Sample records for aasld-fda-nih-phrma hepatotoxicity steering

  1. The 2002 PhRMA Code and Pharmaceutical Marketing: did anybody bother to ask the reps?

    PubMed

    Sillup, George P; Trombetta, Bill; Klimberg, Ronald

    2010-10-01

    After marketing tactics resulted in $1.2 billion fines, the 2002 PhRMA Code attempted to standardize marketing and sales practices. Self-regulation had varied success by other industries and by pharmaceutical industries in other countries. Similarly, the Code addressed negative responses about pharmaceutical's practices but had no provisions for monitoring violations. Representative's (reps) perspectives were assessed using an 18-item instrument with 72 reps from 25 companies. Analyses indicated that reps from bigger companies, PhRMA and non-PhRMA, adhered better. The way reps adhered was split between adhering reluctantly and following faithfully. Two thirds felt it was more difficult to do their jobs, resulting from prior entertainment-based relationships with physicians.

  2. Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA-PWG-PhRMA-DruSafe Workshop.

    PubMed

    Lesko, Lawrence J; Salerno, Ronald A; Spear, Brian B; Anderson, Donald C; Anderson, Timothy; Brazell, Celia; Collins, Jerry; Dorner, Andrew; Essayan, David; Gomez-Mancilla, Baltazar; Hackett, Joseph; Huang, Shiew-Mei; Ide, Susan; Killinger, Joanne; Leighton, John; Mansfield, Elizabeth; Meyer, Robert; Ryan, Stephen G; Schmith, Virginia; Shaw, Peter; Sistare, Frank; Watson, Mark; Worobec, Alexandra

    2003-04-01

    The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory "safe harbor" for exploratory genome-based data, and to provide a forum for industry-regulatory agency dialogue on these important issues.

  3. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience.

    PubMed

    Goldkind, Lawrence; Laine, Loren

    2006-04-01

    Drug-induced hepatotoxicity is the leading cause of acute liver failure (ALF) in the US and the most common adverse event causing drug non-approval and drug withdrawal by the U.S. Food and Drug Administration (FDA). Three different nonsteroidal anti-inflammatory drugs (NSAIDs) have been withdrawn in the UK and/or the US due to hepatotoxicity (bromfenac, ibufenac, and benoxaprofen). A systematic review of clinical trials data for these drugs was performed in an effort to identify possible early signals that could have predicted post-marketing serious hepatoxicity. There were very limited published data on benoxaprofen and none on ibufenac or bromfenac. The publicly accessible archives of the FDA provided information on bromfenac. Flu-like symptoms associated with hepatic enzyme elevation and a case of possible drug-related hepatocellular jaundice may in retrospect have been signals for serious hepatotoxicity in the database of 1195 subjects reviewed by the FDA. Following approval, rates of acute liver failure for bromfenac were estimated to be in the range of 1:10 000. In addition, the safety databases of several drugs also accessed through FDA archives have been reviewed (simvastatin, tacrine, troglitazone, and ximelagatran). These data suggest that while ALT elevations alone do not reliably signal serious hepatotoxicity, elevated transaminases in association with symptomatic hepatitis or jaundice may be predictors of an increased risk of ALF. At present, however, pre-approval databases are generally not large enough to rule out low rates of serious hepatotoxicity. Therefore, it remains critical that clinicians report such cases to the FDA through the MEDWATCH system and that active post-marketing monitoring studies be used to identify potential rare cases of hepatotoxicity. Copyright (c) 2006 John Wiley & Sons, Ltd.

  4. Budgets up at NIH, NCI, and FDA.

    PubMed

    2014-03-01

    The federal budget for 2014, signed into law by President Obama in January, increases funding for the NIH, National Cancer Institute, and U.S. Food and Drug Administration, but it doesn't fully cover the losses they sustained collectively in 2013 due to sequestration.

  5. Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges.

    PubMed

    Senior, John R

    2014-11-01

    Prompted by approval in 1997 of troglitazone and bromfenac, two drugs that promptly began to show serious and sometimes fatal liver toxicity, we began at the Food and Drug Administration (FDA) a series of annual conferences in 1999 to consider issues of drug-induced liver injury (DILI). First inviting reviewers of new drug applications we opened the audiences in 2001 to pharmaceutical industry and academic consultants to industry and FDA, and slides shown at the meetings were posted on the internet to be available at the website of the American Association for the Study of Liver Diseases (AASLD)-go to ( http://www.aasld.org/dili/Pages/default.aspx ). Observations by Dr. Hyman J. Zimmerman that "drug-induced hepatocellular jaundice is a serious lesion" with possible mortality formed a basis for developing a computer program to plot peak serum values for alanine aminotransferase (ALT) and total bilirubin (TBL) in an x-y log-log graph for all subjects enrolled in clinical trials. This program had the capability to show the time course of all liver tests for individuals who had both hepatocellular injury and reduced whole liver function, plus clinical narratives to diagnose the severity and most likely cause of the abnormalities. We called the program eDISH (for evaluation of Drug-Induced Serious Hepatotoxicity), and began in 2004 to use it to assess DILI in clinical trial subjects. From 2008, comments made by the presenters at the conferences about their slides and ensuing discussions have been added to the website. All this has raised awareness of the problem, and since 1997, the FDA has not had to withdraw a single drug because of post-marketing hepatotoxicity. Many issues still remain to be resolved; among the most controversial is the best method to estimate likelihood that a given liver injury was actually caused by the drug in question. On November 9, 2012, a workshop was convened to discuss the best practices for the assessment of drug-induced liver injury

  6. Hepatotoxicity by Drugs: The Most Common Implicated Agents

    PubMed Central

    Björnsson, Einar S.

    2016-01-01

    Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab. PMID:26861310

  7. What is prescription labeling communicating to doctors about hepatotoxic drugs? A study of FDA approved product labeling.

    PubMed

    Willy, Mary E; Li, Zili

    2004-04-01

    The objective of this study was to evaluate the informativeness and consistency of product labeling of hepatotoxic drugs marketed in the United States. We searched the Physicians' Desk Reference-2000 for prescription drugs with hepatic failure and/or hepatic necrosis listed in the labeling. We used a six-item checklist to evaluate the 'informativeness' and consistency of the labeling content. An informativeness score equaled the proportion of checklist items present in each drug's labeling. Ninety-five prescription drugs were included in the study. Eleven (12%) of the drugs had information related to hepatic failure in a Black Boxed Warning, 52 (54%) in the Warnings section and 32 (34%) in the Adverse Reactions section of the label. The mean informativeness score was 35%; the score was significantly higher, 61%, when the risk was perceived to be high. The informativeness of labeling was not affected by the time of the labeling, but differed across the Center for Drug Evaluation and Research (CDER) Review Division responsible for the labeling. The information provided in labeling is variable and affected by many factors, including the perceived level of risk and review division strategy. Product labeling may benefit from current FDA initiatives to improve the consistency of risk-related labeling.

  8. Challenges and opportunities in RSV vaccine development: Meeting report from FDA/NIH workshop.

    PubMed

    Roberts, Jeffrey N; Graham, Barney S; Karron, Ruth A; Munoz, Flor M; Falsey, Ann R; Anderson, Larry J; Marshall, V; Kim, Sonnie; Beeler, Judy A

    2016-09-22

    Respiratory syncytial virus (RSV) is the most common cause of serious acute lower respiratory illness in infants and young children and a significant cause of disease burden in the elderly and immunocompromised. There are no licensed RSV vaccines to address this significant public health need. While advances in vaccine technologies have led to a recent resurgence in RSV vaccine development, the immune correlates of protection against RSV and the immunology of vaccine-associated enhanced respiratory disease (ERD) remain poorly understood. FDA's Center for Biologics Evaluation and Research (CBER) and NIH's National Institute of Allergy and Infectious Diseases (NIAID) organized and co-sponsored an RSV Vaccines Workshop in Bethesda, Maryland on June 1 and 2, 2015. The goal of the conference was to convene scientists, regulators, and industry stakeholders to discuss approaches to RSV vaccine development within the context of three target populations - infants and children, pregnant women, and individuals >60years of age. The agenda included topics related to RSV vaccine development in general, as well as considerations specific to each target population, such as clinical and serological endpoints. The meeting focused on vaccine development for high income countries (HIC), because issues relevant to vaccine development for low and middle income countries (LMIC) have been discussed in other forums. This manuscript summarizes the discussion of clinical, scientific, and regulatory perspectives, research gaps, and lessons learned. Copyright © 2016.

  9. Committee approves bill to boost NIH funding.

    PubMed

    2015-08-01

    A U.S. House of Representatives committee approved the 21st Century Cures Act. If passed by Congress, the bill would boost funding for the NIH and FDA and introduce new strategies for accelerating the approval of drugs and devices. ©2015 American Association for Cancer Research.

  10. Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States

    PubMed Central

    Avigan, Mark I.; Mozersky, Robert P.; Seeff, Leonard B.

    2016-01-01

    In the United States (US), the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA) as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized. PMID:26950122

  11. Effects of 31 FDA approved small-molecule kinase inhibitors on isolated rat liver mitochondria.

    PubMed

    Zhang, Jun; Salminen, Alec; Yang, Xi; Luo, Yong; Wu, Qiangen; White, Matthew; Greenhaw, James; Ren, Lijun; Bryant, Matthew; Salminen, William; Papoian, Thomas; Mattes, William; Shi, Qiang

    2017-08-01

    The FDA has approved 31 small-molecule kinase inhibitors (KIs) for human use as of November 2016, with six having black box warnings for hepatotoxicity (BBW-H) in product labeling. The precise mechanisms and risk factors for KI-induced hepatotoxicity are poorly understood. Here, the 31 KIs were tested in isolated rat liver mitochondria, an in vitro system recently proposed to be a useful tool to predict drug-induced hepatotoxicity in humans. The KIs were incubated with mitochondria or submitochondrial particles at concentrations ranging from therapeutic maximal blood concentrations (Cmax) levels to 100-fold Cmax levels. Ten endpoints were measured, including oxygen consumption rate, inner membrane potential, cytochrome c release, swelling, reactive oxygen species, and individual respiratory chain complex (I-V) activities. Of the 31 KIs examined only three including sorafenib, regorafenib and pazopanib, all of which are hepatotoxic, caused significant mitochondrial toxicity at concentrations equal to the Cmax, indicating that mitochondrial toxicity likely contributes to the pathogenesis of hepatotoxicity associated with these KIs. At concentrations equal to 100-fold Cmax, 18 KIs were found to be toxic to mitochondria, and among six KIs with BBW-H, mitochondrial injury was induced by regorafenib, lapatinib, idelalisib, and pazopanib, but not ponatinib, or sunitinib. Mitochondrial liability at 100-fold Cmax had a positive predictive power (PPV) of 72% and negative predictive power (NPV) of 33% in predicting human KI hepatotoxicity as defined by product labeling, with the sensitivity and specificity being 62% and 44%, respectively. Similar predictive power was obtained using the criterion of Cmax ≥1.1 µM or daily dose ≥100 mg. Mitochondrial liability at 1-2.5-fold Cmax showed a 100% PPV and specificity, though the NPV and sensitivity were 32% and 14%, respectively. These data provide novel mechanistic insights into KI hepatotoxicity and indicate that

  12. Drugs@FDA: FDA Approved Drug Products

    MedlinePlus

    ... Cosmetics Tobacco Products Home Drug Databases Drugs@FDA Drugs@FDA: FDA Approved Drug Products Share Tweet Linkedin Pin it More sharing ... Download Drugs@FDA Express for free Search by Drug Name, Active Ingredient, or Application Number Enter at ...

  13. Review article: Herbal hepatotoxicity--an update on traditional Chinese medicine preparations.

    PubMed

    Teschke, R; Wolff, A; Frenzel, C; Schulze, J

    2014-07-01

    Although evidence for their therapeutic efficacy is limited, herbal traditional Chinese medicine (TCM) preparations increasingly gain popularity. In contrast to other herbal products, adverse effects by herbal TCM including liver toxicity were rarely reported. In recent years, more cases were published, providing new clinical challenges. To summarise comprehensively the literature on herbal TCM hepatotoxicity since 2011. PubMed was searched using key words related to TCM, the results were restricted to full English-language publications and abstracts published since 2011. In addition, the database of the National Institutes of Health (NIH) and LiverTox was accessed under the topic 'Drug record: Chinese and other Asian herbal medicines'. Since 2011, new case reports and case series provided evidence for herbal hepatotoxicity by TCM, focusing on nine TCM herbal mixtures and four individual TCM herbs with potential health hazards. These were the TCM products Ban Tu Wan, Chai Hu, Du Huo, Huang Qin, Jia Wei Xia Yao San, Jiguja, Kamishoyosan, Long Dan Xie Gan Tang, Lu Cha, Polygonum multiflorum products, Shan Chi, 'White flood' containing the herbal TCM Wu Zhu Yu and Qian Ceng Ta, and Xiao Chai Hu Tang. Other developments include the establishment of a new and early diagnostic serum marker for hepatotoxicity caused by pyrrolizidine alkaloids, assessed using ultra performance liquid chromatography-mass spectrometry analysis, and new regulatory details to improve herbal TCM product quality and safety. Stringent evaluation of the risk/benefit ratio is essential to protect traditional Chinese medicines users from health hazards including liver injury. © 2014 John Wiley & Sons Ltd.

  14. Hydrazine inhalation hepatotoxicity.

    PubMed

    Kao, Yung Hsiang; Chong, C H; Ng, W T; Lim, D

    2007-10-01

    Abstract Hydrazine is a hazardous chemical commonly used as a reactant in rocket and jet fuel cells. Animal studies have demonstrated hepatic changes after hydrazine inhalation. Human case reports of hydrazine inhalation hepatotoxicity are rare. We report a case of mild hepatotoxicity following brief hydrazine vapour inhalation in a healthy young man, which resolved completely on expectant management.

  15. Tobramycin-induced hepatotoxicity.

    PubMed

    Nisly, Sarah A; Ray, Shaunta' M; Moye, Robert A

    2007-12-01

    To report a case of tobramycin-induced hepatotoxicity. A 20-year-old female was hospitalized for treatment of Pseudomonas aeruginosa bacteremia and osteomyelitis. Empiric intravenous antibiotic therapy with piperacillin/tazobactam, vancomycin, and ciprofloxacin was started, and based on the results of culture and sensitivity testing, was changed to intravenous ceftazidime and tobramycin 70 mg every 8 hours on hospital day 3. Liver enzyme levels then increased over days 3-6. Tests for hepatitis A, B, and C were all nonreactive, and HIV testing was negative. On day 8, therapy was changed from ceftazidime to piperacillin/tazobactam and the tobramycin dose was increased to 100 mg every 8 hours. Due to a continued increase in total bilirubin, aspartate aminotransferase, and alanine aminotransferase, piperacillin/tazobactam was discontinued and aztreonam was started on day 10. All antibiotics were stopped on day 12 and the elevated liver parameters began to decrease. Aztreonam and ciprofloxacin were restarted on day 16, and most laboratory test results returned to baseline levels by day 19; total bilirubin and alkaline phosphatase decreased to lower than baseline values. This case illustrates a possible occurrence of tobramycin-induced hepatotoxicity. Liver enzymes rose when tobramycin therapy was initiated, markedly increased when the tobramycin dose was increased, then resolved upon discontinuation of therapy. Other medication-related causes were ruled out by temporal relationship or rechallenge (aztreonam). Use of the Naranjo probability scale indicated a possible relationship between hepatotoxicity and tobramycin therapy. Other adverse reaction scales specific for evaluation of drug-induced liver disease were also used. Both the Council for International Organizations of Medical Sciences and Maria and Victorino scales indicated a probable likelihood of tobramycin-induced hepatotoxicity. This patient was not rechallenged with tobramycin due to the highly suggestive

  16. Botanicals and Hepatotoxicity.

    PubMed

    Roytman, Marina M; Poerzgen, Peter; Navarro, Victor

    2018-06-19

    The use of botanicals, often in the form of multi-ingredient herbal dietary supplements (HDS), has grown tremendously in the past three decades despite their unproven efficacy. This is paralleled by an increase in dietary supplement-related health complications, notably hepatotoxicity. This article reviews the demographics and motivations of dietary supplement (DS) consumers and the regulatory framework for DS in the US and other developed countries. It examines in detail three groups of multi-ingredient HDS associated with hepatotoxicity: OxyElite Pro (two formulations), green tea extract-based DS, and "designer anabolic steroids." These examples illustrate the difficulties in identifying and adjudicating causality of suspect compound(s) of multi-ingredient HDS-associated liver injury in the clinical setting. The article outlines future directions for further study of HDS-associated hepatotoxicity as well as measures to safeguard the consumer against it. © 2018, The American Society for Clinical Pharmacology and Therapeutics.

