, Ljiljana Kumcu, Asli Platisa, Milan Vansteenkiste, Ewout Deblaere, Karel Badano, Aldo Philips, Wilfried BE Abbey, CK MelloThoms, CR TI Volumetric detection tasks with varying complexity: Human observer performance SO MEDICAL IMAGING 2012: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY FEB 08-09, 2012 CL San Diego, CA SP SPIE, Agilent Technol, Diamond SA, DQE Instruments, Inc, eMagin, Isuzu Glass Co Ltd, Medtron, Inc, Ocean Thin Films, Inc DE Volumetric Images; Stack Browsing; Detection Task; Human observer; Model Observer; Efficiency ID DORFMAN-BERBAUM-METZ; HOTELLING OBSERVER; LESION-DETECTION; MODEL OBSERVERS; MULTISLICE; NOISE AB This study explores detection performance trends of human observers with respect to two parameters: task complexity determined by the frequency content of background and signal, and image viewing mode: single-slice (ss) versus multi-slice (ms) stack-browsing image presentation. The images are 3D correlated Gaussian noise with a 3D Gaussian signal centered in the image volume. We consider three different noise kernels while keeping the signal spread constant across all images. In ss mode, only the central slice of the volume is presented to the observer, while in ms mode all slices are available. All human readings are conducted in a controlled viewing environment on a 5MP digital mammography medical display. Overall, in line with the literature, we find that human performance increases in ms relative to ss image presentation mode. Furthermore, our experiments indicate that the extent of difference between ms and ss performance is influenced by the properties of image data: the difference in performance increases (from Delta AUC= 0.14 to Delta AUC= 0.30) as the difference in the frequency content of the signal and the background increases. Future studies shall focus on comparing the results of the present study to existing observer models for volumetric images, ultimately aiming at designing an anthropomorphic model observer for volumetric detection tasks. C1 [Platisa, Ljiljana; Kumcu, Asli; Vansteenkiste, Ewout; Philips, Wilfried] Univ Ghent, TELIN IPI IBBT, B-9000 Ghent, Belgium. [Platisa, Milan] TASS NV, Leuven, Belgium. [Deblaere, Karel] Univ Ghent Hosp, Dept Neuroradiol, B-9000 Ghent, Belgium. [Badano, Aldo] CDRH FDA, Silver Spring, MD USA. RP Platisa, L (reprint author), Univ Ghent, TELIN IPI IBBT, B-9000 Ghent, Belgium. EM Ljiljana.Platisa@Telin.UGent.be OI Kumcu, Asli/0000-0002-5144-1258 NR 27 TC 1 Z9 1 U1 0 U2 4 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8967-8 J9 PROC SPIE PY 2012 VL 8318 AR 83180S DI 10.1117/12.911558 PG 12 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BAO45 UT WOS:000304905600025 ER PT S AU Zafar, F Dorband, J Badano, A AF Zafar, Fahad Dorband, John Badano, Aldo BE Abbey, CK MelloThoms, CR TI Computational observer approach for the assessment of stereoscopic visualizations for 3D medical images SO MEDICAL IMAGING 2012: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY FEB 08-09, 2012 CL San Diego, CA SP SPIE, Agilent Technol, Diamond SA, DQE Instruments, Inc, eMagin, Isuzu Glass Co Ltd, Medtron, Inc, Ocean Thin Films, Inc DE Model Observer; Stereo Vision; Volume Rendering AB We present a computational stereoscopic observer approach inspired by the mechanisms of stereopsis in human vision that makes decisions based on a set of image pairs. Our stereo observer is constrained to a left and a right image generated using a visualization operator (ray tracing) to render simulated voxel datasets. We present the formulation of the observer based on model observer theory and discuss issues regarding simulated data generation and processing for this approach. The applicability of this observer extends to stereoscopic displays in the areas of entertainment, industrial, and medical imaging applications. C1 [Zafar, Fahad; Dorband, John] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. RP Badano, A (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM fahad.zafar@fda.hhs.gov; aldo.badano@fad.hhs.gov NR 20 TC 1 Z9 1 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8967-8 J9 PROC SPIE PY 2012 VL 8318 AR 831806 DI 10.1117/12.913661 PG 7 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BAO45 UT WOS:000304905600005 ER PT J AU Othus, M Li, Y Tiwari, R AF Othus, Megan Li, Yi Tiwari, Ram TI Change-point cure models with application to estimating the change-point effect of age of diagnosis among prostate cancer patients SO JOURNAL OF APPLIED STATISTICS LA English DT Article DE cure models; change-point models; right censoring; smoothing; survival analysis ID LIKELIHOOD-RATIO TEST; HAZARD-RATE MODEL; SURVIVAL-DATA; COX REGRESSION; MIXTURE-MODELS; DISPARITIES; THRESHOLD; COVARIATE; OUTCOMES; RATES AB Previous research on prostate cancer survival trends in the United States National Cancer Institute's Surveillance Epidemiology and End Results database has indicated a potential change-point in the age of diagnosis of prostate cancer around age 50. Identifying a change-point value in prostate cancer survival and cure could have important policy and health care management implications. Statistical analysis of this data has to address two complicating features: (1) change-point models are not smooth functions and so present computational and theoretical difficulties; and (2) models for prostate cancer survival need to account for the fact that many men diagnosed with prostate cancer can be effectively cured of their disease with early treatment. We develop a cure survival model that allows for change-point effects in covariates to investigate a potential change-point in the age of diagnosis of prostate cancer. Our results do not indicate that age under 50 is associated with increased hazard of death from prostate cancer. C1 [Othus, Megan] Fred Hutchinson Canc Res Ctr, Seattle, WA 98117 USA. [Li, Yi] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Li, Yi] Harvard Univ, Dept Biostat, Boston, MA 02115 USA. [Tiwari, Ram] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Othus, M (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,M3-C102,POB 19024, Seattle, WA 98117 USA. EM mothus@fhcrc.org FU National Cancer Institute [CA090998] FX The authors thank two referees for comments that led to an improved paper. This work was supported in part by grant CA090998 from the National Cancer Institute. Most of R. Tiwari's work was done during his previous employment at the National Cancer Institute. The views expressed in this article do not necessarily represent those of the USA Food and Drug Administration or the National Cancer Institute. NR 34 TC 3 Z9 3 U1 4 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0266-4763 J9 J APPL STAT JI J. Appl. Stat. PY 2012 VL 39 IS 4 BP 901 EP 911 DI 10.1080/02664763.2011.626849 PG 11 WC Statistics & Probability SC Mathematics GA 947KF UT WOS:000304428200015 PM 22544992 ER PT J AU Forrey, C Douglas, JF Gilson, MK AF Forrey, Christopher Douglas, Jack F. Gilson, Michael K. TI The fundamental role of flexibility on the strength of molecular binding SO SOFT MATTER LA English DT Article ID ENTHALPY-ENTROPY COMPENSATION; INDUCED-FIT; PROTEIN FLEXIBILITY; LIGAND-BINDING; NONCOVALENT INTERACTIONS; CONFORMATIONAL ENTROPY; SEMIFLEXIBLE POLYMERS; DISORDERED PROTEINS; CHAIN STIFFNESS; IMMUNE-SYSTEM AB Non-covalent molecular association underlies a diverse set of biologically and technologically relevant phenomena, including the action of drugs on their biomolecular targets and self- and supra-molecular assembly processes. Computer models employed to model binding frequently use interaction potentials with atomistic detail while neglecting the thermal molecular motions of the binding species. However, errors introduced by this simplification and, more broadly, the thermodynamic consequences of molecular flexibility on binding, are little understood. Here, we isolate the fundamental relationship of molecular flexibility to binding thermodynamics via simulations of simplified molecules with a wide range of flexibilities, but the same interaction potential. Disregarding molecular motion is found to generate large errors in binding entropy, enthalpy and free energy, even for molecules that are nearly rigid. Indeed, small decreases in rigidity markedly reduce affinity for highly rigid molecules. Remarkably, precisely the opposite trend occurs for more flexible molecules, for which increasing flexibility leads to stronger binding affinity. We also find that differences in flexibility suffice to generate binding specificity: for example, a planar surface selectively binds rigid over flexible molecules. Intriguingly, varying molecular flexibility while keeping interaction potentials constant leads to near-linear enthalpy-entropy compensation over a wide range of flexibilities, with the unexpected twist that increasing flexibility produces opposite changes in entropy and enthalpy for molecules in the flexible versus the rigid regime. Molecular flexibility is thus a crucial determinant of binding affinity and specificity and variations in flexibility can lead to strong yet non-intuitive consequences. C1 [Forrey, Christopher] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20903 USA. [Douglas, Jack F.] Natl Inst Stand & Technol, Div Polymers, Gaithersburg, MD 20899 USA. [Gilson, Michael K.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. RP Forrey, C (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM christopher.forrey@fda.hhs.gov FU National Institute of General Medical Sciences of the National Institutes of Health [GM61300] FX This work was initiated at the National Institute for Standards and Technology (NIST) and completed at the Center for Devices and Radiological Health at the FDA. We thank the Division of Electrical and Software Engineering (FDA) for use of the high performance computing facilities and the Division of Imaging and Applied Mathematics (FDA) for computational time. We also thank the Center for Theoretical and Computational Materials Science at NIST for computational time. This publication was made possible in part by grant no. GM61300 from the National Institute of General Medical Sciences of the National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of General Medical Sciences. NR 73 TC 15 Z9 15 U1 2 U2 45 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1744-683X J9 SOFT MATTER JI Soft Matter PY 2012 VL 8 IS 23 BP 6385 EP 6392 DI 10.1039/c2sm25160d PG 8 WC Chemistry, Physical; Materials Science, Multidisciplinary; Physics, Multidisciplinary; Polymer Science SC Chemistry; Materials Science; Physics; Polymer Science GA 945XG UT WOS:000304309300024 PM 22707976 ER PT J AU Wu, K Davison, L Sheehan, AH AF Wu, Kimberly Davison, Lindsay Sheehan, Amy Heck TI Pharmacy Students' Perceptions of and Attitudes Towards Peer Assessment Within a Drug Literature Evaluation Course SO AMERICAN JOURNAL OF PHARMACEUTICAL EDUCATION LA English DT Article DE peer assessment; assessment; peer evaluation; pharmacy students; attitudes ID MEDICAL-STUDENTS; PROFESSIONALISM AB Objective. To assess pharmacy students' perceptions of and attitudes towards the use of peer assessment within a drug literature evaluation course. Methods. A 15-item, electronic survey instrument was sent to 158 second-year pharmacy students enrolled in a 2-credit required literature evaluation course at the Purdue University College of Pharmacy. Results. One hundred fifty-two (96.2%) responses were received. Approximately 95% of students agreed that they had the necessary skills to assess their peers and 91.8% agreed that their peers possessed these skills as well. More students agreed they were comfortable receiving feedback from peers (95.7%) than agreed they were comfortable providing feedback to peers (80%). The majority of students (91.9%) agreed that peer assessment was a skill they will use in their career as a pharmacist. Conclusion. Students were more comfortable receiving feedback from peers than providing peer assessment. This skill is used by pharmacists throughout their career; therefore, students should become familiar and comfortable with the peer assessment process. C1 [Wu, Kimberly; Sheehan, Amy Heck] Purdue Univ, Coll Pharm, Indianapolis, IN 46202 USA. [Wu, Kimberly] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Wu, Kimberly; Davison, Lindsay] US FDA, Silver Spring, MD USA. RP Sheehan, AH (reprint author), Purdue Univ, Coll Pharm, Myers Bldg,W7555,1001 W 10th St, Indianapolis, IN 46202 USA. EM amheck@iupui.edu NR 11 TC 5 Z9 5 U1 0 U2 6 PU AMER ASSOC COLL PHARMACY PI ALEXANDRIA PA 1426 PRINCE STREET, ALEXANDRIA, VA 22314-2815 USA SN 0002-9459 J9 AM J PHARM EDUC JI Am. J. Pharm. Educ. PY 2012 VL 76 IS 4 AR 62 PG 4 WC Education, Scientific Disciplines; Pharmacology & Pharmacy SC Education & Educational Research; Pharmacology & Pharmacy GA 942HM UT WOS:000304034800007 PM 22611271 ER PT J AU Tsai, DH Elzey, S DelRio, FW Keene, AM Tyner, KM Clogston, JD MacCuspie, RI Guha, S Zachariah, MR Hackley, VA AF Tsai, De-Hao Elzey, Sherrie DelRio, Frank W. Keene, Athena M. Tyner, Katherine M. Clogston, Jeffrey D. MacCuspie, Robert I. Guha, Suvajyoti Zachariah, Michael R. Hackley, Vincent A. TI Tumor necrosis factor interaction with gold nanoparticles SO NANOSCALE LA English DT Article ID TRANSFORM-INFRARED-SPECTROSCOPY; DIFFERENTIAL MOBILITY ANALYSIS; PLASMA-PROTEIN ADSORPTION; BOVINE SERUM-ALBUMIN; COLLOIDAL GOLD; SOLID-SURFACES; DRUG-DELIVERY; TNF-ALPHA; POLYMERIC NANOPARTICLES; POLY(ETHYLENE GLYCOL) AB We report on a systematic investigation of molecular conjugation of tumor necrosis factor-alpha (TNF) protein onto gold nanoparticles (AuNPs) and the subsequent binding behavior to its antibody (anti-TNF). We employ a combination of physical and spectroscopic characterization methods, including electrospray-differential mobility analysis, dynamic light scattering, polyacrylamide gel electrophoresis, attenuated total reflectance-Fourier transform infrared spectroscopy, fluorescence assay, and enzyme-linked immunosorbent assay. The native TNF used in this study exists in the active homotrimer configuration prior to conjugation. After binding to AuNPs, the maximum surface density of TNF is (0.09 +/- 0.02) nm(-2) with a binding constant of 3 x 10(6) (mol L-1)(-1). Dodecyl sulfate ions induce desorption of monomeric TNF from the AuNP surface, indicating a relatively weak intermolecular binding within the AuNP-bound TNF trimers. Anti-TNF binds to both TNF-conjugated and citrate-stabilized AuNPs, showing that non-specific binding is significant. Based on the number of anti-TNF molecules adsorbed, a substantially higher binding affinity was observed for the TNF-conjugated surface. The inclusion of thiolated polyethylene glycol (SH-PEG) on the AuNPs inhibits the binding of anti-TNF, and the amount of inhibition is related to the number ratio of surface bound SH-PEG to TNF and the way in which the ligands are introduced. This study highlights the challenges in quantitatively characterizing complex hybrid nanoscale conjugates, and provides insight on TNF-AuNP formation and activity. C1 [Tsai, De-Hao; Elzey, Sherrie; DelRio, Frank W.; MacCuspie, Robert I.; Guha, Suvajyoti; Zachariah, Michael R.; Hackley, Vincent A.] NIST, Mat Measurement Lab, Gaithersburg, MD 20899 USA. [Keene, Athena M.; Tyner, Katherine M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Clogston, Jeffrey D.] NCI Frederick, Nanotechnol Characterizat Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Guha, Suvajyoti; Zachariah, Michael R.] Univ Maryland, Dept Mech Engn, College Pk, MD 20740 USA. [Guha, Suvajyoti; Zachariah, Michael R.] Univ Maryland, Dept Chem, College Pk, MD 20740 USA. RP Hackley, VA (reprint author), NIST, Mat Measurement Lab, Gaithersburg, MD 20899 USA. EM vince.hackley@nist.gov RI Tsai, De-Hao/K-6702-2012; Nanotechnology Characterization Lab, NCL/K-8454-2012; OI Tsai, De-Hao/0000-0002-2669-3007; Guha, Suvajyoti/0000-0002-7622-2721; MacCuspie, Robert/0000-0002-6618-6499; Hackley, Vincent/0000-0003-4166-2724 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Center for Drug Evaluation and Research FX The authors acknowledge Anil Patri and Sarah Skoczen of the National Cancer Institute's Nanotechnology Characterization Laboratory, and Jiwen Zheng at FDA for helpful discussions and for assistance with PAGE measurements. The authors also thank Robert Cook, Sang-Min Lee, Tae Joon Cho, and Lei Zhou at NIST for manuscript review and insightful comments. This research was performed while S. E. held a National Research Council Research Associateship Award at NIST. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. This project was supported in part by an appointment of AMK to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 76 TC 18 Z9 20 U1 3 U2 30 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 J9 NANOSCALE JI Nanoscale PY 2012 VL 4 IS 10 BP 3208 EP 3217 DI 10.1039/c2nr30415e PG 10 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 936QB UT WOS:000303604000033 PM 22481570 ER PT J AU Doell, D Folmer, D Lee, H Honigfort, M Carberry, S AF Doell, D. Folmer, D. Lee, H. Honigfort, M. Carberry, S. TI Updated estimate of trans fat intake by the US population SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE industrially-produced trans fatty acids (IP-TFA); dietary intake; partially hydrogenated oils (PHOs); food products ID ACID COMPOSITION; DIET; TRENDS; FOOD; REFORMULATIONS; ASSOCIATION; CONSUMPTION; PROGRESS; DISEASE; HEALTH AB The dietary intake of industrially-produced trans fatty acids (IP-TFA) was estimated for the US population (aged 2 years or more), children (aged 2-5 years) and teenage boys (aged 13-18 years) using the 2003-2006 National Health and Nutrition Examination Survey (NHANES) food consumption database, market share information and trans fat levels based on label survey data and analytical data for packaged and in-store purchased foods. For fast foods, a Monte Carlo model was used to estimate IP-TFA intake. Further, the intake of trans fat was also estimated using trans fat levels reported in the US Department of Agriculture (USDA) National Nutrient Database for Standard Reference, Release 22 (SR 22, 2009) and the 2003-2006 NHANES food consumption database. The cumulative intake of IP-TFA was estimated to be 1.3 g per person per day (g/p/d) at the mean for the US population. Based on this estimate, the mean dietary intake of IP-TFA has decreased significantly from that cited in the 2003 US Food and Drug Administration (FDA) final rule that established labelling requirements for trans fat (4.6 g/p/d for adults). Although the overall intake of IP-TFA has decreased as a result of the implementation of labelling requirements, individuals with certain dietary habits may still consume high levels of IP-TFA if certain brands or types of food products are frequently chosen. C1 [Doell, D.; Folmer, D.; Lee, H.; Honigfort, M.; Carberry, S.] US FDA, Div Petit Review, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Lee, H (reprint author), US FDA, Div Petit Review, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM hyoung.lee@fda.hhs.gov NR 49 TC 48 Z9 49 U1 1 U2 17 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2012 VL 29 IS 6 BP 861 EP 874 DI 10.1080/19440049.2012.664570 PG 14 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 936JE UT WOS:000303585900001 PM 22439632 ER PT J AU Harp, BP Miranda-Bermudez, E Baron, CI Richard, GI AF Harp, Bhakti Petigara Miranda-Bermudez, Enio Baron, Carolina I. Richard, Gerald I. TI Qualitative identification of permitted and non-permitted colour additives in food products SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE chromatography, HPLC; clean-up; colours; beverages; cereals; confectionary; bakery products ID PERFORMANCE LIQUID-CHROMATOGRAPHY; COAL-TAR COLORS; SYNTHETIC DYES; SOFT DRINKS; SPECTRAL COMPILATION; ARRAY DETECTION; C-18 CARTRIDGE; WATER; FD; FOODSTUFFS AB Colour additives are dyes, pigments or other substances that can impart colour when added or applied to food, drugs, cosmetics, medical devices, or the human body. The substances must be pre-approved by the US Food and Drug Administration (USFDA) and listed in Title 21 of the US Code of Federal Regulations before they may be used in products marketed in the United States. Some also are required to be batch certified by the USFDA prior to their use. Both domestic and imported products sold in interstate commerce fall under USFDA jurisdiction, and the USFDA's district laboratories use a combination of analytical methods for identifying or confirming the presence of potentially violative colour additives. We have developed a qualitative method for identifying 17 certifiable, certification exempt, and non-permitted colour additives in various food products. The method involves extracting the colour additives from a product and isolating them from non-coloured components with a C-18 Sep-Pak cartridge. The colour additives are then separated and identified by liquid chromatography (LC) with photodiode array detection, using an Xterra RP18 column and gradient elution with aqueous ammonium acetate and methanol. Limits of detection (LODs) ranged from 0.02 to 1.49 mg/l. This qualititative LC method supplements the visible spectrophotometric and thin-layer chromatography methods currently used by the USFDA's district laboratories and is less time-consuming and requires less solvent compared to the other methods. The extraction step in the new LC method is a simple and an efficient process that can be used for most food types. C1 [Harp, Bhakti Petigara; Miranda-Bermudez, Enio] US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Baron, Carolina I.; Richard, Gerald I.] US FDA, NE Reg Lab, Off Regulatory Affairs, Jamaica, NY 11433 USA. RP Harp, BP (reprint author), US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM Bhakti.Petigara@fda.hhs.gov NR 29 TC 5 Z9 5 U1 0 U2 24 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2012 VL 29 IS 6 BP 886 EP 896 DI 10.1080/19440049.2012.658526 PG 11 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 936JE UT WOS:000303585900003 PM 22540286 ER PT J AU Tournas, VH Sapp, C Trucksess, MW AF Tournas, V. H. Sapp, C. Trucksess, M. W. TI Occurrence of aflatoxins in milk thistle herbal supplements SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE chromatography - HPLC; aflatoxins; dietary supplements ID MEDICINAL-PLANTS; LIQUID-CHROMATOGRAPHY; FUMONISINS B-1; SILYMARIN; TEA; MYCOTOXINS; DRUG AB Milk thistle (MT) dietary supplements are widely consumed due to their possible liver-health-promoting properties. As botanicals they can be contaminated with a variety of fungi and their secondary metabolites, mycotoxins. The aflatoxigenic fungus Aspergillus flavus has been previously isolated from these commodities. Currently, there is no published method for determining aflatoxins (AFs) in MT. Therefore, a liquid chromatography (LC) method validated for aflatoxin analysis in botanicals was evaluated and applied to MT. The method consisted of acetonitrile/water extraction, immunoaffinity column clean-up, LC separation, post-column photochemical reaction derivatisation and fluorescence detection. The average recoveries for AFs added to MT seeds, herb, oil-based liquid extract and alcohol-based liquid extract were 76% or higher. The mean relative standard deviation was <10%. The limit of detection (LOD) was 0.01 mu g kg(-1) and the limit of quantification (LOQ) was 0.03 mu g kg(-1). The method was used to conduct a small survey. A total of 83 MT samples from the US market were analysed. AFs were detected in 19% of the samples with levels ranging from 0.04 to 2.0 mu g kg(-1). Additionally, an aflatoxigenic A. flavus strain from ATTC and an A. parasiticus strain isolated from MT herb powder were found to produce high amounts of aflatoxins (11,200 and 49,100 mu g kg(-1), respectively) when cultured in MT seed powder. This is the first study reporting on aflatoxin contamination of MT botanical supplements and identifying methodology for AF analysis of these commodities. C1 [Tournas, V. H.; Trucksess, M. W.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Sapp, C.] Univ Maryland, JIFSAN, College Pk, MD 20742 USA. RP Tournas, VH (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM valerie.tournas@fda.hhs.gov NR 19 TC 10 Z9 11 U1 3 U2 24 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2012 VL 29 IS 6 BP 994 EP 999 DI 10.1080/19440049.2012.664788 PG 6 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 936JE UT WOS:000303585900014 PM 22439650 ER PT J AU Fechter, LD Fisher, JW Chapman, GD Mokashi, VP Ortiz, PA Reboulet, JE Stubbs, JE Lear, AM McInturf, SM Prues, SL Gearhart, CA Fulton, S Mattie, DR AF Fechter, L. D. Fisher, J. W. Chapman, G. D. Mokashi, V. P. Ortiz, P. A. Reboulet, J. E. Stubbs, J. E. Lear, A. M. McInturf, S. M. Prues, S. L. Gearhart, C. A. Fulton, S. Mattie, D. R. TI SUBCHRONIC JP-8 JET FUEL EXPOSURE ENHANCES VULNERABILITY TO NOISE-INDUCED HEARING LOSS IN RATS SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES LA English DT Article ID ETHYL BENZENE; INDUCED OTOTOXICITY; CARBON-MONOXIDE; TOLUENE; STYRENE; POTENTIATION; ACRYLONITRILE; PROMOTION; WORKERS AB Both laboratory and epidemiological studies published over the past two decades have identified the risk of excess hearing loss when specific chemical contaminants are present along with noise. The objective of this study was to evaluate the potency of JP-8 jet fuel to enhance noise-induced hearing loss (NIHL) using inhalation exposure to fuel and simultaneous exposure to either continuous or intermittent noise exposure over a 4-wk exposure period using both male and female Fischer 344 rats. In the initial study, male (n = 5) and female (n = 5) rats received inhalation exposure to JP-8 fuel for 6 h/d, 5 d/wk for 4 wk at concentrations of 200, 750, or 1500 mg/m(3). Parallel groups of rats also received nondamaging noise (constant octave band noise at 85 dB(lin)) in combination with the fuel, noise alone (75, 85, or 95 dB), or no exposure to fuel or noise. Significant concentration-related impairment of auditory function measured by distortion product otoacoustic emissions (DPOAE) and compound action potential (CAP) threshold was seen in rats exposed to combined JP-8 plus noise exposure when JP-8 levels of 1500 mg/m(3) were presented with trends toward impairment seen with 750 mg/m(3) JP-8 + noise. JP-8 alone exerted no significant effect on auditory function. In addition, noise was able to disrupt the DPOAE and increase auditory thresholds only when noise exposure was at 95 dB. In a subsequent study, male (n = 5 per group) and female (n = 5 per group) rats received 1000 mg/m(3) JP-8 for 6 h/d, 5 d/wk for 4 wk with and without exposure to 102 dB octave band noise that was present for 15 min out of each hour (total noise duration 90 min). Comparisons were made to rats receiving only noise, and those C1 [Fechter, L. D.; Gearhart, C. A.; Fulton, S.] Jerry L Pettis Mem Vet Adm Med Ctr, Loma Linda, CA 92354 USA. [Fisher, J. W.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chapman, G. D.; Mokashi, V. P.; Ortiz, P. A.; Reboulet, J. E.; Lear, A. M.; McInturf, S. M.; Prues, S. L.] USN, Med Res Unit Dayton, Dayton, OH USA. [Stubbs, J. E.] USAF, Inst Technol, Dept Syst & Engn Management, Dayton, OH USA. RP Fechter, LD (reprint author), Loma Linda VA Med Ctr, 11201 Benton St, Loma Linda, CA 92357 USA. EM larry.fechter@va.gov FU VA Rehabilitation Research and Development Service [6006, C4613L]; U.S. Air Force Surgeon General (SGR) [711 HPW/RHPB]; Henry Jackson Foundation for Military Medicine; Jerry Pettis Memorial VA Medical Center; Navy work unit [61062] FX Support for this research was obtained from the VA Rehabilitation Research and Development Service under Merit award 6006 and Career Scientist Award C4613L. Support for this research was also obtained from the U.S. Air Force Surgeon General (SGR) and managed through 711 HPW/RHPB, Henry Jackson Foundation for Military Medicine, Jerry Pettis Memorial VA Medical Center, and Navy work unit number 61062. The views expressed in this article are those of the authors and do not reflect the official policy or position of the United States Air Force, Department of the Navy, Department of Defense, VA, U.S. FDA or the U.S. government. This article is approved for public release, distribution unlimited. The authors are military service members (or employees of the U.S. government). This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that copyright protection under this title is not available for any work of the United States government. Title 17 U.S.C. 101 defines a U.S. government work as a work prepared by a military service member or employee of the U.S. government as part of that person's official duties. NR 41 TC 6 Z9 6 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1528-7394 J9 J TOXICOL ENV HEAL A JI J. Toxicol. Env. Health Part A PY 2012 VL 75 IS 5 BP 299 EP 317 DI 10.1080/15287394.2012.652060 PG 19 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 936ME UT WOS:000303593700004 PM 22409492 ER PT J AU Lee, T Manjanatha, MG Aidoo, A Moland, CL Branham, WS Fuscoe, JC Ali, AA Desai, VG AF Lee, Taewon Manjanatha, Mugimane G. Aidoo, Anane Moland, Carrie L. Branham, William S. Fuscoe, James C. Ali, Akhtar A. Desai, Varsha G. TI EXPRESSION ANALYSIS OF HEPATIC MITOCHONDRIA-RELATED GENES IN MICE EXPOSED TO ACRYLAMIDE AND GLYCIDAMIDE SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES LA English DT Article ID GLUTATHIONE-S-TRANSFERASES; OXIDATIVE DNA-DAMAGE; MOUSE LYMPHOMA-CELLS; SPRAGUE-DAWLEY RATS; MERCAPTURIC ACID; TOXICITY; BRAIN; LIVER; STRESS; INJURY AB Acrylamide (AA) is an industrial chemical that has been extensively investigated for central nervous system (CNS), reproductive, and genetic toxicity. However, AA effects on the liver, a major organ of drug metabolism, have not been adequately explored. In addition, the role of mitochondria in AA-mediated toxicity is still unclear. Changes in expression levels of genes associated with hepatic mitochondrial function of male transgenic Big Blue (BB) mice administered 500 mg/L AA or an equimolar concentration (600 mg/L) of its reactive metabolite glycidamide (GA) in drinking water for 3 and 4 wk, respectively, were examined. Transcriptional profiling of 542 mitochondria-related genes indicated a significant downregulation of genes associated with the 3-beta-hydroxysteroid dehydrogenase family in AA- and GA-treated mice, suggesting a possible role of both chemicals in altering hepatic steroid metabolism in BB mice. In addition, genes associated with lipid metabolism were altered by both treatments. Interestingly, only the parental compound (AA) significantly induced expression levels of genes associated with oxidative phosphorylation, in particular ATP synthase, which correlated with elevated ATP levels, indicating an increased energy demand in liver during AA exposure. Acrylamide-treated mice also showed significantly higher activity of glutathione S-transferase in association with decreased levels of reduced glutathione (GSH), which may imply an enhanced rate of conjugation of AA with GSH in liver. These results suggest different hepatic mechanisms of action of AA and GA and provide important insights into the involvement of mitochondria during their exposures. C1 [Moland, Carrie L.; Branham, William S.; Fuscoe, James C.; Desai, Varsha G.] US FDA, Ctr Excellence Funct Genom, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Ali, Akhtar A.] US FDA, Ctr Excellence Hepatotox, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Manjanatha, Mugimane G.; Aidoo, Anane] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Lee, Taewon] Korea Univ, Dept Informat & Math, Jochiwon, Chungnam, South Korea. RP Desai, VG (reprint author), US FDA, Ctr Excellence Funct Genom, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM varsha.desai@fda.hhs.gov FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2011-0015128] FX The authors very much appreciate Jessie B. Collins, Office of Scientific Coordination, and Sharon Shelton, Division of Genetic and Molecular Biology, for their excellent technical assistance. Also, the authors thank Drs. Sherry M. Lewis and Nan Mei for their critical review of the article. This research was partly supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0015128). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the FDA. NR 72 TC 10 Z9 10 U1 0 U2 14 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1528-7394 J9 J TOXICOL ENV HEAL A JI J. Toxicol. Env. Health Part A PY 2012 VL 75 IS 6 BP 324 EP 339 DI 10.1080/15287394.2012.668160 PG 16 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 936MF UT WOS:000303593800002 PM 22480170 ER PT J AU Pau, AK Penzak, SR Boyd, SD McLaughlin, M Morse, CG AF Pau, Alice K. Penzak, Scott R. Boyd, Sarita D. McLaughlin, Mary Morse, Caryn G. TI Impaired Maraviroc and Raltegravir Clearance in a Human Immunodeficiency Virus-Infected Patient with End-Stage Liver Disease and Renal Impairment: A Management Dilemma SO PHARMACOTHERAPY LA English DT Article DE maraviroc; raltegravir; human immunodeficiency virus; HIV; liver failure; renal failure; pharmacokinetics; therapeutic drug monitoring; TDM ID TREATMENT-EXPERIENCED PATIENTS; HEALTHY-VOLUNTEERS; HIV-1 INTEGRASE; PHARMACOKINETICS; SAFETY; TOLERABILITY; INHIBITOR; MK-0518 AB Current product labels for maraviroc and raltegravir provide no dosing guidance for patients with end-stage liver disease and worsening renal function. We describe a 41-year-old man with human immunodeficiency virus (HIV) infection and rapidly progressive liver failure and vanishing bile duct syndrome at presentation. Despite discontinuation of all potential offending drugs, the patient's liver function continued to deteriorate. To achieve and maintain HIV suppression while awaiting liver transplantation, a regimen consisting of maraviroc, raltegravir, and enfuvirtide was started. These agents were chosen because the patient was not exposed to them before the onset of liver failure. While receiving product label-recommended twice-daily dosing of these drugs, he achieved and maintained HIV suppression. During a complicated and prolonged hospitalization, the patient also developed renal dysfunction. As hepatic metabolism is the primary route of clearance of maraviroc and raltegravir, we predicted that using approved doses of these drugs could result in significant drug accumulation. Since the safety profiles of supratherapeutic concentrations of these agents are not well defined, we chose to use therapeutic drug monitoring to guide further dosing. The reported concentrations showed severely impaired metabolic clearance of both drugs, with markedly prolonged elimination half-lives of 189 hours for maraviroc and 61 hours for raltegravir. Previously reported half-lives for maraviroc and raltegravir in HIV-infected patients with normal hepatic and renal function are 1418 hours and 9-12 hours, respectively. Based on these results, the dosing intervals were extended from twice/day to twice/week for maraviroc and every 48 hours for raltegravir. Unfortunately, the patient's clinical condition continued to deteriorate, and he eventually died of complications related to end-stage liver disease. This case illustrates the difficulties in managing antiretroviral therapy in an HIV-infected patient with combined severe liver and renal failure. Prolonged excessively high exposure to maraviroc and raltegravir is likely to result in some level of concentration-dependent toxicity. Until more data are available, therapeutic drug monitoring remains the only evidence-based approach to optimize dosage selection of these drugs in this patient population. C1 [Pau, Alice K.] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [McLaughlin, Mary] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Morse, Caryn G.] NIAID, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. [Penzak, Scott R.] NIH, Dept Pharm, Clin Pharmacokinet Lab, Clin Res Ctr, Bethesda, MD 20892 USA. [Boyd, Sarita D.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Pau, AK (reprint author), NIAID, Div Clin Res, NIH, Bldg 10,Room 11C103,MSC 1880,10 Ctr Dr, Bethesda, MD 20892 USA. EM apau@niaid.nih.gov OI Morse, Caryn/0000-0002-1177-4365 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and in part with federal funds from the National Cancer Institute, National Institutes of Health (contract no. HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services, nor does mention of trade. NR 18 TC 5 Z9 5 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD JAN PY 2012 VL 32 IS 1 BP E1 EP E6 DI 10.1002/PHAR.1003 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 933DZ UT WOS:000303341200001 PM 22392831 ER PT J AU Winchell, C Rappaport, BA Roca, R Rosebraugh, CJ AF Winchell, Celia Rappaport, Bob A. Roca, Rigoberto Rosebraugh, Curtis J. TI Reanalysis of Methamphetamine Dependence Treatment Trial SO CNS NEUROSCIENCE & THERAPEUTICS LA English DT Article ID ALCOHOL DEPENDENCE C1 [Winchell, Celia; Rappaport, Bob A.; Roca, Rigoberto; Rosebraugh, Curtis J.] US FDA, Div Anesthesia Analgesia & Addict Prod, Off Drug Evaluat 2, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Winchell, C (reprint author), US FDA, Div Anesthesia Analgesia & Addict Prod, Off Drug Evaluat 2, Ctr Drug Evaluat & Res, New Hampshire Ave, Silver Spring, MD USA. NR 10 TC 16 Z9 16 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-5930 J9 CNS NEUROSCI THER JI CNS Neurosci. Ther. PY 2012 VL 18 IS 5 BP 367 EP 368 DI 10.1111/j.1755-5949.2011.00288.x PG 2 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 931CS UT WOS:000303192700002 PM 22533722 ER PT S AU Kim, DH Welle, C Krauthamer, V AF Kim, Do-Hyun Welle, Cristin Krauthamer, Victor BE Periasamy, A Konig, K So, PTC TI Ray-Tracing Study of the Post-Scanner Variable Beam Expansion Optics in a Two-Photon Microscopy System SO MULTIPHOTON MICROSCOPY IN THE BIOMEDICAL SCIENCES XII SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Multiphoton Microscopy in the Biomedical Sciences XII CY JAN 22-24, 2012 CL San Francisco, CA SP SPIE, Becker & Hickel GmbH, Boston Elect Corp, Carl Zeiss MicroImaging GmbH, Chroma Technol Corp, Coherent Inc, JenLab GmbH, Leica Microsyst, Multiphoton Laser Technol Inc, Newport-Spectra Phys, Olympus Amer Inc, Omega Opt, Inc, Semrock, Inc DE Two photon microscopy; laser beam expander; ray tracing ID MULTIPHOTON MICROSCOPY; EXCITATION AB Due to the low signal levels typical of two-photon microscopy (TPM) in biological samples, optical design optimization is critical. One of the most important factors is overfilling of the back aperture of the objective lens. A variable beam expander is commonly placed before the scanning mirrors to achieve this goal, however, this may cause degradation of image quality due to increased dispersion. Additionally, scanning mirror size restricts the degree of expansion, which often prevents the overfilling of objective lens back aperture. We investigated the implementation of variable beam expansion optics after the scanning mirrors. Ray-tracing analyses confirmed that the post-scanner beam expansion has two key advantages over the conventional pre-scanner beam expansion approach: decreasing the number of optical elements reduces pulse dispersion and reducing the size of the scanning mirror enables faster scanning. Resolution and aberration of a TPM with post-scanner beam expansion optics were analysed. C1 [Kim, Do-Hyun; Welle, Cristin; Krauthamer, Victor] US FDA, Div Phys, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Kim, DH (reprint author), US FDA, Div Phys, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM do-hyun.kim@fda.hhs.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8869-5 J9 PROC SPIE PY 2012 VL 8226 AR 822610 DI 10.1117/12.909144 PG 9 WC Microscopy; Optics SC Microscopy; Optics GA BZR37 UT WOS:000302556900020 ER PT S AU Kim, DH AF Kim, Do-Hyun BE Raghavachari, R Liang, R TI Numerical Comparison of Thermal Damage Threshold from Pulsed and Scanning Laser in a Measurement Aperture SO DESIGN AND QUALITY FOR BIOMEDICAL TECHNOLOGIES V SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Design and Quality for Biomedical Technologies V CY JAN 22-23, 2012 CL San Francisco, CA SP SPIE ID RETINAL INJURY AB Optical radiation hazards of scanning light sources are often evaluated using pulsed light source criteria, with the relevant pulse parameter equivalent to the scanning light source determined by the energy delivered through a measurement aperture. This study utilizes a numerical analysis based upon the melanin granule model to compare the thermal effects of scanning and pulsed light sources through a measurement aperture in the pigmented retinal layer. The numerical analysis calculates the thermal contribution of individual melanin granules with varying temporal sequence, and finds that temperature changes and thermal damage thresholds for the two different types of light sources were not equal. C1 US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Kim, DH (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM do-hyun.kim@fda.hhs.gov NR 11 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8858-9 J9 PROC SPIE PY 2012 VL 8215 AR 821509 DI 10.1117/12.909100 PG 6 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Optics; Imaging Science & Photographic Technology SC Engineering; Optics; Imaging Science & Photographic Technology GA BZR24 UT WOS:000302534400005 ER PT S AU Kim, DH Kim, MS Hwang, J AF Kim, Do-Hyun Kim, Moon S. Hwang, Jeeseong BE Raghavachari, R Liang, R TI Monitoring of Biofilm Formation on Different Material Surfaces of Medical Devices using Hyperspectral Imaging Method SO DESIGN AND QUALITY FOR BIOMEDICAL TECHNOLOGIES V SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Design and Quality for Biomedical Technologies V CY JAN 22-23, 2012 CL San Francisco, CA SP SPIE DE Hyperspectral imaging; microbial biofilm; Escherichia coli AB Contamination of the inner surface of indwelling (implanted) medical devices by microbial biofilm is a serious problem. Some microbial bacteria such as Escherichia coli form biofilms that lead to potentially life-threatening infections. Other types of medical devices such as bronchoscopes and duodenoscopes account for the highest number of reported endoscopic infections where microbial biofilm is one of the major causes for these infections. We applied a hyperspectral imaging method to detect biofilm contamination on the surface of several common materials used for medical devices. Such materials include stainless steel, titanium, and stainless-steel-titanium alloy. Potential uses of hyperspectral imaging technique to monitor biofilm attachment to different material surfaces are discussed. C1 [Kim, Do-Hyun] US FDA, Silver Spring, MD 20993 USA. RP Kim, DH (reprint author), US FDA, Silver Spring, MD 20993 USA. NR 9 TC 2 Z9 2 U1 0 U2 7 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8858-9 J9 PROC SPIE PY 2012 VL 8215 AR 821507 DI 10.1117/12.909980 PG 7 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Optics; Imaging Science & Photographic Technology SC Engineering; Optics; Imaging Science & Photographic Technology GA BZR24 UT WOS:000302534400003 ER PT S AU Pfefer, J Agrawal, A AF Pfefer, Joshua Agrawal, Anant BE Raghavachari, R Liang, R TI A Review of Consensus Test Methods for Established Medical Imaging Modalities and Their Implications for Optical Coherence Tomography SO DESIGN AND QUALITY FOR BIOMEDICAL TECHNOLOGIES V SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Design and Quality for Biomedical Technologies V CY JAN 22-23, 2012 CL San Francisco, CA SP SPIE DE image quality; phantoms; optical coherence tomography; standardization ID ARTIFACTS; PHANTOM; DOMAIN AB In recent years there has been increasing interest in development of consensus, tissue-phantom-based approaches for assessment of biophotonic imaging systems, with the primary goal of facilitating clinical translation of novel optical technologies. Well-characterized test methods based on tissue phantoms can provide useful tools for performance assessment, thus enabling standardization and device inter-comparison during preclinical development as well as quality assurance and re-calibration in the clinical setting. In this review, we study the role of phantom-based test methods as described in consensus documents such as international standards for established imaging modalities including X-ray CT, MRI and ultrasound. Specifically, we focus on three image quality characteristics - spatial resolution, spatial measurement accuracy and image uniformity - and summarize the terminology, metrics, phantom design/construction approaches and measurement/analysis procedures used to assess these characteristics. Phantom approaches described are those in routine clinical use and tend to have simplified morphology and biologically-relevant physical parameters. Finally, we discuss the potential for applying knowledge gained from existing consensus documents in the development of standardized, phantom-based test methods for optical coherence tomography. C1 [Pfefer, Joshua; Agrawal, Anant] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Pfefer, J (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. NR 20 TC 3 Z9 3 U1 0 U2 4 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8858-9 J9 PROC SPIE PY 2012 VL 8215 AR 82150D DI 10.1117/12.912371 PG 10 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Optics; Imaging Science & Photographic Technology SC Engineering; Optics; Imaging Science & Photographic Technology GA BZR24 UT WOS:000302534400008 ER PT S AU Wang, QZ Le, D Ramella-Roman, J Pfefer, J AF Wang, Quanzeng Le, Du Ramella-Roman, Jessica Pfefer, Joshua BE Raghavachari, R Liang, R TI Visualization of Mucosal Vasculature with Narrow Band Imaging: A Theoretical Study SO DESIGN AND QUALITY FOR BIOMEDICAL TECHNOLOGIES V SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Design and Quality for Biomedical Technologies V CY JAN 22-23, 2012 CL San Francisco, CA SP SPIE DE Narrow band imaging; Monte Carlo modeling; reflectance; light-tissue interaction; mucosal cancer ID CONVENTIONAL COLONOSCOPY; DIFFERENTIAL-DIAGNOSIS; MAGNIFYING ENDOSCOPY; FLUORESCENCE-SPECTRA; BARRETTS-ESOPHAGUS; CANCER; TISSUE; LESIONS; SYSTEM; CHROMOENDOSCOPY AB Narrow band imaging (NBI) is a spectrally-selective reflectance imaging technique that is used as an adjunctive approach to endoscopic detection of mucosal abnormalities such as neoplastic lesions. While numerous clinical studies in tissue sites such as the esophagus, oral cavity and lung indicate the efficacy of this approach, it is not well theoretically understood. In this study, we performed Monte Carlo simulations to elucidate the factors that affect NBI device performance. The model geometry involved a two-layer turbid medium based on mucosal tissue optical properties and embedded cylindrical, blood-filled vessels at varying diameters and depths. Specifically, we studied the effect of bandpass filters (415 +/- 15 nm, 540 +/- 10 nm versus white light), blood vessel diameter (20-400 mu m) and depth (30 - 450 mu m), wavelength, and bandwidth on vessel contrast. Our results provide a quantitative evaluation of the two mechanisms that are commonly believed to be the primary components of NBI: (i) the increased contrast provided by high hemoglobin absorption and (ii) increase in the penetration depth produced by the decrease in scattering with increasing wavelength. Our MC model can provide novel, quantitative insight into NBI, may lead to improvements in its performance. C1 [Wang, Quanzeng; Le, Du; Pfefer, Joshua] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Wang, QZ (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM quanzeng.wang@fda.hhs.gov NR 33 TC 0 Z9 0 U1 0 U2 4 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-8858-9 J9 PROC SPIE PY 2012 VL 8215 AR 821505 DI 10.1117/12.906817 PG 9 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Optics; Imaging Science & Photographic Technology SC Engineering; Optics; Imaging Science & Photographic Technology GA BZR24 UT WOS:000302534400002 ER PT J AU Miranda-Bermudez, E Belai, N Harp, BP Yakes, BJ Barrows, JN AF Miranda-Bermudez, E. Belai, N. Harp, B. Petigara Yakes, B. J. Barrows, J. N. TI Qualitative determination of carbon black in food products SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE cheese; confectionary; colours; extraction ID COLOR ADDITIVES; C-18 CARTRIDGE AB Carbon black (C. I. 77266) is an insoluble pigment produced by the partial combustion of hydrocarbons. The pigment is known by several synonyms, including vegetable carbon, lamp black and carbon ash, that correspond to the raw materials and methods used for its production. Vegetable carbon (E153) is permitted for use in colouring food in the European Union. The US Food and Drug Administration (USFDA) has not approved the use of any type of carbon black for colouring food, although the agency batch certifies the pigment as D&C Black No. 2 for use in colouring certain cosmetics. Since carbon black (as vegetable carbon) may be present in food products offered for import into the United States, the USFDA's district laboratories need a qualitative analytical method for determining its presence. We have developed an extraction method for this purpose. A sample is broken down and dissolved with nitric acid. The resulting solution is filtered and treated with hydrochloric acid to dissolve any black iron oxide also present as a colour additive. A black residue remaining on the filter paper indicates the presence of carbon black in the food. We confirmed the presence of carbon black in residues from several standards and food products using Raman spectroscopy. The limit of detection for this method is 0.0001%. C1 [Miranda-Bermudez, E.; Belai, N.; Harp, B. Petigara; Barrows, J. N.] US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Yakes, B. J.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Harp, BP (reprint author), US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM Bhakti.Petigara@fda.hhs.gov RI Yakes, Betsy/K-2646-2012 FU Oak Ridge Institute of Science and Education FX The authors would like to thank the Oak Ridge Institute of Science and Education for providing partial funding for this work. They also thank Magdi Mossoba for his contribution to the Raman spectroscopy investigations. NR 12 TC 2 Z9 2 U1 0 U2 13 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2012 VL 29 IS 1 BP 38 EP 42 DI 10.1080/19440049.2011.616535 PG 5 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 914FI UT WOS:000301934300005 PM 22035229 ER PT J AU Huque, MF Alosh, M AF Huque, Mohammad F. Alosh, Mohamed TI A CONSISTENCY-ADJUSTED STRATEGY FOR ACCOMMODATING AN UNDERPOWERED PRIMARY ENDPOINT SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Composite endpoint; Consistency-adjusted testing strategy; Multiple testing; Subgroup analysis; Underpowered primary endpoint ID PIOGLITAZONE CLINICAL-TRIAL; MACROVASCULAR EVENTS; CARVEDILOL AB A clinical trial might involve more than one clinically important endpoint, each of which can characterize the treatment effect of the experimental drug under investigation. Underlying the concept of using such endpoints interchangeably to establish an efficacy claim, or pooling different endpoints to constitute a composite endpoint, is the assumption that findings from such endpoints are consistent with each other. While such an assumption about consistency of efficacy findings appears to be intuitive, it is seldom considered in the design and analysis literature of clinical trials with multiple endpoints. Failure to account for consistency of efficacy findings of two candidate endpoints to establish efficacy, at the design stage, has led to difficulties in interpreting study findings. This article presents a flexible testing strategy for accommodating findings of an alternative to the designated primary endpoint (or a subgroup) to support an efficacy claim. The method is built on the following two premises: (i) Efficacy findings of the designated primary endpoint, although nonsignificant, need to be supportive of those of the alternative endpoint, and (ii) the significance level allocated for testing the second endpoint is determined adaptively based on the magnitude of the p-value for the designated primary endpoint. The method takes into account the hierarchical ordering of the hypotheses tested and the correlation between the test statistics for the two endpoints to increase the chance of a positive trial. We discuss control of the type I error rate for the proposed test strategy and compare its power with that of other methods. In addition, we consider its application to two clinical trials. C1 [Alosh, Mohamed] US FDA, Div Biometr 3, Off Biostat, OTS,CDER, Silver Spring, MD 20993 USA. [Huque, Mohammad F.] US FDA, Div Biometr 4, OB, OTS,CDER, Silver Spring, MD 20993 USA. [Huque, Mohammad F.] Georgia So Univ, Adjunct Fac, Jiann Ping Hsu Coll Publ Hlth, Statesboro, GA 30460 USA. RP Alosh, M (reprint author), US FDA, Div Biometr 3, Off Biostat, OTS,CDER, Bldg 21,Room 3626,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mohamed.Alosh@fda.hhs.gov NR 18 TC 3 Z9 3 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2012 VL 22 IS 1 BP 160 EP 179 DI 10.1080/10543406.2010.513464 PG 20 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 915YY UT WOS:000302064800011 PM 22204533 ER PT J AU Mumtaz, MM Ray, M Crowell, SR Keys, D Fisher, J Ruiz, P AF Mumtaz, M. Moiz Ray, Meredith Crowell, Susan R. Keys, Deborah Fisher, Jeffrey Ruiz, Patricia TI TRANSLATIONAL RESEARCH TO DEVELOP A HUMAN PBPK MODELS TOOL KIT-VOLATILE ORGANIC COMPOUNDS (VOCS) SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES LA English DT Article ID COMPLEX CHEMICAL-MIXTURES; HUMAN BIOMONITORING DATA; IN-VIVO EXTRAPOLATION; PHARMACOKINETIC MODEL; RISK-ASSESSMENT; CANCER-RISK; PERCUTANEOUS-ABSORPTION; CARBON-TETRACHLORIDE; LACTATIONAL TRANSFER; TOXICITY DATA AB Toxicity and exposure evaluations remain the two of the key components of human health assessment. While improvement in exposure assessment relies on a better understanding of human behavior patterns, toxicity assessment still relies to a great extent on animal toxicity testing and human epidemiological studies. Recent advances in computer modeling of the dose-response relationship and distribution of xenobiotics in humans to important target tissues have advanced our abilities to assess toxicity. In particular, physiologically based pharmacokinetic (PBPK) models are among the tools than can enhance toxicity assessment accuracy. Many PBPK models are available to the health assessor, but most are so difficult to use that health assessors rarely use them. To encourage their use these models need to have transparent and user-friendly formats. To this end the Agency for Toxic Substances and Disease Registry (ATSDR) is using translational research to increase PBPK model accessibility, understandability, and use in the site-specific health assessment arena. The agency has initiated development of a human PBPK tool-kit for certain high priority pollutants. The tool kit comprises a series of suitable models. The models are recoded in a single computer simulation language and evaluated for use by health assessors. While not necessarily being state-of-the-art code for each chemical, the models will be sufficiently accurate to use for screening purposes. This article presents a generic, seven-compartment PBPK model for six priority volatile organic compounds (VOCs): benzene (BEN), carbon tetrachloride (CCl4), dichloromethane (DCM), perchloroethylene (PCE), trichloroethylene (TCE), and vinyl chloride (VC). Limited comparisons of the generic and original model predictions to published kinetic data were conducted. A goodness of fit was determined by calculating the means of the sum of the squared differences (MSSDs) for simulation vs. experimental kinetic data using the generic and original models. Using simplified solvent exposure assumptions for oral ingestion and inhalation, steady-state blood concentrations of each solvent were simulated for exposures equivalent to the ATSDR Minimal Risk Levels (MRLs). The predicted blood levels were then compared to those reported in the National Health and Nutrition Examination Survey (NHANES). With the notable exception of BEN, simulations of combined oral and inhalation MRLs using our generic VOC model yielded blood concentrations well above those reported for the 95th percentile blood concentrations for the U. S. populations, suggesting no health concerns. When the PBPK tool kit is fully developed, risk assessors will have a readily accessible tool for evaluating human exposure to a variety of environmental pollutants. C1 [Mumtaz, M. Moiz] ATSDR, Computat Toxicol Lab, Div Toxicol & Environm Med, Atlanta, GA 30333 USA. [Ray, Meredith] Univ S Carolina, Charleston, SC USA. [Crowell, Susan R.] Pacific NW Natl Lab, Richland, WA USA. [Keys, Deborah] Univ Georgia, Athens, GA 30602 USA. [Fisher, Jeffrey] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Mumtaz, MM (reprint author), ATSDR, Computat Toxicol Lab, Div Toxicol & Environm Med, 1600 Clifton Rd,F-62, Atlanta, GA 30333 USA. EM mgm4@cdc.gov NR 60 TC 9 Z9 9 U1 3 U2 15 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1528-7394 J9 J TOXICOL ENV HEAL A JI J. Toxicol. Env. Health Part A PY 2012 VL 75 IS 1 BP 6 EP 24 DI 10.1080/15287394.2012.625546 PG 19 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 917NJ UT WOS:000302184200002 PM 22047160 ER PT S AU Li, ZG Kwekel, JC Chen, T AF Li, Zhiguang Kwekel, Joshua C. Chen, Tao BE Wang, J Tan, AC Tian, T TI Functional Comparison of Microarray Data Across Multiple Platforms Using the Method of Percentage of Overlapping Functions SO NEXT GENERATION MICROARRAY BIOINFORMATICS: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Microarray; Biological pathway database; Functional comparison; Percentage of overlapping functions; R; Gene expression ID GENE-EXPRESSION MEASUREMENTS; ARISTOLOCHIC ACID; NCBI GEO; CONSISTENCY; PROFILES; KIDNEY; RATS AB Functional comparison across microarray platforms is used to assess the comparability or similarity of the biological relevance associated with the gene expression data generated by multiple microarray platforms. Comparisons at the functional level are very important considering that the ultimate purpose of microarray technology is to determine the biological meaning behind the gene expression changes under a specific condition, not just to generate a list of genes. Herein, we present a method named percentage of overlapping functions (POF) and illustrate how it is used to perform the functional comparison of microarray data generated across multiple platforms. This method facilitates the determination of functional differences or similarities in microarray data generated from multiple array platforms across all the functions that arc presented on these platforms. This method can also be used to compare the functional differences or similarities between experiments, projects, or laboratories. C1 [Li, Zhiguang; Chen, Tao] USDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Kwekel, Joshua C.] USDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Li, ZG (reprint author), USDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. NR 14 TC 2 Z9 2 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-399-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 802 BP 123 EP 139 DI 10.1007/978-1-61779-400-1_9 D2 10.1007/978-1-61779-400-1 PG 17 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA BYQ68 UT WOS:000299796400009 PM 22130878 ER PT J AU Ali, MM Amialchuk, A Gao, S Heiland, F AF Ali, Mir M. Amialchuk, Aliaksandr Gao, Song Heiland, Frank TI Adolescent weight gain and social networks: is there a contagion effect? SO APPLIED ECONOMICS LA English DT Article DE peer effects; obesity; adolescents ID PHYSICAL-ACTIVITY; SECULAR TRENDS; UNITED-STATES; BODY-WEIGHT; ECONOMIC-ANALYSIS; US CHILDREN; OBESITY; OVERWEIGHT; BEHAVIOR; PREVALENCE AB Previous studies on the spread of obesity in social networks have focused on the contemporaneous effect of peer weight outcomes on individuals. This article is the first to investigate the longer term effects, within adolescence and from adolescence into early adulthood, of peers on individual weight outcomes. Using data from the first three waves of the National Longitudinal Study of Adolescent Health (Add Health), and accounting for correlated effects using a number of empirical strategies including school-level fixed effects and accounting for neighbourhood preferences, we show that Body Mass Index (BMI) and overweight status in a person's friendship network influence their BMI and likelihood of being overweight. The evidence suggests that there is some persistence of the effects of past peer weight experiences on individual weight outcomes during adolescence and into early adulthood. The findings are consistent with adolescence being an important formative period of individuals' preference for ideal physique and own body weight aspirations. We conclude that policy makers should be particularly concerned with interventions during childhood and adolescence, in order to slow the spread of obesity by promoting a healthy body image and positive health behaviours. C1 [Ali, Mir M.; Amialchuk, Aliaksandr] Univ Toledo, Dept Econ, Toledo, OH 43606 USA. [Ali, Mir M.] US FDA, Off Regulat Policy & Social Sci, College Pk, MD 20740 USA. [Gao, Song] Cent Univ Finance & Econ, Sch Publ Finance & Publ Policy, Beijing 100011, Peoples R China. [Heiland, Frank] CUNY, CUNY Inst Demog Res, Sch Publ Affairs, Baruch Coll, New York, NY 10010 USA. RP Ali, MM (reprint author), Univ Toledo, Dept Econ, 2801 W Bancroft St, Toledo, OH 43606 USA. EM mir.ali@fda.hhs.gov NR 44 TC 6 Z9 6 U1 3 U2 17 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0003-6846 J9 APPL ECON JI Appl. Econ. PY 2012 VL 44 IS 23 BP 2969 EP 2983 DI 10.1080/00036846.2011.568408 PG 15 WC Economics SC Business & Economics GA 909CX UT WOS:000301540800004 ER PT J AU Montague, TH Potvin, D DiLiberti, CE Hauck, WW Parr, AF Schuirmann, DJ AF Montague, Timothy H. Potvin, Diane DiLiberti, Charles E. Hauck, Walter W. Parr, Alan F. Schuirmann, Donald J. TI Additional results for 'Sequential design approaches for bioequivalence studies with crossover designs' SO PHARMACEUTICAL STATISTICS LA English DT Article DE sequential design; sample size re-estimation; adaptive design; bioequivalence AB In 2008, this group published a paper on approaches for two-stage crossover bioequivalence (BE) studies that allowed for the reestimation of the second-stage sample size based on the variance estimated from the first-stage results. The sequential methods considered used an assumed GMR of 0.95 as part of the method for determining power and sample size. This note adds results for an assumed GMR = 0.90. Two of the methods recommended for GMR = 0.95 in the earlier paper have some unacceptable increases in Type I error rate when the GMR is changed to 0.90. If a sponsor wants to assume 0.90 for the GMR, Method D is recommended. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Hauck, Walter W.] US Pharmacopeia, Rockville, MD 20852 USA. [Montague, Timothy H.] GlaxoSmithKline Inc, King Of Prussia, PA USA. [Potvin, Diane] Theratechnologies Inc, Montreal, PQ, Canada. [DiLiberti, Charles E.] Montclair Bioequivalence Serv LLC, Montclair, NJ USA. [Parr, Alan F.] GlaxoSmithKline Inc, Res Triangle Pk, NC USA. [Schuirmann, Donald J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Hauck, WW (reprint author), US Pharmacopeia, 12601 Twinbrook Pkwy, Rockville, MD 20852 USA. EM wh@usp.org FU PQRI FX The authors thank TingTing Zhan for her assistance with the simulation studies and the PQRI for its support and encouragement of this work. NR 2 TC 15 Z9 15 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1539-1604 J9 PHARM STAT JI Pharm. Stat. PD JAN-FEB PY 2012 VL 11 IS 1 BP 8 EP 13 DI 10.1002/pst.483 PG 6 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 908JT UT WOS:000301487400002 PM 21308974 ER PT J AU Fu, M Weick-Brady, M Tanno, E AF Fu, Maggie Weick-Brady, Mary Tanno, Eleanor TI Medical devices in the home: A unique challenge for the FDA SO WORK-A JOURNAL OF PREVENTION ASSESSMENT & REHABILITATION LA English DT Article DE Caregiver; care recipient; manufacturer; human factors; policy AB Objective: With the rising numbers of elderly populations and those with chronic diseases, the Home Healthcare field has inevitable expanded within the United States. Patients, more specifically home-bound patients, are becoming increasingly dependent on medical technology to help sustain and improve their quality if life. Often times, home care patients, or care recipients, depend on a properly functioning medical device for recovery. As efficient as this method may be, home healthcare also comes along with many challenges involving use and management of medical devices. Difficulties regarding device function, use, the environment, and human factors can all serve as factors to jeopardize patient safety. FDA recognizes that devices need to be safe and capable of meeting needs in an uncontrolled home environment. Participants: Major stakeholders such as manufacturers, distributors, human factor specialists, professional health organizations, healthcare professionals, patient/caregivers, and other government agencies. Result: FDA would assure that manufacturers are designing and testing devices for the home, that proper training and education to use the device are available and completed, and the public knows how to report problems with their devices. Methods: FDA launched the Medical Device Home Use Initiative in April 2010 which proposed different methods that can support safety and safe use of medical devices in the home environment. Conclusion: FDA faces many challenges in assuring safe usage of medical devices in the home. FDA hopes that stakeholders can also become actively involved in working with us to address a total life cycle approach on device safety. C1 [Fu, Maggie; Weick-Brady, Mary; Tanno, Eleanor] Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Weick-Brady, M (reprint author), Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mary.Brady@fda.hhs.gov NR 1 TC 2 Z9 2 U1 0 U2 10 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1051-9815 J9 WORK JI Work PY 2012 VL 41 IS 3 BP 361 EP 365 DI 10.3233/WOR-2012-1305 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 906PZ UT WOS:000301360400016 PM 22398505 ER PT J AU Ali, MM Amialchuk, A Rizzo, JA AF Ali, Mir M. Amialchuk, Aliaksandr Rizzo, John A. TI The influence of body weight on social network ties among adolescents SO ECONOMICS & HUMAN BIOLOGY LA English DT Article DE Social networks; Adolescents; Body weight ID LABOR-MARKET; OBESITY; IMPACT; OUTCOMES; RISK; SIZE; VICTIMIZATION; OVERWEIGHT; CHILDREN; BEHAVIOR AB Evidence of negative stereotypes, prejudice and discrimination towards obese individuals has been widely documented. However, the effect of a larger body size on social network ties or friendship formations is less well understood. In this paper, we explore the extent to which higher body weight results in social marginalization of adolescents. Using data from a nationally representative sample of adolescents, we estimate endogeneity-corrected models including school-level fixed effects that account for bi-directionality and unobserved confounders to ascertain the effect of body weight on social network ties. We find that obese adolescents have fewer friends and are less socially integrated than their non-obese counterparts. We also find that such penalties in friendship networks are present among whites but not African-Americans or Hispanics, with the largest effect among white females. These results are robust to common environmental influences at the school-level and to controls for preferences, risk attitudes, low self-esteem and objective measures of physical attractiveness. Published by Elsevier B.V. C1 [Rizzo, John A.] SUNY Stony Brook, Dept Econ, Stony Brook, NY 11794 USA. [Rizzo, John A.] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Ali, Mir M.] US FDA, Off Regulat Policy & Social Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Ali, Mir M.; Amialchuk, Aliaksandr] Univ Toledo, Dept Econ, Toledo, OH 43606 USA. RP Rizzo, JA (reprint author), SUNY Stony Brook, Dept Econ, Stony Brook, NY 11794 USA. EM mir.ali@fda.hhs.gov; aamialc@utnet.utoledo.edu; john.rizzo@stonybrook.edu FU National Institute of Child Health and Human Development [P01-HD31921]; National Institute of Child Health and Human Development FX The views expressed here are those of the authors and do not necessarily reflect the views of the Food & Drug Administration. This research uses data from Add Health, a program project designed by J. Richard Udry, Peter S. Bearman, and Kathleen Mullan Harris, and funded by a grant P01-HD31921 from the National Institute of Child Health and Human Development, with cooperative funding from 17 other agencies. Special acknowledgement is due Ronald R. Rindfuss and Barbara Entwisle for assistance in the original design. Persons interested in obtaining data files from Add Health should contact Add Health, Carolina Population Center, 123 W. Franklin Street, Chapel Hill, NC 27516-2524 (addhealth@unc.edu). NR 57 TC 15 Z9 15 U1 5 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-677X J9 ECON HUM BIOL JI Econ. Hum. Biol. PD JAN PY 2012 VL 10 IS 1 BP 20 EP 34 DI 10.1016/j.ehb.2011.10.001 PG 15 WC Economics; Public, Environmental & Occupational Health SC Business & Economics; Public, Environmental & Occupational Health GA 904RS UT WOS:000301216200003 PM 22056235 ER PT J AU Biancani, PJ Carmichael, RH Daskin, JH Burkhardt, W Calci, KR AF Biancani, Peter J. Carmichael, Ruth H. Daskin, Joshua H. Burkhardt, William, III Calci, Kevin R. TI Seasonal and Spatial Effects of Wastewater Effluent on Growth, Survival, and Accumulation of Microbial Contaminants by Oysters in Mobile Bay, Alabama SO ESTUARIES AND COASTS LA English DT Article DE Sewage; Stable isotopes; Fecal coliform; Male-specific coliphage ID MALE-SPECIFIC BACTERIOPHAGE; ESCHERICHIA-COLI; ISOTOPE RATIOS; STABLE-ISOTOPE; FOOD; NITROGEN; SEWAGE; EUTROPHICATION; VARIABILITY; PATHOGENS AB We measured seasonal effects of wastewater treatment plant (WTP) effluent on growth, survival, and accumulation of microbes in oysters near a major WTP in Mobile Bay, AL. Despite higher nutrients near the WTP, seasonal conditions rather than distance affected chlorophyll a concentration and oyster growth. In summer and fall, when oyster growth was higher, delta N-15 parts per thousand in oysters near the WTP changed through time to reflect delta N-15 parts per thousand in effluent (approx. -4 parts per thousand). Microbial indicators (male-specific coliphage, fecal coliforms) were highest in oysters near the WTP in all seasons and correlated with delta N-15 parts per thousand in fall and summer. Increased riverine discharge and slower acquisition of delta N-15 parts per thousand likely confounded correlations in winter/spring. Although we did not detect gross ecological effects of wastewater exposure for oysters, data indicated wastewater-derived particles entered the local food web and accumulated in oysters. These data highlight the importance of using multiple indicators of wastewater exposure and considering both seasonal and spatial effects when defining wastewater influence on a system or species. C1 [Biancani, Peter J.; Carmichael, Ruth H.] Dauphin Isl Sea Lab, Dauphin Isl, AL 36528 USA. [Biancani, Peter J.; Carmichael, Ruth H.] Univ S Alabama, Mobile, AL 26688 USA. [Daskin, Joshua H.] MB 0193 Brandeis Univ, Waltham, MA 02454 USA. [Burkhardt, William, III; Calci, Kevin R.] US FDA, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP Carmichael, RH (reprint author), Dauphin Isl Sea Lab, 101 Bienville Blvd, Dauphin Isl, AL 36528 USA. EM rcarmichael@disl.org FU Dauphin Island Sea Lab; US Department of Commerce's National Oceanic and Atmospheric Administration under NOAA [NA06OAR4170078 MASGC]; Mississippi-Alabama Sea Grant Consortium [R/CEH-28]; National Science Foundation at the Dauphin Island Sea Lab [OCE-0453973] FX This work was funded by the Dauphin Island Sea Lab, a grant from the National Sea Grant College Program of the US Department of Commerce's National Oceanic and Atmospheric Administration under NOAA Grant NA06OAR4170078 MASGC., the Mississippi-Alabama Sea Grant Consortium (project number R/CEH-28), and the National Science Foundation Research Experience for Undergraduates Program at the Dauphin Island Sea Lab (#OCE-0453973). Thanks to H. Patterson for sharing stable isotope data in SPM and oysters form control sites in Mobile Bay, K. Park and B. Dzwonkowski for guidance in locating and analyzing freshwater discharge data, and J. McCreadie and K. Park for comments on earlier versions of the paper, including statistical analyses. A. Aven, C. Pabody, N. Taylor, M. Ajamian, K. Robinson, L. Barnes, and G. Miller provided field and lab assistance. NR 40 TC 4 Z9 4 U1 4 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1559-2723 EI 1559-2731 J9 ESTUAR COAST JI Estuaries Coasts PD JAN PY 2012 VL 35 IS 1 BP 121 EP 131 DI 10.1007/s12237-011-9421-7 PG 11 WC Environmental Sciences; Marine & Freshwater Biology SC Environmental Sciences & Ecology; Marine & Freshwater Biology GA 898VW UT WOS:000300771500008 ER PT J AU Akiyama, T Khan, AA AF Akiyama, Tatsuya Khan, Ashraf A. TI Molecular characterization of strains of fluoroquinolone-resistant Salmonella enterica serovar Schwarzengrund carrying multidrug resistance isolated from imported foods SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE ciprofloxacin resistance; ramR; ramA; efflux pumps; CCCP ID MEDIATED QUINOLONE RESISTANCE; ESCHERICHIA-COLI; UNITED-STATES; SEROTYPE TYPHIMURIUM; MUTATIONS; RAMA; EXPRESSION; EFFLUX; SOXS; MUTANTS AB Objectives: To determine the fluoroquinolone resistance determinants in Salmonella enterica serovar Schwarzengrund from imported foods. Methods: Antibiotic susceptibility of Salmonella Schwarzengrund to 16 antibiotics was examined using disc agar diffusion and Etest. Quinolone resistance determinants were examined by sequence analysis of gyrA, gyrB, parC and parE, PCR amplification of qnrA, qnrB and qnrS, and expression of acrB, ramA, marA, soxS and rob using quantitative RT-PCR. The contribution of efflux pump activities to antibiotic resistance was determined by the addition of carbonyl cyanide m-chlorophenylhydrazone (CCCP). The effect of ramR deletion on ciprofloxacin resistance was determined by complementing with wild-type ramR. Results: Salmonella strains 30 and 487 were susceptible to ciprofloxacin and had a single mutation in gyrA as compared with strain 75, which was highly resistant to ciprofloxacin and had a double mutation in gyrA. Increased expression of ramA was associated with high resistance to ciprofloxacin. Strain 75 had a deletion of 315 bp in the ramR gene, which regulates ramA expression. Overexpression of ramA was possibly related to a loss of ramR. Introduction of ramR decreased the MIC of ciprofloxacin from 48 to 24 mg/L. The addition of CCCP did not reduce antibiotic resistance. To our knowledge, this study reports for the first time the natural deletion of ramR in Salmonella Schwarzengrund. Conclusions: This study indicates that fluoroquinolone-resistant Salmonella are prevalent in imported food. Double mutations in gyrA and a loss of ramR were associated with high-level quinolone resistance in multidrug-resistant Salmonella Schwarzengrund strain 75. C1 [Akiyama, Tatsuya; Khan, Ashraf A.