  17. Herbal hepatotoxicity and WHO global introspection method.

    PubMed

    Teschke, Rolf; Eickhoff, Axel; Wolff, Albrecht; Frenzel, Christian; Schulze, Johannes

    2013-01-01

    Herbal hepatotoxicity is a rare but highly disputed disease because numerous confounding variables may complicate accurate causality assessment. Case evaluation is even more difficult when the WHO global introspection method (WHO method) is applied as diagnostic algorithm. This method lacks liver specificity, hepatotoxicity validation, and quantitative items, basic qualifications required for a sound evaluation of hepatotoxicity cases. Consequently, there are no data available for reliability, sensitivity, specificity, positive and negative predictive value. Its scope is also limited by the fact that it cannot discriminate between a positive and a negative causality attribution, thereby stimulating case overdiagnosing and overreporting. The WHO method ignores uncertainties regarding daily dose, temporal association, start, duration, and end of herbal use, time to onset of the adverse reaction, and course of liver values after herb discontinuation. Insufficiently considered or ignored are comedications, preexisting liver diseases, alternative explanations upon clinical assessment, and exclusion of infections by hepatitis A-C, cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and varicella zoster virus (VZV). We clearly prefer as alternative the scale of CIOMS (Council for International Organizations of Medical Sciences) which is structured, quantitative, liver specific, and validated for hepatotoxicity. In conclusion, causality of herbal hepatotoxicity is best assessed by the liver specific CIOMS scale validated for hepatotoxicity rather than the obsolete WHO method that is liver unspecific and not validated for hepatotoxicity. CIOMS based assessments will ensure the correct diagnosis and exclude alternative diagnosis that may require other specific therapies.

  18. Review article: herbal and dietary supplement hepatotoxicity.

    PubMed

    Bunchorntavakul, C; Reddy, K R

    2013-01-01

    Herbal and dietary supplements are commonly used throughout the World. There is a tendency for underreporting their ingestion by patients and the magnitude of their use is underrecognised by Physicians. Herbal hepatotoxicity is not uncommonly encountered, but the precise incidence and manifestations have not been well characterised. To review the epidemiology, presentation and diagnosis of herbal hepatotoxicity. This review will mainly discuss single ingredients and complex mixtures of herbs marketed under a single label. A Medline search was undertaken to identify relevant literature using search terms including 'herbal', 'herbs', 'dietary supplement', 'liver injury', 'hepatitis' and 'hepatotoxicity'. Furthermore, we scanned the reference lists of the primary and review articles to identify publications not retrieved by electronic searches. The incidence rates of herbal hepatotoxicity are largely unknown. The clinical presentation and severity can be highly variable, ranging from mild hepatitis to acute hepatic failure requiring transplantation. Scoring systems for the causality assessment of drug-induced liver injury may be helpful, but have not been validated for herbal hepatotoxicity. Hepatotoxicity features of commonly used herbal products, such as Ayurvedic and Chinese herbs, black cohosh, chaparral, germander, greater celandine, green tea, Herbalife, Hydroxycut, kava, pennyroyal, pyrrolizidine alkaloids, skullcap, and usnic acid, have been individually reviewed. Furthermore, clinically significant herb-drug interactions are also discussed. A number of herbal medicinal products are associated with a spectrum of hepatotoxicity events. Advances in the understanding of the pathogenesis and the risks involved are needed to improve herbal medicine safety. © 2012 Blackwell Publishing Ltd.

  19. Risk prediction of hepatotoxicity in paracetamol poisoning.

    PubMed

    Wong, Anselm; Graudins, Andis

    2017-09-01

    Paracetamol (acetaminophen) poisoning is the most common cause of acute liver failure in the developed world. A paracetamol treatment nomogram has been used for over four decades to help determine whether patients will develop hepatotoxicity without acetylcysteine treatment, and thus indicates those needing treatment. Despite this, a small proportion of patients still develop hepatotoxicity. More accurate risk predictors would be useful to increase the early detection of patients with the potential to develop hepatotoxicity despite acetylcysteine treatment. Similarly, there would be benefit in early identification of those with a low likelihood of developing hepatotoxicity, as this group may be safely treated with an abbreviated acetylcysteine regimen. To review the current literature related to risk prediction tools that can be used to identify patients at increased risk of hepatotoxicity. A systematic literature review was conducted using the search terms: "paracetamol" OR "acetaminophen" AND "overdose" OR "toxicity" OR "risk prediction rules" OR "hepatotoxicity" OR "psi parameter" OR "multiplication product" OR "half-life" OR "prothrombin time" OR "AST/ALT (aspartate transaminase/alanine transaminase)" OR "dose" OR "biomarkers" OR "nomogram". The search was limited to human studies without language restrictions, of Medline (1946 to May 2016), PubMed and EMBASE. Original articles pertaining to the theme were identified from January 1974 to May 2016. Of the 13,975 articles identified, 60 were relevant to the review. Paracetamol treatment nomograms: Paracetamol treatment nomograms have been used for decades to help decide the need for acetylcysteine, but rarely used to determine the risk of hepatotoxicity with treatment. Reported paracetamol dose and concentration: A dose ingestion >12 g or serum paracetamol concentration above the treatment thresholds on the paracetamol nomogram are associated with a greater risk of hepatotoxicity. Paracetamol elimination half

  20. Hepatotoxicity associated with choline magnesium trisalicylate: case report and review of salicylate-induced hepatotoxicity.

    PubMed

    Cersosimo, R J; Matthews, S J

    1987-01-01

    A case of a 21-year-old woman who had developed mild hepatotoxicity while receiving choline magnesium trisalicylate therapy is described. She presented with fever and mild hepatic enzyme elevations before salicylate therapy was instituted. Liver function tests (LFT) returned to normal within five days of hospitalization but she continued to develop daily fevers. Blood, urine, and throat cultures were negative. An acute viral illness or reactivation of systemic lupus erythematosus were the suspected diagnoses. Choline magnesium trisalicylate was then administered in an effort to control her fever, and was successful. After three days of salicylate therapy her LFT values began to rise. They continued to rise for five more days before salicylate hepatotoxicity was suspected. Choline magnesium trisalicylate was discontinued after eight days and the patient's LFT quickly returned to normal. The source of fever was never identified, although infection with cytomegalovirus was considered the most likely cause. Salicylate-induced hepatotoxicity is reviewed.

  1. Lipidomic profiling reveals protective function of fatty acid oxidation in cocaine-induced hepatotoxicity[S

    PubMed Central

    Shi, Xiaolei; Yao, Dan; Gosnell, Blake A.; Chen, Chi

    2012-01-01

    During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor α (PPARα)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury. PMID:22904346

  2. NIH on the web | NIH MedlinePlus the Magazine

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    Skip to main content NIH MedlinePlus the Magazine NIH MedlinePlus Salud Download the Current Issue PDF [3.1 mb] Trusted Health Information from the National Institutes of Health Home Current Issue ...

  3. NIH on the web | NIH MedlinePlus the Magazine

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    Skip to main content NIH MedlinePlus the Magazine NIH MedlinePlus Salud Download the Current Issue PDF [1.5 mb] Trusted Health Information from the National Institutes of Health Home Current Issue ...

  4. FDA Kids' Home Page

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  5. 2016 NIH Research Highlights | NIH MedlinePlus the Magazine

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    ... Research Highlights Follow us Breaking New Ground: NIH Research Highlights With NIH support, scientists across the U.S. ... confirming the long-term benefits of the therapy. Research to treat obesity in new ways Adults have ...

  6. One-way EPR steering and genuine multipartite EPR steering

    NASA Astrophysics Data System (ADS)

    He, Qiongyi; Reid, Margaret D.

    2012-11-01

    We propose criteria and experimental strategies to realise the Einstein-Podolsky-Rosen (EPR) steering nonlocality. One-way steering can be obtained where there is asymmetry of thermal noise on each system. We also present EPR steering inequalities that act as signatures and suggest how to optimise EPR correlations in specific schemes so that the genuine multipartite EPR steering nonlocality (EPR paradox) can also possibly be realised. The results presented here also apply to the spatially separated macroscopic atomic ensembles.

  7. Adrenergic modulation of hepatotoxicity.

    PubMed

    Roberts, S M; DeMott, R P; James, R C

    1997-01-01

    Summaries of the interactions caused by altering adrenoreceptor activity in conjunction with the administration of selected hepatotoxicants are provided in Table 2 and Fig. 1. These hepatotoxicants can be divided into two groups, one whose toxicity is increased by adrenergic agonist drugs (group I) and the other whose toxicity is decreased by adrenergic antagonists (group II). Group I includes carbon tetrachloride, acetaminophen, and methylphenidate. Perhaps the most remarkable aspect these chemicals have in common is the striking potentiation that occurs with cotreatment with certain adrenergic agonist drugs. For each of these, cotreatment with the appropriate adrenergic agent can result in massive hepatocellular necrosis from an otherwise nontoxic dose. In terms of the specific adrenoreceptors involved and mechanisms of potentiation, however, they have little in common. Potentiation of carbon tetrachloride hepatotoxicity appears to be mediated by alpha(2)-adrenoceptor stimulation, acetaminophen is potentiated by alpha(1)-adrenoreceptor agonists, and methylphenidate responds to beta(2)-adrenoreceptor stimulation. Studies of the potentiation of carbon tetrachloride and acetaminophen agree that the timing of adrenergic stimulation relative to the hepatotoxicant dose is critically important to the interaction but markedly different for these two toxicants. Acetaminophen was potentiated only when the adrenergic drug was administered as a 3-h pretreatment. This is apparently a consequence of a mechanism of potentiation that involves adrenergic depression of hepatic glutathione content and a requirement that peak effects on glutathione of both the adrenergic agent and acetaminophen be coincident. The mechanism of potentiation of carbon tetrachloride hepatotoxicity is uncertain but clearly does not involve hepatic glutathione content. In contrast to acetaminophen, adrenergic effects must occur within a time window a few hours after the carbon tetrachloride dose for

  8. Herbal hepatotoxicity: a tabular compilation of reported cases.

    PubMed

    Teschke, Rolf; Wolff, Albrecht; Frenzel, Christian; Schulze, Johannes; Eickhoff, Axel

    2012-11-01

    Herbal hepatotoxicity is a field that has rapidly grown over the last few years along with increased use of herbal products worldwide. To summarize the various facets of this disease, we undertook a literature search for herbs, herbal drugs and herbal supplements with reported cases of herbal hepatotoxicity. A selective literature search was performed to identify published case reports, spontaneous case reports, case series and review articles regarding herbal hepatotoxicity. A total of 185 publications were identified and the results compiled. They show 60 different herbs, herbal drugs and herbal supplements with reported potential hepatotoxicity, additional information including synonyms of individual herbs, botanical names and cross references are provided. If known, details are presented for specific ingredients and chemicals in herbal products, and for references with authors that can be matched to each herbal product and to its effect on the liver. Based on stringent causality assessment methods and/or positive re-exposure tests, causality was highly probable or probable for Ayurvedic herbs, Chaparral, Chinese herbal mixture, Germander, Greater Celandine, green tea, few Herbalife products, Jin Bu Huan, Kava, Ma Huang, Mistletoe, Senna, Syo Saiko To and Venencapsan(®). In many other publications, however, causality was not properly evaluated by a liver-specific and for hepatotoxicity-validated causality assessment method such as the scale of CIOMS (Council for International Organizations of Medical Sciences). This compilation presents details of herbal hepatotoxicity, assisting thereby clinical assessment of involved physicians in the future. © 2012 John Wiley & Sons A/S.

  9. In vitro transcriptomic prediction of hepatotoxicity for early drug discovery

    PubMed Central

    Cheng, Feng; Theodorescu, Dan; Schulman, Ira G.; Lee, Jae K.

    2012-01-01

    Liver toxicity (hepatotoxicity) is a critical issue in drug discovery and development. Standard preclinical evaluation of drug hepatotoxicity is generally performed using in vivo animal systems. However, only a small number of preselected compounds can be examined in vivo due to high experimental costs. A more efficient yet accurate screening technique which can identify potentially hepatotoxic compounds in the early stages of drug development would thus be valuable. Here, we develop and apply a novel genomic prediction technique for screening hepatotoxic compounds based on in vitro human liver cell tests. Using a training set of in vivo rodent experiments for drug hepatotoxicity evaluation, we discovered common biomarkers of drug-induced liver toxicity among six heterogeneous compounds. This gene set was further triaged to a subset of 32 genes that can be used as a multi-gene expression signature to predict hepatotoxicity. This multi-gene predictor was independently validated and showed consistently high prediction performance on five test sets of in vitro human liver cell and in vivo animal toxicity experiments. The predictor also demonstrated utility in evaluating different degrees of toxicity in response to drug concentrations which may be useful not only for discerning a compound’s general hepatotoxicity but also for determining its toxic concentration. PMID:21884709

  10. Hepatotoxicity during Treatment for Tuberculosis in People Living with HIV/AIDS.

    PubMed

    Araújo-Mariz, Carolline; Lopes, Edmundo Pessoa; Acioli-Santos, Bartolomeu; Maruza, Magda; Montarroyos, Ulisses Ramos; Ximenes, Ricardo Arraes de Alencar; Lacerda, Heloísa Ramos; Miranda-Filho, Demócrito de Barros; Albuquerque, Maria de Fátima P Militão de

    2016-01-01

    Hepatotoxicity is frequently reported as an adverse reaction during the treatment of tuberculosis. The aim of this study was to determine the incidence of hepatotoxicity and to identify predictive factors for developing hepatotoxicity after people living with HIV/AIDS (PLWHA) start treatment for tuberculosis. This was a prospective cohort study with PLWHA who were monitored during the first 60 days of tuberculosis treatment in Pernambuco, Brazil. Hepatotoxicity was considered increased levels of aminotransferase, namely those that rose to three times higher than the level before initiating tuberculosis treatment, these levels being associated with symptoms of hepatitis. We conducted a multivariate logistic regression analysis and the magnitude of the associations was expressed by the odds ratio with a confidence interval of 95%. Hepatotoxicity was observed in 53 (30.6%) of the 173 patients who started tuberculosis treatment. The final multivariate logistic regression model demonstrated that the use of fluconazole, malnutrition and the subject being classified as a phenotypically slow acetylator increased the risk of hepatotoxicity significantly. The incidence of hepatotoxicity during treatment for tuberculosis in PLWHA was high. Those classified as phenotypically slow acetylators and as malnourished should be targeted for specific care to reduce the risk of hepatotoxicity during treatment for tuberculosis. The use of fluconazole should be avoided during tuberculosis treatment in PLWHA.

  11. Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

    PubMed Central

    Pantano, Flaminia; Tittarelli, Roberta; Mannocchi, Giulio; Zaami, Simona; Ricci, Serafino; Giorgetti, Raffaele; Terranova, Daniela; Busardò, Francesco P.; Marinelli, Enrico

    2016-01-01

    The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed. PMID:27092496

  12. Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450

    PubMed Central

    Chen, Taosheng

    2017-01-01

    Herbal supplements are a significant source of drug-drug interactions (DDIs), herb-drug interactions, and hepatotoxicity. Cytochrome P450 (CYP450) enzymes metabolize a large number of FDA-approved pharmaceuticals and herbal supplements. This metabolism of pharmaceuticals and supplements can be augmented by concomitant use of either pharmaceuticals or supplements. The xenobiotic receptors constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) can respond to xenobiotics by increasing the expression of a large number of genes that are involved in the metabolism of xenobiotics, including CYP450s. Conversely, but not exclusively, many xenobiotics can inhibit the activity of CYP450s. Induction of the expression or inhibition of the activity of CYP450s can result in DDIs and toxicity. Currently, the United States (US) Food and Drug Administration does not require the investigation of the interactions of herbal supplements and CYP450s. This review provides a summary of herbal supplements that inhibit CYP450s, induce the expression of CYP450s, and/or whose toxicity is mediated by CYP450s. PMID:29117101

  13. Current FDA regulatory guidance on the conduct of drug discrimination studies for NDA review: Does the scientific literature support recent recommendations?