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Khan, AA (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM ashraf.khan@fda.hhs.gov RI Khan, Ashraf/E-8133-2013 FU Postgraduate Research Program FX This work was supported in part by an appointment to the Postgraduate Research Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US FDA. NR 40 TC 13 Z9 15 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD JAN PY 2012 VL 67 IS 1 BP 101 EP 110 DI 10.1093/jac/dkr414 PG 10 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 899RL UT WOS:000300833700015 PM 22010209 ER PT J AU Volokhov, DV Simonyan, V Davidson, MK Chizhikov, VE AF Volokhov, Dmitriy V. Simonyan, Vahan Davidson, Maureen K. Chizhikov, Vladimir E. TI RNA polymerase beta subunit (rpoB) gene and the 16S-23S rRNA intergenic transcribed spacer region (ITS) as complementary molecular markers in addition to the 16S rRNA gene for phylogenetic analysis and identification of the species of the family Mycoplasmataceae SO MOLECULAR PHYLOGENETICS AND EVOLUTION LA English DT Article DE Mycoplasmas; Phylogeny; Bacteria; rpoB; 16S rRNA ID MOLLICUTES DIVISION TENERICUTES; PROPOSED MINIMAL STANDARDS; ET-AL. 1989; SEQUENCE-ANALYSIS; MYCOIDES CLUSTER; COMPARATIVE METABOLISM; RDNA SEQUENCES; DNA-SEQUENCES; COMB.-NOV; EPERYTHROZOON AB Conventional classification of the species in the family Mycoplasmataceae is mainly based on phenotypic criteria, which are complicated, can be difficult to measure, and have the potential to be hampered by phenotypic deviations among the isolates. The number of biochemical reactions suitable for phenotypic characterization of the Mycoplasmataceae is also very limited and therefore the strategy for the final identification of the Mycoplasmataceae species is based on comparative serological results. However, serological testing of the Mycoplasmataceae species requires a performance panel of hyperimmune sera which contains anti-serum to each known species of the family, a high level of technical expertise, and can only be properly performed by mycoplasma-reference laboratories. In addition, the existence of uncultivated and fastidious Mycoplasmataceae species/isolates in clinical materials significantly complicates, or even makes impossible, the application of conventional bacteriological tests. The analysis of available genetic markers is an additional approach for the primary identification and phylogenetic classification of cultivable species and uncultivable or fastidious organisms in standard microbiological laboratories. The partial nucleotide sequences of the RNA polymerase beta-subunit gene (rpoB) and the 16S-23S rRNA intergenic transcribed spacer (ITS) were determined for all known type strains and the available non-type strains of the Mycoplasmataceae species. In addition to the available 16S rRNA gene data, the ITS and rpoB sequences were used to infer phylogenetic relationships among these species and to enable identification of the Mycoplasmataceae isolates to the species level. The comparison of the ITS and rpoB phylogenetic trees with the 16S rRNA reference phylogenetic tree revealed a similar clustering patterns for the Mycoplasmataceae species, with minor discrepancies for a few species that demonstrated higher divergence of their ITS and rpoB in comparison to their neighbor species. Overall, our results demonstrated that the ITS and rpoB gene could be useful complementary phylogenetic markers to infer phylogenetic relationships among the Mycoplasmataceae species and provide useful background information for the choice of appropriate metabolic and serological tests for the final classification of isolates. In summary, three-target sequence analysis, which includes the ITS, rpoB, and 16S rRNA genes, was demonstrated to be a reliable and useful taxonomic tool for the species differentiation within the family Mycoplasmataceae based on their phylogenetic relatedness and pairwise sequence similarities. We believe that this approach might also become a valuable tool for routine analysis and primary identification of new isolates in medical and veterinary microbiological laboratories. Published by Elsevier Inc. C1 [Volokhov, Dmitriy V.] US FDA, Ctr Biol Evaluat & Res, Off Vaccine Res & Review, Div Viral Prod,Lab Methods Dev, Rockville, MD 20852 USA. [Davidson, Maureen K.] US FDA, Ctr Vet Med, Laurel, MD 20708 USA. RP Volokhov, DV (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Vaccine Res & Review, Div Viral Prod,Lab Methods Dev, 1401 Rockville Pike,HFM-470, Rockville, MD 20852 USA. EM dmitriy.volokhov@fda.hhs.gov NR 97 TC 15 Z9 17 U1 0 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1055-7903 J9 MOL PHYLOGENET EVOL JI Mol. Phylogenet. Evol. PD JAN PY 2012 VL 62 IS 1 BP 515 EP 528 DI 10.1016/j.ympev.2011.11.002 PG 14 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 902ED UT WOS:000301020500043 PM 22115576 ER PT J AU Ferguson, SA Ward, WL Paule, MG Hall, RW Anand, KJS AF Ferguson, Sherry A. Ward, Wendy L. Paule, Merle G. Hall, R. Whit Anand, K. J. S. TI A pilot study of preemptive morphine analgesia in preterm neonates: Effects on head circumference, social behavior, and response latencies in early childhood SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Prematurity; Morphine; Preemptive analgesia; Neuropsychology; Cognition; Delayed matching to sample ID LOW-BIRTH-WEIGHT; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; STANFORD-BINET SCORES; INTENSIVE-CARE UNITS; FOR-GESTATIONAL-AGE; PAIN MANAGEMENT; NEURODEVELOPMENTAL OUTCOMES; COGNITIVE PERFORMANCE; CONTROLLED-TRIAL; PROCEDURAL PAIN AB Use of preemptive analgesia in Neonatal Intensive Care Units is recommended for severe and/or invasive procedures. However, the potential long-term consequences of such analgesia, which may be prolonged, are only beginning to be studied. In this pilot study, a subset of subjects previously enrolled in the Neurological Outcomes and Preemptive Analgesia in Neonates (NEOPAIN) trial was assessed at early childhood. These expreterm infants (born at 23-32 weeks of gestational age) required intubation within 72 h postpartum and were randomized to receive either preemptive morphine analgesia (maximum of 14 days) or placebo within 8 h post-intubation. At 5-7 years of age, neuropsychological outcomes, morphometrics, adaptive behavior, parent-rated behavior, motivation, and short-term memory were measured. Although overall IQ and academic achievement did not differ between the morphine treated (n=14) and placebo (n=5) groups, preemptive morphine analgesia was associated with distinct differences in other outcome variables. Head circumference of morphine treated children was approximately 7% smaller (Cohen's d: 2.83, effect size large) and body weight was approximately 4% less (Cohen's d: 0.81, effect size large); however, height did not differ. In the short-term memory task (delayed matching to sample), morphine treated children exhibited significantly longer choice response latencies than placebo children (3.86 +/- 0.33 and 2.71 +/- 0.24 s, respectively) (p<0.03) and completed approximately 27% less of the task than placebo children (Cohen's d: 0.96, effect size large). Parents described morphine treated children as having more social problems, an effect specific to creating and maintaining friendships (Cohen's d: -0.83, effect size large). Despite the small sample size and the preliminary nature of this study, these results are strongly suggestive of long-lasting effects of preemptive morphine analgesia. A larger investigation with more comprehensive assessments of some of these key features will enable a more complete understanding of the relationship between preemptive morphine treatment and long-term neurocognitive, behavioral, and adaptive outcomes. Published by Elsevier Inc. C1 [Ferguson, Sherry A.; Paule, Merle G.] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. [Ferguson, Sherry A.; Ward, Wendy L.; Paule, Merle G.; Hall, R. Whit; Anand, K. J. S.] Arkansas Childrens Hosp, Dept Pediat, Little Rock, AR 72202 USA. [Hall, R. Whit] Univ Arkansas Med Sci, Div Neonatol, Little Rock, AR 72205 USA. [Anand, K. J. S.] Univ Tennessee, Hlth Sci Ctr, Le Bonheur Childrens Hosp, Dept Pediat,Div Crit Care Med, Memphis, TN USA. RP Ferguson, SA (reprint author), US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, HFT 132,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Sherry.Ferguson@fda.hhs.gov FU National Center for Toxicological Research/FDA [7243] FX The authors would like to express their sincere appreciation for the expert technical assistance of Ms. Kris Dudoich and Ms. Sabrina Maham and we are extremely grateful for the careful and detailed assistance of Ms. Andrea Sutton. Ms. Shari S. Kronsberg, M.S. was invaluable in accessing needed information from the original NEOPAIN study. We are appreciative of the expert administration of the neurocognitive assessments by Kelli Harford, Ph.D., Shari Gaudette, Ph.D. and, Julie Pettapiece Weston, Ph.D. We also acknowledge National Center for Research Resources 020146 (RWH). Portions of this study were supported by the National Center for Toxicological Research/FDA (Experiment # 7243) NR 68 TC 29 Z9 29 U1 4 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD JAN-FEB PY 2012 VL 34 IS 1 BP 47 EP 55 DI 10.1016/j.ntt.2011.10.008 PG 9 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 902KN UT WOS:000301037100006 PM 22094261 ER PT J AU Neese, SL Bandara, SB Doerge, DR Helferich, WG Komi, DL Schantz, SL AF Neese, Steven L. Bandara, Suren B. Doerge, Daniel R. Helferich, William G. Komi, Donna L. Schantz, Susan L. TI Effects of multiple daily genistein treatments on delayed alternation and a differential reinforcement of low rates of responding task in middle-aged rats SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Genistein; Phytoestrogens; Aging; Executive function; Prefrontal ID ESTROGEN-RECEPTOR-ALPHA; PRENATAL COCAINE EXPOSURE; SPRAGUE-DAWLEY RATS; OVARIECTOMIZED RATS; SPATIAL ALTERNATION; TISSUE DISTRIBUTION; INTERRESPONSE-TIME; SOY PHYTOESTROGENS; PREFRONTAL CORTEX; ADULT RATS AB The use of extracts that are highly enriched in phytoestrogens, such as genistein, has become popular to promote various aspects of healthy aging, including maintenance of cognitive function. These compounds are promoted to menopausal women as safe, natural alternatives to traditional estrogen therapies, yet their safety and efficacy are poorly understood. Previous research in our lab found that once daily oral treatment of ovariectomized female Long-Evans (LE) rats with the soy phytoestrogen, genistein resulted in subtle deficits in performance on cognitive tasks assessing working memory and response inhibition/timing ability. The present study further modeled exposure of the menopausal woman to genistein by treating 14-month old ovariectomized female LE rats three times daily at a dose of genistein resulting in serum concentrations similar to those that could be achieved in humans consuming either a commercially available soy isofiavone supplement or a diet high in these phytoestrogens. Genistein (3.4 mg/kg) or sucrose control pellets were orally administered to animals daily, 30 min before behavioral testing, and again both 4 and 8 h after the first treatment. The test battery consisted of a delayed spatial alternation task (DSA) that tested working memory and a differential reinforcement of low rates of responding (DRL) task that tested inhibitory control/timing. Genistein treatment impaired DSA performance relative to sucrose controls. Performance on the DRL task was largely unaffected by genistein treatment. Although the impairment measured on DSA was less pronounced than that we have previously reported following chronic treatment with 17 beta-estradiol, the pattern of the deficit was very similar to that observed with 17 beta-estradiol. (C) 2011 Elsevier Inc. All rights reserved. C1 [Neese, Steven L.; Bandara, Suren B.; Schantz, Susan L.] Univ Illinois, Dept Comparat Biosci, Urbana, IL 61802 USA. [Neese, Steven L.; Bandara, Suren B.; Komi, Donna L.; Schantz, Susan L.] Univ Illinois, Neurosci Program, Urbana, IL 61801 USA. [Doerge, Daniel R.] Univ Illinois, Dept Food Sci & Human Nutr, Urbana, IL 61801 USA. [Helferich, William G.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Komi, Donna L.] Univ Illinois, Dept Psychol, Champaign, IL 61820 USA. [Komi, Donna L.] Univ Illinois, Dept Vet Sci, Inst Genom Biol, Urbana, IL 61801 USA. RP Neese, SL (reprint author), Dept Comparat Biosci, 2001 S Lincoln Ave, Urbana, IL 61902 USA. EM stlneese@illinois.edu; surenb@illinois.edu; daniel.doerge@fda.hhs.org; helferich@illinois.edu; dkorol@illinois.edu; schantz@illinois.edu FU National Institute on Aging [P01 AG024387]; ODS [P50 AT006268]; NCAAM; NCI; NSF [IOB 0520876]; National Institute of Environmental Health Sciences [T32 ES007326] FX This research was supported by the National Institute on Aging Grants P01 AG024387 (SLS, WGH) and P50 AT006268 from ODS, NCAAM, and NCI (SLS, WGH). This research was also supported by NSF IOB 0520876 (DLK). Steven Neese also received support from the National Institute of Environmental Health Sciences Grant T32 ES007326. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. NR 74 TC 11 Z9 11 U1 1 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD JAN-FEB PY 2012 VL 34 IS 1 BP 187 EP 195 DI 10.1016/j.ntt.2011.09.002 PG 9 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 902KN UT WOS:000301037100022 PM 21945133 ER PT J AU Harvey, R Hamill, M Robertson, JS Minor, PD Vodeiko, GM Weir, JP Takahashi, H Harada, Y Itamura, S Bamford, P Dalla Pozza, T Engelhardt, OG AF Harvey, Ruth Hamill, Michelle Robertson, James S. Minor, Philip D. Vodeiko, Galina M. Weir, Jerry P. Takahashi, Hitoshi Harada, Yuichi Itamura, Shigeyuki Bamford, Pearl Dalla Pozza, Tania Engelhardt, Othmar G. TI Application of deglycosylation to SDS PAGE analysis improves calibration of influenza antigen standards SO BIOLOGICALS LA English DT Article DE Influenza; Vaccine; Standardisation; HA; Standards; Deglycosylation; Calibration ID HEMAGGLUTININ; VACCINES; VIRUSES AB Each year the production of seasonal influenza vaccines requires antigen standards to be available for the potency assessment of vaccine batches. These are calibrated and assigned a value for haemagglutinin (HA) content. The calibration of an antigen standard is carried out in a collaborative study amongst a small number of national regulatory laboratories which are designated by WHO as Essential Regulatory Laboratories (ERLs) for the purposes of influenza vaccine standardisation. The calibration involves two steps; first the determination of HA protein in a primary liquid standard by measurement of total protein in a purified influenza virus preparation followed by determination of the proportion of HA as determined by PAGE analysis of the sample; and second, the calibration of the freeze-dried reference antigen against the primary standard by single radial immunodiffusion (SRD) assay. Here we describe a collaborative study to assess the effect of adding a deglycosylation step prior to the SDS-PAGE analysis for the assessment of relative HA content. We found that while the final agreed HA value of the samples tested was not significantly different with or without deglycosylation, the deglycosylation step greatly improved between-laboratory agreement. (C) 2012 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved. C1 [Harvey, Ruth; Robertson, James S.; Minor, Philip D.; Engelhardt, Othmar G.] Hlth Protect Agcy, Natl Inst Biol Stand & Control, Div Virol, Potters Bar EN6 3QG, Herts, England. [Vodeiko, Galina M.; Weir, Jerry P.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Takahashi, Hitoshi; Harada, Yuichi; Itamura, Shigeyuki] Natl Inst Infect Dis, Ctr Influenza Virus Res, Musashimurayama, Tokyo 2080011, Japan. [Bamford, Pearl; Dalla Pozza, Tania] Therapeut Goods Adm, Woden, ACT 2606, Australia. RP Engelhardt, OG (reprint author), Hlth Protect Agcy, Natl Inst Biol Stand & Control, Div Virol, Blanche Lane, Potters Bar EN6 3QG, Herts, England. EM othmar.engelhardt@nibsc.hpa.org.uk FU MRC [G0600509] FX This work was funded in part by an MRC grant (number G0600509) awarded to Dr J.S. Robertson. We would like to thank Robert Newman for providing the panel of virus concentrates. NR 10 TC 7 Z9 7 U1 1 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1045-1056 J9 BIOLOGICALS JI Biologicals PD JAN PY 2012 VL 40 IS 1 BP 96 EP 99 DI 10.1016/j.biologicals.2011.12.009 PG 4 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 899HJ UT WOS:000300806700017 PM 22244521 ER PT J AU Thompson, KL Haskins, K Rosenzweig, BA Stewart, S Zhang, J Peters, D Knapton, A Rouse, R Mans, D Colatsky, T AF Thompson, Karol L. Haskins, Kylie Rosenzweig, Barry A. Stewart, Sharron Zhang, Jun Peters, David Knapton, Alan Rouse, Rodney Mans, Daniel Colatsky, Thomas TI Comparison of the Diagnostic Accuracy of Di-22:6-Bis(monoacylglycerol)Phosphate and Other Urinary Phospholipids for Drug-Induced Phospholipidosis or Tissue Injury in the Rat SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article DE phospholipidosis; phospholipids; urine; biomarker; Coralgil; gentamicin; cisplatin; simvastatin; di-22:6-BMP; phospholipiduria ID RENAL PAPILLARY NECROSIS; GENTAMICIN; LIPIDOSIS; KIDNEY; AMINOGLYCOSIDES; BIOMARKERS; MONITOR; DISEASE; LIVER AB Cationic amphiphilic drugs and aminoglycoside antibiotics can induce phospholipidosis (PLD), an abnormal accumulation of phospholipids in lysosome-derived vesicles, in preclinical studies. The incidence of PLD in patients and its clinical relevance are difficult to assess without noninvasive biomarkers. Di-docosahexaenoyl bis(monoacylglycerol)phosphate (di-22:6-BMP) is a phospholipid that is enriched in lysosomal membranes and a proposed urinary biomarker of drug-induced PLD. The specificity of di-22:6-BMP for PLD was compared to other phospholipid species that can increase in urine with nephrotoxicity. Using liquid chromatography coupled to mass spectrometry, 12 phospholipids were assayed in the urine of rats treated with drugs that induced PLD or caused renal or skeletal muscle injury. In receiver operating curve analyses, urinary di-22:6-BMP was a significantly better predictor of PLD and the least predictive of tissue injury of the phospholipids assayed. The data provide evidence supporting the use of di-22:6-BMP as a urinary biomarker of PLD in rats. C1 [Thompson, Karol L.; Haskins, Kylie; Rosenzweig, Barry A.; Stewart, Sharron; Zhang, Jun; Peters, David; Knapton, Alan; Rouse, Rodney; Colatsky, Thomas] US FDA, Ctr Drug Evaluat & Res, Div Drug Safety Res, Silver Spring, MD 20993 USA. [Mans, Daniel] US FDA, Div Pharmaceut Anal, St Louis, MO USA. RP Thompson, KL (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Drug Safety Res, 10903 New Hampshire Ave,Bldg 64,Room 2036, Silver Spring, MD 20993 USA. EM karol.thompson@fda.hhs.gov FU FDA Critical Path Initiative FX The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This project received funding from the FDA Critical Path Initiative. NR 32 TC 5 Z9 5 U1 0 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1091-5818 J9 INT J TOXICOL JI Int. J. Toxicol. PD JAN-FEB PY 2012 VL 31 IS 1 BP 14 EP 24 DI 10.1177/1091581811430167 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 895PP UT WOS:000300508900003 PM 22267869 ER PT J AU McClure, FD Lee, JK AF McClure, Foster D. Lee, Jung K. TI Variances and Uncertainties of the Sample Laboratory-to-Laboratory Variance (s(L)(2)) and Standard Deviation (s(L)) Associated with an Interlaboratory Study SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article AB The validation process for an analytical method usually employs an interlaboratory study conducted as a balanced completely randomized model involving a specified number of randomly chosen laboratories, each analyzing a specified number of randomly allocated replicates. For such studies, formulas to obtain approximate unbiased estimates of the variance and uncertainty of the sample laboratory-to-laboratory (lab-to-lab) STD (S-L) have been developed primarily to account for the uncertainty of S-L when there is a need to develop an uncertainty budget that includes the uncertainty of S-L. For the sake of completeness on this topic, formulas to estimate the variance and uncertainty of the sample lab-to-lab variance (s(L)(2)) were also developed. In some cases, it was necessary to derive the formulas based on an approximate distribution for s(L)(2). C1 [McClure, Foster D.; Lee, Jung K.] US FDA, Ctr Food Safety & Appl Nutr, Off Food Def Commun & Emergency Response, Div Publ Hlth & Biostat, College Pk, MD 20740 USA. RP McClure, FD (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Food Def Commun & Emergency Response, Div Publ Hlth & Biostat, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM fdmc5100@yahoo.com NR 5 TC 0 Z9 0 U1 1 U2 5 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 J9 J AOAC INT JI J. AOAC Int. PD JAN-FEB PY 2012 VL 95 IS 1 BP 244 EP 251 DI 10.5740/jaoacint.11-031 PG 8 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA 899FS UT WOS:000300802400033 PM 22468367 ER PT J AU De Pascalis, R Chou, AY Bosio, CM Huang, CY Follmann, DA Elkins, KL AF De Pascalis, Roberto Chou, Alicia Y. Bosio, Catharine M. Huang, Chiung-Yu Follmann, Dean A. Elkins, Karen L. TI Development of Functional and Molecular Correlates of Vaccine-Induced Protection for a Model Intracellular Pathogen, F. tularensis LVS SO PLOS PATHOGENS LA English DT Article ID VIRULENT TYPE-A; NECROSIS-FACTOR-ALPHA; T-CELL RESPONSES; FRANCISELLA-TULARENSIS; MYCOBACTERIUM-TUBERCULOSIS; AEROSOL CHALLENGE; INTERFERON-GAMMA; IMMUNOREACTIVE ANTIGENS; TULAREMIA VACCINES; MEMBRANE-PROTEIN AB In contrast with common human infections for which vaccine efficacy can be evaluated directly in field studies, alternative strategies are needed to evaluate efficacy for slowly developing or sporadic diseases like tularemia. For diseases such as these caused by intracellular bacteria, serological measures of antibodies are generally not predictive. Here, we used vaccines varying in efficacy to explore development of clinically useful correlates of protection for intracellular bacteria, using Francisella tularensis as an experimental model. F. tularensis is an intracellular bacterium classified as Category A bioterrorism agent which causes tularemia. The primary vaccine candidate in the U. S., called Live Vaccine Strain (LVS), has been the subject of ongoing clinical studies; however, safety and efficacy are not well established, and LVS is not licensed by the U. S. FDA. Using a mouse model, we compared the in vivo efficacy of a panel of qualitatively different Francisella vaccine candidates, the in vitro functional activity of immune lymphocytes derived from vaccinated mice, and relative gene expression in immune lymphocytes. Integrated analyses showed that the hierarchy of protection in vivo engendered by qualitatively different vaccines was reflected by the degree of lymphocytes' in vitro activity in controlling the intramacrophage growth of Francisella. Thus, this assay may be a functional correlate. Further, the strength of protection was significantly related to the degree of up-regulation of expression of a panel of genes in cells recovered from the assay. These included IFN-gamma, IL-6, IL-12R beta 2, T-bet, SOCS-1, and IL-18bp. Taken together, the results indicate that an in vitro assay that detects control of bacterial growth, and/or a selected panel of mediators, may ultimately be developed to predict the outcome of vaccine efficacy and to complement clinical trials. The overall approach may be applicable to intracellular pathogens in general. C1 [De Pascalis, Roberto; Chou, Alicia Y.; Elkins, Karen L.] US FDA, Lab Mycobacterial Dis & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Bosio, Catharine M.] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Huang, Chiung-Yu; Follmann, Dean A.] NIAID, Biostat Res Branch, Div Clin Res, NIH, Hamilton, MT USA. RP De Pascalis, R (reprint author), US FDA, Lab Mycobacterial Dis & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. EM karen.elkins@fda.hhs.gov RI Bosio, Catharine/D-7456-2015 FU National Institute of Allergy and Infectious Diseases [Y1-AI-6153-01/224-06-1322] FX This work was supported in part by an interagency agreement with the National Institute of Allergy and Infectious Diseases (Y1-AI-6153-01/224-06-1322). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 19 Z9 19 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD JAN PY 2012 VL 8 IS 1 AR e1002494 DI 10.1371/journal.ppat.1002494 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 898UI UT WOS:000300767100037 PM 22275868 ER PT J AU Doucette, GJ Mikulski, CM King, KL Roth, PB Wang, ZH Leandro, LF DeGrasse, SL White, KD De Biase, D Gillett, RM Rolland, RM AF Doucette, Gregory J. Mikulski, Christina M. King, Kristen L. Roth, Patricia B. Wang, Zhihong Leandro, Luis F. DeGrasse, Stacey L. White, Kevin D. De Biase, Daniela Gillett, Roxanne M. Rolland, Rosalind M. TI Endangered North Atlantic right whales (Eubalaena glacialis) experience repeated, concurrent exposure to multiple environmental neurotoxins produced by marine algae SO ENVIRONMENTAL RESEARCH LA English DT Article DE Domoic acid; Eubalaena glacialis; Harmful algal blooms; Paralytic shellfish toxins; Reproductive failure; Saxitoxin ID LIONS ZALOPHUS-CALIFORNIANUS; FREE-FLOATING FECES; DOMOIC ACID; SEA LIONS; EASTERN CANADA; FUNDY; BAY; HEALTH; TOXICITY; TOXINS AB The western North Atlantic population of right whales (Eubalaena glacialis) is one of the most critically endangered of any whale population in the world. Among the factors considered to have potentially adverse effects on the health and reproduction of E. glacialis are biotoxins produced by certain microalgae responsible for causing harmful algal blooms. The worldwide incidence of these events has continued to increase dramatically over the past several decades and is expected to remain problematic under predicted climate change scenarios. Previous investigations have demonstrated that N. Atlantic right whales are being exposed to at least two classes of algal-produced environmental neurotoxins-paralytic shellfish toxins (PSTs) and domoic acid (DA). Our primary aims during this six-year study (2001-2006) were to assess whether the whales' exposure to these algal biotoxins occurred annually over multiple years, and to what extent individual whales were exposed repeatedly and/or concurrently to one or both toxin classes. Approximately 140 right whale fecal samples obtained across multiple habitats in the western N. Atlantic were analyzed for PSTs and DA. About 40% of these samples were attributed to individual whales in the North Atlantic Right Whale Catalog, permitting analysis of biotoxin exposure according to sex, age class, and reproductive status/history. Our findings demonstrate clearly that right whales are being exposed to both of these algal biotoxins on virtually an annual basis in multiple habitats for periods of up to six months (April through September), with similar exposure rates for females and males (PSTs: similar to 70-80%; DA: similar to 25-30%). Notably, only one of 14 lactating females sampled did not contain either PSTs or DA, suggesting the potential for maternal toxin transfer and possible effects on neonatal animals. Moreover, 22% of the fecal samples tested for PSTs and DA showed concurrent exposure to both neurotoxins, leading to questions of interactive effects. Targeted studies employing both in vivo and in vitro model systems represent the next logical step in assessing how and to what extent these algal biotoxins might compromise the health and reproduction of this endangered population. Published by Elsevier Inc. C1 [Doucette, Gregory J.; Mikulski, Christina M.; King, Kristen L.; Wang, Zhihong; Leandro, Luis F.] NOAA Natl Ocean Serv, Marine Biotoxins Program, Charleston, SC 29412 USA. [Roth, Patricia B.] Coll Charleston, Grice Marine Lab, Charleston, SC 29412 USA. [DeGrasse, Stacey L.; White, Kevin D.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [De Biase, Daniela] Sapienza Univ Roma, Ist Pasteur, Fdn Cenci Bolognetti, Dipartimento Sci Biotecnol Med Chirurg, I-04100 Latina, Italy. [Gillett, Roxanne M.] Trent Univ, Nat Resources DNA Profiling & Forens Ctr, Dept Biol, Peterborough, ON K9J 7B8, Canada. [Rolland, Rosalind M.] New England Aquarium, Res Dept, Boston, MA 02110 USA. RP Doucette, GJ (reprint author), NOAA Natl Ocean Serv, Marine Biotoxins Program, Charleston, SC 29412 USA. EM greg.doucette@noaa.gov RI Doucette, Gregory/M-3283-2013; OI DeGrasse, Stacey/0000-0001-7808-4193; De Biase, Daniela/0000-0003-3536-9927 FU NOAA/NMFS [50-EANF-0-00047, EA133F-02-SE-0155, DG133F-04-CN-0056]; Northeast Consortium [02-557]; Morris Animal Foundation; Island Foundation; International Fund for Animal Welfare; Bernice Barbour Foundation; NOAA/NOS FX Funding for the collection, processing and analysis of samples, and analysis of the resulting data was provided in part by grants to R.M.R. from NOAA/NMFS (#s 50-EANF-0-00047, EA133F-02-SE-0155, DG133F-04-CN-0056), Northeast Consortium (02-557), Morris Animal Foundation, Island Foundation, International Fund for Animal Welfare, and Bernice Barbour Foundation, and in part by NOAA/NOS operational funds to G.J.D. NR 58 TC 15 Z9 15 U1 3 U2 63 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 J9 ENVIRON RES JI Environ. Res. PD JAN PY 2012 VL 112 BP 67 EP 76 DI 10.1016/j.envres.2011.09.010 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 885TX UT WOS:000299804800008 PM 22018895 ER PT J AU Wilmoth, DR AF Wilmoth, Daniel R. TI Intelligence and past use of recreational drugs SO INTELLIGENCE LA English DT Article DE Intelligence; Alcohol; Drugs ID COGNITIVE-ABILITY; CAUSAL INFERENCE; CHILDHOOD; HEALTH; SMOKING; STATISTICS; ADULTHOOD; BEHAVIOR; DELAY; SELF AB One motivation for trying recreational drugs is the desire for novel experiences. More intelligent people tend to value novelty more highly and may therefore be more likely to have tried recreational drugs. Using data from a national survey, it is shown that intelligence tends to be positively related to the probabilities of having tried alcohol, marijuana, cocaine and several other recreational drugs. Evidence is also presented that those relationships typically disappear or change sign at high levels of intelligence. These patterns persist after accounting for a wide range of personal characteristics. Published by Elsevier Inc. C1 [Wilmoth, Daniel R.] Cornell Univ, Dept Econ, Ithaca, NY 14853 USA. RP Wilmoth, DR (reprint author), US FDA, 10903 New Hampshire Ave,WO 32-3261, Silver Spring, MD 20993 USA. EM daniel.wilmoth@fda.hhs.gov NR 44 TC 3 Z9 3 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0160-2896 J9 INTELLIGENCE JI Intelligence PD JAN-FEB PY 2012 VL 40 IS 1 BP 15 EP 22 DI 10.1016/j.intell.2011.10.005 PG 8 WC Psychology, Multidisciplinary SC Psychology GA 891FF UT WOS:000300201900002 ER PT J AU Wang, F Jiang, L Ge, BL AF Wang, Fei Jiang, Lin Ge, Beilei TI Loop-Mediated Isothermal Amplification Assays for Detecting Shiga Toxin-Producing Escherichia coli in Ground Beef and Human Stools SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; RAPID DETECTION; VIBRIO-VULNIFICUS; VIRULENCE FACTORS; UNITED-STATES; RAW OYSTERS; GENES; LAMP; INFECTION; STRAINS AB Shiga toxin-producing Escherichia coli (STEC), encompassing E. coli O157 and non-O157 STEC, is a significant cause of food-borne illnesses and deaths in the United States and worldwide. Shiga toxins (encoded by stx) and intimin (encoded by eae) are important virulence factors for STEC strains linked to severe human illnesses such as hemorrhagic colitis and hemolytic-uremic syndrome. In this study, the stx(1), stx(2), and eae genes were chosen as targets to design loop-mediated isothermal amplification (LAMP) assays for the rapid, specific, sensitive, and quantitative detection of STEC strains. The assay performances in pure culture and spiked ground beef and human stools were evaluated and compared with those of quantitative PCR (qPCR). No false-positive or false-negative results were observed among 90 bacterial strains used to evaluate assay specificity. The limits of detection for seven STEC strains of various serogroups (O26, O45, O103, O111, O121, O145, and O157) were approximately 1 to 20 CFU/reaction in pure culture and 10(3) to 10(4) CFU/g in spiked ground beef, which were comparable to the results of qPCR. Standard curves generated suggested good linear relationships between STEC cell numbers and LAMP turbidity signals. When applied in ground beef samples spiked with two low levels (1 to 2 and 10 to 20 CFU/25 g) of STEC cultures, the LAMP assays achieved accurate detection after 6 to 8 h enrichment. The assays also consistently detected STEC in human stool specimens spiked with 10(3) or 10(4) CFU/0.5 g stool after 4 h enrichment, while qPCR required 4 to 6 h. In conclusion, the LAMP assays developed in this study may facilitate rapid and reliable identification of STEC contaminations in high-risk food commodities and also facilitate prompt diagnosis of STEC infections in clinical laboratories. C1 [Wang, Fei; Jiang, Lin; Ge, Beilei] Louisiana State Univ, Ctr Agr, Dept Food Sci, Baton Rouge, LA 70803 USA. RP Ge, BL (reprint author), US FDA, Div Anim & Food Microbiol, Off Res Ctr Vet Med, Laurel, MD USA. EM beilei.ge@fda.hhs.gov RI Wang, Fei/J-4353-2014 NR 47 TC 38 Z9 41 U1 1 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JAN PY 2012 VL 50 IS 1 BP 91 EP 97 DI 10.1128/JCM.05612-11 PG 7 WC Microbiology SC Microbiology GA 888IH UT WOS:000299996600018 PM 22031701 ER PT J AU Kawabata, T Weaver, J Thomas, D Rowe, M Wang, F Kamperschroer, C Haggerty, H AF Kawabata, Thomas Weaver, James Thomas, Dolca Rowe, Martin Wang, Fred Kamperschroer, Cris Haggerty, Helen TI Summary of roundtable discussion meeting: Non-human primates to assess risk for EBV-related lymphomas in humans SO JOURNAL OF IMMUNOTOXICOLOGY LA English DT Article DE Immunotoxicology; immunotoxicity; Epstein-Barr virus; non-human primates; monkey; lymphoma ID EPSTEIN-BARR-VIRUS; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER; T-CELL RESPONSE; VIRAL LOAD; TRANSPLANT RECIPIENTS; RHEUMATOID-ARTHRITIS; RHESUS LYMPHOCRYPTOVIRUS; CYNOMOLGUS MONKEYS; GAMMA-HERPESVIRUS; IMMUNE EVASION AB Epstein-Barr virus (EBV)-associated lymphomas are a known risk for immunosuppressed individuals. Non-clinical methods to determine the potential of new immunomodulatory compounds to produce EBV-associated lymphomas (hazard identification) have not been developed. Since lymphocryptovirus (LCV) in non-human primates (NHP) has similar characteristics to EBV in humans, a Roundtable meeting was held in October 2010 to explore how the potential for EBV-related lymphomas in humans can be assessed by using surrogate biomarkers for lymphoma risk in NHP toxicity studies. Stakeholders from regulatory agencies, academia, and industry came together to determine the research gaps and potential benefits and considerations of such an approach given the current state-of-the-science. Key conclusions from the discussion included considerations raised about the potential usefulness of LCV-related biomarkers from NHP studies since there is significant controversy over the reliability of using EBV viral load or EBV-specific T-lymphocytes to predict for lymphoproliferative disorders in transplant patients. In addition, there are technical challenges that need to be further addressed in order to develop methods to measure LCV viral load and LCV-specific T-lymphocytes from cynomolgus monkeys. C1 [Kawabata, Thomas; Kamperschroer, Cris] Pfizer Inc, Drug Safety R&D, Groton, CT 06340 USA. [Weaver, James] US FDA, Div Drug Safety Res, Ctr Drug Evaluat, Silver Spring, MD USA. [Thomas, Dolca] Bristol Myers Squibb Co, Global Clin Res, Princeton, NJ USA. [Rowe, Martin] Univ Birmingham, Coll Med & Dent Sci, Birmingham, W Midlands, England. [Wang, Fred] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Infect Dis, Boston, MA 02115 USA. [Haggerty, Helen] Bristol Myers Squibb Co, Drug Safety Evaluat, New Brunswick, NJ USA. RP Kawabata, T (reprint author), Pfizer Inc, Drug Safety R&D, MS 8274-1206, Groton, CT 06340 USA. EM thomas.t.kawabata@pfizer.com RI Rowe, Martin/B-2880-2009 OI Rowe, Martin/0000-0003-4139-7326 FU HESI; National Institutes of Health [DE14388, DE18926, CA68051, CA89172] FX Funding for this Roundtable was provided by HESI. Research funding for Dr Fred Wang's work is provided by the National Institutes of Health including grant numbers DE14388, DE18926, CA68051, and CA89172. NR 25 TC 5 Z9 5 U1 0 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1547-691X J9 J IMMUNOTOXICOL JI J. Immunotoxicol. PD JAN-MAR PY 2012 VL 9 IS 1 BP 121 EP 127 DI 10.3109/1547691X.2011.635166 PG 7 WC Toxicology SC Toxicology GA 887CF UT WOS:000299902300013 PM 22136193 ER PT J AU Singh, P Foley, SL Nayak, R Kwon, YM AF Singh, Pallavi Foley, Steven L. Nayak, Rajesh Kwon, Young Min TI Multilocus sequence typing of Salmonella strains by high-throughput sequencing of selectively amplified target genes SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE Multiplex amplification; Next generation sequencing; PCR; Salmonella; Strain typing ID FIELD GEL-ELECTROPHORESIS; MULTIPLEX AMPLIFICATION; ENTERICA SEROVARS; PCR; MICROORGANISMS AB Rapid development of next generation sequencing (NGS) technologies in recent years has made whole genome sequencing of bacterial genomes widely accessible. However, it is often unnecessary or not feasible to sequence the whole genome for most applications of genetic analyses in bacteria. Selectively capturing defined genomic regions followed by NGS analysis could be a promising approach for high-resolution molecular typing of a large set of strains. In this study, we describe a novel and straightforward PCR-based target-capturing method, hairpin-primed multiplex amplification (HPMA), which allows for simultaneous amplification of numerous target genes. To test the feasibility of NGS-based strain typing using HPMA, 20 target gene sequences were simultaneously amplified with barcode tagging in each of 41 Salmonella strains. The amplicons were then pooled and analyzed by 454 pyrosequencing. Analysis of the sequence data, as an extension of multilocus sequence typing (MIST), demonstrated the utility and potential of this novel typing method. MLST-seq, as a high-resolution strain typing method. With the rapidly increasing sequencing capacity of NGS, MLST-seq or its variations using different target enrichment methods can be expected to become a high-resolution typing method in the near future for high-throughput analysis of a large collection of bacterial strains. (C) 2011 Elsevier B.V. All rights reserved. C1 [Kwon, Young Min] Univ Arkansas, Dept Poultry Sci, Fayetteville, AR 72701 USA. [Singh, Pallavi; Kwon, Young Min] Univ Arkansas, Cell & Mol Biol Program, Fayetteville, AR 72701 USA. [Foley, Steven L.; Nayak, Rajesh] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Kwon, YM (reprint author), Univ Arkansas, Dept Poultry Sci, Fayetteville, AR 72701 USA. EM ykwon@uark.edu OI Singh, Pallavi/0000-0002-0283-7459 FU USDA Food Safety Consortium FX This project has been funded by the USDA Food Safety Consortium grant. NR 23 TC 11 Z9 11 U1 0 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 J9 J MICROBIOL METH JI J. Microbiol. Methods PD JAN PY 2012 VL 88 IS 1 BP 127 EP 133 DI 10.1016/j.mimet.2011.11.004 PG 7 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 888BA UT WOS:000299977600020 PM 22108494 ER PT J AU Sweet, MP Fillinger, MF Morrison, TM Abel, D AF Sweet, Matthew P. Fillinger, Mark F. Morrison, Tina M. Abel, Dorothy TI The influence of gender and aortic aneurysm size on eligibility for endovascular abdominal aortic aneurysm repair (vol 54, pg 931, 2011) SO JOURNAL OF VASCULAR SURGERY LA English DT Correction C1 [Sweet, Matthew P.; Fillinger, Mark F.] Dartmouth Hitchcock Med Ctr, Vasc Surg Sect, Lebanon, NH 03766 USA. [Morrison, Tina M.; Abel, Dorothy] US FDA, Rockville, MD 20857 USA. RP Sweet, MP (reprint author), Dartmouth Hitchcock Med Ctr, Vasc Surg Sect, Lebanon, NH 03766 USA. NR 1 TC 2 Z9 2 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JAN PY 2012 VL 55 IS 1 BP 310 EP 310 PG 1 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 871YF UT WOS:000298772900048 ER PT J AU Zhang, J Hanig, JP De Felice, AF AF Zhang, Jun Hanig, Joseph P. De Felice, Albert F. TI Biomarkers of endothelial cell activation: Candidate markers for drug-induced vasculitis in patients or drug-induced vascular injury in animals SO VASCULAR PHARMACOLOGY LA English DT Review DE ANCA-associated small vessel vasculitis; Drug-induced vasculitis; Endothelial cell activation; Endothelial biomarkers ID SOLUBLE ADHESION MOLECULES; TUMOR-NECROSIS-FACTOR; ANCA-ASSOCIATED VASCULITIS; SMALL-VESSEL VASCULITIS; VON-WILLEBRAND-FACTOR; C-REACTIVE PROTEIN; SYSTEMIC LUPUS-ERYTHEMATOSUS; SPRAGUE-DAWLEY RATS; ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODIES; ANTIBODY-ASSOCIATED VASCULITIS AB There is a pressing need for vascular biomarkers for studies of drug-induced vasculitis in patients and drug-induced vascular injury (DIVI) in animals. We previously reviewed a variety of candidate biomarkers of endothelial cell (EC) activation (Zhang et al., 2010). Now we update information on EC activation biomarkers from animal data on DIVI and clinical data of vasculitic patients, particularly patients with primary antineutrophil cytoplasmic autoantibody (ANCA)-associated small vessel vasculitis (primary AAVs), including Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and necrotizing crescentic glomerulonephritis. Drug-associated ANCA-positive small vessel vasculitis (drug-AAVs) can closely resemble primary AAVs, suggesting the large overlap between primary idiopathic systemic vasculitis and drug-induced vasculitis. AAVs in patients and DIVI in animals vary considerably; however, there is close resemblance between AAVs and DIVI in some respects: (1) the immunopathogenetic mechanisms (activation of primed neutrophils, ECs and T cells by ANCA in patients and activation of ECs, mast cells, and macrophages by drugs in animals); (2) the morphologic changes (fibrinoid necrosis of the vessel wall and neutrophilic infiltration); (3) the preferable sites (small arteries, arterioles, capillaries and venules); and (4) elevation of vascular biomarkers suggestive of an endothelial origin. The present review discusses soluble and cell component biomarkers and provides a rationale for the potential utility of EC activation biomarkers in nonclinical and clinical studies during new drug development. Further investigation, however, is needed to assess their potential utility. Published by Elsevier Inc. C1 [Zhang, Jun] US FDA, Div Drug Safety Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Hanig, Joseph P.] US FDA, Off Testing & Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [De Felice, Albert F.] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Zhang, J (reprint author), US FDA, Div Drug Safety Res, Ctr Drug Evaluat & Res, HFD-910,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jun.zhang@fda.hhs.gov FU The Office of Testing and Research, CDER, FDA FX This work was supported by The Office of Testing and Research, CDER, FDA. The authors thank Drs. Vilker Vincent and Thomas Colastky (CDER, FDA) for critical review of this manuscript. NR 143 TC 9 Z9 11 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1537-1891 J9 VASC PHARMACOL JI Vasc. Pharmacol. PD JAN-FEB PY 2012 VL 56 IS 1-2 BP 14 EP 25 DI 10.1016/j.vph.2011.09.002 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 890BZ UT WOS:000300121400003 PM 21968053 ER PT J AU Godar, DE Pope, SJ Grant, WB Holick, MF AF Godar, Dianne Eyvonn Pope, Stanley James Grant, William Burgess Holick, Michael Francis TI Solar UV Doses of Young Americans and Vitamin D-3 Production SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE cancer; environment; sunlight; sunscreen; vitamin D ID 25-HYDROXYVITAMIN D LEVELS; SUN EXPOSURE; SERUM 25-HYDROXYVITAMIN-D; HUMAN-SKIN; IN-VITRO; CIRCULATING CONCENTRATIONS; CONVERSION FACTORS; D DEFICIENCY; MELANOMA; CHILDREN AB BACKGROUND: Sunlight contains ultraviolet B (UVB) radiation (290-315 nm) that affects human health in both detrimental (skin cancers) and beneficial (vitamin D-3) ways. Serum 25-hydroxy-vitamin D concentrations from young Americans (<= 19 years) show that many have deficient (< 50 nmol/L, 20 ng/mL) or insufficient (< 75 nmol/L, 30 ng/mL) vitamin D levels, indicating that they are not getting enough sun exposure. Those findings are in conflict with some calculated, published values that suggest people make "ample" vitamin D-3 (similar to 1,000 IU/day) from their "casual," or everyday, outdoor exposures even if they diligently use sunscreens with sun protection factor (SPF) 15. OBJECTIVE: We estimated how much vitamin D-3 young Americans (n = similar to 2,000) produce from their everyday outdoor ultraviolet doses in the North (45 degrees N) and South (35 degrees N) each season of the year with and without vacationing. METHODS: For these vitamin D-3 calculations, we used geometric conversion factors that change planar to whole-body doses, which previous calculations did not incorporate. RESULTS: Our estimates suggest that American children may not be getting adequate outdoor UVB exposures to satisfy their vitamin D-3 needs all year, except some Caucasians during the summer if they do not diligently wear sunscreens except during beach vacations. CONCLUSION: These estimates suggest that most American children may not be going outside enough to meet their minimal (similar to 600 IU/day) or optimal (>= 1,200 IU/day) vitamin D requirements. C1 [Godar, Dianne Eyvonn] US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. [Pope, Stanley James] Sun Syst & Serv Inc, Oak Pk, MI USA. [Grant, William Burgess] Sunlight Nutr & Hlth Res Ctr, San Francisco, CA USA. [Holick, Michael Francis] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Godar, DE (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,HFZ 120, Silver Spring, MD 20993 USA. EM Dianne.Godar@FDA.HHS.GOV RI Grant, William/B-8311-2009; Osborne, Nicholas/N-4915-2015; OI Grant, William/0000-0002-1439-3285; Osborne, Nicholas/0000-0002-6700-2284; Holick, Michael/0000-0001-6023-9062; GODAR, DIANNE/0000-0002-7690-5223 FU UV Foundation (McLean, VA, USA); Sunlight Research Forum (Veldhoven, Netherlands); Bio-Tech-Pharmacal (Fayetteville, AR, USA); Vitamin D Council (San Lois Obispo, CA, USA); Danish Sunbed Federation (Middelfart, Denmark); UV Foundation (McClean, VA, USA) FX W.B.G. receives funding from the UV Foundation (McLean, VA, USA), the Sunlight Research Forum (Veldhoven, Netherlands), Bio-Tech-Pharmacal (Fayetteville, AR, USA), the Vitamin D Council (San Lois Obispo, CA, USA), and the Danish Sunbed Federation (Middelfart, Denmark). M.F.H. receives funding from the UV Foundation (McClean, VA, USA). The other authors declare they have no actual or potential competing financial interests. NR 57 TC 16 Z9 17 U1 0 U2 17 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JAN PY 2012 VL 120 IS 1 BP 139 EP 143 DI 10.1289/ehp.1003195 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 883RC UT WOS:000299650400038 PM 21852226 ER PT J AU Cheeseman, MA AF Cheeseman, Mitchell A. TI Artificial Food Color Additives and Child Behavior SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID FEINGOLD HYPOTHESIS; HYPERACTIVITY; HYPERKINESIS C1 US FDA, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Cheeseman, MA (reprint author), US FDA, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM mitchell.cheeseman@fda.hhs.gov NR 12 TC 4 Z9 4 U1 5 U2 26 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JAN PY 2012 VL 120 IS 1 BP A15 EP A16 DI 10.1289/ehp.1104409 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 883RC UT WOS:000299650400006 PM 22214569 ER PT J AU Archer, DL AF Archer, Douglas L. TI Letter to the Editor: Inactivating SEA SO JOURNAL OF FOOD SCIENCE LA English DT Letter C1 [Archer, Douglas L.] UF IFAS, Gainesville, FL 32611 USA. [Archer, Douglas L.] Florida Agr Expt Stn, Gainesville, FL USA. [Archer, Douglas L.] US FDA, Div Microbiol, CFSAN, Rockville, MD 20857 USA. RP Archer, DL (reprint author), UF IFAS, Gainesville, FL 32611 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-1147 J9 J FOOD SCI JI J. Food Sci. PD JAN PY 2012 VL 77 IS 1 BP IX EP IX DI 10.1111/j.1750-3841.2011.02568_1.x PG 1 WC Food Science & Technology SC Food Science & Technology GA 878KX UT WOS:000299257000002 ER PT J AU Nice, FJ Luo, AC AF Nice, Frank J. Luo, Amy C. TI Medications and breast-feeding: Current concepts SO JOURNAL OF THE AMERICAN PHARMACISTS ASSOCIATION LA English DT Article DE Breast-feeding; pharmacists; medications; counseling (patient); pharmacokinetics; nursing; women's health; lactation ID ACTIVE-TRANSPORT; HUMAN-MILK; LACTATION; INFANTS; CIMETIDINE; EXCRETION; NICOTINE; ALCOHOL; SMOKING; MOTHERS AB Objectives: To describe the various factors that come into play when a breast-feeding mother is taking medications, including use of prescription drugs, over-the-counter medications, recreational drugs, galactogogues, and herbal remedies and to provide a framework used for counseling breast-feeding women. Setting: Community and hospital pharmacy and health care settings. Practice description: Consultative services provided to breast-feeding mothers who had been prescribed or were using medications. Main outcome measures: Use of pharmacokinetic factors, maternal and child factors, a list of questions to ask breast-feeding mothers, and a stepwise approach to counsel breast-feeding mothers on the compatibility of using medications while breast-feeding. Results: By positive intervention of pharmacists and health care providers, up to 1 million breast-feeding mothers, who must use medications, can continue to breast-feed while taking medications. Conclusion: Objectively weighing the benefits of drugs and breast-feeding versus the risks of drugs and not breast-feeding, in most cases, allows for pharmacists to give current and practical advice to mothers and other health professionals who counsel mothers. C1 [Nice, Frank J.] US FDA, Rockville, MD 20857 USA. [Luo, Amy C.] Rutgers State Univ, Sch Pharm, New Brunswick, NJ 08903 USA. RP Nice, FJ (reprint author), 7409 Algona Ct, Derwood, MD 20855 USA. EM frank.nice@fda.hhs.gov NR 29 TC 13 Z9 14 U1 0 U2 7 PU AMER PHARMACEUTICAL ASSOC PI WASHINGTON PA 2215 CONSTITUTION AVE NW, WASHINGTON, DC 20037 USA SN 1544-3191 J9 J AM PHARM ASSOC JI J. Am. Pharm. Assoc. PD JAN-FEB PY 2012 VL 52 IS 1 BP 86 EP 94 DI 10.1331/JAPhA.2012.10139 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 881WV UT WOS:000299523100013 PM 22257621 ER PT J AU Shaikh, B Rummel, N Gieseker, C Cheely, CS Reimschuessel, R AF Shaikh, Badar Rummel, Nathan Gieseker, Charles Cheely, Christie-Sue Reimschuessel, Renate TI Residue Depletion of Tritium-Labeled Ivermectin in the Muscle Tissues of Aquacultured Atlantic Salmon, Tilapia, and Catfish following Oral Treatment SO NORTH AMERICAN JOURNAL OF AQUACULTURE LA English DT Article ID GATED CHLORIDE CHANNELS; ANTI-PARASITIC AGENT; RAINBOW-TROUT; SALAR; POTENT AB The residue depletion and metabolism profiles of tritium-labeled ivermectin in the muscle tissues of aquacultured Atlantic salmon Salmo salar, hybrid tilapia (Nile tilapia Oreochromis niloticus x Mozambique tilapia O. mossambicus; hereafter, " tilapia") and channel catfish Ictalurus punctatus following oral treatment are reported. Fish were administered H-3-ivermectin at the dose level of 0.1 mg/kg of body weight (9-10 mu curies [Ci]) in a gel capsule via a stomach tube. At each postdose withdrawal time (1, 7, 14, 21, and 28 d), six fish of each species were sedated, euthanized, bled, and scaled, and fillets with adhering skin (except for catfish) were collected. The muscle fillets were homogenized in dry ice and an aliquot of each was extracted in acetonitrile followed by a high-performance liquid chromatographic analysis to determine the presence of parent ivermectin and its potential metabolites. The analysis of the muscle extracts revealed that the parent 3H-ivermectin is the major residue present for the three fish species studied. The results showed that the highest radioactive residue concentrations (ivermectin equivalents) of 21 and 6 ng/g were obtained on postdose day 1 for channel catfish and tilapia, respectively. For Atlantic salmon, the highest concentration of 14 ng/g was detected on day 7. By postdose day 21, the ivermectin radioactive residue depleted to less than 10 ng/g for all three species. No significant radioactive residue concentrations of metabolites were detected on any of the sampling days. These results suggest that parent ivermectin could serve as a marker residue to monitor its unauthorized use in Atlantic salmon, tilapia, and channel catfish. C1 [Shaikh, Badar; Rummel, Nathan; Gieseker, Charles; Cheely, Christie-Sue; Reimschuessel, Renate] US FDA, Ctr Vet Med, Res Off, Laurel, MD 20708 USA. RP Shaikh, B (reprint author), US FDA, Ctr Vet Med, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM badaruddin.shaikh@fda.hhs.gov NR 24 TC 1 Z9 3 U1 0 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1522-2055 J9 N AM J AQUACULT JI N. Am. J. Aqualcult. PY 2012 VL 74 IS 1 BP 27 EP 33 DI 10.1080/15222055.2011.638417 PG 7 WC Fisheries SC Fisheries GA 881SV UT WOS:000299510000004 ER PT J AU Platt, R Carnahan, RM Brown, JS Chrischilles, E Curtis, LH Hennessy, S Nelson, JC Racoosin, JA Robb, M Schneeweiss, S Toh, S Weiner, MG AF Platt, Richard Carnahan, Ryan M. Brown, Jeffrey S. Chrischilles, Elizabeth Curtis, Lesley H. Hennessy, Sean Nelson, Jennifer C. Racoosin, Judith A. Robb, Melissa Schneeweiss, Sebastian Toh, Sengwee Weiner, Mark G. TI The U.S. Food and Drug Administration's Mini-Sentinel program: status and direction SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE Mini-Sentinel; FDA; U; S; Food and Drug Administration; Sentinel Initiative; FDA Amendments Act of 2007 AB The Mini-Sentinel is a pilot program that is developing methods, tools, resources, policies, and procedures to facilitate the use of routinely collected electronic healthcare data to perform active surveillance of the safety of marketed medical products, including drugs, biologics, and medical devices. The U.S. Food and Drug Administration (FDA) initiated the program in 2009 as part of its Sentinel Initiative, in response to a Congressional mandate in the FDA Amendments Act of 2007. After two years, Mini-Sentinel includes 31 academic and private organizations. It has developed policies, procedures, and technical specifications for developing and operating a secure distributed data system comprised of separate data sets that conform to a common data model covering enrollment, demographics, encounters, diagnoses, procedures, and ambulatory dispensing of prescription drugs. The distributed data sets currently include administrative and claims data from 2000 to 2011 for over 300 million person-years, 2.4 billion encounters, 38 million inpatient hospitalizations, and 2.9 billion dispensings. Selected laboratory results and vital signs data recorded after 2005 are also available. There is an active data quality assessment and characterization program, and eligibility for medical care and pharmacy benefits is known. Systematic reviews of the literature have assessed the ability of administrative data to identify health outcomes of interest, and procedures have been developed and tested to obtain, abstract, and adjudicate full-text medical records to validate coded diagnoses. Mini-Sentinel has also created a taxonomy of study designs and analytical approaches for many commonly occurring situations, and it is developing new statistical and epidemiologic methods to address certain gaps in analytic capabilities. Assessments are performed by distributing computer programs that are executed locally by each data partner. The system is in active use by FDA, with the majority of assessments performed using customizable, reusable queries (programs). Prospective and retrospective assessments that use customized protocols are conducted as well. To date, several hundred unique programs have been distributed and executed. Current activities include active surveillance of several drugs and vaccines, expansion of the population, enhancement of the common data model to include additional types of data from electronic health records and registries, development of new methodologic capabilities, and assessment of methods to identify and validate additional health outcomes of interest. Copyright c 2012 John Wiley & Sons, Ltd. C1 [Platt, Richard; Brown, Jeffrey S.; Toh, Sengwee] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02114 USA. [Platt, Richard; Brown, Jeffrey S.; Toh, Sengwee] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Carnahan, Ryan M.; Chrischilles, Elizabeth] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [Curtis, Lesley H.] Duke Univ, Duke Clin Res Inst, Sch Med, Durham, NC USA. [Curtis, Lesley H.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Hennessy, Sean] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Nelson, Jennifer C.] Grp Hlth Res Inst, Biostat Unit, Seattle, WA USA. [Racoosin, Judith A.; Robb, Melissa] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Schneeweiss, Sebastian] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. [Weiner, Mark G.] Univ Penn, Dept Med, Div Gen Internal Med, Perelman Sch ofMedicine, Philadelphia, PA 19104 USA. RP Platt, R (reprint author), Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02114 USA. EM Richard_Platt@harvard.edu RI Schneeweiss, Sebastian/C-2125-2013; Toh, Sengwee/D-7567-2017; OI Toh, Sengwee/0000-0002-5160-0810; Carnahan, Ryan/0000-0002-7478-4739 FU Food and Drug Administration through Department of Health and Human Services [HHSF223200910006I] FX Mini-Sentinel is funded by the Food and Drug Administration through Department of Health and Human Services Contract Number HHSF223200910006I. NR 43 TC 127 Z9 129 U1 2 U2 21 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2012 VL 21 SU 1 BP 1 EP 8 DI 10.1002/pds.2343 PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 878JU UT WOS:000299253900001 PM 22262586 ER PT J AU Robb, MA Racoosin, JA Sherman, RE Gross, TP Ball, R Reichman, ME Midthun, K Woodcock, J AF Robb, Melissa A. Racoosin, Judith A. Sherman, Rachel E. Gross, Thomas P. Ball, Robert Reichman, Marsha E. Midthun, Karen Woodcock, Janet TI The US Food and Drug Administration's Sentinel Initiative: Expanding the horizons of medical product safety SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE FDA; Sentinel System; active surveillance; medical product safety; common data model; patient privacy C1 [Robb, Melissa A.; Racoosin, Judith A.; Sherman, Rachel E.] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Gross, Thomas P.] US FDA, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Ball, Robert] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Reichman, Marsha E.] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Robb, MA (reprint author), US FDA, Off Med Policy, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Room 6360, Silver Spring, MD 20993 USA. EM Melissa.Robb@fda.hhs.gov FU Technology for Economic and Clinical Health (HITECH) Act FX The Health Information Technology for Economic and Clinical Health (HITECH) Act, part of the American Recovery and Reinvestment Act of 2009, designated funding to modernize the health care system by promoting and expanding the adoption of health information technology. HITECH supports the rapid adoption of health information technology by hospitals and clinicians through Medicare and Medicaid incentive payments to physicians and hospitals for meaningful use of electronic health records. It also authorizes grant programs and contracts that support HIT adoption by providing technical assistance to health care providers, especially rural and underserved communities, training a HIT workforce, as well as developing standards for certification of electronic health record privacy and security. NR 5 TC 40 Z9 41 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2012 VL 21 SU 1 BP 9 EP 11 DI 10.1002/pds.2311 PG 3 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 878JU UT WOS:000299253900002 PM 22262587 ER PT J AU Forrow, S Campion, DM Herrinton, LJ Nair, VP Robb, MA Wilson, M Platt, R AF Forrow, Susan Campion, Daniel M. Herrinton, Lisa J. Nair, Vinit P. Robb, Melissa A. Wilson, Marcus Platt, Richard TI The organizational structure and governing principles of the Food and Drug Administration's Mini-Sentinel pilot program SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE FDA; mini-sentinel; organizational structure; principles; policies AB The US Food and Drug Administration's Mini-Sentinel pilot program is developing an organizational structure as well as principles and policies to govern its operations. These will inform the structure and function of the eventual Sentinel System. Mini-Sentinel is a collaboration that includes 25 participating institutions. We describe the program's current organizational structure and its major principles and policies. The organization includes a coordinating center with program leadership provided by a principal investigator; a planning board and subcommittees; an operations center; and data, methods, and protocol cores. Ad hoc workgroups are created as needed. A privacy panel advises about protection of individual health information. Principles and policies are intended to ensure that Mini-Sentinel conforms to the principles of fair information practices, protects the privacy of individual health information, maintains the security and integrity of data, assures the confidentiality of proprietary information, provides accurate and timely communications, prevents or manages conflicts of interest, and preserves respect for intellectual property rights. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Forrow, Susan; Platt, Richard] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA 02215 USA. [Forrow, Susan; Platt, Richard] Harvard Univ, Sch Med, Boston, MA USA. [Campion, Daniel M.] Outcome Sci Inc, Washington, DC USA. [Herrinton, Lisa J.] Kaiser Permanente Ctr Effectiveness & Safety Res, Oakland, CA USA. [Nair, Vinit P.] Humana, Miami, FL USA. [Robb, Melissa A.] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Wilson, Marcus] HealthCore Inc, Wilmington, DE USA. RP Forrow, S (reprint author), Harvard Pilgrim Hlth Care Inst, Dept Populat Med, 133 Brookline Ave, Boston, MA 02215 USA. EM susan_forrow@harvardpilgrim.org FU Food and Drug Administration through the Department of Health and Human Services [HHSF223200910006I] FX FDA contract number: Mini-Sentinel is funded by the Food and Drug Administration through the Department of Health and Human Services Contract Number HHSF223200910006I. NR 9 TC 19 Z9 20 U1 0 U2 1 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2012 VL 21 SU 1 BP 12 EP 17 DI 10.1002/pds.2242 PG 6 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 878JU UT WOS:000299253900003 PM 22262588 ER PT J AU Maclure, M Fireman, B Nelson, JC Hua, W Shoaibi, A Paredes, A Madigan, D AF Maclure, Malcolm Fireman, Bruce Nelson, Jennifer C. Hua, Wei Shoaibi, Azadeh Paredes, Antonio Madigan, David TI When should case-only designs be used for safety monitoring of medical products? SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE methods; safety monitoring; self-controlled designs; crossover ID CASE-CROSSOVER DESIGN; CASE SERIES; EXPOSURES; TRENDS AB Purpose To assess case-only designs for surveillance with administrative databases. Methods We reviewed literature on two designs that are observational analogs to crossover experiments: the self-controlled case series (SCCS) and the case-crossover (CCO) design. Results SCCS views the ` experiment' prospectively, comparing outcome risks in windows with different exposures. CCO retrospectively compares exposure frequencies in case and control windows. The main strength of case-only designs is they entail self-controlled analyses that eliminate confounding and selection bias by time-invariant characteristics not recorded in healthcare databases. They also protect privacy and are computationally efficient, as they require fewer subjects and variables. They are better than cohort designs for investigating transient effects of accurately recorded preventive agents, for example, vaccines. They are problematic if timing of self-administration is sporadic and dissociated from dispensing times, for example, analgesics. They tend to have less exposure misclassification bias and time-varying confounding if exposures are brief. Standard SCCS designs are bidirectional (using time both before and after the first exposure event), so they are more susceptible than CCOs to reverse-causality bias, including immortal-time bias. This is true also for sequence symmetry analysis, a simplified SCCS. Unidirectional CCOs use only time before the outcome, so they are less affected by reverse causality but susceptible to exposure-trend bias. Modifications of SCCS and CCO partially deal with these biases. The head-to-head comparison of multiple products helps to control residual biases. Conclusion The case-only analyses of intermittent users complement the cohort analyses of prolonged users because their different biases compensate for one another. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Maclure, Malcolm] Univ British Columbia, Dept Anesthesiol Pharmacol & Therapeut, Victoria, BC V8W 1Y2, Canada. [Maclure, Malcolm] BC Minist Hlth, Pharmaceut Serv Div, Victoria, BC, Canada. [Fireman, Bruce] Kaiser Permanente, Div Res, Oakland, CA USA. [Nelson, Jennifer C.] Grp Hlth Res Inst, Biostat Unit, Seattle, WA USA. [Nelson, Jennifer C.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Hua, Wei; Shoaibi, Azadeh; Paredes, Antonio] US FDA, Rockville, MD 20857 USA. [Madigan, David] Columbia Univ, Dept Stat, New York, NY USA. RP Maclure, M (reprint author), Univ British Columbia, Dept Anesthesiol Pharmacol & Therapeut, 204-1110 Govt St, Victoria, BC V8W 1Y2, Canada. EM malcolm.maclure@gov.bc.ca FU Food and Drug Administration through the Department of Health and Human Services [HHSF223200910006I] FX This work was supported by the Mini-Sentinel which is funded by the Food and Drug Administration through the Department of Health and Human Services contract number HHSF223200910006I. The authors thank Kerry Patriarche for assistance with reviewing papers. This review of published papers was not reviewed by an ethics committee. NR 20 TC 49 Z9 49 U1 0 U2 13 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2012 VL 21 SU 1 BP 50 EP 61 DI 10.1002/pds.2330 PG 12 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 878JU UT WOS:000299253900008 PM 22262593 ER PT J AU Cook, AJ Tiwari, RC Wellman, RD Heckbert, SR Li, LL Heagerty, P Marsh, T Nelson, JC AF Cook, Andrea J. Tiwari, Ram C. Wellman, Robert D. Heckbert, Susan R. Li, Lingling Heagerty, Patrick Marsh, Tracey Nelson, Jennifer C. TI Statistical approaches to group sequential monitoring of postmarket safety surveillance data: current state of the art for use in the Mini-Sentinel pilot SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE incident user cohort; observational study; postmarket; group sequential monitoring; signal refinement; surveillance ID CLINICAL-TRIALS; HEALTH NETWORKS; ADVERSE EVENTS; VACCINE; BOUNDARIES; DESIGNS; MODELS; RISK AB Purpose This manuscript describes the current statistical methodology available for active postmarket surveillance of pre-specified safety outcomes using a prospective incident user concurrent control cohort design with existing electronic healthcare data. Methods Motivation of the active postmarket surveillance setting is provided using the Food and Drug Administration's Mini-Sentinel Pilot as an example. Four sequential monitoring statistical methods are presented including the Lan-Demets error spending approach, a matched likelihood ratio test statistic approach with the binomial MaxSPRT as a special case, the conditional sequential sampling procedure with stratification, and a generalized estimating equation regression approach using permutation. Information on the assumptions, limitations, and advantages of each approach is provided, including how each method defines sequential monitoring boundaries, what test statistic is used, and how robust it is to settings of rare events or frequent testing. Results A hypothetical example of how the approaches could be applied to data comparing a medical product of interest, drug A, to a concurrent control drug, drug B, is presented including providing the type of information one would have available for monitoring such drugs. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Cook, Andrea J.; Wellman, Robert D.; Nelson, Jennifer C.] Grp Hlth Res Inst, Biostat Unit, Seattle, WA 98101 USA. [Cook, Andrea J.; Heagerty, Patrick; Nelson, Jennifer C.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Tiwari, Ram C.] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan R.] Univ Washington, Dept Pharm, Seattle, WA 98195 USA. [Li, Lingling] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Li, Lingling] Harvard Univ, Sch Med, Boston, MA USA. RP Cook, AJ (reprint author), Grp Hlth Res Inst, Biostat Unit, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM cook.aj@ghc.org FU Food and Drug Administration (FDA) through the Department of Health and Human Services (HHS) [HHSF223200910006I] FX Mini-Sentinel is funded by the Food and Drug Administration (FDA) through the Department of Health and Human Services (HHS) Contract Number HHSF223200910006I. The views expressed in this article do not necessarily represent those of the Food and Drug Administration. NR 20 TC 19 Z9 20 U1 0 U2 2 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2012 VL 21 SU 1 BP 72 EP 81 DI 10.1002/pds.2320 PG 10 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 878JU UT WOS:000299253900010 PM 22262595 ER PT J AU Cutrona, SL Toh, S Iyer, A Foy, S Cavagnaro, E Forrow, S Racoosin, JA Goldberg, R Gurwitz, JH AF Cutrona, Sarah L. Toh, Sengwee Iyer, Aarthi Foy, Sarah Cavagnaro, Elizabeth Forrow, Susan Racoosin, Judith A. Goldberg, Robert Gurwitz, Jerry H. TI Design for validation of acute myocardial infarction cases in Mini-Sentinel SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE myocardial infarction; coronary artery disease; validation; administrative data ID POSITIVE PREDICTIVE-VALUE; UNIVERSAL DEFINITION; HEART-DISEASE; DIAGNOSIS; POPULATION; ACCURACY; VALIDITY; DATABASE AB Purpose To describe the acute myocardial infarction (AMI) validation project, a test case for health outcome validation within the US Food and Drug Administration-funded Mini-Sentinel pilot program. Methods The project consisted of four parts: (i) case identification-developing an algorithm based on the International Classification of Diseases, Ninth Revision, to identify hospitalized AMI patients within the Mini-Sentinel Distributed Database; (ii) chart retrieval-establishing procedures that ensured patient privacy (collection and transfer of minimum necessary amount of information, and redaction of direct identifiers to validate potential cases of AMI); (iii) abstraction and adjudication-trained nurse abstractors gathered key data using a standardized form with cardiologist adjudication; and (iv) calculation of the positive predictive value of the constructed algorithm. Results Key decision points included (i) breadth of the AMI algorithm, (ii) centralized versus distributed abstraction, and (iii) approaches to maintaining patient privacy and to obtaining charts for public health purposes. We used an algorithm limited to International Classification of Diseases, Ninth Revision, codes 410.x0-410.x1. Centralized data abstraction was performed because of the modest number of charts requested (< 155). The project's public health status accelerated chart retrieval in most instances. Conclusions We have established a process to validate AMI within Mini-Sentinel, which may be used for other health outcomes. Challenges include the following: (i) ensuring that only minimum necessary data are transmitted by Data Partners for centralized chart review, (ii) establishing procedures to maintain data privacy while still allowing for timely access to medical charts, and (iii) securing access to charts for public health uses that do not require approval from an institutional review board while maintaining patient privacy. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Cutrona, Sarah L.; Foy, Sarah; Goldberg, Robert; Gurwitz, Jerry H.] Univ Massachusetts, Sch Med, Fallon Community Hlth Plan & Fallon Clin, Meyers Primary Care Inst, Worcester, MA USA. [Toh, Sengwee; Iyer, Aarthi; Cavagnaro, Elizabeth; Forrow, Susan] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Toh, Sengwee; Iyer, Aarthi; Cavagnaro, Elizabeth; Forrow, Susan] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Racoosin, Judith A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Cutrona, SL (reprint author), 377 Plantation St,Biotech 4,Suite 315, Worcester, MA 01605 USA. EM Sarah.cutrona@umassmemorial.org RI Toh, Sengwee/D-7567-2017 OI Toh, Sengwee/0000-0002-5160-0810 FU FDA through the Department of Health and Human Services [HHSF223200910006I] FX Mini-Sentinel is funded by the FDA through the Department of Health and Human Services contract number HHSF223200910006I. NR 26 TC 9 Z9 11 U1 0 U2 3 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2012 VL 21 SU 1 BP 274 EP 281 DI 10.1002/pds.2314 PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 878JU UT WOS:000299253900032 PM 22262617 ER PT J AU Fireman, B Toh, S Butler, MG Go, AS Joffe, HV Graham, DJ Nelson, JC Daniel, GW Selby, JV AF Fireman, Bruce Toh, Sengwee Butler, Melissa G. Go, Alan S. Joffe, Hylton V. Graham, David J. Nelson, Jennifer C. Daniel, Gregory W. Selby, Joe V. TI A protocol for active surveillance of acute myocardial infarction in association with the use of a new antidiabetic pharmaceutical agent SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE acute myocardial infarction; diabetes mellitus; drug safety; drug surveillance; saxagliptin ID CLINICAL-TRIALS; PROPENSITY SCORES; RISK; DISEASE; DESIGN AB Purpose To describe a protocol for active surveillance of acute myocardial infarction (AMI) in users of a recently approved oral antidiabetic medication, saxagliptin, and to provide the rationale for decisions made in drafting the protocol. Methods A new-user cohort design is planned for evaluating data from at least four Mini-Sentinel data partners from 1 August 2009 (following US Food and Drug Administration's approval of saxagliptin) through mid-2013. New users of saxagliptin will be compared in separate analyses with new users of sitagliptin, pioglitazone, long-acting insulins, and second-generation sulfonylureas. Two approaches to controlling for confounding will be evaluated: matching by exposure propensity score and stratification by AMI risk score. The primary analyses will use Cox regression models specified in a way that does not require pooling of patient-level data from the data partners. The Cox models are fit to summarized data on risk sets composed of saxagliptin users and similar comparator users at the time of an AMI. Secondary analyses will use alternative methods including Poisson regression and will explore whether further adjustment for covariates available only at some data partners (e. g., blood pressure) modifies results. Results The results of this study are pending. Conclusions The proposed protocol describes a design for surveillance to evaluate the safety of a newly marketed agent as postmarket experience accrues. It uses data from multiple partner organizations without requiring sharing of patient-level data and compares alternative approaches to controlling for confounding. It is hoped that this initial active surveillance project of the Mini-Sentinel will provide insights that inform future population-based surveillance of medical product safety. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Fireman, Bruce; Go, Alan S.; Selby, Joe V.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Toh, Sengwee] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Toh, Sengwee] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Butler, Melissa G.] Kaiser Permanente Georgia, Ctr Hlth Res SE, Atlanta, GA USA. [Joffe, Hylton V.; Graham, David J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Nelson, Jennifer C.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Daniel, Gregory W.] HealthCore Inc, Govt & Acad Res, Alexandria, VA USA. RP Fireman, B (reprint author), Kaiser Permanente, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM bruce.fireman@kp.org RI Toh, Sengwee/D-7567-2017 OI Toh, Sengwee/0000-0002-5160-0810 FU FDA through the Department of Health and Human Services [HHSF223200910006I] FX The authors thank Sebastian Schneeweiss for contributions to the design of the proposed surveillance and Nicolas Beaulieu for overseeing and programming the collection of preliminary data from participating Mini-Sentinel data partners. Mini-Sentinel is funded by the FDA through the Department of Health and Human Services Contract Number HHSF223200910006I. NR 30 TC 13 Z9 14 U1 0 U2 3 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2012 VL 21 SU 1 BP 282 EP 290 DI 10.1002/pds.2337 PG 9 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 878JU UT WOS:000299253900033 PM 22262618 ER PT J AU Nguyen, M Ball, R Midthun, K Lieu, TA AF Michael Nguyen Ball, Robert Midthun, Karen Lieu, Tracy A. TI The Food and Drug Administration's Post-Licensure Rapid Immunization Safety Monitoring program: strengthening the federal vaccine safety enterprise SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE vaccines; immunizations; safety; active surveillance; monitoring ID INFLUENZA VACCINE; ADVERSE EVENTS; UNITED-STATES; FEBRUARY 1; INTUSSUSCEPTION; SURVEILLANCE; POPULATION; RISK AB In 2009, the Department of Health and Human Services created the new Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program, which used data from national health insurance plans and immunization registries to monitor the safety of the H1N1 influenza vaccine. PRISM has now been integrated into the FDA's Mini-Sentinel pilot program. It strengthens the federal vaccine safety enterprise in two important ways. First, PRISM monitors the largest US general population cohort designated for active surveillance of vaccine safety. Second, PRISM links data from health plans with data from state and city immunization registries, which were a crucial source of exposure data in the H1N1 vaccine evaluation. The Mini-Sentinel data that support PRISM are updated quarterly, and PRISM can conduct medical record review for validation of computerized data. The FDA has structured PRISM as a program that includes specific vaccine evaluations, development of an operational framework to guide the design of vaccine safety evaluations, and development of new statistical methods. A human papillomavirus vaccine, Gardasil, and two rotavirus vaccines, RotaTeq and Rotarix, have been chosen for surveillance in the current cycle because their evaluations would benefit most from PRISM's large cohort size. The PRISM program creates important opportunities by offering a robust, responsive new surveillance program with features complementary to existing systems. Methodological and logistical lessons can be shared among PRISM and other surveillance systems, offering potential synergies. FDA and PRISM will work to maximize the program's unique strengths and contributions to a unified federal vaccine safety enterprise. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Michael Nguyen; Ball, Robert; Midthun, Karen] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Lieu, Tracy A.] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA 02215 USA. [Lieu, Tracy A.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Lieu, Tracy A.] Childrens Hosp Boston, Div Gen Pediat, Boston, MA 02115 USA. RP Nguyen, M (reprint author), 1401 Rockville Pike,Suite 400S,HFM-222,Woodmont O, Rockville, MD 20852 USA. EM michael.nguyen@fda.hhs.gov FU Food and Drug Administration (FDA) through Department of Health and Human Services (HHS) [HHSF223200910006I] FX Mini-Sentinel is funded by the Food and Drug Administration (FDA) through Department of Health and Human Services (HHS) Contract Number HHSF223200910006I. NR 31 TC 41 Z9 42 U1 3 U2 10 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2012 VL 21 SU 1 BP 291 EP 297 DI 10.1002/pds.2323 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 878JU UT WOS:000299253900034 PM 22262619 ER PT J AU Lin, WJ Chen, JJ AF Lin, Wei-Jiun Chen, James J. TI Biomarker classifiers for identifying susceptible subpopulations for treatment decisions SO PHARMACOGENOMICS LA English DT Article DE biomarkers of susceptibility; class prediction; imbalanced class size; personalized medicine; susceptible subpopulation ID RANDOMIZED CLINICAL-TRIALS; GENE-EXPRESSION DATA; PREDICTIVE TOXICOLOGY; PRECLINICAL TOXICITY; BREAST-CANCER; SAMPLE-SIZE; CLASSIFICATION; MICROARRAY; DESIGN; HEPATOTOXICITY AB Aim: A main goal of pharmacogenomics is to develop genomic signatures to predict patients' responses to a drug or therapy for treatment decisions. Identification of patients who would have no beneficial effect or have the risk of developing adverse effects from an unnecessary treatment could save enormous cost in the healthcare system and clinical trials. This article presents an approach for developing a biomarker classifier for identifying a fraction of susceptible patients, who should be spared unnecessary treatment prior to treatment. Materials & methods: The identification of susceptible patients involves two steps. The first step is to identify biomarkers of susceptibility from a mixture of biomarkers of susceptibility and biomarkers of response; the second step is to develop a classifier using an ensemble classification algorithm, as the number of susceptible patients is generally much smaller than the number of nonsusceptible patients. Results: Selection of the biomarkers of susceptibility is essential to achieve good prediction accuracy. The ensemble algorithm significantly improves the prediction accuracy compared with the standard classifiers. Conclusion: The study shows that classifiers developed based on the biomarkers obtained by comparing the genomic profiles of responders to those of nonresponders may lead to a high misclassification error rate. Classifiers to identify a small fraction of the subpopulation should take imbalanced class sizes into consideration. A large sample size may be needed in order to ensure detection of a sufficient number of biomarkers and a sufficient number of susceptible subjects for classifier development and validation. Original submitted: 21 June 2011; Revision submitted: 23 September 2011 C1 [Lin, Wei-Jiun; Chen, James J.] US FDA, Natl Ctr Toxicol Res, Div Personalized Nutr & Med, Jefferson, AR 72079 USA. [Chen, James J.] China Med Univ, Grad Inst Biostat, Taichung, Taiwan. [Chen, James J.] China Med Univ, Ctr Biostat, Taichung, Taiwan. [Lin, Wei-Jiun] Feng Chia Univ, Dept Appl Math, Taichung 40724, Taiwan. RP Chen, JJ (reprint author), US FDA, Natl Ctr Toxicol Res, Div Personalized Nutr & Med, Jefferson, AR 72079 USA. EM jamesj.chen@fda.hhs.gov NR 38 TC 4 Z9 5 U1 0 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 EI 1744-8042 J9 PHARMACOGENOMICS JI Pharmacogenomics PD JAN PY 2012 VL 13 IS 2 BP 147 EP 157 DI 10.2217/PGS.11.139 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 886OP UT WOS:000299864000010 PM 22188363 ER PT J AU Zhang, M Chen, MJ Tong, WD AF Zhang, Min Chen, Minjun Tong, Weida TI Is Toxicogenomics a More Reliable and Sensitive Biomarker than Conventional Indicators from Rats To Predict Drug-Induced Liver Injury in Humans? SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID GENE-EXPRESSION PROFILES; GENOMIC BIOMARKERS; HEPATOTOXICITY; TOXICITY; ACETAMINOPHEN; VALIDATION; METABOLISM; INDUCTION; EXPOSURE AB Around 40% of drug-induced liver injury (DILI) cases are not detected in preclinical studies using the conventional indicators. It has been hypothesized that genomic biomarkers will be more sensitive than conventional markers in detecting human hepatotoxicity signals in preclinical studies. For example, it has been hypothesized and demonstrated in some cases that (1) genomic biomarkers from the rat liver can discriminate drug candidates that have a greater or lesser potential to cause DILL in susceptible patients despite no conventional indicators of liver toxicity being observed in preclinical studies, and (2) more sensitive biomarkers for early detection of DILI can be derived from a "subtoxic dose" at which the injury in the liver occurs at the molecular but not the phenotypic level. With a public TGx data set derived from short-term in vivo studies using rats, we divided drugs exhibiting human hepatotoxicity into three groups according to whether elevated alanine aminotransferase (ALT) or total bilirubin (TBL) were observed in the treated rats: (A) The elevation was observed in the treated rats, (B) no elevation was observed for all of the treated rats, and (C) no elevation could be observed at a lower dose and shorter duration but occur when a higher or longer treatment was applied. A control group (D) was comprised of drugs known not to cause human hepatotoxicity and for which no rats exhibited elevated ALT or TBL. We developed classifiers for groups A, B, and C against group D and found that the gene signature from scenario A could achieve 83% accuracy for human hepatotoxicity potential of drugs in a leave-one-compound-out cross-validation process, much higher than scenarios B (average 45%) and C (61%). Furthermore, the signature derived from scenario A exhibited relevance to hepatotoxicity in a pathway-based analysis and performed well on two independent public TGx data sets using different chemical treatments and profiled with different microarray platforms. Our study implied that the human hepatotoxicity potential of a drug can be reasonably assessed using TGx analysis of short-term in vivo studies only if it produces significant elevation of ALT or TBL in the treated rats. The study further revealed that the value of "sensitive" biomarkers derived from scenario C was not promising as expected for DILI assessment using the reported TGx design. The study will facilitate further research to understand the role of genomic biomarkers from rats for assessing human hepatotoxicity. C1 [Zhang, Min; Chen, Minjun; Tong, Weida] US FDA, Ctr Excellence Bioinformat, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Tong, WD (reprint author), US FDA, Ctr Excellence Bioinformat, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM weida.tong@fda.hhs.gov FU National Center for Toxicological Research (NCTR) of the U.S. Food and Drug Administration (FDA); Oak Ridge Institute for Science and Education (ORISE); FDA's Critical Path Initiative; Office of Women's Health; Chief Scientist Challenge Grant FX M.Z. is grateful to the National Center for Toxicological Research (NCTR) of the U.S. Food and Drug Administration (FDA) for postdoctoral support through the Oak Ridge Institute for Science and Education (ORISE). This study was supported by the FDA's Critical Path Initiative, Office of Women's Health, and the Chief Scientist Challenge Grant. NR 43 TC 22 Z9 23 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD JAN PY 2012 VL 25 IS 1 BP 122 EP 129 DI 10.1021/tx200320e PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 875KL UT WOS:000299028700014 PM 22122743 ER PT J AU Messinger, YH Mendelsohn, NJ Rhead, W Dimmock, D Hershkovitz, E Champion, M Jones, SA Olson, R White, A Wells, C Bali, D Case, LE Young, SP Rosenberg, AS Kishnani, PS AF Messinger, Yoav H. Mendelsohn, Nancy J. Rhead, William Dimmock, David Hershkovitz, Eli Champion, Michael Jones, Simon A. Olson, Rebecca White, Amy Wells, Cara Bali, Deeksha Case, Laura E. Young, Sarah P. Rosenberg, Amy S. Kishnani, Priya S. TI Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease SO GENETICS IN MEDICINE LA English DT Article DE immune tolerance; methotrexate; Pompe disease; rituximab ID ACID ALPHA-GLUCOSIDASE; SEVERE HEMOPHILIA-A; NEUTRALIZING ANTIBODIES; MUCOPOLYSACCHARIDOSIS-I; RITUXIMAB; TERM; INHIBITORS; BOY AB Purpose: Infantile Pompe disease resulting from a deficiency of lysosomal acid alpha-glucosidase (GAA) requires enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Cross-reactive immunologic material negative (CRIM-negative) Pompe patients develop high-titer antibody to the rhGAA and do poorly. We describe successful tolerance induction in CRIM-negative patients. Methods: Two CRIM-negative patients with preexisting anti-GAA antibodies were treated therapeutically with rituximab, methotrexate, and gammaglobulins. Two additional CRIM-negative patients were treated prophylactically with a short course of rituximab and methotrexate, in parallel with initiating rhGAA. Results: In both patients treated therapeutically, anti-rhGAA was eliminated after 3 and 19 months. All four patients are immune tolerant to rhGAA, off immune therapy, showing B-cell recovery while continuing to receive ERT at ages 36 and 56 months (therapeutic) and 18 and 35 months (prophylactic). All patients show clinical response to ERT, in stark contrast to the rapid deterioration of their nontolerized CRIM-negative counterparts. Conclusion: The combination of rituximab with methotrexate +/- intravenous gammaglobulins (IVIG) is an option for tolerance induction of CRIM-negative Pompe to ERT when instituted in the naive setting or following antibody development. It should be considered in other conditions in which antibody response to the therapeutic protein elicits robust antibody response that interferes with product efficacy. C1 [Messinger, Yoav H.; Mendelsohn, Nancy J.; Olson, Rebecca] Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. [Rhead, William; Dimmock, David; White, Amy; Wells, Cara] Med Coll Wisconsin, Dept Pediat, Div Genet, Milwaukee, WI 53226 USA. [Rhead, William; Dimmock, David; White, Amy; Wells, Cara] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Hershkovitz, Eli] Soroka Med Ctr, Pediat Endocrinol & Metab Unit, IL-84101 Beer Sheva, Israel. [Champion, Michael] Evelina Childrens Hosp, Dept Inherited Metabol Dis, London, England. [Jones, Simon A.] Cent Manchester Univ, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Bali, Deeksha; Young, Sarah P.; Kishnani, Priya S.] Duke Univ, Med Ctr, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. [Case, Laura E.] Duke Univ, Med Ctr, Dept Community & Family Med, Div Phys Therapy, Durham, NC 27710 USA. [Rosenberg, Amy S.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. RP Messinger, YH (reprint author), Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. EM yoav.messinger@childrensmn.org RI Hershkovitz, Eli/F-1922-2012; Dimmock, David/I-7913-2015; OI Dimmock, David/0000-0001-6690-2523; Case, Laura/0000-0002-2941-2186 FU Genzyme; PTC Therapeutics; Leal Foundation; SMA; National Skeletal Muscle Research Center FX Y.H.M.: Consultant for Genzyme and received honorarium from Genzyme. N.J.M.: Consultant for Genzyme. S.A.J.: Consultant for Genzyme and received honorarium from Genzyme. D.B.: Received honorarium and research funding from Genzyme. L.E.C.: Received honorarium from Genzyme; Research supported by Genzyme, PTC Therapeutics, Leal Foundation, and families of SMA; Received grant support from National Skeletal Muscle Research Center; Member of Pompe Registry Board of Advisors for Genzyme. S.P.Y.: Received honorarium and research funding from Genzyme. P.S.K.: Received honorarium and research funding from Genzyme; Member of Pompe and Gaucher Disease Registry Advisory Boards for Genzyme. W.R.: Received honorarium and clinical trial funding from Genzyme. A.W.: Received honorarium from Genzyme. NR 27 TC 84 Z9 85 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JAN PY 2012 VL 14 IS 1 BP 135 EP 142 DI 10.1038/gim.2011.4 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 873NI UT WOS:000298889600017 PM 22237443 ER PT J AU Esperat, MCR Hanson-Turton, T Richardson, M Tyree Debisette, A Rupinta, C AF Esperat, Maria Christina R. Hanson-Turton, Tine Richardson, Michele Tyree Debisette, Annette Rupinta, Catherine TI Nurse-managed health centers: Safety-net care through advanced nursing practice SO JOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS LA English DT Article DE Nurse-managed clinics; nurse practitioners; practice models; safety net; vulnerable populations ID UNITED-STATES AB Purpose: To describe the nurse-managed health center (NMHC) as a model for effective health delivery in providing safety-net care to medically underserved populations. Data sources: Although the literature regarding outcomes of the model is still building, mounting evidence shows that NMHCs provide quality and costeffective care to their target populations. The Division of Nursing of the Health Resources and Services Administration has ample data to support the findings that NMHCs are a significant component of the primary healthcare system in providing access particularly for medically underserved and vulnerable populations. Furthermore, NMHCs are a powerful source of clinical experiences to train nurses and nurse practitioners as part of the healthcare workforce. Conclusions: The financial challenges facing NMHCs are significant; it will take an enormous push from organized fronts of the NMHC movement to give individual NMHCs a fighting chance to survive within the competitive healthcare climate. Implications for practice: Policy changes are essential to assure that NMHCs are an integral part of the primary healthcare safety net for America's vulnerable populations, and that advance practice nurses are at the forefront of policy initiatives. C1 [Esperat, Maria Christina R.] Texas Tech Univ, Hlth Sci Ctr, Sch Nursing, Lubbock, TX 79430 USA. [Hanson-Turton, Tine] Philadelphia Hlth Management Corp, Natl Nursing Ctr Consortium, Philadelphia, PA USA. [Richardson, Michele] US Hlth Resources & Serv Adm, Div Nursing, US Dept HHS, Rockville, MD 20857 USA. [Tyree Debisette, Annette] Food & Drug Adm Off Regulatory Affairs, Rockville, MD USA. [Rupinta, Catherine] US Hlth Resources & Serv Adm, Div Med & Dent, Bur Hlth Profess, Rockville, MD 20857 USA. RP Esperat, MCR (reprint author), Texas Tech Univ, Hlth Sci Ctr, Sch Nursing, 3601 4th St, Lubbock, TX 79430 USA. EM christina.esperat@ttuhsc.edu NR 15 TC 14 Z9 14 U1 3 U2 15 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1041-2972 J9 J AM ACAD NURSE PRAC JI J. Am. Acad. Nurse Pract. PD JAN PY 2012 VL 24 IS 1 BP 24 EP 31 DI 10.1111/j.1745-7599.2011.00677.x PG 8 WC Health Care Sciences & Services; Nursing SC Health Care Sciences & Services; Nursing GA 876IY UT WOS:000299102400005 PM 22243678 ER PT J AU Moore, AC Bixler, SL Lewis, MG Verthelyi, D Mattapallil, JJ AF Moore, Andrew C. Bixler, Sandra L. Lewis, Mark G. Verthelyi, Daniela Mattapallil, Joseph J. TI Mucosal and Peripheral Lin(-) HLA-DR+ CD11c/123(-) CD13(+) CD14(-) Mononuclear Cells Are Preferentially Infected during Acute Simian Immunodeficiency Virus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID CD4(+) T-CELLS; CD16(+) MONOCYTE SUBSET; ACUTE SIV INFECTION; HIV-1 INFECTION; RHESUS-MACAQUES; GASTROINTESTINAL-TRACT; VIRAL REPLICATION; BONE-MARROW; ALVEOLAR MACROPHAGES; BLOOD MONOCYTES AB Massive infection of memory CD4T cells is a hallmark of early simian immunodeficiency virus (SIV) infection, with viral infection peaking at day 10 postinfection (p.i.), when a majority of memory CD4T cells in mucosal and peripheral tissues are infected. It is not clear if mononuclear cells from the monocyte and macrophage lineages are similarly infected during this early phase of explosive HIV and SIV infections. Here we show that, at day 10 p.i., Lin(-) HLA-DR+ CD11c/123(-) CD13(+) CD14(-) macrophages in the jejunal mucosa were infected, albeit at lower levels than CD4 memory T cells. Interestingly, Lin(-) HLA-DR+ CD11c/123(-) CD13(+) CD14(-) macrophages in peripheral blood, like their mucosal counterparts, were preferentially infected compared to Lin(-) HLA-DR+ CD11c/123(-) CD13(+) CD14(+) monocytes, suggesting that differentiated macrophages were selectively infected by SIV. CD13(+) CD14(-) macrophages expressed low levels of CD4 compared to CD4T cells but expressed similar levels of CCR5 as lymphocytes. Interestingly, CD13(+) CD14(-) macrophages expressed Apobec3G at lower levels than CD13(+) CD14(+) monocytes, suggesting that intracellular restriction may contribute to the differential infection of mononuclear subsets. Taken together, our results suggest that CD13(+) CD14(-) macrophages in mucosal and peripheral tissues are preferentially infected very early during the course of SIV infection. C1 [Moore, Andrew C.; Bixler, Sandra L.; Mattapallil, Joseph J.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Lewis, Mark G.] Bioqual Inc, Rockville, MD USA. [Verthelyi, Daniela] US FDA, CDER, Bethesda, MD 20014 USA. RP Mattapallil, JJ (reprint author), Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. EM jmattapallil@usuhs.mil FU National Cancer Institute, National Institutes of Health [NO1-CO-124000]; [AI07812]; [DE018339]; [DE019397] FX The project was supported by AI07812, DE018339, and DE019397 awarded to J.J.M. Studies were supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract NO1-CO-124000. NR 62 TC 10 Z9 10 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN PY 2012 VL 86 IS 2 BP 1069 EP 1078 DI 10.1128/JVI.06372-11 PG 10 WC Virology SC Virology GA 870MW UT WOS:000298674600038 PM 22090100 ER PT J AU Chen, JJ Knudsen, S Mazin, W Dahlgaard, J Zhang, BL AF Chen, Jun-Jie Knudsen, Steen Mazin, Wiktor Dahlgaard, Jesper Zhang, Baolin TI A 71-Gene Signature of TRAIL Sensitivity in Cancer Cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID APOPTOSIS-INDUCING LIGAND; BREAST-CANCER; DEATH RECEPTORS; ANTITUMOR-ACTIVITY; IN-VIVO; CHEMOSENSITIVITY; COMBINATION; ENDOCYTOSIS; EXPRESSION; PREDICTION AB TNF-related apoptosis inducing ligand( TRAIL) is a promising anticancer agent because of its ability to selectively induce apoptosis in cancer cells but not in most normal cells. However, some cancer cells are resistant to TRAIL cytotoxicity thereby limiting its therapeutic efficacy. Using genome-wide mRNA expression profiles from the NCI60 panel and their differential sensitivities to TRAIL-induced apoptosis, we have identified 71 genes whose expression levels are systemically higher in TRAIL-sensitive cell lines than resistant lines. The elevated expression of the 71 genes was able to accurately predict TRAIL sensitivity in the NCI60 training set and two test sets consisting of a total of 95 human cancer cell lines. Interestingly, the 71-gene signature is dominated by two functionally related gene families-interferon (IFN)-induced genes and the MHC genes. Consistent with this result, treatment with IFN-gamma augmented TRAIL-induced apoptosis. The 71-gene signature could be evaluated clinically for predicting tumor response to TRAIL-related therapies. Mol Cancer Ther; 11( 1); 34-44. (C) 2011 AACR. C1 [Chen, Jun-Jie; Zhang, Baolin] Food & Drug Adm, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Knudsen, Steen; Mazin, Wiktor; Dahlgaard, Jesper] Med Prognosis Inst, Horsholm, Denmark. RP Zhang, BL (reprint author), Food & Drug Adm, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. EM Baolin.zhang@fda.hhs.gov RI Chen, Jun-Jie/E-1894-2012 FU U.S. FDA Critical Path Research; Danish Council for Strategic Research FX This project was supported by funding from the U.S. FDA Critical Path Research and the Danish Council for Strategic Research. NR 31 TC 16 Z9 16 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JAN PY 2012 VL 11 IS 1 BP 34 EP 44 DI 10.1158/1535-7163.MCT-11-0620 PG 11 WC Oncology SC Oncology GA 879CV UT WOS:000299308200004 PM 22027696 ER PT J AU Chenna, V Hu, CX Pramanik, D Aftab, BT Karikari, C Campbell, NR Hong, SM Zhao, M Rudek, MA Khan, SR Rudin, CM Maitra, A AF Chenna, Venugopal Hu, Chaoxin Pramanik, Dipankar Aftab, Blake T. Karikari, Collins Campbell, Nathaniel R. Hong, Seung-Mo Zhao, Ming Rudek, Michelle A. Khan, Saeed R. Rudin, Charles M. Maitra, Anirban TI A Polymeric Nanoparticle Encapsulated Small-Molecule Inhibitor of Hedgehog Signaling (NanoHHI) Bypasses Secondary Mutational Resistance to Smoothened Antagonists SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID PANCREATIC-CANCER; PATHWAY; MEDULLOBLASTOMA; GENE; IDENTIFICATION; REQUIREMENT; BLOCKADE; THERAPY; TUMORS; CELLS AB Aberrant activation of the hedgehog (Hh) signaling pathway is one of the most prevalent abnormalities in human cancer. Tumors with cell autonomous Hh activation (e. g., medulloblastomas) can acquire secondary mutations at the Smoothened (Smo) antagonist binding pocket, which render them refractory to conventional Hh inhibitors. A class of Hh pathway inhibitors (HPI) has been identified that block signaling downstream of Smo; one of these compounds, HPI-1, is a potent antagonist of the Hh transcription factor Gli1 and functions independent of upstream components in the pathway. Systemic administration of HPI-1 is challenging due to its minimal aqueous solubility and poor bioavailability. We engineered a polymeric nanoparticle from [poly (lactic-co-glycolic acid); (PLGA)] conjugated with polyethylene glycol (PEG), encapsulating HPI-1 (NanoHHI). NanoHHI particles have an average diameter of approximately 60 nm, forms uniform aqueous suspension, and improved systemic bioavailability compared with the parent compound. In contrast to the prototype targeted Smo antagonist, HhAntag (Genentech), NanoHHI markedly inhibits the growth of allografts derived from Ptch(-/+); Trp53(-/+) mouse medulloblastomas that harbor a Smo(D477G) binding site mutation (P < 0.001), which is accompanied by significant downregulation of mGli1 as well as bona fide Hh target genes (Akna, Cltb, and Olig2). Notably, NanoHHI combined with gemcitabine also significantly impedes the growth of orthotopic Pa03C pancreatic cancer xenografts that have a ligand-dependent, paracrine mechanism of Hh activation when compared with gemcitabine alone. No demonstrable hematologic or biochemical abnormalities were observed with NanoHHI administration. NanoHHI should be amenable to clinical translation in settings where tumors acquire mutational resistance to current Smo antagonists. Mol Cancer Ther; 11(1); 165-73. (C) 2011 AACR. C1 [Chenna, Venugopal; Hu, Chaoxin; Pramanik, Dipankar; Karikari, Collins; Campbell, Nathaniel R.; Hong, Seung-Mo; Maitra, Anirban] Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD 21231 USA. [Aftab, Blake T.; Zhao, Ming; Rudek, Michelle A.; Khan, Saeed R.; Rudin, Charles M.; Maitra, Anirban] Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Oncol, Baltimore, MD 21231 USA. [Khan, Saeed R.] Food & Drug Adm, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Maitra, A (reprint author), Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Room 345,CRB 2,1550 Orleans St, Baltimore, MD 21231 USA. EM amaitra1@jhmi.edu RI Chenna, Venugopal/B-6196-2012; OI Hong, Seung-Mo/0000-0002-8888-6007 FU NCI NIH HHS [U54 CA151838, R01 CA113669, U54 CA151838-03, R01 CA113669-08] NR 33 TC 31 Z9 32 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JAN PY 2012 VL 11 IS 1 BP 165 EP 173 DI 10.1158/1535-7163.MCT-11-0341 PG 9 WC Oncology SC Oncology GA 879CV UT WOS:000299308200016 PM 22027695 ER PT J AU Yang, LY Horibe, T Kohno, M Haramoto, M Ohara, K Puri, RK Kawakami, K AF Yang, Liying Horibe, Tomohisa Kohno, Masayuki Haramoto, Mari Ohara, Koji Puri, Raj K. Kawakami, Koji TI Targeting Interleukin-4 Receptor alpha with Hybrid Peptide for Effective Cancer Therapy SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID PHASE-I TRIAL; BREAST-CARCINOMA CELLS; GAMMA-CHAIN; FUNCTIONAL COMPONENT; PSEUDOMONAS EXOTOXIN; ANTITUMOR-ACTIVITY; CHIMERIC PROTEIN; LYTIC PEPTIDES; IL-4 RECEPTORS; TUMOR-CELLS AB Interleukin-4 receptor alpha (IL-4R alpha) chain is highly expressed on the surface of various human solid tumors. We designed a novel hybrid peptide termed IL-4R alpha-lytic peptide that targets the IL-4R alpha chain. The IL-4R alpha-lytic peptide contains a target moiety to bind to IL-4R alpha and a cellular toxic lytic peptide that selectively kills cancer cells. The anticancer activity of the IL-4R alpha-lytic peptide was evaluated in vitro and in vivo. It was found that the IL-4R alpha-lytic peptide has cytotoxic activity in cancer cell lines expressing IL-4R alpha, determined by quantitative real-time PCR. The IC(50) ratios of the lytic peptide to the IL-4R alpha-lytic peptide correlated well with the expression levels of IL-4R alpha on cancer cells (r = 0.80). In addition, IL-4R alpha-lytic peptide administered either intratumoraly or intravenously significantly inhibited tumor growth in xenograft model of human pancreatic cancer (BXPC-3) in mice. These results indicate that the IL-4R alpha-lytic peptide generated in this study has a potent and selective anticancer potential against IL-4R alpha-positive solid cancers. Mol Cancer Ther; 11(1); 235-43. (C) 2011 AACR. C1 [Yang, Liying; Horibe, Tomohisa; Kohno, Masayuki; Haramoto, Mari; Ohara, Koji; Kawakami, Koji] Kyoto Univ, Grad Sch Med & Publ Hlth, Dept Pharmacoepidemiol, Sakyo Ku, Kyoto 6068501, Japan. [Kohno, Masayuki] Upstream Infin Inc, Minato Ku, Tokyo, Japan. [Puri, Raj K.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Kawakami, K (reprint author), Kyoto Univ, Grad Sch Med & Publ Hlth, Dept Pharmacoepidemiol, Sakyo Ku, Yoshida Konoecho, Kyoto 6068501, Japan. EM kawakami.koji.4e@kyoto-u.ac.jp FU Olympus Corporation FX The study was conducted by a research fund from Olympus Corporation. NR 39 TC 13 Z9 14 U1 2 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JAN PY 2012 VL 11 IS 1 BP 235 EP 243 DI 10.1158/1535-7163.MCT-11-0363 PG 9 WC Oncology SC Oncology GA 879CV UT WOS:000299308200023 PM 22084165 ER PT J AU Shi, Z Sellers, J Moult, J AF Shi, Zhen Sellers, Jenn Moult, John TI Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE missense mutation; machine learning; support vector machine; protein structure; protein stability; phenylketonuria ID GENOTYPE-PHENOTYPE CORRELATIONS; EXPRESSION ANALYSIS; PHENYLKETONURIA MUTATIONS; VITRO EXPRESSION; PKU MUTATIONS; PAH GENE; DEFICIENCY; PREDICTION; DISEASE; TETRAHYDROBIOPTERIN AB A previous computational analysis of missense mutations linked to monogenic disease found a high proportion of missense mutations affect protein stability, rather than other aspects of protein structure and function. The purpose of this study is to relate the presence of such stability damaging missense mutations to the levels of a particular protein present under in vivo like conditions, and to test the reliability of the computational methods. Experimental data on a set of missense mutations of the enzyme phenylalanine hydroxylase (PAH) associated with the monogenic disease phenylketonuria (PKU) have been compared with the expected in vivo impact on protein function, obtained using SNPs3D, an in silico analysis package. A high proportion of the PAH mutations are predicted to be destabilizing. The overall agreement between predicted stability impact and experimental evidence for lower protein levels is in accordance with the estimated error rates of the methods. For these mutations, destabilization of protein three-dimensional structure is the major molecular mechanism leading to PKU, and results in a substantial reduction of in vivo PAH protein concentration. Although of limited scale, the results support the view that destabilization is the most common mechanism by which missense mutations cause monogenic disease. In turn, this conclusion suggests the general therapeutic strategy of developing drugs targeted at restoring wild type stability. Proteins 2012;. (C) 2011 Wiley Periodicals, Inc. C1 [Shi, Zhen; Moult, John] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. [Shi, Zhen] Univ Maryland, Mol & Cell Biol Grad Program, College Pk, MD 20742 USA. [Sellers, Jenn] US FDA, Silver Spring, MD 20993 USA. [Moult, John] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. RP Moult, J (reprint author), Univ Maryland, Inst Biosci & Biotechnol Res, 9600 Gudelsky Dr, Rockville, MD 20850 USA. EM jmoult@umd.edu OI Moult, John/0000-0002-3012-2282 FU National Library of Medicine [R01 LM07174] FX Grant sponsor: National Library of Medicine; Grant number: R01 LM07174 NR 50 TC 11 Z9 11 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0887-3585 J9 PROTEINS JI Proteins PD JAN PY 2012 VL 80 IS 1 BP 61 EP 70 DI 10.1002/prot.23159 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 869LF UT WOS:000298598800006 PM 21953985 ER PT J AU Kandagaddala, LD Kang, MJ Chung, BC Patterson, TA Kwon, OS AF Kandagaddala, Lakshmi Devi Kang, Min-Jung Chung, Bong Chul Patterson, Tucker A. Kwon, Oh-Seung TI Expression and activation of matrix metalloproteinase-9 and NADPH oxidase in tissues and plasma of experimental autoimmune encephalomyelitis in mice SO EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY LA English DT Article DE MMP-9; NADPH oxidase; EAE; CNS tissues; Spleen; Mice ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MYELIN BASIC-PROTEIN; CENTRAL-NERVOUS-SYSTEM; MULTIPLE-SCLEROSIS; GELATINASE-B; CEREBROSPINAL-FLUID; LEWIS RAT; T-CELLS; SUPPRESSION; INDUCTION AB Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for multiple sclerosis (MS) that can be induced by immunization with myelin antigens such as myelin oligodendrocyte glycoprotein (MOG). The objective of this study was (i) to investigate how matrix metalloproteinase-9 (MMP-9) and NADPH oxidase enzymes are affected in the EAE mouse model and (ii) to know whether peripheral organs also express these enzymes in the EAE model. MOG(33-55) was administered subcutaneously on two sites over the back. Pertussis toxin was administered intraperitoneally immediately after MOG and again two days later. A significant difference was observed in body weights and clinical signs of EAE-induced mice. MMP-9 and NADPH oxidase enzymes were measured in central nervous system (CNS) tissues, peripheral tissues and plasma of EAE-induced mice. The primary findings include the distribution pattern of MMP-9 in CNS and peripheral tissues, and alterations in the enzymatic expression of MMP-9 and NADPH oxidase in the CNS tissues, spleen and plasma of EAE-induced mice. From these results, it can be considered that the spleen as well as the CNS can act as target organs in EAE disease, and plasma MMP-9 and NADPH oxidase may contribute to the pathogenesis of the disease. (C) 2010 Published by Elsevier GmbH. C1 [Kandagaddala, Lakshmi Devi; Kang, Min-Jung; Chung, Bong Chul; Kwon, Oh-Seung] Korea Inst Sci & Technol, Toxicol Lab, Seoul 136791, South Korea. [Kandagaddala, Lakshmi Devi; Kang, Min-Jung; Chung, Bong Chul; Kwon, Oh-Seung] Univ Sci & Technol, Taejon 305333, South Korea. [Patterson, Tucker A.] Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. RP Kwon, OS (reprint author), Korea Inst Sci & Technol, Toxicol Lab, Hawolgok Dong 39-1, Seoul 136791, South Korea. EM oskwon@kist.re.kr FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology FX This research was supported, in part, by the Happy Tech. Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology. NR 38 TC 14 Z9 19 U1 0 U2 3 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0940-2993 J9 EXP TOXICOL PATHOL JI Exp. Toxicol. Pathol. PD JAN PY 2012 VL 64 IS 1-2 BP 109 EP 114 DI 10.1016/j.etp.2010.07.002 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA 875LC UT WOS:000299030400016 PM 20810258 ER PT J AU Martin, SA Campbell, JL Tremblay, RT Fisher, JW AF Martin, Sheppard A. Campbell, Jerry L., Jr. Tremblay, Raphael T. Fisher, Jeffrey W. TI Development of a physiologically based pharmacokinetic model for inhalation of jet fuels in the rat SO INHALATION TOXICOLOGY LA English DT Article DE JP-8; S-8; n-alkanes; PBPK modeling; inhalation; aerosol; hydrocarbon mixtures ID PERMISSIBLE EXPOSURE LIMIT; IN-VITRO; NEUROTRANSMITTER LEVELS; PARTITION-COEFFICIENTS; HYDROCARBON MIXTURES; PULMONARY-FUNCTION; FISCHER-344 RATS; TERM EXPOSURE; N-ALKANES; LIVER S9 AB The pharmacokinetic behavior of the majority of jet fuel constituents has not been previously described in the framework of a physiologically based pharmacokinetic (PBPK) model for inhalation exposure. Toxic effects have been reported in multiple organ systems, though exposure methods varied across studies, utilizing either vaporized or aerosolized fuels. The purpose of this work was to assess the pharmacokinetics of aerosolized and vaporized fuels, and develop a PBPK model capable of describing both types of exposures. To support model development, n-tetradecane and n-octane exposures were conducted at 89 mg/m(3) aerosol+vapor and 1000-5000 ppm vapor, respectively. Exposures to JP-8 and S-8 were conducted at similar to 900-1000 mg/m(3), and similar to 200 mg/m(3) to a 50:50 blend of both fuels. Sub-models were developed to assess the behavior of representative constituents and grouped unquantified constituents, termed "lumps", accounting for the remaining fuel mass. The sub-models were combined into the first PBPK model for petroleum and synthetic jet fuels. Inhalation of hydrocarbon vapors was described with simple gas-exchange assumptions for uptake and exhalation. For aerosol droplets systemic uptake occurred in the thoracic region. Visceral tissues were described using perfusion and diffusion-limited equations. The model described kinetics at multiple fuel concentrations, utilizing a chemical "lumping" strategy to estimate parameters for fractions of speciated and unspeciated hydrocarbons and gauge metabolic interactions. The model more accurately simulated aromatic and lower molecular weight (MW) n-alkanes than some higher MW chemicals. Metabolic interactions were more pronounced at high (similar to 2700-1000 mg/m(3)) concentrations. This research represents the most detailed assessment of fuel pharmacokinetics to date. C1 [Martin, Sheppard A.; Tremblay, Raphael T.] Univ Georgia, Interdisciplinary Toxicol Program, Athens, GA 30602 USA. [Campbell, Jerry L., Jr.] Hamner Inst Hlth Sci, Res Triangle Pk, NC USA. [Fisher, Jeffrey W.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Martin, SA (reprint author), US EPA, Neurotoxicol Branch MD B105 03, Tox Assessment Div, Natl Hlth & Environm Effects Res Lab,Off Res & De, Res Triangle Pk, NC 27711 USA. EM martin.sheppard@epa.gov FU Air Force Office of Scientific Research (AFOSR) [FA9550-07-1-0132, FA9550-04-1-0334] FX This work was supported by Air Force Office of Scientific Research (AFOSR) grant FA9550-07-1-0132 and an equipment grant, FA9550-04-1-0334. NR 53 TC 3 Z9 3 U1 3 U2 10 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0895-8378 J9 INHAL TOXICOL JI Inhal. Toxicol. PD JAN PY 2012 VL 24 IS 1 BP 1 EP 26 DI 10.3109/08958378.2011.631297 PG 26 WC Toxicology SC Toxicology GA 873DI UT WOS:000298860700001 PM 22188408 ER PT J AU Peer, CJ Spencer, SD VanDenBerg, DAH Pacanowski, MA Horenstein, RB Figg, WD AF Peer, Cody J. Spencer, Shawn D. VanDenBerg, Dustin A. H. Pacanowski, Michael A. Horenstein, Richard B. Figg, William D. TI A sensitive and rapid ultra HPLC-MS/MS method for the simultaneous detection of clopidogrel and its derivatized active thiol metabolite in human plasma SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Clopidogrel; Active metabolite; Ultra HPLC-MS/MS ID CARBOXYLIC-ACID METABOLITE; CHROMATOGRAPHY/TANDEM MASS-SPECTROMETRY; LC-MS/MS; PHARMACOKINETICS; QUANTIFICATION; POLYMORPHISMS; VALIDATION; PRASUGREL; MS AB A sensitive, selective, and rapid ultra-high performance liquid chromatography-tandem mass spectrometry (uHPLC-MS/MS) was developed for the simultaneous quantification of clopidogrel (Plavix (R)) and its derivatized active metabolite (CAMD) in human plasma. Derivatization of the active metabolite in blood with 2-bromo-3'-methoxy acetophenone (MPB) immediately after collection ensured metabolite stability during sample handling and storage. Following addition of ticlopidine as an internal standard and simple protein precipitation, the analytes were separated on a Waters Acquity UPLC (TM) sub-2 mu m-C(18) column via gradient elution before detection on a triple-quadrupole MS with multiple-reaction-monitoring via electrospray ionization. The method was validated across the clinically relevant concentration range of 0.01-50 ng/mL for parent clopidogrel and 0.1-150 ng/mL (r(2) =0.99) for CAMD, with a fast run time of 1.5 min to support pharmacokinetic studies using 75, 150, or 300 mg oral doses of clopidogrel. The analytical method measured concentrations of clopidogrel and CAMD with accuracy (%DEV) <+/- 12% and precision (%CV) of <+/- 6%. The method was successfully applied to measure the plasma concentrations of clopidogrel and CAMD in three subjects administered single oral doses of 75, 150, and 300 mg clopidogrel. It was further demonstrated that the derivatizing agent (MPB) does not affect clopidogrel levels, thus from one aliquot of blood drawn clinically, this method can simultaneously quantify both clopidogrel and CAMD with sensitivity in the picogram per mL range. Published by Elsevier B.V. C1 [Peer, Cody J.; VanDenBerg, Dustin A. H.; Figg, William D.] NCI, Clin Pharmacol Program, Off Clin Director, Bethesda, MD 20892 USA. [Spencer, Shawn D.] SAIC Frederick Inc, Appl & Dev Res, NCI, Frederick, MD USA. [Pacanowski, Michael A.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Horenstein, Richard B.] Univ Maryland, Div Endocrinol Diabet & Nutr, Sch Med, Baltimore, MD 21201 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, Off Clin Director, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wf13e@nih.gov RI Figg Sr, William/M-2411-2016 FU National Institutes of Health [128475]; National Institute of General Medicine Science [U01GM074518-05S1]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This study was funded by the Bench to Bedside Program of the National Institutes of Health (128475) and the National Institute of General Medicine Science (U01GM074518-05S1).; This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No.HHSN261200800001E. NR 24 TC 28 Z9 32 U1 2 U2 33 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 1 PY 2012 VL 880 BP 132 EP 139 DI 10.1016/j.jchromb.2011.11.029 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 877QS UT WOS:000299197600019 PM 22169056 ER PT J AU Kase, JA Borenstein, S Blodgett, RJ Feng, PCH AF Kase, Julie A. Borenstein, Stacey Blodgett, Robert J. Feng, Peter C. H. TI Microbial Quality of Bagged Baby Spinach and Romaine Lettuce: Effects of Top versus Bottom Sampling SO JOURNAL OF FOOD PROTECTION LA English DT Article ID MICROBIOLOGICAL QUALITY AB Contamination with Escherichia coli O157:H7 and Salmonella have called into question the safety and microbial quality of bagged ready-to-eat leafy greens. This study expands on previous findings that these goods have high total bacteria counts (TBC) and coliform counts, variation in counts among different lots, that Escherichia coli is present, and disparities in counts when bags are top or bottom sampled. Nearly 100 bags of baby spinach and hearts of romaine lettuce from a single brand were subjected to both top and bottom sampling. Product was blended, and a portion serially diluted and plated to obtain TBC. Total coliform and E. coli levels were estimated by the most-probable-number (MPN) technique with ColiComplete discs. Top-sampled TBC from bags of baby spinach (48 bags, 13 different lots) ranged from 3.9 to 8.1 log CFU/g and bottom-sampled TBC ranged from 4.0 to 8.2 log CFU/g, with 52% of the bags (or 39% of the lots) producing TBC higher in bottom samples. For hearts of romaine (47 bags from 19 different lots), top-sampled bags had TBC ranging from 2.4 to 7.0 log, and bottom-sampled bags had TBC from 3.3 to 7.3 log, with 64% of the bags (or 63% of the lots) showing higher TBC in bottom samples. However, we are unable to reject the hypothesis that the top and bottom samples from either commodity contain the same TBC (P >= 0.08). No E. coli was detected and total coliform bacteria counts were, with few exceptions, >= 210 MPN/g, irrespective of TBC. In general, lots with the most number of days before the printed "use-by" date had lower TBC. However, the R-2 values for either baby spinach (0.4085) or hearts of romaine (0.2946) suggest that age might not be a very good predictor of higher TBC. TBC varied widely between lots and even more so within same-lot samples, as indicated by the sum of squares results. This finding, along with higher TBC in bottom samples, suggests further consideration when a microbiological sampling scheme of bagged produce is designed. C1 [Kase, Julie A.; Feng, Peter C. H.] US FDA, Off Regulatory Sci, Div Microbiol, College Pk, MD 20740 USA. [Blodgett, Robert J.] US FDA, Off Food Def Commun & Emergency Response, Div Publ Hlth & Biostat, College Pk, MD 20740 USA. [Borenstein, Stacey] Oak Ridge Res Inst Sci & Educ, Oak Ridge, TN 37830 USA. RP Kase, JA (reprint author), US FDA, Off Regulatory Sci, Div Microbiol, College Pk, MD 20740 USA. EM julie.kase@fda.hhs.gov NR 20 TC 8 Z9 9 U1 3 U2 17 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD JAN PY 2012 VL 75 IS 1 BP 132 EP 136 DI 10.4315/0362-028X.JFP-11-097 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 875VJ UT WOS:000299063000018 PM 22221365 ER PT J AU Dement-Brown, J Newton, CS Ise, T Damdinsuren, B Nagata, S Tolnay, M AF Dement-Brown, Jessica Newton, Christopher S. Ise, Tomoko Damdinsuren, Bazarragchaa Nagata, Satoshi Tolnay, Mate TI Fc receptor-like 5 promotes B cell proliferation and drives the development of cells displaying switched isotypes SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE cell differentiation; receptors; gene expression ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MEDIATED ACTIVATION; MULTIPLE-MYELOMA; T-CELLS; DIVISION; EXPRESSION; DIFFERENTIATION; LYMPHOMA; PROTEIN; MUTATION AB The biological roles of B cell membrane proteins in the FCRL family are enigmatic. FCRL proteins, including FCRL5, were shown to modulate early BCR signaling, although the subsequent, functional consequences of receptor engagement are poorly understood. We found that FCRL5 surface protein itself was induced temporarily upon BCR stimulation of human, naive B cells, indicating precise control over timing of FCRL5 engagement. Cross-linking of FCRL5 on cells induced to express FCRL5 enhanced B cell proliferation significantly. This enhancement required costimulation of the BCR and TLR9, two signals required for optimal proliferation of naive B cells, whereas T cell help in the form of anti-CD40 and IL-2 was dispensable. In addition, we found that FCRL5 stimulation generated a high proportion of cells displaying surface IgG and IgA. Optimal development of cells expressing switched isotypes required T cell help, in addition to stimuli found necessary for enhanced proliferation. Surprisingly, cells that developed upon FCRL5 stimulation simultaneously displayed surface IgM, IgG, and IgA. Cells expressing multiple Ig isotypes were described in hairy cell leukemia, a disease in which FCRL5 is overexpressed. Enhanced proliferation and downstream isotype expression upon FCRL5 stimulation could reflect a physiological role for FCRL5 in the expansion and development of antigen-primed B cells. In addition, FCRL5 may promote growth of malignant cells in hairy cell leukemia and other FCRL5-expressing tumors. J. Leukoc. Biol. 91: 59-67; 2012. C1 [Dement-Brown, Jessica; Newton, Christopher S.; Damdinsuren, Bazarragchaa; Tolnay, Mate] US FDA, Div Monoclonal Antibodies, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Ise, Tomoko; Nagata, Satoshi] Sanford Res Univ S Dakota, Canc Biol Res Ctr, Sioux Falls, SD USA. RP Tolnay, M (reprint author), US FDA, Div Monoclonal Antibodies, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,HFD 123,NIH Bldg,29B, Silver Spring, MD 20993 USA. EM mate.tolnay@fda.hhs.gov FU CDER/FDA; CDER; FDA; Leukemia Research Foundation; Chronic Lymphocytic Leukemia Global Research Foundation FX This work was supported by the Intramural Research Program of CDER/FDA. C.S.N. was supported through the Research Fellowship Program for CDER, administered by the Oak Ridge Associated Universities. B.D. was supported by the FDA Commissioner's Fellowship Program. S.N. was supported by grants from the Leukemia Research Foundation and Chronic Lymphocytic Leukemia Global Research Foundation. We thank Drs. Francisco Borrego, David Frucht, Ed Max, Marjorie Shapiro, and Jennifer Swisher for suggestions and the anonymous blood donors. NR 42 TC 10 Z9 10 U1 2 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JAN PY 2012 VL 91 IS 1 BP 59 EP 67 DI 10.1189/jlb.0211096 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 877HO UT WOS:000299168600008 PM 22028333 ER PT J AU Puig, M Tosh, KW Schramm, LM Grajkowska, LT Kirschman, KD Tami, C Beren, J Rabin, RL Verthelyi, D AF Puig, Montserrat Tosh, Kevin W. Schramm, Lynnsie M. Grajkowska, Lucja T. Kirschman, Kevin D. Tami, Cecilia Beren, Joel Rabin, Ronald L. Verthelyi, Daniela TI TLR9 and TLR7 agonists mediate distinct type I IFN responses in humans and nonhuman primates in vitro and in vivo SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE interferon subtypes; CpG ODN; imiquimod; macaques; skin ID PLASMACYTOID DENDRITIC CELLS; NUCLEIC-ACID RECOGNITION; IMIQUIMOD 5-PERCENT CREAM; INTERFERON-ALPHA SUBTYPES; TOLL-LIKE RECEPTORS; CPG OLIGODEOXYNUCLEOTIDES; TOLL-LIKE-RECEPTOR-9 ACTIVATION; ANTIVIRAL ACTIVITIES; B-CELL; INDUCTION AB Human I-IFNs include IFN-beta and 13 independently regulated subtypes of IFN-alpha (I-IFNs). TLR7 and -9 induce I-IFNs, but it is unknown whether their subtype repertoire is similar. This study used new PCR arrays that selectively amplify individual I-IFN subtype genes of human and nonhuman primates to characterize the TLR7- and -9-mediated IFN response in vitro and in vivo. We show that in human PBMCs, TLR7 agonists induce a rapid burst of I-IFN transcripts, consisting primarily of IFN-alpha 1/13, -alpha 2, and -alpha 14. In contrast, TLR9 agonists, regardless of the type used (CpG C-, B-, or D-ODN), prompted slower but sustained expression of IFN-alpha 1/13, -alpha 2, -alpha 7, -alpha 8, -alpha 10, -alpha 14, -alpha 16, and -alpha 21. These qualitative differences were translated downstream as differences in the pattern of IFN-inducible genes. In macaque PBMCs, imiquimod produced a short burst of IFN mRNA, dominated by IFN-alpha 8, whereas C- or D-ODN induced a greater than tenfold increase in transcripts for all I-IFN subtypes by 12 h of culture. Differences were more evident in vivo, where TLR7 and -9 agonists induced significantly different levels of I-IFN transcripts in skin. Although the rates of gene transcription differed significantly for individual TLR9 agonists, their IFN-alpha subtype signature was almost identical, indicating that the type of receptor dictates the quality of the I-IFN response in vitro and in vivo. These results may underlie the differential therapeutic effects of TLR7 and -9 agonists and should inform future clinical studies. J. Leukoc. Biol. 91: 147-158; 2012. C1 [Puig, Montserrat; Tosh, Kevin W.; Grajkowska, Lucja T.; Tami, Cecilia; Verthelyi, Daniela] US FDA, Immunol Lab, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Schramm, Lynnsie M.; Kirschman, Kevin D.; Rabin, Ronald L.] US FDA, Lab Bacterial Parasite & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Beren, Joel] US FDA, Div Vet Sci, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Verthelyi, D (reprint author), US FDA, Immunol Lab, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bldg 29A,Room 3B19,8800 Rockville Pike, Bethesda, MD 20892 USA. EM daniela.verthelyi@fda.hhs.gov FU ORISE; US Department of Energy; US Food and Drug Administration FX The authors thank Dr. Ray Donnelly, Dr. Howard Young, and Claire Grunes for reviewing the manuscript. Salary support for K.W.T. and L.T.G. was provided through ORISE as an interagency agreement between the US Department of Energy and the US Food and Drug Administration. In addition, we thank Dr. Phil Snoy, Lewis Shankle, and the Animal Care Facility staff for their expert care of the nonhuman primates included in this study. NR 60 TC 12 Z9 14 U1 0 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JAN PY 2012 VL 91 IS 1 BP 147 EP 158 DI 10.1189/jlb.0711371 PG 12 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 877HO UT WOS:000299168600016 PM 22058422 ER PT J AU Miller, DL Balter, S Dixon, RG Nikolic, B Bartal, G Cardella, JF Dauer, LT Stecker, MS AF Miller, Donald L. Balter, Stephen Dixon, Robert G. Nikolic, Boris Bartal, Gabriel Cardella, John F. Dauer, Lawrence T. Stecker, Michael S. CA Soc Interventional Radiology Stand TI Quality Improvement Guidelines for Recording Patient Radiation Dose in the Medical Record for Fluoroscopically Guided Procedures SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID INTERVENTIONAL RADIOLOGY PROCEDURES; SKIN INJURIES; AREA PRODUCT; CARDIAC-CATHETERIZATION; RAD-IR; EXPOSURE; MANAGEMENT; CARDIOLOGY; DOSIMETRY; FILMS C1 [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Miller, Donald L.] Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, F Edward Hebert Sch Med, Bethesda, MD USA. [Balter, Stephen] Columbia Univ, Dept Radiol, New York, NY 10027 USA. [Balter, Stephen] Columbia Univ, Dept Med, New York, NY 10027 USA. [Dauer, Lawrence T.] Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10021 USA. [Dixon, Robert G.] Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. [Nikolic, Boris] Albert Einstein Med Ctr, Dept Radiol, Philadelphia, PA 19141 USA. [Cardella, John F.] Geisinger Hlth Syst, Dept Radiol, Danville, PA USA. [Bartal, Gabriel] Meir Med Ctr, Dept Diagnost & Intervent Radiol, Kefar Sava, Israel. [Stecker, Michael S.] Brigham & Womens Hosp, Div Angiog & Intervent Radiol, Boston, MA 02115 USA. RP Miller, DL (reprint author), 3975 Fair Ridge Dr,Suite 400 N, Fairfax, VA 22033 USA. EM donald.miller@fda.hhs.gov OI Dauer, Lawrence/0000-0002-5629-8462 NR 70 TC 38 Z9 40 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JAN PY 2012 VL 23 IS 1 BP 11 EP 18 DI 10.1016/j.jvir.2011.09.004 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 877BL UT WOS:000299151400003 PM 22057151 ER PT J AU Dauer, LT Thornton, RH Miller, DL Damilakis, J Dixon, RG Marx, V Schueler, BA Vano, E Venkatesan, A Bartal, G Tsetis, D Cardella, JF AF Dauer, Lawrence T. Thornton, Raymond H. Miller, Donald L. Damilakis, John Dixon, Robert G. Marx, Victoria Schueler, Beth A. Vano, Eliseo Venkatesan, Aradhana Bartal, Gabriel Tsetis, Dimitrios Cardella, John F. CA Soc Interventional Radiology Cardiovasc Interventional TI Radiation Management for Interventions Using Fluoroscopic or Computed Tomographic Guidance during Pregnancy: A Joint Guideline of the Society of Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe with Endorsement by the Canadian Interventional Radiology Association SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID EXPOSED IN-UTERO; CT PULMONARY ANGIOGRAPHY; SEVERE MENTAL-RETARDATION; MONTE-CARLO SIMULATIONS; BOMB SURVIVORS; X-RAY; IONIZING-RADIATION; CHILDHOOD-CANCER; MULTIDETECTOR CT; RADIOGRAPHIC EXAMINATIONS C1 [Dauer, Lawrence T.] Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10021 USA. [Thornton, Raymond H.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Miller, Donald L.] Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, F Edward Hebert Sch Med, Bethesda, MD USA. [Venkatesan, Aradhana] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Damilakis, John] Univ Crete, Dept Med Phys, Fac Med, Iraklion, Greece. [Tsetis, Dimitrios] Univ Crete, Dept Radiol, Fac Med, Iraklion, Greece. [Tsetis, Dimitrios] Univ Hosp Herakl, Dept Radiol, Iraklion, Greece. [Dixon, Robert G.] Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. Los Angeles Cty, Dept Radiol, Los Angeles, CA USA. Univ So Calif, Med Ctr, Los Angeles, CA USA. [Schueler, Beth A.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Vano, Eliseo] Univ Complutense, Dept Radiol, E-28040 Madrid, Spain. [Bartal, Gabriel] Meir Med Ctr, Dept Diagnost & Intervent Radiol, Kefar Sava, Israel. [Cardella, John F.] Geisinger Hlth Syst, Dept Radiol, Danville, PA USA. RP Dauer, LT (reprint author), Care of Katsarelis D, SIR, 3975 Fair Ridge Dr,Suite 400 N, Fairfax, VA 22033 USA. EM dauerl@mskcc.org OI Dauer, Lawrence/0000-0002-5629-8462 NR 119 TC 21 Z9 22 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JAN PY 2012 VL 23 IS 1 BP 19 EP 32 DI 10.1016/j.jvir.2011.09.007 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 877BL UT WOS:000299151400004 PM 22112899 ER PT J AU Braid, HE Deeds, J DeGrasse, SL Wilson, JJ Osborne, J Hanner, RH AF Braid, Heather Elizabeth Deeds, Jonathan DeGrasse, Stacey Lea Wilson, John James Osborne, Josephine Hanner, Robert Harland TI Preying on commercial fisheries and accumulating paralytic shellfish toxins: a dietary analysis of invasive Dosidicus gigas (Cephalopoda Ommastrephidae) stranded in Pacific Canada SO MARINE BIOLOGY LA English DT Article ID GULF-OF-CALIFORNIA; JUMBO SQUID; DOMOIC ACID; DNA BARCODES; MONTEREY BAY; SAXITOXIN; FOOD; USA AB In fall of 2009, several mass strandings of Humboldt squid (Dosidicus gigas) occurred on Vancouver Island (49 degrees 7' 60N 125 degrees 54'0W). Morphological dissections coupled with DNA barcoding of stomach contents revealed Sardinops sagax (Pacific sardine) and Clupea pallasii (Pacific herring) as their primary prey. Plastic nurdles, fishing line, bull kelp, eelgrass, and a guillemot feather were also discovered. The primary prey, Pacific sardines and Pacific herring, are known to bioaccumulate paralytic shellfish toxins (PSTs); additionally, both PSTs and domoic acid (DA) have been implicated in other mass strandings. Therefore, stomach contents, and other tissues when possible, were tested for PSTs and DA. Testing revealed DA concentrations below regulatory guidance levels for human consumption, yet PSTs were well in excess. Though we cannot conclude that PSTs were the definitive cause of the strandings, our findings are the first report of PSTs in D. gigas. C1 [Braid, Heather Elizabeth; Wilson, John James; Hanner, Robert Harland] Univ Guelph, Dept Integrat Biol, Guelph, ON N1G 2W1, Canada. [Deeds, Jonathan; DeGrasse, Stacey Lea] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Osborne, Josephine] Raincoast Educ Soc, Tofino, BC V0R 2Z0, Canada. RP Braid, HE (reprint author), Auckland Univ Technol, Sch Appl Sci, Earth & Ocean Sci Res Inst, Auckland 1010, New Zealand. EM heather.braid@gmail.com; jonathan.deeds@fda.hhs.gov; stacey.degrasse@fda.hhs.gov; wilso04@gmail.com; josie.osborne@gmail.com; rhanner@uoguelph.ca RI Wilson, John James/C-4656-2012; OI DeGrasse, Stacey/0000-0001-7808-4193 FU University of Guelph URA; Work Study programs; Canadian Barcode of Life Network via Genome Canada (through the Ontario Genomics Institute); Natural Sciences and Engineering Research Council (NSERC); Ontario Ministry of Research and Innovation FX We would like to thank the following people for their insights and comments on an earlier draft of this manuscript: Timothy Bartley, Amanda Naaum, Elizabeth Clare, Robin Floyd, and Kevin Kerr. Andy Braid, Joan Rafter, and the people at VIA Rail assisted in transporting the specimens. We would also like to thank the kind people at Takis' Taverna for storing our specimens in their freezer while logistical transportation issues were being resolved. We acknowledge the University of Guelph URA and Work Study programs for support of HB, as well as funding from the Canadian Barcode of Life Network via Genome Canada (through the Ontario Genomics Institute), the Natural Sciences and Engineering Research Council (NSERC), and the Ontario Ministry of Research and Innovation, for sequencing and informatics support as provided by the Biodiversity Institute of Ontario. NR 38 TC 21 Z9 22 U1 5 U2 38 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0025-3162 J9 MAR BIOL JI Mar. Biol. PD JAN PY 2012 VL 159 IS 1 BP 25 EP 31 DI 10.1007/s00227-011-1786-4 PG 7 WC Marine & Freshwater Biology SC Marine & Freshwater Biology GA 877RF UT WOS:000299198900003 ER PT J AU Pogribny, IP James, SJ Beland, FA AF Pogribny, Igor P. James, S. Jill Beland, Frederick A. TI Molecular alterations in hepatocarcinogenesis induced by dietary methyl deficiency SO MOLECULAR NUTRITION & FOOD RESEARCH LA English DT Review DE DNA methylation; Hepatocarcinogenesis; Histone methylation; Methyl-deficient diet; MicroRNA ID ADENOSYL-L-METHIONINE; ACID-DEFINED DIET; PROTEIN-KINASE-C; GLOBAL DNA HYPOMETHYLATION; RAT-LIVER CARCINOGENESIS; CHOLINE-DEFICIENT; NONALCOHOLIC STEATOHEPATITIS; S-ADENOSYLMETHIONINE; HEPATOCELLULAR CARCINOMAS; HISTONE MODIFICATIONS AB A chronic deficiency of major dietary methyl group donors methionine, choline, folic acid, and vitamin B12 can induce the development of liver cancer in rodents. Feeding methyl-deficient diets causes several molecular alterations, including altered lipid metabolism, oxidative stress, deregulated one-carbon metabolism, and a number of epigenetic abnormalities that result in progressive liver injury culminating in the development of primary liver tumors. Importantly, this methyl-deficient model of endogenous hepatocarcinogenesis is one of the most relevant models of human liver carcinogenesis that allows studying liver cancer pathogenesis by substantially complementing many shortcomings of humans-only studies. In this review, we describe molecular changes and their role in pathogenesis of liver carcinogenesis induced by methyl deficiency. C1 [Pogribny, Igor P.; Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [James, S. Jill] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov NR 111 TC 22 Z9 23 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1613-4125 EI 1613-4133 J9 MOL NUTR FOOD RES JI Mol. Nutr. Food Res. PD JAN PY 2012 VL 56 IS 1 BP 116 EP 125 DI 10.1002/mnfr.201100524 PG 10 WC Food Science & Technology SC Food Science & Technology GA 871NM UT WOS:000298744900009 PM 22095781 ER PT J AU Marler, JR AF Marler, John R. TI Secondary Analysis of Clinical Trials-A Cautionary Note SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review DE Secondary analysis; Clinical trial; Methodology ID SUBGROUP ANALYSES AB There is concern in published reports and reviews that patients are being harmed or denied effective treatment by the use of questionable results from secondary analyses of data from clinical trials. A well-reported secondary analysis must make clear to the reader the uncertainty of the result -so clear, in fact, that it should be an obvious part of the conclusions that implementation should await confirmation as the primary outcome in an adequately powered trial. Those who write, review and publish these reports have a responsibility to ensure that reports accurately describe the sources of uncertainty, explain complex methods and their weaknesses with clarity, and convince readers to require better evidence before changing their practice. (Prog Cardiovasc Dis 2012;54:335-337) Published by Elsevier Inc. C1 US FDA, Div Neurol Prod, CDER, Silver Spring, MD 20993 USA. RP Marler, JR (reprint author), US FDA, Div Neurol Prod, CDER, Silver Spring, MD 20993 USA. EM john.marler@fda.hhs.gov NR 10 TC 3 Z9 3 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-0620 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD JAN-FEB PY 2012 VL 54 IS 4 BP 335 EP 337 DI 10.1016/j.pcad.2011.09.006 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 875JT UT WOS:000299026900003 PM 22226000 ER PT J AU Perlstein, TS Goldhaber, SZ Nelson, K Joshi, V Morgan, TV Lesko, LJ Lee, JY Gobburu, J Schoenfeld, D Kucherlapati, R Freeman, MW Creager, MA AF Perlstein, Todd S. Goldhaber, Samuel Z. Nelson, Kerrie Joshi, Victoria Morgan, T. Vance Lesko, Lawrence J. Lee, Joo-Yeon Gobburu, Jogarao Schoenfeld, David Kucherlapati, Raju Freeman, Mason W. Creager, Mark A. TI The Creating an Optimal Warfarin Nomogram (CROWN) Study SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Pharmacogenetics; warfarin; clinical trial ID ORAL ANTICOAGULATION; ATRIAL-FIBRILLATION; LABELING DECISIONS; VKORC1 HAPLOTYPES; DRUG APPLICATIONS; CLINICAL FACTORS; CHINESE PATIENTS; CYP2C9 VARIANTS; IMPACT; GENOTYPE AB A significant proportion of warfarin dose variability is explained by variation in the genotypes of the cytochrome P450 CYP2C9 and the vitamin K epoxide reductase complex, VKORC1, enzymes that influence warfarin metabolism and sensitivity, respectively. We sought to develop an optimal pharmacogenetic warfarin dosing algorithm that incorporated clinical and genetic information. We enroled patients initiating warfarin therapy. Genotyping was performed of the VKORC1, -1639G>A, the CYP2C9*2, 430C>T, and the CYP2C9*3,1075C>A genotypes. The initial warfarin dosing algorithm (Algorithm A) was based upon established clinical practice and published warfarin pharmacogenetic information. Subsequent dosing algorithms (Algorithms B and Algorithm C) were derived from pharmacokinetic / pharmacodynamic (PK/PD) modelling of warfarin dose, international normalised ratio (INR), clinical and genetic factors from patients treated by the preceding algorithm(s). The primary outcome was the time in the therapeutic range, considered an INR of 1.8 to 3.2.A total of 344 subjects are included in the study analyses. The mean percentage time within the therapeutic range for each subject increased progressively from Algorithm A toAlgorithm C from 58.9 (22.0), to 59.7 (23.0), to 65.8 (16.9) percent (p = 0.04). Improvement also occurred in most secondary endpoints, which included the per-patient percentage of INRs outside of the therapeutic range (p = 0.004), the time to the first therapeutic INR (p = 0.07), and the time to achieve stable therapeutic anticoagulation (p < 0.001). In conclusion, warfarin pharmacogenetic dosing can be optimised in real time utilising observed PK/PD information in an adaptive fashion. C1 [Perlstein, Todd S.; Goldhaber, Samuel Z.; Creager, Mark A.