    PubMed

    Gauvin, David V; Zimmermann, Zachary J; Kallman, Mary Jeanne

    2016-11-01

    The Controlled Substances Staff of the Center for Drug Evaluation and Research at the US Food and Drug Administration and the Pharmaceutical Research Manufacturers Association (PhRMA) conducted a series of open forum dialog sessions between 2006 and 2016. A Cross Company Abuse Liability Council (CCALC) was formed during the process of this unique collaborative effort between Industry and Federal Regulators whose goals were to establish the development of standards for the preclinical screening of new molecular entities for schedule control actions required as part of every New Drug Application process. The draft guidance document was published and disseminated in 2010, which allowed for alternative approaches to each study protocol requirement needed for NDA review, if the approach satisfied the requirements of the applicable statutes and regulations (i.e., the controlled substance act). In a series of recent pre-study protocol reviews requested by confidential Pharmaceutical Sponsors of MPI Research, the CSS staff appeared to change its policy and set forth to require all drug discrimination study data to be generated under "extinction" test sessions. MPI Research is a Contract Research Organization acting on behalf of pharmaceutical companies and bound under separate confidentiality agreements. The purpose of this review is to highlight the data appearing in peer-reviewed scientific journals that do not support the regulatory administrative constraints on one specific testing methodology (extinction) to the exclusion of another (reinforced test sessions). This mind shift represents a restrictive administrative policy by the FDA that is not supported by the published data. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Research outcomes and recommendations for the assessment of progression in cancer clinical trials from a PhRMA working group.

    PubMed

    Stone, A M; Bushnell, W; Denne, J; Sargent, D J; Amit, O; Chen, C; Bailey-Iacona, R; Helterbrand, J; Williams, G

    2011-08-01

    Progression free survival (PFS) is increasingly used as a primary end-point in oncology clinical trials. This paper provides recommendations for optimal trial design, conduct and analysis in situations where PFS has the potential to be an acceptable end-point for regulatory approval. These recommendations are based on research performed by the Pharmaceutical Research and Manufacturers Association (PhRMA) sponsored PFS Working Group, including the re-analysis of 28 randomised Phase III trials from 12 companies/institutions. (1) In the assessment of PFS, there is a critical distinction between measurement error that results from random variation, which by itself tends to attenuate treatment effect, versus bias which increases the probability of a false negative or false positive finding. Investigator bias can be detected by auditing a random sample of patients by blinded, independent, central review (BICR). (2) ITT analyses generally resulted in smaller treatment effects (HRs closer to 1) than analyses that censor patients for potentially informative events (such as starting other anti-cancer therapy). (3) Interval censored analyses (ICA) are more robust to time-evaluation bias than the log-rank test. A sample based BICR audit may be employed in open or partially blinded trials and should not be required in true double-blind trials. Patients should be followed until progression even if they have discontinued treatment to be consistent with the ITT principle. ICAs should be a standard sensitivity analysis to assess time-evaluation bias. Implementation of these recommendations would standardize and in many cases simplify phase III oncology clinical trials that use a PFS primary end-point. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. Paracetamol poisoning in children and hepatotoxicity.

    PubMed Central

    Penna, A; Buchanan, N

    1991-01-01

    1. Paracetamol is one of the most common drugs that children accidentally ingest. Unlike the situation in adults, death and hepatotoxicity in children from paracetamol poisoning are exceedingly uncommon events. A review of the literature has revealed only seven deaths and fourteen cases of hepatotoxicity in children, with most of the cases resulting from chronic poisoning and not acute poisoning. 2. Children may be less prone to paracetamol hepatotoxicity because of developmental differences in the drug's metabolism and its pathways of detoxification. In the therapeutic setting of treatment of fever and pain in children, paracetamol is regarded as a drug with a higher therapeutic index, and as such, there seems to be little concern with strict adherence to dosage regimes. 3. Scrutiny of the above paediatric cases associated with chronic paracetamol poisoning suggests that the margin of safety of frequent therapeutic doses of paracetamol in infants and young children to be a lot lower than previously appreciated. This review highlights the need to re-evaluate the safety of paracetamol in the context of chronic therapy in infants and young children. PMID:1931463

  16. Research Advances on Hepatotoxicity of Herbal Medicines in China.

    PubMed

    Liu, Changxiao; Fan, Huirong; Li, Yazhuo; Xiao, Xiaohe

    2016-01-01

    In general, herbal medicines have been considered as safe by the general public, since they are naturally occurring and have been applied in treatment for over thousands of years. As the use of herbal medicine is rapidly increasing globally, the potential toxicity of herbal drugs, in particular drug-induced liver injury (DILI), has now become a serious medical issue. According to the literature, the authors analyzed and discussed the hepatotoxicity problem of Chinese herbal medicines (CHM), including global overview on herbal-induced liver injury (HILI), current research progress on toxic CHM, diagnosis and treatment of HILI, and modern approaches and technologies of study of hepatotoxicity. As to promote the recognition of HILI and tackle the issue, a guideline for the diagnosis and treatment of HILI has recently been drafted by Chinese scientists. As suggested by the guideline, the hepatotoxicity issue of CHM, as a matter of fact, is overestimated. Up to date, the investigation of hepatotoxicity of CHM is now booming with worldwide application of CHM. This review therefore provides useful information for investigating hepatotoxicity of herbal medicine and characterizing DILI caused by CHM. In addition, authors describe in which way further efforts should be made to study the rationale of CHM and liver injury.

  17. Research Advances on Hepatotoxicity of Herbal Medicines in China

    PubMed Central

    Fan, Huirong; Li, Yazhuo; Xiao, Xiaohe

    2016-01-01

    In general, herbal medicines have been considered as safe by the general public, since they are naturally occurring and have been applied in treatment for over thousands of years. As the use of herbal medicine is rapidly increasing globally, the potential toxicity of herbal drugs, in particular drug-induced liver injury (DILI), has now become a serious medical issue. According to the literature, the authors analyzed and discussed the hepatotoxicity problem of Chinese herbal medicines (CHM), including global overview on herbal-induced liver injury (HILI), current research progress on toxic CHM, diagnosis and treatment of HILI, and modern approaches and technologies of study of hepatotoxicity. As to promote the recognition of HILI and tackle the issue, a guideline for the diagnosis and treatment of HILI has recently been drafted by Chinese scientists. As suggested by the guideline, the hepatotoxicity issue of CHM, as a matter of fact, is overestimated. Up to date, the investigation of hepatotoxicity of CHM is now booming with worldwide application of CHM. This review therefore provides useful information for investigating hepatotoxicity of herbal medicine and characterizing DILI caused by CHM. In addition, authors describe in which way further efforts should be made to study the rationale of CHM and liver injury. PMID:28078299

  18. Asthma: NIH-Sponsored Research and Clinical Trials | NIH MedlinePlus the Magazine

    MedlinePlus

    ... turn Javascript on. Feature: Asthma Asthma: NIH-Sponsored Research and Clinical Trials Past Issues / Fall 2011 Table of Contents NIH-Sponsored Research Asthma in the Inner City: Recognizing that asthma ...

  19. 78 FR 19715 - Implementation of the FDA Food Safety Modernization Act Provision Requiring FDA To Establish...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-02

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-1153] Implementation of the FDA Food Safety Modernization Act Provision Requiring FDA To Establish Pilot Projects and...: The Food and Drug Administration (FDA) is extending the comment period for the notice entitled...

  20. OpenFDA: an innovative platform providing access to a wealth of FDA's publicly available data.

    PubMed

    Kass-Hout, Taha A; Xu, Zhiheng; Mohebbi, Matthew; Nelsen, Hans; Baker, Adam; Levine, Jonathan; Johanson, Elaine; Bright, Roselie A

    2016-05-01

    The objective of openFDA is to facilitate access and use of big important Food and Drug Administration public datasets by developers, researchers, and the public through harmonization of data across disparate FDA datasets provided via application programming interfaces (APIs). Using cutting-edge technologies deployed on FDA's new public cloud computing infrastructure, openFDA provides open data for easier, faster (over 300 requests per second per process), and better access to FDA datasets; open source code and documentation shared on GitHub for open community contributions of examples, apps and ideas; and infrastructure that can be adopted for other public health big data challenges. Since its launch on June 2, 2014, openFDA has developed four APIs for drug and device adverse events, recall information for all FDA-regulated products, and drug labeling. There have been more than 20 million API calls (more than half from outside the United States), 6000 registered users, 20,000 connected Internet Protocol addresses, and dozens of new software (mobile or web) apps developed. A case study demonstrates a use of openFDA data to understand an apparent association of a drug with an adverse event. With easier and faster access to these datasets, consumers worldwide can learn more about FDA-regulated products. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved.

  1. 78 FR 14309 - Implementation of the FDA Food Safety Modernization Act Provision Requiring FDA To Establish...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-05

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-1153] Implementation of the FDA Food Safety Modernization Act Provision Requiring FDA To Establish Pilot Projects and... information. SUMMARY: In September 2011, the Food and Drug Administration (FDA or the Agency) asked the...

  2. Solving the Undiagnosed Disease Puzzle at NIH | NIH MedlinePlus the Magazine

    MedlinePlus

    Skip to main content NIH MedlinePlus the Magazine NIH MedlinePlus Salud Download the Current Issue PDF [2.68 mb] Trusted Health Information from the National Institutes of Health Home Current Issue ...

  3. Role of metabolism in drug-induced idiosyncratic hepatotoxicity.

    PubMed

    Walgren, Jennie L; Mitchell, Michael D; Thompson, David C

    2005-01-01

    Rare adverse reactions to drugs that are of unknown etiology, or idiosyncratic reactions, can produce severe medical complications or even death in patients. Current hypotheses suggest that metabolic activation of a drug to a reactive intermediate is a necessary, yet insufficient, step in the generation of an idiosyncratic reaction. We review evidence for this hypothesis with drugs that are associated with hepatotoxicity, one of the most common types of idiosyncratic reactions in humans. We identified 21 drugs that have either been withdrawn from the U.S. market due to hepatotoxicity or have a black box warning for hepatotoxicity. Evidence for the formation of reactive metabolites was found for 5 out of 6 drugs that were withdrawn, and 8 out of 15 drugs that have black box warnings. For the other drugs, either evidence was not available or suitable studies have not been carried out. We also review evidence for reactive intermediate formation from a number of additional drugs that have been associated with idiosyncratic hepatotoxicity but do not have black box warnings. Finally, we consider the potential role that high dosages may play in these adverse reactions.

  4. Steer-PROP: a GRASE-PROPELLER sequence with interecho steering gradient pulses.

    PubMed

    Srinivasan, Girish; Rangwala, Novena; Zhou, Xiaohong Joe

    2018-05-01

    This study demonstrates a novel PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) pulse sequence, termed Steer-PROP, based on gradient and spin echo (GRASE), to reduce the imaging times and address phase errors inherent to GRASE. The study also illustrates the feasibility of using Steer-PROP as an alternative to single-shot echo planar imaging (SS-EPI) to produce distortion-free diffusion images in all imaging planes. Steer-PROP uses a series of blip gradient pulses to produce N (N = 3-5) adjacent k-space blades in each repetition time, where N is the number of gradient echoes in a GRASE sequence. This sampling strategy enables a phase correction algorithm to systematically address the GRASE phase errors as well as the motion-induced phase inconsistency. Steer-PROP was evaluated on phantoms and healthy human subjects at both 1.5T and 3.0T for T 2 - and diffusion-weighted imaging. Steer-PROP produced similar image quality as conventional PROPELLER based on fast spin echo (FSE), while taking only a fraction (e.g., 1/3) of the scan time. The robustness against motion in Steer-PROP was comparable to that of FSE-based PROPELLER. Using Steer-PROP, high quality and distortion-free diffusion images were obtained from human subjects in all imaging planes, demonstrating a considerable advantage over SS-EPI. The proposed Steer-PROP sequence can substantially reduce the scan times compared with FSE-based PROPELLER while achieving adequate image quality. The novel k-space sampling strategy in Steer-PROP not only enables an integrated phase correction method that addresses various sources of phase errors, but also minimizes the echo spacing compared with alternative sampling strategies. Steer-PROP can also be a viable alternative to SS-EPI to decrease image distortion in all imaging planes. Magn Reson Med 79:2533-2541, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic

  5. NIH Research on Concussion and the Brain | NIH MedlinePlus the Magazine

    MedlinePlus

    ... Feature: Concussion NIH Research on Concussion and the Brain Past Issues / Summer 2015 Table of Contents Dr. ... chronic traumatic encephalopathy (CTE). "Boxing, Football and the Brain" One study, funded in part by NIH, is ...

  6. Monogamy of quantum steering

    NASA Astrophysics Data System (ADS)

    Milne, Antony; Jennings, David; Jevtic, Sania; Rudolph, Terry; Wiseman, Howard

    The quantum steering ellipsoid formalism naturally extends the Bloch vector picture for qubits to provide a visualisation of two-qubit systems. If Alice and Bob share a correlated state then a local measurement by Bob steers Alice's qubit inside the Bloch sphere; given all possible measurements by Bob, the set of states to which Alice can be steered form her steering ellipsoid. We apply the formalism to a three-party scenario and find that steering ellipsoid volumes obey a simple monogamy relation. This gives us a novel derivation of the well-known CKW (Coffman-Kundu-Wootters) inequality for entanglement monogamy. The geometric perspective also identifies a new measure of quantum correlation, `obesity', and a set of `maximally obese' states that saturate the steering monogamy bound. These states are found to have extremal quantum correlation properties that are significant in the steering ellipsoid picture and for the study of two-qubit states in general.

  7. Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease.

    PubMed

    Wong, D R; Coenen, M J H; Derijks, L J J; Vermeulen, S H; van Marrewijk, C J; Klungel, O H; Scheffer, H; Franke, B; Guchelaar, H-J; de Jong, D J; Engels, L G J B; Verbeek, A L M; Hooymans, P M

    2017-02-01

    Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations. To determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment. The cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase ≥5. Forty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 × 10 8 erythrocytes was defined. Analysis of patients on stable thiopurine dose (n = 174) showed that those exceeding the 6-MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8-8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6-MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75-0.91)]. 6-MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4-4.3), and general malaise: OR = 2.0 (95% CI: 1.1-3.7). In more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure. © 2016 John Wiley & Sons Ltd.

  8. FDA regulation of tobacco: blessing or curse for FDA professionals?

    PubMed

    O'Reilly, James T

    2009-01-01

    Upwards of 400,000 Americans will die that year from the effects of cigarettes, which FDA will now "regulate" very gently, with its hands tied by a slick statutory protection for the largest existing tobacco marketers. Career FDA professionals will be criticized as enablers of mega-marketers' continued sales, working at the margins, arranging the paperwork for protection of megafirms' market share, and sitting by as the deaths and addictive behaviors continue. "Join the Public Health Service, inspired by a public health mission," they were told, and yet they will be unable to do much regulating of the addictive and fatal products for which they now have titular responsibility. This essay observes that these fine FDA professionals are handed the sticky remains of a messy bargain, negotiated in a distracted Congress by expensive lawyers with clients who were potent contributors to political action committees. The only formula that is not secret about the 2009 law is the way in which industry purchased sufficient allegiance to gather the votes for its adoption. The remaining mystery is how FDA could be expected to do these tasks without losing its best and brightest professionals to other fields.

  9. A new model to compute the desired steering torque for steer-by-wire vehicles and driving simulators

    NASA Astrophysics Data System (ADS)

    Fankem, Steve; Müller, Steffen

    2014-05-01

    This paper deals with the control of the hand wheel actuator in steer-by-wire (SbW) vehicles and driving simulators (DSs). A novel model for the computation of the desired steering torque is presented. The introduced steering torque computation does not only aim to generate a realistic steering feel, which means that the driver should not miss the basic steering functionality of a modern conventional steering system such as an electric power steering (EPS) or hydraulic power steering (HPS), and this in every driving situation. In addition, the modular structure of the steering torque computation combined with suitably selected tuning parameters has the objective to offer a high degree of customisability of the steering feel and thus to provide each driver with his preferred steering feel in a very intuitive manner. The task and the tuning of each module are firstly described. Then, the steering torque computation is parameterised such that the steering feel of a series EPS system is reproduced. For this purpose, experiments are conducted in a hardware-in-the-loop environment where a test EPS is mounted on a steering test bench coupled with a vehicle simulator and parameter identification techniques are applied. Subsequently, how appropriate the steering torque computation mimics the test EPS system is objectively evaluated with respect to criteria concerning the steering torque level and gradient, the feedback behaviour and the steering return ability. Finally, the intuitive tuning of the modular steering torque computation is demonstrated for deriving a sportier steering feel configuration.

  10. FDA & digital mammography: why has FDA required full field digital mammography systems to be regulated as potentially dangerous devices for more than 10 years?