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Nelson, Kerrie; Schoenfeld, David] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Schoenfeld, David] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Freeman, Mason W.] Massachusetts Gen Hosp, Lipid Metab Unit, Boston, MA 02114 USA. [Freeman, Mason W.] Massachusetts Gen Hosp, Div Endocrine, Boston, MA 02114 USA. [Joshi, Victoria] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Joshi, Victoria] Brigham & Womens Hosp, Partners Ctr Personalized Genet Med, Boston, MA 02115 USA. [Morgan, T. Vance; Kucherlapati, Raju] Harvard Univ, Sch Med, Ctr Personalized Genet Med, Boston, MA USA. [Lesko, Lawrence J.; Lee, Joo-Yeon; Gobburu, Jogarao] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Creager, MA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM mcreager@partners.org FU Partners HealthCare; National Heart, Lung, and Blood Institute [K12-HL083786] FX This work was funded by Partners HealthCare through a grant to the Harvard Partners Center for Personalized Genetic Medicine. Dr Perlstein received support from the National Heart, Lung, and Blood Institute Research Career Development Award K12-HL083786. Dr. Creager is the Simon C. Fireman Scholar in Cardiovascular Medicine at Brigham and Women's Hospital. NR 37 TC 7 Z9 7 U1 0 U2 8 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD JAN PY 2012 VL 107 IS 1 BP 59 EP 68 DI 10.1160/TH11-08-0568 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 879UO UT WOS:000299357900012 PM 22116191 ER PT J AU Ernst, PB Erickson, LD Loo, WM Scott, KG Wiznerowicz, EB Brown, CC Torres-Velez, FJ Alam, MS Black, SG McDuffie, M Feldman, SH Wallace, JL McKnight, GW Padol, IT Hunt, RH Tung, KS AF Ernst, P. B. Erickson, L. D. Loo, W. M. Scott, K. G. Wiznerowicz, E. B. Brown, C. C. Torres-Velez, F. J. Alam, M. S. Black, S. G. McDuffie, M. Feldman, S. H. Wallace, J. L. McKnight, G. W. Padol, I. T. Hunt, R. H. Tung, K. S. TI Spontaneous autoimmune gastritis and hypochlorhydria are manifest in the ileitis-prone SAMP1/YitFcs mice SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE parietal cell; autoantibodies; autoimmune gastritis; model of Crohn's disease ID INFLAMMATORY-BOWEL-DISEASE; REGULATORY T-CELLS; HELICOBACTER-PYLORI; CROHNS-DISEASE; MURINE MODEL; INTESTINAL INFLAMMATION; CYTOKINE PRODUCTION; CUTTING EDGE; B-CELLS; MOUSE AB Ernst PB, Erickson LD, Loo WM, Scott KG, Wiznerowicz EB, Brown CC, Torres-Velez FJ, Alam MS, Black SG, McDuffie M, Feldman SH, Wallace JL, McKnight GW, Padol IT, Hunt RH, Tung KS. Spontaneous autoimmune gastritis and hypochlorhydria are manifest in the ileitis-prone SAMP1/YitFcs mice. Am J Physiol Gastrointest Liver Physiol 302: G105-G115, 2012. First published September 15, 2011; doi:10.1152/ajpgi.00194.2011.-SAMP1/YitFcs mice serve as a model of Crohn's disease, and we have used them to assess gastritis. Gastritis was compared in SAMP1/YitFcs, AKR, and C57BL/6 mice by histology, immunohistochemistry, and flow cytometry. Gastric acid secretion was measured in ligated stomachs, while anti-parietal cell antibodies were assayed by immunofluorescence and enzyme-linked immunosorbent spot assay. SAMP1/YitFcs mice display a corpus-dominant, chronic gastritis with multifocal aggregates of mononuclear cells consisting of T and B lymphocytes. Relatively few aggregates were observed elsewhere in the stomach. The infiltrates in the oxyntic mucosa were associated with the loss of parietal cell mass. AKR mice, the founder strain of the SAMP1/YitFcs, also have gastritis, although they do not develop ileitis. Genetic studies using SAMP1/YitFcs-C57BL/6 congenic mice showed that the genetic regions regulating ileitis had comparable effects on gastritis. The majority of the cells in the aggregates expressed the T cell marker CD3 or the B cell marker B220. Adoptive transfer of SAMP1/YitFcs CD(4+) T helper cells, with or without B cells, into immunodeficient recipients induced a pangastritis and duodenitis. SAMP1/YitFcs and AKR mice manifest hypochlorhydria and anti-parietal cell antibodies. These data suggest that common genetic factors controlling gastroenteric disease in SAMP1/YitFcs mice regulate distinct pathogenic mechanisms causing inflammation in separate sites within the digestive tract. C1 [Ernst, P. B.; Erickson, L. D.; Loo, W. M.] Univ Virginia, Dept Microbiol, Charlottesville, VA 22908 USA. [Ernst, P. B.; Wiznerowicz, E. B.; Black, S. G.] Univ Virginia, Dept Med, Charlottesville, VA 22908 USA. [McDuffie, M.] Univ Virginia, Dept Pediat, Charlottesville, VA 22908 USA. [Tung, K. S.] Univ Virginia, Dept Pathol, Charlottesville, VA 22908 USA. [Feldman, S. H.] Univ Virginia, Ctr Comparat Med, Charlottesville, VA 22908 USA. [Scott, K. G.] Univ Manitoba, Dept Biol, Winnipeg, MB, Canada. [Wallace, J. L.; McKnight, G. W.; Padol, I. T.; Hunt, R. H.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Wallace, J. L.; McKnight, G. W.; Padol, I. T.; Hunt, R. H.] McMaster Univ, Farncombe Inst, Hamilton, ON, Canada. [Brown, C. C.] Univ Georgia, Coll Vet Med, Dept Pathol, Athens, GA 30602 USA. [Torres-Velez, F. J.] NIAID, Infect Dis Pathogenesis Sect, Bethesda, MD 20892 USA. [Alam, M. S.] US FDA, Immunobiol Branch, Ctr Food Safety & Nutr, Laurel, MD USA. RP Ernst, PB (reprint author), Univ Calif San Diego, Dept Pathol, Div Comparat Pathol & Med, 9500 Gilman Dr,MC 0063, La Jolla, CA 92093 USA. EM pernst@ucsd.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [DK-051677, DK-84063]; Canadian Association of Gastroenterology; National Institute of Allergy and Infectious Diseases [AI-41236, AI-51420, DK 57880] FX This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-051677 and DK-84063 (to P. B. Ernst), a Research Fellowship from the Canadian Association of Gastroenterology (to K. G. Scott), National Institute of Allergy and Infectious Diseases AI-41236 and AI-51420 (to K. S. Tung), and DK 57880 (M. McDuffie). NR 45 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD JAN PY 2012 VL 302 IS 1 BP G105 EP G115 DI 10.1152/ajpgi.00194.2011 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 869ZZ UT WOS:000298640200011 PM 21921286 ER PT J AU Sander, LC Bedner, M Tims, MC Yen, JH Duewer, DL Porter, B Christopher, SJ Day, RD Long, SE Molloy, JL Murphy, KE Lang, BE Lieberman, R Wood, LJ Payne, MJ Roman, MC Betz, JM NguyenPho, A Sharpless, KE Wise, SA AF Sander, L. C. Bedner, M. Tims, M. C. Yen, J. H. Duewer, D. L. Porter, B. Christopher, S. J. Day, R. D. Long, S. E. Molloy, J. L. Murphy, K. E. Lang, B. E. Lieberman, R. Wood, L. J. Payne, M. J. Roman, M. C. Betz, J. M. NguyenPho, A. Sharpless, K. E. Wise, S. A. TI Development and certification of green tea-containing standard reference materials SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Green tea; Camellia sinensis; Standard Reference Material; Catechins; Xanthines; Toxic elements; Theanine ID PERFORMANCE LIQUID-CHROMATOGRAPHY; MICELLAR ELECTROKINETIC CHROMATOGRAPHY; COULOMETRIC ARRAY DETECTION; IONIZATION MASS-SPECTROMETRY; MS-ELECTROSPRAY DETECTION; COMMERCIAL CANNED GREEN; SOLID-PHASE EXTRACTION; GALLIC ACID; PURINE ALKALOIDS; INDIVIDUAL CATECHINS AB A suite of three green tea-containing Standard Reference Materials (SRMs) has been issued by the National Institute of Standards and Technology (NIST): SRM 3254 Camellia sinensis (Green Tea) Leaves, SRM 3255 Camellia sinensis (Green Tea) Extract, and SRM 3256 Green Tea-Containing Solid Oral Dosage Form. The materials are characterized for catechins, xanthine alkaloids, theanine, and toxic elements. As many as five methods were used in assigning certified and reference values to the constituents, with measurements carried out at NIST and at collaborating laboratories. The materials are intended for use in the development and validation of new analytical methods, and for use as control materials as a component in the support of claims of metrological traceability. C1 [Sander, L. C.; Bedner, M.; Tims, M. C.; Duewer, D. L.; Porter, B.; Long, S. E.; Molloy, J. L.; Murphy, K. E.; Lieberman, R.; Wood, L. J.; Sharpless, K. E.; Wise, S. A.] NIST, Div Analyt Chem, Gaithersburg, MD 20899 USA. [Yen, J. H.] NIST, Stat Engn Div, Gaithersburg, MD 20899 USA. [Christopher, S. J.; Day, R. D.] NIST, Div Analyt Chem, Charleston, SC 29412 USA. [Lang, B. E.] NIST, Div Biochem Sci, Gaithersburg, MD 20899 USA. [Payne, M. J.] Hershey Co, Hershey, PA 17033 USA. [Roman, M. C.] Tampa Bay Analyt Res Inc, Largo, FL 33777 USA. [Betz, J. M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [NguyenPho, A.] US FDA, Ctr Drug Evaluat & Res CDER, Silver Spring, MD 20993 USA. RP Sander, LC (reprint author), NIST, Div Analyt Chem, Gaithersburg, MD 20899 USA. EM lane.sander@nist.gov FU National Institutes of Health, Office of Dietary Supplements FX Partial funding for this work was provided by the National Institutes of Health, Office of Dietary Supplements. M. Schantz and E. McGaw (NIST) are acknowledged for pesticide screening of the three SRMs. NR 59 TC 15 Z9 15 U1 0 U2 13 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JAN PY 2012 VL 402 IS 1 BP 473 EP 487 DI 10.1007/s00216-011-5472-7 PG 15 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 871PE UT WOS:000298749300051 PM 22127575 ER PT J AU Ashutosh Garg, M Sundar, S Duncan, R Nakhasi, HL Goyal, N AF Ashutosh Garg, Mansi Sundar, Shyam Duncan, Robert Nakhasi, Hira L. Goyal, Neena TI Downregulation of Mitogen-Activated Protein Kinase 1 of Leishmania donovani Field Isolates Is Associated with Antimony Resistance SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID TRIOXIDE-INDUCED APOPTOSIS; INDUCED OXIDATIVE STRESS; INDIAN KALA-AZAR; GENE-EXPRESSION; VISCERAL LEISHMANIASIS; ARSENIC TRIOXIDE; DRUG-RESISTANCE; FLAGELLAR LENGTH; LEUKEMIA-CELLS; MAP KINASES AB Emergence of resistance to pentavalent antimonials has become a severe obstacle in the treatment of visceral leishmaniasis (VL) on the Indian subcontinent. The mechanisms operating in laboratory-generated strains are somewhat known, but the determinants of clinical antimony resistance are not well understood. By utilizing a DNA microarray expression profiling approach, we identified a gene encoding mitogen-activated protein kinase 1 (MAPK1) for the kinetoplast protozoan Leishmania donovani (LdMAPK1) that was consistently downregulated in antimony-resistant field isolates. The expression level of the gene was validated by real-time PCR. Furthermore, decreased expression of LdMAPK1 was also confirmed at the protein level in resistant isolates. Primary structure analysis of LdMAPK1 revealed the presence of all of the characteristic features of MAPK1. When expressed in Escherichia coli, the recombinant enzyme showed kinase activity with myelin basic protein as the substrate and was inhibited by staurosporine. Interestingly, overexpression of this gene in a drug-sensitive laboratory strain and a resistant field isolate resulted in increased the sensitivity of the transfectants to potassium antimony tartrate, suggesting that it has a role in antimony resistance. Our results demonstrate that downregulation of LdMAPK1 may be in part correlated with antimony drug resistance in Indian VL isolates. C1 [Ashutosh; Goyal, Neena] Cent Drug Res Inst, Div Biochem, Council Sci & Ind Res, Lucknow 226001, Uttar Pradesh, India. [Sundar, Shyam] Banaras Hindu Univ, Inst Med Sci, Varanasi 221005, Uttar Pradesh, India. [Duncan, Robert] FDA, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Bethesda, MD USA. RP Goyal, N (reprint author), Cent Drug Res Inst, Div Biochem, Council Sci & Ind Res, Chattar Manzil Pl, Lucknow 226001, Uttar Pradesh, India. EM neenacdri@yahoo.com OI Singhal, Ashutosh/0000-0002-9172-1916 FU Department of Science and Technology, India [SR/SO/BB-037/2009]; Department of Biotechnology, India [BT/PR2792/Med/14/383/2001]; CSIR FX This work was supported by Department of Science and Technology, India (SR/SO/BB-037/2009), and Department of Biotechnology, India (BT/PR2792/Med/14/383/2001), grants. CSIR is gratefully acknowledged for financial support to Ashutosh and Mansi Garg. NR 62 TC 9 Z9 9 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2012 VL 56 IS 1 BP 518 EP 525 DI 10.1128/AAC.00736-11 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 866TB UT WOS:000298404900062 PM 22064540 ER PT J AU Rajabi, M Struble, E Zhou, ZH Karnaukhova, E AF Rajabi, Mohsen Struble, Evi Zhou, Zhaohua Karnaukhova, Elena TI Potentiation of C1-esterase inhibitor by heparin and interactions with C1s protease as assessed by surface plasmon resonance SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE C1-esterase inhibitor; C1s; Heparin; Surface plasmon resonance ID PROTAMINE-INDUCED CONSUMPTION; CIRCULAR-DICHROISM SPECTRA; HEREDITARY ANGIOEDEMA; SECONDARY STRUCTURE; HUMAN C1-INHIBITOR; TERNARY COMPLEX; DEXTRAN SULFATE; C INHIBITOR; BINDING; MECHANISM AB Background: Human C1-esterase inhibitor (C1-INH) is a multifunctional plasma protein with a wide range of inhibitory and non-inhibitory properties, mainly recognized as a key down-regulator of the complement and contact cascades. The potentiation of C1-INH by heparin and other glycosaminoglycans (GAGs) regulates a broad spectrum of C1-INH activities in vivo both in normal and disease states. Scope of research: We have studied the potentiation of human C1-INH by heparin using Surface Plasmon Resonance (SPR), circular dichroism (CD) and a functional assay. To advance a SPR for multiple-unit interaction studies of C1-INH we have developed a novel (consecutive double capture) approach exploring different immobilization and layout. Major conclusions: Our SPR experiments conducted in three different design versions showed marked acceleration in C1-INH interactions with complement protease C1s as a result of potentiation of C1-INH by heparin (from 5- to 11-fold increase of the association rate). Far-UV CD studies suggested that heparin binding did not alter C1-INH secondary structure. Functional assay using chromogenic substrate confirmed that heparin does not affect the amidolytic activity of C1s, but does accelerate its consumption due to C1-INH potentiation. General significance: This is the first report that directly demonstrates a significant acceleration of the C1-INH interactions with C1s due to heparin by using a consecutive double capture SPR approach. The results of this study may be useful for further C-INH therapeutic development, ultimately for the enhancement of current C1-INH replacement therapies. Published by Elsevier B.V. C1 [Rajabi, Mohsen; Karnaukhova, Elena] US FDA, Lab Biochem & Vasc Biol, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Struble, Evi] US FDA, Lab Plasma Derivat, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Zhou, Zhaohua] US FDA, Div Monoclonal Antibodies, Ctr Drugs Evaluat & Res, Bethesda, MD 20892 USA. RP Karnaukhova, E (reprint author), US FDA, Lab Biochem & Vasc Biol, Div Hematol, Ctr Biol Evaluat & Res, 8800 Rockville Pike,Natl Inst Hlth Bldg 29, Bethesda, MD 20892 USA. EM elena.karnaukhova@fda.hhs.gov FU Oak Ridge Institute for Science and Education (ORISE) FX The authors are thankful to Dr. Michael Murphy (GE Healthcare) for the consultation and discussion of the SPR results and to Dr. Abdu Alayash (Center for Biologics Evaluation and Research, FDA) for critical reading of the manuscript and helpful comments. MR is grateful to the Oak Ridge Institute for Science and Education (ORISE) for fellowship. NR 45 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD JAN PY 2012 VL 1820 IS 1 BP 56 EP 63 DI 10.1016/j.bbagen.2011.10.008 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 867NO UT WOS:000298461300006 PM 22040724 ER PT J AU Jeffrey, M McGovern, G Chambers, EV King, D Gonzalez, L Manson, JC Ghetti, B Piccardo, P Barron, RM AF Jeffrey, Martin McGovern, Gillian Chambers, Emily V. King, Declan Gonzalez, Lorenzo Manson, Jean C. Ghetti, Bernardino Piccardo, Pedro Barron, Rona M. TI Mechanism of PrP-Amyloid Formation in Mice Without Transmissible Spongiform Encephalopathy SO BRAIN PATHOLOGY LA English DT Article DE amyloid plaques; Gerstmann-Straussler-Scheinker; neurodegeneration; prion protein; scrapie ID STRAUSSLER-SCHEINKER-DISEASE; PROTEASE-RESISTANT STATE; SCRAPIE-ASSOCIATED FORM; ABNORMAL PRION PROTEIN; 87V MURINE SCRAPIE; KURU PLAQUES; ANTIBODIES; P102L; BRAIN; AGENT AB GerstmannStrausslerScheinker (GSS) P102L disease is a familial form of a transmissible spongiform encephalopathy (TSE) that can present with or without vacuolation of neuropil. Inefficient disease transmission into 101LL transgenic mice was previously observed from GSS P102L without vacuolation. However, several aged, healthy mice had large plaques composed of abnormal prion protein (PrPd). Here we perform the ultrastructural characterization of such plaques and compare them with PrPd aggregates found in TSE caused by an infectious mechanism. PrPd plaques in 101LL mice varied in maturity, with some being composed of deposits without visible amyloid fibrils. PrPd was present on cell membranes in the vicinity of all types of plaques. In contrast to the unicentric plaques seen in infectious murine scrapie, the plaques seen in the current model were multicentric and were initiated by protofibrillar forms of PrPd situated on oligodendroglia, astrocytes and neuritic cell membranes. We speculate that the initial conversion process leading to plaque formation begins with membrane-bound PrPC but that subsequent fibrillization does not require membrane attachment. We also observed that the membrane alterations consistently seen in murine scrapie and other infectious TSEs were not present in 101LL mice with plaques, suggesting differences in the pathogenesis of these conditions. C1 [Jeffrey, Martin; McGovern, Gillian; Gonzalez, Lorenzo] Anim Hlth Vet Labs Agcy, Bush Loan Penicuik, Midlothian, Scotland. [Chambers, Emily V.; King, Declan; Manson, Jean C.; Piccardo, Pedro; Barron, Rona M.] Univ Edinburgh, Neuropathogenesis Div, Roslin Inst, Roslin, Midlothian, Scotland. [Chambers, Emily V.; King, Declan; Manson, Jean C.; Piccardo, Pedro; Barron, Rona M.] Univ Edinburgh, RD SVS, Roslin, Midlothian, Scotland. [Ghetti, Bernardino; Piccardo, Pedro] Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA. [Ghetti, Bernardino; Piccardo, Pedro] Indiana Univ Sch Med, Div Neuropathol, Indianapolis, IN USA. [Piccardo, Pedro] US FDA, Lab Bacterial & TSE Agents, Rockville, MD 20857 USA. RP Jeffrey, M (reprint author), Vet Labs Agcy, Pentlands Sci Pk, Bush Loan Penicuik EH26 0PZ, Midlothian, Scotland. EM martin.jeffrey@ahvla.gsi.gov.uk RI Gonzalez, Lorenzo/A-5325-2010; Barron, Rona/C-7703-2013; Jeffrey, Martin/D-2251-2009; McGOVERN, GILLIAN/C-3441-2011; APHA, Staff publications/E-6082-2010; OI Gonzalez, Lorenzo/0000-0003-4199-4526; McGOVERN, GILLIAN/0000-0001-5344-5909; Barron, Rona/0000-0003-4512-9177 FU Biotechnology and Biological Sciences Research Council (BBSRC); Defra [Se1790]; NIH-NIAID [Y1-AI-4893-02]; FDA [224-05-1307]; [PHS P30 AG 10133] FX Thanks to Byron Caughey, Rocky Mountain Laboratories, MT, USA for antibodies R18, R20, R24 and R30. These studies were partly funded by the Biotechnology and Biological Sciences Research Council (BBSRC), Defra grant Se1790 and NIH-NIAID Agreement No. Y1-AI-4893-02 and FDA Agreement No. 224-05-1307. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy.; Professor Ghetti is supported by grant PHS P30 AG 10133. NR 45 TC 15 Z9 15 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1015-6305 J9 BRAIN PATHOL JI Brain Pathol. PD JAN PY 2012 VL 22 IS 1 BP 58 EP 66 DI 10.1111/j.1750-3639.2011.00508.x PG 9 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 860CL UT WOS:000297924900006 PM 21645162 ER PT J AU Wang, CG Wang, Z Prows, DR Wu, RL AF Wang, Chenguang Wang, Zhong Prows, Daniel R. Wu, Rongling TI A computational framework for the inheritance pattern of genomic imprinting for complex traits SO BRIEFINGS IN BIOINFORMATICS LA English DT Article ID ACUTE LUNG INJURY; MAMMALIAN DEVELOPMENT; LOCI; GENE; MODEL; EXPRESSION; SURVIVAL; CROSSES; MICE AB Genetic imprinting, by which the expression of a gene depends on the parental origin of its alleles, may be subjected to reprogramming through each generation. Currently, such reprogramming is limited to qualitative description only, lacking more precise quantitative estimation for its extent, pattern and mechanism. Here, we present a computational framework for analyzing the magnitude of genetic imprinting and its transgenerational inheritance mode. This quantitative model is based on the breeding scheme of reciprocal backcrosses between reciprocal F(1) hybrids and original inbred parents, in which the transmission of genetic imprinting across generations can be tracked. We define a series of quantitative genetic parameters that describe the extent and transmission mode of genetic imprinting and further estimate and test these parameters within a genetic mapping framework using a new powerful computational algorithm. The model and algorithm described will enable geneticists to identify and map imprinted quantitative trait loci and dictate a comprehensive atlas of developmental and epigenetic mechanisms related to genetic imprinting. We illustrate the new discovery of the role of genetic imprinting in regulating hyperoxic acute lung injury survival time using a mouse reciprocal backcross design. C1 [Wang, Zhong; Wu, Rongling] Penn State Univ, Ctr Stat Genet, University Pk, PA 16802 USA. [Wu, Rongling] Beijing Forestry Univ, Ctr Computat Biol, Beijing, Peoples R China. [Wang, Chenguang] US FDA, Ctr Devices & Radiol Hlth, Off Surveillance & Biometr, Rockville, MD 20857 USA. [Prows, Daniel R.] Univ Cincinnati, Coll Medicine, Cincinnati, OH 45221 USA. RP Wu, RL (reprint author), Penn State Canc Inst, 500 Univ Dr, Hershey, PA 17033 USA. EM rwu@hes.hmc.psu.edu RI Wang, Zhong/C-3737-2014 FU Changjiang Scholars Award; Beijing Forestry University; [DMS/NIGMS-0540745] FX Joint grant DMS/NIGMS-0540745; the Changjiang Scholars Award; 'One-thousand Person Plan' Award at Beijing Forestry University. NR 31 TC 12 Z9 12 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1467-5463 J9 BRIEF BIOINFORM JI Brief. Bioinform. PD JAN PY 2012 VL 13 IS 1 BP 34 EP 45 DI 10.1093/bib/bbr023 PG 12 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 873MU UT WOS:000298888200003 PM 21565936 ER PT J AU Sutherland, JB Bridges, BM Heinze, TM Adams, MR Delio, PJ Hotchkiss, C Rafii, F AF Sutherland, John B. Bridges, Brad M. Heinze, Thomas M. Adams, Michael R. Delio, Patrick J. Hotchkiss, Charlotte Rafii, Fatemeh TI Comparison of the Effects of Antimicrobial Agents from Three Different Classes on Metabolism of Isoflavonoids by Colonic Microflora Using Etest Strips SO CURRENT MICROBIOLOGY LA English DT Article ID INTESTINAL BACTERIA; SOY ISOFLAVONES; DAIDZEIN; EQUOL; CHILDREN; ADULTS; HEALTH; RATS AB Daidzein (4',7-dihydroxyisoflavone), a phytoestrogen found in soybeans mainly in the form of its glycoside daidzin, is metabolized by colonic bacteria to compounds with altered estrogenic activities, which may affect human health. Antibacterial agents used for the treatment of infections can alter the composition of bacterial populations in the colon and therefore can affect daidzein metabolism. To rapidly detect the effects of different concentrations of antibiotics on daidzein metabolism by colonic bacteria of monkeys and identify the subpopulation involved in daidzein metabolism, Etest strips containing antibacterial agents from three classes (tetracyclines, fluoroquinolones, and beta-lactams) were used to eliminate the colonic bacteria that were susceptible to 0-32 mu g/ml of each antibacterial agent and test the surviving bacteria for their ability to metabolize daidzein. The metabolism of daidzein by the colonic microflora was measured before and after the colonic bacterial population was exposed to antibacterial agents. The metabolites were detected by high performance liquid chromatography and mass spectrometry after incubation of the cultures for various times. Exposure of colonic microflora to antibiotics had various effects on daidzein metabolism. Tetracycline completely removed the bacteria metabolizing daidzein, metabolism of daidzein was not changed in cultures of bacteria after ceftriaxone treatment, and ciprofloxacin enriched for the bacteria metabolizing daidzein. In liquid cultures treated with various concentrations of ciprofloxacin, 4 mu g/ml of ciprofloxacin favored the growth of bacteria that metabolized daidzein. This is the first time in which the Etest has been used to show that, whereas some antibiotics eliminate phytoestrogen-metabolizing bacteria in colonic microflora, others enrich them by eliminating the non-metabolizing strains in the population. C1 [Sutherland, John B.; Bridges, Brad M.; Heinze, Thomas M.; Rafii, Fatemeh] Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. [Adams, Michael R.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Delio, Patrick J.; Hotchkiss, Charlotte] Univ Washington, Washington Natl Res Primate Ctr, Seattle, WA 98195 USA. RP Rafii, F (reprint author), Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. EM Fatemeh.Rafii@fda.hhs.gov FU National Center for Toxicological Research; U.S. Department of Energy; U.S. Food and Drug Administration FX We offer special thanks to Dr. Anane Aidoo and Dr. Mugimane Manjanatha for reviewing the manuscript and Dr. Carl E. Cerniglia for his research support. This study was supported in part by an appointment (B.M.B.) to the Summer Student Research Program at the National Center for Toxicological Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The views presented in this article do not necessarily reflect those of the FDA. NR 21 TC 3 Z9 3 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0343-8651 J9 CURR MICROBIOL JI Curr. Microbiol. PD JAN PY 2012 VL 64 IS 1 BP 60 EP 65 DI 10.1007/s00284-011-0020-4 PG 6 WC Microbiology SC Microbiology GA 870ET UT WOS:000298652600008 PM 22006071 ER PT J AU Menis, M Anderson, SA Izurieta, HS Kumar, S Burwen, DR Gibbs, J Kropp, G Erten, T MaCurdy, TE Worrall, CM Kelman, JA Walderhaug, MO AF Menis, Mikhail Anderson, Steven A. Izurieta, Hector S. Kumar, Sanjai Burwen, Dale R. Gibbs, Jonathan Kropp, Garner Erten, Tugce MaCurdy, Thomas E. Worrall, Christopher M. Kelman, Jeffrey A. Walderhaug, Mark O. TI Babesiosis among Elderly Medicare Beneficiaries, United States, 2006-2008 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID TRANSFUSION AB We used administrative databases to assess babesiosis among elderly persons in the United States by year, sex, age, race, state of residence, and diagnosis months during 2006 2008. The highest babesiosis rates were in Connecticut, Rhode Island, New York, and Massachusetts, and findings suggested babesiosis expansion to other states. C1 [Menis, Mikhail] US FDA, Analyt Epidemiol Branch, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res,Div Epidemiol, Rockville, MD 20852 USA. [Gibbs, Jonathan; Kropp, Garner; Erten, Tugce; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [Worrall, Christopher M.; Kelman, Jeffrey A.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. RP Menis, M (reprint author), US FDA, Analyt Epidemiol Branch, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res,Div Epidemiol, 1401 Rockville Pike,HFM-225, Rockville, MD 20852 USA. EM mikhail.menis@fda.hhs.gov FU Food and Drug Administration FX The research was supported through internal Food and Drug Administration funds. NR 15 TC 8 Z9 8 U1 0 U2 2 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JAN PY 2012 VL 18 IS 1 BP 128 EP 131 DI 10.3201/eid1801.110305 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 874QK UT WOS:000298973000024 PM 22257500 ER PT J AU Kamikawa, TL Mikolajczyk, MG Kennedy, M Zhong, LL Zhang, P Setterington, EB Scott, DE Alocilja, EC AF Kamikawa, Tracy L. Mikolajczyk, Malgorzata G. Kennedy, Michael Zhong, Lilin Zhang, Pei Setterington, Emma B. Scott, Dorothy E. Alocilja, Evangelyn C. TI Pandemic Influenza Detection by Electrically Active Magnetic Nanoparticles and Surface Plasmon Resonance SO IEEE TRANSACTIONS ON NANOTECHNOLOGY LA English DT Article DE Biosensor; direct-charge transfer; electrically active; immunomagnetic; influenza ID CHARGE TRANSFER BIOSENSOR; BACILLUS-ANTHRACIS SPORES; ESCHERICHIA-COLI O157-H7; MOLECULAR-INTERACTIONS; POLYANILINE; VIRUS; NANOCOMPOSITES; ELECTRODES; ASSAY; HEMAGGLUTININ AB Influenza A virus (FLUAV), the causative agent of influenza infection, has received extensive attention due to the recent swine-origin H1N1 pandemic. FLUAV has long been the cause of annual epidemics as well as less frequent but more severe global pandemics. Here, we describe a biosensor utilizing electrically active magnetic (EAM) polyaniline-coated nanoparticles as the transducer in an electrochemical biosensor for rapidly identifying FLUAV strains based on receptor specificity, which will be useful to monitor animal influenza infections and to characterize pandemic potential of strains that have transmitted from animals to humans. Pandemic potential requires human-to-human transmissibility, which is dependent upon FLUAV hemagglutinin (HA) specificity for host glycan receptors. Avian FLUAV preferentially bind to alpha 2,3-linked receptors, while human FLUAV bind to alpha 2,6-linked receptors. EAM nanoparticles were prepared by synthesizing aniline monomer around gamma iron (III) oxide (gamma-Fe(2)O(3)) cores, yielding 25-100-nm diameter nanoparticles that were structurally characterized by transmission electron microscopy and electron diffraction. The EAM nanoparticles were coated with monoclonal antibodies specific to H5N1 (A/Vietnam/1203/04). Specificity of binding between glycans and H5 was demonstrated. The biosensor results were correlative to supporting data from a surface plasmon resonance assay that characterized HA/glycan binding and alpha-H5 antibody activity. This novel study applies EAM nanoparticles as the transducer in a specific, portable, easy-to-use biosensor with great potential for disease monitoring and biosecurity applications. C1 [Kamikawa, Tracy L.; Mikolajczyk, Malgorzata G.; Kennedy, Michael; Zhong, Lilin; Zhang, Pei; Scott, Dorothy E.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Setterington, Emma B.; Alocilja, Evangelyn C.] Michigan State Univ, Dept Biosyst & Agr Engn, E Lansing, MI 48824 USA. RP Kamikawa, TL (reprint author), US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM tracy.kamikawa@fda.hhs.gov; malgorzata.mikolajczyk@fda.hhs.gov; michael.kennedy@fda.hhs.gov; lilin.zhong@fda.hhs.gov; pei.zhang@fda.hhs.gov; ebs@msu.edu; dorothy.scott@fda.hhs.gov; alocilja@msu.edu FU U.S. Food and Drug Administration, Center for Biologics Evaluation and Research FX This work was supported by Critical Path Funding from the U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. "The findings and conclusions in this publication have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy." The review of this paper was arranged by Associate Editor J. O. Jensen. NR 50 TC 3 Z9 3 U1 3 U2 42 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1536-125X J9 IEEE T NANOTECHNOL JI IEEE Trans. Nanotechnol. PD JAN PY 2012 VL 11 IS 1 BP 88 EP 96 DI 10.1109/TNANO.2011.2157936 PG 9 WC Engineering, Electrical & Electronic; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Engineering; Science & Technology - Other Topics; Materials Science; Physics GA 874ZQ UT WOS:000298998400014 ER PT J AU Nonnecke, BJ Waters, WR Goff, JP Foote, MR AF Nonnecke, B. J. Waters, W. R. Goff, J. P. Foote, M. R. TI Adaptive immunity in the colostrum-deprived calf: Response to early vaccination with Mycobacterium bovis strain bacille Calmette Guerin and ovalbumin SO JOURNAL OF DAIRY SCIENCE LA English DT Article DE preruminant calf; neonatal vaccination; colostrum deprived; bacille Calmette Guerin vaccination ID NATURAL-KILLER-CELLS; NEONATAL CALVES; MONONUCLEAR LEUKOCYTES; IMMUNOLOGICAL RESPONSES; INFECTED MACROPHAGES; ANTIBODY-RESPONSES; MATERNAL ANTIBODY; MEDIATED-IMMUNITY; MILK REPLACER; NEWBORN CALF AB Responses of the newborn calf to vaccination are frequently characterized by marginal antibody (Ab) responses. The present study evaluated effects of colostrum ingestion on the adaptive immune response of the preruminant calf to early vaccination. Colostrum-fed (CF) and colostrum-deprived (CD) calves were vaccinated at 2 d of age with Mycobacterium bovis, Pasteur strain of bacille Calmette Guerin (BCG), and ovalbumin (OVA) to track development of the adaptive immune response during the first 8 wk of life. Dams were also vaccinated with BCG prepartum. At wk 0, serum IgG(1), IgG(2), IgA, and IgM were elevated in CF calves, with IgG(1) predominating. In these calves, IgG(2), IgA, and IgM concentrations decreased with age. The CD calves, in contrast, had very low or undetectable serum immunoglobulin concentrations at wk 0 followed by an age-related increase in IgG(1), IgG(2), and IgM concentrations, suggesting endogenous production of these immunoglobulin classes. Immunoblot and ELISA analyses of Ab response to BCG vaccination indicated that colostrum ingestion was associated with measurable serum anti-mycobacterial Ab in CF calves during the first month postpartum, with substantially lower levels at 7 wk of age. Although mycobacteria-specific Ab was undetectable in CD calves at wk 0, it was present at 4 and 7 wk of age, suggesting that these calves, unlike CF calves, were capable of generating an Ab response to BCG vaccination. Antibody responses of CF and CD calves to vaccination with OVA, an antigen not present in the natural environment of dairy cattle, were of comparable magnitude and characterized by a progressive increase in Ab levels from birth (wk 0) to 7 wk of age. The disparate Ab responses of CF calves to BCG and OVA suggest that maternal antigenic experience or exposure influences Ab responses of the colostrum-fed preruminant calf to early vaccination. Ex vivo, antigen [OVA and M. bovis-derived purified protein derivative (PPDb)]-induced IFN-gamma and nitric oxide responses of blood mononuclear cells (PBMC) from CF and CD calves were comparable at wk 0 and wk 7. As expected, responses were very low or nonexistent at wk 0. Responses for all calves were greater at wk 7 than at wk 0, suggesting a colostrum-independent maturation of the cell-mediated immune response capacity of the preruminant calf. The consistently greater proliferative responses of antigen-stimulated T-cell subsets at wk 7 versus wk 0 indicate the development of antigen-specific lymphocyte responses to early vaccination. Total numbers of blood leukocytes as well as numbers of lymphocytes and monocytes were unaffected by colostrum feeding; however, granulocyte numbers were higher in CD than in CF calves at wk 0. Granulocyte numbers decreased and monocyte numbers increased with age in all calves. Within the lymphocyte population, only natural killer (NK(+)) cell percentages were affected by colostrum ingestion, with higher percentages of NK(+) cells in CD calves at wk 0 and wk 7. Antigen-induced proliferation of lymphocyte subsets including IgM(+) cells was unaffected by colostrum ingestion. In conclusion, ingestion of colostrum within hours after birth inhibited the capacity of the calf to produce antigen-specific immunoglobulin (i.e., antibody) in response to vaccination, with little or no effect on cell-mediated immune responses. Although colostrum appeared to block endogenous antibody production, certain B-cell functions were retained. These findings will aid in development of ew vaccination strategies for improving health of the preruminant calf. C1 [Nonnecke, B. J.; Goff, J. P.] USDA Agr Res Serv, Natl Ctr Anim Hlth, Ruminant Dis & Immunol Res Unit, Ames, IA 50010 USA. [Waters, W. R.] USDA Agr Res Serv, Natl Ctr Anim Hlth, Infect Bacterial Dis Cattle Res Unit, Ames, IA 50010 USA. [Foote, M. R.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20817 USA. RP Nonnecke, BJ (reprint author), USDA Agr Res Serv, Natl Ctr Anim Hlth, Ruminant Dis & Immunol Res Unit, 1920 Dayton Rd, Ames, IA 50010 USA. EM brian.nonnecke@ars.usda.gov NR 43 TC 9 Z9 10 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-0302 J9 J DAIRY SCI JI J. Dairy Sci. PD JAN PY 2012 VL 95 IS 1 BP 221 EP 239 DI 10.3168/jds.2011-4712 PG 19 WC Agriculture, Dairy & Animal Science; Food Science & Technology SC Agriculture; Food Science & Technology GA 864KV UT WOS:000298239800024 PM 22192201 ER PT J AU Epstein, S AF Epstein, Suzanne TI T-Cell Immune Responses and Asymptomatic H5N1 Influenza Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID AVIAN INFLUENZA; A H5N1 C1 US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Epstein, S (reprint author), US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, 1401 Rockville Pike,HFM 730, Rockville, MD 20852 USA. EM suzanne.epstein@fda.hhs.gov NR 13 TC 2 Z9 2 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 1 PY 2012 VL 205 IS 1 BP 4 EP 6 DI 10.1093/infdis/jir692 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 866MW UT WOS:000298386200002 PM 22080097 ER PT J AU Chen, IL Gao, WY Johnson, AP Niak, A Troiani, J Korvick, J Snow, N Estes, K Taylor, A Griebel, D AF Chen, Ii-Lun Gao, Wen-Yi Johnson, Aisha P. Niak, Ali Troiani, John Korvick, Joyce Snow, Nancy Estes, Kristina Taylor, Amy Griebel, Donna TI Proton Pump Inhibitor Use in Infants: FDA Reviewer Experience SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Review DE Advisory Committee; clinical trials; efficacy; GERD; infants; proton pump inhibitor; safety ID ACID; THERAPY; REFLUX; SECRETION; ASSOCIATION; SYMPTOMS; BIRTH AB The Food and Drug Administration has completed its review of 4 clinical trials evaluating the use of proton pump inhibitors (PPIs) in infants (ages 1 month to < 12 months) for the treatment of gastroesophageal reflux disease (GERD). An Advisory Committee meeting was held in November 2010 to discuss the potential reasons why PPI use in these trials failed to show a benefit in infants with GERD, and directions for future study. The present review summarizes the findings from the clinical trials. Potential mechanisms for the failed clinical trials are discussed. The safety of long-term use is also discussed. As a result of our analysis and review, the authors agree with the Advisory Committee members that PPIs should not be administered to treat the symptoms of GERD in the otherwise healthy infant without the evidence of acid-induced disease. C1 [Chen, Ii-Lun; Gao, Wen-Yi; Johnson, Aisha P.; Niak, Ali; Troiani, John; Korvick, Joyce; Snow, Nancy; Griebel, Donna] Food & Drug Adm, Div Gastroenterol & Inborn Errors Prod, Silver Spring, MD 20993 USA. [Taylor, Amy] Food & Drug Adm, Pediat & Maternal Hlth Staff, Off New Drugs, Silver Spring, MD 20993 USA. [Estes, Kristina] Food & Drug Adm, Div Clin Pharmacol 3, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Gao, WY (reprint author), Food & Drug Adm, Div Gastroenterol & Inborn Errors Prod, Bldg 22,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM wen-yi.gao@fda.hhs.gov NR 33 TC 37 Z9 40 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD JAN PY 2012 VL 54 IS 1 BP 8 EP 14 DI 10.1097/MPG.0b013e31823890b4 PG 7 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 868UG UT WOS:000298550800005 PM 21946832 ER PT J AU Rubin, SA Link, MA Sauder, CJ Zhang, C Ngo, L Rima, BK Duprex, WP AF Rubin, Steven A. Link, Malen A. Sauder, Christian J. Zhang, Cheryl Ngo, Laurie Rima, Bert K. Duprex, W. Paul TI Recent Mumps Outbreaks in Vaccinated Populations: No Evidence of Immune Escape SO JOURNAL OF VIROLOGY LA English DT Article ID HEMAGGLUTININ-NEURAMINIDASE PROTEIN; JERYL-LYNN; MONOCLONAL-ANTIBODIES; UNIVERSITY-STUDENTS; UNITED-STATES; VIRUS-VACCINE; FOLLOW-UP; STRAIN; SEQUENCE; LIVE AB Recently, numerous large-scale mumps outbreaks have occurred in vaccinated populations. Clinical isolates sequenced from these outbreaks have invariably been of genotypes distinct from those of vaccine viruses, raising concern that certain mumps virus strains may escape vaccine-induced immunity. To investigate this concern, sera obtained from children 6 weeks after receipt of measles, mumps, and rubella (MMR) vaccine were tested for the ability to neutralize a carefully selected group of genetically diverse mumps virus strains. Although the geometric mean neutralizing antibody titer of the sera was lower against some virus strains than others, all viruses were readily neutralized, arguing against immune escape. C1 [Rubin, Steven A.; Link, Malen A.; Sauder, Christian J.; Zhang, Cheryl; Ngo, Laurie] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Rima, Bert K.] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Belfast, Antrim, North Ireland. [Duprex, W. Paul] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Rubin, SA (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. EM steven.rubin@fda.hhs.gov OI Duprex, W Paul/0000-0003-1716-6376 FU National Vaccine Program Office FX This work was supported in part by a grant by the National Vaccine Program Office administered by the Oak Ridge Institute for Science and Education. NR 63 TC 28 Z9 29 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN PY 2012 VL 86 IS 1 BP 615 EP 620 DI 10.1128/JVI.06125-11 PG 6 WC Virology SC Virology GA 865YV UT WOS:000298347700062 PM 22072778 ER PT J AU Sahiner, B Chan, HP Hadjiiski, LM Helvie, MA Wei, J Zhou, C Lu, Y AF Sahiner, Berkman Chan, Heang-Ping Hadjiiski, Lubomir M. Helvie, Mark A. Wei, Jun Zhou, Chuan Lu, Yao TI Computer-aided detection of clustered microcalcifications in digital breast tomosynthesis: A 3D approach SO MEDICAL PHYSICS LA English DT Article DE digital breast tomosynthesis; computer-aided detection; microcalcification ID SCREENING MAMMOGRAPHY; DETECTION SYSTEM; CANCER-DETECTION; RECONSTRUCTION ALGORITHMS; MASS DETECTION; CT SCANS; PERFORMANCE; CLASSIFICATION; EXPERIENCE; ENHANCEMENT AB Purpose: To design a computer-aided detection (CADe) system for clustered microcalcifications in reconstructed digital breast tomosynthesis (DBT) volumes and to perform a preliminary evaluation of the CADe system. Methods: IRB approval and informed consent were obtained in this study. A data set of two-view DBT of 72 breasts containing microcalcification clusters was collected from 72 subjects who were scheduled to undergo breast biopsy. Based on tissue sampling results, 17 cases had breast cancer and 55 were benign. A separate data set of two-view DBT of 38 breasts free of clustered microcalcifications from 38 subjects was collected to independently estimate the number of false-positives (FPs) generated by the CADe system. A radiologist experienced in breast imaging marked the biopsied cluster of microcalcifications with a 3D bounding box using all available clinical and imaging information. A CADe system was designed to detect microcalcification clusters in the reconstructed volume. The system consisted of prescreening, clustering, and false-positive reduction stages. In the prescreening stage, the conspicuity of microcalcification-like objects was increased by an enhancement-modulated 3D calcification response function. An iterative thresholding and 3D object growing method was used to detect cluster seed objects, which were used as potential centers of microcalcification clusters. In the cluster detection stage, microcalcification candidates were identified using a second iterative thresholding procedure, which was applied to the signal-to-noise ratio (SNR) enhanced image voxels with a positive calcification response. Starting with each cluster seed object as the initial cluster center, a dynamic clustering algorithm formed a cluster candidate by including microcalcification candidates within a 3D neighborhood of the cluster seed object that satisfied the clustering criteria. The number, size, and SNR of the microcalcifications in a cluster candidate and the cluster shape were used to reduce the number of FPs. Results: The prescreening stage detected a cluster seed object in 94% of the biopsied microcalcification clusters at a threshold of 100 cluster seed objects per DBT volume. After clustering, the detection sensitivity was 90% at 15 marks per DBT volume. After FP reduction, at 85% sensitivity, the average number of FPs estimated using the data set containing microcalcification clusters was 3.8 per DBT volume, and that estimated using the data set free of microcalcification clusters was 3.4. The detection performance for malignant microcalcification clusters was superior to that for benign clusters. Conclusions: Our study indicates the feasibility of the 3D approach to the detection of clustered microcalcifications in DBT and that the newly designed enhancement-modulated 3D calcification response function is promising for prescreening. Further work is needed to assess the generalizability of our approach and to improve its performance. (C) 2012 American Association of Physicists in Medicine. [DOI: 10.1118/1.3662072] C1 [Sahiner, Berkman; Chan, Heang-Ping; Hadjiiski, Lubomir M.; Helvie, Mark A.; Wei, Jun; Zhou, Chuan; Lu, Yao] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. RP Sahiner, B (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM berki@umich.edu FU USPHS [R01 CA151443, R33 CA120234, CA91713] FX This work is supported by USPHS Grant Nos. R01 CA151443 and R33 CA120234. The content of this paper does not necessarily reflect the position of the funding agencies and no official endorsement of any equipment and product of any companies mentioned should be inferred. The digital breast tomosynthesis system was developed by the GE Global Research Group, with input and some revisions from the University of Michigan investigators through the Biomedical Research Partnership (USPHS Grant No. CA91713, PI: Paul Carson, Ph.D.). NR 41 TC 22 Z9 24 U1 0 U2 11 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JAN PY 2012 VL 39 IS 1 BP 28 EP 39 DI 10.1118/1.3662072 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 872LX UT WOS:000298812200005 PM 22225272 ER PT J AU Fang, Y Badal, A Allec, N Karim, KS Badano, A AF Fang, Yuan Badal, Andreu Allec, Nicholas Karim, Karim S. Badano, Aldo TI Spatiotemporal Monte Carlo transport methods in x-ray semiconductor detectors: Application to pulse-height spectroscopy in a-Se SO MEDICAL PHYSICS LA English DT Article DE Swank factor; semiconductor detector; Monte Carlo; amorphous selenium ID AMORPHOUS SELENIUM; PHOTOGENERATION; RECOMBINATION; MAMMOGRAPHY; SIMULATION AB Purpose: The authors describe a detailed Monte Carlo (MC) method for the coupled transport of ionizing particles and charge carriers in amorphous selenium (a-Se) semiconductor x-ray detectors, and model the effect of statistical variations on the detected signal. Methods: A detailed transport code was developed for modeling the signal formation process in semiconductor x-ray detectors. The charge transport routines include three-dimensional spatial and temporal models of electron-hole pair transport taking into account recombination and trapping. Many electron-hole pairs are created simultaneously in bursts from energy deposition events. Carrier transport processes include drift due to external field and Coulombic interactions, and diffusion due to Brownian motion. Results: Pulse-height spectra (PHS) have been simulated with different transport conditions for a range of monoenergetic incident x-ray energies and mammography radiation beam qualities. Two methods for calculating Swank factors from simulated PHS are shown, one using the entire PHS distribution, and the other using the photopeak. The latter ignores contributions from Compton scattering and K-fluorescence. Comparisons differ by approximately 2% between experimental measurements and simulations. Conclusions: The a-Se x-ray detector PHS responses simulated in this work include three-dimensional spatial and temporal transport of electron-hole pairs. These PHS were used to calculate the Swank factor and compare it with experimental measurements. The Swank factor was shown to be a function of x-ray energy and applied electric field. Trapping and recombination models are all shown to affect the Swank factor. Swank factor. (C) 2012 American Association of Physicists in Medicine. [DOI: 10.1118/1.3669486] C1 [Fang, Yuan; Badal, Andreu; Badano, Aldo] US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Fang, Yuan; Allec, Nicholas; Karim, Karim S.] Univ Waterloo, Dept Elect & Comp Engn, Waterloo, ON N2L 3G1, Canada. RP Fang, Y (reprint author), US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM yuan.fang@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 FU Carl A. Pollock postgraduate fellowship award; Center for Devices and Radiological Health; Natural Sciences and Engineering Council (NSERC) FX The authors wish to thank the support of Robert J. Jennings for the computer software used for generation of standard beam qualities. The author (Y.F.) acknowledges support from Carl A. Pollock postgraduate fellowship award, and funding by appointments to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U. S. Department of Energy and the U. S. Food and Drug Administration. This work was also supported in part by the Natural Sciences and Engineering Council (NSERC). The mention of commercial products herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. This is a contribution of the U. S. Food and Drug Administration and is not subject to copyright. NR 34 TC 11 Z9 11 U1 0 U2 8 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JAN PY 2012 VL 39 IS 1 BP 308 EP 319 DI 10.1118/1.3669486 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 872LX UT WOS:000298812200034 PM 22225301 ER PT J AU Easter, RN Barry, CG Pyne-Geithman, G Caruso, JA AF Easter, Renee N. Barry, Colin G. Pyne-Geithman, Gail Caruso, Joseph A. TI Significant proteins affecting cerebral vasospasm using complementary ICPMS and MALDI-MS SO METALLOMICS LA English DT Article ID ABDOMINAL AORTIC-ANEURYSMS; GLOMERULAR-FILTRATION-RATE; THIOL-SPECIFIC ANTIOXIDANT; CYSTATIN-C DEFICIENCY; SUBARACHNOID HEMORRHAGE; AMYLOID ANGIOPATHY; GLUTATHIONE-PEROXIDASE; SERUM CONCENTRATION; CARBONIC-ANHYDRASE; CYSTEINE PROTEASES AB Cerebral vasospasm (CV) following subarachnoid hemorrhagic stroke affects more than one million people each year. The etiology and prevention of CV is currently of great interest to researchers in various fields of medical science. More recently, the idea that selenium could be playing a major role in the onset of cerebral vasospasm has come into the spotlight. This study focused on using newly established metallomics techniques in order to explore the proteome associated with CV and if selenium might affect the discovered proteins. Size exclusion chromatography coupled to inductively coupled plasma mass spectrometry, along with LC-MALDI-TOF/TOF were both essential in determining protein identifications in three different sample types; a control (normal, healthy patient, CSF control), SAH stroke patients (no vasospasm, CSF C) and SAH CV patients (CSF V). The results of this study, although preliminary, indicate the current methods are applicable and warrant further application to these clinically important targets. C1 [Easter, Renee N.; Caruso, Joseph A.] Univ Cincinnati, Dept Chem, Cincinnati, OH 45221 USA. [Easter, Renee N.; Barry, Colin G.] US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. [Pyne-Geithman, Gail] Univ Cincinnati, Dept Neurosurg, Cincinnati, OH 45267 USA. RP Caruso, JA (reprint author), Univ Cincinnati, Dept Chem, Cincinnati, OH 45221 USA. EM joseph.caruso@uc.edu FU US FDA FX The authors wish to thank Agilent Technologies for instrumentation support and the US FDA STEP program for financial support for RNE. We would also like to thank Todd Abruzzo, MD, Mayfield Clinic, for Fig. 1. NR 53 TC 2 Z9 2 U1 2 U2 7 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1756-5901 EI 1756-591X J9 METALLOMICS JI Metallomics PY 2012 VL 4 IS 1 BP 48 EP 55 DI 10.1039/c1mt00079a PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 873ED UT WOS:000298862900006 PM 21976047 ER PT J AU Chen, T Li, ZG Yan, J Yang, X Salminen, W AF Chen, Tao Li, Zhiguang Yan, Jian Yang, Xi Salminen, William TI MicroRNA expression profiles distinguish the carcinogenic effects of riddelliine in rat liver SO MUTAGENESIS LA English DT Article ID DNA ADDUCT FORMATION; ETHYL-N-NITROSOUREA; COMFREY SYMPHYTUM-OFFICINALE; BLUE TRANSGENIC RATS; S-PHASE SYNTHESIS; PYRROLIZIDINE ALKALOIDS; ARISTOLOCHIC ACID; GENE-EXPRESSION; MEDICINAL-PLANTS; METABOLIC-ACTIVATION AB Pyrrolizidine alkaloids (PAs) are the most common plant constituents that poison livestock, wildlife and humans. Riddelliine is a prototype genotoxic PA and has been nominated to be classified as a reasonably anticipated human carcinogen by the US National Toxicology Program (NTP) in the 12th Report on Carcinogens. Riddelliine's nomination is due to the high incidence of liver tumours that were observed in both mice and rats in the NTP tumourigenicity bioassay study. In this current study, we explored whether riddelliine treatment could alter microRNA (miRNA) expression in rat liver and whether the possible deregulation of miRNA was related to mutagenicity and carcinogenicity of riddelliine. Groups of six rats were administered riddelliine at a mutagenic dose of 1 mg/kg body weight or with control vehicle 5 days a week for 12 weeks. A group of six rats treated with aristolochic acid, a renal carcinogen, was used as a tissue-specific negative control. The animals were sacrificed 1 day after the last treatment and the livers were isolated for miRNA expression analysis using miRNA microarrays. miRNA expression was significantly altered by riddelliine treatment. Principal component analysis and hierarchical clustering analysis showed that the miRNA expression profiles were clearly classified into two groups, riddelliine treatment versus other samples. Forty-seven miRNAs were significantly dysregulated by riddelliine treatment, among which 38 were up-regulated and 9 were down-regulated. Functional analysis of these differentially expressed miRNAs by riddelliine revealed that these miRNAs were involved in liver carcinogenicity and toxicity, such as liver proliferation, liver necrosis/cell death, hepatocellular carcinoma, liver hepatomegaly, liver inflammation and liver fibrosis. These results suggest that miRNAs actively respond to a mutagenic dose of riddelliine and the pattern of miRNA expression has the potential to be used as a biomarker of genotoxicity and carcinogenicity for riddelliine and possibly other PAs. C1 [Chen, Tao; Li, Zhiguang; Yan, Jian] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Yang, Xi; Salminen, William] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. RP Chen, T (reprint author), US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM tao.chen@fda.hhs.gov FU National Center for Toxicological Research; US Department of Energy; US Food and Drug Administration. Disclaimer FX We would like to thank Drs Mugimane Manjanatha and Wei Ding for their review and comments. Drs Zhiguang Li and Xi Yang are supported by the Research Participation Program at the National Center for Toxicological Research administrated by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. Disclaimer: This article is not an official guidance or policy statement of the US Food and Drug Administration (FDA). No official support or endorsement by the US FDA is intended or should be inferred. NR 60 TC 12 Z9 12 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 J9 MUTAGENESIS JI Mutagenesis PD JAN PY 2012 VL 27 IS 1 BP 59 EP 66 DI 10.1093/mutage/ger060 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 866MP UT WOS:000298385400006 PM 21976715 ER PT J AU Pogribny, IP Beland, FA AF Pogribny, Igor P. Beland, Frederick A. TI Long-term epigenetic effects of methyl-deficiency SO MUTAGENESIS LA English DT Meeting Abstract C1 [Pogribny, Igor P.; Beland, Frederick A.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 J9 MUTAGENESIS JI Mutagenesis PD JAN PY 2012 VL 27 IS 1 MA 35 BP 115 EP 115 PG 1 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 866MP UT WOS:000298385400046 ER PT J AU Reddy, UM Bettegowda, VR Dias, T Yamada-Kushnir, T Ko, CW Willinger, M AF Reddy, Uma M. Bettegowda, Vani R. Dias, Todd Yamada-Kushnir, Tomoko Ko, Chia-Wen Willinger, Marian TI Concept of Gestational Age in "Completed Weeks": Lost in Translation Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. March Dimes, White Plains, NY USA. US FDA, Silver Spring, MD USA. RP Reddy, UM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JAN PY 2012 VL 119 IS 1 BP 185 EP 185 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 869YN UT WOS:000298636400032 ER PT J AU Chang, CW AF Chang, Ching-Wei TI Towards identifying potential liver toxicity genomic biomarkers SO PERSONALIZED MEDICINE LA English DT Editorial Material DE drug-induced liver toxicity; genomic biomarkers; toxicogenomics ID GENE; SAFETY; DRUGS C1 US FDA, Natl Ctr Toxicol Res, Div Personalized Nutr & Med, Jefferson, AR 72079 USA. RP Chang, CW (reprint author), US FDA, Natl Ctr Toxicol Res, Div Personalized Nutr & Med, Jefferson, AR 72079 USA. EM ching-wei.chang@fda.hhs.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 J9 PERS MED JI Pers. Med. PD JAN PY 2012 VL 9 IS 1 BP 1 EP 3 DI 10.2217/PME.11.84 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 867UR UT WOS:000298480800001 ER PT J AU Perakslis, ED Shon, J AF Perakslis, Eric D. Shon, John TI Translational informatics in personalized medicine SO PERSONALIZED MEDICINE LA English DT Review DE biomarkers; companion diagnostics; consumer genomics; patient stratification; personalized medicine; targeted therapies ID CELL LUNG-CANCER; GENOME; ASSOCIATION; DISCOVERY; SCIENCE; PROMISE AB Personalized medicine is often associated and discussed in the context of advances from the human genome project. It is true that significant breakthroughs and advancement of deep sequencing and other analytical technologies have greatly expanded the pool of available biological data, but integrating this data into medically meaningful knowledge via translational informatics remains an area of opportunity that is far from being fully realized. Significant opportunities remain for informatics to drive progress towards wide use and utility of personalized medicine by focusing and exploitation of multimodal biomarkers, precompetitive data sharing and a balance between high-content data and rich phenotypic data, such as real observational medical outcomes. C1 [Perakslis, Eric D.] US FDA, Silver Spring, MD 20993 USA. [Shon, John] Johnson & Johnson Pharmaceut Res & Dev LLC, Raritan, NJ 08869 USA. RP Perakslis, ED (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM eperakslis@gmail.com NR 39 TC 2 Z9 2 U1 1 U2 13 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 EI 1744-828X J9 PERS MED JI Pers. Med. PD JAN PY 2012 VL 9 IS 1 BP 39 EP 45 DI 10.2217/PME.11.88 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 867UR UT WOS:000298480800010 ER PT J AU Winterstein, AG Hampp, C Saidi, A AF Winterstein, Almut G. Hampp, Christian Saidi, Arwa TI Effectiveness of palivizumab prophylaxis in infants and children in Florida SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE respiratory syncytial virus; cohort studies; infant; palivizumab; prophylaxis ID RESPIRATORY-SYNCYTIAL-VIRUS; INTENSIVE-CARE-UNIT; HIGH-RISK INFANTS; PREMATURE-INFANTS; BRONCHOPULMONARY DYSPLASIA; OUTCOMES REGISTRY; YOUNG-CHILDREN; PREVENTION; INFECTION; BRONCHIOLITIS AB Purpose Palivizumab effectiveness data on respiratory syncytial virus (RSV) infections are limited to trial settings and vary considerably between selected high-risk populations. This study aimed to evaluate effectiveness in a community-based sample. Methods We conducted a cohort study of children with >= 3 months Florida Medicaid fee-for-service eligibility between 1998 and 2004 who also had matching birth certificates. Children entered the cohort at the beginning of the RSV season, after a minimum of 60 days in ambulatory care, and were followed until the earliest of the following: season end, second birthday, loss of eligibility, hospitalization, or death. Study endpoint was the first RSV-related hospitalization. To evaluate the presence of confounding, a second endpoint, hospitalizations for pneumonia or bronchiolitis secondary to specified bacterial or viral pathogens other than RSV, was used. Palivizumab exposure defined as first use (day 1-30 of first dose), subsequent use (days 1-30 of each subsequent dose), and former use (days 31-60 after any dose if delays or no readministration occurred) was compared with non-use with a Cox regression model, adjusting for confounders. Results Hazard ratios (HRs) for RSV hospitalizations were 0.89 (95% CI, 0.71-1.12), 0.56 (95% CI, 0.46-0.69), and 0.71 (95% CI, 0.51-0.97) for first, subsequent, and former use, respectively. HRs for hospitalization because of non-RSV infections were 1.31 (95% CI, 1.04-1.65), 1.03 (95% CI, 0.86-1.23), and 1.05 (95% CI, 0.78-1.41), indicating residual confounding for first but not for subsequent and former use. Conclusion In this community-based study, palivizumab was associated with a reduction in severe RSV infections of a magnitude comparable to the lower clinical trial efficacy estimates. Protection appears to extend beyond the currently recommended monthly dosing schedule. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Winterstein, Almut G.] Univ Florida, Coll Pharm, Dept Pharmaceut Outcomes & Policy, Gainesville, FL 32610 USA. [Winterstein, Almut G.] Univ Florida, Coll Med, Dept Epidemiol, Gainesville, FL 32610 USA. [Winterstein, Almut G.] Univ Florida, Coll Publ Hlth & Hlth Profess, Dept Epidemiol, Gainesville, FL 32610 USA. [Hampp, Christian] US FDA, Div Epidemiol 1, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol,Ctr Drug Evaluat & R, Silver Spring, MD USA. [Saidi, Arwa] Univ Florida, Coll Med, Dept Pediat, Gainesville, FL 32610 USA. RP Winterstein, AG (reprint author), Univ Florida, Coll Pharm, Dept Pharmaceut Outcomes & Policy, POB 100496, Gainesville, FL 32610 USA. EM Almut@cop.ufl.edu RI winterstein, Almut/A-3017-2014; OI winterstein, Almut/0000-0002-6518-5961; Hampp, Christian/0000-0002-1094-6364 FU Florida Agency of Healthcare Administration, AHCA FX This study was funded by a grant from the Florida Agency of Healthcare Administration, AHCA. This study was conducted at the University of Florida and in collaboration with the University of Florida Center for Medicaid and the Uninsured. We would like to thank Public Health Statistics, Office of Vital Statistics, Florida Department of Health, for provision of vital statistics data. We thank Efe Odia, MS, and Nerrissa Alday, BS, for their support in finalizing the manuscript. This manuscript contains original data, and both Dr Almut Winterstein and Dr Christian Hampp had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. NR 28 TC 9 Z9 9 U1 1 U2 8 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2012 VL 21 IS 1 BP 53 EP 60 DI 10.1002/pds.2246 PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 874UK UT WOS:000298983400007 PM 21919115 ER PT J AU Duggirala, HJ Herz, ND Canos, DA Sullivan, RA Schaaf, R Pinnow, E Marinac-Dabic, D AF Duggirala, Hesha J. Herz, Naomi D. Canos, Daniel Arthur Sullivan, Roberta A. Schaaf, Richard Pinnow, Ellen Marinac-Dabic, Danica TI Disproportionality analysis for signal detection of implantable cardioverter-defibrillator-related adverse events in the Food and Drug Administration Medical Device Reporting System SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE data mining; disproportionality analysis; leads; adverse events; safety; MAUDE AB Background The Food and Drug Administration (FDA) became aware of lead fracture and inappropriate shock events related to Sprint Fidelis leads in January 2007. The manufacturer announced a voluntary market withdrawal in October 2007. Aim Our aim was to retrospectively evaluate this safety signal using disproportionality analysis to estimate whether disproportionality analysis could have detected this particular safety signal earlier than actually occurred. Materials and Methods The Manufacturer and User Facility Device Experience (MAUDE) database contains reports on device-related adverse events, of which, FDA receives several hundred thousand every year. For each manufacturer, a list of the top lead brand names was ranked by frequency of reports. We used the Multi-item Gamma Poisson Shrinker (MGPS) method for analysis. We isolated 11 top-reported implantable cardioverter defibrillator (ICD) lead brand names. Using MGPS methodology, we calculated the one-sided 95% lower confidence bound EB05 on the empirical Bayes geometric mean of the reporting ratio. Results We performed individual MGPS analysis for each of the top reported adverse events in 2006 for ICD leads. Fidelis had the highest EB05 scores for lead fractures and inappropriate shock. Discussion Through disproportionality analysis of the MAUDE database, we were able to identify known safety signals associated with the Medtronic Sprint Fidelis lead. Conclusion If utilized at the time, this disproportionality analysis would have identified signals earlier for lead fractures, oversensing, high impedance, and inappropriate shock. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Duggirala, Hesha J.; Herz, Naomi D.; Canos, Daniel Arthur; Pinnow, Ellen; Marinac-Dabic, Danica] US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Sullivan, Roberta A.] US FDA, Div Postmarket Surveillance, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Schaaf, Richard] Oracle Corp, Oracle Hlth Sci Global Business Unit, Waltham, MA USA. RP Duggirala, HJ (reprint author), US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,WO66-4208, Silver Spring, MD 20993 USA. EM Hesha.duggirala@fda.hhs.gov FU FDA FX H. J. D., N. D. H., D. A. C., R. A. S., E. P., and D. M. D. declare no conflicts of interest. Phase Forward Inc. (now OracleAmerica Inc.) provided services under contract to FDA to maintain the Empirica Signal software, which was used to produce the disproportionality analysis results. R. S. is an employee of Oracle. FDA is the sponsor of this work. NR 9 TC 3 Z9 3 U1 1 U2 4 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2012 VL 21 IS 1 BP 87 EP 93 DI 10.1002/pds.2261 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 874UK UT WOS:000298983400011 PM 22095760 ER PT J AU Coleman, CN Whitcomb, RC Miller, CW Noska, MA AF Coleman, C. Norman Whitcomb, Robert C., Jr. Miller, Charles W. Noska, Michael A. TI Commentary on the Combined Disaster in Japan SO RADIATION RESEARCH LA English DT Editorial Material C1 [Coleman, C. Norman] NCI, Radiat Res Program, Bethesda, MD 20892 USA. [Coleman, C. Norman] Off Assistant Secretary Preparedness & Response, Bethesda, MD USA. [Whitcomb, Robert C., Jr.; Miller, Charles W.] Ctr Dis Control & Prevent, Radiat Studies Branch, Atlanta, GA USA. [Noska, Michael A.] US Dept HHS, US FDA, Silver Spring, MD USA. RP Coleman, CN (reprint author), Execut Plaza N,6130 Execut Blvd,Rm 6014, Rockville, MD 20852 USA. EM ccoleman@mail.nih.gov FU Intramural CDC HHS [CC999999] NR 5 TC 1 Z9 1 U1 1 U2 1 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JAN PY 2012 VL 177 IS 1 BP 15 EP 17 DI 10.1667/RRXX40.1 PG 3 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 874FA UT WOS:000298939600002 PM 22103272 ER PT J AU Teeguarden, JG Calafat, AM Doerge, DR AF Teeguarden, Justin G. Calafat, Antonia M. Doerge, Daniel R. TI Adhering to Fundamental Principles of Biomonitoring, BPA Pharmacokinetics, and Mass Balance Is No "Flaw" SO TOXICOLOGICAL SCIENCES LA English DT Letter ID BISPHENOL-A BPA; HUMAN EXPOSURE; URINARY CONCENTRATIONS; TOXICITY; MONKEYS; SAMPLES C1 [Teeguarden, Justin G.] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Calafat, Antonia M.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Sci Lab, Atlanta, GA 30341 USA. [Doerge, Daniel R.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Teeguarden, JG (reprint author), Pacific NW Natl Lab, Div Biol Sci, 902 Battelle Blvd, Richland, WA 99352 USA. EM justin.teeguarden@pnl.gov NR 26 TC 3 Z9 4 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JAN PY 2012 VL 125 IS 1 BP 321 EP 325 DI 10.1093/toxsci/kfr275 PG 5 WC Toxicology SC Toxicology GA 871JP UT WOS:000298734400030 ER PT J AU Stormer, M Arroyo, A Brachert, J Carrero, H Devine, D Epstein, JS Gabriel, C Gelber, C Goodrich, R Hanschmann, KM Heath, DG Jacobs, MR Keil, S de Korte, D Lambrecht, B Lee, CK Marcelis, J Marschner, S McDonald, C McGuane, S McKee, M Muller, TH Muthivhi, T Pettersson, A Radziwon, P Ramirez-Arcos, S Reesink, HW Rojo, J Rood, I Schmidt, M Schneider, CK Seifried, E Sicker, U Wendel, S Wood, EM Yomtovian, RA Montag, T AF Stoermer, M. Arroyo, A. Brachert, J. Carrero, H. Devine, D. Epstein, J. S. Gabriel, C. Gelber, C. Goodrich, R. Hanschmann, K. -M. Heath, D. G. Jacobs, M. R. Keil, S. de Korte, D. Lambrecht, B. Lee, C. -K. Marcelis, J. Marschner, S. McDonald, C. McGuane, S. McKee, M. Mueller, T. H. Muthivhi, T. Pettersson, A. Radziwon, P. Ramirez-Arcos, S. Reesink, H. W. Rojo, J. Rood, I. Schmidt, M. Schneider, C. K. Seifried, E. Sicker, U. Wendel, S. Wood, E. M. Yomtovian, R. A. Montag, T. TI Establishment of the first International Repository for Transfusion-Relevant Bacteria Reference Strains: ISBT Working Party Transfusion-Transmitted Infectious Diseases (WP-TTID), Subgroup on Bacteria SO VOX SANGUINIS LA English DT Article DE bacteria reference strains; bacterial contamination; international reference material; pathogen reduction; platelet screening; repository; validation ID BLOOD COMPONENTS; PHOTOCHEMICAL TREATMENT; ULTRAVIOLET-LIGHT; PATHOGEN INACTIVATION; CONTAMINATION; REDUCTION; CULTURE; DIVERSION; PLATELETS; PLASMA AB Background Bacterial contamination of platelet concentrates (PCs) still remains a significant problem in transfusion with potential important clinical consequences, including death. The International Society of Blood Transfusion Working Party on Transfusion-Transmitted Infectious Diseases, Subgroup on Bacteria, organised an international study on Transfusion-Relevant Bacteria References to be used as a tool for development, validation and comparison of both bacterial screening and pathogen reduction methods. Material and Methods Four Bacteria References (Staphylococcus epidermidis PEI-B-06, Streptococcus pyogenes PEI-B-20, Klebsiella pneumoniae PEI-B-08 and Escherichia coli PEI-B-19) were selected regarding their ability to proliferate to high counts in PCs and distributed anonymised to 14 laboratories in 10 countries for identification, enumeration and bacterial proliferation in PCs after low spiking (0 3 and 0 03 CFU/ml), to simulate contamination occurring during blood donation. Results Bacteria References were correctly identified in 98% of all 52 identifications. S. pyogenes and E. coli grew in PCs in 11 out of 12 laboratories, and K. pneumoniae and S. epidermidis replicated in all participating laboratories. The results of bacterial counts were very consistent between laboratories: the 95% confidence intervals were for S. epidermidis: 1.19-1.32 x 10(7) CFU/ml, S. pyogenes: 0.58-0.69 x 10(7) CFU/ml, K. pneumoniae: 18.71-20.26 x 10(7) CFU/ml and E. coli: 1.78-2.10 x 10(7) CFU/ml. Conclusion The study was undertaken as a proof of principle with the aim to demonstrate (i) the quality, stability and suitability of the bacterial strains for low-titre spiking of blood components, (ii) the property of donor-independent proliferation in PCs, and (iii) their suitability for worldwide shipping of deep frozen, blinded pathogenic bacteria. These aims were successfully fulfilled. The WHO Expert Committee Biological Standardisation has approved the adoption of these four bacteria strains as the first Repository for Transfusion-Relevant Bacteria Reference Strains and, additionally, endorsed as a project the addition of six further bacteria strain preparations suitable for control of platelet contamination as the next step of enlargement of the repository. C1 [Stoermer, M.; Brachert, J.; Hanschmann, K. -M.; Schneider, C. K.; Sicker, U.; Montag, T.] Paul Ehrlich Inst, Sect Microbial Safety, D-63225 Langen, Germany. [Arroyo, A.; Rojo, J.] Ctr Nacl Transfus Sanguinea, Mexico City, DF, Mexico. [Carrero, H.; Heath, D. G.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Devine, D.; Ramirez-Arcos, S.] Canadian Blood Serv, Ottawa, ON, Canada. [Epstein, J. S.] US FDA, Rockville, MD 20857 USA. [Gabriel, C.] Austrian Red Cross, Blutzentrale Linz, Austria. [Gelber, C.; McKee, M.] Amer Type Culture Collect, Manassas, VA USA. [Goodrich, R.; Keil, S.; Marschner, S.] CaridianBCT Biotechnol, Lakewood, CO USA. [Jacobs, M. R.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [de Korte, D.; Marcelis, J.; Rood, I.] Sanquin Blood Supply Fdn, Amsterdam, Netherlands. [Lambrecht, B.; Mueller, T. H.] NSTOB, German Red Cross, Springe, Germany. [Lee, C. -K.] Hong Kong Red Cross Blood Transfus Serv, Hong Kong, Hong Kong, Peoples R China. [McDonald, C.; McGuane, S.] NHS Blood & Transplant, London, England. [Muthivhi, T.] S African Natl Blood Serv, Weltevreden Pk, South Africa. [Pettersson, A.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Radziwon, P.] Reg Ctr Transfus Med, Bialystok, Poland. [Reesink, H. W.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Schmidt, M.; Seifried, E.] German Red Cross, Frankfurt, Germany. [Wendel, S.] Hosp Sirio Libanes, Sao Paulo, Brazil. [Wood, E. M.] Australian Red Cross Blood Serv, Melbourne, Vic, Australia. [Yomtovian, R. A.] Louis Stokes Vet Adm Med Ctr, Cleveland, OH USA. RP Stormer, M (reprint author), Paul Ehrlich Inst, Sect Microbial Safety, Paul Ehrlich Str 51-59, D-63225 Langen, Germany. EM Melanie.Stoermer@pei.de RI Gabriel, Christian/A-1689-2014 OI Gabriel, Christian/0000-0003-2043-9320 NR 35 TC 16 Z9 16 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JAN PY 2012 VL 102 IS 1 BP 22 EP 31 DI 10.1111/j.1423-0410.2011.01510.x PG 10 WC Hematology SC Hematology GA 869MO UT WOS:000298602400004 PM 21732948 ER PT S AU Hatcliff, J King, A Lee, I MacDonald, A Fernando, A Robkin, M Vasserman, E Weininger, S Goldman, JM AF Hatcliff, John King, Andrew Lee, Insup MacDonald, Alasdair Fernando, Anura Robkin, Michael Vasserman, Eugene Weininger, Sandy Goldman, Julian M. GP IEEE Comp Soc TI Rationale and Architecture Principles for Medical Application Platforms SO 2012 IEEE/ACM THIRD INTERNATIONAL CONFERENCE ON CYBER-PHYSICAL SYSTEMS (ICCPS 2012) SE ACM-IEEE International Conference on Cyber-Physical Systems LA English DT Proceedings Paper CT 3rd IEEE/ACM International Conference on Cyber-Physical Systems (ICCPS) CY APR 17-19, 2012 CL Beijing, PEOPLES R CHINA SP ACM, IEEE Comp Soc, IEEE DE computing platform; medical device; interoperability; safety-critical systems; certification AB The concept of "system of systems" architecture is increasingly prevalent in many critical domains. Such systems allow information to be pulled from a variety of sources, analyzed to discover correlations and trends, stored to enable realtime and post-hoc assessment, mined to better inform decision-making, and leveraged to automate control of system units. In contrast, medical devices typically have been developed as monolithic stand-alone units. However, a vision is emerging of a notion of a medical application platform (MAP) that would provide device and health information systems (HIS) interoperability, safety critical network middleware, and an execution environment for clinical applications ("apps") that offer numerous advantages for safety and effectiveness in health care delivery. In this paper, we present the clinical safety/effectiveness and economic motivations for MAPs, and describe key characteristics of MAPs that are guiding the search for appropriate technology, regulatory, and ecosystem solutions. We give an overview of the Integrated Clinical Environment (ICE) - one particular achitecture for MAPs, and the Medical Device Coordination Framework - a prototype implementation of the ICE architecture. C1 [Hatcliff, John; Vasserman, Eugene] Kansas State Univ, Manhattan, KS 66506 USA. [King, Andrew; Lee, Insup] Univ Penn, Philadelphia, PA 19104 USA. [MacDonald, Alasdair] eHlth Technol, West Henrietta, NY USA. [Fernando, Anura] Underwriters Labs, Northbrook, IL USA. [Robkin, Michael] Anakena Solut, Woodland Hills, CA USA. [Weininger, Sandy] US FDA, Rockville, MD 20857 USA. [Goldman, Julian M.] Massachusetts Gen Hosp, CIMIT MD PnP Program, Boston, MA 02114 USA. RP Hatcliff, J (reprint author), Kansas State Univ, Manhattan, KS 66506 USA. FU National Science Foundation [0734204, 0932289, 1065887]; NIH/NIBIB Quantum program FX This work is supported in part by the National Science Foundation under Grants #0734204, 0932289, 1065887, and by the NIH/NIBIB Quantum program. NR 11 TC 5 Z9 5 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 2375-8317 BN 978-0-7695-4695-7 J9 ACM IEEE INT CONF CY PY 2012 BP 3 EP 12 DI 10.1109/ICCPS.2012.9 PG 10 WC Computer Science, Information Systems; Computer Science, Software Engineering; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BG9NL UT WOS:000393451600001 ER PT B AU Kohlstadt, I AF Kohlstadt, Ingrid BE Kohlstadt, I TI Advancing Medicine with Food and Nutrients Second Edition Preface SO ADVANCING MEDICINE WITH FOOD AND NUTRIENTS, 2ND EDITION LA English DT Editorial Material; Book Chapter C1 [Kohlstadt, Ingrid] Amer Coll Prevent Med, Washington, DC USA. [Kohlstadt, Ingrid] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kohlstadt, Ingrid] Johns Hopkins, Baltimore, MD USA. [Kohlstadt, Ingrid] Ctr Dis Control & Prevent, Atlanta, GA USA. [Kohlstadt, Ingrid] Indian Hlth Serv, Hyderabad, Andhra Pradesh, India. [Kohlstadt, Ingrid] Florida Orthoped Inst, Valrico, FL USA. [Kohlstadt, Ingrid] Johns Hopkins Weight Management Ctr, Baltimore, MD USA. [Kohlstadt, Ingrid] US FDA, Rockville, MD 20857 USA. [Kohlstadt, Ingrid] USDA, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-8774-5; 978-1-4398-8772-1 PY 2012 BP XIII EP XIV D2 10.1201/b13694 PG 2 WC Integrative & Complementary Medicine; Nutrition & Dietetics SC Integrative & Complementary Medicine; Nutrition & Dietetics GA BC5HE UT WOS:000353284300001 ER PT S AU Holloway, C Mueller-Berghaus, J Lima, BS Lee, S Wyatt, JS Nicholas, JM Crommelin, DJA AF Holloway, Chris Mueller-Berghaus, Jan Lima, Beatriz Silva Lee, Sau (Larry) Wyatt, Janet S. Nicholas, J. Michael Crommelin, Daan J. A. GP Annals NY Acad Sci TI Scientific considerations for complex drugs in light of established and emerging regulatory guidance SO ANNALS MEETING REPORTS 2013 SE Annals of the New York Academy of Sciences LA English DT Article DE biosimilars; follow-on biologics; complex drug; NBCD ID SALMON-CALCITONIN; AGGREGATION; IMMUNOGENICITY; CONFORMATION; PRODUCTS; EFFICACY; SCIENCE; DISEASE; BONE AB On March 9, 2012, the New York Academy of Sciences brought together experts representing a variety of perspectives-including academic, industrial, regulatory, as well as those from physicians and consumers-to discuss considerations for the non-biological complex drug (NBCD) regulatory approval pathway, given the emerging regulatory guidelines for biosimilars (follow-on biological complex drugs). Some of the organizers of the conference expressed their belief that NBCDs share a number of characteristic features with biologicals: the structure cannot be fully defined by the available (physicochemical) analytical tests, and quality assurance is based on in-depth knowledge, consistency, and control of the production process. However, their view on NBCDs was not universally accepted among the experts who participated in the conference. Plenary sessions addressed the most recent regulatory developments, experimental design, interchangeability, and immunogenicity issues for follow-on versions of complex drugs from the perspective of key audiences, including industry, regulatory agencies, physicians, and consumers. This report summarizes these various perspectives on NBCDs and the scientific and regulatory considerations associated with complex drug categories. C1 [Holloway, Chris] ERA Consulting Grp, Walsrode, Germany. [Mueller-Berghaus, Jan] Paul Ehrlich Inst, Fed Inst Vaccines & Biomed, Langen, Germany. [Lima, Beatriz Silva] Univ Lisbon, P-1699 Lisbon, Portugal. [Lee, Sau (Larry)] US FDA, Silver Spring, MD USA. [Wyatt, Janet S.] Inst Pediat Nursing, Gaithersburg, MD USA. [Nicholas, J. Michael] Teva Pharmaceut, Petah Tiqwa, Israel. [Crommelin, Daan J. A.] Univ Utrecht, Utrecht, Netherlands. RP Holloway, C (reprint author), ERA Consulting Grp, Walsrode, Germany. EM annals@nyas.org RI Silva Lima, Beatriz/A-4284-2014; iMed.ULisboa, iMed.ULisboa/C-6292-2014 OI Silva Lima, Beatriz/0000-0003-0910-7245; FU Teva Pharmaceutical Industries LTD FX This meeting report presents research featured at the March 9, 2012 conference "Scientific Considerations for Complex Drugs in Light of Established Regulatory Guidance", which was presented by the New York Academy of Sciences in New York City. The conference was supported by Platinum Sponsor Teva Pharmaceutical Industries LTD. NR 38 TC 13 Z9 14 U1 0 U2 1 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1276 BP 26 EP 36 DI 10.1111/j.1749-6632.2012.06811.x PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA BHO44 UT WOS:000326095100002 PM 23193987 ER PT B AU Chuaqui, RF Herold, KE Rasooly, A AF Chuaqui, R. F. Herold, Keith E. Rasooly, Avraham BE Herold, KE Rasooly, A TI Cancer and the Use of Biosensors for Cancer Clinical Testing SO BIOSENSORS AND MOLECULAR TECHNOLOGIES FOR CANCER DIAGNOSTICS SE Series in Sensors LA English DT Article; Book Chapter ID CIRCULATING TUMOR-CELLS; GROWTH-FACTOR RECEPTOR; PARAFFIN-EMBEDDED TISSUES; METASTATIC BREAST-CANCER; CHRONIC MYELOID-LEUKEMIA; POLYMERASE-CHAIN-REACTION; IMMUNOCYTOCHEMISTRY IN-VITRO; CHRONIC LYMPHOCYTIC-LEUKEMIA; SURFACE-PLASMON RESONANCE; PROSTATE-SPECIFIC ANTIGEN C1 [Chuaqui, R. F.] NCI, NIH, Rockville, MD 20892 USA. [Herold, Keith E.] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Rasooly, Avraham] NCI, Div Canc Treatment & Diag, Rockville, MD USA. [Rasooly, Avraham] US FDA, Div Biol, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Chuaqui, RF (reprint author), NCI, NIH, Rockville, MD 20892 USA. NR 267 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-4166-2; 978-1-4398-4165-5 J9 SER SENSORS PY 2012 BP 3 EP 39 D2 10.1201/b12138 PG 37 WC Biophysics; Biotechnology & Applied Microbiology; Oncology SC Biophysics; Biotechnology & Applied Microbiology; Oncology GA BD6CZ UT WOS:000362079300002 ER PT B AU Herold, KE Rasooly, A AF Herold, Keith E. Rasooly, Avraham BE Herold, KE Rasooly, A TI BIOSENSORS AND MOLECULAR TECHNOLOGIES FOR CANCER DIAGNOSTICS Preface SO BIOSENSORS AND MOLECULAR TECHNOLOGIES FOR CANCER DIAGNOSTICS SE Series in Sensors LA English DT Editorial Material; Book Chapter C1 [Herold, Keith E.] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Rasooly, Avraham] NCI, Div Canc Treatment & Diag, Rockville, MD USA. [Rasooly, Avraham] US FDA, Div Biol, Cen icr Devices & Radiol Hlth, Silver Spring, MD USA. RP Herold, KE (reprint author), Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-4166-2; 978-1-4398-4165-5 J9 SER SENSORS PY 2012 BP XI EP XIII D2 10.1201/b12138 PG 3 WC Biophysics; Biotechnology & Applied Microbiology; Oncology SC Biophysics; Biotechnology & Applied Microbiology; Oncology GA BD6CZ UT WOS:000362079300001 ER PT B AU Carney, EW Ellis, AL Tyl, RW Foster, PMD Scialli, AR Thompson, K Kim, JH AF Carney, Edward W. Ellis, Amy L. Tyl, Rochelle W. Foster, Paul M. D. Scialli, Anthony R. Thompson, Kary Kim, James H. BE Hood, RD TI Critical evaluation of current developmental toxicity testing strategies-A case of babies and their bathwater SO DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, 3RD EDITION LA English DT Article; Book Chapter ID HUMAN RISK-ASSESSMENT; MATERNAL TOXICITY; FETAL MALFORMATIONS; ETHYLENE-GLYCOL; SCORING SYSTEM; WAVY RIBS; RABBIT; REACH; RAT; ORGANOGENESIS AB This chapter emanated from a workshop entitled "Developmental Toxicology-New Directions," which was sponsored by the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee. This review analyzes the strengths and weaknesses of the current developmental safety testing approaches in an effort to identify those strengths that should be retained in the future versus the weaknesses that should be eliminated. Workshop participants considered the following to be key strengths of current testing approaches: the integrated biology of pregnant animal models including pharmacokinetic and pharmacodynamic processes, the ability to detect low incidence malformations as well as maternally mediated toxicity, and the long history of use coupled with extensive historical data. A number of weaknesses were related to the resource-intensive nature of developmental toxicity testing (e.g., large number of animals, high costs, low throughput, and the inability to keep pace with the demand for more toxicity data). Other weaknesses included the use of very high dose levels that often far exceed human exposure levels, the confounding influence of maternal toxicity, sparse understanding of basic developmental mechanisms and genetics of standard animal models compared with mouse or lower organisms, difficulties interpreting low incidence findings, and issues surrounding the interpretation of minor skeletal variations. An appreciation of these strengths and weaknesses is critical for the design of new approaches to developmental toxicity testing in the 21st century. C1 [Carney, Edward W.] Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. [Ellis, Amy L.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Tyl, Rochelle W.] RTI Int, Discovery & Analyt Sci, Res Triangle Pk, NC USA. [Foster, Paul M. D.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Scialli, Anthony R.] Tetra Tech Sci, Arlington, VA USA. [Thompson, Kary] Bristol Myers Squibb Co, Reprod Toxicol, New Brunswick, NJ USA. [Kim, James H.] ILSI Hlth & Environm Sci Inst HESI, Washington, DC USA. RP Carney, EW (reprint author), Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. NR 55 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL ST, LONDON, EC2A 4LQ, ENGLAND BN 978-1-84184-821-1; 978-1-84184-777-1 PY 2012 BP 592 EP 601 PG 10 WC Toxicology SC Toxicology GA BC8IU UT WOS:000355700500025 ER PT B AU Fisher, JE Lee, GS Gruber, MF Tassinari, MS AF Fisher, J. Edward, Jr. Lee, Grace S. Gruber, Marion F. Tassinari, Melissa S. BE Hood, RD TI Perspectives in risk assessment-Drug and vaccine safety SO DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, 3RD EDITION LA English DT Article; Book Chapter ID DEVELOPMENTAL TOXICITY; MONOCLONAL-ANTIBODIES; CYNOMOLGUS MONKEYS; REPRODUCTIVE-SYSTEM; FERTILITY; DESIGN; CYCLE; PHARMACEUTICALS; PREGNANCY; GROWTH C1 [Fisher, J. Edward, Jr.; Lee, Grace S.; Tassinari, Melissa S.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Gruber, Marion F.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Fisher, JE (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 58 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL ST, LONDON, EC2A 4LQ, ENGLAND BN 978-1-84184-821-1; 978-1-84184-777-1 PY 2012 BP 708 EP 729 PG 22 WC Toxicology SC Toxicology GA BC8IU UT WOS:000355700500029 ER PT B AU Calvo, MS AF Calvo, Mona S. BE Anderson, JJB Garner, SC Klemmer, PJ TI Inorganic Phosphorus Do Higher Dietary Levels Affect Phosphorus Homeostasis and Bone? SO DIET, NUTRIENTS, AND BONE HEALTH LA English DT Article; Book Chapter ID SERUM PARATHYROID-HORMONE; LOW-CALCIUM DIETS; PHOSPHATE HOMEOSTASIS; YOUNG-ADULTS; VASCULAR CALCIFICATION; VITAMIN-D; ADDITIVES; WOMEN; METABOLISM; FOODS C1 Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. RP Calvo, MS (reprint author), Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. NR 55 TC 0 Z9 0 U1 1 U2 1 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-1956-2; 978-1-4398-1955-5 PY 2012 BP 141 EP 156 PG 16 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA BC4WX UT WOS:000352984800010 ER PT B AU Trumbo, PR AF Trumbo, Paula R. BE Cho, SS Almeida, N TI Regulations for the Food Labeling of Dietary Fiber SO DIETARY FIBER AND HEALTH LA English DT Article; Book Chapter ID PRODUCTS C1 US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20993 USA. RP Trumbo, PR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20993 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-9937-3; 978-1-4398-9929-8 PY 2012 BP 33 EP 39 D2 10.1201/b12156 PG 7 WC Gastroenterology & Hepatology; Nutrition & Dietetics SC Gastroenterology & Hepatology; Nutrition & Dietetics GA BC4WU UT WOS:000352984500005 ER PT J AU Reiter, CEN Alayash, AI AF Reiter, Chad E. N. Alayash, Abdu I. TI Effects of carbon monoxide (CO) delivery by a CO donor or hemoglobin on vascular hypoxia inducible factor 1 alpha and mitochondrial respiration SO FEBS OPEN BIO LA English DT Article DE Hemoglobin; Hypoxia-inducible factor; Mitochondria; Carbon monoxide AB We examined carbon monoxide (CO) delivery by carbon monoxide-releasing molecule 2 (CORM-2) or hemoglobin (Hb) on cellular oxygen sensing and mitochondrial respiration in bovine aortic endothelial cells (BAECs). CORM-2 reduced hypoxia-inducible factor-1 alpha (HIF-1 alpha) and endothelin-1 (ET-1) expression in normoxic and hypoxic cells, but while Hb alone significantly reduced HIF-1a stabilization in hypoxic cells, CO delivered by Hb (Hb-CO) had no effect on HIF-1 alpha stabilization. CO dose-dependently increased basal oxygen consumption and reduced overall mitochondrial respiratory capacity. Hb-CO increased basal oxygen consumption but did not alter respiratory capacity. Together, CO reduced ET-1, and, at low doses, had no effect on endothelial mitochondria oxygen consumption. CO ligation to Hb may be developed further as non-vasoactive oxygen therapeutic without compromising mitochondrial function. Published by Elsevier B. V. on behalf of the Federation of European Biochemical Societies. C1 [Reiter, Chad E. N.; Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Div Hematol, CBER, Bethesda, MD 20892 USA. RP Alayash, AI (reprint author), US FDA, Lab Biochem & Vasc Biol, CBER, 8800 Rockville Pike,NIH Bldg 29,Room 112, Bethesda, MD 20892 USA. EM abdu.alayash@fda.hhs.gov FU FDA Critical Path Initiative (AIA); FDA Commissioner's Fellowship Program (CENR) FX Financial support was provided by the FDA Critical Path Initiative (AIA) and the FDA Commissioner's Fellowship Program (CENR). The sponsors had no role in study design; collection, analysis, and interpretation of data; in writing this report; or in the decision to submit the article for publication. NR 27 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 2211-5463 J9 FEBS OPEN BIO JI FEBS Open Bio PY 2012 VL 2 BP 113 EP 118 DI 10.1016/j.fob.2012.05.003 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA V33GL UT WOS:000209007200019 PM 23650589 ER PT S AU Capar, SG Szefer, P AF Capar, Stephen G. Szefer, Piotr BE Otles, S TI Determination and Speciation of Trace Elements in Foods SO METHODS OF ANALYSIS OF FOOD COMPONENTS AND ADDITIVES, 2ND EDITION SE Chemical and Functional Properties of Food Components Series LA English DT Article; Book Chapter ID ATOMIC-ABSORPTION-SPECTROMETRY; PLASMA-MASS SPECTROMETRY; PERFORMANCE LIQUID-CHROMATOGRAPHY; NEUTRON-ACTIVATION ANALYSIS; HPLC-ICP-MS; OPTICAL-EMISSION-SPECTROMETRY; MICROWAVE-ASSISTED DIGESTION; DAILY DIETARY-INTAKE; REFINED BEET SUGAR; CATHODIC STRIPPING VOLTAMMETRY C1 [Capar, Stephen G.] US FDA, College Pk, MD 20740 USA. [Szefer, Piotr] Med Univ Gdansk, Gdansk, Poland. RP Capar, SG (reprint author), US FDA, College Pk, MD 20740 USA. NR 369 TC 0 Z9 0 U1 0 U2 3 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA SN 1555-5127 BN 978-1-4398-1553-3; 978-1-4398-1552-6 J9 CHEM FUNCT PROP FOOD PY 2012 BP 165 EP 210 PG 46 WC Food Science & Technology SC Food Science & Technology GA BC6MR UT WOS:000354124700009 ER PT S AU Williams, KM Trucksess, MW Raybourne, RB Orlandi, PA Levy, D Lampel, KA Westphal, CD AF Williams, Kristina M. Trucksess, Mary W. Raybourne, Richard B. Orlandi, Palmer A. Levy, Dan Lampel, Keith A. Westphal, Carmen D. BE Otles, S TI Determination of Food Allergens and Genetically Modified Components SO METHODS OF ANALYSIS OF FOOD COMPONENTS AND ADDITIVES, 2ND EDITION SE Chemical and Functional Properties of Food Components Series LA English DT Article; Book Chapter ID LINKED-IMMUNOSORBENT-ASSAY; MAJOR SOYBEAN ALLERGEN; IGE-BINDING EPITOPES; ENZYME-IMMUNOASSAY; PEANUT ALLERGEN; MODIFIED ORGANISMS; PROCESSED FOODS; SANDWICH ELISA; QUANTITATIVE-ANALYSIS; MUTATIONAL ANALYSIS C1 [Williams, Kristina M.; Raybourne, Richard B.; Orlandi, Palmer A.; Levy, Dan; Lampel, Keith A.; Westphal, Carmen D.] US FDA, Laurel, MD 20993 USA. [Trucksess, Mary W.] US FDA, College Pk, MD USA. RP Williams, KM (reprint author), US FDA, Laurel, MD 20993 USA. NR 96 TC 0 Z9 0 U1 1 U2 2 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA SN 1555-5127 BN 978-1-4398-1553-3; 978-1-4398-1552-6 J9 CHEM FUNCT PROP FOOD PY 2012 BP 349 EP 373 PG 25 WC Food Science & Technology SC Food Science & Technology GA BC6MR UT WOS:000354124700014 ER PT S AU Hayward, DG AF Hayward, Douglas G. BE Otles, S TI Determination of Pollutants in Foods SO METHODS OF ANALYSIS OF FOOD COMPONENTS AND ADDITIVES, 2ND EDITION SE Chemical and Functional Properties of Food Components Series LA English DT Article; Book Chapter ID DIBENZO-PARA-DIOXINS; 2-DIMENSIONAL GAS-CHROMATOGRAPHY; ORTHO POLYCHLORINATED-BIPHENYLS; SUPERCRITICAL-FLUID EXTRACTION; POLYBROMINATED DIPHENYL ETHERS; RESOLUTION MASS-SPECTROMETRY; HUMAN ADIPOSE-TISSUE; P-DIOXINS; ENVIRONMENTAL-SAMPLES; BIOLOGICAL SAMPLES C1 US FDA, College Pk, MD 20740 USA. RP Hayward, DG (reprint author), US FDA, College Pk, MD 20740 USA. NR 78 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA SN 1555-5127 BN 978-1-4398-1553-3; 978-1-4398-1552-6 J9 CHEM FUNCT PROP FOOD PY 2012 BP 405 EP 421 PG 17 WC Food Science & Technology SC Food Science & Technology GA BC6MR UT WOS:000354124700016 ER PT B AU McAnulty, PA Dayan, AD Ganderup, NC Hastings, KL AF McAnulty, Peter A. Dayan, Anthony D. Ganderup, Niels-Christian Hastings, Kenneth L. BE McAnulty, PA Dayan, AD Ganderup, NC Hastings, KL TI The MINIPIG in BIOMEDICAL RESEARCH Preface SO MINIPIG IN BIOMEDICAL RESEARCH LA English DT Editorial Material; Book Chapter C1 [McAnulty, Peter A.] Univ Cambridge, Cambridge CB2 1TN, England. [McAnulty, Peter A.] Strangeways Res Lab, Cambridge, England. [McAnulty, Peter A.] LSR, Delhi, India. [McAnulty, Peter A.] Amer Board Toxicol, Board Directors, Res Triangle Pk, NC USA. [Dayan, Anthony D.] Univ London, Toxicol, London WC1E 7HU, England. [Dayan, Anthony D.] Univ Dept Toxicol, London, England. [Ganderup, Niels-Christian] Ellegaard Gottingen Minipigs, Gottingen, Germany. [Hastings, Kenneth L.] Minist Hlth, Peace Corps Serv, Suva, Fiji. [Hastings, Kenneth L.] Univ Arizona, Coll Med, Dept Anesthesiol, Tucson, AZ 85721 USA. [Hastings, Kenneth L.] US FDA, Ctr Drug Evaluat & Res, Div Antiviral Drug Prod, Rockville, MD 20857 USA. [Hastings, Kenneth L.] US FDA, Off New Drugs, Rockville, MD 20857 USA. [Hastings, Kenneth L.] Sanofi Aventis, Regulatory Policy, Washington, DC USA. [Hastings, Kenneth L.] Amer Coll Toxicol, Reston, VA USA. [Hastings, Kenneth L.] Amer Board Toxicol, Res Triangle Pk, NC USA. RP McAnulty, PA (reprint author), Univ Cambridge, Cambridge CB2 1TN, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-1119-1; 978-1-4398-1118-4 PY 2012 BP XI EP XI PG 1 WC Medicine, Research & Experimental; Veterinary Sciences SC Research & Experimental Medicine; Veterinary Sciences GA BC6GS UT WOS:000353913300001 ER PT B AU Jacobs, A van der Laan, JW AF Jacobs, Abigail van der Laan, Jan-Willem BE McAnulty, PA Dayan, AD Ganderup, NC Hastings, KL TI Regulatory Aspects: Pharmaceuticals, Medical Devices, Food Additives Minipigs and Global Safety Regulations SO MINIPIG IN BIOMEDICAL RESEARCH LA English DT Article; Book Chapter ID DRUG-METABOLISM; PIG-LIVER; TOXICITY; OLESTRA; CYP2A C1 [Jacobs, Abigail] Ctr Drug Evaluat & Res, Off New Drugs, Silver Spring, MD 20993 USA. [van der Laan, Jan-Willem] Natl Inst Publ Hlth & Environm, Ctr Biol Med & Med Technol, NL-3720 BA Bilthoven, Netherlands. RP Jacobs, A (reprint author), Ctr Drug Evaluat & Res, Off New Drugs, Silver Spring, MD 20993 USA. NR 49 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-1119-1; 978-1-4398-1118-4 PY 2012 BP 565 EP 571 PG 7 WC Medicine, Research & Experimental; Veterinary Sciences SC Research & Experimental Medicine; Veterinary Sciences GA BC6GS UT WOS:000353913300039 ER PT B AU Han, J Shaheen, BW Foley, SL Nayak, R AF Han, Jing Shaheen, Bashar W. Foley, Steven L. Nayak, Rajesh BE Khan, AU Zarrilli, R TI Prevalence, Mechanisms and Dissemination of Antimicrobial Resistance in Enteric Foodborne Bacteria SO MULTIDRUG RESISTANCE: A GLOBAL CONCERN LA English DT Article; Book Chapter DE Salmonella; Campylobacter; E. coli; antimicrobial resistance; foodborne pathogens ID ESCHERICHIA-COLI STRAINS; LEVEL FLUOROQUINOLONE RESISTANCE; MEDIATED QUINOLONE RESISTANCE; SPECTRUM BETA-LACTAMASES; MULTIPLE ANTIBIOTIC-RESISTANCE; CAMPYLOBACTER-JEJUNI STRAINS; SALMONELLA GENOMIC ISLAND-1; CMEABC EFFLUX PUMP; FIELD GEL-ELECTROPHORESIS; URINARY-TRACT-INFECTIONS AB Since the early 1990s, there has been a substantial increase in the emergence and dissemination of antimicrobial resistance in foodborne and zoonotic pathogens, such as Campylobacter, Salmonella and Escherichia coli causing human infections in several developed countries. This increase has been attributed to the potential use of antimicrobials for prophylactic treatment of food animals and humans. While these drugs were successful in the treatment of most diseases in animals and humans, they have contributed to the emergence of drug-resistant bacteria. Several studies have addressed the public health significance of antimicrobial resistance in foodborne pathogens. Attention has been particularly focused on the pros and cons of short term and long term use of antimicrobial agents in food of animals for growth promotion and disease prevention. The public health risk of emergence, spread and transmission of drug-resistant foodborne pathogens in the farm-to-the-fork continuum warrants appropriate actions by both the scientific community and the regulatory agencies in advocating restrictions on the approval and use of new and existing drugs. In this chapter, we have described the prevalence, specific mechanisms (based on the class of drugs) and dissemination of antimicrobial resistance in Campylobacter, Salmonella and E. coli. These three pathogens were selected because they constitute the bulk of bacterial illnesses worldwide. The review will highlight the importance of addressing the issue of conventional and emerging drug-resistant foodborne bacteria in foods, animals and humans so that steps can be taken to minimize their spread in the environment. C1 [Han, Jing; Shaheen, Bashar W.; Foley, Steven L.; Nayak, Rajesh] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Nayak, R (reprint author), US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. EM Rajesh.Nayak@fda.hhs.gov NR 255 TC 0 Z9 0 U1 0 U2 0 PU BENTHAM SCIENCE PUBL PI BUSUM PA PO BOX 294, BUSUM, 1400 AG, NETHERLANDS BN 978-1-60805-292-9; 978-1-60805-255-4 PY 2012 BP 151 EP 175 D2 10.2174/97816080529291120101 PG 25 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA BE1YO UT WOS:000368728700012 ER PT B AU Casey, BJ Dair, BJ AF Casey, B. J. Dair, B. J. BE Laudon, M Romanowicz, B TI Assessing the Antimicrobial Activity of Silver Nanoparticles Leached from Medical Devices SO NANOTECHNOLOGY 2012, VOL 1: ADVANCED MATERIALS, CNTS, PARTICLES, FILMS AND COMPOSITES LA English DT Proceedings Paper CT NSTI Nanotechnology Conference and Expo (Nanotech 2012) CY JUN 18-21, 2012 CL Santa Clara, CA SP ACCT Canada, Anaheim Ctr New Energy Technol, Angel Capital Assoc, Antenna Syst Magazine, Appl Mat, Arsenal Venture Partners, Austin Energy, AUTM, BASF, Battery Power Magazine, Carbon Credit Capital, CHInano2011, Clean Technol & Sustainable Ind, Org CTSI, Circuits Multi Projets, Constellat Energy, Eco Business com, EcoSeed, European Patent Off, Fraunhofer TechBridge, GigaOM, Green Blog Network, Greenberg Traurig, Hitachi High Technol Am Inc, Inst Civil Engineers, Insight InterAsia, IOP Publish, Jackson Walker LLP, Japan Technol Grp, Kauffman Fdn, Lam Res Corp, Licens Execut Soc, Lux Res, Mead Westvaco, MEMS Ind Grp, Nano Sci & Technol Inst, nano tech Japan, Natl Grid, Natl Venture Capital Assoc, Nanotechnol Ind Assoc, NE Utilities, PPG Ind, SciTech Patent Art, Shell GameChanger, SK Innovat, So California Edison, Taylor & Francis Grp LLC - CRC Press, TechConnect, Texas Nanotechnol Initiat, Env Business Cluster, Natl Assoc Seed & Venture, Funds NASVF, Zyvex Technol DE Silver nanoparticle; medical device; leachate; Escherichia coli; antimicrobial ID GENERATION AB Numerous analytical techniques including dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), ultraviolet-visible light spectroscopy (UV-Vis), atomic force microscopy (AFM), and transmission electron microscopy (TEM) were utilized to characterize the physical structure of particles leached from a silver nanoparticulate containing wound dressing. Concurrent research was conducted to investigate the effect that nanoparticle size has on antimicrobial activity. Antimicrobial activity was quantified by determining the reduction of viable colony forming units relative to a control. Results indicate that the size of the silver nanoparticle drastically influences antimicrobial activity providing further support for the proper characterization of leachates evolving from nanoparticulate containing medical devices. C1 [Casey, B. J.; Dair, B. J.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Chem & Mat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Casey, BJ (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Chem & Mat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM brendan.casey@fda.hhs.gov; benita.dair@fda.hhs.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4665-6274-5 PY 2012 BP 532 EP 534 PG 3 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA BG7DX UT WOS:000391247800141 ER PT B AU Casey, BJ Silverstein, JS Kofinas, P Dair, BJ AF Casey, B. J. Silverstein, J. S. Kofinas, P. Dair, B. J. BE Laudon, M Romanowicz, B TI Understanding How Nanopatterning Affects Protein Deposition SO NANOTECHNOLOGY 2012, VOL 1: ADVANCED MATERIALS, CNTS, PARTICLES, FILMS AND COMPOSITES LA English DT Proceedings Paper CT NSTI Nanotechnology Conference and Expo (Nanotech 2012) CY JUN 18-21, 2012 CL Santa Clara, CA SP ACCT Canada, Anaheim Ctr New Energy Technol, Angel Capital Assoc, Antenna Syst Magazine, Appl Mat, Arsenal Venture Partners, Austin Energy, AUTM, BASF, Battery Power Magazine, Carbon Credit Capital, CHInano2011, Clean Technol & Sustainable Ind, Org CTSI, Circuits Multi Projets, Constellat Energy, Eco Business com, EcoSeed, European Patent Off, Fraunhofer TechBridge, GigaOM, Green Blog Network, Greenberg Traurig, Hitachi High Technol Am Inc, Inst Civil Engineers, Insight InterAsia, IOP Publish, Jackson Walker LLP, Japan Technol Grp, Kauffman Fdn, Lam Res Corp, Licens Execut Soc, Lux Res, Mead Westvaco, MEMS Ind Grp, Nano Sci & Technol Inst, nano tech Japan, Natl Grid, Natl Venture Capital Assoc, Nanotechnol Ind Assoc, NE Utilities, PPG Ind, SciTech Patent Art, Shell GameChanger, SK Innovat, So California Edison, Taylor & Francis Grp LLC - CRC Press, TechConnect, Texas Nanotechnol Initiat, Env Business Cluster, Natl Assoc Seed & Venture, Funds NASVF, Zyvex Technol DE block copolymer; thiol-ene; nanopattern; poly(styrene)-block-poly(1,2-butadiene); protein adsorption ID NANOTOPOGRAPHY; ADHESION AB A photochemical, thiol-ene based modification scheme was utilized to functionalize block copolymers (BCPs) from the parent polymer poly(styrene)-block-poly(1,2-butadiene) (PS/PB). The films were then processed using suitable solvent systems, spin-coated, and dried which resulted in the development of functionalized, nanopatterned films. Protein (fibrinogen, albumin, cytochrome C, IgG) deposition experiments were conducted in both static and dynamic conditions utilizing a Q-Sense E4 Auto quartz crystal microbalance with dissipation technology (QCM-D). Results indicate that the functional group, pattern, and experimental conditions (e.g. static or dynamic) all influence protein adsorption dynamics. The results have direct implications for the development of testing protocols to assess the safety and efficacy of medical devices consisting of surfaces that have been manipulated on the nanoscale. C1 [Casey, B. J.; Silverstein, J. S.; Dair, B. J.] US FDA, Ctr Devices & Radiol Hlth, Div Chem & Mat Sci, Off Sci & Engn Labs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Kofinas, P.] Univ Maryland, College Pk, MD 20742 USA. RP Casey, BJ (reprint author), US FDA, Ctr Devices & Radiol Hlth, Div Chem & Mat Sci, Off Sci & Engn Labs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM brendan.casey@fda.hhs.gov; joshua.silverstein@fda.hhs.gov; kofinas@umd.edu; benita.dair@fda.hhs.gov OI Kofinas, Peter/0000-0001-6657-3037 NR 9 TC 0 Z9 0 U1 1 U2 1 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4665-6274-5 PY 2012 BP 683 EP 685 PG 3 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA BG7DX UT WOS:000391247800180 ER PT B AU Hong, HX Xu, L Mendrick, DL Tong, WD AF Hong, Huixiao Xu, Lei Mendrick, Donna L. Tong, Weida BE Barh, D Blum, K Madigan, MA TI Genome-Wide Association Studies of Type 2 Diabetes Current Status, Open Challenges, and Future Perspectives SO OMICS: BIOMEDICAL PERSPECTIVES AND APPLICATIONS LA English DT Article; Book Chapter ID FALSE DISCOVERY RATE; COMPLEX TRAITS; RISK LOCI; SUSCEPTIBILITY LOCI; TRIGLYCERIDE LEVELS; GENETIC-VARIATION; FASTING GLUCOSE; PROSTATE-CANCER; INSULIN-RELEASE; CANDIDATE GENES C1 [Hong, Huixiao; Xu, Lei; Mendrick, Donna L.; Tong, Weida] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Hong, HX (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 73 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-5009-1; 978-1-4398-5008-4 PY 2012 BP 401 EP 429 PG 29 WC Biology; Engineering, Biomedical SC Life Sciences & Biomedicine - Other Topics; Engineering GA BD6HO UT WOS:000362221500023 ER PT J AU Shaheen, BW Nayak, R Boothe, DM AF Shaheen, Bashar W. Nayak, Rajesh Boothe, Dawn M. BE Wang, C Kaltenboeck, B Freeman, MD TI Antimicrobial Resistance in Bacterial Pathogens: Mechanisms and PCR-Based Detection Technologies SO VETERINARY PCR DIAGNOSTICS LA English DT Article; Book Chapter DE Antimicrobial resistance; polymerase chain reaction; mechanisms of resistance; susceptibility testing; molecular methods; bacterial pathogens; antimicrobials; DNA sequencing; detection ID REAL-TIME PCR; POLYMERASE-CHAIN-REACTION; ESCHERICHIA-COLI STRAINS; ENTERICA SEROVAR TYPHIMURIUM; FRAGMENT LENGTH POLYMORPHISM; STRAND CONFORMATION POLYMORPHISM; COAGULASE-NEGATIVE STAPHYLOCOCCI; MEDIATED QUINOLONE RESISTANCE; SPECTRUM BETA-LACTAMASES; LEVEL FLUOROQUINOLONE RESISTANCE AB In the last decade, antimicrobial resistance has been widespread in several bacterial species. This increase in resistance could be associated with an increase in the use of different antimicrobials to treat infections caused by pathogenic bacteria. While resistance to antimicrobials is often attributed to known mechanisms, other mechanisms are still under investigation for many bacterial species. Detection of antimicrobial resistance often involves conventional agar, broth or disk diffusion assays. However, these methods can be cumbersome and time consuming compared to molecular methods. Consequently, several polymerase chain reaction (PCR) techniques have been developed to expedite the detection of antimicrobial resistance in bacterial pathogens. PCR-based technologies are rapid, sensitive and specific for detecting antimicrobial resistance. Application of such technologies in diagnostic laboratories can provide insight into emerging mechanisms of antimicrobial resistance in veterinary pathogens. In this chapter, we describe molecular mechanisms of drug resistance in microbial pathogens and the potential advantages and disadvantages of PCR-based methods. C1 [Shaheen, Bashar W.; Nayak, Rajesh] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. [Boothe, Dawn M.] Auburn Univ, Coll Vet Med, Dept Anat Physiol & Pharmacol, Auburn, AL 36849 USA. RP Shaheen, BW (reprint author), US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. EM bashar.shaheen@fda.hhs.gov NR 281 TC 0 Z9 0 U1 4 U2 5 PU BENTHAM SCIENCE PUBL PI BUSUM PA PO BOX 294, BUSUM, 1400 AG, NETHERLANDS BN 978-1-60805-348-3 PY 2012 BP 33 EP 58 PG 26 WC Veterinary Sciences SC Veterinary Sciences GA BD4LB UT WOS:000360888900005 ER PT J AU Kanungo, J Chandrasekharappa, SC AF Kanungo, Jyotshnabala Chandrasekharappa, Settara C. TI Menin induces endodermal differentiation in aggregated P19 stem cells by modulating the retinoic acid receptors SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE Menin; Endodermal differentiation; Stem cells; Retinoic acid receptor; Cytokeratin Endo A ID EMBRYONAL CARCINOMA-CELLS; MULTIPLE ENDOCRINE NEOPLASIA; HISTONE METHYLTRANSFERASE COMPLEX; TUMOR-SUPPRESSOR MENIN; HOX GENE-EXPRESSION; NEURONAL DIFFERENTIATION; CELLULAR AGGREGATION; TRANSCRIPTION FACTOR; SKELETAL MYOGENESIS; TERMINAL KINASE AB Menin, a ubiquitously expressed protein, is the product of the multiple endocrine neoplasia type I (Men1) gene, mutations of which cause tumors primarily of the parathyroid, endocrine pancreas, and anterior pituitary. Menin-null mice display early embryonic lethality, and thus imply a critical role for menin in early development. In this study, using the P19 embryonic carcinoma stem cells, we studied menin's role in cell differentiation. Menin expression is induced in P19 cell aggregates by retinoic acid (RA). Menin over-expressing stable clones proliferated in a significantly reduced rate compared to the empty vector harboring cells. RA induced cell death in aggregated menin over-expressing cells. However, in the absence of RA, specific populations of the aggregated menin over-expressing cells displayed the characteristic of an endodermal phenotype by the acquisition of cytokeratin Endo A expression (TROMA-1), a marker for the primitive endoderm, with a concomitant loss of the stem cell marker SSEA-1. Menin's ability to induce endodermal differentiation in specific populations of the aggregated cells in the absence of RA implied that menin could substitute RA by inducing a set of target genes that are RA responsive. Menin over-expressing cells upon aggregation showed a robust expression of RA receptors (RAR), RAR alpha, beta, and gamma relative to the empty vector-harboring cells. Moreover, endodermal differentiation was inhibited by the pan-RAR antagonist Ro41-5253, suggesting that menin could induce endodermal differentiation of uncommitted cells by functionally modulating the RARs. C1 [Kanungo, Jyotshnabala; Chandrasekharappa, Settara C.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Kanungo, Jyotshnabala] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Chandrasekharappa, SC (reprint author), NHGRI, Canc Genet Branch, NIH, 50 S Dr,Bldg 50,Room 5232, Bethesda, MD 20892 USA. EM chandra@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health, USA FX This study was supported by Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, USA. NR 48 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD JAN PY 2012 VL 359 IS 1-2 BP 95 EP 104 DI 10.1007/s11010-011-1003-2 PG 10 WC Cell Biology SC Cell Biology GA 850DK UT WOS:000297174700011 PM 21833538 ER PT J AU Chang, C Wang, JW Zhao, C Fostel, J Tong, WD Bushel, PR Deng, YP Pusztai, L Symmans, WF Shi, TL AF Chang, Chang Wang, Junwei Zhao, Chen Fostel, Jennifer Tong, Weida Bushel, Pierre R. Deng, Youping Pusztai, Lajos Symmans, W. Fraser Shi, Tieliu TI Maximizing biomarker discovery by minimizing gene signatures SO BMC GENOMICS LA English DT Article ID SUPPORT VECTOR MACHINES; PRIMARY BREAST-CANCER; EXPRESSION PROFILES; MICROARRAY ANALYSIS; ESTROGEN; CLASSIFICATION; CHEMOTHERAPY; PREDICTION; ALPHA; SENSITIVITY AB Background: The use of gene signatures can potentially be of considerable value in the field of clinical diagnosis. However, gene signatures defined with different methods can be quite various even when applied the same disease and the same endpoint. Previous studies have shown that the correct selection of subsets of genes from microarray data is key for the accurate classification of disease phenotypes, and a number of methods have been proposed for the purpose. However, these methods refine the subsets by only considering each single feature, and they do not confirm the association between the genes identified in each gene signature and the phenotype of the disease. We proposed an innovative new method termed Minimize Feature's Size (MFS) based on multiple level similarity analyses and association between the genes and disease for breast cancer endpoints by comparing classifier models generated from the second phase of MicroArray Quality Control (MAQC-II), trying to develop effective meta-analysis strategies to transform the MAQC-II signatures into a robust and reliable set of biomarker for clinical applications. Results: We analyzed the similarity of the multiple gene signatures in an endpoint and between the two endpoints of breast cancer at probe and gene levels, the results indicate that disease-related genes can be preferably selected as the components of gene signature, and that the gene signatures for the two endpoints could be interchangeable. The minimized signatures were built at probe level by using MFS for each endpoint. By applying the approach, we generated a much smaller set of gene signature with the similar predictive power compared with those gene signatures from MAQC-II. Conclusions: Our results indicate that gene signatures of both large and small sizes could perform equally well in clinical applications. Besides, consistency and biological significances can be detected among different gene signatures, reflecting the studying endpoints. New classifiers built with MFS exhibit improved performance with both internal and external validation, suggesting that MFS method generally reduces redundancies for features within gene signatures and improves the performance of the model. Consequently, our strategy will be beneficial for the microarray-based clinical applications. C1 [Chang, Chang; Wang, Junwei; Zhao, Chen; Shi, Tieliu] E China Normal Univ, Sch Life Sci, Ctr Bioinformat, Shanghai 200241, Peoples R China. [Chang, Chang; Wang, Junwei; Zhao, Chen; Shi, Tieliu] E China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai 200241, Peoples R China. [Fostel, Jennifer] NIEHS, SRA Global Hlth Sect, Res Triangle Pk, NC 27709 USA. [Tong, Weida] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Bushel, Pierre R.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Deng, Youping] Rush Univ, Med Ctr, Dept Internal Med, Ctr Canc, Chicago, IL 60612 USA. [Pusztai, Lajos; Symmans, W. Fraser] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77230 USA. [Pusztai, Lajos; Symmans, W. Fraser] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77230 USA. RP Shi, TL (reprint author), E China Normal Univ, Sch Life Sci, Ctr Bioinformat, 500 Dongchuan Rd, Shanghai 200241, Peoples R China. EM tlshi@sibs.ac.cn FU State Key Program of Basic Research of China [2010CB945401, 2007CB108800]; National High Technology Research, Development Program of China (863 project) [2006AA02Z313]; National Natural Science Foundation of China [30870575]; Research Platform of Cell Signaling Networks from the Science and Technology Commission of Shanghai Municipality [11DZ2260300]; NIH; NIEHS; Division of Intramural Research of the NIEHS [HHSN273200700046U] FX We are grateful to the MAQC Consortium to provide the datasets. This research was supported by the State Key Program of Basic Research of China grants (2010CB945401 and 2007CB108800), the National High Technology Research, Development Program of China (863 project) (Grant No. 2006AA02Z313), National Natural Science Foundation of China grants (30870575) and Research Platform of Cell Signaling Networks from the Science and Technology Commission of Shanghai Municipality (11DZ2260300). This research was also supported, in part by, the Intramural Research Program of the NIH and NIEHS. JF was supported by the Division of Intramural Research of the NIEHS under contract HHSN273200700046U. NR 40 TC 4 Z9 4 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD DEC 23 PY 2011 VL 12 SU 5 AR S6 DI 10.1186/1471-2164-12-S5-S6 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 940WB UT WOS:000303922700007 PM 22369133 ER PT J AU Zhao, C Shi, LM Tong, WD Shaughnessy, JD Oberthuer, A Pusztai, L Deng, YP Symmans, WF Shi, TL AF Zhao, Chen Shi, Leming Tong, Weida Shaughnessy, John D., Jr. Oberthuer, Andre Pusztai, Lajos Deng, Youping Symmans, W. Fraser Shi, Tieliu TI Maximum predictive power of the microarray-based models for clinical outcomes is limited by correlation between endpoint and gene expression profile SO BMC GENOMICS LA English DT Article ID BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; BAYESIAN-ANALYSIS; STAGING SYSTEMS AB Background: Microarray data have been used for gene signature selection to predict clinical outcomes. Many studies have attempted to identify factors that affect models' performance with only little success. Fine-tuning of model parameters and optimizing each step of the modeling process often results in over-fitting problems without improving performance. Results: We propose a quantitative measurement, termed consistency degree, to detect the correlation between disease endpoint and gene expression profile. Different endpoints were shown to have different consistency degrees to gene expression profiles. The validity of this measurement to estimate the consistency was tested with significance at a p-value less than 2.2e-16 for all of the studied endpoints. According to the consistency degree score, overall survival milestone outcome of multiple myeloma was proposed to extend from 730 days to 1561 days, which is more consistent with gene expression profile. Conclusion: For various clinical endpoints, the maximum predictive powers of different microarray-based models are limited by the correlation between endpoint and gene expression profile of disease samples as indicated by the consistency degree score. In addition, previous defined clinical outcomes can also be reassessed and refined more coherent according to related disease gene expression profile. Our findings point to an entirely new direction for assessing the microarray-based predictive models and provide important information to gene signature based clinical applications. C1 [Zhao, Chen; Shi, Tieliu] E China Normal Univ, Sch Life Sci, Ctr Bioinformat, Shanghai 200241, Peoples R China. [Zhao, Chen; Shi, Tieliu] E China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai 200241, Peoples R China. [Shi, Leming; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Shaughnessy, John D., Jr.] Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Lab Myeloma Genet, Little Rock, AR 72205 USA. [Oberthuer, Andre] Univ Cologne, Dept Pediat Oncol & Hematol, Childrens Hosp, MD, D-50924 Cologne, Germany. [Pusztai, Lajos; Symmans, W. Fraser] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77230 USA. [Pusztai, Lajos; Symmans, W. Fraser] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77230 USA. [Deng, Youping] Rush Univ, Med Ctr, Dept Internal Med, Ctr Canc, Chicago, IL 60612 USA. RP Shi, TL (reprint author), E China Normal Univ, Sch Life Sci, Ctr Bioinformat, Shanghai 200241, Peoples R China. EM tlshi@sibs.ac.cn FU National 973 Key Basic Research Program [2010CB945401, 2007CB108800]; National Natural Science Foundation of China [30870575, 31071162, 31000590]; Science and Technology Commission of Shanghai Municipality [11DZ2260300] FX We are grateful to MAQC-II consortium for providing the datasets and the valuable suggestions from Drs. Xiaotao Li, Jiemin Wong and Shanlou Qiao. This work was supported by the National 973 Key Basic Research Program (Grant Nos. 2010CB945401 and 2007CB108800), the National Natural Science Foundation of China (Grant No. 30870575, 31071162, 31000590), and the Science and Technology Commission of Shanghai Municipality (11DZ2260300). NR 18 TC 2 Z9 2 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD DEC 23 PY 2011 VL 12 SU 5 AR S3 DI 10.1186/1471-2164-12-S5-S3 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 940WB UT WOS:000303922700004 PM 22369035 ER PT J AU Ren, DB Xie, H Zhang, WH Hassan, F Petralia, RS Yu, SQ Lim, DJ Gu, XX AF Ren, Dabin Xie, Hang Zhang, Wenhong Hassan, Ferdaus Petralia, Ronald S. Yu, Shengqing Lim, David J. Gu, Xin-Xing TI Intranasal Immunization of the Combined Lipooligosaccharide Conjugates Protects Mice from the Challenges with Three Serotypes of Moraxella catarrhalis SO PLOS ONE LA English DT Article ID OUTER-MEMBRANE PROTEIN; BRANHAMELLA-CATARRHALIS; MONOCLONAL-ANTIBODIES; VACCINE CANDIDATES; OTITIS-MEDIA; LIPOPOLYSACCHARIDE; OLIGOSACCHARIDES; INFECTIONS; RESPONSES; ANTIGENS AB Background: There are no licensed vaccines available against Moraxella catarrhalis, a significant human respiratory pathogen. Lipooligosaccharide (LOS) based conjugate vaccines derived from individual serotype M. catarrhalis only showed partial protection coverage. A vaccine combining LOS conjugates of two or three serotypes might provide a broader protection. Methods: Mice were immunized intranasally with the combined conjugates consisting of LOS from serotype A and B or serotype A, B, and C followed by challenge with different M. catarrhalis strains of three serotypes. Mouse lungs, nasal washes, and sera were collected after each challenge for bacterial counts, histological evaluation, cytokine profiles, antibody level and binding activity determinations. Results: Intranasal administration of the combined LOS conjugates not only enhanced pulmonary bacterial clearance of all three serotypes of M. catarrhalis strains in vaccinated mice, but also elevated serotype-specific anti-LOS immunoglobulin (Ig)A and IgG titers in nasal wash and serum respectively. Mice vaccinated with the combined LOS conjugates also showed increased interferon (IFN)-gamma, interleukin (IL)-12, and IL-4 in the lungs after challenges. Compared to the control group, mice immunized with the combined LOS conjugates also showed reduced lung inflammation after M. catarrhalis infections. The hyperimmune sera induced by the combined conjugates exhibited a broad cross-reactivity toward all three serotypes of M. catarrhalis under transmission electron microscopy. Conclusions: The combined vaccine of serotype A and B LOS conjugates provides protection against most M. catarrhalis strains by eliciting humoral and cellular immune responses. C1 [Ren, Dabin; Zhang, Wenhong; Hassan, Ferdaus; Yu, Shengqing; Gu, Xin-Xing] NIDCD, Vaccine Res Sect, NIH, Rockville, MD USA. [Xie, Hang] US FDA, Lab Resp Viral Dis, Off Vaccines Res & Review, Div Viral Prod,Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Petralia, Ronald S.] NIDCD, Sect Neurotransmitter Receptor Biol, NIH, Bethesda, MD USA. [Lim, David J.] House Ear Res Inst, Sect Pathogenesis Ear Dis, Los Angeles, CA USA. RP Ren, DB (reprint author), Mercer Univ, Sch Med, Div Basic Med Sci, Macon, GA 31207 USA. EM guxx@mail.nih.gov RI Ren, Dabin/H-6263-2013 FU National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), United States of America [NIH0010103632] FX This research was supported by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), United States of America (#NIH0010103632). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 5 Z9 5 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 22 PY 2011 VL 6 IS 12 AR e29553 DI 10.1371/journal.pone.0029553 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 884DI UT WOS:000299684700068 PM 22216312 ER PT J AU Wang, X Zoueva, O Zhao, JQ Ye, ZP Hewlett, I AF Wang, Xue Zoueva, Olga Zhao, Jiangqin Ye, Zhiping Hewlett, Indira TI Stability and infectivity of novel pandemic influenza A (H1N1) virus in blood-derived matrices under different storage conditions SO BMC INFECTIOUS DISEASES LA English DT Article ID VIREMIA; PLASMA AB Background: Influenza A virus has been detected in the blood of some infected individuals, and may pose a safety concern for collection, handling and transport of specimens for epidemiological and public health investigations if infectious virus is present in samples. Furthermore the effect of storage on virus stability and infectivity has not been well studied. Methods: We examined the stability of novel pandemic influenza A (H1N1) virus RNA when the virus was stored in phosphate buffered saline (PBS), plasma, or buffy coated blood at either room temperature or 4 degrees C using a sensitive Taqman RT-PCR assay. We also investigated virus infectivity using the EID50 assay when virus was stored in PBS, plasma, or buffy coats isolated from blood at 4 degrees C. Results: Viral RNA stability was affected by the matrix used for storage. The recovery of viral RNA was highest when virus was stored in PBS with lower amounts being recovered from plasma and buffy coats at either room temperature or 4 degrees C. Incubation time did not appear to be a major factor for viral RNA stability, although there was gradual decline after longer periods post-incubation. Both sample matrix and incubation time affected virus infectivity. The decay in virus infectivity was greatest in PBS followed by buffy coats and plasma. Virus infectivity was abolished in buffy coats at day 20 post-incubation when virus concentrations were low. Conclusion: These data indicate that encapsidated viral RNA was stable overall in all three liquid matrices at room temperature or 4 degrees C although it was most stable in PBS; virus infectivity in buffy coats at 4 degrees C decayed in a time dependent manner while it remained unchanged in plasma. These findings have implications for storage, handling and transport of blood derived samples from influenza patients for epidemiological and laboratory investigations. It should be noted that there is little known about influenza viremia, and whether influenza viruses can be transmitted by blood or blood derived samples. C1 [Wang, Xue; Zhao, Jiangqin; Hewlett, Indira] US FDA, Mol Virol Lab, Div Emerging & Transfus Transmitted Dis, CBER, Bethesda, MD 20892 USA. [Zoueva, Olga; Ye, Zhiping] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Wang, X (reprint author), US FDA, Mol Virol Lab, Div Emerging & Transfus Transmitted Dis, CBER, Bldg 29B,Rm 4NN22,8800 Rockville Pike, Bethesda, MD 20892 USA. EM xue.wang@fda.hhs.gov; indira.hewlett@fda.hhs.gov NR 16 TC 5 Z9 5 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD DEC 22 PY 2011 VL 11 AR 354 DI 10.1186/1471-2334-11-354 PG 6 WC Infectious Diseases SC Infectious Diseases GA 877ZK UT WOS:000299221000001 PM 22192363 ER PT J AU Huang, Y Lei, YF Zhang, H Hou, LC Zhang, MJ Dayton, AI AF Huang, Yong Lei, YingFeng Zhang, Hai Hou, LiChao Zhang, Mingjie Dayton, Andrew I. TI MicroRNA regulation of STAT4 protein expression: rapid and sensitive modulation of IL-12 signaling in human natural killer cells SO BLOOD LA English DT Article ID INTERFERON-GAMMA-PRODUCTION; RECOMBINANT HUMAN INTERLEUKIN-12; NECROSIS-FACTOR-ALPHA; T-CELLS; DENDRITIC CELLS; IMMUNE-SYSTEM; NAIVE CD4(+); IFN-GAMMA; ACTIVATION; RESPONSES AB IL-12 exerts several regulatory effects on natural killer (NK) cells by activating IL-12 signaling. IL-12 signaling is tightly autoregulated to control its onset and termination, with prolonged IL-12 treatment resulting in IL-12 hyporesponsiveness. However, the mechanisms underlying IL-12 auto-regulation are still unclear. In this study we report that prolonged IL-12 treatment significantly up-regulates microRNAs (miRNAs), including miR-132, -212, and -200a in primary human NK cells. This up-regulation correlates temporally with gradually decreasing STAT4 levels and decreasing IFN-gamma expression, after an initial increase within the first 16 hours of IL-12 treatment. The IL-12 hyporesponsiveness is dependent on IL-12 concentration, and associated up-regulation of miR-132, -212, and -200a. Furthermore, IL-12-hyporesponsive cells regain responsiveness of IFN-gamma production 24 hours after IL-12 removal, which correlates with decreases in miR-132, -212, and -200a levels. Overexpression of miR-132, -212, and -200a by transfection into NK cells mimics IL-12 priming, inducing IL-12 hyporesponsiveness, whereas transfection of miR-132, -212, and -200a inhibitors largely abolishes IL-12 induction of IL-12 hyporesponsiveness. These data suggest that miR-132, -212, and -200a up-regulation during prolonged IL-12 treatment, negatively regulates the IL-12 signaling pathway by reducing STAT4 expression in primary human NK cells. (Blood.2011;118(26):6793-6802) C1 [Huang, Yong; Lei, YingFeng; Zhang, Hai; Hou, LiChao; Zhang, Mingjie; Dayton, Andrew I.] US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Huang, Yong] NW A&F Univ, Coll Vet Med, Yangling, Peoples R China. [Lei, YingFeng] Fourth Mil Med Univ, Dept Microbiol, Xian 710032, Peoples R China. [Zhang, Hai] Fourth Mil Med Univ, Lab Anim Res Ctr, Xian 710032, Peoples R China. [Zhang, Mingjie; Dayton, Andrew I.] NW Polytech Univ, Dept Life Sci, Xian 710072, Peoples R China. RP Dayton, AI (reprint author), US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, 1401 Rockville Pike, Bethesda, MD 20892 USA. EM ming.zhang@fda.hhs.gov; andrew.dayton@fda.hhs.gov RI Huang, Yong/G-9365-2011 NR 40 TC 28 Z9 33 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 22 PY 2011 VL 118 IS 26 BP 6793 EP 6802 DI 10.1182/blood-2011-05-356162 PG 10 WC Hematology SC Hematology GA 866RY UT WOS:000298401000016 PM 22077060 ER PT J AU Esserman, LJ Woodcock, J AF Esserman, Laura J. Woodcock, Janet TI Accelerating Identification and Regulatory Approval of Investigational Cancer Drugs SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Esserman, Laura J.] Univ Calif San Francisco, San Francisco, CA 94115 USA. [Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Esserman, LJ (reprint author), Univ Calif San Francisco, 1600 Divisadero St,POB 1710, San Francisco, CA 94115 USA. EM laura.esserman@ucsfmedctr.org NR 9 TC 26 Z9 27 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 21 PY 2011 VL 306 IS 23 BP 2608 EP 2609 DI 10.1001/jama.2011.1837 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 864YQ UT WOS:000298276800023 PM 22187281 ER PT J AU Sandbulte, MR Westgeest, KB Gao, J Xu, XY Klimov, AI Russell, CA Burke, DF Smith, DJ Fouchier, RAM Eichelberger, MC AF Sandbulte, Matthew R. Westgeest, Kim B. Gao, Jin Xu, Xiyan Klimov, Alexander I. Russell, Colin A. Burke, David F. Smith, Derek J. Fouchier, Ron A. M. Eichelberger, Maryna C. TI Discordant antigenic drift of neuraminidase and hemagglutinin in H1N1 and H3N2 influenza viruses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HONG-KONG INFLUENZA; A VIRUS; ANTIBODY; VACCINE; IMMUNITY; RESISTANCE; EVOLUTION; INFECTION; VARIANTS; SEQUENCE AB Seasonal epidemics caused by influenza virus are driven by antigenic changes (drift) in viral surface glycoproteins that allow evasion from preexisting humoral immunity. Antigenic drift is a feature of not only the hemagglutinin (HA), but also of neuraminidase (NA). We have evaluated the antigenic evolution of each protein in H1N1 and H3N2 viruses used in vaccine formulations during the last 15 y by analysis of HA and NA inhibition titers and antigenic cartography. As previously shown for HA, genetic changes in NA did not always lead to an antigenic change. The noncontinuous pattern of NA drift did not correspond closely with HA drift in either subtype. Although NA drift was demonstrated using ferret sera, we show that these changes also impact recognition by NA-inhibiting antibodies in human sera. Remarkably, a single point mutation in the NA of A/Brisbane/59/2007 was primarily responsible for the lack of inhibition by polyclonal antibodies specific for earlier strains. These data underscore the importance of NA inhibition testing to define antigenic drift when there are sequence changes in NA. C1 [Sandbulte, Matthew R.; Gao, Jin; Eichelberger, Maryna C.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Westgeest, Kim B.; Smith, Derek J.; Fouchier, Ron A. M.] Erasmus MC, Dept Virol, NL-3000 CA Rotterdam, Netherlands. [Xu, Xiyan; Klimov, Alexander I.] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Russell, Colin A.; Burke, David F.; Smith, Derek J.] Univ Cambridge, Dept Zool, Cambridge CB2 3EJ, England. [Smith, Derek J.] NIH, Fogarty & Int Ctr, Bethesda, MD 20892 USA. RP Eichelberger, MC (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM maryna.eichelberger@fda.hhs.gov RI burke, david/C-2091-2013; Fouchier, Ron/A-1911-2014; OI Fouchier, Ron/0000-0001-8095-2869; burke, david/0000-0001-8830-3951; Russell, Colin/0000-0002-2113-162X FU Center for Biologics Evaluation and Research; VICI of the Netherlands Organization for Scientific Research; National Institutes of Health [DP1-OD000490-01]; European Union [223498, 278976]; Human Frontier Science Program [P0050/2008]; Royal Society FX We thank Zhiping Ye and Vladimir Lugovtsev for viruses; Robert Webster for plasmids; Olga Zoueva and Arash Hassantoufighi for technical support in preparing reassortant viruses; Theo Bestebroer and Stefan van der Vliet for excellent technical assistance with hemagglutination inhibition assays; and Timothy Straight for provision of human sera. This study used the CamGrid distributed computing resource and was supported by Center for Biologics Evaluation and Research Pandemic Influenza funds (to M.C.E.); a VICI grant of the Netherlands Organization for Scientific Research (to R.A.M.F.); a National Institutes of Health Director's Pioneer Award (DP1-OD000490-01 to D.J.S.), European Union FP7 programs EMPERIE (223498 to D.J.S.) and ANTIGONE (278976 to D.J.S.), a Human Frontier Science Program grant (P0050/2008 to D.J.S.), and a University Research Fellowship from the Royal Society (to C.A.R.). NR 32 TC 51 Z9 52 U1 0 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 20 PY 2011 VL 108 IS 51 BP 20748 EP 20753 DI 10.1073/pnas.1113801108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 865CW UT WOS:000298289400095 PM 22143798 ER PT J AU Jiang, JY Ablan, SD Derebail, S Hercik, K Soheilian, F Thomas, JA Tang, SX Hewlett, I Nagashima, K Gorelick, RJ Freed, EO Levin, JG AF Jiang, Jiyang Ablan, Sherimay D. Derebail, Suchitra Hercik, Kamil Soheilian, Ferri Thomas, James A. Tang, Shixing Hewlett, Indira Nagashima, Kunio Gorelick, Robert J. Freed, Eric O. Levin, Judith G. TI The interdomain linker region of HIV-1 capsid protein is a critical determinant of proper core assembly and stability SO VIROLOGY LA English DT Article DE HIV-1 capsid protein; HIV-1 assembly; HIV-1 cores; VSV-G pseudotyping; Interdomain linker; In vitro assembly; TRIM5 proteins; Host restriction; Virus disassembly; Reverse transcription ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; VESICULAR STOMATITIS-VIRUS; REVERSE TRANSCRIPTION COMPLEXES; FUSION INHIBITOR T-20; ROUS-SARCOMA-VIRUS; N-TERMINAL DOMAIN; IN-VITRO; NUCLEOCAPSID PROTEIN; TRIM5-ALPHA PROTEIN AB The HIV-1 capsid protein consists of two independently folded domains connected by a flexible peptide linker (residues 146-150), the function of which remains to be defined. To investigate the role of this region in virus replication, we made alanine or leucine substitutions in each linker residue and two flanking residues. Three classes of mutants were identified: (i) S146A and T148A behave like wild type (WT); (ii) Y145A, 1150A, and L151A are noninfectious, assemble unstable cores with aberrant morphology, and synthesize almost no viral DNA; and (iii) P147L and S149A display a poorly infectious, attenuated phenotype. Infectivity of P147L and S149A is rescued specifically by pseudotyping with vesicular stomatitis virus envelope glycoprotein. Moreover, despite having unstable cores, these mutants assemble WT-like structures and synthesize viral DNA, although less efficiently than WT. Collectively, these findings demonstrate that the linker region is essential for proper assembly and stability of cores and efficient replication. Published by Elsevier Inc. C1 [Jiang, Jiyang; Derebail, Suchitra; Hercik, Kamil; Levin, Judith G.] Eunice Kennedy Shriver Natl Inst Child Hlth, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Soheilian, Ferri; Nagashima, Kunio] NCI, Image Anal Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Thomas, James A.; Gorelick, Robert J.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Tang, Shixing; Hewlett, Indira] US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Levin, JG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bldg 6B,Room 216,6 Ctr Dr, Bethesda, MD 20892 USA. EM levinju@mail.nih.gov FU National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development); National Cancer Institute, Center for Cancer Research; Office of Science and Health Coordination, Food and Drug Administration, National Heart, Lung, and Blood Institute, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; SAIC-Frederick, Inc. FX We thank Christopher Aiken for his generous gift of OMK cells and the HIV-1-GFP reporter construct as well as for helpful advice regarding the TRIMCyp assay, Michael Summers for kindly providing a CA construct and protocol for bacterial expression and purification of HIV-1 CA, Jane Burns for the VSV-G expression vector (pHCMV-Genv), and the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH for antisera, cells, and plasmids, as detailed in the text. We are also indebted to Angela M. Gronenborn and In-Ja L. Byeon for valuable discussion. This work was supported in part by the Intramural Research Program at the National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development [J.J., S.D., K.H., and J.G.L.] and the National Cancer Institute, Center for Cancer Research S.D.A. and E.O.F.]) and in part by the Office of Science and Health Coordination, Food and Drug Administration, National Heart, Lung, and Blood Institute, National Institutes of Health (S.T. and I.H.). This project has also been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E with SAIC-Frederick, Inc. (F.S., K.N., J.A.T., and R.J.G.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 113 TC 20 Z9 20 U1 0 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD DEC 20 PY 2011 VL 421 IS 2 BP 253 EP 265 DI 10.1016/j.virol.2011.09.012 PG 13 WC Virology SC Virology GA 850GU UT WOS:000297183900019 PM 22036671 ER PT J AU Li, XJ Zhang, L Shao, YT Liang, ZW Shao, C Wang, B Guo, BF Li, N Zhao, XJ Li, Y Xu, DQ AF Li, Xiaojie Zhang, Ling Shao, Yueting Liang, Zuowen Shao, Chen Wang, Bo Guo, Baofeng Li, Na Zhao, Xuejian Li, Yang Xu, Deqi TI Effects of a human plasma membrane-associated sialidase siRNA on prostate cancer invasion SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Neu3; siRNA; MMP; Invasion; Migration ID CELL MOTILITY; PROGRESSION; SALMONELLA; MIGRATION; GLYCOSYLATION; TYPHIMURIUM; SUPPRESSION; EXPRESSION; MALIGNANCY; CARCINOMA AB Human plasma membrane-associated sialidase (Neu3) is one of several sialidases that hydrolyze sialic acids in the terminal position of the carbohydrate groups of glycolipids and glycoproteins. Neu3 is mainly localized in plasma membranes and plays crucial roles in the regulation of cell surface functions. In this study, we investigated the effects and molecular mechanisms of Neu3 on cell invasion and migration in vivo and in vitro. Initially, we found that the levels of Neu3 expression were higher in prostate cancer tissues and cell lines than in normal prostate tissues based on RT-PCR and Western blotting analyses. We then applied a Neu3 siRNA approach to block Neu3 signaling using PC-3M cells as model cells. Transwell invasion assays and wound assays showed significantly decreased invasion and migration potential in the Neu3 siRNA-transfected cells. RT-PCR and Western blotting analyses revealed that Neu3 knockdown decreased the expressions of the matrix metalloproteinases MMP-2 and MMP-9. In vivo, mice injected with PC-3M cell tumors were evaluated by SPECT/CT to determine the presence of bone metastases. Mice treated with attenuated Salmonella carrying the Neu3 siRNA developed fewer bone metastases than mice treated with attenuated Salmonella carrying a control Scramble siRNA, attenuated Salmonella alone or PBS. The results for bone metastasis detection by pathology were consistent with the data obtained by SPECT/CT. Tumor blocks were evaluated by histochemical, RT-PCR and Western blotting analyses. The results revealed decreased expressions of MMP-2 and MMP-9 at the mRNA and protein levels. Taken together, the present findings suggest that Neu3 is a promising molecular target for the prevention of prostate cancer metastasis. (C) 2011 Elsevier Inc. All rights reserved. C1 [Li, Xiaojie; Zhang, Ling; Shao, Yueting; Liang, Zuowen; Shao, Chen; Wang, Bo; Guo, Baofeng; Li, Na; Zhao, Xuejian; Li, Yang] Jilin Univ, Dept Pathophysiol, Prostate Dis Prevent & Treatment Res Ctr, Norman Bethune Med Sch, Changchun 130021, Peoples R China. [Li, Xiaojie] Taizhou Polytech Coll, Taizhou, Peoples R China. [Xu, Deqi] US FDA, Lab Enter & Sexually Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Li, Y (reprint author), Jilin Univ, Dept Pathophysiol, Prostate Dis Prevent & Treatment Res Ctr, Norman Bethune Med Sch, Xinmin St, Changchun 130021, Peoples R China. EM lyang@jlu.edu.cn FU National Natural Science Foundation of China [30801354, 30970791]; Jilin Provincial Science & Technology Department [20070728-1, 20080154] FX The authors are grateful to Professor Frederick Orr for his critical reading and revision of our manuscript. The authors thank Professor Taeko Miyagi for helpful discussions through the course of these studies. This work was funded by the National Natural Science Foundation of China (Nos. 30801354 and 30970791) and the Jilin Provincial Science & Technology Department (Nos. 20070728-1 and 20080154). NR 26 TC 10 Z9 11 U1 0 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 16 PY 2011 VL 416 IS 3-4 BP 270 EP 276 DI 10.1016/j.bbrc.2011.11.001 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 872RU UT WOS:000298827800008 PM 22093819 ER PT J AU Manalo, DJ Baek, JH Buehler, PW Struble, E Abraham, B Alayash, AI AF Manalo, Dominador J. Baek, Jin Hyen Buehler, Paul W. Struble, Evi Abraham, Bindu Alayash, Abdu I. TI Inactivation of prolyl hydroxylase domain (PHD) protein by epigallocatechin (EGCG) stabilizes hypoxia-inducible factor (HIF-1 alpha) and induces hepcidin (Hamp) in rat kidney SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE EGCG; Hypoxia; PHD2; HIP-1 alpha a; Iron homeostasis; Hepcidin ID REGULATORY PEPTIDE HEPCIDIN; TEA POLYPHENOLS; IRON OVERLOAD; DEGRADATION; ERYTHROPOIESIS; INFLAMMATION; ANTIOXIDANT; PROTECTION; TRANSPORT; BINDING AB HIF-1 alpha plays a key role in iron uptake and transport in the liver, whose activity is tightly linked to the repression of hepcidin (Hamp). Hump prevents intestinal iron uptake and cellular efflux by negatively modulating ferroportin. Hump is also expressed in the kidneys, where transcriptional control by HIF-1 alpha remains poorly understood. We show that the administration of epigallocatechin gallate (EGCG) results in a considerable Hump expression in rat kidneys. We also provide evidence to show that EGCG inhibited prolyl hydroxylase (PHD) activity, essential for HIF-1 alpha degradation in vivo and in vitro. Rats that were dosed with EGCG (60 mg/kg, intraperitoneal) over a 7 day time course stabilized HIF-1 alpha protein in kidney tissues. Interestingly. Hump gene expression was induced, even after subjecting rats to a 4 h hypoxia treatment (8% oxygen). Using Hep3B cells, we determined that EGCG conferred its inhibitory action by complexing with PHD, altering its catalytic iron center and thus preventing HIF-1 alpha hydroxylation. These data demonstrate EGCG's therapeutic potential in modulating hepcidin expression in diseases associated with altered iron metabolism. Published by Elsevier Inc. C1 [Manalo, Dominador J.; Baek, Jin Hyen; Buehler, Paul W.; Struble, Evi; Abraham, Bindu; Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Div Hematol, Ctr Biol Evaluat & Research, Bethesda, MD 20892 USA. RP Alayash, AI (reprint author), US FDA, CBER, NIH Bldg 29,Rm 112,8800 Rockville Pike, Bethesda, MD 20892 USA. EM abdu.alayash@fda.hhs.gov FU DARPA (Defense Advanced Research Project Agency) FX This work was supported by Grants from DARPA (Defense Advanced Research Project Agency). NR 33 TC 7 Z9 7 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 16 PY 2011 VL 416 IS 3-4 BP 421 EP 426 DI 10.1016/j.bbrc.2011.11.085 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 872RU UT WOS:000298827800033 PM 22138393 ER PT J AU Keller, AC Ma, J Kavalier, A He, K Brillantes, AMB Kennelly, EJ AF Keller, Amy C. Ma, Jun Kavalier, Adam He, Kan Brillantes, Anne-Marie B. Kennelly, Edward J. TI Saponins from the traditional medicinal plant Momordica charantia stimulate insulin secretion in vitro SO PHYTOMEDICINE LA English DT Article DE Momordica charantia; Bitter melon; Alternative medicine; Hypoglycemia; Insulin secretion; Diabetes ID TYPE-2 DIABETIC MICE; ALTERNATIVE MEDICINE; BLOOD-GLUCOSE; TRITERPENOIDS; COMPLEMENTARY; CONSTITUENTS; INCREASES; RECEPTOR; FRUIT; FAT AB The antidiabetic activity of Momordica charantia (L.). Cucurbitaceae, a widely-used treatment for diabetes in a number of traditional medicine systems, was investigated in vitro. Antidiabetic activity has been reported for certain saponins isolated from M. charantia. In this study insulin secretion was measured in MIN6 beta-cells incubated with an ethanol extract, saponin-rich fraction, and five purified saponins and cucurbitane triterpenoids from M. charantia, 3 beta,7 beta,25-trihydroxycucurbita-5,23(E)-dien-19-al (1), momordicine I (2), momordicine II (3). 