    PubMed

    Nields, Morgan W

    2010-05-01

    Digital mammography is routinely used in the US to screen asymptomatic women for breast cancer and currently over 50% of US screening centers employ the technology. In spite of FDAs knowledge that digital mammography requires less radiation than film mammography and that its equivalence has been proven in a prospective randomized trial, the agency has failed to allow the technology market access via the 510(k) pre market clearance pathway. As a result of the restrictive Pre Market Approval process, only four suppliers have received FDA approval. The resulting lack of a competitive market has kept costs high, restricted technological innovation, and impeded product improvements as a result of PMA requirements. Meanwhile, at least twelve companies are on the market in the EU and the resulting competitive market has lowered costs and provided increased technological choice. A cultural change with new leadership occurred in the early 90's at FDA. The historical culture at the Center for Devices and Radiological Health of collaboration and education gave way to one characterized by a lack of reliance on outside scientific expertise, tolerance of decision making by unqualified reviewers, and an emphasis on enforcement and punishment. Digital mammography fell victim to this cultural change and as a result major innovations like breast CT and computer aided detection technologies are also withheld from the market. The medical device law, currently under review by the Institute of Medicine, should be amended by the Congress so that new technologies can be appropriately classified in accordance with the risk based assessment classification system detailed in Chapter V of the Federal Food, Drug, and Cosmetic Act. A panel of scientific experts chartered by the NIH or IOM should determine the classification appropriate for new technologies that have no historical regulatory framework. This would be binding on FDA. Unless the law is changed we will likely again experience

  11. 52. Patent steering gear, hatch and steering compass binnacle, view ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    52. Patent steering gear, hatch and steering compass binnacle, view from starboard looking aft. Photograph by Jet Lowe, April 1988. - Ship BALCLUTHA, 2905 Hyde Street Pier, San Francisco, San Francisco County, CA

  12. FDA Issues Final Guidance Clarifying FDA and EPA Jurisdiction over Mosquito-Related Products

    EPA Pesticide Factsheets

    FDA finalized guidance to provide information on FDA and EPA jurisdiction over the regulation of mosquito-related products intended to function as pesticides, including those products intended to function as pesticides

  13. 77 FR 14404 - Guidance for the Public, Food and Drug Administration (FDA) Advisory Committee Members, and FDA...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-09

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2002-D-0094; (formerly Docket No. 02D-0049)] Guidance for the Public, Food and Drug Administration (FDA) Advisory... Food and Drug Administration (FDA) is announcing the availability of a guidance for the public, FDA...

  14. Microbiota transplantation reveals beneficial impact of berberine on hepatotoxicity by improving gut homeostasis.

    PubMed

    Qin, Chenjie; Zhang, Huilu; Zhao, Linghao; Zeng, Min; Huang, Weijian; Fu, Gongbo; Zhou, Weiping; Wang, Hongyang; Yan, Hexin

    2017-11-29

    Berberine has been shown to reduce acute liver injury although the underlying mechanism is not fully understood. Because of the anatomic connection, the liver is constantly exposed to gut-derived bacterial products and metabolites. In this study, we showed that berberine has beneficial effects on both hepatotoxicity and intestinal damage in a rat model of chronic or acute liver injury. Microbiota transplantation from the rats with chronic hepatotoxicity could aggravate acute hepatotoxicity in mice treated with diethylnitrosamine (DEN). In rat models with gut homeostasis disruption induced by penicillin or dextran sulfate sodium (DSS), their fecal microbiota could also cause an enhanced hepatotoxicity of recipient mice. When treated with berberine, the DSS-induced enteric dysbacteriosis could be mitigated and their fecal bacteria were able to reduce acute hepatotoxicity in recipient mice. This study indicates that berberine could improve intestinal dysbacteriosis, which reduces the hepatotoxicity caused by pathological or pharmacological intervention. Fecal microbiota transplantation might be a useful method to directly explore homeostatic alteration in gut microbiota.

  15. Levels of steering control: Reproduction of steering-wheel movements

    NASA Technical Reports Server (NTRS)

    Godthelp, H.

    1982-01-01

    A schematic description of the steering control process is presented. It is shown that this process can be described in terms of levels of control. Level of control will depend on driver's skill in making use of 'clever' strategies which may be related to knowledge about the path to follow (input) and/or the vehicle under control. This knowledge may be referred to as an internal model of a particular task element. Internal information, as derived from these internal models will probably be used together with proprioceptive feedback. It is hypothesized that the efficiency of the higher levels of control will be dependent on the accuracy of both the internal and proprioceptive information. Based on this research philosophy a series of experiments is carried out. Two primary experiments were done in order to analyse subjects' ability to reproduce steering-wheel positions and movements without visual feedback. Steering-wheel angle amplitude, steering force and movement frequency were involved as independent variables.

  16. 49 CFR 570.7 - Steering systems.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 6 2011-10-01 2011-10-01 false Steering systems. 570.7 Section 570.7... Pounds or Less § 570.7 Steering systems. (a) System play. Lash or free play in the steering system shall... in the steering system. Table 1—Steering System Free Play Values Steering wheel diameter (inches...

  17. 49 CFR 570.7 - Steering systems.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 6 2012-10-01 2012-10-01 false Steering systems. 570.7 Section 570.7... Pounds or Less § 570.7 Steering systems. (a) System play. Lash or free play in the steering system shall... in the steering system. Table 1—Steering System Free Play Values Steering wheel diameter (inches...

  18. 49 CFR 570.7 - Steering systems.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 6 2014-10-01 2014-10-01 false Steering systems. 570.7 Section 570.7... Pounds or Less § 570.7 Steering systems. (a) System play. Lash or free play in the steering system shall... in the steering system. Table 1—Steering System Free Play Values Steering wheel diameter (inches...

  19. 49 CFR 570.7 - Steering systems.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 6 2010-10-01 2010-10-01 false Steering systems. 570.7 Section 570.7... Pounds or Less § 570.7 Steering systems. (a) System play. Lash or free play in the steering system shall... in the steering system. Table 1—Steering System Free Play Values Steering wheel diameter (inches...

  20. 49 CFR 570.60 - Steering system.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 6 2014-10-01 2014-10-01 false Steering system. 570.60 Section 570.60... 10,000 Pounds § 570.60 Steering system. (a) System play. Lash or free play in the steering system... excessive lash or free play in the steering system. Table 2. Steering Wheel Free Play Values Steering wheel...

  1. 49 CFR 570.60 - Steering system.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 6 2012-10-01 2012-10-01 false Steering system. 570.60 Section 570.60... 10,000 Pounds § 570.60 Steering system. (a) System play. Lash or free play in the steering system... excessive lash or free play in the steering system. Table 2. Steering Wheel Free Play Values Steering wheel...

  2. 49 CFR 570.60 - Steering system.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 6 2011-10-01 2011-10-01 false Steering system. 570.60 Section 570.60... 10,000 Pounds § 570.60 Steering system. (a) System play. Lash or free play in the steering system... excessive lash or free play in the steering system. Table 2. Steering Wheel Free Play Values Steering wheel...

  3. 49 CFR 570.60 - Steering system.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 6 2010-10-01 2010-10-01 false Steering system. 570.60 Section 570.60... 10,000 Pounds § 570.60 Steering system. (a) System play. Lash or free play in the steering system... excessive lash or free play in the steering system. Table 2. Steering Wheel Free Play Values Steering wheel...

  4. Thermal modeling of NiH2 batteries

    NASA Technical Reports Server (NTRS)

    Ponthus, Agnes-Marie; Alexandre, Alain

    1994-01-01

    The following are discussed: NiH2 battery mission and environment; NiH2 cell heat dissipation; Nodal software; model development general philosophy; NiH2 battery model development; and NiH2 experimental developments.

  5. Steering Bell-diagonal states

    PubMed Central

    Quan, Quan; Zhu, Huangjun; Liu, Si-Yuan; Fei, Shao-Ming; Fan, Heng; Yang, Wen-Li

    2016-01-01

    We investigate the steerability of two-qubit Bell-diagonal states under projective measurements by the steering party. In the simplest nontrivial scenario of two projective measurements, we solve this problem completely by virtue of the connection between the steering problem and the joint-measurement problem. A necessary and sufficient criterion is derived together with a simple geometrical interpretation. Our study shows that a Bell-diagonal state is steerable by two projective measurements iff it violates the Clauser-Horne-Shimony-Holt (CHSH) inequality, in sharp contrast with the strict hierarchy expected between steering and Bell nonlocality. We also introduce a steering measure and clarify its connections with concurrence and the volume of the steering ellipsoid. In particular, we determine the maximal concurrence and ellipsoid volume of Bell-diagonal states that are not steerable by two projective measurements. Finally, we explore the steerability of Bell-diagonal states under three projective measurements. A simple sufficient criterion is derived, which can detect the steerability of many states that are not steerable by two projective measurements. Our study offers valuable insight on steering of Bell-diagonal states as well as the connections between entanglement, steering, and Bell nonlocality. PMID:26911250

  6. IL-1RN and IL-1β Polymorphism and ARV-Associated Hepatotoxicity

    PubMed Central

    Samani, Dharmesh; Nema, Vijay; Gangakhedkar, R. R.

    2018-01-01

    The severity of hepatic injury depends upon cytokines. Previous studies associated IL-1RN allele 2 with IL-1β production. Hence, we examined the association of IL-1 RN and IL-1β polymorphisms with ARV-associated hepatotoxicity. Genotyping of IL-1RN (VNTR), IL-1β (-511C/T) polymorphisms was done in 162 HIV-infected patients, 34 with ARV hepatotoxicity, 128 without hepatotoxicity, and 152 healthy controls using PCR and PCR-RFLP method. The haplotypes 1T and 2C enhanced the risk for severe hepatotoxicity (OR = 1.41, P = 0.25; OR = 1.67, P = 0.31). IL-1β-511TT genotype significantly represented among tobacco using HIV-infected individuals compared to nonusers (OR = 3.74, P = 0.05). IL-1β-511TT genotype among alcohol users increased the risk for hepatotoxicity (OR = 1.80, P = 0.90). IL-1β-511CT and -511TT genotypes overrepresented in alcohol using HIV-infected individuals (OR = 2.29, P = 0.27; OR = 2.64, P = 0.19). IL-RN 2/2 and 1/3 genotypes represented higher in nevirapine using hepatotoxicity patients (OR = 1.42, P = 0.64, OR = 8.79, P = 0.09). IL-1β-511CT and -511 TT genotypes among nevirapine users enhanced the risk for severe hepatotoxicity (OR = 4.29, P = 0.20; OR = 1.95, P = 0.56). IL-1β-511CT and -511TT genotypes were overrepresented in combined nevirapine and alcohol using HIV-infected individuals as compared to nevirapine users and alcohol nonusers (OR = 2.56, P = 0.26; OR = 2.84, P = 0.24). IL-1β-511TT genotype with tobacco, alcohol, and nevirapine usage revealed a trend of risk for the development of ARV-associated hepatotoxicity and its severity.

  7. Experimental verification of multidimensional quantum steering

    NASA Astrophysics Data System (ADS)

    Li, Che-Ming; Lo, Hsin-Pin; Chen, Liang-Yu; Yabushita, Atsushi

    2018-03-01

    Quantum steering enables one party to communicate with another remote party even if the sender is untrusted. Such characteristics of quantum systems not only provide direct applications to quantum information science, but are also conceptually important for distinguishing between quantum and classical resources. While concrete illustrations of steering have been shown in several experiments, quantum steering has not been certified for higher dimensional systems. Here, we introduce a simple method to experimentally certify two different kinds of quantum steering: Einstein-Podolsky-Rosen (EPR) steering and single-system (SS) steering (i.e., temporal steering), for dimensionality (d) up to d = 16. The former reveals the steerability among bipartite systems, whereas the latter manifests itself in single quantum objects. We use multidimensional steering witnesses to verify EPR steering of polarization-entangled pairs and SS steering of single photons. The ratios between the measured witnesses and the maximum values achieved by classical mimicries are observed to increase with d for both EPR and SS steering. The designed scenario offers a new method to study further the genuine multipartite steering of large dimensionality and potential uses in quantum information processing.

  8. A case of lacosamide-induced hepatotoxicity.

    PubMed

    Sunwoo, Jun-Sang; Byun, Jung-Ick; Lee, Sang Kun

    2015-06-01

    Lacosamide is a novel antiepileptic drug that acts mainly via the selective enhancement of slow inactivation of voltage-gated sodium channels. It has been reported that lacosamide is effective and generally tolerable as an adjuvant treatment in patients with partial seizures. There are few reports regarding liver damage caused by lacosamide. We describe a case of a patient with drug-resistant epilepsy who developed symptomatic hepatotoxicity after lacosamide administration. A 22-year-old female with a 2-year history of temporal lobe epilepsy was admitted to our hospital because of nausea, dizziness, and abnormal liver function tests. Lacosamide was added for further seizure control 9 days before the current presentation. Her liver enzymes were markedly increased: aspartate aminotransferase, 635 U/L; alanine aminotransferase, 697 U/L. Lacosamide was ceased immediately, whereas other medications (zonisamide, clobazam, and tianeptine) were not withdrawn. The level of liver enzymes improved significantly within a few days, and a diagnosis of lacosamide-induced hepatitis was made based on the obvious temporal relationship. This case report demonstrates that hepatotoxicity may develop in association with lacosamide therapy. Liver function tests should be prompted in patients with symptoms suggestive of adverse effects after the initiation of lacosamide. Further research is required to identify predisposing factors of lacosamideinduced hepatotoxicity.

  9. Experimental temporal quantum steering

    PubMed Central

    Bartkiewicz, Karol; Černoch, Antonín; Lemr, Karel; Miranowicz, Adam; Nori, Franco

    2016-01-01

    Temporal steering is a form of temporal correlation between the initial and final state of a quantum system. It is a temporal analogue of the famous Einstein-Podolsky-Rosen (spatial) steering. We demonstrate, by measuring the photon polarization, that temporal steering allows two parties to verify if they have been interacting with the same particle, even if they have no information about what happened with the particle in between the measurements. This is the first experimental study of temporal steering. We also performed experimental tests, based on the violation of temporal steering inequalities, of the security of two quantum key distribution protocols against individual attacks. Thus, these results can lead to applications for secure quantum communications and quantum engineering. PMID:27901121

  10. FDA Warns About Stem Cell Therapies

    MedlinePlus

    ... For Consumers Consumer Updates FDA Warns About Stem Cell Therapies Share Tweet Linkedin Pin it More sharing ... the boxed section below for more advice. Stem Cell Uses and FDA Regulation The FDA has the ...

  11. [Hepatotoxicity associated with the use of Herbalife].

    PubMed

    Jóhannsson, Magnús; Ormarsdóttir, Sif; Olafsson, Sigurdur

    2010-03-01

    Many herbal products are known to be hepatotoxic. In a recent survey in Iceland concerning adverse reactions related to herbal medicines, Herbalife products were implicated in the majority of the reported cases of hepatotoxicity. The clinical presentations of five cases of Herbalife related liver injury during the period of 1999-2008 are analysed. Causality was assessed by using the WHO-UMC system for causality assessment and the RUCAM method. Of the five cases there were four females and one male; median age was 46 years (range 29-78). Herbalife had been used for 1 to 7 months prior to presentation. Four patients presented with a hepatocellular and one with a cholestatic reaction. Median values were for bilirubin 190 micromol/L (range: 26-311; ref. < 20 micromol/L), ALP 407 U/L (range: 149-712; ref. 35-105 U/L) and ALT 24 87 U/L (range: 456-2637; ref. 70 and 45 U/L for males and females, respectively). Liver biopsy was performed in 2 patients and was consistent with toxic hepatitis in both cases. Other causes of hepatitis were excluded by appropriate serological testing and ultrasound. Causality assessment according to RUCAM was probable in three cases and possible in two. Using the WHO-UMC criteria causality was certain in one case, probable in two and possible in two cases. Hepatotoxicity is probably associated with the use of Herbalife products. Hepatotoxicity due to herbal remedies is an important differential diagnosis in the diagnostic work-up of liver injury.

  12. 75 FR 76992 - Guidance for the Public, FDA Advisory Committee Members, and FDA Staff: The Open Public Hearing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-10

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2005-D-0072] (formerly Docket No. 2005D-0042) Guidance for the Public, FDA Advisory Committee Members, and FDA Staff: The Open Public Hearing at FDA Advisory Committee Meetings; Availability AGENCY: Food and Drug...