3-hydroxycucurbita-5,24-dien-19-al-7,23-di-O-beta-glucopyranoside (4), and kuguaglycoside G (5). Treatments were compared to incubation with high glucose (27 mM) and the insulin secretagogue, glipizide (50 mu M). At 125 mu g/ml, an LC-ToF-MS characterized saponin-rich fraction stimulated insulin secretion significantly more than the DMSO vehicle, p = 0.02. At concentrations 10 and 25 mu g/ml, compounds 3 and 5 also significantly stimulated insulin secretion as compared to the vehicle, p <= 0.007, and p = 0.002, respectively. This is the first report of a saponin-rich fraction, and isolated compounds from M. charantia, stimulating insulin secretion in an in vitro, static incubation assay. (C) 2011 Elsevier GmbH. All rights reserved. C1 [Keller, Amy C.; Kavalier, Adam; Kennelly, Edward J.] CUNY, Lehman Coll, Bronx, NY 10468 USA. [Keller, Amy C.; Kavalier, Adam; Kennelly, Edward J.] CUNY, Grad Ctr, Bronx, NY 10468 USA. [Ma, Jun] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [He, Kan] Naturex Inc, S Hackensack, NJ 07606 USA. [Brillantes, Anne-Marie B.] Armgo Pharma Inc, New York, NY 10032 USA. RP Kennelly, EJ (reprint author), CUNY, Lehman Coll, Bronx, NY 10468 USA. EM kennelly@lehman.cuny.edu FU PSC-CUNY; NIH-NCCAM [F31-AT004548] FX This work was supported by PSC-CUNY and NIH-NCCAM F31-AT004548 "Antidiabetic Constituents from the Dominican Medicinal Plant Momordica charantia" (A.C.K.). The contents of this study are solely the responsibility of the authors and do not necessarily represent the official views of NIH-NCCAM. NR 29 TC 45 Z9 53 U1 3 U2 40 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0944-7113 J9 PHYTOMEDICINE JI Phytomedicine PD DEC 15 PY 2011 VL 19 IS 1 BP 32 EP 37 DI 10.1016/j.phymed.2011.06.019 PG 6 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 881CA UT WOS:000299456900006 PM 22133295 ER PT J AU Doerge, DR Twaddle, NC Vanlandingham, M Fisher, JW AF Doerge, Daniel R. Twaddle, Nathan C. Vanlandingham, Michelle Fisher, Jeffrey W. TI Pharmacokinetics of Bisphenol A in neonatal and adult CD-1 mice: Inter-species comparisons with Sprague-Dawley rats and rhesus monkeys SO TOXICOLOGY LETTERS LA English DT Article DE Bisphenol A; Estrogen receptors; Mass spectrometry; Pharmacokinetics ID REPRODUCTIVE TOXICITY; EXPOSURE; ROUTE; GLUCURONIDATION; METABOLISM; SERUM; URINE; DIET; FOOD AB Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA metabolites in urine of >90% of Americans aged 6-60 suggests ubiquitous and frequent exposure at levels largely below 1 mu g/kg bw/d. The current study used LC/MS/MS to measure serum pharmacokinetics of unconjugated (active) and conjugated (inactive) BPA in adult and neonatal CD-1 mice by oral and subcutaneous (SC) injection routes. Deuterated BPA was used to avoid issues of background contamination. Significant inverse relationships were observed between postnatal age and measures of internal exposures (C-max) to unconjugated BPA after oral administration. Phase II conjugation, area under the time-concentration curve (AUC), and elimination half-time of unconjugated BPA were also inversely related to age. In postnatal day (PND) 3 mice, the combination of under-developed Phase II metabolism, rapid absorption, and slow elimination kinetics led to equivalent internal exposures for unconjugated BPA from oral and SC routes; however, maturing metabolic capabilities in PND 10 and older mice, led to large and significant route effects. The significant inverse age-related developmental profiles from PND 3 through adulthood for unconjugated BPA internal exposure metrics from oral administration to CD-1 mice and Sprague-Dawley rats were remarkably similar: however, the developmental profile was quite different for neonatal rhesus monkeys in which small insignificant age-related differences were observed. These results suggest that an adverse effect from BPA observed in rodent models, attributable to exposure during a discrete time period of neonatal development, would be less likely for comparable neonatal primate dosing based on internal dosimetry. On the other hand in all adults of all species studied, including humans, a low oral dose of BPA produced similarly small internal exposures for the unconjugated form, reflecting the dominant effect of presystemic Phase II metabolism. Published by Elsevier Ireland Ltd. C1 [Doerge, Daniel R.; Twaddle, Nathan C.; Vanlandingham, Michelle; Fisher, Jeffrey W.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Doerge, DR (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM daniel.doerge@fda.hhs.gov FU NCTR/FDA [FDA 224-07-0007]; National Institute of Environmental Health Sciences/National Toxicology Program [NIH Y1ES1027] FX This research was supported in part by an Interagency Agreement (FDA 224-07-0007; NIH Y1ES1027) between NCTR/FDA and the National Institute of Environmental Health Sciences/National Toxicology Program. The authors are grateful to Drs. Barry Delclos and Luisa Camacho, NCTR, for helpful discussions. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. NR 42 TC 36 Z9 37 U1 2 U2 21 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 EI 1879-3169 J9 TOXICOL LETT JI Toxicol. Lett. PD DEC 15 PY 2011 VL 207 IS 3 BP 298 EP 305 DI 10.1016/j.toxlet.2011.09.020 PG 8 WC Toxicology SC Toxicology GA 854WK UT WOS:000297525300013 PM 21983029 ER PT J AU Gonzalez, C Salazar-Garcia, S Palestino, G Martinez-Cuevas, PP Ramirez-Lee, MA Jurado-Manzano, BB Rosas-Hernandez, H Gaytan-Pacheco, N Martel, G Espinosa-Tanguma, R Biris, AS Ali, SF AF Gonzalez, Carmen Salazar-Garcia, Samuel Palestino, Gabriela Martinez-Cuevas, Pedro P. Ramirez-Lee, Manuel A. Jurado-Manzano, Brenda B. Rosas-Hernandez, Hector Gaytan-Pacheco, Noemi Martel, Guadalupe Espinosa-Tanguma, Ricardo Biris, Alexandru S. Ali, Syed F. TI Effect of 45 nm silver nanoparticles (AgNPs) upon the smooth muscle of rat trachea: Role of nitric oxide SO TOXICOLOGY LETTERS LA English DT Article DE Trachea; Silver nanoparticles; Hyper-reactivity; Acetylcholine; NO ID PARTICULATE AIR-POLLUTION; SPRAGUE-DAWLEY RATS; INHALATION TOXICITY; INFLAMMATION; PARTICLES; EXPOSURE; SYNTHASE; DISEASE; HEALTH; RELAXATION AB AgNPs have been used to manufacture nanomaterials with new biophysical properties and functions. However, few experimental approaches have been used to assess their potential toxic or beneficial effects on human health, in association with the size, concentration, and biological target. The aim of this work was to evaluate the effects of the AgNPs on the smooth muscle of rat trachea. A single administration of AgNPs did not modify the smooth muscle tone, but, when the trachea rings were pre-treated with acetylcholine (ACh), AgNPs produced a contractile effect. Simultaneous administration of AgNPs and ACh resulted in a slight increase of smooth muscle contractility induced by ACh. AgNPs pretreatment followed by ACh administration showed that AgNPs exerted an important contraction effect induced by ACh after which muscle tone did not return to the basal level. This effect was associated with an increase in the production of nitric oxide (NO). The contractile response of the AgNPs induced by ACh was completely blocked when the rings were incubated, after the ACh but before the AgNPs administration, with 1400 W (NO blocker). The contractile effect was also abolished by atropine, which suggests that AgNPs alter ACh muscarinic receptor signaling. These data also show that AgNPs modify the contractile action of ACh through NO production and possibly induce hyper-reactivity of tracheal smooth muscle. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Gonzalez, Carmen; Salazar-Garcia, Samuel; Palestino, Gabriela; Martinez-Cuevas, Pedro P.; Ramirez-Lee, Manuel A.; Jurado-Manzano, Brenda B.; Rosas-Hernandez, Hector] Univ Autonoma San Luis Potosi, Fac Ciencias Quim, San Luis Potosi 78210, Mexico. [Gaytan-Pacheco, Noemi; Martel, Guadalupe; Espinosa-Tanguma, Ricardo] Univ Autonoma San Luis Potosi, Fac Med, San Luis Potosi 78210, Mexico. [Biris, Alexandru S.] Univ Arkansas, Nanotechnol Ctr, Little Rock, AR 72204 USA. [Gonzalez, Carmen; Ali, Syed F.] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Gonzalez, C (reprint author), Univ Autonoma San Luis Potosi, Fac Ciencias Quim, Av Manuel Nava 6, San Luis Potosi 78210, Mexico. EM gonzalez.castillocarmen@fcq.uaslp.mx RI Biris, Alexandru/A-8507-2010; Hector, Rosas-Hernandez/J-5130-2015; OI Rosas-Hernandez, Hector/0000-0002-2736-8302 FU National Council of Science and Technology of Mexico [105056]; Integral Program for Institutional Support [C10-PIFI-09-07.36, C10-FAI-05-15.42] FX We want to thank Ms. Salma Jimenez Badillo for technical assistance. The editorial assistance of Dr. Marinette Ringer is also acknowledged. This work was supported by the National Council of Science and Technology of Mexico Grant 105056 and Integral Program for Institutional Support Grants C10-PIFI-09-07.36 and C10-FAI-05-15.42. NR 32 TC 3 Z9 3 U1 1 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD DEC 15 PY 2011 VL 207 IS 3 BP 306 EP 313 DI 10.1016/j.toxlet.2011.09.024 PG 8 WC Toxicology SC Toxicology GA 854WK UT WOS:000297525300014 PM 21983655 ER PT J AU Chowdhury, BA Seymour, SM Michele, TM Durmowicz, AG Liu, DM Rosebraugh, CJ AF Chowdhury, Badrul A. Seymour, Sally M. Michele, Theresa M. Durmowicz, Anthony G. Liu, Dongmei Rosebraugh, Curtis J. TI The Risks and Benefits of Indacaterol - The FDA's Review SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Chowdhury, Badrul A.; Seymour, Sally M.; Michele, Theresa M.; Durmowicz, Anthony G.] US FDA, Div Pulm Allergy & Rheumatol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Liu, Dongmei] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Rosebraugh, Curtis J.] US FDA, Off Drug Evaluat 2, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Chowdhury, BA (reprint author), US FDA, Div Pulm Allergy & Rheumatol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 5 TC 25 Z9 25 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 15 PY 2011 VL 365 IS 24 BP 2247 EP 2249 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 861PN UT WOS:000298031800002 PM 22168640 ER PT J AU Xie, H Li, X Gao, J Lin, ZS Jing, XH Plant, E Zoueva, O Eichelberger, MC Ye, ZP AF Xie, Hang Li, Xing Gao, Jin Lin, Zhengshi Jing, Xianghong Plant, Ewan Zoueva, Olga Eichelberger, Maryna C. Ye, Zhiping TI Revisiting the 1976 "Swine Flu" Vaccine Clinical Trials: Cross-reactive Hemagglutinin and Neuraminidase Antibodies and Their Role in Protection Against the 2009 H1N1 Pandemic Virus in Mice SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID INFLUENZA-VIRUS; SEROLOGIC RESPONSES; ADULTS; SERUM; IMMUNITY; IMMUNOGENICITY; MONOVALENT; INFECTION; AGE AB Background. The 2009 H1N1 pandemic viruses are genetically similar to A/New Jersey/76 H1N1 virus (NJ/76), the strain selected for the 1976 "swine flu" vaccines. Approximately 45 million people in the United States were vaccinated against NJ/76 30 years ago, but the impact of this nationwide immunization on the current pandemic is largely unknown. Methods. Archived human serum samples collected during the 1976 swine flu vaccine trials were assessed for cross-reactive antibody responses to the 2009 H1N1 pandemic viruses. Results. Administration of an NJ/76 monovalent vaccine or the combination of a bivalent vaccine (NJ/76 H1N1 and A/Victoria/75 H3N2) plus a B/Hong Kong/72 monovalent vaccine increased hemagglutinin inhibition (HAI) and neuraminidase inhibition (NAI) antibodies cross-reacting with the 2009 H1N1 pandemic viruses. We showed that cross-reactive human HAI antibodies elicited by the 1976 swine flu vaccination played a dominant role in protecting recipient mice against the wild-type A/California/04/2009. Cross-reactive human NAI antibodies were also protective in recipient mice after a lethal challenge with a hemagglutinin mismatched virus bearing the A/California/04/2009 neuraminidase gene. Transfer of human serum samples with an original HAI titer of 43 or an original NAI titer of 472 was estimated to protect 50% of recipient mice from a lethal infection under the experimental conditions described. Conclusions. The 1976 swine flu vaccination induced cross-reactive HAI and NAI antibodies that were functionally protective in mice, suggesting that this vaccination campaign might have had a positive impact on older adults (>= 50 years) in the United States during the 2009 H1N1 pandemic. C1 [Xie, Hang; Li, Xing; Gao, Jin; Lin, Zhengshi; Jing, Xianghong; Plant, Ewan; Zoueva, Olga; Eichelberger, Maryna C.; Ye, Zhiping] US FDA, Lab Resp Viral Dis, Div Viral Prod, Off Vaccine Res & Review,Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Xie, H (reprint author), US FDA, Lab Resp Viral Dis, Div Viral Prod, Off Vaccine Res & Review,Ctr Biol Evaluat & Res, 29A Lincoln Dr,Rm 1B11, Bethesda, MD 20892 USA. EM Hang.xie@fda.hhs.gov OI Plant, Ewan/0000-0003-0166-5939 FU CBER/FDA FX This work was supported by the institutional research funds provided by CBER/FDA. NR 31 TC 9 Z9 9 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2011 VL 53 IS 12 BP 1179 EP 1187 DI 10.1093/cid/cir693 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 851OF UT WOS:000297279700004 PM 21976461 ER PT J AU Matheny, ME Normand, SLT Gross, TP Marinac-Dabic, D Loyo-Berrios, N Vidi, VD Donnelly, S Resnic, FS AF Matheny, Michael E. Normand, Sharon-Lise T. Gross, Thomas P. Marinac-Dabic, Danica Loyo-Berrios, Nilsa Vidi, Venkatesan D. Donnelly, Sharon Resnic, Frederic S. TI Evaluation of an automated safety surveillance system using risk adjusted sequential probability ratio testing SO BMC MEDICAL INFORMATICS AND DECISION MAKING LA English DT Article ID CONTROL CHART METHODS; CARDIAC-SURGERY; INTERVENTIONAL CARDIOLOGY AB Background: Automated adverse outcome surveillance tools and methods have potential utility in quality improvement and medical product surveillance activities. Their use for assessing hospital performance on the basis of patient outcomes has received little attention. We compared risk-adjusted sequential probability ratio testing (RA-SPRT) implemented in an automated tool to Massachusetts public reports of 30-day mortality after isolated coronary artery bypass graft surgery. Methods: A total of 23,020 isolated adult coronary artery bypass surgery admissions performed in Massachusetts hospitals between January 1, 2002 and September 30, 2007 were retrospectively re-evaluated. The RA-SPRT method was implemented within an automated surveillance tool to identify hospital outliers in yearly increments. We used an overall type I error rate of 0.05, an overall type II error rate of 0.10, and a threshold that signaled if the odds of dying 30-days after surgery was at least twice than expected. Annual hospital outlier status, based on the state-reported classification, was considered the gold standard. An event was defined as at least one occurrence of a higher-than-expected hospital mortality rate during a given year. Results: We examined a total of 83 hospital-year observations. The RA-SPRT method alerted 6 events among three hospitals for 30-day mortality compared with 5 events among two hospitals using the state public reports, yielding a sensitivity of 100% (5/5) and specificity of 98.8% (79/80). Conclusions: The automated RA-SPRT method performed well, detecting all of the true institutional outliers with a small false positive alerting rate. Such a system could provide confidential automated notification to local institutions in advance of public reporting providing opportunities for earlier quality improvement interventions. C1 [Matheny, Michael E.] Vet Adm, Tennessee Valley Healthcare Syst, GRECC, Nashville, TN USA. [Matheny, Michael E.] Vet Adm, Tennessee Valley Healthcare Syst, Ctr Hlth Serv Res, Nashville, TN USA. [Matheny, Michael E.] Vanderbilt Univ, Med Ctr, Div Gen Internal Med & Publ Hlth, Nashville, TN USA. [Matheny, Michael E.] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Gross, Thomas P.; Marinac-Dabic, Danica; Loyo-Berrios, Nilsa] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Vidi, Venkatesan D.; Donnelly, Sharon; Resnic, Frederic S.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. RP Matheny, ME (reprint author), Vet Adm, Tennessee Valley Healthcare Syst, GRECC, Nashville, TN USA. EM michael.matheny@vanderbilt.edu OI Matheny, Michael/0000-0003-3217-4147 FU National Library of Medicine [R01-LM-008142]; Food and Drug Administration [FDA-SOL-08-00837A]; Veteran's Administration Health Services Research and Development Service [VA HSRD CDP-09-387] FX This study was funded in part by grants R01-LM-008142 from the National Library of Medicine, FDA-SOL-08-00837A from the Food and Drug Administration, and VA HSR&D CDP-09-387 from the Veteran's Administration Health Services Research and Development Service. We would like to acknowledge Richard Cope and Coping Systems for their technical expertise and programming work. NR 17 TC 5 Z9 5 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6947 J9 BMC MED INFORM DECIS JI BMC Med. Inform. Decis. Mak. PD DEC 14 PY 2011 VL 11 AR 75 DI 10.1186/1472-6947-11-75 PG 8 WC Medical Informatics SC Medical Informatics GA 890RY UT WOS:000300163800001 PM 22168892 ER PT J AU Eppinger, M Mammel, MK Leclerc, JE Ravel, J Cebula, TA AF Eppinger, Mark Mammel, Mark K. Leclerc, Joseph E. Ravel, Jacques Cebula, Thomas A. TI Genomic anatomy of Escherichia coli O157:H7 outbreaks SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE foodborne pathogen; comparative phylogenomics; SNP typing; infectious disease ID HEMOLYTIC-UREMIC SYNDROME; SPINACH-ASSOCIATED OUTBREAK; O157-H7; O157H7; VIRULENCE; CATTLE; EVOLUTION; SEQUENCE; STRAINS; GASTROENTERITIS AB The rapid emergence of Escherichia coli O157:H7 from an unknown strain in 1982 to the dominant hemorrhagic E. coli serotype in the United States and the cause of widespread outbreaks of human food-borne illness highlights a need to evaluate critically the extent to which genomic plasticity of this important enteric pathogen contributes to its pathogenic potential and its evolution as well as its adaptation in different ecological niches. Aimed at a better understanding of the evolution of the E. coli O157:H7 pathogenome, the present study presents the high-quality sequencing and comparative phylogenomic analysis of a comprehensive panel of 25 E. coli O157:H7 strains associated with three nearly simultaneous food-borne outbreaks of human disease in the United States. Here we present a population genetic analysis of more than 200 related strains recovered from patients, contaminated produce, and zoonotic sources. High-resolution phylogenomic approaches allow the dynamics of pathogenome evolution to be followed at a high level of phylogenetic accuracy and resolution. SNP discovery and study of genome architecture and prophage content identified numerous biomarkers to assess the extent of genetic diversity within a set of clinical and environmental strains. A total of 1,225 SNPs were identified in the present study and are now available for typing of the E. coli O157:H7 lineage. These data should prove useful for the development of a refined phylogenomic framework for forensic, diagnostic, and epidemiological studies to define better risk in response to novel and emerging E. coli O157:H7 resistance and virulence phenotypes. C1 [Eppinger, Mark; Ravel, Jacques] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Eppinger, Mark; Ravel, Jacques] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Mammel, Mark K.; Leclerc, Joseph E.] US FDA, Off Appl Res & Safety Assessment, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Cebula, Thomas A.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Ravel, J (reprint author), Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. EM jravel@som.umaryland.edu; tcebula1@jhu.edu OI Ravel, Jacques/0000-0002-0851-2233 FU National Institute of Allergy and Infectious Diseases (NAID), National Institutes of Health, US Department of Health and Human Services [N01 AI- 30071] FX This work was supported with federal funds from the National Institute of Allergy and Infectious Diseases (NAID), National Institutes of Health, US Department of Health and Human Services, under NIAID Contract N01 AI- 30071. NR 40 TC 78 Z9 821 U1 6 U2 36 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 13 PY 2011 VL 108 IS 50 BP 20142 EP 20147 DI 10.1073/pnas.1107176108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 861QR UT WOS:000298034800062 PM 22135463 ER PT J AU Levis, S Xu, P Doerge, DR Krischer, J AF Levis, Silvina Xu, Ping Doerge, Daniel R. Krischer, Jeffrey TI Soy Isoflavone Supplementation in Menopausal Women In reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID TRIAL C1 [Levis, Silvina] Univ Miami, Dept Med, Miller Sch Med, Miami, FL 33101 USA. [Levis, Silvina] Miami Vet Affairs Healthcare Syst, Geriatr Res Educ & Clin Ctr, Miami, FL USA. [Xu, Ping; Krischer, Jeffrey] Univ S Florida, Dept Pediat, Tampa, FL 33620 USA. [Doerge, Daniel R.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Levis, S (reprint author), Univ Miami, Dept Med, Miller Sch Med, POB 016960,D-503, Miami, FL 33101 USA. EM slevis@med.miami.edu NR 3 TC 0 Z9 0 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD DEC 12 PY 2011 VL 171 IS 22 BP 2067 EP 2068 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 860VD UT WOS:000297975100031 ER PT J AU Kim, DH James, RH Landry, RJ Calogero, D Anderson, J Ilev, IK AF Kim, Do-Hyun James, Robert H. Landry, Robert J. Calogero, Don Anderson, James Ilev, Ilko K. TI Quantification of glistenings in intraocular lenses using a ballistic-photon removing integrating-sphere method SO APPLIED OPTICS LA English DT Article ID SCHEIMPFLUG PHOTOGRAPHY AB An alternative method for quantification of glistenings in intraocular lenses (IOLs) using an integrating sphere with an adjustable back aperture to remove ballistic photons is presented. Glistenings in soft IOLs have been known for more than a decade; however, their severity and visual impact are still under investigation. Anumber of studies have been made to quantitatively describe glistenings in IOLs. Quantization and precise grading of IOLs will provide needed information to evaluate the severity and visual impact of glistenings in patients. We investigated the use of a simple modification of an integrating-sphere method to eliminate ballistic photons to quantitatively measure scattered light from glistenings in IOLs. The method described in this paper provides a simple and effective way to quantitatively characterize glistenings in vitro. It may be especially useful to quantify scattering associated with low-grade glistenings where the density of the scattering centers is low. Finally, the modified integrating-sphere method may also be generally applicable to quantitatively characterize scattering from other optical media. C1 [Kim, Do-Hyun; James, Robert H.; Landry, Robert J.; Anderson, James; Ilev, Ilko K.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Calogero, Don] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Anderson, James] Harvey Mudd Coll, Claremont, CA 91711 USA. RP Kim, DH (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM do-hyun.kim@fda.hhs.gov NR 17 TC 4 Z9 4 U1 1 U2 3 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1559-128X EI 2155-3165 J9 APPL OPTICS JI Appl. Optics PD DEC 10 PY 2011 VL 50 IS 35 BP 6461 EP 6467 DI 10.1364/AO.50.006461 PG 7 WC Optics SC Optics GA 876NL UT WOS:000299114200007 PM 22193122 ER PT J AU Xu, Q Paik, MC Rundek, T Elkind, MSV Sacco, RL AF Xu, Qiang Paik, Myunghee Cho Rundek, Tatjana Elkind, Mitchell S. V. Sacco, Ralph L. TI Reweighting estimators for Cox regression with missing covariate data: Analysis of insulin resistance and risk of stroke in the Northern Manhattan Study SO STATISTICS IN MEDICINE LA English DT Article DE missing covariate; proportional hazards model; weighted estimating equation ID PROPORTIONAL HAZARDS REGRESSION; ISCHEMIC-STROKE; MODELS AB Incomplete covariates often obscure analysis results from a Cox regression. In an analysis of the Northern Manhattan Study (NOMAS) to determine the influence of insulin resistance on the incidence of stroke in nondiabetic individuals, insulin level is unknown for 34.1% of the subjects. The available data suggest that the missingness mechanism depends on outcome variables, which may generate biases in estimating the parameters of interest if only using the complete observations. This article aimed to introduce practical strategies to analyze the NOMAS data and present sensitivity analyses by using the reweighting method in standard statistical packages. When the data set structure is in counting process style, the reweighting estimates can be obtained by built- in procedures with variance estimated by the jackknife method. Simulation results indicate that the jackknife variance estimate provides reasonable coverage probability in moderate sample sizes. We subsequently conducted sensitivity analyses for the NOMAS data, showing that the risk estimates are robust to a variety of missingness mechanisms. At the end of this article, we present the core SAS and R programs used in the analysis. Copyright (C) 2011 JohnWiley & Sons, Ltd. C1 [Xu, Qiang] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Paik, Myunghee Cho] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY 10032 USA. [Rundek, Tatjana; Sacco, Ralph L.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Elkind, Mitchell S. V.] Columbia Univ, Dept Neurol, New York, NY 10032 USA. RP Xu, Q (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Qiang.Xu@fda.hhs.gov FU NINDS NIH HHS [R01 NS029993] NR 12 TC 3 Z9 3 U1 2 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD DEC 10 PY 2011 VL 30 IS 28 BP 3328 EP 3340 DI 10.1002/sim.4380 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 860YO UT WOS:000297985000006 PM 21965165 ER PT J AU Parra, M Derrick, SC Yang, A Tian, JH Kolibab, K Oakley, M Perera, LP Jacobs, WR Kumar, S Morris, SL AF Parra, Marcela Derrick, Steven C. Yang, Amy Tian, JinHua Kolibab, Kristopher Oakley, Miranda Perera, Liyanage P. Jacobs, William R. Kumar, Sanjai Morris, Sheldon L. TI Malaria Infections Do Not Compromise Vaccine-Induced Immunity against Tuberculosis in Mice SO PLOS ONE LA English DT Article ID CALMETTE-GUERIN VACCINE; MYCOBACTERIUM-TUBERCULOSIS; PROTECTIVE IMMUNITY; BOVIS BCG; ENVIRONMENTAL MYCOBACTERIA; PUBLISHED LITERATURE; PLASMODIUM-YOELII; TGF-BETA; IN-VITRO; T-CELLS AB Background: Given the considerable geographic overlap in the endemic regions for malaria and tuberculosis, it is probable that co-infections with Mycobacterium tuberculosis and Plasmodium species are prevalent. Thus, it is quite likely that both malaria and TB vaccines may be used in the same populations in endemic areas. While novel vaccines are currently being developed and tested individually against each of these pathogens, the efficacy of these vaccines has not been evaluated in co-infection models. To further assess the effectiveness of these new immunization strategies, we investigated whether co-infection with malaria would impact the anti-tuberculosis protection induced by four different types of TB vaccines in a mouse model of pulmonary tuberculosis. Principal Findings: Here we show that the anti-tuberculosis protective immunity induced by four different tuberculosis vaccines was not impacted by a concurrent infection with Plasmodium yoelii NL, a nonlethal form of murine malaria. After an aerogenic challenge with virulent M. tuberculosis, the lung bacterial burdens of vaccinated animals were not statistically different in malaria infected and malaria naive mice. Multi-parameter flow cytometric analysis showed that the frequency and the median fluorescence intensities (MFI) for specific multifunctional T (MFT) cells expressing IFN-gamma, TNF-alpha, and/or IL-2 were suppressed by the presence of malaria parasites at 2 weeks following the malaria infection but was not affected after parasite clearance at 7 and 10 weeks post-challenge with P. yoelii NL. Conclusions: Our data indicate that the effectiveness of novel TB vaccines in protecting against tuberculosis was unaffected by a primary malaria co-infection in a mouse model of pulmonary tuberculosis. While the activities of specific MFT cell subsets were reduced at elevated levels of malaria parasitemia, the T cell suppression was short-lived. Our findings have important relevance in developing strategies for the deployment of new TB vaccines in malaria endemic areas. C1 [Parra, Marcela; Derrick, Steven C.; Yang, Amy; Tian, JinHua; Kolibab, Kristopher; Oakley, Miranda; Morris, Sheldon L.] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Review, Bethesda, MD 20014 USA. [Perera, Liyanage P.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jacobs, William R.] Yeshiva Univ Albert Einstein Coll Med, Howard Hughes Med Inst, Bronx, NY 10461 USA. [Jacobs, William R.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Kumar, Sanjai] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Review, Bethesda, MD 20014 USA. RP Parra, M (reprint author), US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Review, Bethesda, MD 20014 USA. EM steven.derrick@fda.hhs.gov FU FDA FX Annual lab budget allocation from the FDA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 3 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 9 PY 2011 VL 6 IS 12 AR e28164 DI 10.1371/journal.pone.0028164 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 870JO UT WOS:000298665600004 PM 22205939 ER PT J AU Kachko, A Kochneva, G Sivolobova, G Grazhdantseva, A Lupan, T Zubkova, I Wells, F Merchlinsky, M Williams, O Watanabe, H Ivanova, A Shvalov, A Loktev, V Netesov, S Major, ME AF Kachko, Alla Kochneva, Galina Sivolobova, Galina Grazhdantseva, Antonina Lupan, Tatyana Zubkova, Iryna Wells, Frances Merchlinsky, Michael Williams, Ollie Watanabe, Hisayoshi Ivanova, Alla Shvalov, Aleksander Loktev, Valeriy Netesov, Sergei Major, Marian E. TI New neutralizing antibody epitopes in hepatitis C virus envelope glycoproteins are revealed by dissecting peptide recognition profiles SO VACCINE LA English DT Article DE Vaccine; Cross neutralization; Binding affinity; Antibody blocking; Antibody purification ID CELLULAR IMMUNE-RESPONSES; CYTOTOXIC T-LYMPHOCYTES; CD81 BINDING; INFECTION; E2; CHIMPANZEES; PARTICLES; PSEUDOPARTICLES; IMMUNIZATION; REPLICATION AB One of the greatest challenges to HCV vaccine development is the induction of effective immune responses using recombinant proteins or vectors. In order to better understand which vaccine-induced antibodies contribute to neutralization of HCV the quality of polyclonal anti-E1E2 antibody responses in immunized mice and chimpanzees was assessed at the level of epitope recognition using peptide scanning and neutralization of chimeric 1/2a, 1/2a and 2a HCVcc after blocking or affinity elution of specific antibodies. Mice and chimpanzees were immunized with genotype la (H77) HCV gpE1E2; all samples contained cross-neutralizing antibody against HCVcc. By functionally dissecting the polyclonal immune responses we identified three new regions important for neutralization within E1 (aa264-318) and E2 (aa448-483 and aa496-515) of the HCV glycoproteins, the third of which (aa496-515) is highly conserved (85-95%) amongst genotypes. Antibodies to aa496-515 were isolated by affinity binding and elution from the serum of a vaccinated chimpanzee and found to specifically neutralize chimeric 1/2a, 1/2a and 2a HCVcc. IC50 titres (IgG ng/mL) for the aa496-515 eluate were calculated as 142.1, 239.37 and 487.62 against 1a/2a, 1b/2a and 2a HCVcc, respectively. Further analysis demonstrated that although antibody to this new, conserved neutralization epitope is efficiently induced with recombinant proteins in mice and chimpanzees; it is poorly induced during natural infection in patients and chimpanzees (7 out of 68 samples positive) suggesting the epitope is poorly presented to the immune system in the context of the viral particle. These findings have important implications for the development of HCV vaccines and strategies designed to protect against heterologous viruses. The data also suggest that recombinant or synthetic antigens may be more efficient at inducing neutralizing antibodies to certain epitopes and that screening virally infected patients may not be the best approach for finding new cross-reactive epitopes. Published by Elsevier Ltd. C1 [Kachko, Alla; Zubkova, Iryna; Wells, Frances; Major, Marian E.] US FDA, Lab Hepatitis Viruses, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Kochneva, Galina; Sivolobova, Galina; Grazhdantseva, Antonina; Lupan, Tatyana; Ivanova, Alla; Shvalov, Aleksander; Loktev, Valeriy; Netesov, Sergei] State Res Ctr Virol & Biotechnol VECTOR, Lab Viral Hepatitis, Novosibirsk 630559, Russia. [Merchlinsky, Michael; Williams, Ollie] US FDA, Lab DNA Viruses, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Watanabe, Hisayoshi] Yamagata Univ, Sch Med, Dept Gastroenterol, Yamagata 9909585, Japan. RP Major, ME (reprint author), US FDA, Lab Hepatitis Viruses, Div Viral Prod, Ctr Biol Evaluat & Res, Bldg 29A,Rm 1D10-HEM 448,8800 Rockville Pike, Bethesda, MD 20892 USA. EM alla.kachko@fda.hhs.gov; kochneva@vector.nsc.ru; sgf@vector.nsc.ru; gaa@vector.nsc.ru; Lupan@ngs.ru; lryna.zubkova@fda.hhs.gov; frances.wells@fda.hhs.gov; Michael.Merchlinsky@hhs.gov; ollie.williams@fda.hhs.gov; h-watanabe@med.id.yamagata-u.ac.jp; ali@vector.nsc.ru; shvalov@mail.ru; loktev@vector.nsc.ru; nauka@nsu.ru; marian.major@fda.hhs.gov RI Kochneva, Galina/B-7356-2012; Loktev, Valery/J-5195-2012; Netesov, Sergey/A-3751-2013; Shvalov, Alexander/A-6611-2014 OI Netesov, Sergey/0000-0002-7786-2464; Shvalov, Alexander/0000-0001-6890-1575 FU Food and Drug Administration; Biotechnology Engagement Program (BTEP) [116-ISTC, 3255]; National Vaccine Program FX We would like to thank Dr. Charles Rice for providing J6/JFH1 cDNA and Dr. Takaji Wakita for providing JFH1 cDNA. This work was supported by internal funding from the Food and Drug Administration and by grants from the Biotechnology Engagement Program (BTEP) (BTEP#116-ISTC#3255) and the National Vaccine Program. NR 43 TC 18 Z9 18 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD DEC 9 PY 2011 VL 30 IS 1 BP 69 EP 77 DI 10.1016/j.vaccine.2011.10.045 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 868NA UT WOS:000298528800011 PM 22041300 ER PT J AU Holleboom, AG Karlsson, H Lin, RS Beres, TM Sierts, JA Herman, DS Stroes, ESG Aerts, JM Kastelein, JJP Motazacker, MM Dallinga-Thie, GM Levels, JHM Zwinderman, AH Seidman, JG Seidman, CE Ljunggren, S Lefeber, DJ Morava, E Wevers, RA Fritz, TA Tabak, LA Lindahl, M Hovingh, GK Kuivenhoven, JA AF Holleboom, Adriaan G. Karlsson, Helen Lin, Ruei-Shiuan Beres, Thomas M. Sierts, Jeroen A. Herman, Daniel S. Stroes, Erik S. G. Aerts, Johannes M. Kastelein, John J. P. Motazacker, Mohammad M. Dallinga-Thie, Geesje M. Levels, Johannes H. M. Zwinderman, Aeilko H. Seidman, Jonathan G. Seidman, Christine E. Ljunggren, Stefan Lefeber, Dirk J. Morava, Eva Wevers, Ron A. Fritz, Timothy A. Tabak, Lawrence A. Lindahl, Mats Hovingh, G. Kees Kuivenhoven, Jan Albert TI Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man SO CELL METABOLISM LA English DT Article ID APOLIPOPROTEIN-C-III; 2-DIMENSIONAL GEL-ELECTROPHORESIS; ANGIOPOIETIN-LIKE PROTEIN-3; LIPOPROTEIN-LIPASE S447X; RICH LIPOPROTEINS; MASS-SPECTROMETRY; HEPATIC-UPTAKE; GLYCOSYLATION; METABOLISM; APOPROTEINS AB Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGal-NAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGaINAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGaINAc-T2 can affect lipid metabolism through apoC-III glyco-sylation, thereby establishing GALNT2 as a lipid-modifying gene. C1 [Holleboom, Adriaan G.; Stroes, Erik S. G.; Kastelein, John J. P.; Dallinga-Thie, Geesje M.; Hovingh, G. Kees] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Sierts, Jeroen A.; Motazacker, Mohammad M.; Dallinga-Thie, Geesje M.; Levels, Johannes H. M.; Kuivenhoven, Jan Albert] Univ Amsterdam, Acad Med Ctr, Dept Expt Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Aerts, Johannes M.] Univ Amsterdam, Acad Med Ctr, Dept Med Biochem, NL-1105 AZ Amsterdam, Netherlands. [Zwinderman, Aeilko H.] Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, NL-1105 AZ Amsterdam, Netherlands. [Karlsson, Helen] Cty Council Ostergotland, Ctr Occupat & Environm Med, S-58185 Linkoping, Sweden. [Lin, Ruei-Shiuan; Beres, Thomas M.; Tabak, Lawrence A.] Natl Inst Dent & Craniofacial Res, Sect Biol Chem, NIH, Bethesda, MD 20892 USA. [Herman, Daniel S.; Seidman, Jonathan G.; Seidman, Christine E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Karlsson, Helen; Ljunggren, Stefan; Lindahl, Mats] Linkoping Univ, Dept Clin & Expt Med, S-58185 Linkoping, Sweden. [Lefeber, Dirk J.] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, NL-6525 GA Nijmegen, Netherlands. [Lefeber, Dirk J.; Wevers, Ron A.] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, NL-6525 GA Nijmegen, Netherlands. [Lefeber, Dirk J.; Morava, Eva; Wevers, Ron A.] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, NL-6525 GA Nijmegen, Netherlands. [Morava, Eva] Radboud Univ Nijmegen, Med Ctr, Dept Pediat, NL-6525 GA Nijmegen, Netherlands. [Fritz, Timothy A.] US FDA, Rockville, MD 20852 USA. [Kuivenhoven, Jan Albert] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, NL-9713 AV Groningen, Netherlands. RP Hovingh, GK (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM g.k.hovingh@amc.uva.nl; j.a.kuivenhoven@umcg.nl RI lefeber, dirk/G-5063-2012; Lefeber, Dirk/A-2146-2014; Wevers, Ron/H-8116-2014; Morava, E./L-4529-2015; Aerts, Johannes/A-1028-2009; OI Wevers, Ron/0000-0003-2278-9746; Karlsson, Helen/0000-0002-1620-6180; Ljunggren, Stefan/0000-0003-3984-3964 FU European Union [FP6-2005-LIFESCIHEALTH-6, 037631]; Fondation Leducq Transatlantic Networks of Excellence; NWO [40-00506-98-9001]; National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health; Netherlands Organisation for Scientific Research [021.001.035]; Netherlands Heart Foundation [2010T082] FX We are indebted to the study participants and thank C.A. Koch, A.W. Schimmel, J. Coelho Amado de Azevedo, J. Peter, J. Legemate, A. van der Made, and B. van den Bogaard for their help facilitating this family study. We thank the Sanquin Blood Bank for providing control DNA samples, M. Nieuwdorp for his help designing the desialylation experiments, and Xenon Genetics for financing the collection of DNA. This study was supported by the European Union (FP6-2005-LIFESCIHEALTH-6; STREP contract number 037631), Fondation Leducq Transatlantic Networks of Excellence (2010), NWO Medium Investment Grant (40-00506-98-9001 to D.J.L.), and the Intramural Research Program of the National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health. A.G.H. is supported by the Netherlands Organisation for Scientific Research (021.001.035). J.J.P.K. received the Lifetime Achievement Award of the Netherlands Heart Foundation (2010T082). NR 38 TC 43 Z9 43 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD DEC 7 PY 2011 VL 14 IS 6 BP 811 EP 818 DI 10.1016/j.cmet.2011.11.005 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 862VO UT WOS:000298122400014 PM 22152306 ER PT J AU Robinson, R AF Robinson, Rebecca TI Three Rs of Animal Testing for Regenerative Medicine Products SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material AB Considerations of animal welfare have spurred the design of "smarter" preclinical studies intended to ultimately benefit patients. C1 [Robinson, Rebecca] US Food & Drug Adm FDA, Commissioners Fellowship Program, Off Commissioner, Silver Spring, MD 20993 USA. [Robinson, Rebecca] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Robinson, Rebecca] US FDA, Off Cellular Tissue & Gene Therapies, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Robinson, R (reprint author), US Food & Drug Adm FDA, Commissioners Fellowship Program, Off Commissioner, Silver Spring, MD 20993 USA. EM rebecca.robinson@fda.hhs.gov NR 8 TC 1 Z9 1 U1 2 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD DEC 7 PY 2011 VL 3 IS 112 AR 112fs11 DI 10.1126/scitranslmed.3003394 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 862HN UT WOS:000298081000001 PM 22158858 ER PT J AU Grijalva, CG Chen, L Delzell, E Baddley, JW Beukelman, T Winthrop, KL Griffin, MR Herrinton, LJ Liu, LY Ouellet-Hellstrom, R Patkar, NM Solomon, DH Lewis, JD Xie, FL Saag, KG Curtis, JR AF Grijalva, Carlos G. Chen, Lang Delzell, Elizabeth Baddley, John W. Beukelman, Timothy Winthrop, Kevin L. Griffin, Marie R. Herrinton, Lisa J. Liu, Liyan Ouellet-Hellstrom, Rita Patkar, Nivedita M. Solomon, Daniel H. Lewis, James D. Xie, Fenglong Saag, Kenneth G. Curtis, Jeffrey R. TI Initiation of Tumor Necrosis Factor-alpha Antagonists and the Risk of Hospitalization for Infection in Patients With Autoimmune Diseases SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MODIFYING ANTIRHEUMATIC DRUGS; RHEUMATOID-ARTHRITIS PATIENTS; SERIOUS BACTERIAL-INFECTIONS; PLACEBO-CONTROLLED TRIALS; HAZARDS REGRESSION-MODEL; OPPORTUNISTIC INFECTIONS; BIOLOGICS-REGISTER; BRITISH-SOCIETY; FACTOR THERAPY; METAANALYSIS AB Context Although tumor necrosis factor (TNF)-alpha antagonists are increasingly used in place of nonbiologic comparator medications, their safety profile remains incomplete. Objectives To determine whether initiation of TNF-alpha antagonists compared with nonbiologic comparators is associated with an increased risk of serious infections requiring hospitalization. Design, Setting, and Patients Within a US multi-institutional collaboration, we assembled retrospective cohorts (1998-2007) of patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, psoriatic arthritis, or ankylosing spondylitis (psoriasis and spondyloarthropathies) combining data from Kaiser Permanente Northern California, New Jersey and Pennsylvania Pharmaceutical Assistance programs, Tennessee Medicaid, and national Medicaid/Medicare. TNF-alpha antagonists and nonbiologic regimens were compared in disease-specific propensity score (PS)-matched cohorts using Cox regression models with nonbiologics as the reference. Baseline glucocorticoid use was evaluated as a separate covariate. Main Outcome Measure Infections requiring hospitalization (serious infections) during the first 12 months after initiation of TNF-alpha antagonists or nonbiologic regimens. Results Study cohorts included 10 484 RA, 2323 IBD, and 3215 psoriasis and spondyloarthropathies matched pairs using TNF-alpha antagonists and comparator medications. Overall, we identified 1172 serious infections, most of which (53%) were pneumonia and skin and soft tissue infections. Among patients with RA, serious infection hospitalization rates were 8.16 (TNF-alpha antagonists) and 7.78 (comparator regimens) per 100 person-years (adjusted hazard ratio [aHR], 1.05 [95% CI, 0.91-1.21]). Among patients with IBD, rates were 10.91 (TNF-alpha antagonists) and 9.60 (comparator) per 100 person-years (aHR, 1.10 [95% CI, 0.83-1.46]). Among patients with psoriasis and spondyloarthropathies, rates were 5.41 (TNF-alpha antagonists) and 5.37 (comparator) per 100 person-years (aHR, 1.05 [95% CI, 0.76-1.45]). Among patients with RA, infliximab was associated with a significant increase in serious infections compared with etanercept (aHR, 1.26 [95% CI, 1.07-1.47]) and adalimumab (aHR, 1.23 [95% CI, 1.02-1.48]). Baseline glucocorticoid use was associated with a dose-dependent increase in infections. Conclusion Among patients with autoimmune diseases, compared with treatment with nonbiologic regimens, initiation of TNF-alpha antagonists was not associated with an increased risk of hospitalizations for serious infections. JAMA. 2011;306(21):2331-2339 Published online November 6, 2011. doi:10.1001/jama.2011.1692 C1 [Grijalva, Carlos G.] Vanderbilt Univ, Sch Med, Div Pharmacoepidemiol, Dept Prevent Med, Nashville, TN 37212 USA. [Chen, Lang; Delzell, Elizabeth; Baddley, John W.; Beukelman, Timothy; Patkar, Nivedita M.; Xie, Fenglong; Saag, Kenneth G.; Curtis, Jeffrey R.] Univ Alabama Birmingham, Birmingham, AL USA. [Baddley, John W.] Birmingham VA Med Ctr, Birmingham, AL USA. [Winthrop, Kevin L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Herrinton, Lisa J.; Liu, Liyan] Kaiser Permanente No Calif, Oakland, CA USA. [Ouellet-Hellstrom, Rita] US FDA, Silver Spring, MD USA. [Solomon, Daniel H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Solomon, Daniel H.] Harvard Univ, Boston, MA 02115 USA. [Lewis, James D.] Univ Penn, Dept Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Lewis, James D.] Univ Penn, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Grijalva, CG (reprint author), Vanderbilt Univ, Sch Med, Div Pharmacoepidemiol, Dept Prevent Med, 1500 21st Ave S,Ste 2600, Nashville, TN 37212 USA. EM carlos.grijalva@vanderbilt.edu FU Amgen; Genentech; Centocor; Procter Gamble; Abbott; Eli Lilly; Bristol-Myers Squibb; Takeda; Shire; Pfizer; Roche/Genentech; UCB biopharma; CORRONA; Crescendo; Food and Drug Administration (FDA); US Department of Health and Human Services (DHHS); Agency for Healthcare Research and Quality (AHRQ) [U18 HS17919, R01HS018517]; National Institutes of Health (NIH) [AR053351]; NIH via the University of Alabama at Birmingham Center for Clinical and Translational Science [5KL2 RR025776-03]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [5P60AR56116] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Delzell reported receiving research support from Amgen. Dr Baddley reported consulting for Abbott and Merck. Dr Herrinton reported receiving research support from Genentech, Centocor, and Procter & Gamble. Dr Solomon reported receiving research support from Amgen, Abbott, Eli Lilly, and Bristol-Myers Squibb. Dr Lewis reported consulting for Genentech, Abbott, CORRONA (Consortium of Rheumatology Researchers of North America Inc), Millennium Pharmaceuticals, Elan, AstraZeneca, Procter & Gamble, GlaxoSmithKline, Alios Therapeutics, Roche, and Amgen; he also reported receiving research support from Centocor, Takeda, and Shire, and consultant honoraria from Amgen and Pfizer. Dr Winthrop reported receiving consultant fees from Genentech and Abbott, research support from Pfizer, and speakers honoraria from Amgen and Pfizer. Dr Saag reported receiving research support from Amgen, Genentech, and Pfizer. Dr Curtis reported receiving consultant fees and research grants from Roche/Genentech, UCB biopharma, Centocor, CORRONA, Amgen, Pfizer, Bristol-Myers Squibb, Crescendo, and Abbott. Other authors reported no conflicts.; This work was supported by the Food and Drug Administration (FDA), US Department of Health and Human Services (DHHS), and the Agency for Healthcare Research and Quality (AHRQ) grant U18 HS17919. Dr Curtis receives support from the National Institutes of Health (NIH; AR053351) and AHRQ (R01HS018517). Dr Beukelman was supported by NIH grant 5KL2 RR025776-03 via the University of Alabama at Birmingham Center for Clinical and Translational Science. Drs Grijalva and Griffin receive support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, grant 5P60AR56116. NR 51 TC 140 Z9 145 U1 1 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 7 PY 2011 VL 306 IS 21 BP 2331 EP 2339 DI 10.1001/jama.2011.1692 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 856YH UT WOS:000297680300018 PM 22056398 ER PT J AU Chen, G Li, RY Shi, LM Qi, JY Hu, PZ Luo, J Liu, MY Shi, TL AF Chen, Geng Li, Ruiyuan Shi, Leming Qi, Junyi Hu, Pengzhan Luo, Jian Liu, Mingyao Shi, Tieliu TI Revealing the missing expressed genes beyond the human reference genome by RNA-Seq SO BMC GENOMICS LA English DT Article ID COPY-NUMBER; MICROARRAY; ALIGNMENT; TRANSCRIPTOME; SEQUENCES; TOOL AB Background: The complete and accurate human reference genome is important for functional genomics researches. Therefore, the incomplete reference genome and individual specific sequences have significant effects on various studies. Results: we used two RNA-Seq datasets from human brain tissues and 10 mixed cell lines to investigate the completeness of human reference genome. First, we demonstrated that in previously identified similar to 5 Mb Asian and similar to 5 Mb African novel sequences that are absent from the human reference genome of NCBI build 36, similar to 211 kb and similar to 201 kb of them could be transcribed, respectively. Our results suggest that many of those transcribed regions are not specific to Asian and African, but also present in Caucasian. Then, we found that the expressions of 104 RefSeq genes that are unalignable to NCBI build 37 in brain and cell lines are higher than 0.1 RPKM. 55 of them are conserved across human, chimpanzee and macaque, suggesting that there are still a significant number of functional human genes absent from the human reference genome. Moreover, we identified hundreds of novel transcript contigs that cannot be aligned to NCBI build 37, RefSeq genes and EST sequences. Some of those novel transcript contigs are also conserved among human, chimpanzee and macaque. By positioning those contigs onto the human genome, we identified several large deletions in the reference genome. Several conserved novel transcript contigs were further validated by RT-PCR. Conclusion: Our findings demonstrate that a significant number of genes are still absent from the incomplete human reference genome, highlighting the importance of further refining the human reference genome and curating those missing genes. Our study also shows the importance of de novo transcriptome assembly. The comparative approach between reference genome and other related human genomes based on the transcriptome provides an alternative way to refine the human reference genome. C1 [Chen, Geng; Qi, Junyi; Hu, Pengzhan; Luo, Jian; Liu, Mingyao; Shi, Tieliu] E China Normal Univ, Ctr Bioinformat & Computat Biol, Shanghai 200241, Peoples R China. [Chen, Geng; Qi, Junyi; Hu, Pengzhan; Luo, Jian; Liu, Mingyao; Shi, Tieliu] E China Normal Univ, Inst Biomed Sci, Sch Life Sci, Shanghai 200241, Peoples R China. [Li, Ruiyuan] Huazhong Agr Univ, Natl Key Lab Crop Genet Improvement, Wuhan 430070, Peoples R China. [Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Shi, Tieliu] Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Informat Ctr Life Sci, Shanghai 200031, Peoples R China. RP Shi, TL (reprint author), E China Normal Univ, Ctr Bioinformat & Computat Biol, Shanghai 200241, Peoples R China. EM tlshi@sibs.ac.cn FU National 973 Key Basic Research Program [2010CB945401, 2007CB108800]; National Natural Science Foundation of China [30870575, 31071162, 31000590]; Science and Technology Commission of Shanghai Municipality [11DZ2260300] FX We thank Weidong Zang and Peng Li for help discussions. This work was supported by the National 973 Key Basic Research Program (Grant Nos. 2010CB945401 and 2007CB108800), the National Natural Science Foundation of China (Grant No. 30870575, 31071162 and 31000590) and the Science and Technology Commission of Shanghai Municipality (11DZ2260300). NR 34 TC 20 Z9 20 U1 1 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD DEC 2 PY 2011 VL 12 AR 590 DI 10.1186/1471-2164-12-590 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 907RX UT WOS:000301436500001 PM 22133125 ER PT J AU Pandiri, AR Sills, RC Hoenerhoff, MJ Peddada, SD Ton, TVT Hong, HHL Flake, GP Malarkey, DE Olson, GR Pogribny, IP Walker, NJ Boudreau, MD AF Pandiri, Arun R. Sills, Robert C. Hoenerhoff, Mark J. Peddada, Shyamal D. Ton, Thai-Vu T. Hong, Hue-Hua L. Flake, Gordon P. Malarkey, David E. Olson, Greg R. Pogribny, Igor P. Walker, Nigel J. Boudreau, Mary D. TI Aloe vera Non-Decolorized Whole Leaf Extract-Induced Large Intestinal Tumors in F344 Rats Share Similar Molecular Pathways with Human Sporadic Colorectal Tumors SO TOXICOLOGIC PATHOLOGY LA English DT Article DE Aloe vera; colon; F344 rat; human; colorectal tumors ID INDUCED COLON CARCINOGENESIS; GENE-EXPRESSION; BETA-CATENIN; CANCER-CELLS; SIGNALING PATHWAY; EPITHELIAL-CELLS; MUTATIONS; TUMORIGENESIS; ADENOMAS; INVASION AB Aloe vera is one of the most commonly used botanicals for various prophylactic and therapeutic purposes. Recently, NTP/NCTR has demonstrated a dose-dependent increase in large intestinal tumors in F344 rats chronically exposed to Aloe barbadensis Miller (Aloe vera) non-decolorized whole leaf extract (AVNWLE) in drinking water. The morphological and molecular pathways of AVNWLE-induced large intestinal tumors in the F344 rats were compared to human colorectal cancer (hCRC) literature. Defined histological criteria were used to compare AVNWLE-induced large intestinal tumors with hCRC. The commonly mutated genes (Kras, Ctnnb1, and Tp53) and altered signaling pathways (MAPK, WNT, and TGF-beta) important in hCRC were evaluated within AVNWLE-induced large intestinal tumors. Histological evaluation of the large intestinal tumors indicated eight of twelve adenomas (Ads) and four of twelve carcinomas (Cas). Mutation analysis of eight Ads and four Cas identified point mutations in exons 1 and 2 of the Kras gene (two of eight Ads, two of four Cas), and in exon 2 of the Ctnnb1 gene (three of eight Ads, one of four Cas). No Tp53 (exons 5-8) mutations were found in Ads or Cas. Molecular pathways important in hCRC such as MAPK, WNT, and TGF-beta signaling were also altered in AVNWLE-induced Ads and Cas. In conclusion, the AVNWLE-induced large intestinal tumors in F344 rats share several similarities with hCRC at the morphological and molecular levels. C1 [Pandiri, Arun R.; Sills, Robert C.; Hoenerhoff, Mark J.; Ton, Thai-Vu T.; Hong, Hue-Hua L.; Flake, Gordon P.; Malarkey, David E.] NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Pandiri, Arun R.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Peddada, Shyamal D.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Olson, Greg R.] Toxicol Pathol Associates, Jefferson, AR USA. [Pogribny, Igor P.; Boudreau, Mary D.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Walker, Nigel J.] NTP NIEHS, Res Triangle Pk, NC USA. RP Pandiri, AR (reprint author), BG 101 RM B358 MSC B3-06,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM pandiriak@niehs.nih.gov RI Walker, Nigel/D-6583-2012; Peddada, Shyamal/D-1278-2012 OI Walker, Nigel/0000-0002-9111-6855; FU IAG [224-07-0007]; FDA; NTP; NIEHS/DHHS FX The authors would like to thank Dr. Darlene Dixon and Dr. Michael Devito for their review of this manuscript; Dr. Keith Shockley and Dr. Grace Kissling for help with statistics; and Ms. Natasha Clayton and Ms. Beth Mahler for their excellent technical assistance. This study was supported in part by IAG #224-07-0007 between the FDA and the NTP as well as by the intramural research program at NIEHS/DHHS. NR 49 TC 7 Z9 7 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD DEC PY 2011 VL 39 IS 7 BP 1065 EP 1074 DI 10.1177/0192623311422081 PG 10 WC Pathology; Toxicology SC Pathology; Toxicology GA 961IV UT WOS:000305459000005 PM 21937742 ER PT J AU Herman, EH Knapton, A Rosen, E Thompson, K Rosenzweig, B Estis, J Agee, S Lu, QA Todd, JA Lipshultz, S Hasinoff, B Zhang, J AF Herman, Eugene H. Knapton, Alan Rosen, Elliot Thompson, Karol Rosenzweig, Barry Estis, Joel Agee, Sara Lu, Quynh-Anh Todd, John A. Lipshultz, Steven Hasinoff, Brian Zhang, Jun TI A Multifaceted Evaluation of Imatinib-induced Cardiotoxicity in the Rat SO TOXICOLOGIC PATHOLOGY LA English DT Article DE apoptosis; autophagy; cardiac troponin 1; drug-induced cardiotoxicity; LAMP-2; tyrosine kinase inhibitors; spontaneously hypertensive rats; and Sprague Dawley rats ID CHRONIC MYELOID-LEUKEMIA; CONGESTIVE-HEART-FAILURE; KINASE INHIBITOR SUNITINIB; CARDIAC TROPONIN-T; RECEIVING IMATINIB; CARDIOVASCULAR-DISEASE; NATRIURETIC PEPTIDE; DOXORUBICIN; MYOCYTES; MECHANISMS AB Cardiotoxicity was an unanticipated side effect elicited by the clinical use of imatinib (Imb). This toxicity has been examined in only a limited number of experimental studies. The present study sought, by a variety of approaches, to identify important characteristics of Imb-induced cardiac alterations. Male spontaneously hypertensive rats (SHRs) received oral doses of 10, 30, or 50 mg/kg Imb or water daily for 10 d. Cardiac lesions, detected at all doses, were characterized by cytoplasmic vacuolization and myofibrillar loss. In a second experiment, cardiac lesions were found in Sprague Dawley (SD) and SHR rats given 50 or 100 mg/kg Imb for 14 d. Mean cardiac lesion scores and serum levels of cardiac troponin I were higher in SHRs than in SD rats. Imb induced myocyte death by necrosis, autophagy, and apoptosis. Dose-related increases in cardiac expression were observed for several genes associated with endoplasmic reticulum stress response, protein folding, and vascular development and remodeling. Imb caused alterations in isolated myocytes (myofibrillar loss, highly disrupted and disorganized sarcomeric alpha-actinin, apoptosis, and increased lactate dehydrogenase release) at low concentrations (5 mM). The authors conclude that Imb exerts cardiotoxic effects that are manifest through a complex pattern of cellular alterations, the severity of which can be influenced by arterial blood pressure. C1 [Herman, Eugene H.] US FDA, Div Appl Pharmacol Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Estis, Joel; Agee, Sara; Lu, Quynh-Anh; Todd, John A.] Singulex Inc, Alameda, CA USA. [Lipshultz, Steven] Univ Miami, Dept Pediat, Leonard M Miller Sch Med, Mailman Ctr Child Dev, Miami, FL 33152 USA. [Hasinoff, Brian] Univ Manitoba, Fac Pharm, Apotex Ctr, Winnipeg, MB R3T 2N2, Canada. RP Herman, EH (reprint author), US FDA, Div Appl Pharmacol Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM eugene.herman@fda.hhs.gov FU Canadian Institutes of Health Research; Canada Research Chairs Program FX The authors declared no potential conflicts of interests with respect to the authorship and/or publication of this article. The authors declared the following source of financial support for the research and/or authorship of this article: Dr Hasinoff received a grant from the Canadian Institutes of Health Research, the Canada Research Chairs Program. NR 61 TC 22 Z9 22 U1 0 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD DEC PY 2011 VL 39 IS 7 BP 1091 EP 1106 DI 10.1177/0192623311419524 PG 16 WC Pathology; Toxicology SC Pathology; Toxicology GA 961IV UT WOS:000305459000008 PM 21937741 ER PT J AU Zhu, H Wang, YN AF Zhu, Hao Wang, Yaning TI Evaluation of false positive rate based on exposure-response analyses for two compounds in fixed-dose combination products SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Article DE Exposure-response analysis; Type I error; Fixed-dose combination products ID DECISIONS; IMPACT AB We explored the type I error rate (false positive rate) associated with exposure-response (ER) analyses for two compounds in a fixed-dose combination product through simulations. In the simulations, at least one compound was assumed to be inactive, whereas the active compound followed E-max model at different concentration ranges. The simulated data were independently evaluated by pre-specified univariate or multivariate linear, log-linear models, and mixed linear log-linear models. The type I error rate was evaluated by comparing the total number of falsely identified significant slope estimates with the total number of models with successful convergence. We demonstrated that ER analyses results based on data from fixed-dose combination products at various dose levels should be interpreted with caution. A univariate analysis, even though is appropriate to guide dose selection, is inadequate to identify the active compound. Multivariate analyses can be applied to determine the active compound only when the underlying ER relationship for each compound (especially for the active compound) has been adequately defined or approximated. The false positive rate in determining a significant ER relationship is elevated, when the underlying ER relationship (especially for the active compound) is erroneously or inadequately defined. Without the assurance of the correct structural models, the identified significant ER relationship does not necessarily indicate that the compound associated with the significant slope estimate is pharmacologically active. C1 [Zhu, Hao; Wang, Yaning] FDA, CDER, Off Clin Pharmacol, Div Pharmacometr, Silver Spring, MD 20993 USA. RP Zhu, H (reprint author), FDA, CDER, Off Clin Pharmacol, Div Pharmacometr, 10903 New Hampshire Ave,Room 3150,Bldg 51, Silver Spring, MD 20993 USA. EM Hao.Zhu@fda.hhs.gov NR 7 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD DEC PY 2011 VL 38 IS 6 BP 671 EP 696 DI 10.1007/s10928-011-9214-4 PG 26 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 890VJ UT WOS:000300173500001 PM 21898140 ER PT J AU Kuselman, I Schumacher, I Pennecchi, F Burns, C Fajgelj, A de Zorzi, P AF Kuselman, Ilya Schumacher, Ilana Pennecchi, Francesca Burns, Cathy Fajgelj, Ales de Zorzi, Paolo TI Long-term stability study of drug products and out-of-specification test results SO ACCREDITATION AND QUALITY ASSURANCE LA English DT Article; Proceedings Paper CT 4th International Conference on Metrology - Measurement-and-Testing-in-the-Service-of-Society CY MAY 23-24, 2011 CL Jerusalem, ISRAEL SP Measurement & Testing Serv Soc, Israeli Metrolog Soc, ISAS Int Seminars DE Stability study; Regression analysis; Out-of-specification test results; Measurement uncertainty; Producer's risk; Consumer's risk ID UNCERTAINTY AB A metrological approach for investigating out-of-specification (OOS) test results in long-term stability study of drug products was used. It is shown that OOS test results can indicate an actual change in a measured property of a product or be metrologically related with a certain confidence probability, i.e., be caused by the measurement problems, while the product still meets the quality requirements at the time of testing. As examples, results of testing sodium chloride injections in 500-mL plastic containers and of epinephrine (L-adrenaline) injections in 1-mL ampoules were discussed. Regression analysis of the data was performed, as well as warning and action lines for shelf life of the products calculated for relevant measurement uncertainties and confidence probabilities. Producer's and consumer's risks of the established shelf life values were also estimated. C1 [Kuselman, Ilya] Natl Phys Lab Israel INPL, IL-91904 Jerusalem, Israel. [Schumacher, Ilana] Israel Def Forces, Res & Qual Control Lab, Med Corps, Jerusalem, Israel. [Pennecchi, Francesca] Ist Nazl Ric Metrol INRIM, I-10135 Turin, Italy. [Burns, Cathy] US FDA, Denver, CO 80225 USA. [Fajgelj, Ales] IAEA, Vienna Int Ctr, A-1400 Vienna, Austria. [de Zorzi, Paolo] ISPRA, I-00128 Rome, Italy. RP Kuselman, I (reprint author), Natl Phys Lab Israel INPL, IL-91904 Jerusalem, Israel. EM ilya.kuselman@moital.gov.il RI Pennecchi, Francesca/G-9812-2015 OI Pennecchi, Francesca/0000-0003-1328-3858 NR 27 TC 5 Z9 5 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0949-1775 J9 ACCREDIT QUAL ASSUR JI Accredit. Qual. Assur. PD DEC PY 2011 VL 16 IS 12 BP 615 EP 622 DI 10.1007/s00769-011-0813-y PG 8 WC Chemistry, Analytical; Instruments & Instrumentation SC Chemistry; Instruments & Instrumentation GA 889NG UT WOS:000300079800006 ER PT J AU Boehmer, JL AF Boehmer, Jamie L. TI Proteomic Analyses of Host and Pathogen Responses during Bovine Mastitis SO JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA LA English DT Article DE Proteomics; Mastitis; Milk proteins; Mastitis pathogens; Biomarkers ID PERFORMANCE LIQUID-CHROMATOGRAPHY; TWO-DIMENSIONAL ELECTROPHORESIS; IONIZATION MASS-SPECTROMETRY; ESCHERICHIA-COLI MASTITIS; STAPHYLOCOCCUS-AUREUS; MILK PROTEINS; CLINICAL MASTITIS; SACCHAROMYCES-CEREVISIAE; SHOTGUN PROTEOMICS; GENE-EXPRESSION AB The pursuit of biomarkers for use as clinical screening tools, measures for early detection, disease monitoring, and as a means for assessing therapeutic responses has steadily evolved in human and veterinary medicine over the past two decades. Concurrently, advances in mass spectrometry have markedly expanded proteomic capabilities for biomarker discovery. While initial mass spectrometric biomarker discovery endeavors focused primarily on the detection of modulated proteins in human tissues and fluids, recent efforts have shifted to include proteomic analyses of biological samples from food animal species. Mastitis continues to garner attention in veterinary research due mainly to affiliated financial losses and food safety concerns over antimicrobial use, but also because there are only a limited number of efficacious mastitis treatment options. Accordingly, comparative proteomic analyses of bovine milk have emerged in recent years. Efforts to prevent agricultural-related food-borne illness have likewise fueled an interest in the proteomic evaluation of several prominent strains of bacteria, including common mastitis pathogens. The interest in establishing biomarkers of the host and pathogen responses during bovine mastitis stems largely from the need to better characterize mechanisms of the disease, to identify reliable biomarkers for use as measures of early detection and drug efficacy, and to uncover potentially novel targets for the development of alternative therapeutics. The following review focuses primarily on comparative proteomic analyses conducted on healthy versus mastitic bovine milk. However, a comparison of the host defense proteome of human and bovine milk and the proteomic analysis of common veterinary pathogens are likewise introduced. C1 US FDA, Ctr Vet Med, Laurel, MD 20708 USA. RP Boehmer, JL (reprint author), US FDA, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM jamie.boehmer@fda.hhs.gov NR 84 TC 18 Z9 18 U1 2 U2 19 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1083-3021 J9 J MAMMARY GLAND BIOL JI J. Mammary Gland Biol. Neoplasia PD DEC PY 2011 VL 16 IS 4 BP 323 EP 338 DI 10.1007/s10911-011-9229-x PG 16 WC Oncology; Endocrinology & Metabolism; Physiology SC Oncology; Endocrinology & Metabolism; Physiology GA 890UU UT WOS:000300171800005 PM 21892748 ER PT J AU Huang, Y Zhang, K Kang, JU Calogero, D James, RH Ilev, IK AF Huang, Yong Zhang, Kang Kang, Jin U. Calogero, Don James, Robert H. Ilev, Ilko K. TI Noncontact common-path Fourier domain optical coherence tomography method for in vitro intraocular lens power measurement SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE cataract; intraocular lens dioptric power; common-path Fourier domain optical coherence tomography ID FOCAL LENGTH; REFRACTION CORRECTION; ACCURACY AB We propose a novel common-path Fourier domain optical coherence tomography (CP-FD-OCT) method for noncontact, accurate, and objective in vitro measurement of the dioptric power of intraocular lenses (IOLs) implants. The CP-FD-OCT method principle of operation is based on simple two-dimensional scanning common-path Fourier domain optical coherence tomography. By reconstructing the anterior and posterior IOL surfaces, the radii of the two surfaces, and thus the IOL dioptric power are determined. The CP-FD-OCT design provides high accuracy of IOL surface reconstruction. The axial position detection accuracy is calibrated at 1.22 mu m in balanced saline solution used for simulation of in situ conditions. The lateral sampling rate is controlled by the step size of linear scanning systems. IOL samples with labeled dioptric power in the low-power (5D), mid-power (20D and 22D), and high-power (36D) ranges under in situ conditions are tested. We obtained a mean power of 4.95/20.11/22.09/36.25 D with high levels of repeatability estimated by a standard deviation of 0.10/0.18/0.2/0.58 D and a relative error of 2/0.9/0.9/1.6%, based on five measurements for each IOL respectively. The new CP-FD-OCT method provides an independent source of IOL power measurement data as well as information for evaluating other optical properties of IOLs such as refractive index, central thickness, and aberrations. (C) 2011 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI: 10.1117/1.3660313] C1 [Huang, Yong; Kang, Jin U.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Huang, Yong; Calogero, Don; James, Robert H.; Ilev, Ilko K.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Zhang, Kang] GE Global Res, Niskayuna, NY 12309 USA. RP Huang, Y (reprint author), Johns Hopkins Univ, Dept Elect & Comp Engn, 3400 N Charles St,Barton Hall 402, Baltimore, MD 21218 USA. EM yhuang60@jhu.edu RI Kang, Jin/A-3228-2010; Huang, Yong/B-3102-2014 FU Oak Ridge Institute for Science and Education (ORISE); China Scholarship Council (CSC) FX This work is supported by Oak Ridge Institute for Science and Education (ORISE). Yong Huang is partially supported by China Scholarship Council (CSC). We would like to thank Dr. Xuan Liu for constructive discussion. NR 24 TC 4 Z9 4 U1 0 U2 4 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD DEC PY 2011 VL 16 IS 12 AR 126005 DI 10.1117/1.3660313 PG 6 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 881MH UT WOS:000299490300017 PM 22191922 ER PT J AU Kim, DH AF Kim, Do-Hyun TI Using a melanin granule lattice model to study the thermal effects of pulsed and scanning light irradiations through a measurement aperture SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE laser safety; eye protection; optical standards; photothermal effects; scanning laser; pulsed laser; melanin granule model ID RETINAL INJURY; LASER; OPHTHALMOSCOPES; TISSUE; DAMAGE AB Optical radiation hazards of scanning light sources are often evaluated using pulsed light source criteria, with the relevant pulse parameter equivalent to the scanning light source determined by the energy delivered through a measurement aperture. However, physical equivalence has not been completely understood: a pulsed light source is temporally dynamic but spatially stationary, while a scanning light source is temporally stationary but spatially dynamic. This study introduces a numerical analysis based upon the melanin granule lattice model to investigate the equivalence of scanning and pulsed light sources through a measurement aperture and their respective thermal effects in the pigmented retinal layer. The numerical analysis calculates the thermal contribution of individual melanin granules with varying temporal sequence, and finds that temperature changes and thermal damage thresholds for the two different types of light sources were not equal. However, dwell times of 40 to 200 mu sec did not produce significant differences between pulsed and scanning light sources in temperature change and thermal damage thresholds to the sample tissue. (C) 2011 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI: 10.1117/1.3656746] C1 US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Kim, DH (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 62,Room 1133, Silver Spring, MD 20993 USA. EM do-hyun.kim@fda.hhs.gov NR 21 TC 1 Z9 1 U1 0 U2 2 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD DEC PY 2011 VL 16 IS 12 AR 125002 DI 10.1117/1.3656746 PG 8 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 881MH UT WOS:000299490300010 PM 22191915 ER PT J AU Huang, L Zalkikar, J Tiwari, RC AF Huang, Lan Zalkikar, Jyoti Tiwari, Ram C. TI A Likelihood Ratio Test Based Method for Signal Detection With Application to FDA's Drug Safety Data SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE AERS database; Disproportionality signal detection; False discovery rate; Reporting rate; Simulation ID DATA-MINING ALGORITHMS; REPORTING SYSTEM; PHARMACOVIGILANCE; GENERATION; EVENTS AB Several statistical methods that are available in the literature to analyze postmarket safety databases, such as the U.S. Federal Drug Administration's (FDA) adverse event reporting system (AERS), for identifying drug-event combinations with disproportionately high frequencies, are subject to high false discovery rates. Here, we propose a likelihood ratio test (LRT) based method and show, via an extensive simulation study, that the proposed method while retaining good power and sensitivity for identifying signals, controls both the Type I error and false discovery rates. The application of the LRT method to the AERS database is illustrated using two datasets; a small dataset consisting of suicidal behavior and mood change-related AE cases for the drug Montelukast, and a large dataset consisting of all possible AE cases reported to FDA during 2004-2008 for the drug Heparin. This article has supplementary material online. C1 [Huang, Lan] US FDA, DBV, OB, CDER, Silver Spring, MD 20993 USA. [Tiwari, Ram C.] US FDA, Off Biostat, CDER, Silver Spring, MD 20993 USA. RP Huang, L (reprint author), US FDA, DBV, OB, CDER, Silver Spring, MD 20993 USA. EM lan.huang@fda.hhs.gov; Jyoti.zalkikar@fda.hhs.gov; Ram.tiwari@fda.hhs.gov NR 27 TC 17 Z9 17 U1 1 U2 4 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD DEC PY 2011 VL 106 IS 496 BP 1230 EP 1241 DI 10.1198/jasa.2011.ap10243 PG 12 WC Statistics & Probability SC Mathematics GA 883VL UT WOS:000299662900002 ER PT J AU Zhou, YT Yin, JJ Lo, YM AF Zhou, Yu-Ting Yin, Jun-Jie Lo, Y. Martin TI Application of ESR spin label oximetry in food science SO MAGNETIC RESONANCE IN CHEMISTRY LA English DT Review DE ESR; oximetry; spin label; oxidation; lipid; antioxidant; noninvasive ID POLYUNSATURATED FATTY-ACIDS; LIPID-PEROXIDATION; BACTERIORHODOPSIN MUTANTS; RECONSTITUTED MEMBRANES; CONCENTRATION PRODUCTS; OXYGEN-CONSUMPTION; RETINYL PALMITATE; METHYL LINOLEATE; FUMONISIN B-1; FREE-RADICALS AB Lipid oxidation attributed to the presence of oxygen has long been a focal area for food science research due in early years mainly to its broad impact on the quality and shelf stability. The need to effectively strategize interventions to detect and eventually eliminate lipid oxidation in food remains as evidence on nutritional and health implications continue to accumulate. Electron spin resonance (ESR) spin label oximetry has been shown capable of detecting dissolved oxygen concentration in both liquid and gaseous phases based on the collision between oxygen and stable free radicals. This review aimed to summarize not just the principles and rationale of ESR spin label oximetry but also the wide spectrum of ESR spin label oximetry applications to date. The feasibility to identify in very early stage oxygen generation and consumption offers a promising tool for controlling lipid oxidation in food and biological systems. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Zhou, Yu-Ting; Lo, Y. Martin] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Lo, YM (reprint author), Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. EM ymlo@umd.edu RI Zhou, Yuting/I-9125-2012; Yin, Jun Jie /E-5619-2014 NR 62 TC 8 Z9 8 U1 0 U2 26 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0749-1581 J9 MAGN RESON CHEM JI Magn. Reson. Chem. PD DEC PY 2011 VL 49 SU 1 SI SI BP S105 EP S112 DI 10.1002/mrc.2822 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 884EL UT WOS:000299687600014 PM 22290700 ER PT J AU Landry, B Roque-Albelo, L Hayden, JE AF Landry, Bernard Roque-Albelo, Lazaro Hayden, James E. TI A new genus and species of Spilomelinae (Lepidoptera, Pyralidae) from the Galapagos Islands, Ecuador SO REVUE SUISSE DE ZOOLOGIE LA English DT Article AB A new genus and species of Spilomelinae (Lepidoptera, Pyralidae) from the Galapagos Islands, Ecuador. - Cheverella galapagensis Landry, gen. n. and sp. n. is described as an endemic of the Galapagos Islands, Ecuador. Based on a combination of two apomorphies (reduced uncus and presence of setose pads on anterodorsal extensions of the male valva medially) this taxon is possibly related to Choristostigma Warren, now placed in the Hydriris group of Munroe (1995), but Cheverella lacks the setose projection at base of the valve's costa present in Choristostigma. The female has a clearly circumscribed corpus bursae with a short, spine-like signum. Cheverella also shares a few characters with members of the Siga group. The larva is a borer in stems of the endemic Tournefortia pubescens Hook. f (Boraginaceae). C1 [Landry, Bernard] Museum Hist Nat, CH-1211 Geneva 6, Switzerland. [Roque-Albelo, Lazaro] Curtin Univ, Curtin Inst Biodivers & Climate, Perth, WA 6845, Australia. [Roque-Albelo, Lazaro] Ecol Environm, Perth, WA, Australia. [Hayden, James E.] Florida State Collect Arthropods, FDACS, Div Plant Ind, Gainesville, FL 32614 USA. RP Landry, B (reprint author), Museum Hist Nat, CP 6434, CH-1211 Geneva 6, Switzerland. EM bernard.landry@ville-ge.ch; lazaro.roque-albelo@ecologia.com.au; james.hayden@freshfromflorida.com FU Natural Sciences and Engineering Research Council of Canada; Charles Darwin Foundation; Galapagos Conservation Trust (UK); CMNH, Pittsburgh FX We are thankful to the authorities of Parque Nacional Galapagos and those of the CDRS for allowing and facilitating the field work of B. Landry and L. Roque, and for permits to export specimens. BL is greatly indebted to Stewart B. Peck, his Ph.D. advisor at Carleton University, Ottawa, for taking him on to explore the Galapagos in 1989 and 1992, and for his inspiring companionship in the field. This fieldwork was supported by an operating grant to S. B. Peck from the Natural Sciences and Engineering Research Council of Canada for field research on arthropod evolution. Other much appreciated field companions during one or more of BL's five expeditions to the Galapagos were Novarino Castillo, Charlotte Causton, Joyce Cook, Moraima Inca, Jose Loaiza, Ricardo Palma, L. Roque-Albelo, Patrick Schmitz, Bradley J. Sinclair, and Eduardo Vilema. BL is also grateful to the Charles Darwin Foundation and the Galapagos Conservation Trust (UK) for providing financial support for his investigations at the BMNH in 2000 and in the Galapagos in 2002. In the BMNH we would like to acknowledge the great support received from curators Michael Shaffer (deceased) and Kevin Tuck. JEH was supported by a Rea Postdoctoral Fellowship (CMNH, Pittsburgh) during his study of Spilomelinae. JEH thanks Alma Solis for providing a manuscript of a revision of the Polygrammodes group by E.G. Munroe (deceased), which partly informed the discussion of the Siga group. Finally, we thank Philippe Wagneur (WING) for his photos of the moths shown here, Florence Marteau (MHNG) for producing the plates, Louis Marcotte (Gatineau, Canada) for helping with GPS data and jargon, pyraloid workers E. Munroe, M. Nuss, M. Shaffer, and Alma Solis for their expertise on this species' taxonomic and systematic status, and the reviewers for their comments. NR 11 TC 2 Z9 2 U1 0 U2 3 PU MUSEUM HISTOIRE NATURELLE PI GENEVA 6 PA CASE POSTALE 6434, ATTN:DENISE MAIER ADMN REV SUISSE DE ZOOLOGIE, CH-L211 GENEVA 6, SWITZERLAND SN 0035-418X J9 REV SUISSE ZOOL JI Rev. Suisse Zool. PD DEC PY 2011 VL 118 IS 4 BP 639 EP 649 PG 11 WC Zoology SC Zoology GA 887DW UT WOS:000299908100002 ER PT J AU Wright, DJ Minck, DR Nowak, J Warner, G Cukierski, M AF Wright, David J. Minck, Daniel R. Nowak, John Warner, Garvin Cukierski, Mark TI Assessment of immunization against recombinant human bone morphogenetic protein-2 (dibotermin alpha) on reproduction and development in rabbits SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Article DE BMP-2; BMP-2 antibody; pregnancy; development; fetus ID MOUSE; OSSIFICATION; LIMB AB BACKGROUND: To determine if the fetus was affected by maternal antibodies to BMP-2, the antibody response and developmental effects in fetuses from does immunized against recombinant human BMP-2 were evaluated. METHODS: Female New Zealand White rabbits received four intramuscular injections (on premating days 1, 8, 22, and 43 [3 days before mating]) of saline and adjuvant (TiterMax (R) Gold [control]) or recombinant human BMP-2 (2 mg/dose) and adjuvant (treated). On GD 29, fetuses were examined, and maternal and fetal anti-BMP-2 titer levels and neutralizing activity were assessed. RESULTS: Anti-BMP-2 antibodies were detected in 17 of 18 treated does (127 of 151 fetuses), and low levels were detected in 2 of 16 control does (no fetal exposure observed). In general, levels of fetal anti-BMP-2 antibodies were similar to those in the does, and pregnancy did not boost the immune response to BMP-2. There were no effects of immunization or anti-BMP-2 antibody titer levels on embryo-fetal viability, fetal weight, or fetal external, visceral, or skeletal development. Only a small number of fetuses (n = 4) displayed detectable neutralizing anti-BMP-2 antibodies, but there were no treatment-related effects in those fetuses. CONCLUSIONS: The lack of embryo-fetal effects may be due to dosage effects of neutralizing anti-BMP-2 antibodies, timing of exposure (stage and duration) to neutralizing anti-BMP-2 antibodies, and/or redundancy of effects of the various BMPs. Birth Defects Res (Part B) 92:543552, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Wright, David J.; Cukierski, Mark] Pfizer, Drug Safety Res & Dev, Groton, CT 06340 USA. [Minck, Daniel R.] FDA, Div Metab & Endocrinol Prod, Silver Spring, MD USA. [Nowak, John] Pfizer, Clin Assay Grp, Andover, MA USA. [Warner, Garvin] Alnylam Pharmaceut, Cambridge, MA USA. RP Wright, DJ (reprint author), Pfizer, Drug Safety Res & Dev, Groton, CT 06340 USA. EM david.wright@pfizer.com NR 22 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1542-9733 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD DEC PY 2011 VL 92 IS 6 BP 543 EP 552 DI 10.1002/bdrb.20324 PG 10 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA 860CB UT WOS:000297923200007 PM 21922636 ER PT J AU Booth, B AF Booth, Brian TI When do you need a validated assay? SO BIOANALYSIS LA English DT Article DE bioanalysis; regulatory; validated; validation; US FDA C1 US FDA, Ctr Drug Res & Evaluat Res, Off Clin Pharmacol, Div Clin Pharmacol 5, Silver Spring, MD 20993 USA. RP Booth, B (reprint author), US FDA, Ctr Drug Res & Evaluat Res, Off Clin Pharmacol, Div Clin Pharmacol 5, Silver Spring, MD 20993 USA. EM brian.booth@fda.hhs.gov NR 3 TC 18 Z9 18 U1 0 U2 0 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1757-6180 J9 BIOANALYSIS JI Bioanalysis PD DEC PY 2011 VL 3 IS 24 BP 2729 EP 2730 DI 10.4155/BIO.11.250 PG 2 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 878GT UT WOS:000299244200014 PM 22185272 ER PT J AU Goblick, GN Anbarchian, JM Woods, J Burkhardt, W Calci, K AF Goblick, Gregory N. Anbarchian, Julie Mayer Woods, Jacquelina Burkhardt, William, III Calci, Kevin TI EVALUATING THE DILUTION OF WASTEWATER TREATMENT PLANT EFFLUENT AND VIRAL IMPACTS ON SHELLFISH GROWING AREAS IN MOBILE BAY, ALABAMA SO JOURNAL OF SHELLFISH RESEARCH LA English DT Article DE wastewater; shellfish; growing area; treatment plant ID HEPATITIS-A VIRUS; MERCENARIA-MERCENARIA; MOLLUSCAN SHELLFISH; ESCHERICHIA-COLI; ACCUMULATION; INDICATOR; DEPURATION; BIOACCUMULATION; BACTERIOPHAGE; PERSISTENCE AB The U.S. Food and Drug Administration (FDA) provides guidance to state shellfish control authorities on establishing prohibitive closure zones in proximity to wastewater treatment plant (WWTP) discharges with the purpose of minimizing the exposure of molluscan shellfish to health hazards posed by bacterial and viral pathogens present in wastewater effluents. For more than 25 years, the FDA has recognized conditional area management as an option to minimize the size of a prohibitive closure zone, and to enlarge the size and productivity of shellfish growing areas. To use this option, the FDA has recommended achieving a 1,000:1 dilution of effluent within the perimeter of the prohibited closure zone. Using newly available analytical methods and hydrographic equipment, the FDA is undertaking studies to determine whether its 1,000:1 dilution recommendation is supported by the findings. From 2007 through 2009, the FDA conducted field investigations to assess the impacts of wastewater effluent from a large municipal WWTP that discharges into Alabama's Mobile Bay. The dilution of the effluent in the bay was ascertained by conducting a hydrographic dye study using rhodamine WT tracer dye. Submersible fluorometers fastened to oyster cages at sentinel stations were used to determine continuously the dilution of the dye-tagged effluent throughout a 4-day study period. In addition, dilution and dispersion of the dye-tagged effluent was tracked throughout Mobile Bay by fluorometric measurements made while conducting boat transects. The microbiological impacts of the wastewater on molluscan shellfish were assessed by testing oysters placed in cages at sentinel stations at various distances along the anticipated path of the effluent. Levels of fecal coliforms. Escherichia coli, male-specific coliphage, and norovirus genogroups I and II were determined. Norovirus genogroup II was detected in oysters that were located as far as 5.74 km from the discharge, an area in close proximity to the calculated 1,000:1 dilution line. Results also showed that the levels of indicator microorganisms and viral pathogens in the shellfish inversely correlated with increased dilutions of the wastewater effluent in Mobile Bay. C1 [Goblick, Gregory N.; Anbarchian, Julie Mayer] US FDA, Off Food Safety, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Woods, Jacquelina; Burkhardt, William, III; Calci, Kevin] US FDA, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP Goblick, GN (reprint author), US FDA, Off Food Safety, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,HFS-325, College Pk, MD 20740 USA. EM gregory.goblick@fda.hhs.gov NR 29 TC 6 Z9 6 U1 0 U2 7 PU NATL SHELLFISHERIES ASSOC PI GROTON PA C/O DR. SANDRA E. SHUMWAY, UNIV CONNECTICUT, 1080 SHENNECOSSETT RD, GROTON, CT 06340 USA SN 0730-8000 EI 1943-6319 J9 J SHELLFISH RES JI J. Shellfish Res. PD DEC PY 2011 VL 30 IS 3 BP 979 EP 987 DI 10.2983/035.030.0341 PG 9 WC Fisheries; Marine & Freshwater Biology SC Fisheries; Marine & Freshwater Biology GA 876WO UT WOS:000299138700041 ER PT J AU Liu, ZC Shi, Q Ding, D Kelly, R Fang, H Tong, WD AF Liu, Zhichao Shi, Qiang Ding, Don Kelly, Reagan Fang, Hong Tong, Weida TI Translating Clinical Findings into Knowledge in Drug Safety Evaluation - Drug Induced Liver Injury Prediction System (DILIps) SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID INDUCED HEPATOTOXICITY; MOLECULAR DESCRIPTORS; RISK-FACTORS; GENOME-WIDE; POLYMORPHISM; ASSOCIATION; DETERMINANT; CONCORDANCE; DISCOVERY; WORKSHOP AB Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity. C1 [Liu, Zhichao; Shi, Qiang; Tong, Weida] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Ding, Don; Kelly, Reagan; Fang, Hong] ICF Int Co, FDAs Natl Ctr Toxicol Res, Jefferson, AZ USA. RP Liu, ZC (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM weida.tong@fda.hhs.gov RI Liu, Zhichao/C-4035-2011 FU FDA; Chief Scientist Challenge Grant; FDA's National Center for Toxicological Research; National Center for Toxicological Research (NCTR) of U.S. Food and Drug Administration (FDA) FX The report study is a part of FDA's Liver Toxicity Knowledge Base (LTKB) project that is supported by the FDA's Critical Path program and Chief Scientist Challenge Grant. This is an internal project supported by the FDA's National Center for Toxicological Research. ZL is grateful to the National Center for Toxicological Research (NCTR) of U.S. Food and Drug Administration (FDA) for postdoctoral support through the Oak Ridge Institute for Science and Education (ORISE). The views presented in this article do not necessarily reflect those of the U. S. Food and Drug Administration. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 29 Z9 29 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD DEC PY 2011 VL 7 IS 12 AR e1002310 DI 10.1371/journal.pcbi.1002310 PG 13 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 877HH UT WOS:000299167800030 PM 22194678 ER PT J AU Patrick, DL Burke, LB Gwaltney, CJ Leidy, NK Martin, ML Molsen, E Ring, L AF Patrick, Donald L. Burke, Laurie B. Gwaltney, Chad J. Leidy, Nancy Kline Martin, Mona L. Molsen, Elizabeth Ring, Lena TI Content Validity-Establishing and Reporting the Evidence in Newly Developed Patient-Reported Outcomes (PRO) Instruments for Medical Product Evaluation: ISPOR PRO Good Research Practices Task Force Report: Part 1-Eliciting Concepts for a New PRO Instrument SO VALUE IN HEALTH LA English DT Article DE content validity; European Medicines Agency; Food and Drug Administration; patient reported outcomes; quality of life ID QUALITATIVE RESEARCH; FOCUS GROUPS; DATA SATURATION; HEALTH-CARE; RECOMMENDATIONS; PERSPECTIVE; INTERVIEWS; CRITERIA; INQUIRY AB The importance of content validity in developing patient reported outcomes (PRO) instruments is stressed by both the US Food and Drug Administration and the European Medicines Agency. Content validity is the extent to which an instrument measures the important aspects of concepts that developers or users purport it to assess. A PRO instrument measures the concepts most significant and relevant to a patient's condition and its treatment. For PRO instruments, items and domains as reflected in the scores of an instrument should be important to the target population and comprehensive with respect to patient concerns. Documentation of target population input in item generation, as well as evaluation of patient understanding through cognitive interviewing, can provide the evidence for content validity. Developing content for, and assessing respondent understanding of, newly developed PRO instruments for medical product evaluation will be discussed in this two-part ISPOR PRO Good Research Practices Task Force Report. Topics include the methods for generating items, documenting item development, coding of qualitative data from item generation, cognitive interviewing, and tracking item development through the various stages of research and preparing this tracking for submission to regulatory agencies. Part 1 covers elicitation of key concepts using qualitative focus groups and/or interviews to inform content and structure of a new PRO instrument. Part 2 covers the instrument development process, the assessment of patient understanding of the draft instrument using cognitive interviews and steps for instrument revision. The two parts are meant to be read together. They are intended to offer suggestions for good practices in planning, executing, and documenting qualitative studies that are used to support the content validity of PRO instruments to be used in medical product evaluation. C1 [Patrick, Donald L.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Burke, Laurie B.] Food & Drug Adm, Ctr Drug Evaluat Res, Off New Drugs, Silver Spring, MD USA. [Gwaltney, Chad J.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Gwaltney, Chad J.] PRO Consulting, Pittsburgh, PA USA. [Leidy, Nancy Kline] United BioSource Corp, Bethesda, MD USA. [Martin, Mona L.] Hlth Res Associates Inc, Seattle, WA USA. [Molsen, Elizabeth] Int Soc Pharmacoecon & Outcomes Res, Lawrenceville, NJ USA. [Ring, Lena] AstraZeneca, Hlth Econ & Outcomes Res Div, Sodertalje, Sweden. [Ring, Lena] Uppsala Univ, Dept Pharm, Uppsala, Sweden. RP Patrick, DL (reprint author), Univ Washington Hlth Serv, POB 359455,SeaQoL Grp, Seattle, WA 98195 USA. EM donald@u.washington.edu NR 44 TC 156 Z9 156 U1 3 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD DEC PY 2011 VL 14 IS 8 BP 967 EP 977 DI 10.1016/j.jval.2011.06.014 PG 11 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 876BM UT WOS:000299081900002 PM 22152165 ER PT J AU Patrick, DL Burke, LB Gwaltney, CJ Leidy, NK Martin, ML Molsen, E Ring, L AF Patrick, Donald L. Burke, Laurie B. Gwaltney, Chad J. Leidy, Nancy Kline Martin, Mona L. Molsen, Elizabeth Ring, Lena TI Content Validity-Establishing and Reporting the Evidence in Newly Developed Patient-Reported Outcomes (PRO) Instruments for Medical Product Evaluation: ISPOR PRO Good Research Practices Task Force Report: Part 2-Assessing Respondent Understanding SO VALUE IN HEALTH LA English DT Article DE content validity; instrument development; patient-reported outcomes; qualitative research; regulatory ID PAPER; RECOMMENDATIONS; TRANSLATION AB The importance of content validity in developing patient reported outcomes (PRO) instruments is stressed by both the US Food and Drug Administration and the European Medicines Agency. Content validity is the extent to which an instrument measures the important aspects of concepts developers or users purport it to assess. A PRO instrument measures the concepts most relevant and important to a patient's condition and its treatment. For PRO instruments, items and domains as reflected in the scores of an instrument should be important to the target population and comprehensive with respect to patient concerns. Documentation of target population input in item generation, as well as evaluation of patient understanding through cognitive interviewing, can provide the evidence for content validity. Part 1 of this task force report covers elicitation of key concepts using qualitative focus groups and/or interviews to inform content and structure of a new PRO instrument. Building on qualitative interviews and focus groups used to elicit concepts, cognitive interviews help developers craft items that can be understood by respondents in the target population and can ultimately confirm that the final instrument is appropriate, comprehensive, and understandable in the target population. Part 2 details: 1) the methods for conducting cognitive interviews that address patient understanding of items, instructions, and response options; and 2) the methods for tracking item development through the various stages of research and preparing this tracking for submission to regulatory agencies. The task force report's two parts are meant to be read together. They are intended to offer suggestions for good practice in planning, executing, and documenting qualitative studies that are used to support the content validity of PRO instruments to be used in medical product evaluation. C1 [Patrick, Donald L.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Burke, Laurie B.] Food & Drug Adm, Ctr Drug Evaluat Res, Off New Drugs, Silver Spring, MD USA. [Gwaltney, Chad J.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Gwaltney, Chad J.] PRO Consulting, Pittsburgh, PA USA. [Leidy, Nancy Kline] United BioSource Corp, Bethesda, MD USA. [Martin, Mona L.] Hlth Res Associates Inc, Seattle, WA USA. [Molsen, Elizabeth] Int Soc Pharmacoecon & Outcomes Res, Lawrenceville, NJ USA. [Ring, Lena] AstraZeneca, Hlth Econ & Outcomes Res Div, Sodertalje, Sweden. [Ring, Lena] Uppsala Univ, Dept Pharm, Uppsala, Sweden. RP Patrick, DL (reprint author), Univ Washington, Dept Hlth Serv, POB 359455,SeaQoL Grp, Seattle, WA 98195 USA. EM donald@u.washington.edu NR 27 TC 156 Z9 156 U1 2 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD DEC PY 2011 VL 14 IS 8 BP 978 EP 988 DI 10.1016/j.jval.2011.06.013 PG 11 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 876BM UT WOS:000299081900003 PM 22152166 ER PT J AU Liu, HL Gao, Y Yu, LR Jones, RC Elkins, CA Hart, ME AF Liu, Huanli Gao, Yuan Yu, Li-Rong Jones, Richard C. Elkins, Christopher A. Hart, Mark E. TI Inhibition of Staphylococcus aureus by Lysostaphin-Expressing Lactobacillus plantarum WCFS1 in a Modified Genital Tract Secretion Medium SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID TOXIC-SHOCK-SYNDROME; AGGREGATION-PROMOTING FACTOR; GRAM-POSITIVE BACTERIA; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; BINDING-PROTEIN; ANTIMICROBIAL ACTIVITY; ENTEROTOXIN-F; LYSM DOMAIN; CELL-WALL; IN-VITRO AB Lactobacillus species are a predominant member of the vaginal microflora and are critical in maintaining an acidic vaginal environment thought to contribute to the prevention of a number of urogenital diseases. However, during menstruation the pH of the vaginal environment increases to neutrality, a pH conducive for Staphylococcus aureus proliferation and the production of toxic shock syndrome toxin 1 (TSST-1) in susceptible women. In order to generate Lactobacillus species capable of expressing lysostaphin (an endopeptidase that cleaves the cell wall of S. aureus) in a modified genital tract secretion medium (mGTS) under neutral-pH conditions, six prominent proteins from Lactobacillus plantarum WCFS1 spent medium were identified by mass spectrometry. Sequences for promoters, signal peptides, and mature lysostaphin were used to construct plasmids that were subsequently transformed into L. plantarum WCFS1. The promoter and signal sequences of Lp_3014 (putatively identified as a transglycosylase) or the promoter sequence of Lp_0789 (putatively identified as glyceraldehyde 3-phosphate dehydrogenase) with the signal sequence of Lp_3014 exhibited lysostaphin activity on buffered medium containing heat-killed S. aureus. The cassettes were integrated into the chromosome of L. plantarum WCFS1, but only the cassette containing the promoter and signal sequence from Lp_3014 had integrated into the appropriate site. Coculture assays using buffered mGTS showed that lysostaphin expressed from L. plantarum WCFS1 reduced the growth of TSST-1-producing strains of S. aureus under neutral-pH conditions. This study provides the basis for determining whether lysostaphin-producing Lactobacillus strains could potentially be used as a means to inhibit the growth of S. aureus during menstruation. C1 [Liu, Huanli; Hart, Mark E.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Gao, Yuan; Yu, Li-Rong] US FDA, Ctr Prote, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Jones, Richard C.] MSBioworks, Ann Arbor, MI 48108 USA. [Elkins, Christopher A.] US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Hart, ME (reprint author), US FDA, Div Microbiol HFT 250, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM mark.hart@fda.hhs.gov RI Hart, Mark/B-8976-2013 FU Office of Women's Health of the U.S. Food and Drug Administration [E0728601, E0725501]; National Center for Toxicological Research FX This study was funded by the Office of Women's Health of the U.S. Food and Drug Administration under protocol numbers E0728601 and E0725501. Support for Huanli Liu was provided by the Postdoctoral Research Program at the National Center for Toxicological Research, which is administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 80 TC 4 Z9 4 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD DEC PY 2011 VL 77 IS 24 BP 8500 EP 8508 DI 10.1128/AEM.06755-11 PG 9 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 863JE UT WOS:000298157800005 PM 21984245 ER PT J AU Zineh, I Huang, SM AF Zineh, Issam Huang, Shiew-Mei TI Biomarkers in drug development and regulation: a paradigm for clinical implementation of personalized medicine SO BIOMARKERS IN MEDICINE LA English DT Review DE biomarker; companion diagnostics; pharmacogenetics; pharmacogenomics; regulatory science; US FDA ID CONSORTIUM GUIDELINES; AMERICAN SOCIETY; PHARMACOGENETICS; THERAPY; CARE; GENOTYPE; TESTS AB The post-genomic era has been hallmarked by significant enthusiasm for therapeutic individualization through the use of pharmacogenomic and other biomarkers. This enthusiasm has been dampened by limited examples of widespread clinical adoption. The current clinical implementation paradigm may not be adequate to facilitate uptake of pharmacogenetics for a variety of reasons. This paper discusses certain limitations of the classical clinical implementation paradigm and describes the drug development paradigm as an additional, powerful mechanism to facilitate clinical implementation of individualized therapeutics. C1 [Zineh, Issam; Huang, Shiew-Mei] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Zineh, I (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Room 3182, Silver Spring, MD 20993 USA. EM Issam.zineh@fda.hhs.gov NR 28 TC 10 Z9 11 U1 1 U2 11 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 J9 BIOMARK MED JI Biomark. Med. PD DEC PY 2011 VL 5 IS 6 BP 705 EP 713 DI 10.2217/BMM.11.90 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 867XN UT WOS:000298488200003 PM 22103607 ER PT J AU Spencer, DH Lockwood, C Topol, E Evans, JP Green, RC Mansfield, E Tezak, Z AF Spencer, David H. Lockwood, Christina Topol, Eric Evans, James P. Green, Robert C. Mansfield, Elizabeth Tezak, Zivana TI Direct-to-Consumer Genetic Testing: Reliable or Risky? SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 [Spencer, David H.; Lockwood, Christina] Washington Univ, Barnes Jewish Hosp, St Louis, MO 63110 USA. [Topol, Eric] Scripps Res Inst, Scripps Translat Sci Inst, La Jolla, CA 92037 USA. [Evans, James P.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Green, Robert C.] Harvard Univ, Sch Med, Boston, MA USA. [Green, Robert C.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Mansfield, Elizabeth; Tezak, Zivana] US FDA, Silver Spring, MD USA. RP Spencer, DH (reprint author), Washington Univ, Barnes Jewish Hosp, Box 8118,660 S Euclid Ave, St Louis, MO 63110 USA. EM dspencer@path.wustl.edu OI Topol, Eric/0000-0002-1478-4729 NR 0 TC 9 Z9 9 U1 0 U2 3 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD DEC PY 2011 VL 57 IS 12 BP 1641 EP 1644 DI 10.1373/clinchem.2011.167197 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 862UM UT WOS:000298119600003 PM 21885623 ER PT J AU Dertinger, SD Heflich, RH AF Dertinger, Stephen D. Heflich, Robert H. TI In Vivo Assessment of Pig-a Gene Mutation-Recent Developments and Assay Validation SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Editorial Material ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; ETHYL-N-NITROSOUREA; RED-BLOOD-CELLS; SPLEEN T-CELLS; ANCHOR BIOSYNTHESIS; FLOW-CYTOMETRY; DIAGNOSIS; LOCUS; CDNA; RAT C1 [Dertinger, Stephen D.] Litron Labs, Rochester, NY USA. [Heflich, Robert H.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Dertinger, SD (reprint author), Litron Labs, Rochester, NY USA. FU NIEHS NIH HHS [R44ES018017] NR 29 TC 12 Z9 13 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD DEC PY 2011 VL 52 IS 9 BP 681 EP 684 DI 10.1002/em.20685 PG 4 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 871IY UT WOS:000298732700001 PM 22167884 ER PT J AU Dertinger, SD Phonethepswath, S Weller, P Nicolette, J Murray, J Sonders, P Vohr, HW Shi, J Krsmanovic, L Gleason, C Custer, L Henwood, A Sweder, K Stankowski, LF Roberts, DJ Giddings, A Kenny, J Lynch, AM Defrain, C Nesslany, F van der Leede, BJM Van Doninck, T Schuermans, A Tanaka, K Hiwata, Y Tajima, O Wilde, E Elhajouji, A Gunther, WC Thiffeault, CJ Shutsky, TJ Fiedler, RD Kimoto, T Bhalli, JA Heflich, RH MacGregor, JT AF Dertinger, Stephen D. Phonethepswath, Souk Weller, Pamela Nicolette, John Murray, Joel Sonders, Paul Vohr, Hans-Werner Shi, Jing Krsmanovic, Ljubica Gleason, Carol Custer, Laura Henwood, Andrew Sweder, Kevin Stankowski, Leon F., Jr. Roberts, Daniel J. Giddings, Amanda Kenny, Julia Lynch, Anthony M. Defrain, Celine Nesslany, Fabrice van der Leede, Bas-jan M. Van Doninck, Terry Schuermans, Ann Tanaka, Kentaro Hiwata, Yoshie Tajima, Osamu Wilde, Eleanor Elhajouji, Azeddine Gunther, William C. Thiffeault, Catherine J. Shutsky, Thomas J. Fiedler, Ronald D. Kimoto, Takafumi Bhalli, Javed A. Heflich, Robert H. MacGregor, James T. TI International Pig-a Gene Mutation Assay Trial: Evaluation of Transferability Across 14 Laboratories SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE Pig-a; mutation; flow cytometry; interlaboratory trial; genotoxicity ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; SPLEEN T-CELLS; RAT AB A collaborative international trial was conducted to evaluate the reproducibility and transferability of an in vivo mutation assay based on the enumeration of CD59-negative rat erythrocytes, a phenotype that is indicative of Pig-a gene mutation. Fourteen laboratories participated in this study, where anti-CD59-PE, SYTO 13 dye, and flow cytometry were used to determine the frequency of CD59-negative erythrocytes (RBC(CD59-)) and CD59-negative reticulocytes (RET(CD59-)). To provide samples with a range of mutant phenotype cell frequencies, male rats were exposed to N-ethyl-N-nitrosourea (ENU) via oral gavage for three consecutive days (Days 1-3). Each laboratory studied 0, 20, and 40 mg ENU/kg/day (n = 5 per group). Three sites also evaluated 4 mg/kg/day. At a minimum, blood samples were collected three times: predosing and on Days 15 and 30. Blood samples were processed according to a standardized sample processing and data ac-quisition protocol, and three endpoints were measured: %reticulocytes, frequency of RET(CD59-), and frequency of RBC(CD59-). The methodology was found to be reproducible, as the analysis of technical replicates resulted in experimental coefficients of variation that approached theoretical values. Good transferability was evident from the similar kinetics and magnitude of the dose-related responses that were observed among different laboratories. Concordance correlation coefficients showed a high level of agreement between the reference site and the test sites (range: 0.87-0.99). Collectively, these data demonstrate that with adequate training of personnel, flow cytometric analysis is capable of reliably enumerating mutant phenotype erythrocytes, thereby providing a robust in vivo mutation assay that is readily transferable across laboratories. Environ. Mol. Mutagen. 52: 690-698, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Dertinger, Stephen D.; Phonethepswath, Souk; Weller, Pamela] Litron Labs, Rochester, NY 14623 USA. [Nicolette, John; Murray, Joel; Sonders, Paul] Abbott Labs, Abbott Pk, IL 60064 USA. [Vohr, Hans-Werner] Bayer Pharma AG, Wuppertal, Germany. [Shi, Jing; Krsmanovic, Ljubica] BioReliance Corp, Rockville, MD USA. [Gleason, Carol; Custer, Laura; Henwood, Andrew; Sweder, Kevin] Bristol Myers Squibb Co, Syracuse, NY USA. [Stankowski, Leon F., Jr.; Roberts, Daniel J.] Covance Labs, Vienna, VA USA. [Giddings, Amanda; Kenny, Julia; Lynch, Anthony M.] GlaxoSmithKline Inc, Ware, Herts, England. [Defrain, Celine; Nesslany, Fabrice] Inst Pasteur, F-59019 Lille, France. [van der Leede, Bas-jan M.; Van Doninck, Terry; Schuermans, Ann] Janssen Pharmaceut Co Johnson & Johnson, Drug Safety Sci, Beerse, Belgium. [Tanaka, Kentaro; Hiwata, Yoshie; Tajima, Osamu] Kirin Grp Off Co Ltd, Kanazawa Ku, Yokohama, Kanagawa, Japan. [Wilde, Eleanor; Elhajouji, Azeddine] Novartis Inst Biomed Res Preclin Safety Genet Tox, Basel, Switzerland. [Gunther, William C.; Thiffeault, Catherine J.; Shutsky, Thomas J.; Fiedler, Ronald D.] Pfizer Global R&D, Groton, CT USA. [Kimoto, Takafumi] Teijin Pharma Ltd, Tokyo, Japan. [Bhalli, Javed A.; Heflich, Robert H.] US FDA, NCTR, Jefferson, AR USA. [MacGregor, James T.] Toxicol Consulting Serv, Arnold, MD USA. RP Dertinger, SD (reprint author), Litron Labs, 200 Canal View Blvd, Rochester, NY 14623 USA. EM sdertinger@litronlabs.com FU National Institute of Health/National Institute of Environmental Health Sciences (NIEHS) [R44ES015940, R44ES018017] FX Grant sponsor: National Institute of Health/National Institute of Environmental Health Sciences (NIEHS); Grant Number R44ES015940 and R44ES018017. NR 20 TC 42 Z9 47 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD DEC PY 2011 VL 52 IS 9 BP 690 EP 698 DI 10.1002/em.20672 PG 9 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 871IY UT WOS:000298732700003 PM 21910140 ER PT J AU Cammerer, Z Bhalli, JA Cao, XF Coffing, SL Dickinson, D Dobo, KL Dobrovolsky, VN Engel, M Fiedler, RD Gunther, WC Heflich, RH Pearce, MG Shaddock, JG Shutsky, T Thiffeault, CJ Schuler, M AF Cammerer, Zoryana Bhalli, Javed A. Cao, Xuefei Coffing, Stephanie L. Dickinson, Donna Dobo, Krista L. Dobrovolsky, Vasily N. Engel, Maria Fiedler, Ronald D. Gunther, William C. Heflich, Robert H. Pearce, Mason G. Shaddock, Joseph G. Shutsky, Thomas Thiffeault, Catherine J. Schuler, Maik TI Report on Stage III Pig-a Mutation Assays Using N-ethyl-N-nitrosourea-Comparison With Other In Vivo Genotoxicity Endpoints SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE gene mutation; rats; CD59; flow cytometry; Hprt; comet assay; micronucleus assay; reticulocytes ID LIVER MICRONUCLEUS ASSAY; RATS; METHANESULFONATE; TOXICOLOGY; EXPOSURE; CELLS AB N-Ethyl-N-nitrosourea (ENU) was evaluated as part of the Stage III trial for the rat Pig-a gene mutation assay. Groups of six-to eight-week-old male Sprague Dawley (SD) or Fischer 344 (F344) rats were given 28 daily doses of the phosphate buffered saline vehicle, or 2.5, 5, or 10 mg/kg ENU, and evaluated for a variety of genotoxicity endpoints in peripheral blood, spleen, liver, and colon. Blood was sampled predose (Day-1) and at various time points up to Day 57. Pig-a mutant frequencies were determined in total red blood cells (RBCs) and reticulocytes (RETs) as RBC(CD59-) and RET(CD59-) frequencies. Consistent with the results from a reference laboratory, RBC(CD59-) and RET(CD59-) frequencies increased in a dose-and time-dependent manner, producing significant increases at all doses by Day 15, with similar frequencies seen in both rat strains. ENU also induced small but significant increases in % micro-nucleated RETs on Days 4 and 29. No significant increases in micronuclei were seen in the liver or colon of the ENU-treated SD rats. Hprt and Pig-a lymphocyte mutation assays conducted on spleno-cytes from Day 56 F344 rats detected two-to fourfold stronger responses for Hprt than Pig-a mutations. Results from the in vivo Comet assay in SD rats at Day 29 showed generally weak increases in DNA damage in all tissues evaluated. The results with ENU indicate that the Pig-a RET and RBC assays are reproducible, transferable, and complement other genotoxicity endpoints that could potentially be integrated into 28-day repeat-dose rat studies. Environ. Mol. Mutagen. 52:721730, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Cammerer, Zoryana; Coffing, Stephanie L.; Dickinson, Donna; Dobo, Krista L.; Engel, Maria; Fiedler, Ronald D.; Gunther, William C.; Shutsky, Thomas; Thiffeault, Catherine J.; Schuler, Maik] Pfizer Global Res & Dev, Genet Toxicol Ctr Emphasis, Groton, CT 06350 USA. [Bhalli, Javed A.; Cao, Xuefei; Dobrovolsky, Vasily N.; Heflich, Robert H.; Pearce, Mason G.; Shaddock, Joseph G.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Schuler, M (reprint author), Pfizer PGRD, Genet Toxicol Ctr Emphasis, Eastern Point Rd, Groton, CT 06340 USA. EM maik.schuler@pfizer.com FU NIH-NIEHS [R44ES015940]; Oak Ridge Institute for Science and Education FX Grant sponsor: NIH-NIEHS; Grant Number R44ES015940; Grant sponsor: Oak Ridge Institute for Science and Education. NR 20 TC 28 Z9 30 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD DEC PY 2011 VL 52 IS 9 BP 721 EP 730 DI 10.1002/em.20686 PG 10 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 871IY UT WOS:000298732700006 PM 22167886 ER PT J AU Bhalli, JA Shaddock, JG Pearce, MG Dobrovolsky, VN Cao, XF Heflich, RH Vohr, HW AF Bhalli, Javed A. Shaddock, Joseph G. Pearce, Mason G. Dobrovolsky, Vasily N. Cao, Xuefei Heflich, Robert H. Vohr, Hans-Werner TI Report on Stage III Pig-a Mutation Assays Using Benzo[a] pyrene SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE phosphatidyl inositol glycan class A gene; flow cytometry; CD59; proaerolysin; micronucleus assay ID ETHYL-N-NITROSOUREA; POLYCYCLIC AROMATIC-HYDROCARBONS; PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; CELLS FOLLOWING TREATMENT; HAMSTER OVARY CELLS; SPLEEN T-CELLS; HPRT GENE; LARGE DELETIONS; BONE-MARROW; RAT STRAINS AB Genotoxicity assays were conducted on rats treated with benzo[a] pyrene (BaP) as part of Stage III of a validation study on the Pig-a gene mutation assay. Assays were performed at the U.S. FDA-NCTR and Bayer-Germany. Starting on Day 1, groups of five 6-to 7-week-old male Fischer 344 (F344, used at FDA-NCTR) and Han Wistar rats (Bayer) were given 28 daily doses of 0, 37.5, 75, or 150 mg/kg BaP; blood was sampled on Days 21, 4, 15, 29, and 56. Pig-a mutant frequencies were determined on Days 21, 15, 29, and 56 in total red blood cells (RBCs) and reticulocytes (RETs) as RBC(CD59-) and RET(CD59-) frequencies; percent micronucleated-RETs (%MN-RET) were measured on Days 4 and 29. RBC(CD59-) and RET(CD59-) frequencies increased in a dose-and time-dependent manner, producing significant increases by Day 29 in both rat models. The responses for RETs were stronger than those for RBCs, and the responses in F344 rats were stronger than in Han Wistar rats. BaP also produced significant increases in %MN-RET frequency at Days 4 and 29, with the responses being greater in F344 than Han Wistar rats. The overall findings were consistent with those of the reference laboratory using Han Wistar rats. Finally, mutation assays performed on splenocytes from Day 56 F344 rats indicated that BaP mutant frequencies were three to fivefold higher for the Hprt gene than the Pig-a gene. The results indicate that the Pig-a RET and RBC assays are reproducible, transferable, and show promise for integrating gene mutation into 28-day repeat-dose studies. Environ. Mol. Mutagen. 52:731-737, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Bhalli, Javed A.; Shaddock, Joseph G.; Pearce, Mason G.; Dobrovolsky, Vasily N.; Cao, Xuefei; Heflich, Robert H.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Vohr, Hans-Werner] Bayer HealthCare, Dept Toxicol, Wuppertal, Germany. RP Heflich, RH (reprint author), US FDA, Div Genet & Mol Toxicol, NCTR, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM robert.heflich@fda.hhs.gov FU Oak Ridge Institute for Science and Education FX Grant sponsor: Oak Ridge Institute for Science and Education. NR 37 TC 26 Z9 29 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD DEC PY 2011 VL 52 IS 9 BP 731 EP 737 DI 10.1002/em.20675 PG 7 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 871IY UT WOS:000298732700007 PM 22052432 ER PT J AU Bhalli, JA Pearce, MG Dobrovolsky, VN Heflich, RH AF Bhalli, Javed A. Pearce, Mason G. Dobrovolsky, Vasily N. Heflich, Robert H. TI Manifestation and Persistence of Pig-a Mutant Red Blood Cells in C57BL/6 Mice Following Single and Split Doses of N-Ethyl-N-Nitrosourea SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE glycosylphosphatidyl inositol; phosphatidylinositol glycan complementation class A gene; flow cytometry; CD24; micronucleus assay ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; GENE MUTATION ASSAY; ERYTHROCYTE LIFE-SPAN; FLOW-CYTOMETRY; ANCHOR; PROTEINS; LOCUS; RATS AB Treating rats with single doses of N-ethyl-N-nitrosourea (ENU) results in a time-dependent accumulation of Pig-a-mutant phenotype peripheral red blood cells (RBCs), reaching a plateau at about 6-weeks posttreatment, with the response persisting for at least 26 weeks. In the present study, groups of 5 C57BL/6 male mice were administered single i.p. doses of up to 140 mg/kg ENU, and blood samples were collected up to 26 weeks posttreatment. The samples were analyzed by flow cytometry for the frequency of CD24-deficient (presumed Pig-a mutant) reticulocytes (RETs) and total RBCs; micronucleated RET frequencies were evaluated at 1 day posttreatment. Mean Pig-a mutant frequencies and micronucleated RET frequencies increased in a dose-responsive manner, with maximum Pig-a frequencies in RETs and RBCs observed at Week 2 and Week 4 posttreatment, respectively. Mutant frequencies in RETs and RBCs generally decreased slowly with time after reaching their maxima. In a second experiment, groups of five male C57BL/6 mice were given single i.p. injections of 8, 32, or 160 mg/kg ENU, or four weekly doses of 8 or 40 mg/kg ENU (split doses totaling 32 and 160 mg/kg, respectively). In each case the maximum RET and RBC mutant frequencies produced by the split doses were similar to but not as great as the mutant frequencies produced by the equivalent single doses. The data indicate that ENU-induced Pig-a mutant RBC frequencies accumulate in mice as they do in rats; however, mice and rats differ in the manifestation kinetics and the persistence of the responses. Environ. Mol. Mutagen. 52:766-773, 2011. Published 2011 Wiley Periodicals, Inc. C1 [Bhalli, Javed A.; Pearce, Mason G.; Dobrovolsky, Vasily N.; Heflich, Robert H.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Heflich, RH (reprint author), US FDA, Div Genet & Mol Toxicol, NCTR, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM robert.heflich@fda.hhs.gov FU Oak Ridge Institute for Science and Education FX Grant sponsor: Oak Ridge Institute for Science and Education.; J. A. Bhalli was supported by a postdoctoral fellowship administered by the Oak Ridge Institute for Science and Education. The views expressed in this report are not necessarily those of the U.S. Food and Drug Administration. NR 19 TC 21 Z9 22 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD DEC PY 2011 VL 52 IS 9 BP 766 EP 773 DI 10.1002/em.20682 PG 8 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 871IY UT WOS:000298732700011 PM 22167887 ER PT J AU Kimoto, T Chikura, S Suzuki, K Kobayashi, XM Itano, Y Horibata, K Honma, M Dobrovolsky, VN Heflich, RH Miura, D Kasahara, Y AF Kimoto, Takafumi Chikura, Satsuki Suzuki, Kumiko Kobayashi, Xiao Mei Itano, Yasuhiro Horibata, Katsuyoshi Honma, Masamitsu Dobrovolsky, Vasily N. Heflich, Robert H. Miura, Daishiro Kasahara, Yoshinori TI Further Development of the Rat Pig-a Mutation Assay: Measuring Rat Pig-a Mutant Bone Marrow Erythroids and a High Throughput Assay for Mutant Peripheral Blood Reticulocytes SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE Pig-a; N-ethyl-N-nitrosourea; reticulocytes; bone marrow erythroids; in vivo gene mutation assay; flow cytometry ID ETHYL-N-NITROSOUREA; SPLEEN T-CELLS; FLOW-CYTOMETRIC DETECTION; GENE; ERYTHROCYTES; CDNA AB Recent studies indicate that the Pig-a assay is a promising tool for evaluating in vivo mutagenicity. We have developed novel rat Pig-a assays that facilitate measuring mutant frequencies in two early arising populations of blood cells, bone marrow erythroids (BMEs) and peripheral blood (PB) reticulocytes (RETs). In these assays, bone marrow cells of erythroid origin and PB red blood cells (RBCs) were identified using an antibody against rat erythroid-specific marker HIS49. In addition, RETs were selectivity enriched from PB using magnetic separation of cells positive for CD71, a transferrin receptor expressed on the surface of BMEs and RETs, but not on the surface of mature RBCs. With magnetic enrichment, more than 1 x 10(6) CD71-positive RETs could be evaluated by flow cytometry for Pig-a mutant frequency within 5 to 8 min. CD59-deficient RET and BME frequencies of more than 100 x 10(-6) and 80 x 10(-6) were detected 1 week after treating rats with 40 mg/kg N-ethyl-N-nitrosourea; by comparison, the frequency of CD59-deficient total RBCs in these rats was 13.2 x 10(-6). The frequency of spontaneous Pig-a mutant RETs and BMEs was less than 5 x 10(-6) and 15 x 10(-6), respectively. Since similar to 98% of nucleated cells in the BME fraction were erythroblasts, it should be possible to use BMEs to determine the spectrum of CD59-deficient Pig-a mutations in cells of erythroid lineage. Conducting concurrent Pig-a assays on RETs and BMEs may be useful for evaluating the in vivo mutagenicity of chemicals, especially when prolonged mutant manifestation is not feasible or when the confirmation of mutation induction is necessary. Environ. Mol. Mutagen. 52:774-783, 2011. Published 2011 Wiley Periodicals, Inc. C1 [Kimoto, Takafumi; Chikura, Satsuki; Suzuki, Kumiko; Kobayashi, Xiao Mei; Itano, Yasuhiro; Miura, Daishiro; Kasahara, Yoshinori] Teijin Pharma Ltd, Hino, Tokyo 1918512, Japan. [Horibata, Katsuyoshi; Honma, Masamitsu] Natl Inst Hlth Sci Japan, Tokyo, Japan. [Dobrovolsky, Vasily N.; Heflich, Robert H.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Kimoto, T (reprint author), Teijin Pharma Ltd, 4-3-2 Asahigaoka, Hino, Tokyo 1918512, Japan. EM t.kimoto@teijin.co.jp FU Japan Health Sciences Foundation [KHB1006] FX Grant sponsor: Japan Health Sciences Foundation; Grant Number KHB1006. NR 18 TC 32 Z9 33 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD DEC PY 2011 VL 52 IS 9 BP 774 EP 783 DI 10.1002/em.20677 PG 10 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 871IY UT WOS:000298732700012 PM 22167888 ER PT J AU Dobrovolsky, VN Elespuru, RK Bigger, CAH Robison, TW Heflich, RH AF Dobrovolsky, Vasily N. Elespuru, Rosalie K. Bigger, C. Anita H. Robison, Timothy W. Heflich, Robert H. TI Monitoring Humans for Somatic Mutation in the Endogenous PIG-A Gene Using Red Blood Cells SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE flow cytometry; chemotherapy; glycosyl phosphatidyl inositol anchor; glycophorin; CD59 surface marker; clastogen ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; FLOW-CYTOMETRIC DETECTION; NORMAL HEMATOPOIESIS; ANCHORED PROTEINS; ASSAY; ERYTHROCYTES; GENOTOXICITY; POPULATIONS; DIAGNOSIS; AEROLYSIN AB The endogenous X-linked PIG-A gene is involved in the synthesis of glycosyl phosphatidyl inositol (GPI) anchors that tether specific protein markers to the exterior of mammalian cell cytoplasmic membranes. Earlier studies in rodent models indicate that Pig-a mutant red blood cells (RBCs) can be induced in animals treated with genotoxic agents, and that flow cytometry can be used to identify rare RBCs deficient in the GPI-anchored protein, CD59, as a marker of Pig-a gene mutation. We investigated if a similar approach could be used for detecting gene mutation in humans. We first determined the frequency of spontaneous CD59-deficient RBCs (presumed PIG-A mutants) in 97 self-identified healthy volunteers. For most subjects, the frequency of CD59-deficient RBCs was low (average of 5.1 +/- 4.9 x 10(-6); median of 3.8 x 10(-6) and mutant frequency less than 8 x 10(-6) for 75% of subjects), with a statistically significant difference in median mutant frequencies between males and females. PIG-A RBC mutant frequency displayed poor correlation with the age and no correlation with the smoking status of the subjects. Also, two individuals had markedly increased CD59-deficient RBC frequencies of similar to 300 x 10(-6) and similar to 100 x 10(-6). We then monitored PIG-A mutation in 10 newly diagnosed cancer patients undergoing chemotherapy with known genotoxic drugs. The frequency of CD59-deficient RBCs in the blood of the patients was measured before the start of chemotherapy and three times over a period of similar to 6 months while on/after chemotherapy. Responses were generally weak, most observations being less than the median mutant frequency for both males and females; the greatest response was an approximate three-fold increase in the frequency of CD59-deficient RBCs in one patient treated with a combination of cisplatin and etoposide. These results suggest that the RBC PIG-A assay can be adopted to measuring somatic cell mutation in humans. Further research is necessary to determine the assay's sensitivity in detecting mutations induced by genotoxic agents acting via different mechanisms. Environ. Mol. Mutagen. 52:784-794, 2011. Published 2011 Wiley Periodicals, Inc. C1 [Dobrovolsky, Vasily N.; Heflich, Robert H.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Elespuru, Rosalie K.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Bigger, C. Anita H.; Robison, Timothy W.] US FDA, Ctr Drug Evaluat & Res, White Oak, MD USA. RP Dobrovolsky, VN (reprint author), US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 120, Jefferson, AR 72079 USA. EM vasily.dobrovolsky@fda.hhs.gov FU Critical Path Initiative-U.S. FDA's National Strategy FX Grant sponsor: Critical Path Initiative-U.S. FDA's National Strategy. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. NR 35 TC 21 Z9 22 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD DEC PY 2011 VL 52 IS 9 BP 784 EP 794 DI 10.1002/em.20667 PG 11 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 871IY UT WOS:000298732700013 PM 21826740 ER PT J AU Lathers, CM Koehler, SA Wecht, CH Schraeder, PL AF Lathers, C. M. Koehler, S. A. Wecht, C. H. Schraeder, P. L. TI Forensic antiepileptic drug levels in autopsy cases of epilepsy SO EPILEPSY & BEHAVIOR LA English DT Article DE Forensic antiepileptic drug levels; Sudden unexpected death in epilepsy; Epilepsy; Retrospective study; Death certificates/corner autopsies ID SUDDEN UNEXPECTED DEATH; UNEXPLAINED DEATH; CLINICAL-PHARMACOLOGY; HAIR ANALYSIS; RISK-FACTORS; CARBAMAZEPINE; MEDICATION; PHENYTOIN; MORTALITY; SUDEP AB A 1-year retrospective coroner-based forensic examination of causes of death among persons with a history of epilepsy was conducted at the Allegheny County Coroner's Office to evaluate the phenomenon of sudden unexplained/unexpected death in epilepsy (SUDEP), a diagnosis of exclusion. All cases at the Coroner's Office from January 1, 2001 through December 31, 2001, were examined. Review of a total of 1200 autopsied deaths revealed 12 cases with a past medical history of seizure disorder on the death certificate, which listed seizure disorder as the immediate cause of death or contributory cause of the death. Of the 7 men with seizure disorders, 5 were categorized as definite SUDEP and 2 as possible SUDEP. Of the 5 women with seizure disorders, 2 were listed as definite SUDEP, 2 as possible, and 1 as non-SUDEP because the convulsive seizures developed from a grade II glial tumor. Postmortem findings were evaluated for 11 cases; 1 body was decomposed. Toxicological screens were carried out on blood, bile, urine, and eye fluid for all 12. Antiepileptic drug (AED) levels detected in postmortem toxicological analysis were examined. AED levels were determined in 7 cases. Four of 7 had subtherapeutic AED levels, 2 had therapeutic levels, and only 1 victim of SUDEP had levels above the therapeutic range. Five cases had no detectable AED levels. AED levels at autopsy were either absent or subtherapeutic in 9 of 10 SUDEP cases, findings consistent with the likelihood of poor AED compliance. Subtherapeutic levels of AEDs may be a risk factor for SUDEP that could contribute to increased interictal and/or ictal epileptiform activity with associated autonomic dysfunction leading to disturbance of heart rate, heart rhythm, and/or blood pressure. (C) 2011 Elsevier Inc. All rights reserved. C1 [Lathers, C. M.] US FDA, Ctr Vet Med, Rockville, MD 20857 USA. [Koehler, S. A.; Wecht, C. H.] Off Coroner, Pittsburgh, PA USA. [Schraeder, P. L.] Drexel Univ, Coll Med, Dept Neurol, Philadelphia, PA 19104 USA. RP Lathers, CM (reprint author), 115 S Manning Blvd, Albany, NY 12203 USA. EM Lathers@ATIGlobal.net NR 51 TC 3 Z9 3 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-5050 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD DEC PY 2011 VL 22 IS 4 BP 778 EP 785 DI 10.1016/j.yebeh.2011.10.011 PG 8 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA 862CO UT WOS:000298067600024 PM 22088487 ER PT J AU Minor, T AF Minor, Travis TI THE EFFECT OF DIABETES ON FEMALE LABOR FORCE DECISIONS: NEW EVIDENCE FROM THE NATIONAL HEALTH INTERVIEW SURVEY SO HEALTH ECONOMICS LA English DT Article DE diabetes; labor supply; wages; instrumental variables ID WORK PRODUCTIVITY; IMPACT; COSTS; WAGES; PARTICIPATION; EMPLOYMENT; VARIABLES; MELLITUS; SAMPLE AB This paper estimates the effect of diabetes on labor-force participation, hours worked, days-out-of-work due to illness, and earnings using data from the National Health Interview Survey. Findings indicate that diabetes, estimated wholly, is significantly detrimental to most labor market outcomes. However, separation of type I and II diabetes shows that much of the negative effect is due to type II diabetes. On average a female with type II diabetes can experience a wage penalty of almost 50% relative to a healthy individual. Additionally, estimates of specifically type II diabetes may be subject to endogeneity bias. To account for this, I utilize whether an individual's biological mother has been diagnosed with diabetes as an instrumental variable. This instrument provides both theoretical and statistical explanatory power to separate the causal effect of type II diabetes on labor-force decisions. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 US FDA, Ctr Food Safety & Appl Nutr, Dept Econ, College Pk, MD 20910 USA. RP Minor, T (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Dept Econ, CPK1 HFS 020,5100 Paint Branch Pkwy, College Pk, MD 20910 USA. EM Travis.Minor@fda.hhs.gov OI Minor, Travis/0000-0002-5297-7695 NR 28 TC 8 Z9 8 U1 2 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1057-9230 J9 HEALTH ECON JI Health Econ. PD DEC PY 2011 VL 20 IS 12 BP 1468 EP 1486 DI 10.1002/hec.1685 PG 19 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 854RC UT WOS:000297510900005 PM 22025390 ER PT J AU Ali, SF Binienda, ZK Imam, SZ AF Ali, Syed F. Binienda, Zbigniew K. Imam, Syed Z. TI Molecular Aspects of Dopaminergic Neurodegeneration: Gene-Environment Interaction in Parkin Dysfunction SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Review DE Parkinson's disease; parkin; gene; environment; dopaminergic ID UBIQUITIN-PROTEASOME SYSTEM; CELL-DEATH; OXIDATIVE STRESS; S-NITROSYLATION; ALPHA-SYNUCLEIN; LIGASE ACTIVITY; PROTEIN LIGASE; BODY FORMATION; NITRIC-OXIDE; RISK-FACTORS AB Parkinson's disease (PD) is a common neurodegenerative movement disorder that is characterized pathologically by a progressive loss of midbrain dopaminergic neurons and by protein inclusions, designated Lewy bodies and Lewy neurites. PD is one of the most common neurodegenerative diseases, affecting almost 1% of the population over 60 years old. Although the symptoms and neuropathology of PD have been well characterized, the underlying mechanisms and causes of the disease are still not clear. Genetic mutations can provide important clues to disease mechanism, but most PD cases are sporadic rather than familial; environmental factors have long been suspected to contribute to the disease. Although more than 90% of PD cases occur sporadically and are thought to be due, in part, to oxidative stress and mitochondrial dysfunction, the study of genetic mutations has provided great insight into the molecular mechanisms of PD. Furthermore, rotenone, a widely used pesticide, and paraquat and maneb cause a syndrome in rats and mice that mimics, both behaviorally and neurologically, the symptoms of PD. In the current review, we will discuss various aspects of gene-environment interaction that lead to progressive dopaminergic neurodegenration, mainly focusing on our current finding based on stress-mediated parkin dysfunction. C1 [Ali, Syed F.; Binienda, Zbigniew K.; Imam, Syed Z.] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72029 USA. RP Ali, SF (reprint author), US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72029 USA. EM syed.ali@fda.hhs.gov; zbigniew.binienda@fda.hhs.gov; syed.imam@fda.hhs.gov NR 50 TC 16 Z9 19 U1 0 U2 5 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD DEC PY 2011 VL 8 IS 12 BP 4702 EP 4713 DI 10.3390/ijerph8124702 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 866TL UT WOS:000298406600018 PM 22408597 ER PT J AU Xia, QS Boudreau, MD Zhou, YT Yin, JJ Fu, PP AF Xia, Qingsu Boudreau, Mary D. Zhou, Yu-Ting Yin, Jun-Jie Fu, Peter P. TI UVB Photoirradiation of Aloe Vera - Formation of Free Radicals, Singlet Oxygen, Superoxide, and Induction of Lipid Peroxidation SO JOURNAL OF FOOD AND DRUG ANALYSIS LA English DT Article DE Aloe vera; UVB; Photoirradiation; Lipid peroxidation; Reactive oxygen species (ROS); ESR ID HERBAL DIETARY-SUPPLEMENTS; PYRROLIZIDINE ALKALOIDS; SOYBEAN LIPOXYGENASE; QUALITY-ASSURANCE; LIVER-INJURY; TOXICITY; EMODIN; DAMAGE; LIGHT; DNA AB Aloe vera whole leaf extracts are incorporated into a wide variety of topically applied commercial products. Aloe vera whole leaf extracts contain anthraquinones, which can generate reactive oxygen species (ROS) upon UVA light irradiation. In this study, the phototoxicity of two Aloe vera whole leaf extracts, Aloe A and Aloe B, were examined. The Aloe B extract was prepared by treating the Aloe A extract with activated carbon (1%, wt/wt) and filtration to remove the Aloe latex components, including the anthraquinones. UVB irradiation of the Aloe vera whole leaf extracts induced lipid peroxidation in the presence of a lipid, methyl linoleate. The amounts of lipid peroxides formed were higher in the Aloe B, which contained lower amounts of anthraquinones than Aloe A. Sodium azide inhibited and deuterium oxide enhanced the formation of lipid peroxides by Aloe B, suggesting that singlet oxygen was involved in the mechanism. When superoxide dismutase was incorporated prior to irradiation, lipid peroxidation was inhibited, indicating that superoxide was produced during the photoirradiation of Aloe B. In addition, electron spin resonance (ESR) spectroscopy was also used to investigate the generation of free radicals by the UVB photoirradiated Aloe B. ESR measurements indicated that the UVB photoirradiation of Aloe B produced carbon-centered free radicals. These results suggested that, as with the exposure to UVA light, the exposure of Aloe vera whole leaf extracts to UVB light can also generate ROS and induce lipid peroxidation. C1 [Zhou, Yu-Ting; Yin, Jun-Jie] US FDA, Ctr Food Safety Appl Nutr, College Pk, MD USA. [Xia, Qingsu; Boudreau, Mary D.; Fu, Peter P.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Yin, JJ (reprint author), US FDA, Ctr Food Safety Appl Nutr, College Pk, MD USA. EM junjie.yin@fda.hhs.gov RI Zhou, Yuting/I-9125-2012; Yin, Jun Jie /E-5619-2014 NR 38 TC 7 Z9 7 U1 1 U2 7 PU BUREAU FOOD DRUG ANALYSIS PI TAIPEI PA 161-2 KUNYANG STREET, NANGANG, TAIPEI, 00000, TAIWAN SN 1021-9498 J9 J FOOD DRUG ANAL JI J. Food Drug Anal. PD DEC PY 2011 VL 19 IS 4 BP 396 EP 402 PG 7 WC Food Science & Technology; Pharmacology & Pharmacy SC Food Science & Technology; Pharmacology & Pharmacy GA 871YR UT WOS:000298774100002 ER PT J AU Abbott, MA Prater, SN Banugaria, SG Richards, SM Young, SP Rosenberg, AS Kishnani, PS AF Abbott, Mary-Alice Prater, Sean N. Banugaria, Suhrad G. Richards, Susan M. Young, Sarah P. Rosenberg, Amy S. Kishnani, Priya S. TI Atypical immunologic response in a patient with CRIM-negative Pompe disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Glycogen storage disease type II; Pompe disease; Enzyme replacement therapies; Immunologic response; Antibodies ID ENZYME-REPLACEMENT THERAPY; LYSOSOMAL STORAGE DISORDER; ACID ALPHA-GLUCOSIDASE; ALGLUCOSIDASE ALPHA; CLINICAL-OUTCOMES; IMMUNE-RESPONSE; INFANTS; ANTIBODIES; EFFICACY; CHILDREN AB We report the clinical course of a patient with severe infantile onset Pompe disease [cross-reactive immunologic material (CRIM) negative, R854X/R854X] who was diagnosed prenatally and received standard dosing of alglucosidase alfa (Myozyme (R)) enzyme replacement therapy (ERT) from day 10 of life until she passed away at the age of 3 years 9 months. In the immediate neonatal period there was cardiomegaly on chest X-ray, cardiac hypertrophy by echocardiogram, and development of a wide complex tachycardia. CRIM negative (CN) status was suspected based on her family history, and the available data at the time indicated that CN patients had limited survival even with ERT. However, given the opportunity for very early treatment, the treating provider and family elected to initiate treatment with ERT, without immune modulation. By 9 months of age echocardiogram was normal. Early motor development was within normal limits but by 2 years of age her developmental progress had slowed. She seroconverted by the 4th month of ERT, and anti-rhGAA antibody titers peaked at 25,600 in the 27th month. Immunomodulatory therapy was considered but declined by family. She acquired Influenza A at 2 years 6 months, which led to a prolonged hospitalization with invasive respiratory support, and placement of tracheostomy and gastrostomy tube. Her developmental progress ceased, and she died suddenly at home from a presumed cardiac event at age 3 years 9 months. The poor outcomes observed in CN patients have been attributed to the development of high sustained antibody titers. Although this CN patient's anti-rhGAA response was elevated and sustained, it is unlike any of the 3 patterns that have been previously described: high titer CN, high titer CRIM positive (HTCP), and low titer CP (LTCP) patients. This patient's clinical course, with achievement of 24 months of motor gains, 30 months of ventilator-free survival and 45 month survival, is like that of only a fraction of ERT treated CN patients, yet it is identical to other reported CN patients in its relentless progression and early fatality. The immunologic response (moderate sustained antibody titers) described here has not been previously reported and may have played a role in the overall pattern of developmental decline. In light of proposed universal newborn screening for Pompe disease, there is an urgent need for improved understanding of the interplay between immunologic responses to the only available treatment, ERT, and the relentless nature of this disease in CN patients. (C) 2011 Elsevier Inc. All rights reserved. C1 [Abbott, Mary-Alice] Baystate Med Ctr, Springfield, MA 01199 USA. [Prater, Sean N.; Banugaria, Suhrad G.; Young, Sarah P.; Kishnani, Priya S.] Duke Univ, Med Ctr, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. [Richards, Susan M.] Genzyme Corp, Framingham, MA 01701 USA. [Rosenberg, Amy S.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Abbott, MA (reprint author), Baystate Med Ctr, 759 Chestnut St, Springfield, MA 01199 USA. EM maryalice.abbott@bhs.org FU NINDS NIH HHS [U54 NS065768] NR 19 TC 11 Z9 11 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD DEC PY 2011 VL 104 IS 4 BP 583 EP 586 DI 10.1016/j.ymgme.2011.08.003 PG 4 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 861LV UT WOS:000298021400022 PM 21889385 ER PT J AU Narayan, R Goering, P AF Narayan, Roger Goering, Peter TI Laser micro- and nanofabrication of biomaterials SO MRS BULLETIN LA English DT Article ID FREE-ELECTRON LASER; OPHTHALMIC ACRYLIC BIOMATERIALS; OPTICAL MASER OSCILLATION; TRANSDERMAL DRUG-DELIVERY; DIAMOND-LIKE; THIN-FILMS; SURFACE MODIFICATION; MEDICAL APPLICATIONS; MICRONEEDLE ARRAY; GLASS/POLYIMIDE MICROJOINTS AB Over the past half century, rapid progress has been made in laser-based medical diagnosis and treatment as well as in laser-based medical device fabrication. Lasers have unique capabilities for coating, machining, melting, polymerizing, sintering, and welding materials that are used in implantable and transdermal medical devices. In this review, academic and industrial developments involving laser processing of materials for dental, orthopedic, neural, ophthalmic, cardiovascular, and transdermal applications are described. In addition, laser processing of nanoscale materials for medical applications is discussed. Finally, challenges associated with commercialization of laser biomaterials are considered. Due to the unique capabilities provided by laser-based processes, it is anticipated that the use of laser biomaterials in implantable and transdermal medical devices will markedly increase over the coming years. C1 [Narayan, Roger] UNC NCSU, Joint Dept Biomed Engn, Raleigh, NC 27695 USA. [Goering, Peter] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Narayan, R (reprint author), UNC NCSU, Joint Dept Biomed Engn, Raleigh, NC 27695 USA. EM roger_narayan@msn.com; peter.goering@fda.hhs.gov NR 120 TC 7 Z9 8 U1 3 U2 39 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0883-7694 EI 1938-1425 J9 MRS BULL JI MRS Bull. PD DEC PY 2011 VL 36 IS 12 BP 973 EP 982 DI 10.1557/mrs.2011.302 PG 10 WC Materials Science, Multidisciplinary; Physics, Applied SC Materials Science; Physics GA 878DB UT WOS:000299231900018 ER PT J AU Cohen, MH Johnson, JR Justice, R Pazdur, R AF Cohen, Martin H. Johnson, John R. Justice, Robert Pazdur, Richard TI Approval Summary: Letrozole (Femara (R) Tablets) for Adjuvant and Extended Adjuvant Postmenopausal Breast Cancer Treatment: Conversion of Accelerated to Full Approval SO ONCOLOGIST LA English DT Article DE Letrozole; Femara (R); Postmenopausal breast cancer; Adjuvant treatment ID BIG 1-98 TRIAL; RECEPTOR-POSITIVE TUMORS; ENDOCRINE THERAPY; AROMATASE INHIBITORS; ESTROGEN-RECEPTOR; RANDOMIZED-TRIAL; PHASE-III; BONE LOSS; WOMEN; TAMOXIFEN AB On April 30, 2010, the U.S. Food and Drug Administration converted letrozole (Femara (R); Novartis Pharmaceuticals Corporation, East Hanover, NJ) from accelerated to full approval for adjuvant and extended adjuvant (following 5 years of tamoxifen) treatment of postmenopausal women with hormone receptor-positive early breast cancer. The initial accelerated approvals of letrozole for adjuvant and extended adjuvant treatment on December 28, 2005 and October 29, 2004, respectively, were based on an analysis of the disease-free survival (DFS) outcome of patients followed for medians of 26 months and 28 months, respectively. Both trials were double-blind, multicenter studies. Both trials were unblinded early when an interim analysis showed a favorable letrozole effect on DFS. In updated intention-to-treat analyses of both trials, the risk for a DFS event was lower with letrozole than with tamoxifen (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.77-0.99; p = .03) in the adjuvant trial and was lower than with placebo (HR, 0.89; 95% CI, 0.76-1.03; p = .12) in the extended adjuvant trial. The latter analysis ignores the interim switch of 60% of placebo-treated patients to letrozole. Bone fractures and osteoporosis were reported more frequently following treatment with letrozole whereas tamoxifen was associated with a higher risk for endometrial proliferation and endometrial cancer. Myocardial infarction was more frequently reported with letrozole than with tamoxifen, but the incidence of thromboembolic events was higher with tamoxifen than with letrozole. Lipid-lowering medications were required for 25% of patients on letrozole and 16% of patients on tamoxifen. The Oncologist 2011;16:1762-1770 C1 [Cohen, Martin H.; Johnson, John R.; Justice, Robert; Pazdur, Richard] US FDA, Off Oncol Drug Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Cohen, MH (reprint author), US FDA, Off Oncol Drug Prod, Ctr Drug Evaluat & Res, White Oak Campus,10903 New Hampshire Ave,Bldg 22,, Silver Spring, MD 20993 USA. EM martin.cohen@fda.hhs.gov RI Inov Farmaceutica, Inct/K-2313-2013 NR 33 TC 2 Z9 2 U1 1 U2 4 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PD DEC PY 2011 VL 16 IS 12 BP 1762 EP 1770 DI 10.1634/theoncologist.2011-0287 PG 9 WC Oncology SC Oncology GA 870HW UT WOS:000298661000014 PM 22089970 ER PT J AU Zineh, I Mummaneni, P Lyndly, J Amur, S La Grenade, LA Chang, SH Rogers, H Pacanowski, MA AF Zineh, Issam Mummaneni, Padmaja Lyndly, Jenna Amur, Shashi La Grenade, Lois A. Chang, Stephen H. Rogers, Hobart Pacanowski, Michael A. TI Allopurinol pharmacogenetics: assessment of potential clinical usefulness SO PHARMACOGENOMICS LA English DT Article DE adverse reaction; allopurinol; HLA-B*5801; safety; SCAR; Stevens-Johnson syndrome; US FDA ID TOXIC EPIDERMAL NECROLYSIS; STEVENS-JOHNSON-SYNDROME; HLA-B; GOUT; HLA-B-ASTERISK-5801; HYPERSENSITIVITY; MANAGEMENT; ALLELE; DRUGS AB Use of pharmacogenetics to inform treatment decisions remains a priority for clinicians, patients and public health agencies. We previously developed a framework for systematically assessing whether pharmacogenetic test information would likely bring value to clinical decision-making and enjoy practical uptake. We applied this tool to allopurinol to determine potential usefulness of HLA genetic information in assessing risk for allopurinol-induced severe cutaneous adverse reactions. We quantified allopurinol use data and the magnitude of adverse event signals using US FDA databases, reviewed reported cases of allopurinol-associated severe cutaneous adverse reactions to assess whether clinical subtypes of patients could be identified, performed pooled analyses of associations between HLA variation and allopurinol-induced severe cutaneous adverse reactions and described considerations in clinical implementation of allopurinol pharmacogenetics. C1 [Zineh, Issam; Mummaneni, Padmaja; Amur, Shashi; Rogers, Hobart; Pacanowski, Michael A.] US FDA, Genom Grp, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Lyndly, Jenna] US FDA, Div Biostat 6, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [La Grenade, Lois A.] US FDA, Div Pharmacovigilance, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Chang, Stephen H.] Off Surveillance & Epidemiol, Div Epidemiol, Silver Spring, MD USA. RP Zineh, I (reprint author), US FDA, Genom Grp, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM issam.zineh@fda.hhs.gov NR 22 TC 17 Z9 18 U1 0 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD DEC PY 2011 VL 12 IS 12 BP 1741 EP 1749 DI 10.2217/PGS.11.131 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 868DH UT WOS:000298503400016 PM 22118056 ER PT J AU Gregori, L Yang, H Anderson, S AF Gregori, Luisa Yang, Hong Anderson, Steven TI Estimation of variant Creutzfeldt-Jakob disease infectivity titers in human blood SO TRANSFUSION LA English DT Article ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY; PRION DISEASES; TRANSFUSION; VCJD; COMPONENTS; PATIENT; SHEEP; RISK AB BACKGROUND: Blood of individuals with variant Creutzfeldt-Jakob disease (vCJD) is infectious but the titer is unknown. Current estimates of possible vCJD infectivity titers in blood have largely relied on an assumption that the titers of vCJD agent in human blood are likely to be similar to those in blood of rodents infected with model transmissible spongiform encephalopathy agents, assayed by intracerebral inoculations of rodents of the same species. STUDY DESIGN AND METHODS: We analyzed published descriptions of experimental transfusion-transmitted (TT) bovine spongiform encephalopathy and scrapie in sheep and reports of TTvCJD in humans, applying statistical approaches to estimate the probable number of intravenous infectious doses (ID(iv)) per unit of transfused blood (ID(iv)/unit). For humans, ID(iv)/unit of nonleukoreduced red blood cells (NLR-RBCs) were estimated by two statistical models. RESULTS: Sheep blood collected at or near onset of clinical illness contained a mean of 0.80 ID(iv)/unit. Estimates of infectivity in NLR-RBCs from donors incubating vCJD indicated a probable mean infectivity of 0.29 ID(iv)/unit (Model 1) and 0.75 ID(iv)/unit (Model 2). The analysis predicted a mean of 21 vCJD-infected recipients expected in a cohort transfused with vCJD-implicated NLR-RBCs in the United Kingdom. CONCLUSION: Our analysis suggested that, while less than one ID(iv) is likely to be present in a given unit of NLR-RBCs collected from a donor incubating vCJD, there is a high probability of TT infection among recipients of vCJD-implicated blood components. The analysis supports continuing measures currently recommended to reduce the risk of TTvCJD. C1 [Gregori, Luisa] FDA, CBER, OBRR, DETTD, Rockville, MD 20852 USA. FDA, CBER, Off Biostat & Epidemiol, Rockville, MD 20852 USA. RP Gregori, L (reprint author), FDA, CBER, OBRR, DETTD, 1401 Rockville Pike,FDA HFM-313, Rockville, MD 20852 USA. EM luisa.gregori@fda.hhs.gov FU US Food and Drug Administration FX This work was funded by the US Food and Drug Administration. NR 27 TC 17 Z9 17 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD DEC PY 2011 VL 51 IS 12 BP 2596 EP 2602 DI 10.1111/j.1537-2995.2011.03199.x PN 1 PG 7 WC Hematology SC Hematology GA 865VZ UT WOS:000298340300013 PM 21645006 ER PT J AU Lee, CE Ostroff, C McMeekin, J Sheppemon, S Deveau, I AF Lee, Charles E. Ostroff, Craig McMeekin, Judith Sheppemon, Stanley Deveau, Ian TI Unapproved Prescription Cough, Cold, and Allergy Medications SO CHEST LA English DT Letter C1 [Lee, Charles E.; McMeekin, Judith; Sheppemon, Stanley; Deveau, Ian] US FDA, Off Unapproved Drugs & Labeling Compliance, Silver Spring, MD 20993 USA. [Ostroff, Craig] US FDA, Off Compliance, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Lee, CE (reprint author), US FDA, Off Unapproved Drugs & Labeling Compliance, 10903 New Hampshire Ave,Bldg 51,Room 5184, Silver Spring, MD 20993 USA. EM charles.lee@fda.hhs.gov NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 2011 VL 140 IS 6 BP 1672 EP 1673 DI 10.1378/chest.11-2129 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 860RX UT WOS:000297966500051 PM 22147834 ER PT J AU MacKerrow, S Farb, A Sullivan, R AF MacKerrow, Stephen Farb, Andrew Sullivan, Roberta TI Inflammatory Pseudothrombus on a Patent Foramen Ovale Occluder Device SO TEXAS HEART INSTITUTE JOURNAL LA English DT Article DE Cardiac surgical procedures/instrumentation; cerebrovascular disorders/etiology; foramen ovale, patent/complications/therapy; heart septal, defects, atrial/complications/diagnosis/pathology/ultrasonography; migraine disorders/prevention & control; postoperative complications; prostheses and implants/adverse effects/instrumentation/utilization; risk factors; thrombosis/etiology; treatment outcome ID ATRIAL SEPTAL-DEFECT; THROMBUS FORMATION; PERCUTANEOUS CLOSURE; AMPLATZER; STARFLEX; STROKE; TRIAL; SIZE AB Herein, we describe late complications after the transcatheter device closure of a patent foramen ovate in a patient with migraine headaches. The clinical presentation included acute neurologic symptoms and new-onset atrial fibrillation. A mass on the left atrial side of the occluder was surgically removed. Histologic results showed an inflammatory lesion that consisted predominantly of lymphocytes, plasma cells, and macrophages. Despite complete surgical closure and the termination of atrial fibrillation, the patient continued to experience neurologic events. Although transcatheter patent foramen ovale closure is associated with low complication rates, a careful risk benefit evaluation is warranted in view of the potentially severe complications and the current lack of robust pathophysiologic and clinical trial data to support this therapy in the treatment of migraine headaches. (Tex Heart Inst J 2011;38(6):710-3) C1 [MacKerrow, Stephen] Pueblo Cardiol Associates, Pueblo, CO 81004 USA. [Farb, Andrew; Sullivan, Roberta] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Sullivan, R (reprint author), White Oak 66,Rm 3326,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM roberta.sullivan@fda.hhs.gov NR 19 TC 0 Z9 0 U1 0 U2 0 PU TEXAS HEART INST PI HOUSTON PA PO BOX 20345, HOUSTON, TX 77225-0345 USA SN 0730-2347 J9 TEX HEART I J JI Tex. Heart Inst. J. PD DEC PY 2011 VL 38 IS 6 BP 710 EP 713 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 860QP UT WOS:000297963100027 PM 22199445 ER PT J AU Piccardo, P Cervenakova, L Vasilyeva, I Yakovleva, O Bacik, I Cervenak, J McKenzie, C Kurillova, L Gregori, L Pomeroy, K Asher, DM AF Piccardo, Pedro Cervenakova, Larisa Vasilyeva, Irina Yakovleva, Oksana Bacik, Igor Cervenak, Juraj McKenzie, Carroll Kurillova, Lubica Gregori, Luisa Pomeroy, Kitty Asher, David M. TI Candidate Cell Substrates, Vaccine Production, and Transmissible Spongiform Encephalopathies SO EMERGING INFECTIOUS DISEASES LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; PRION PROTEIN; BLOOD-TRANSFUSION; SCRAPIE AGENT; INFECTION; LINES; ASSAY; VCJD; MICE AB Transmissible spongiform encephalopathy (TSE) agents have contaminated human tissue-derived medical products, human blood components, and animal vaccines. The objective of this study was to determine the potential susceptibility to infection of 5 cell lines used or proposed for manufacture of biological products, as well as other lines. Cell lines were exposed to the infectious agents of sporadic and variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy (BSE). Exposed cultures were tested for TSE-associated prion protein (PrP(TSE)) and TSE infectivity by assay in rodents and nonhuman primates. No PrP(TSE) or infectivity has been detected in any exposed cell line under study so far. Animals inoculated with BSE brain homogenate developed typical spongiform encephalopathy. In contrast, animals inoculated with cells exposed to the BSE agent remained asymptomatic. All cell lines we studied resisted infection with 3 TSE agents, including the BSE agent. C1 [Piccardo, Pedro; Bacik, Igor; Cervenak, Juraj; Kurillova, Lubica; Gregori, Luisa; Pomeroy, Kitty; Asher, David M.] US FDA, Kensington, MD USA. [Piccardo, Pedro] Univ Edinburgh, Easter Bush, Scotland. [Cervenakova, Larisa; Vasilyeva, Irina; Yakovleva, Oksana; McKenzie, Carroll] Holland Lab Amer Red Cross, Rockville, MD USA. RP Piccardo, P (reprint author), FDA HFM 313,1401 Rockville Pike, Rockville, MD 20852 USA. EM pedro.piecardo@fda.hhs.