  13. Hepatotoxic constituents and toxicological mechanism of Xanthium strumarium L. fruits.

    PubMed

    Xue, Li-Ming; Zhang, Qiao-Yan; Han, Ping; Jiang, Yi-Ping; Yan, Rong-Di; Wang, Yang; Rahman, Khalid; Jia, Min; Han, Ting; Qin, Lu-Ping

    2014-03-14

    In the recent years, the international community has attached increasing importance to possible toxicity associated with Traditional Chinese Medicine (TCM). And hepatotoxicity is one of the major concerns, a fundamental pathological process induced by toxicant. This paper is in an attempt to identify the hepatotoxic components in Xanthium strumarium L. fruits (XSF) and interpret the toxicological mechanism induced by XSF. XSF extract was prepared and seven characteristic components were isolated and identified in XSF water extracts. We evaluated their hepatotoxicity effect on cell proliferation and lactate dehydrogenase (LDH) activity in L-02 and BRL liver cell line. An integrated metabonomics study using high-resolution (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy combined with multivariate statistical analysis was undertake to elucidate the hepatotoxicity mechanism induced in rats by XSF. The urine and serum metabolites were measured after treatment of rats with XSF (7.5, 15.0 and 30.0 g/kg/day) for 5 days. The results showed that atractyloside, carboxyatractyloside, 4'-desulphate-atractyloside and XSF induced significant cytotoxic effects in both L-02 and BRL liver cell lines, indicating that atractyloside, carboxyatractyloside, and 4'-desulphate-atractyloside were the toxic components of XSF. When rats were treated with XSF at 30.0 g/kg the hepatotoxicity was reflected in the changes observed in serum biochemical profiles and by the histopathological examination of the liver. The levels of VLDL/LDL, 3-HB, lactate, acetate, acetone and glutamate in serum were increased in this group, while d-glucose, choline and valine were decreased. The elevation in the levels of succinate, citrate, 2-oxo-glutamate, glycine, 3-HB, acetate, lactate, hippurate, dimethylglycine, methylamine, dimethylamine, phenylalanine and tryptophan was observed in urine, in contrast a reduction in the intensities of taurine, d-glucose, N-acetyl-glucoprotein and trimethylamine

  14. Clinical trial watch: reports from the AASLD Liver Meeting®, Boston, November 2014.

    PubMed

    Londoño, María-Carlota; Abraldes, Juan G; Altamirano, José; Decaens, Thomas; Forns, Xavier

    2015-05-01

    The late and fast developments in the field of viral hepatitis were highly expected in the 2014 AASLD Liver Meeting®. Several combinations using direct acting antivirals (DAAs) showed high rates of sustained virological response (∼95%). Importantly, high cure rates were also demonstrated in patients with previous treatment failures, decompensated cirrhosis and hepatitis C recurrence after transplantation, making it clear that the interferon era is over (not so clear for ribavirin, which might still have a role in difficult-to-treat populations). Importantly, sustained virological response was associated with an improvement in liver function (MELD and Child-Pugh scores) in patients with advanced liver disease. In the field of liver cirrhosis, there were relevant data assessing the optimal empirical antibiotic therapy in patients with spontaneous bacterial peritonitis and high risk of resistant bacteria, as well as studies evaluating the role of terlipressin in type I hepatorenal syndrome and in septic shock. Regarding hepatic encephalopathy, two randomized trials suggest that the manipulation of the microbioma in patients with cirrhosis may have a role in the management of this complication. Some novel data on NASH support the beneficial effect of bariatric surgery (after failure of lifestyle intervention) in morbid obese patients with such diagnosis: clinical and histological improvements after surgery were evident in most patients with sufficient follow-up. A few controlled studies focused on the treatment of severe acute alcoholic hepatitis. Finally, several studies on hepatocellular carcinoma (HCC) were presented, covering topics such as ultrasound screening in cirrhosis, cryoablation treatment of early HCC and the relevance of downstaging in patients with HCC awaiting liver transplantation. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  15. A Hierarchical Model Predictive Tracking Control for Independent Four-Wheel Driving/Steering Vehicles with Coaxial Steering Mechanism

    NASA Astrophysics Data System (ADS)

    Itoh, Masato; Hagimori, Yuki; Nonaka, Kenichiro; Sekiguchi, Kazuma

    2016-09-01

    In this study, we apply a hierarchical model predictive control to omni-directional mobile vehicle, and improve the tracking performance. We deal with an independent four-wheel driving/steering vehicle (IFWDS) equipped with four coaxial steering mechanisms (CSM). The coaxial steering mechanism is a special one composed of two steering joints on the same axis. In our previous study with respect to IFWDS with ideal steering, we proposed a model predictive tracking control. However, this method did not consider constraints of the coaxial steering mechanism which causes delay of steering. We also proposed a model predictive steering control considering constraints of this mechanism. In this study, we propose a hierarchical system combining above two control methods for IFWDS. An upper controller, which deals with vehicle kinematics, runs a model predictive tracking control, and a lower controller, which considers constraints of coaxial steering mechanism, runs a model predictive steering control which tracks the predicted steering angle optimized an upper controller. We verify the superiority of this method by comparing this method with the previous method.

  16. Hepatotoxicity of NONI juice: Report of two cases

    PubMed Central

    Stadlbauer, Vanessa; Fickert, Peter; Lackner, Carolin; Schmerlaib, Jutta; Krisper, Peter; Trauner, Michael; Stauber, Rudolf E

    2005-01-01

    AIM: NONI juice (Morinda citrifolia) is an increasingly popular wellness drink claimed to be beneficial for many illnesses. No overt toxicity has been reported to date. We present two cases of novel hepatotoxicity of NONI juice. Causality of liver injury by NONI juice was asses-sed. Routine laboratory tests and transjugular or percutaneous liver biopsy were performed. The first patient underwent successful liver transplantation while the second patient recovered spontaneously after cessation of NONI juice. A 29-year-old man with previous toxic hepatitis associated with small doses of paracetamol developed sub-acute hepatic failure following consumption of 1.5 L NONI juice over 3 wk necessitating urgent liver transplantation. A 62-year-old woman without evidence of previous liver disease developed an episode of self-limited acute hepatitis following consumption of 2 L NONI juice for over 3 mo. The most likely hepatotoxic components of Morinda citrifolia were anthraquinones. Physicians should be aware of potential hepatotoxicity of NONI juice. PMID:16094725

  17. TV Star Jim Parsons Shines Light on NIH Research | NIH MedlinePlus the Magazine

    MedlinePlus

    ... TV Star Jim Parsons Shines Light on NIH Research Documentary highlights key sickle cell and cancer trials ... Americans about the investment we make in medical research through NIH? As taxpayers whose money helps fund ...

  18. Mulptiple Sclerosis, Symptoms, Diagnosis, Treatment and Latest NIH Research | NIH MedlinePlus the Magazine

    MedlinePlus

    ... Multiple Sclerosis: Symptoms, Diagnosis, Treatment and Latest NIH Research Past Issues / Spring 2012 Table of Contents Symptoms ... my MS will ever go away? Latest NIH Research Scientists continue their extensive efforts to create new ...

  19. View aft of compartment D23, aft steering station; note steering ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View aft of compartment D-23, aft steering station; note steering unit with crosshead and shaft bearing supports. Note framing supports for armored protective deck at top of photo. (p60) - USS Olympia, Penn's Landing, 211 South Columbus Boulevard, Philadelphia, Philadelphia County, PA

  20. Internet Database Review: The FDA BBS.

    ERIC Educational Resources Information Center

    Tomaiuolo, Nicholas G.

    1993-01-01

    Describes the electronic bulletin board system (BBS) of the Food and Drug Administration (FDA) that is accessible through the Internet. Highlights include how to gain access; the menu-driven software; other electronic sources of FDA information; and adding value. Examples of the FDA BBS menu and the help screen are included. (LRW)

  1. FDA 101: Regulating Biological Products

    MedlinePlus

    ... Home For Consumers Consumer Updates FDA 101: Regulating Biological Products Share Tweet Linkedin Pin it More sharing ... about this diverse and highly important field. What biological products does FDA regulate? The Center for Biologics ...

  2. Deep Vein Thrombosis: Symptoms, Diagnosis, Treatment and Latest NIH Research | NIH MedlinePlus the Magazine

    MedlinePlus

    ... Vein Thrombosis: Symptoms, Diagnosis, Treatment and Latest NIH Research Past Issues / Spring 2011 Table of Contents Symptoms ... without the monitoring required for warfarin. Latest NIH Research The National Heart, Lung, and Blood Institute (NHLBI) ...

  3. NIH Research Addresses Aging Issues and Disparities in Oral Health | NIH MedlinePlus the Magazine

    MedlinePlus

    ... JavaScript on. Feature: Oral Health and Aging NIH Research Addresses Aging Issues and Disparities in Oral Health ... NIH Why is it important to have a research focus on older adults? One reason is that ...

  4. Subscribe to NIH MedlinePlus the Magazine

    MedlinePlus

    ... turn Javascript on. Subscribe to NIH MedlinePlus the magazine NIH MedlinePlus the magazine is published quarterly, in print and on the ... up for a free subscription to NIH MedlinePlus Magazine. Librarians may order this magazine in bulk . Please ...

  5. Latest NIH Research | NIH MedlinePlus the Magazine

    MedlinePlus

    ... this page please turn Javascript on. Feature: Quit Smoking Latest NIH Research Past Issues / Winter 2011 Table ... with chest X-rays. Clinical Trials Related to Smoking Clinical trials are scientific studies that try to ...

  6. Current FDA directives for promoting public health

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hayes, A.H. Jr.

    1982-03-01

    The current directions of the FDA are outlined. The underlying philosophy of the FDA under the Reagan Administration is that both the private sector and the government must address the responsibilities to which they are best suited for the health-care system to work more efficiently. To facilitate this, FDA is conducting comprehensive reviews of FDA regulations and the drug-evaluation process. There are many dimensions to promoting public health, and the FDA alone cannot assure an adequate supply of safe and effective drugs. Innovative science and technology are needed to develop new drugs, followed by maximum potentiation (maximum good and leastmore » harm) after FDA approval. Hospital pharmacists have a role in maximizing the potential benefits of drugs through pharmacy and therapeutics committees. The current status of the pilot program for patient package inserts is described. The response at a recent hearing on the program indicates that the responsibility to protect the public health is shared by the government, health professions, industry, and the public. The FDA's campaign on sodium is based on that shared responsibility. By improving communication and building upon their common objections, both pharmacy and the FDA can do their jobs successfully.« less

  7. Neonicotinoid formaldehyde generators: possible mechanism of mouse-specific hepatotoxicity/hepatocarcinogenicity of thiamethoxam.

    PubMed

    Swenson, Tami L; Casida, John E

    2013-02-04

    Thiamethoxam (TMX), an important insecticide, is hepatotoxic and hepatocarcinogenic in mice but not rats. Studies of Syngenta Central Toxicology Laboratory on species specificity in metabolism established that TMX is a much better substrate for mouse liver microsomal CYPs than the corresponding rat or human enzymes in forming desmethyl-TMX (dm-TMX), which is also hepatotoxic, and clothianidin (CLO), which is not hepatotoxic or hepatocarcinogenic. They proposed that TMX hepatotoxicity/hepatocarcinogencity is due to dm-TMX and a further metabolite desmethyl-CLO (dm-CLO) (structurally analogous to a standard inducible nitric oxide synthase inhibitor) acting synergistically. The present study considers formation of formaldehyde (HCHO) and N-methylol intermediates as an alternative mechanism of TMX hepatotoxicity/hepatocarcinogenicity. Comparison of neonicotinoid metabolism by mouse, rat and human microsomes with NADPH showed two important points. First, TMX and dm-TMX yield more HCHO than any other commercial neonicotinoid. Second, mouse microsomes give much higher conversion than rat or human microsomes. These observations provide an alternative hypothesis of HCHO and N-methylol intermediates from CYP-mediated oxidative oxadiazinane ring cleavage as the bioactivated hepatotoxicants. However, the proposed mono-N-methylol CYP metabolites are not observed, possibly further reacting in situ. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  8. 46 CFR 182.610 - Main steering gear.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Main steering gear. 182.610 Section 182.610 Shipping...) MACHINERY INSTALLATION Steering Systems § 182.610 Main steering gear. (a) A vessel must be provided with a main steering gear that is: (1) Of adequate strength and capable of steering the vessel at all service...

  9. Hepatotoxicity due to first-line anti-tuberculosis drugs: a five-year experience in a Taiwan medical centre.

    PubMed

    Shu, C-C; Lee, C-H; Lee, M-C; Wang, J-Y; Yu, C-J; Lee, L-N

    2013-07-01

    Hepatotoxicity with first-line drugs, a major complication of anti-tuberculosis treatment, has not been studied by time-dependent analysis. Adult patients diagnosed with pulmonary tuberculosis (PTB) from 2005 to 2009 were reviewed retrospectively. Hepatotoxicity during anti-tuberculosis treatment was defined by symptomatic elevation of liver transaminases ≥3 times the upper limit of normal, or ≥5 times if asymptomatic. Risk factors for hepatotoxicity were investigated using time-dependent Cox regression analysis. Of 926 patients identified and followed for 4122.9 person-months (pm), 111 (12.0%) developed hepatotoxicity after a median 38.0 days from start of treatment. Around 3.5% had severe hepatotoxicity. The most common symptoms were general malaise and poor appetite. The incidence rate of hepatotoxicity was 0.59, 0.69 and 3.71/100 pm for isoniazid, rifampicin (RMP) and pyrazinamide (PZA), respectively. Old age, female sex, autoimmune disease, human immunodeficiency virus infection, more days with PZA in the last 8-14 days, and fewer days with RMP in the last 15-21 days before hepatotoxicity were independent risk factors for hepatotoxicity during treatment. A significant number of adult patients on first-line treatment experience hepatotoxicity. PZA is the most common causative drug. For high-risk patients, careful adjustment of the anti-tuberculosis regimen and regular monitoring of liver transaminases are necessary.

  10. Eclipse SteerTech liquid lenslet beam steering technology

    NASA Astrophysics Data System (ADS)

    Westfall, Raymond T.; Rogers, Stanley; Shannon, Kenneth C., III

    2007-09-01

    Eclipse SteerTech TM transmissive fluid state electrowetting technology has successfully demonstrated the ability to control the shape and position of a fluid lenslet. In its final form, the technology will incorporate a dual fluid lenslet approach capable of operating in extremely high acceleration environments. The beam steering system works on the principle of electro-wetting. A substrate is covered with a closely spaced array of, independently addressable, transparent, electrically conductive pixels utilizing Eclipse's proprietary EclipseTEC TM technology. By activating and deactivating selected EclipseTEC TM pixels in the proper sequence, the shape and position of fluid lenslets or arrays of lenslets can be dynamically changed at will. The position and shape of individual fluid lenslets may be accurately controlled on any flat, simply curved, or complex curved, transparent or reflective surface. The smaller the pixels the better control of the position and shape of the fluid lenslets. Information on the successful testing of the Eclipse SteerTech TM lenslet and discussion of its use in a de-centered lenslet array will be presented.

  11. Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity.

    PubMed

    Buness, Andreas; Roth, Adrian; Herrmann, Annika; Schmitz, Oliver; Kamp, Hennicke; Busch, Kristina; Suter, Laura

    2014-01-01

    Early and accurate pre-clinical and clinical biomarkers of hepatotoxicity facilitate the drug development process and the safety monitoring in clinical studies. We selected eight known model compounds to be administered to male Wistar rats to identify biomarkers of drug induced liver injury (DILI) using transcriptomics, metabolite profiling (metabolomics) and conventional endpoints. We specifically explored early biomarkers in serum and liver tissue associated with histopathologically evident acute hepatotoxicity. A tailored data analysis strategy was implemented to better differentiate animals with no treatment-related findings in the liver from animals showing evident hepatotoxicity as assessed by histopathological analysis. From the large number of assessed parameters, our data analysis strategy allowed us to identify five metabolites in serum and five in liver tissue, 58 transcripts in liver tissue and seven clinical chemistry markers in serum that were significantly associated with acute hepatotoxicity. The identified markers comprised metabolites such as taurocholic acid and putrescine (measured as sum parameter together with agmatine), classical clinical chemistry markers like AST (aspartate aminotransferase), ALT (alanine aminotransferase), and bilirubin, as well as gene transcripts like Igfbp1 (insulin-like growth factor-binding protein 1) and Egr1 (early growth response protein 1). The response pattern of the identified biomarkers was concordant across all types of parameters and sample matrices. Our results suggest that a combination of several of these biomarkers could significantly improve the robustness and accuracy of an early diagnosis of hepatotoxicity.