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases [Y1-AI-4893-02]; FDA [224-05-1307] FX This work was generously funded by the National Institutes of Health, National Institute of Allergy and Infectious Diseases, agreement no. Y1-AI-4893-02; and FDA agreement no. 224-05-1307. NR 34 TC 3 Z9 3 U1 0 U2 3 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD DEC PY 2011 VL 17 IS 12 BP 2262 EP 2269 DI 10.3201/eid1712.110607 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 859KD UT WOS:000297874400011 PM 22172513 ER PT J AU Daniel, JH Lewis, LW Redwood, YA Kieszak, S Breiman, RF Flanders, WD Bell, C Mwihia, J Ogana, G Likimani, S Straetemans, M McGeehin, MA AF Daniel, Johnni H. Lewis, Lauren W. Redwood, Yanique A. Kieszak, Stephanie Breiman, Robert F. Flanders, W. Dana Bell, Carlos Mwihia, John Ogana, George Likimani, Sopiato Straetemans, Masja McGeehin, Michael A. TI Comprehensive Assessment of Maize Aflatoxin Levels in Eastern Kenya, 2005-2007 SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE aflatoxicosis; aflatoxin; contamination; Kenya; maize ID DEVELOPING-COUNTRIES; CONTAMINATION; OUTBREAK; HEALTH; FOOD; MYCOTOXINS; EXPOSURE; DISEASE; AFRICA; BENIN AB BACKGROUND: Aflatoxin, a potent fungal toxin, contaminates 25% of crops worldwide. Since 2004, 477 aflatoxin poisonings associated with eating contaminated maize have been documented in Eastern Kenya, with a case-fatality rate of 40%. OBJECTIVE: We characterized maize aflatoxin contamination during the high-risk season (April June) after the major harvests in 2005, 2006 (aflatoxicosis outbreak years), and 2007 (a non-outbreak year). METHODS: Households were randomly selected each year from the region in Kenya where outbreaks have consistently occurred. At each household, we obtained at least one maize sample (n = 716) for aflatoxin analysis using immunoaffinity methods and administered a questionnaire to determine the source (i.e., homegrown, purchased, or relief) and amount of maize in the household. RESULTS: During the years of outbreaks in 2005 and 2006, 41% and 51% of maize samples, respectively, had aflatoxin levels above the Kenyan regulatory limit of 20 ppb in grains that were for human consumption. In 2007 (non-outbreak year), 16% of samples were above the 20-ppb limit. In addition, geometric mean (GM) aflatoxin levels were significantly higher in 2005 (GM = 12.92, maximum = 48,000 ppb) and 2006 (GM = 26.03, maximum = 24,400 ppb) compared with 2007 (GM = 1.95, maximum = 2,500 ppb) (p-value < 0.001). In all 3 years combined, maize aflatoxin levels were significantly higher in homegrown maize (GM = 17.96) when compared with purchased maize (GM = 3.64) or relief maize (GM = 0.73) (p-value < 0.0001). CONCLUSIONS: Aflatoxin contamination is extreme within this region, and homegrown maize is the primary source of contamination. Prevention measures should focus on reducing homegrown maize contamination at the household level to avert future outbreaks. C1 [Daniel, Johnni H.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Hlth Studies Branch, Atlanta, GA 30341 USA. [Breiman, Robert F.] Ctr Dis Control & Prevent, Nairobi, Kenya. [Bell, Carlos] US FDA, Rockville, MD 20857 USA. [Mwihia, John; Ogana, George] Kenya Natl Publ Hlth Lab, Nairobi, Kenya. [Likimani, Sopiato] Kenya Minist Publ Hlth & Sanitat, Nairobi, Kenya. [Straetemans, Masja] KNCV TB Fdn, The Hague, Netherlands. RP Daniel, JH (reprint author), Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Hlth Studies Branch, 4770 Buford Hwy MS F-57, Atlanta, GA 30341 USA. EM bez2@cdc.gov FU Division of Environmental Hazards and Health Effects; U.S. Centers for Disease Control and Prevention's National Center for Environmental Health FX The Division of Environmental Hazards and Health Effects and the U.S. Centers for Disease Control and Prevention's National Center for Environmental Health provided funding. NR 31 TC 17 Z9 17 U1 2 U2 22 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD DEC PY 2011 VL 119 IS 12 BP 1794 EP 1799 DI 10.1289/ehp.1003044 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 857IH UT WOS:000297711200035 PM 21843999 ER PT J AU Ashar, BS Dang, JM Krause, D Luke, MC AF Ashar, B. S. Dang, J. M. Krause, D. Luke, M. C. TI Performing clinical studies involving hernia mesh devices: what every investigator should know about the FDA investigational device exemption (IDE) process SO HERNIA LA English DT Article DE Mesh; Hernia; FDA; Regulation; IDE; preIDE AB The FDA's Center for Devices and Radiological Health (CDRH) is responsible for providing reasonable assurance of safety and effectiveness of all medical devices marketed within the US. To date, CDRH has cleared numerous hernia mesh devices for general use, but has not cleared/approved any mesh devices intended for certain specific uses, such as for infected wounds, hernia prevention, biofilm reduction, or prevention of adhesions. CDRH is requesting that manufacturers seeking specific hernia mesh device labeling claims consult with the Agency to determine the level of evidence necessary for justifying such claims. C1 [Ashar, B. S.; Dang, J. M.; Krause, D.; Luke, M. C.] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20850 USA. RP Ashar, BS (reprint author), US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,WO 66,Room 422, Silver Spring, MD 20850 USA. EM Binita.Ashar@fda.hhs.gov NR 0 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1265-4906 J9 HERNIA JI Hernia PD DEC PY 2011 VL 15 IS 6 BP 603 EP 605 DI 10.1007/s10029-011-0872-3 PG 3 WC Surgery SC Surgery GA 858AL UT WOS:000297768000002 PM 21909977 ER PT J AU Gottlieb, K Kammermann, L Rajpal, A Mulberg, A Griebel, D AF Gottlieb, Klaus Kammermann, Lisa Rajpal, Anil Mulberg, Andrew Griebel, Donna TI Modernizing clinical trial design: Could C-Reactive Protein (CRP) serve as an enrichment biomarker in Crohn's disease trials? SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract C1 [Gottlieb, Klaus; Kammermann, Lisa; Rajpal, Anil; Mulberg, Andrew; Griebel, Donna] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD DEC PY 2011 VL 17 SU 2 BP S23 EP S24 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857RB UT WOS:000297735300074 ER PT J AU Johnson, A Marks, Z Lee, J Griebel, D AF Johnson, Aisha Marks, Zana Lee, Jessica Griebel, Donna TI FDA review of primary efficacy endpoints in Ulcerative Colitis registration trials SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract C1 [Johnson, Aisha; Marks, Zana; Lee, Jessica; Griebel, Donna] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD DEC PY 2011 VL 17 SU 2 BP S21 EP S22 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857RB UT WOS:000297735300069 ER PT J AU Korvick, J Corken-Mackey, A AF Korvick, Joyce Corken-Mackey, Ann TI Assessment and communication by the food and Drug Administration (FDA) of hepatosplenic T-cell lymphoma (HSTCL) risk in children and young adults with Inflammatory Bowel Disease (IBD) treated with tumor Necrosis Factor (TNF) antagonists and thiopurines SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract C1 [Korvick, Joyce; Corken-Mackey, Ann] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD DEC PY 2011 VL 17 SU 2 BP S60 EP S60 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857RB UT WOS:000297735300190 ER PT J AU Mehrotra, N Garnett, C Zhang, L Fang, LY Wang, YM Fiorentino, RP AF Mehrotra, Nitin Garnett, Christine Zhang, Li Fang, Lanyan Wang, Yow-Ming Fiorentino, Robert P. TI Role of exposure-response analysis to guide dose selection in pediatric drug development when extrapolating efficacy from adults SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract C1 [Mehrotra, Nitin; Garnett, Christine; Zhang, Li] US FDA, Off Clin Pharmacol, Div Pharmacometr, Silver Spring, MD USA. [Fang, Lanyan; Wang, Yow-Ming] US FDA, Div Clin Pharmacol 3, Off Clin Pharmacol, Silver Spring, MD USA. [Fiorentino, Robert P.] US FDA, Off New Drugs, Div Gastroenterol & Inborn Errors Prod, Silver Spring, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD DEC PY 2011 VL 17 SU 2 BP S5 EP S6 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857RB UT WOS:000297735300014 ER PT J AU Wang, YM Fang, LY Zhou, L Wang, J Ahn, HY AF Wang, Yow-Ming Fang, Lanyan Zhou, Lin Wang, Jie Ahn, Hae-Young TI Immunogenicity of biologic products - An FDA perspective on current challenges in assessment and interpretation SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract C1 [Wang, Yow-Ming; Fang, Lanyan; Zhou, Lin; Wang, Jie; Ahn, Hae-Young] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD DEC PY 2011 VL 17 SU 2 BP S25 EP S25 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 857RB UT WOS:000297735300080 ER PT J AU Guha, S Pease, LF Brorson, KA Tarlov, MJ Zachariah, MR AF Guha, Suvajyoti Pease, Leonard F., III Brorson, Kurt A. Tarlov, Michael J. Zachariah, Michael R. TI Evaluation of electrospray differential mobility analysis for virus particle analysis: Potential applications for biomanufacturing SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Electrospray; Differential mobility analyzer; Virus; ICH Q2; Gas phase electrophoretic molecular mobility analysis (GEMMA) ID MASS-SPECTROMETRY; ION-MOBILITY; COMPLEXES; PROTEINS; SIZE; IDENTIFICATION; NANOPARTICLES; IONIZATION AB The technique of electrospray differential mobility analysis (ES-DMA) was examined as a potential potency assay for routine virus particle analysis in biomanufacturing environments (e.g., evaluation of vaccines and gene delivery products for lot release) in the context of the International Committee of Harmonisation (ICH) Q2 guidelines. ES-DMA is a rapid particle sizing method capable of characterizing certain aspects of the structure (such as capsid proteins) and obtaining complete size distributions of viruses and virus-like particles. It was shown that ES-DMA can distinguish intact virus particles from degraded particles and measure the concentration of virus particles when calibrated with nanoparticles of known concentration. The technique has a measurement uncertainty of approximate to 120%, is linear over nearly 3 orders of magnitude, and has a lower limit of detection of approximate to 10(9) particles/mL This quantitative assay was demonstrated for non-enveloped viruses. It is expected that ES-DMA will be a useful method for applications involving production and quality control of vaccines and gene therapy vectors for human use. (C) 2011 Published by Elsevier B.V. C1 [Guha, Suvajyoti; Zachariah, Michael R.] Univ Maryland, Dept Mech Engn Chem & Biochem, College Pk, MD 20742 USA. [Guha, Suvajyoti; Pease, Leonard F., III; Tarlov, Michael J.; Zachariah, Michael R.] Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA. [Pease, Leonard F., III] Univ Utah, Dept Chem Engn, Salt Lake City, UT 84112 USA. [Pease, Leonard F., III] Univ Utah, Dept Pharmaceut & Pharmaceut Chem, Salt Lake City, UT 84112 USA. [Pease, Leonard F., III] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA. [Brorson, Kurt A.] US FDA, CDER, Silver Spring, MD 20903 USA. RP Zachariah, MR (reprint author), Univ Maryland, Dept Mech Engn Chem & Biochem, 2125 Glenn L Martin Hall,Bldg 088, College Pk, MD 20742 USA. EM mrz@umd.edu OI Guha, Suvajyoti/0000-0002-7622-2721 NR 36 TC 16 Z9 16 U1 3 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD DEC PY 2011 VL 178 IS 1-2 BP 201 EP 208 DI 10.1016/j.jviromet.2011.09.012 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 853UQ UT WOS:000297451600028 PM 21963394 ER PT J AU Williams-Woods, J Gonzalez-Escalona, N Burkhardt, W AF Williams-Woods, Jacquelina Gonzalez-Escalona, Narjol Burkhardt, William, III TI Direct sequencing of hepatitis A virus and norovirus RT-PCR products from environmentally contaminated oyster using M13-tailed primers SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Norovirus; Hepatitis A virus; RT-PCR; Real-time RT-qPCR; M13 primers; Virus detection ID NORWALK-LIKE VIRUSES; REVERSE TRANSCRIPTION-PCR; UNITED-STATES; BIVALVE SHELLFISH; VIRAL PATHOGENS; CLASSIFICATION; SURVEILLANCE; OUTBREAKS; ASSAY AB Human norovirus (HuNoV) and hepatitis A (HAV) are recognized as leading causes of non-bacterial food-borne associated illnesses in the United States. DNA sequencing is generally considered the standard for accurate viral genotyping in support of epidemiological investigations. Due to the genetic diversity of noroviruses (NoV), degenerate primer sets are often used in conventional reverse transcription (RT) PCR and real-time RT-quantitative PCR (RT-qPCR) for the detection of these viruses and cDNA fragments are generally cloned prior to sequencing. HAV detection methods that are sensitive and specific for real-time RT-qPCR yields small fragments sizes of 89-150 bp, which can be difficult to sequence. In order to overcome these obstacles, norovirus and HAV primers were tailed with M13 forward and reverse primers. This modification increases the sequenced product size and allows for direct sequencing of the amplicons utilizing complementary M13 primers. HuNoV and HAV cDNA products from environmentally contaminated oysters were analyzed using this method. Alignments of the sequenced samples revealed >= 95% nucleotide identities. Tailing NoV and HAV primers with M13 sequence increases the cDNA product size, offers an alternative to cloning, and allows for rapid, accurate and direct sequencing of cDNA products produced by conventional or real time RT-qPCR assays. Published by Elsevier B.V. C1 [Williams-Woods, Jacquelina; Burkhardt, William, III] US FDA, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. [Gonzalez-Escalona, Narjol] US FDA, College Pk, MD USA. RP Williams-Woods, J (reprint author), US FDA, Gulf Coast Seafood Lab, 1 Iberville Dr, Dauphin Isl, AL 36528 USA. EM jacquelina.woods@fda.hhs.gov OI Gonzalez-Escalona, Narjol/0000-0003-4568-0022 NR 25 TC 5 Z9 5 U1 1 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD DEC PY 2011 VL 178 IS 1-2 BP 253 EP 257 DI 10.1016/j.jviromet.2011.09.014 PG 5 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 853UQ UT WOS:000297451600037 PM 21963395 ER PT J AU Wang, W De Feo, CJ Zhuang, M Vassell, R Weiss, CD AF Wang, Wei De Feo, Christopher J. Zhuang, Min Vassell, Russell Weiss, Carol D. TI Selection with a Peptide Fusion Inhibitor Corresponding to the First Heptad Repeat of HIV-1 gp41 Identifies Two Genetic Pathways Conferring Cross-Resistance to Peptide Fusion Inhibitors Corresponding to the First and Second Heptad Repeats (HR1 and HR2) of gp41 SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; GP120 ENVELOPE GLYCOPROTEIN; TRANSMEMBRANE PROTEIN GP41; TYPE-1 GP41; 6-HELIX BUNDLE; ENTRY INHIBITORS; MEMBRANE-FUSION; MUTATIONAL ANALYSIS; LENTIVIRAL VECTOR; POTENT INHIBITORS AB We generated four HIV-1 cultures that are resistant to a peptide fusion inhibitor corresponding to the first heptad repeat of gp41 in order to study mechanisms of resistance and gain insights into envelope glycoprotein-mediated membrane fusion. Two genetic pathways emerged that were defined by acquisition of a specific mutation in either the first or second heptad repeat region of gp41 (HR1 or the HR2, respectively). Each pathway was enriched in mutations that clustered in either HR2 and V3 or in HR1 and residues in or near CD4 contact sites. The gp41 mutations in both pathways not only accounted for resistance to the selecting HR1 peptide but also conferred cross-resistance to HR2 peptide fusion inhibitors and enhanced the stability of the six-helix bundle formed by the self-assembly of HR1 and HR2. The gp120 mutations alone enhanced fusion but did not appear to directly contribute to resistance. The implications of these findings for resistance mechanisms and regulation of envelope-mediated fusion are discussed. C1 [Wang, Wei; De Feo, Christopher J.; Zhuang, Min; Vassell, Russell; Weiss, Carol D.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Weiss, CD (reprint author), US FDA, Ctr Biol Evaluat & Res, HFM 466,Bldg 29,Room 532,29 Lincoln Dr, Bethesda, MD 20892 USA. EM carol.weiss@fda.hhs.gov FU FDA; National Institutes of Health FX This work was supported in part by institutional funds from the FDA and the Intramural AIDS Targeted Antiviral Program from the National Institutes of Health. NR 84 TC 7 Z9 7 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2011 VL 85 IS 24 BP 12929 EP 12938 DI 10.1128/JVI.05391-11 PG 10 WC Virology SC Virology GA 856LI UT WOS:000297642000011 PM 21994458 ER PT J AU Marti, GE Stetler-Stevenson, M Grant, ND White, T Figg, WD Tohnya, T Jaffe, ES Dunleavy, K Janik, JE Steinberg, SM Wilson, WH AF Marti, Gerald E. Stetler-Stevenson, Maryalice Grant, Nicole Drbohlav White, Therese Figg, William D. Tohnya, Tanyifor Jaffe, Elaine S. Dunleavy, Kieron Janik, John E. Steinberg, Seth M. Wilson, Wyndham H. TI Phase I trial of 7-hydroxystaurosporine and fludararbine phosphate: in vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia SO LEUKEMIA & LYMPHOMA LA English DT Article DE Cell death; CLL; flow cytometry; protein kinase inhibitor ID ADVANCED SOLID TUMORS; DEPENDENT KINASE INHIBITOR; LOW-GRADE LYMPHOMA; FLUDARABINE PHOSPHATE; LYSIS SYNDROME; UCN-01 7-HYDROXYSTAUROSPORINE; ALPHA(1)-ACID GLYCOPROTEIN; ALTERED PHARMACOKINETICS; ANTICANCER DRUG; CLINICAL-TRIALS AB This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 2-6. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes. C1 [Marti, Gerald E.; Stetler-Stevenson, Maryalice; Grant, Nicole Drbohlav; White, Therese; Figg, William D.; Tohnya, Tanyifor; Jaffe, Elaine S.; Dunleavy, Kieron; Janik, John E.; Steinberg, Seth M.; Wilson, Wyndham H.] NCI, NIH, Bethesda, MD 20892 USA. RP Marti, GE (reprint author), CBER FDA NIH, CDR, Lab Stem Cell Biol,Cellular & Tissue Therapy Bran, Div Cell & Gene Therapies,Off Cellular Tissues &, Bdg 29B,Rm 2NN08,8800 Rockville Pike, Bethesda, MD 20892 USA. EM gemarti@helix.nih.gov RI Figg Sr, William/M-2411-2016; OI Jaffe, Elaine/0000-0003-4632-0301 NR 43 TC 7 Z9 7 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD DEC PY 2011 VL 52 IS 12 BP 2284 EP 2292 DI 10.3109/10428194.2011.589547 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 857FD UT WOS:000297700900012 PM 21745173 ER PT J AU Lee, JY Gobburu, JVS AF Lee, Joo Yeon Gobburu, Jogarao V. S. TI Bayesian Quantitative Disease-Drug-Trial Models for Parkinson's Disease to Guide Early Drug Development SO AAPS JOURNAL LA English DT Article DE Bayesian method; drug development; prior knowledge; quantitative disease-drug-trial model ID LABELING DECISIONS; CLINICAL-TRIALS; POWER PRIOR; PROGRESSION; APPROVAL; LEVODOPA; BELIEFS; IMPACT AB The problem we have faced in drug development is in its efficiency. Almost a half of registration trials are reported to fail mainly because pharmaceutical companies employ one-size-fits-all development strategies. Our own experience at the regulatory agency suggests that failure to utilize prior experience or knowledge from previous trials also accounts for trial failure. Prior knowledge refers to both drug-specific and nonspecific information such as placebo effect and the disease course. The information generated across drug development can be systematically compiled to guide future drug development. Quantitative disease-drug-trial models are mathematical representations of the time course of biomarker and clinical outcomes, placebo effects, a drug's pharmacologic effects, and trial execution characteristics for both the desired and undesired responses. Applying disease-drug-trial model paradigms to design a future trial has been proposed to overcome current problems in drug development. Parkinson's disease is a progressive neurodegenerative disorder characterized by bradykinesia, rigidity, tremor, and postural instability. A symptomatic effect of drug treatments as well as natural rate of disease progression determines the rate of disease deterioration. Currently, there is no approved drug which claims disease modification. Regulatory agency has been asked to comment on the trial design and statistical analysis methodology. In this work, we aim to show how disease-drug-trial model paradigm can help in drug development and how prior knowledge from previous studies can be incorporated into a current trial using Parkinson's disease model as an example. We took full Bayesian methodology which can allow one to translate prior information into probability distribution. C1 [Lee, Joo Yeon; Gobburu, Jogarao V. S.] US FDA, Div Pharmacometr, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Lee, JY (reprint author), US FDA, Div Pharmacometr, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Room 3198,Bldg 51, Silver Spring, MD 20993 USA. EM jooyeon2.lee@fda.hhs.gov NR 35 TC 6 Z9 6 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD DEC PY 2011 VL 13 IS 4 BP 508 EP 518 DI 10.1208/s12248-011-9293-6 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 852KZ UT WOS:000297358100002 PM 21792701 ER PT J AU Chen, ML Shah, VP Crommelin, DJ Shargel, L Bashaw, D Bhatti, M Blume, H Dressman, J Ducharme, M Fackler, P Hyslop, T Lutter, L Morais, J Ormsby, E Thomas, S Tsang, YC Velagapudi, R Yu, LX AF Chen, Mei-Ling Shah, Vinod P. Crommelin, Daan J. Shargel, Leon Bashaw, Dennis Bhatti, Masood Blume, Henning Dressman, Jennifer Ducharme, Murray Fackler, Paul Hyslop, Terry Lutter, Lorelei Morais, Jose Ormsby, Eric Thomas, Saji Tsang, Yu Chung Velagapudi, Raja Yu, Lawrence X. TI Harmonization of Regulatory Approaches for Evaluating Therapeutic Equivalence and Interchangeability of Multisource Drug Products: Workshop Summary Report SO AAPS JOURNAL LA English DT Article DE bioequivalence; harmonization; interchangeability; regulatory standards; therapeutic equivalence ID OPIOID RECEPTOR AGONIST; SPIRADOLINE U-62066E; IN-VITRO; PHARMACOKINETICS; PHARMACODYNAMICS; PROLACTIN; NEUROENDOCRINE; MODELS; PREDICTION; CLEARANCE AB Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products. C1 [Chen, Mei-Ling] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Shah, Vinod P.] Int Pharmaceut Federat FIP, The Hague, Netherlands. [Crommelin, Daan J.] Utrecht Inst Pharmaceut Sci, Utrecht, Netherlands. [Shargel, Leon] Appl Biopharmaceut LLC, Raleigh, NC USA. [Bhatti, Masood; Lutter, Lorelei] Bio Pharma Serv Inc, Toronto, ON, Canada. [Blume, Henning] SocraTec R&D, Oberursel, Germany. [Dressman, Jennifer] Goethe Univ Frankfurt, Frankfurt, Germany. [Ducharme, Murray] Cetero Res, Cary, NC USA. [Fackler, Paul] Merck Res Labs, Rahway, NJ USA. [Hyslop, Terry] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Morais, Jose] Univ Lisbon, P-1699 Lisbon, Portugal. [Ormsby, Eric] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Thomas, Saji] Par Pharmaceut Inc, Spring Valley, NY USA. [Tsang, Yu Chung] Apotex Inc, Toronto, ON, Canada. [Velagapudi, Raja] Teva Pharmaceut, Woodcliff Lake, NJ USA. [Yu, Lawrence X.] US FDA, Rockville, MD 20857 USA. RP Chen, ML (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 4108, Silver Spring, MD 20993 USA. EM meiling.chen@fda.hhs.gov RI Morais, Jose/E-6322-2014 OI Morais, Jose/0000-0002-0007-3299 NR 36 TC 3 Z9 3 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD DEC PY 2011 VL 13 IS 4 BP 556 EP 575 DI 10.1208/s12248-011-9294-5 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 852KZ UT WOS:000297358100005 PM 21845486 ER PT J AU Martinez, MN AF Martinez, Marilyn N. TI Factors Influencing the Use and Interpretation of Animal Models in the Development of Parenteral Drug Delivery Systems SO AAPS JOURNAL LA English DT Review DE animal model; interspecies differences; parenteral drug delivery; pharmacokinetics ID COLLOID OSMOTIC-PRESSURE; PLASMA-PROTEIN BINDING; LIPOSOMAL AMPHOTERICIN-B; SPECIES-DIFFERENCES; GENE-THERAPY; RAT PLASMA; IN-VITRO; SUBCUTANEOUS ABSORPTION; LYMPHATIC ABSORPTION; LABORATORY-ANIMALS AB Depending upon the drug and drug delivery platform, species-specific physiological differences can lead to errors in the interspecies extrapolation of drug performance. This manuscript provides an overview of the species-specific physiological variables that can influence the performance of parenteral dosage forms such as in situ forming delivery systems, nanoparticles, microspheres, liposomes, targeted delivery systems, lipophilic solutions, and aqueous suspensions. Also discussed are those factors that can influence the partitioning of therapeutic compounds into tumors, the central nervous system and the lymphatics. Understanding interspecies differences in the movement and absorption of molecules is important to the interpretation of data generated through the use of animal models when studying parenteral drug delivery. C1 US FDA, Ctr Vet Med, Rockville, MD 20855 USA. RP Martinez, MN (reprint author), US FDA, Ctr Vet Med, Rockville, MD 20855 USA. EM marilyn.martinez@fda.hhs.gov NR 109 TC 8 Z9 9 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD DEC PY 2011 VL 13 IS 4 BP 632 EP 649 DI 10.1208/s12248-011-9303-8 PG 18 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 852KZ UT WOS:000297358100011 PM 21971647 ER PT J AU Arlt, VM Singh, R Stiborova, M da Costa, GG Frei, E Evans, JD Farmer, PB Wolf, CR Henderson, CJ Phillips, DH AF Arlt, Volker M. Singh, Rajinder Stiborova, Marie da Costa, Goncalo Gamboa Frei, Eva Evans, James D. Farmer, Peter B. Wolf, C. Roland Henderson, Colin J. Phillips, David H. TI Effect of Hepatic Cytochrome P450 (P450) Oxidoreductase Deficiency on 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA Adduct Formation in P450 Reductase Conditional Null Mice SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID ANTICANCER DRUG ELLIPTICINE; DNA-ADDUCTS; HETEROCYCLIC AMINES; METABOLIC-ACTIVATION; ENVIRONMENTAL-POLLUTANT; GASTROINTESTINAL-TRACT; COLORECTAL-CANCER; CARCINOGENESIS; CYP1A2; PHIP AB 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), formed during the cooking of foods, induces colon cancer in rodents. PhIP is metabolically activated by cytochromes P450 (P450s). To evaluate the role of hepatic P450s in the bioactivation of PhIP, we used Reductase Conditional Null (RCN) mice, in which cytochrome P450 oxidoreductase (POR), the unique electron donor to P450s, can be specifically deleted in hepatocytes by pretreatment with 3-methylcholanthrene (3-MC), resulting in the loss of essentially all hepatic P450 function. RCN mice were treated orally with 50 mg/kg b.wt. PhIP daily for 5 days, with and without 3-MC pretreatment. PhIP-DNA adducts (i.e., N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [dG-C8-PhIP]), measured by liquid chromatography-tandem mass spectrometry, were highest in colon (1362 adducts/10(8) deoxynucleosides), whereas adduct levels in liver were similar to 3.5-fold lower. Whereas no differences in PhIP-DNA adduct levels were found in livers with active POR versus inactivated POR, adduct levels were on average similar to 2-fold lower in extrahepatic tissues of mice lacking hepatic POR. Hepatic microsomes from RCN mice with or without 3-MC pretreatment were also incubated with PhIP and DNA in vitro. PhIP-DNA adduct formation was similar to 8-fold lower with hepatic microsomes from POR-inactivated mice than with those with active POR. Most of the hepatic microsomal activation of PhIP in vitro was attributable to CYP1A. Our results show that PhIP-DNA adduct formation in colon involves hepatic N-oxidation, circulation of activated metabolites via the bloodstream to extrahepatic tissues, and further activation, resulting in the formation of dG-C8-PhIP. Besides hepatic P450s, PhIP may be metabolically activated mainly by a non-P450 pathway in liver. C1 [Arlt, Volker M.; Evans, James D.; Phillips, David H.] Inst Canc Res, Sect Mol Carcinogenesis, Sutton SM2 5NG, Surrey, England. [Singh, Rajinder; Farmer, Peter B.] Univ Leicester, Canc Biomarkers & Prevent Grp, Leicester, Leics, England. [Stiborova, Marie] Charles Univ Prague, Dept Biochem, Fac Sci, Prague, Czech Republic. [da Costa, Goncalo Gamboa] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Frei, Eva] German Canc Res Ctr, Natl Ctr Tumor Dis, Div Prevent Oncol, D-6900 Heidelberg, Germany. [Wolf, C. Roland; Henderson, Colin J.] Biomed Res Inst, Canc Res UK Mol Pharmacol Unit, Dundee, Scotland. RP Arlt, VM (reprint author), Inst Canc Res, Sect Mol Carcinogenesis, Brookes Lawley Bldg, Sutton SM2 5NG, Surrey, England. EM volker.arlt@icr.ac.uk RI Singh, Raj/A-5398-2011; Stiborova, Marie/A-5982-2015; OI Stiborova, Marie/0000-0001-5430-4403; Henderson, Colin/0000-0002-4764-639X; Phillips, David/0000-0001-8509-3485; Arlt, Volker Manfred/0000-0003-4314-9318; Wolf, Charles Roland/0000-0002-6969-0113 FU Environmental Cancer Risk, Nutrition and Individual Susceptibility as part of the European Union [513943]; Cancer Research UK; Grant Agency of the Czech Republic [P301/10/0356] FX This work was supported by Environmental Cancer Risk, Nutrition and Individual Susceptibility as part of the European Union 6th Framework, Priority 5: "Food Quality and Safety" [Contract 513943]; Cancer Research UK; and the Grant Agency of the Czech Republic [Grant P301/10/0356]. NR 38 TC 8 Z9 9 U1 1 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD DEC PY 2011 VL 39 IS 12 BP 2169 EP 2173 DI 10.1124/dmd.111.041343 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 852AU UT WOS:000297317000002 PM 21940903 ER PT J AU Faupel-Badger, JM van Bemmel, DM Wiest, JS Nelson, DE AF Faupel-Badger, Jessica M. van Bemmel, Dana M. Wiest, Jonathan S. Nelson, David E. TI Expanding Cancer Prevention Education to National and International Audiences: The National Cancer Institute's Principles and Practice of Cancer Prevention and Control Annual Summer Course SO JOURNAL OF CANCER EDUCATION LA English DT Article DE International; Training; Epidemiology; Public health AB The Summer Curriculum in Cancer Prevention has been sponsored by the National Cancer Institute's Cancer Prevention Fellowship Program for over two decades. This curriculum includes a 4-week course entitled "Principles and Practice of Cancer Prevention and Control." The ultimate goal of this course is to present the most current cancer prevention research to a diverse workforce of researchers and practitioners eager to address the current challenges in this field. The course covers the current status of cancer prevention research and practice, ranging from epidemiology and clinical practice, and from basic to behavioral science research. It is comprised of lectures grouped into nine modules representing broad and specific topics relevant to cancer prevention. Course participants come from a broad cross-section of career stages, professions, and research interests, and are from across the USA and other countries. Over time and in response to feedback from participants, the course has developed to meet the needs and expectations of this diverse audience, and may serve as a model for those interested in cancer prevention education and training in other countries. C1 [Faupel-Badger, Jessica M.; Wiest, Jonathan S.; Nelson, David E.] NCI, Ctr Canc Training, Bethesda, MD 20892 USA. [Faupel-Badger, Jessica M.; Nelson, David E.] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [van Bemmel, Dana M.] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Faupel-Badger, JM (reprint author), NCI, Ctr Canc Training, Bethesda, MD 20892 USA. EM badgerje@mail.nih.gov FU NCI FX We would like to thank past CPFP staff members, Ms. Barbara Redding and Dr. Douglas L. Weed, for their insightful discussions about the summer course and formaintaining detailed records on course format and attendance since its inception, and Ms. Studly Auguste, a current CPFP staff member, for her efforts to make the summer course a success. We also thank members of NCI's Office of International Affairs (OIA), Drs. Joe Harford and Makeda Williams and Ms. Isabel Otero, who discussed the history of OIA's involvement with the course and their follow-up efforts of international course participants with us. Lastly, we thank the NCI leadership for their continued support of the Summer Curriculum in Cancer Prevention. NR 11 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD DEC PY 2011 VL 26 IS 4 BP 619 EP 625 DI 10.1007/s13187-011-0257-4 PG 7 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 852IO UT WOS:000297351400006 PM 21785976 ER PT J AU Rutten, LJF Blake, KD Hesse, BW Augustson, EM Evans, S AF Rutten, Lila J. Finney Blake, Kelly D. Hesse, Bradford W. Augustson, Erik M. Evans, Sarah TI Illness Representations of Lung Cancer, Lung Cancer Worry, and Perceptions of Risk by Smoking Status SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Smoking; Lung cancer worry; Risk perceptions ID HEALTH-PROTECTIVE BEHAVIOR; MODEL AB We examined perceived risk, worry, and illness representations of lung cancer by smoking status using data from the 2005 Health Information National Trends Survey (n = 1,765). Perceived lung cancer risk was rated "very high" more frequently by current (15.2%) than former (1.9%) and never (1.6%) smokers. Current smokers more frequently reported worry about lung cancer (18.4%) than former (3.1%) and never smokers (1.8%). Confusion about lung cancer prevention was higher among current (55.2%) than former (41.3%) or never smokers (38.2%). Agreement that lung cancer is caused by a person's behavior was higher among never (86.1%) and former (82.6%) than current smokers (75.4%). In multivariable models, never (OR = .07) and former smokers (OR = .16) were less likely than current smokers to perceive their lung cancer risk as high. Never smokers (OR = .21) were significantly less likely than current smokers to report worrying about lung cancer, while former and current smokers did not differ. C1 [Rutten, Lila J. Finney] NCI, Clin Monitoring Res Program, SAIC, Inc Frederick, Frederick, MD 21704 USA. [Blake, Kelly D.; Hesse, Bradford W.; Augustson, Erik M.] NCI, Bethesda, MD 20892 USA. [Evans, Sarah] US FDA, Silver Spring, MD USA. RP Rutten, LJF (reprint author), NCI, Clin Monitoring Res Program, SAIC, Inc Frederick, Frederick, MD 21704 USA. EM finneyl@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 20 TC 9 Z9 9 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD DEC PY 2011 VL 26 IS 4 BP 747 EP 753 DI 10.1007/s13187-011-0247-6 PG 7 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 852IO UT WOS:000297351400023 ER PT J AU Marsik, FJ Nambiar, S AF Marsik, Frederic J. Nambiar, Sumathi TI Review of Carbapenemases and AmpC-beta Lactamases SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Editorial Material DE beta-lactamases; carbapenemases; Enterobacteriaceae ID ENTEROBACTERIACEAE; RESISTANT; INFECTIONS; COLISTIN C1 [Marsik, Frederic J.; Nambiar, Sumathi] US FDA, Ctr Drug Evaluat & Res, Off Antimicrobial Prod, Silver Spring, MD 20993 USA. RP Nambiar, S (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Antimicrobial Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. NR 14 TC 5 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD DEC PY 2011 VL 30 IS 12 BP 1094 EP 1095 DI 10.1097/INF.0b013e31823c0e47 PG 2 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 853DJ UT WOS:000297406100019 PM 22105420 ER PT J AU Wang, KC Filice, RW Philbin, JF Siegel, EL Nagy, PG AF Wang, Kenneth C. Filice, Ross W. Philbin, James F. Siegel, Eliot L. Nagy, Paul G. TI Five Levels of PACS Modularity: Integrating 3D and Other Advanced Visualization Tools SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE PACS; 3D imaging (imaging, three-dimensional); Computer systems; Advanced visualization; Server-based rendering; Application hosting ID CT ANGIOGRAPHY; COLONOGRAPHY; ARTERIES; ARCHIVE; 3D-CT; MDCT AB The current array of PACS products and 3D visualization tools presents a wide range of options for applying advanced visualization methods in clinical radiology. The emergence of server-based rendering techniques creates new opportunities for raising the level of clinical image review. However, best-of-breed implementations of core PACS technology, volumetric image navigation, and application-specific 3D packages will, in general, be supplied by different vendors. Integration issues should be carefully considered before deploying such systems. This work presents a classification scheme describing five tiers of PACS modularity and integration with advanced visualization tools, with the goals of characterizing current options for such integration, providing an approach for evaluating such systems, and discussing possible future architectures. These five levels of increasing PACS modularity begin with what was until recently the dominant model for integrating advanced visualization into the clinical radiologist's workflow, consisting of a dedicated stand-alone post-processing workstation in the reading room. Introduction of context-sharing, thin clients using server-based rendering, archive integration, and user-level application hosting at successive levels of the hierarchy lead to a modularized imaging architecture, which promotes user interface integration, resource efficiency, system performance, supportability, and flexibility. These technical factors and system metrics are discussed in the context of the proposed five-level classification scheme. C1 [Wang, Kenneth C.; Siegel, Eliot L.] Baltimore VA Med Ctr, Dept Radiol, Baltimore, MD 21201 USA. [Filice, Ross W.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Philbin, James F.; Nagy, Paul G.] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. RP Wang, KC (reprint author), Baltimore VA Med Ctr, Dept Radiol, Rm 1B-112,10 N Greene St, Baltimore, MD 21201 USA. EM kenwang@stanfordalumni.org FU RSNA Research and Education Foundation [FT0904]; Walter and Mary Ciceric Research Award FX KCW gratefully acknowledges the support of RSNA Research and Education Foundation Fellowship Training Grant #FT0904, as well as that of the Walter and Mary Ciceric Research Award. NR 25 TC 4 Z9 4 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0897-1889 J9 J DIGIT IMAGING JI J. Digit. Imaging PD DEC PY 2011 VL 24 IS 6 BP 1096 EP 1102 DI 10.1007/s10278-011-9366-1 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 846FL UT WOS:000296882500014 PM 21301923 ER PT J AU Li, Y Mei, H Wu, QG Zhang, SH Fang, JL Shi, LM Guo, L AF Li, Yan Mei, Hu Wu, Qiangen Zhang, Suhui Fang, Jia-Long Shi, Leming Guo, Lei TI Methysticin and 7,8-Dihydromethysticin are Two Major Kavalactones in Kava Extract to Induce CYP1A1 SO TOXICOLOGICAL SCIENCES LA English DT Article DE aryl hydrocarbon receptor; CYP1A1; kava extract; kavalactone; molecular docking ID ARYL-HYDROCARBON RECEPTOR; HERB-DRUG INTERACTIONS; COMFREY SYMPHYTUM-OFFICINALE; GENE-EXPRESSION CHANGES; PIPER-METHYSTICUM; IN-VITRO; HEPATIC CYTOCHROME-P450; ALTERNATIVE MEDICINE; METABOLIZING-ENZYMES; ANXIETY DISORDERS AB Kava is a plant traditionally used for making beverages in Pacific Basin countries and has been used for the treatment of nervous disorders in the United States. The pharmacological activity of kava is achieved through kavalactones in kava extract, which include kawain, 7,8-dihydrokawain, yangonin, 5,6-dehydrokawain, methysticin, and 7,8-dihydromethysticin. Recent studies have shown that kava extract induces hepatic CYP1A1 enzyme; however, the mechanisms of CYP1A1 induction have not been elucidated, and the kavalactones responsible for CYP1A1 induction have not yet been identified. Using a combination of biochemical assays and molecular docking tools, we determined the functions of kava extract and kavalactones and delineated the underlying mechanisms involved in CYP1A1 induction. The results showed that kava extract displayed a concentration-dependent effect on CYP1A1 induction. Among the six major kavalactones, methysticin triggered the most profound inducing effect on CYP1A1 followed by 7,8-dihydromethysticin. The other four kavalactones (yangonin, 5,6-dehydrokawain, kawain, and 7,8-dihydrokawain) did not show significant effects on CYP1A1. Consistent with the experimental results, in silico molecular docking studies based on the aryl hydrocarbon receptor (AhR)-ligand binding domain homology model also revealed favorable binding to AhR for methysticin and 7,8-dihydromethysticin compared with the remaining kavalactones. Additionally, results from a luciferase gene reporter assay suggested that kava extract, methysticin, and 7,8-dihydromethysticin were able to activate the AhR signaling pathway. Moreover, kava extract-, methysticin-, and 7,8-dihydromethysticin-mediated CYP1A1 induction was blocked by an AhR antagonist and abolished in AhR-deficient cells. These findings suggest that kava extract induces the expression of CYP1A1 via an AhR-dependent mechanism and that methysticin and 7,8-dihydromethysticin contribute to CYP1A1 induction. The induction of CYP1A1 indicates a potential interaction between kava or kavalactones and CYP1A1-mediated chemical carcinogenesis. C1 [Wu, Qiangen; Fang, Jia-Long; Guo, Lei] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Li, Yan; Mei, Hu; Zhang, Suhui; Shi, Leming] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Guo, L (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM lei.guo@fda.hhs.gov RI Li, Yan/F-9560-2012; Li, Yan/G-5158-2012; Wu, Qiangen/F-7581-2014 OI Wu, Qiangen/0000-0002-7595-2837 FU National Center for Toxicological Research; U.S. FDA FX Y.L., H.M., and Q.W. were supported by the appointments to the Postgraduate Research Program at the National Center for Toxicological Research administered by Oak Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. S.Z. was supported by the U.S. FDA's International Scientist Exchange Program. NR 71 TC 11 Z9 12 U1 1 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD DEC PY 2011 VL 124 IS 2 BP 388 EP 399 DI 10.1093/toxsci/kfr235 PG 12 WC Toxicology SC Toxicology GA 850TY UT WOS:000297223600015 PM 21908763 ER PT J AU Shaheen, BW Nayak, R Foley, SL Kweon, O Deck, J Park, M Rafii, F Boothe, DM AF Shaheen, Bashar W. Nayak, Rajesh Foley, Steven L. Kweon, Ohgew Deck, Joanna Park, Miseon Rafii, Fatemeh Boothe, Dawn M. TI Molecular Characterization of Resistance to Extended-Spectrum Cephalosporins in Clinical Escherichia coli Isolates from Companion Animals in the United States SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID BETA-LACTAM RESISTANCE; FOOD-PRODUCING ANIMALS; CTX-M; ANTIMICROBIAL RESISTANCE; SALMONELLA; STRAINS; DOGS; PLASMIDS; CTX-M-15; HEALTHY AB Resistance to extended-spectrum cephalosporins (ESC) among members of the family Enterobacteriaceae occurs worldwide; however, little is known about ESC resistance in Escherichia coli strains from companion animals. Clinical isolates of E. coli were collected from veterinary diagnostic laboratories throughout the United States from 2008 to 2009. E. coli isolates (n = 54) with reduced susceptibility to ceftazidime or cefotaxime (MIC >= 16 mu g/ml) and extended-spectrum-beta-lactamase (ESBL) phenotypes were analyzed. PCR and sequencing were used to detect mutations in ESBL-encoding genes and the regulatory region of the chromosomal gene ampC. Conjugation experiments and plasmid identification were conducted to examine the transferability of resistance to ESCs. All isolates carried the bla(CTX-M-1)-group beta-lactamase genes in addition to one or more of the following beta-lactamase genes: bla(TEM), bla(SHV-3), bla(CMY-2), bla(CTX-M-14-like), and bla(OXA-1). Different bla(TEM) sequence variants were detected in some isolates (n = 40). Three isolates harbored a bla(TEM-181) gene with a novel mutation resulting in an Ala184Val substitution. Approximately 78% of the isolates had mutations in promoter/attenuator regions of the chromosomal gene ampC, one of which was a novel insertion of adenine between bases -28 and -29. Plasmids ranging in size from 11 to 233 kbp were detected in the isolates, with a common plasmid size of 93 kbp identified in 60% of isolates. Plasmid-mediated transfer of beta-lactamase genes increased the MICs (>= 16-fold) of ESCs for transconjugants. Replicon typing among isolates revealed the predominance of IncI and IncFIA plasmids, followed by IncFIB plasmids. This study shows the emergence of conjugative plasmid-borne ESBLs among E. coli strains from companion animals in the United States, which may compromise the effective therapeutic use of ESCs in veterinary medicine. C1 [Shaheen, Bashar W.; Nayak, Rajesh; Foley, Steven L.; Kweon, Ohgew; Deck, Joanna; Park, Miseon; Rafii, Fatemeh] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Boothe, Dawn M.] Auburn Univ, Coll Vet Med, Dept Anat Physiol & Pharmacol, Auburn, AL 36849 USA. RP Shaheen, BW (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM bashar.shaheen@fda.hhs.gov FU Oak Ridge Institute for Science and Education FX Bashar W. Shaheen is supported by the Oak Ridge Institute for Science and Education. Views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. NR 50 TC 38 Z9 39 U1 0 U2 15 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD DEC PY 2011 VL 55 IS 12 BP 5666 EP 5675 DI 10.1128/AAC.00656-11 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 846RJ UT WOS:000296920600034 PM 21947397 ER PT J AU He, YS Guo, DJ Yang, JY Tortorello, ML Zhang, W AF He, Yingshu Guo, Dongjing Yang, Jingyun Tortorello, Mary Lou Zhang, Wei TI Survival and Heat Resistance of Salmonella enterica and Escherichia coli O157:H7 in Peanut Butter SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID THERMAL INACTIVATION; ENTERITIDIS; MODEL; FOODS AB Significant differences (P < 0.05) were found between the survival rates of Salmonella enterica and Escherichia coli O157:H7 in peanut butter with different formulations and water activity. High carbohydrate content in peanut butter and low incubation temperature resulted in higher levels of bacterial survival during storage but lower levels of bacterial resistance to heat treatment. C1 [He, Yingshu; Guo, Dongjing; Zhang, Wei] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. [Yang, Jingyun] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK 73104 USA. [Tortorello, Mary Lou] US FDA, Bedford Pk, IL 60501 USA. RP Zhang, W (reprint author), IIT, Inst Food Safety & Hlth, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. EM zhangw@iit.edu FU Food Research Initiative, USDA National Institute of Food Agriculture, Food Safety and Epidemiology [2010-65201-20593, 93231] FX This work was supported by the Food Research Initiative grant no. 2010-65201-20593 from the USDA National Institute of Food Agriculture, Food Safety and Epidemiology: Biological Approaches for Food Safety program (program code 93231). NR 18 TC 19 Z9 20 U1 3 U2 33 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD DEC PY 2011 VL 77 IS 23 BP 8434 EP 8438 DI 10.1128/AEM.06270-11 PG 5 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 849ZL UT WOS:000297164100030 PM 21965404 ER PT J AU Volpe, DA AF Volpe, Donna A. TI Drug-permeability and transporter assays in Caco-2 and MDCK cell lines SO FUTURE MEDICINAL CHEMISTRY LA English DT Review ID CANINE KIDNEY-CELLS; IN-VITRO EVALUATION; INTESTINAL EPITHELIAL-CELLS; P-GLYCOPROTEIN INHIBITION; EFFLUX TRANSPORTERS; PEPTIDE TRANSPORTER; FUNCTIONAL-CHARACTERISTICS; MEDIATED TRANSPORT; SLC-TRANSPORTERS; GENE-EXPRESSION AB The human colon adenocarcinoma Caco-2 and Madin-Darby canine kidney epithelial cell lines provide in vitro tools to assess a drug's permeability and transporter interactions during discovery and development. The cells, when cultured on semiporous filters, form confluent monolayers that model the intestinal epithelial barrier for permeability, transporter and drug-interaction assays. The applications of these assays in pharmaceutical research include qualitative prediction and ranking of absorption, determining mechanism(s) of permeability, formulation effects on drug permeability, and the potential for transporter-mediated drug-drug interactions. This review focuses on recent examples of Caco-2 and Madin-Darby canine kidney cells assays for drug permeability including transfected and knock-down cells, miniaturization and automation, and assay combinations to better understand and predict intestinal drug absorption. C1 US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Volpe, DA (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM donna.volpe@fda.hhs.gov NR 97 TC 46 Z9 50 U1 6 U2 48 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 J9 FUTURE MED CHEM JI Future Med. Chem. PD DEC PY 2011 VL 3 IS 16 BP 2063 EP 2077 DI 10.4155/FMC.11.149 PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 849YP UT WOS:000297161800014 PM 22098353 ER PT J AU Shen, EY Ali, SF Meyer, JS AF Shen, Erica Y. Ali, Syed F. Meyer, Jerrold S. TI Chronic administration of THC prevents the behavioral effects of intermittent adolescent MDMA administration and attenuates MDMA-induced hyperthermia and neurotoxicity in rats SO NEUROPHARMACOLOGY LA English DT Article DE MDMA; THC; Behavior; Neurotoxicity ID ECSTASY MDMA; ADULT RATS; BODY-TEMPERATURE; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; AMBIENT-TEMPERATURE; INCREASED ANXIETY; COLLEGE-STUDENTS; CB1 RECEPTORS; POLYDRUG USE; HOLE-BOARD AB Most recreational users of 3, 4-methylenedioxymethamphetamine (MDMA or "ecstasy") also take cannabis, in part because cannabis can reduce the dysphoric symptoms of the ecstasy come-down such as agitation and insomnia. Although previous animal studies have examined the acute effects of co-administering MDMA and Delta(9)-tetrahydrocannabinol (THC), which is the major psychoactive ingredient in cannabis, research on chronic exposure to this drug combination is lacking. Therefore, the present study was conducted to investigate the effects of chronic adolescent administration of both THC and MDMA on behavior and on regional serotonin transporter (SERT) binding and serotonin (5-HT) concentrations as indices of serotonergic system integrity. Male Sprague-Dawley rats were divided into four drug administration groups: (1) MDMA alone, (2) THC alone, (3) MDMA plus THC, and (4) vehicle controls. MDMA (2 x 10 mg/kg x 4 h) was administered every fifth day from postnatal day (PD) 35 to 60 to simulate intermittent recreational ecstasy use, whereas THC (5 mg/kg) was given once daily over the same time period to simulate heavy cannabis use. THC unexpectedly produced a modest hyperthermic effect when administered alone, but in animals co-treated with both THC and MDMA, there was an attenuation of MDMA-induced hyperthermia on dosing days. Subsequent testing conducted after a drug washout period revealed that THC reduced MDMA-related behavioral changes in the emergence and social interaction tests of anxiety-like behavior and also blunted the MDMA-induced decrease in exploratory behavior in the hole-board test. THC additionally attenuated MDMA -induced decreases in 5-HT levels and in SERT binding in the frontal cortex, parietal cortex, and striatum, but not in the hippocampus. These results suggest that chronic co-administration of THC during adolescence can provide some protection against various adverse physiological, behavioral, and neurochemical effects produced by MDMA. Published by Elsevier Ltd. C1 [Shen, Erica Y.; Meyer, Jerrold S.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. [Shen, Erica Y.; Meyer, Jerrold S.] Univ Massachusetts, Neurosci & Behav Program, Amherst, MA 01003 USA. [Ali, Syed F.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Shen, EY (reprint author), Univ Massachusetts, Dept Psychol, Tobin Hall, Amherst, MA 01003 USA. EM yshen@cns.umass.edu OI Meyer, Jerrold/0000-0002-8382-7075 FU NIDA [R03 DA025839]; NIMH [5T32 MH020051] FX Animal care was provided by Pinnie Sears. Animal behaviors were coded by Thomas R. Barnes, China N. Byrns, Erin S. Calipari, Frederico S. Fernandes, Jamie S. Richmond, Christopher D. Sacco and Alex J. Weiner. MDMA and THC were provided by the NIDA Drug Supply Program. This research was supported by NIDA grant R03 DA025839 to Dr. Jerrold S. Meyer. Erica Y. Shen was supported by NIMH training grant 5T32 MH020051. NR 67 TC 11 Z9 11 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD DEC PY 2011 VL 61 IS 8 BP 1183 EP 1192 DI 10.1016/j.neuropharm.2011.07.002 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 848VB UT WOS:000297082100001 PM 21763331 ER PT J AU Lee, KW Li, GX Lillehoj, HS Lee, SH Jang, SI Babu, US Lillehoj, EP Neumann, AP Siragusa, GR AF Lee, Kyung-Woo Li, Guangxing Lillehoj, Hyun S. Lee, Sung-Hyen Jang, Seung I. Babu, Uma S. Lillehoj, Erik P. Neumann, Anthony P. Siragusa, Gregory R. TI Bacillus subtilis-based direct-fed microbials augment macrophage function in broiler chickens SO RESEARCH IN VETERINARY SCIENCE LA English DT Article DE Direct-fed microbials; Innate immunity; Macrophage; Nitric oxide; Phagocytosis AB The present study was conducted to evaluate the function of Bacillus subtilis-based direct-fed microbials (DFMs) on macrophage functions, i.e., nitric oxide (NO) production and phagocytosis in broiler chickens. DFMs used in this study were eight single strains designated as Bs2084, LSSAO1, 3AP4, Bs18, 15AP4, 22CP1, Bs27, and Bs278, and one multiple strain DFM product (Avicorr(TM)) containing equal amount of Bs2084, LSSAO1 and 15AP4. NO concentrations were monitored in plasma and in the supernatants from the peripheral blood-derived monocytic cells (PBMC)-derived macrophages stimulated by either chicken recombinant interferon gamma (IFN gamma) or lipopolysaccharide (LPS) from Escherichia coil or Salmonella typhi. In addition, phagocytosis of fluorescent beads and green fluorescent protein (CFP)-labeled Salmonella by PBMC-derived macrophage was assayed. Plasma NO levels were significantly higher in groups given 3AP4 or Bs27 diets compared with the control group at days 7 and 14. NO production by PBMC-derived macrophages stimulated with IFN gamma or LPS was apparent, although the effect was strain-dependent. Phagocytosis of fluorescent beads or CFP-labeled Salmonella by macrophages was augmented in groups on DFM-supplemented diets compared with those fed the control diet. This study describes the immunomodulatory effects of Bacillus-based DFMs on innate immunity in broiler chickens. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Lee, Kyung-Woo; Li, Guangxing; Lillehoj, Hyun S.; Lee, Sung-Hyen; Jang, Seung I.] ARS, Anim Parasit Dis Lab, Anim & Nat Resources Inst, USDA, Beltsville, MD 20705 USA. [Babu, Uma S.] US FDA, Immunobiol Branch, Div Virulence Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Lillehoj, Erik P.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Neumann, Anthony P.; Siragusa, Gregory R.] Danisco Agtech Prod Inc, Waukesha, WI 53186 USA. [Li, Guangxing] Northeast Agr Univ, Coll Vet Med, Harbin 150030, Peoples R China. RP Lillehoj, HS (reprint author), ARS, Anim Parasit Dis Lab, Anim & Nat Resources Inst, USDA, Beltsville, MD 20705 USA. EM Hyun.Lillehoj@ARS.USDA.GOV OI Lee, Kyung-Woo/0000-0002-3533-7979 FU ARS-USDA; Danisco; ARS [1265-32000-086-00D] FX This project was supported by a Trust agreement established between ARS-USDA and Danisco and partially by the ARS in-house project 1265-32000-086-00D. We thank Marjorie Nichols and Stacy Torreyson for their technical assistance. Guangxing Li was a short-term overseas visiting scholar of the China Scholarship Council to Animal Parasitic Diseases Laboratory, ANRI, USDA-ARS from Northeast Agricultural University, Harbin, PR China. NR 34 TC 8 Z9 9 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0034-5288 EI 1532-2661 J9 RES VET SCI JI Res. Vet. Sci. PD DEC PY 2011 VL 91 IS 3 BP E87 EP E91 DI 10.1016/j.rvsc.2011.01.018 PG 5 WC Veterinary Sciences SC Veterinary Sciences GA V40ML UT WOS:000209482600016 PM 21338997 ER PT J AU Nakamura, N AF Nakamura, Noriko TI Reduced aldehyde dehydrogenase activity and arginine vasopressin receptor 2 expression in the kidneys of male TALLYHO/JngJ mice of prediabetic age SO ENDOCRINE LA English DT Article DE Aldehyde dehydrogenase activity; TALLYHO/JngJ mice; Arginine vasopressin receptor 2; Kidney; Swr/J mice ID NEPHROGENIC DIABETES-INSIPIDUS; ANIMAL-MODELS; X-CHROMOSOME; MOUSE MODELS; UREA LEVEL; APOPTOSIS; MELLITUS; ENZYMES; STRESS; LEARN AB The TALLYHO/JngJ (TH) mouse is a novel polygenic model of type 2 diabetes and exhibits obesity, hyperglycemia (males), hyperinsulinemia, hyperlipidemia, and enlarged pancreatic islets. Since the kidney is damaged by hyperglycemia in other animal models, the present study aimed to determine the kidney phenotype of TH mice using immunoblot and histological analyses of the kidneys of 6-week-old (prediabetic) and 16-week-old TH mice. Interestingly, even 6-week-old male TH mice showed significant increases in kidney weight, compared to C57BL/B6 (B6) mice. Cuboidal parietal epithelium was observed in the Bowman's capsule in male TH mice at the prediabetic age. Water accumulated inside the kidneys of male TH mice in an age-dependent manner, but not in B6 mice. Since Swr/J mice are reported to develop diabetes insipidus and share 86.8% genotype homology with TH mice, the expression level of arginine vasopressin receptor 2 (AVPR2), a candidate protein for diabetes insipidus, was examined and determined to be significantly reduced in the kidneys of prediabetic male TH mice, compared to B6 mice. Aldehyde dehydrogenase (ALDH) activity in the kidneys of prediabetic male TH mice was significantly lower than that in age-matched male B6 mice, while there were no differences between female TH and B6 mice. These results suggest that the kidney phenotype of prediabetic TH mice occurs only in males, accompanied by a reduction in ALDH activity and AVPR2 expression. The kidney phenotype of male TH mice at a prediabetic age becomes evident before the onset of diabetes. C1 [Nakamura, Noriko] Marshall Univ, Dept Pharmacol Physiol & Toxicol, Joan C Edwards Sch Med, Huntington, WV 25755 USA. RP Nakamura, N (reprint author), US FDA, Natl Ctr Toxicol Res, Div Personalized Nutr & Med, Jefferson, AR 72079 USA. EM Noriko.Nakamura@fda.hhs.gov NR 32 TC 3 Z9 3 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1355-008X J9 ENDOCRINE JI Endocrine PD DEC PY 2011 VL 40 IS 3 BP 379 EP 385 DI 10.1007/s12020-011-9528-4 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 844YA UT WOS:000296788000007 PM 21879339 ER PT J AU Khurana, S Sasono, P Fox, A Kinh, NV Mai, LQ Thai, PQ Hien, NT Liem, NT Horby, P Golding, H AF Khurana, Surender Sasono, Pretty Fox, Annette Nguyen Van Kinh Le Quynh Mai Pham Quang Thai Nguyen Tran Hien Nguyen Thanh Liem Horby, Peter Golding, Hana TI H5N1-SeroDetect EIA and Rapid Test: a Novel Differential Diagnostic Assay for Serodiagnosis of H5N1 Infections and Surveillance SO JOURNAL OF VIROLOGY LA English DT Article ID AVIAN INFLUENZA-VIRUS; ANTIBODY-RESPONSE; STRIP TEST; VACCINE; CHINA; EVOLUTION; MULTIPLE; SUBTYPE; PROTEIN; PB1-F2 AB Continuing evolution of highly pathogenic (HP) H5N1 influenza viruses in wild birds with transmission to domestic poultry and humans poses a pandemic threat. There is an urgent need for a simple and rapid serological diagnostic assay which can differentiate between antibodies to seasonal and H5N1 strains and that could provide surveillance tools not dependent on virus isolation and nucleic acid technologies. Here we describe the establishment of H5N1 SeroDetect enzyme-linked immunosorbent assay (ELISA) and rapid test assays based on three peptides in HA2 (488-516), PB1-F2 (2-75), and M2e (2-24) that are highly conserved within H5N1 strains. These peptides were identified by antibody repertoire analyses of H5N1 influenza survivors in Vietnam using whole-genome-fragment phage display libraries (GFPDLs). To date, both platforms have demonstrated high levels of sensitivity and specificity in detecting H5N1 infections (clade 1 and clade 2.3.4) in Vietnamese patients as early as 7 days and up to several years postinfection. H5N1 virus-uninfected individuals in Vietnam and the United States, including subjects vaccinated with seasonal influenza vaccines or with confirmed seasonal virus infections, did not react in the H5N1-SeroDetect assays. Moreover, sera from individuals vaccinated with H5N1 subunit vaccine with moderate anti-H5N1 neutralizing antibody titers did not react positively in the H5N1-SeroDetect ELISA or rapid test assays. The simple H5N1-SeroDetect ELISA and rapid tests could provide an important tool for large-scale surveillance for potential exposure to HP H5N1 strains in both humans and birds. C1 [Khurana, Surender; Golding, Hana] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20892 USA. [Sasono, Pretty] Natl Inst Hlth Res & Dev, Jakarta, Indonesia. [Fox, Annette; Horby, Peter] Wellcome Trust Major Overeas Program Oxford Univ, Hanoi, Vietnam. [Nguyen Van Kinh] Natl Hosp Trop Dis, Hanoi, Vietnam. [Le Quynh Mai; Pham Quang Thai; Nguyen Tran Hien] Natl Inst Hyg & Epidemiol, Hanoi, Vietnam. [Nguyen Thanh Liem] Natl Hosp Pediat, Hanoi, Vietnam. RP Khurana, S (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bldg 29B,Rm 4NN02,8800 Rockville Pike, Bethesda, MD 20892 USA. EM surender.khurana@fda.hhs.gov RI Horby, Peter/D-1585-2013; OI Horby, Peter/0000-0002-9822-1586 NR 29 TC 6 Z9 7 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2011 VL 85 IS 23 BP 12455 EP 12463 DI 10.1128/JVI.06023-11 PG 9 WC Virology SC Virology GA 843WU UT WOS:000296708100032 PM 21957281 ER PT J AU Keene, AM Allaway, RJ Sadrieh, N Tyner, KM AF Keene, Athena M. Allaway, Robert J. Sadrieh, Nakissa Tyner, Katherine M. TI Gold nanoparticle trafficking of typically excluded compounds across the cell membrane in JB6 C1 41-5a cells causes assay interference SO NANOTOXICOLOGY LA English DT Article DE Nanoparticles; nano-surfaces ID TOXICITY AB Nanoparticles (NP) often interfere with the mechanism and interpretation of high throughput in vitro toxicity assays. This interference may occur at any time during the assay and spans most NP systems. This study reports on a specific type of gold NP assay interference, where unmodified gold NPs were able to traffic certain assay molecules that contained primary amines across the cell membrane resulting in false positive results for toxicity assays. The enhanced assay molecule permeability was eliminated when the gold NP surface was both sterically and chemically blocked by polyethylene glycol (PEG). The results support the growing consensus that appropriate controls and assay validation should occur prior to interpretation of results of assays using NP. C1 [Keene, Athena M.; Allaway, Robert J.; Sadrieh, Nakissa; Tyner, Katherine M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Tyner, KM (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM katherine.tyner@fda.hhs.gov NR 17 TC 8 Z9 8 U1 0 U2 4 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1743-5390 J9 NANOTOXICOLOGY JI Nanotoxicology PD DEC PY 2011 VL 5 IS 4 BP 469 EP 478 DI 10.3109/17435390.2010.533792 PG 10 WC Nanoscience & Nanotechnology; Toxicology SC Science & Technology - Other Topics; Toxicology GA 842WS UT WOS:000296633100002 PM 21090919 ER PT J AU Trickler, WJ Lantz, SM Murdock, RC Schrand, AM Robinson, BL Newport, GD Schlager, JJ Oldenburg, SJ Paule, MG Slikker, W Hussain, SM Ali, SF AF Trickler, William J. Lantz, Susan M. Murdock, Richard C. Schrand, Amanda M. Robinson, Bonnie L. Newport, Glenn D. Schlager, John J. Oldenburg, Steven J. Paule, Merle G. Slikker, William, Jr. Hussain, Saber M. Ali, Syed F. TI Brain microvessel endothelial cells responses to gold nanoparticles: In vitro pro-inflammatory mediators and permeability SO NANOTOXICOLOGY LA English DT Article DE Blood-brain-barrier; neuroinflammation; gold nanoparticles; brain microvessel endothelial cells; neurotoxicity ID NECROSIS-FACTOR-ALPHA; BARRIER PERMEABILITY; PARTICLE-SIZE; RAT-BRAIN; TNF-ALPHA; EXPOSURE; MODEL; TRANSPORT; INCREASES; COMPLEXES AB This report examined blood-brain barrier (BBB) related proinflammatory mediators and permeability changes in response to various sized gold nanoparticles (Au-NPs) (3, 5, 7, 10, 30 and 60 nm) in vitro using primary rat brain microvessel endothelial cells (rBMEC). The Au-NPs were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and laser Doppler velocimetry (LDV). The accumulation of Au-NPs was determined spectrophotometrically. The rBMEC cytotoxicity of Au-NPs was evaluated by cell proliferation assay (XTT) (concentration range 0.24-15.63 mu g/cm(2), for 24 h). The time-dependent changes (0, 2, 4 and 8 h) of several proinflammatory mediators (IL-1 beta, IL-2, TNF alpha and PGE(2)) were evaluated by ELISA. The smaller Au-NPs (3-7 nm) showed higher rBMEC accumulation compared to larger Au-NPs (10-60 nm), while only moderate decreased cell viability was observed with small Au-NPs (3 nm) at high concentrations (>= 7.8 mu g/cm(2)). Even though slight changes in cell viability were observed with small Au-NPs, the basal levels of the various proinflammatory mediators remained unchanged with all treatments except LPS (positive control). rBMEC morphology appeared unaffected 24 h after exposure to Au-NPs with only mild changes in fluorescein permeability indicating BBB integrity was unaltered. Together, these data suggest the responses of the cerebral microvasculature to Au-NPs have a significant relationship with the Au-NPs unique size-dependent physiochemical properties. C1 [Trickler, William J.; Lantz, Susan M.; Robinson, Bonnie L.; Newport, Glenn D.; Paule, Merle G.; Slikker, William, Jr.; Ali, Syed F.] Natl Ctr Toxicol Res FDA, Div Neurotoxicol, Neurochem Lab, Jefferson, AR 72079 USA. [Murdock, Richard C.; Schrand, Amanda M.; Schlager, John J.; Hussain, Saber M.] USAF, Appl Biotechnol Branch, Human Effectiveness Directorate, Res Lab, Wright Patterson AFB, OH 45433 USA. [Oldenburg, Steven J.] NanoComposix Inc, San Diego, CA USA. RP Ali, SF (reprint author), Natl Ctr Toxicol Res FDA, Div Neurotoxicol, Neurochem Lab, HFT 132,3900 NCTR Rd, Jefferson, AR 72079 USA. EM syed.ali@fda.hhs.gov FU U. S. Air Force Research Laboratory at the National Center for Toxicological Research/FDA; U. S. Department of Energy, U. S. Air Force Research Laboratory/RHPB; U. S. Food and Drug Administration/NCTR FX This research was supported in part by an appointment to the Postgraduate Research Participation Program with the U. S. Air Force Research Laboratory at the National Center for Toxicological Research/FDA (Jefferson, AR) administered by the Oak Ridge Institute of Science and Education (Oak Ridge, TN) through an interagency agreement between U. S. Department of Energy, U. S. Air Force Research Laboratory/RHPB and the U. S. Food and Drug Administration/NCTR. NR 36 TC 19 Z9 20 U1 0 U2 8 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1743-5390 J9 NANOTOXICOLOGY JI Nanotoxicology PD DEC PY 2011 VL 5 IS 4 BP 479 EP 492 DI 10.3109/17435390.2010.540356 PG 14 WC Nanoscience & Nanotechnology; Toxicology SC Science & Technology - Other Topics; Toxicology GA 842WS UT WOS:000296633100003 PM 21175299 ER EF