  12. Quantum steering in cascaded four-wave mixing processes.

    PubMed

    Wang, Li; Lv, Shuchao; Jing, Jietai

    2017-07-24

    Quantum steering is used to describe the "spooky action-at-a-distance" nonlocality raised in the Einstein-Podolsky-Rosen (EPR) paradox, which is important for understanding entanglement distribution and constructing quantum networks. Here, in this paper, we study an experimentally feasible scheme for generating quantum steering based on cascaded four-wave-mixing (FWM) processes in hot rubidium (Rb) vapor. Quantum steering, including bipartite steering and genuine tripartite steering among the output light fields, is theoretically analyzed. We find the corresponding gain regions in which the bipartite and tripartite steering exist. The results of bipartite steering can be used to establish a hierarchical steering model in which one beam can steer the other two beams in the whole gain region; however, the other two beams cannot steer the first beam simultaneously. Moreover, the other two beams cannot steer with each other in the whole gain region. More importantly, we investigate the gain dependence of the existence of the genuine tripartite steering and we find that the genuine tripartite steering exists in most of the whole gain region in the ideal case. Also we discuss the effect of losses on the genuine tripartite steering. Our results pave the way to experimental demonstration of quantum steering in cascaded FWM process.

  13. Influence of different shoulder-elbow configurations on steering precision and steering velocity in automotive context.

    PubMed

    Schmidt, Susanne; Seiberl, Wolfgang; Schwirtz, Ansgar

    2015-01-01

    Ergonomic design requirements are needed to develop optimum vehicle interfaces for the driver. The majority of the current specifications consider only anthropometric conditions and subjective evaluations of comfort. This paper examines specific biomechanical aspects to improve the current ergonomic requirements. Therefore, a research which involved 40 subjects was carried out to obtain more knowledge in the field of steering movement while driving a car. Five different shoulder-elbow joint configurations were analyzed using a driving simulator to find optimum posture for driving in respect of steering precision and steering velocity. Therefore, a 20 s precision test and a test to assess maximum steering velocity over a range of 90° steering motion have been conducted. The results show that driving precision, as well as maximum steering velocity, are significantly increased in mid-positions (elbow angles of 95° and 120°) compared to more flexed (70°) or extended (145° and 160°) postures. We conclude that driver safety can be enhanced by implementing these data in the automotive design process because faster and highly precise steering can be important during evasive actions and in accident situations. In addition, subjective comfort rating, analyzed with questionnaires, confirmed experimental results. Copyright © 2014 Elsevier Ltd and The Ergonomics Society. All rights reserved.

  14. Levofloxacin-induced hepatotoxicity and death.

    PubMed

    Gulen, Muge; Ay, Mehmet Oguzhan; Avci, Akkan; Acikalin, Ayca; Icme, Ferhat

    2015-01-01

    Drug-induced hepatotoxicity is a major cause of hepatocellular injury in patients admitting to emergency services with acute liver failure. Hepatic necrosis may be at varying degrees from mild elevations in transaminases to fulminant hepatitis, and even death. The case of a 53-year-old female patient with toxic hepatitis due to levofloxacin and multiple organ failure secondary to toxic hepatitis is presented. Patient suffered itching, redness, and rash after receiving a single dose of 750 mg of levofloxacin tablets for pulmonary infection 10 days ago. Skin lesions had regressed within 3 days, but desquamation formed all over the body. After the fifth day of drug intake, complaints of abdominal pain, vomiting, and yellowing in skin color had started. The patient was referred to our emergency department with these complaints 10 days after drug intake. Patient was thought as a candidate for liver transplant, but cardiopulmonary arrest occurred, and the patient died before she could be referred to a transplant center. This case is important because hepatotoxicity and death due to levofloxacin is uncommon in the literature.

  15. Children and Complementary Health Approaches

    MedlinePlus

    ... were natural products 2 (fish oil, melatonin, and probiotics), and chiropractic or osteopathic manipulation. For children, complementary ... nih.gov E-mail: ods@nih.gov U.S. Food and Drug Administration (FDA) The FDA oversees the ...

  16. Robot-Assisted Needle Steering

    PubMed Central

    Reed, Kyle B.; Majewicz, Ann; Kallem, Vinutha; Alterovitz, Ron; Goldberg, Ken; Cowan, Noah J.; Okamura, Allison M.

    2012-01-01

    Needle insertion is a critical aspect of many medical treatments, diagnostic methods, and scientific studies, and is considered to be one of the simplest and most minimally invasive medical procedures. Robot-assisted needle steering has the potential to improve the effectiveness of existing medical procedures and enable new ones by allowing increased accuracy through more dexterous control of the needle tip path and acquisition of targets not accessible by straight-line trajectories. In this article, we describe a robot-assisted needle steering system that uses three integrated controllers: a motion planner concerned with guiding the needle around obstacles to a target in a desired plane, a planar controller that maintains the needle in the desired plane, and a torsion compensator that controls the needle tip orientation about the axis of the needle shaft. Experimental results from steering an asymmetric-tip needle in artificial tissue demonstrate the effectiveness of the system and its sensitivity to various environmental and control parameters. In addition, we show an example of needle steering in ex vivo biological tissue to accomplish a clinically relevant task, and highlight challenges of practical needle steering implementation. PMID:23028210

  17. A Guide to the FDA.

    ERIC Educational Resources Information Center

    Miller, Annetta K.

    The United States Food and Drug Administration (FDA) collects information in seven areas: foods, cosmetics, human drugs, animal drugs and feeds, medical devices, biologics, and electronic radiological products. By using procedures outlined in the Freedom of Information Act, the public may get specific information from such FDA files as inspection…

  18. 21 CFR 60.34 - FDA action on petitions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FDA action on petitions. 60.34 Section 60.34 Food... RESTORATION Due Diligence Petitions § 60.34 FDA action on petitions. (a) Within 90 days after FDA receives a... during the regulatory review period. FDA will publish its due diligence determination in the Federal...

  19. 21 CFR 60.34 - FDA action on petitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FDA action on petitions. 60.34 Section 60.34 Food... RESTORATION Due Diligence Petitions § 60.34 FDA action on petitions. (a) Within 90 days after FDA receives a... during the regulatory review period. FDA will publish its due diligence determination in the Federal...

  20. 21 CFR 60.34 - FDA action on petitions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FDA action on petitions. 60.34 Section 60.34 Food... RESTORATION Due Diligence Petitions § 60.34 FDA action on petitions. (a) Within 90 days after FDA receives a... during the regulatory review period. FDA will publish its due diligence determination in the Federal...

  1. 21 CFR 60.34 - FDA action on petitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FDA action on petitions. 60.34 Section 60.34 Food... RESTORATION Due Diligence Petitions § 60.34 FDA action on petitions. (a) Within 90 days after FDA receives a... during the regulatory review period. FDA will publish its due diligence determination in the Federal...

  2. 21 CFR 60.34 - FDA action on petitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FDA action on petitions. 60.34 Section 60.34 Food... RESTORATION Due Diligence Petitions § 60.34 FDA action on petitions. (a) Within 90 days after FDA receives a... during the regulatory review period. FDA will publish its due diligence determination in the Federal...

  3. Doing business with the NIH

    PubMed Central

    Ben-Menachem, Gil; Ferguson, Steven M; Balakrishnan, Krishna

    2009-01-01

    Young biotech startups can benefit hugely from the US National Institutes of Health (NIH), not least because of the agency's non-dilutive funding, guidance, and opportunities for collaboration. Increasingly, however, there is a fair bit of misunderstanding about what the NIH can and cannot do for a biotech entrepreneur. PMID:16475248

  4. Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats.

    PubMed

    Jiang, Peng; Zhang, Xiuwen; Huang, Yutong; Cheng, Nengneng; Ma, Yueming

    2017-10-25

    Our previous study showed that kurarinone was the main hepatotoxic ingredient of Sophora flavescens , accumulating in the liver. This study characterized the mechanism of Sophora flavescens extract (ESF) hepatotoxicity and hepatic accumulation of kurarinone. ESF impaired hepatic function and caused fat accumulation in the liver after oral administration (1.25 and 2.5 g/kg for 14 days in rats). Serum metabolomics evaluation based on high-resolution mass spectrometry was conducted and real-time PCR was used to determine the expression levels of CPT-1, CPT-2, PPAR-α, and LCAD genes. Effects of kurarinone on triglyceride levels were evaluated in HL-7702 cells. Tissue distribution of kurarinone and kurarinone glucuronides was analyzed in rats receiving ESF (2.5 g/kg). Active uptake of kurarinone and kurarinone glucuronides was studied in OAT2-, OATP1B1-, OATP2B1-, and OATP1B3-transfected HEK293 cells. Our results revealed that after oral administration of ESF in rats, kurarinone glucuronides were actively transported into hepatocytes by OATP1B3 and hydrolyzed into kurarinone, which inhibited fatty acid β-oxidation through the reduction of l-carnitine and the inhibition of PPAR-α pathway, ultimately leading to lipid accumulation and liver injury. These findings contribute to understanding hepatotoxicity of kurarinone after oral administration of ESF.

  5. Analysis of 90 cases of antithyroid drug-induced severe hepatotoxicity over 13 years in China.

    PubMed

    Yang, Jun; Li, Lin-Fa; Xu, Qin; Zhang, Jun; Weng, Wan-Wen; Zhu, Yang-Jun; Dong, Meng-Jie

    2015-03-01

    Antithyroid drug (ATD)-induced severe hepatotoxicity is a rare but serious complication of ATD therapy. The characteristics of severe hepatotoxicity have been reported in only a small number of patients. Ninety patients with ATD-induced severe hepatotoxicity presenting during a 13 year period (2000-2013) who were about to undergo nuclear medicine therapy with (131)I from a sample of 8864 patients with hyperthyroidism were studied, and the outcomes were evaluated. The mean age of the patients with ATD-induced severe hepatotoxicity was 41.6±12.5 years (mean±standard deviation), and the female to male ratio was 2.2:1. The methimazole (MMI) dose given at the onset was 19.1±7.4 mg/day. The propylthiouracil (PTU) dose given at the onset was 212.8±105.0 mg/day. ATD-induced severe hepatotoxicity occurred in 63.3%, 75.6%, and 81.1% of patients within 4, 8, and 12 weeks of the onset of ATD therapy, respectively. The types of severe hepatotoxicity did not differ significantly between the MMI and PTU groups (p=0.188). The frequency of the cholestatic type in the MMI group (35.3%, 18/51) was higher than that in the PTU group (17.9%, 7/39), but these frequencies were not significantly different (p=0.069). The patients who were treated with (131)I received an average dose of 279.1±86.1 MBq (n=84). Therapy was successful in 60 of the 67 patients (89.6%). The success rate was equivalent (p=0.696) between the groups receiving MMI (91.7%, 33/36) and PTU (87.1%, 27/31). Severe hepatotoxicity tends to occur within the first three months after the onset of ATD therapy. The type of ATD-induced severe hepatotoxicity did not differ between the MMI and PTU groups. (131)I therapy is an effective treatment approach for patients with ATD-induced severe hepatotoxicity.

  6. Hepatotoxicity induced by methimazole in a previously healthy patient.

    PubMed

    Gallelli, Luca; Staltari, Orietta; Palleria, Caterina; De Sarro, Giovambattista; Ferraro, Maria

    2009-09-01

    We report a case of hepatotoxicity induced by methimazole treatment in a patient affected by hyperthyroidism. A 54-year-old man, presented to our observation for palpitations, excessive sweating, weakness, heat intolerance and weight loss. On physical examination, his blood pressure was 140/90 mmHg and heart beat was 100/min regular. He had mild tremors and left exophthalmos. Laboratory test revealed a significant increase in serum thyroid hormone levels with a decrease in thyroid stimulating hormone levels. A diagnosis of hyperthyroidism was made and he began treatment with methimazole (30 mg/day). Fourteen days later, he returned for the development of scleral icterus, followed by dark urine, and abdominal pain in the right upper quadrant. Laboratory examinations and liver biopsy performed a diagnosis of cholestatic hepatitis, secondary to methimazole usage. Methimazole was promptly withdrawn and cholestyramine, ursodeoxycholic acid, and chlorpheniramine were given. After five days, abdominal pain resolved and laboratory parameters returned to normal. Naranjo probability scale indicated a probable relationship between hepatotoxicity and methimazole therapy. In conclusion physicians should be aware the risk of hepatotoxicity related with methimazole.

  7. Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI.

    PubMed

    Bliven-Sizemore, E E; Sterling, T R; Shang, N; Benator, D; Schwartzman, K; Reves, R; Drobeniuc, J; Bock, N; Villarino, M E

    2015-09-01

    Nine months of daily isoniazid (9H) and 3 months of once-weekly rifapentine plus isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear. To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity. Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 x ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV. Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors. The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred.

  8. NIH Researchers Identify OCD Risk Gene

    MedlinePlus

    ... News From NIH NIH Researchers Identify OCD Risk Gene Past Issues / Summer 2006 Table of Contents For ... and Alcoholism (NIAAA) have identified a previously unknown gene variant that doubles an individual's risk for obsessive- ...

  9. No-cloning of quantum steering

    NASA Astrophysics Data System (ADS)

    Chiu, Ching-Yi; Lambert, Neill; Liao, Teh-Lu; Nori, Franco; Li, Che-Ming

    2016-06-01

    Einstein-Podolsky-Rosen (EPR) steering allows two parties to verify their entanglement, even if one party’s measurements are untrusted. This concept has not only provided new insights into the nature of non-local spatial correlations in quantum mechanics, but also serves as a resource for one-sided device-independent quantum information tasks. Here, we investigate how EPR steering behaves when one-half of a maximally entangled pair of qudits (multidimensional quantum systems) is cloned by a universal cloning machine. We find that EPR steering, as verified by a criterion based on the mutual information between qudits, can only be found in one of the copy subsystems but not both. We prove that this is also true for the single-system analogue of EPR steering. We find that this restriction, which we term ‘no-cloning of quantum steering’, elucidates the physical reason why steering can be used to secure sources and channels against cloning-based attacks when implementing quantum communication and quantum computation protocols.

  10. [Hepatotoxicity in healthy infants exposed to nevirapine during pregnancy].

    PubMed

    Iveli, Pablo; Noguera-Julian, Antoni; Soler-Palacín, Pere; Martín-Nalda, Andrea; Rovira-Girabal, Núria; Fortuny-Guasch, Clàudia; Figueras-Nadal, Concepció

    2016-01-01

    The use of nevirapine in HIV-infected pregnant women is discouraged due to its potential to cause hepatotoxicity. There is limited information available on the toxicity in non-HIV infected newborn exposed to this drug during pregnancy. The aim of the study is to determine the extent of hepatotoxicity in the newborn exposed to nevirapine and HIV during pregnancy. A cross-sectional, observational, multicenter study was conducted on a cohort of healthy infants born to HIV-infected mothers, in whom the first determination of alanine aminotransferase (ALT), before 6weeks of age, was collected. Patients were allocated to 2groups according to exposure to nevirapine during pregnancy. Hepatotoxicity was rated according to the AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS). This study included 160newborns from 159pregnancies (88exposed to nevirapine-based regimens and 71 exposed to protease inhibitors-based therapies). No cases of hepatotoxicity were observed according to the DAIDS Table for Grading. Two cases of ALT above normal values (2.8%; 95%CI: 0.3-9.8%) were observed in patients not exposed to nevirapine, and one case (1.1%; 95%CI: 0.0-6.1%) in the group exposed to nevirapine (P=.585). The lack of differences between groups suggests that highly active antiretroviral treatment regimens including nevirapine administered during pregnancy do not involve a higher risk of liver disease compared to other treatment combinations. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  11. A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity

    PubMed Central

    Patel, Suraj J; Luther, Jay; Bohr, Stefan; Iracheta-Vellve, Arvin; Li, Matthew; King, Kevin R; Chung, Raymond T; Yarmush, Martin L

    2016-01-01

    Objectives: Acetaminophen (APAP)-induced hepatotoxicity is a major cause of morbidity and mortality. The current pharmacologic treatment for APAP hepatotoxicity, N-acetyl cysteine (NAC), targets the initial metabolite-driven injury but does not directly affect the host inflammatory response. Because of this, NAC is less effective if given at later stages in the disease course. Resolvins, a novel group of lipid mediators shown to attenuate host inflammation, may be a therapeutic intervention for APAP hepatotoxicity. Methods: The temporal patterns of liver injury and neutrophil activation were investigated in a murine model of APAP hepatotoxicity. In addition, the effect of neutrophil depletion and resolvin administration on the severity of liver injury induced by APAP was studied. In vitro studies to investigate the mechanism of resolvin effect on hepatocyte injury and neutrophil adhesion were performed. Results: We demonstrate that hepatic neutrophil activation occurs secondary to the initial liver injury induced directly by APAP. We also show that neutrophil depletion attenuates APAP-induced liver injury, and administration of resolvins hours after APAP challenge not only attenuates liver injury, but also extends the therapeutic window eightfold compared to NAC. Mechanistic in vitro analysis highlights resolvins' ability to inhibit neutrophil attachment to endothelial cells in the presence of the reactive metabolite of APAP. Conclusions: This study highlights the ability of resolvins to protect against APAP-induced liver injury and extend the therapeutic window compared to NAC. Although the mechanism for resolvin-mediated hepatoprotection is likely multifactorial, inhibition of neutrophil infiltration and activation appears to play an important role. PMID:26986653

  12. Skin Cancer: NIH Research to Results

    MedlinePlus

    ... Javascript on. Feature: Skin Cancer NIH Research to Results Past Issues / Summer 2013 Table of Contents Scientists ... Healthcare Checkup Catches Melanoma Early / NIH Research to Results / Skin and Sun – Safety First / Quiz: Test Your ...

  13. Investigation of Motorcycle Steering Torque Components

    NASA Astrophysics Data System (ADS)

    Cossalter, V.; Lot, R.; Massaro, M.; Peretto, M.

    2011-10-01

    When driving along a circular path, the rider controls a motorcycle mainly by the steering torque. This work addresses an in-depth analysis of the steady state cornering and in particular the decomposition of the motorcycle steering torque in its main components, such as road-tyre forces, gyroscopic torques, centrifugal and gravity effects. A detailed and experimentally validated multibody model of the motorcycle is used herein to analyze the steering torque components at different speeds and lateral accelerations. First the road tests are compared with the numerical results for three different vehicles and then a numerical investigation is carried out to decompose the steering torque. Finally, the effect of longitudinal acceleration and deceleration on steering torque components is presented.

  14. Acute Hepatotoxicity of Intravenous Amiodarone: Case Report and Review of the Literature.

    PubMed

    Chen, Chia-Chi; Wu, Chien-Chih

    2016-01-01

    Amiodarone is a class III antiarrhythmic drug widely used for the treatment of both supraventricular and ventricular arrhythmias in intensive care unit. Hepatotoxicity of amiodarone is usually mild and delayed onset. Acute hepatotoxicity is a rare side effect and usually correlated to intravenous form use. In this case, acute hepatocellular injury occurred within 24 hours after the administration of intravenous amiodarone. Liver enzyme significantly improved after holding intravenous amiodarone use. Because ventricular arrhythmia persisted and side effects occurred to alternative therapy, low dose of oral amiodarone was resumed and hepatotoxicity did not occur afterward. Acute hepatotoxicity of intravenous amiodarone is possibly related to polysorbate 80, the solubilizer of amiodarone infusion or higher dose. As a result, when intravenous amiodarone is prescribed, closely monitoring liver enzyme is highly suggested. If acute hepatitis takes place secondary to intravenous amiodarone, oral therapy should not be resumed afterward. If there is no alternative treatment, lower dose of oral amiodarone (≤200 mg/d) could be tried and should monitor liver function regularly.

  15. 46 CFR 169.251 - Steering apparatus.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 7 2011-10-01 2011-10-01 false Steering apparatus. 169.251 Section 169.251 Shipping... Inspection and Certification Inspections § 169.251 Steering apparatus. At each inspection for certification and periodic inspection the steering apparatus is inspected and operationally tested to determine that...

  16. 46 CFR 169.251 - Steering apparatus.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Steering apparatus. 169.251 Section 169.251 Shipping... Inspection and Certification Inspections § 169.251 Steering apparatus. At each inspection for certification and periodic inspection the steering apparatus is inspected and operationally tested to determine that...

  17. 77 FR 54584 - Final Action Under the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-05

    ... National Institutes of Health (NIH) Office of Biotechnology Activities, Office of Science Policy (NIH/OBA... in the life sciences, such as directed molecular evolution and viral reverse genetics, has the... synthetic biology), and (2) a recommendation from the National Science Advisory Board for Biosecurity (NSABB...

  18. 8th GCC: consolidated feedback to US FDA on the 2013 draft FDA guidance on bioanalytical method validation.

    PubMed

    Bower, Joseph; Fast, Douglas; Garofolo, Fabio; Gouty, Dominique; Hayes, Roger; Lowes, Steve; Nicholson, Robert; LeLacheur, Richard; Bravo, Jennifer; Shoup, Ronald; Dumont, Isabelle; Carbone, Mary; Zimmer, Jennifer; Ortuno, Jordi; Caturla, Maria Cruz; Datin, Jim; Lansing, Tim; Fatmi, Saadya; Struwe, Petra; Sheldon, Curtis; Islam, Rafiqul; Yu, Mathilde; Hulse, Jim; Kamerud, John; Lin, John; Doughty, John; Kurylak, Kai; Tang, Daniel; Buonarati, Mike; Blanchette, Alexandre; Levesque, Ann; Gagnon-Carignan, Sofi; Lin, Jenny; Ray, Gene; Liu, Yanseng; Khan, Masood; Xu, Allan; El-Sulayman, Gibran; DiMarco, Chantal; Bouhajib, Mohammed; Tacey, Dick; Jenkins, Rand; der Strate, Barry van; Briscoe, Chad; Karnik, Shane; Rhyne, Paul; Garofolo, Wei; Schultz, Gary; Roberts, Andrew; Redrup, Mike; DuBey, Ira; Conliffe, Phyllis; Pekol, Teri; Hantash, Jamil; Cojocaru, Laura; Allen, Mike; Reuschel, Scott; Watson, Andrea; Farrell, Colin; Groeber, Elizabeth; Malone, Michele; Nowatzke, William; Fang, Xinping

    2014-01-01

    The 8th GCC Closed Forum for Bioanalysis was held in Baltimore, MD, USA on 5 December 2013, immediately following the 2013 AAPS Workshop (Crystal City V): Quantitative Bioanalytical Methods Validation and Implementation--The 2013 Revised FDA Guidance. This GCC meeting was organized to discuss the contents of the draft revised FDA Guidance on bioanalytical method validation that was published in September 2013 and consolidate the feedback of the GCC members. In attendance were 63 senior-level participants, from seven countries, representing 46 bioanalytical CRO companies/sites. This event represented a unique opportunity for CRO bioanalytical experts to share their opinions and concerns regarding the draft FDA Guidance, and to build unified comments to be provided to the FDA.

  19. The role of chronic hepatitis in isoniazid hepatotoxicity during treatment for latent tuberculosis infection.

    PubMed

    Bliven, E E; Podewils, L J

    2009-09-01

    To examine chronic viral hepatitis (CVH) as a risk factor for hepatotoxicity during isoniazid (INH) treatment for latent tuberculosis infection (LTBI). A search of MEDLINE (1966-May 2008) was conducted using the terms 'tuberculosis', 'antitubercular', 'therapeutics', 'treatment', 'prevention', 'prophylaxis', 'hepatitis', 'toxic hepatitis', 'hepatotoxic', 'liver' and 'injury'. Peer-reviewed, English-language articles describing the relationship between a history of CVH and occurrence of hepatotoxicity during LTBI treatment were selected. We limited CVH diagnoses to reports with positive serological test or biopsy for hepatitis B or C. Risk ratios and 95% confidence intervals were abstracted or derived. We reviewed 486 abstracts, and 11 studies met the selection criteria. Populations included in the studies were the general population (n = 6) and transplant recipients (n = 5). The variability in study designs and case finding practices precluded performing a quantitative meta-analysis. Two studies of former or current drug users reported a consistent, positive association between chronic hepatitis C infection and INH hepatotoxicity. Other risk ratios did not significantly or consistently show any association between CVH in patients treated for LTBI and the development of INH hepatotoxicity. Owing to the limited number of published papers, CVH was not established as a risk factor for INH hepatotoxicity during LTBI treatment. Controlled studies are needed to define the safety and tolerability of LTBI treatment in those with CVH and to provide an evidence base for recommendations for LTBI treatment in persons with CVH.

  20. Identifying 2 prenylflavanones as potential hepatotoxic compounds in the ethanol extract of Sophora flavescens.

    PubMed

    Yu, Qianqian; Cheng, Nengneng; Ni, Xiaojun

    2013-11-01

    Zhixue capsule is a prescription for hemorrhoid commonly used in traditional Chinese medicine. This drug was recalled by the State Food and Drug Administration in 2008 because of severe adverse hepatic reactions. Zhixue capsule is composed of ethanol extracts of Cortex Dictamni (ECD) and Sophora flavescens (ESF). In our preliminary study, we observed the hepatotoxic effects of ESF on rat primary hepatocytes. However, ECD did not exhibit hepatotoxicity at the same concentration range. In this study, ESF was evaluated for its potential hepatotoxic effects on rats. Bioassay-guided isolation was used to identify the material basis for hepatotoxicity. Treatment with 1.25 g/kg and 2.5 g/kg ESF significantly elevated the alanine aminotransferase and aspartate aminotransferase levels in the serum. The changes in the levels of transaminases were supported by the remarkable fatty degeneration of liver histopathology. Further investigations using bioassay-guided isolation and analysis indicated that prenylated flavanones accounted for the positive hepatotoxic results. Two isolated compounds were identified, kurarinone and sophoraflavanone G, using nuclear magnetic resonance and mass spectrometry techniques. These compounds have potent toxic effects on primary rat hepatocytes (with IC50 values of 29.9 μM and 16.5 μM) and human HL-7702 liver cells (with IC50 values of 48.2 μM and 40.3 μM), respectively. Consequently, the hepatotoxic constituents of S. flavescens were determined to be prenylated flavanones, kurarinone, and sophoraflavanone G. © 2013 Institute of Food Technologists®

  1. 46 CFR 176.814 - Steering systems.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 7 2014-10-01 2014-10-01 false Steering systems. 176.814 Section 176.814 Shipping COAST...) INSPECTION AND CERTIFICATION Material Inspections § 176.814 Steering systems. At each initial and subsequent inspection for certification the owner or managing operator shall be prepared to test the steering systems of...

  2. 46 CFR 176.814 - Steering systems.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 7 2013-10-01 2013-10-01 false Steering systems. 176.814 Section 176.814 Shipping COAST...) INSPECTION AND CERTIFICATION Material Inspections § 176.814 Steering systems. At each initial and subsequent inspection for certification the owner or managing operator shall be prepared to test the steering systems of...

  3. 46 CFR 176.814 - Steering systems.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Steering systems. 176.814 Section 176.814 Shipping COAST...) INSPECTION AND CERTIFICATION Material Inspections § 176.814 Steering systems. At each initial and subsequent inspection for certification the owner or managing operator shall be prepared to test the steering systems of...

  4. Quantification of Gaussian quantum steering.

    PubMed

    Kogias, Ioannis; Lee, Antony R; Ragy, Sammy; Adesso, Gerardo

    2015-02-13

    Einstein-Podolsky-Rosen steering incarnates a useful nonclassical correlation which sits between entanglement and Bell nonlocality. While a number of qualitative steering criteria exist, very little has been achieved for what concerns quantifying steerability. We introduce a computable measure of steering for arbitrary bipartite Gaussian states of continuous variable systems. For two-mode Gaussian states, the measure reduces to a form of coherent information, which is proven never to exceed entanglement, and to reduce to it on pure states. We provide an operational connection between our measure and the key rate in one-sided device-independent quantum key distribution. We further prove that Peres' conjecture holds in its stronger form within the fully Gaussian regime: namely, steering bound entangled Gaussian states by Gaussian measurements is impossible.

  5. ANTAGONISM OF CHLOROBENZENE-INDUCED HEPATOTOXICITY BY LINDANE

    EPA Science Inventory

    In a 2x2 factorial designed experiment involving chlorobenzene and gamma-hexachlorocyclohexane (lindane), the hepatotoxicity induced by a challenge dose of chlorobenzene was altered by the pretreatments due to selective changes in various metabolic pathways. These changes resulte...

  6. FDA Approves Lutathera for Neuroendocrine Tumors

    Cancer.gov

    FDA has approved Lutathera® for some people with neuroendocrine tumors (NETs) that affect the digestive tract. On January 29, FDA approved Lutathera® for adult patients with advanced NETs that affect the pancreas or gastrointestinal tract, known as GEP-NETs.

  7. 46 CFR 115.814 - Steering systems.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 4 2011-10-01 2011-10-01 false Steering systems. 115.814 Section 115.814 Shipping COAST... Inspections § 115.814 Steering systems. At each initial and subsequent inspection for certification the owner or managing operator shall be prepared to test the steering systems of the vessel and make them...

  8. 46 CFR 115.814 - Steering systems.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 4 2012-10-01 2012-10-01 false Steering systems. 115.814 Section 115.814 Shipping COAST... Inspections § 115.814 Steering systems. At each initial and subsequent inspection for certification the owner or managing operator shall be prepared to test the steering systems of the vessel and make them...

  9. 46 CFR 115.814 - Steering systems.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 4 2013-10-01 2013-10-01 false Steering systems. 115.814 Section 115.814 Shipping COAST... Inspections § 115.814 Steering systems. At each initial and subsequent inspection for certification the owner or managing operator shall be prepared to test the steering systems of the vessel and make them...

  10. 33 CFR 401.18 - Steering lights.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Steering lights. 401.18 Section... TRANSPORTATION SEAWAY REGULATIONS AND RULES Regulations Condition of Vessels § 401.18 Steering lights. Every vessel shall be equipped with: (a) A steering light located on the centerline at or near the stem of the...

  11. 33 CFR 401.18 - Steering lights.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 3 2014-07-01 2014-07-01 false Steering lights. 401.18 Section... TRANSPORTATION SEAWAY REGULATIONS AND RULES Regulations Condition of Vessels § 401.18 Steering lights. Every vessel shall be equipped with: (a) A steering light located on the centerline at or near the stem of the...

  12. 33 CFR 401.18 - Steering lights.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 3 2013-07-01 2013-07-01 false Steering lights. 401.18 Section... TRANSPORTATION SEAWAY REGULATIONS AND RULES Regulations Condition of Vessels § 401.18 Steering lights. Every vessel shall be equipped with: (a) A steering light located on the centerline at or near the stem of the...

  13. 33 CFR 401.18 - Steering lights.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Steering lights. 401.18 Section... TRANSPORTATION SEAWAY REGULATIONS AND RULES Regulations Condition of Vessels § 401.18 Steering lights. Every vessel shall be equipped with: (a) A steering light located on the centerline at or near the stem of the...

  14. 33 CFR 401.18 - Steering lights.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 3 2012-07-01 2012-07-01 false Steering lights. 401.18 Section... TRANSPORTATION SEAWAY REGULATIONS AND RULES Regulations Condition of Vessels § 401.18 Steering lights. Every vessel shall be equipped with: (a) A steering light located on the centerline at or near the stem of the...

  15. Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose.

    PubMed

    Wong, Anselm; Sivilotti, Marco L A; Graudins, Andis

    2017-06-01

    The paracetamol-aminotransferase multiplication product (APAP × ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses. The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose. We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L. Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product <10,000 mg/L × IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500 mg/L × IU/L. When calculated within eight hours of ingestion, mild elevations of the multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity. In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L × IU/L, it was very strongly associated with the development

  16. NIH Research on Treating Pain | NIH MedlinePlus the Magazine

    MedlinePlus

    ... please turn Javascript on. Feature: Chronic Pain NIH Research on Treating Pain Past Issues / Spring 2011 Table of Contents Among the many research projects related to chronic pain that are under ...

  17. CCCT - Patient Advocate Steering Committee

    Cancer.gov

    The Patient Advocate Steering Committee (PASC) works to ensure advocates involved with the Scientific Steering Committees (SSCs) are completely integrated in the development, implementation, and monitoring of clinical trials within those groups.

  18. Allopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity.

    PubMed

    Giamanco, Nicole M; Cunningham, Bethany S; Klein, Laura S; Parekh, Dina S; Warwick, Anne B; Lieuw, Kenneth

    2016-03-01

    6-Mercaptopurine (6-MP) is the mainstay of treatment for acute lymphoblastic leukemia and lymphoblastic lymphoma. It is metabolized into the pharmacologically active, 6-thioguanine nucleotide (6-TGN), and 6-methyl mercaptopurine nucleotides (6-MMPN), which is associated with hepatotoxicity that jeopardizes antileukemic therapy. Allopurinol alters the metabolism of 6-MP to increase 6-TGN levels and decreases 6-methyl mercaptopurine nucleotides levels. We report 2 cases in which combination therapy of allopurinol with 6-MP was used successfully to avoid hepatotoxicity while delivering adequate 6-TGN levels. We suggest that this combination therapy can be used safely to change the metabolite production in patients who develop excessive hepatotoxicity.

  19. 36 CFR 13.980 - Other FDA closures and restrictions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 36 Parks, Forests, and Public Property 1 2013-07-01 2013-07-01 false Other FDA closures and... Preserve Frontcountry Developed Area (fda) § 13.980 Other FDA closures and restrictions. The Superintendent may prohibit or otherwise restrict activities in the FDA to protect public health, safety, or park...

  20. 36 CFR 13.980 - Other FDA closures and restrictions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 36 Parks, Forests, and Public Property 1 2014-07-01 2014-07-01 false Other FDA closures and... Preserve Frontcountry Developed Area (fda) § 13.980 Other FDA closures and restrictions. The Superintendent may prohibit or otherwise restrict activities in the FDA to protect public health, safety, or park...

  1. 36 CFR 13.980 - Other FDA closures and restrictions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 1 2011-07-01 2011-07-01 false Other FDA closures and... Preserve Frontcountry Developed Area (fda) § 13.980 Other FDA closures and restrictions. The Superintendent may prohibit or otherwise restrict activities in the FDA to protect public health, safety, or park...

  2. 36 CFR 13.980 - Other FDA closures and restrictions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 36 Parks, Forests, and Public Property 1 2012-07-01 2012-07-01 false Other FDA closures and... Preserve Frontcountry Developed Area (fda) § 13.980 Other FDA closures and restrictions. The Superintendent may prohibit or otherwise restrict activities in the FDA to protect public health, safety, or park...

  3. 36 CFR 13.980 - Other FDA closures and restrictions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false Other FDA closures and... Preserve Frontcountry Developed Area (fda) § 13.980 Other FDA closures and restrictions. The Superintendent may prohibit or otherwise restrict activities in the FDA to protect public health, safety, or park...

  4. RACE, ETHNICITY, AND NIH RESEARCH AWARDS

    PubMed Central

    Ginther, Donna K.; Schaffer, Walter T.; Schnell, Joshua; Masimore, Beth; Liu, Faye; Haak, Laurel L.; Kington, Raynard

    2012-01-01

    We investigated the association between a U.S. National Institutes of Health (NIH) R01 applicant’s self-identified race or ethnicity and the probability of receiving an award by using data from the NIH IMPAC II grant database, the Thomson Reuters Web of Science, and other sources. Although proposals with strong priority scores were equally likely to be funded regardless of race, we find that Asians are 4 percentage points and black or African-American applicants are 13 percentage points less likely to receive NIH investigator-initiated research funding compared with whites. After controlling for the applicant’s educational background, country of origin, training, previous research awards, publication record, and employer characteristics, we find that black or African-American applicants remain 10 percentage points less likely than whites to be awarded NIH research funding. Our results suggest some leverage points for policy intervention. PMID:21852498

  5. Beam Steering Devices Reduce Payload Weight

    NASA Technical Reports Server (NTRS)

    2012-01-01

    Scientists have long been able to shift the direction of a laser beam, steering it toward a target, but often the strength and focus of the light is altered. For precision applications, where the quality of the beam cannot be compromised, scientists have typically turned to mechanical steering methods, redirecting the source of the beam by swinging the entire laser apparatus toward the target. Just as the mechanical methods used for turning cars has evolved into simpler, lighter, power steering methods, so has the means by which researchers can direct lasers. Some of the typical contraptions used to redirect lasers are large and bulky, relying on steering gimbals pivoted, rotating supports to shift the device toward its intended target. These devices, some as large and awkward as a piece of heavy luggage, are subject to the same issues confronted by mechanical parts: Components rub, wear out, and get stuck. The poor reliability and bulk not to mention the power requirements to run one of the machines have made mechanical beam steering components less than ideal for use in applications where weight, bulk, and maneuverability are prime concerns, such as on an unmanned aerial vehicle (UAV) or a microscope. The solution to developing reliable, lighter weight, nonmechanical steering methods to replace the hefty steering boxes was to think outside the box, and a NASA research partner did just that by developing a new beam steering method that bends and redirects the beam, as opposed to shifting the entire apparatus. The benefits include lower power requirements, a smaller footprint, reduced weight, and better control and flexibility in steering capabilities. Such benefits are realized without sacrificing aperture size, efficiency, or scanning range, and can be applied to myriad uses: propulsion systems, structures, radiation protection systems, and landing systems.

  6. 10 New NIH Research Highlights | NIH MedlinePlus the Magazine

    MedlinePlus

    ... Translational Sciences, and other NIH components. Researchers Identify Energy-Burning Fat Cells Humans have both white and brown fat cells. Brown fat burns energy and helps maintain body temperature, while white fat ...

  7. 42 CFR 405.203 - FDA categorization of investigational devices.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 2 2010-10-01 2010-10-01 false FDA categorization of investigational devices. 405... Coverage Decisions That Relate to Health Care Technology § 405.203 FDA categorization of investigational devices. (a) The FDA assigns a device with an FDA-approved IDE to one of two categories: (1) Experimental...

  8. 21 CFR 314.102 - Communications between FDA and applicants.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Communications between FDA and applicants. 314.102... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.102 Communications between FDA and applicants. (a) General...

  9. 42 CFR 405.203 - FDA categorization of investigational devices.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 2 2014-10-01 2014-10-01 false FDA categorization of investigational devices. 405... Coverage Decisions That Relate to Health Care Technology § 405.203 FDA categorization of investigational devices. (a) The FDA assigns a device with an FDA-approved IDE to one of two categories: (1) Experimental...

  10. 42 CFR 405.203 - FDA categorization of investigational devices.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 2 2013-10-01 2013-10-01 false FDA categorization of investigational devices. 405... Coverage Decisions That Relate to Health Care Technology § 405.203 FDA categorization of investigational devices. (a) The FDA assigns a device with an FDA-approved IDE to one of two categories: (1) Experimental...

  11. 21 CFR 314.102 - Communications between FDA and applicants.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Communications between FDA and applicants. 314.102... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.102 Communications between FDA and applicants. (a) General...

  12. 21 CFR 314.102 - Communications between FDA and applicants.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Communications between FDA and applicants. 314.102... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.102 Communications between FDA and applicants. (a) General...

  13. 21 CFR 314.102 - Communications between FDA and applicants.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Communications between FDA and applicants. 314.102... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.102 Communications between FDA and applicants. (a) General...

  14. 42 CFR 405.203 - FDA categorization of investigational devices.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 2 2011-10-01 2011-10-01 false FDA categorization of investigational devices. 405... Coverage Decisions That Relate to Health Care Technology § 405.203 FDA categorization of investigational devices. (a) The FDA assigns a device with an FDA-approved IDE to one of two categories: (1) Experimental...

  15. 42 CFR 405.203 - FDA categorization of investigational devices.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 2 2012-10-01 2012-10-01 false FDA categorization of investigational devices. 405... Coverage Decisions That Relate to Health Care Technology § 405.203 FDA categorization of investigational devices. (a) The FDA assigns a device with an FDA-approved IDE to one of two categories: (1) Experimental...

  16. 21 CFR 314.102 - Communications between FDA and applicants.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Communications between FDA and applicants. 314.102... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.102 Communications between FDA and applicants. (a) General...

  17. Hepatotoxicity of illegal home-made alcohols.

    PubMed

    Gökce, Hasan; Akcan, Ramazan; Celikel, Adnan; Zeren, Cem; Ortanca, Ibrahim; Demirkiran, Sumeyra

    2016-10-01

    Alcohol-related hepatotoxicity is not only caused by excessive alcohol consumption but also caused and even accelerated by hepatotoxic ingredients other than ethanol. Concentrations of hepatotoxic substances might be significantly high, particularly in illegally produced home-made alcohols. In this study we aim to analyze the hepatotoxic effects of a home-made alcohol traditionally called "bogma raki" in Turkey. Fifty Wistar albino male rats were used. Five groups were randomly formed with ten animals in each. Besides laboratory diets, groups were fed as follows: Group 1 (control group) distilled water; Group 2 bogma raki with distilled water (%44 (v/v), 9.2 ml/kg/day); Group 3 bogma raki with distilled water (%44 (v/v), 9.2 ml/kg/day)+walnut (10 g/kg/day); Group 4 whisky with distilled water (%40 (v/v), 9.2 ml/kg/day); Group 5 distilled water + walnut (10 g/kg/day), for 28 days. The toxicological analysis of The spirits were analyzed using Hewlett-Packard (Palo Alto, CA) GC/MS system with HP 6890 gas chromatograph, an HP 5972 mass selective detector (MSD) and an HP 6890 automatic liquid sampler GC/MS; the pressure of the carrier gas helium was 6.0 bar and the split value with a ratio of 1:100. The injection unit temperature set to 250 °C and MS quadrupole temperature set to 280 °C. The MS quadrupole detector ionization energy set to 70 eV. The initial column temperature was 60 °C (for 4 min) programmed by 6 °C/min to final temperature 160 °C and kept for 8 min at 160 °C. Utilized whisky and bogma raki samples were analyzed for the amounts of trans-anethole, ethanol, methanol, 1-propanolol, butanol, 2-butanol, 2-methyl-1-propanolol (isobutanol) and 3-methylbutanol (isoamyl alcohol). Histopathological changes in liver tissues were graded as follows; normal = 0 (<10%), mild = 1 (10%-40%), moderate = 2 (40%-70%), severe = 3 (above 70%). Chemical composition of illegally produced raki sample (%v/v) was as follows: trans-anethole %1

  18. Molindone and hepatotoxicity.

    PubMed

    Bhatia, S C; Banta, L E; Ehrlich, D W

    1985-10-01

    An adolescent male with chronic schizophrenic disorder, paranoid type, was treated with molindone. He developed hepatotoxicity in the early treatment phase as evidenced by flu-like symptoms and laboratory abnormalities of liver functions. These symptoms and his hepatic functions improved on discontinuing molindone. Similar liver function trends were seen on reintroduction and subsequent withdrawal of the drug. Hepatic hypersensitivity has not been reported previously with the use of this drug. It is suggested that clinicians should be aware of this association and should assess hepatic functions in patients who develop a prodromal flu-like syndrome with this drug, especially in the early treatment phase.

  19. Rocuronium is more hepatotoxic than succinylcholine in vitro.

    PubMed

    Sauer, Martin; Piel, Ines; Haubner, Cristof; Richter, Georg; Mann, Miriam; Nöldge-Schomburg, Gabriele; Mencke, Thomas

    2017-09-01

    The development of liver failure is a major problem in critically ill patients. The hepatotoxicity of many drugs, as one important reason for liver failure, is poorly screened for in human models. Rocuronium and succinylcholine are neuromuscular blocking agents used for tracheal intubation and for rapid-sequence induction. We used an in-vitro test with a permanent cell line and compared rocuronium and succinylcholine for hepatotoxicity. In-vitro study. A basic science laboratory, University Hospital Rostock, Germany. The basic test compound is the permanent human liver cell line HepG2/C3A. In a standardised microtitre plate assay the toxicity of different concentrations of rocuronium, succinylcholine and plasma control was tested. After two incubation periods of 3 days, the viability of cells (XTT test, lactate dehydrogenase release and trypan blue staining), micro-albumin synthesis and the cytochrome 1A2 activity (metabolism of ethoxyresorufin) were measured. Differences between rocuronium and succinylcholine were assessed using the Kruskal-Wallis one-way test and two-tailed Mann-Whitney U test. Rocuronium, but not succinylcholine, led to a significant dose-dependent decrease of viability, albumin synthesis and cytochrome 1A2 activity of test cells. An in-vitro test with a cell line showed hepatotoxicity of rocuronium that was dose-dependent. Further studies are needed to investigate the underlying mechanisms of the effects of rocuronium on hepatic cellular integrity. Not suitable.

  20. 21 CFR 312.86 - Focused FDA regulatory research.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

  1. 21 CFR 312.86 - Focused FDA regulatory research.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

  2. 21 CFR 312.86 - Focused FDA regulatory research.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

  3. 21 CFR 312.86 - Focused FDA regulatory research.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

  4. 21 CFR 312.86 - Focused FDA regulatory research.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

  5. Driver behavior following an automatic steering intervention.

    PubMed

    Fricke, Nicola; Griesche, Stefan; Schieben, Anna; Hesse, Tobias; Baumann, Martin

    2015-10-01

    The study investigated driver behavior toward an automatic steering intervention of a collision mitigation system. Forty participants were tested in a driving simulator and confronted with an inevitable collision. They performed a naïve drive and afterwards a repeated exposure in which they were told to hold the steering wheel loosely. In a third drive they experienced a false alarm situation. Data on driving behavior, i.e. steering and braking behavior as well as subjective data was assessed in the scenarios. Results showed that most participants held on to the steering wheel strongly or counter-steered during the system intervention during the first encounter. Moreover, subjective data collected after the first drive showed that the majority of drivers was not aware of the system intervention. Data from the repeated drive in which participants were instructed to hold the steering wheel loosely, led to significantly more participants holding the steering wheel loosely and thus complying with the instruction. This study seems to imply that without knowledge and information of the system about an upcoming intervention, the most prevalent driving behavior is a strong reaction with the steering wheel similar to an automatic steering reflex which decreases the system's effectiveness. Results of the second drive show some potential for countermeasures, such as informing drivers shortly before a system intervention in order to prevent inhibiting reactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. 49 CFR 393.209 - Steering wheel systems.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS PARTS AND ACCESSORIES...) Steering column. The steering column must be securely fastened. (d) Steering system. Universal joints and...

  7. 49 CFR 393.209 - Steering wheel systems.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS PARTS AND ACCESSORIES...) Steering column. The steering column must be securely fastened. (d) Steering system. Universal joints and...

  8. 49 CFR 393.209 - Steering wheel systems.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS PARTS AND ACCESSORIES...) Steering column. The steering column must be securely fastened. (d) Steering system. Universal joints and...

  9. 49 CFR 393.209 - Steering wheel systems.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS PARTS AND ACCESSORIES...) Steering column. The steering column must be securely fastened. (d) Steering system. Universal joints and...

  10. 49 CFR 393.209 - Steering wheel systems.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS PARTS AND ACCESSORIES...) Steering column. The steering column must be securely fastened. (d) Steering system. Universal joints and...

  11. Methoxyflurane enhances allyl alcohol hepatotoxicity in rats. Possible involvement of increased acrolein formation.

    PubMed

    Kershaw, W C; Barsotti, D A; Leonard, T B; Dent, J G; Lage, G L

    1989-01-01

    The effect of methoxyflurane anesthesia on allyl alcohol-induced hepatotoxicity and the metabolism of allyl alcohol was studied in male rats. Hepatotoxicity was assessed by the measurement of serum alanine aminotransferase activity and histopathological examination. Allyl alcohol-induced hepatotoxicity was enhanced when allyl alcohol (32 mg/kg) was administered 4 hr before or up to 8 days after a single 10-min exposure to methoxyflurane vapors. The possibility that methoxyflurane increases alcohol dehydrogenase-dependent oxidation of allyl alcohol to acrolein, the proposed toxic metabolite, was evaluated by measuring the rate of acrolein formation in the presence of allyl alcohol and liver cytosol. The effect of methoxyflurane on alcohol dehydrogenase activity in liver cytosol was also assessed by measuring the rate of NAD+ utilization in the presence of ethyl alcohol or allyl alcohol. Alcohol dehydrogenase activity and rate of acrolein formation were elevated in methoxyflurane-pretreated rats. The results suggest that a modest increase in alcohol dehydrogenase activity and rate of acrolein formation markedly enhances allyl alcohol-induced hepatotoxicity.

  12. Highly sensitive beam steering with plasmonic antenna

    PubMed Central

    Rui, Guanghao; Zhan, Qiwen

    2014-01-01

    In this work, we design and study a highly sensitive beam steering device that integrates a spiral plasmonic antenna with a subwavelength metallic waveguide. The short effective wavelength of the surface plasmon polaritons (SPPs) mode supported by the metallic waveguide is exploited to dramatically miniaturize the device and improve the sensitivity of the beam steering. Through introducing a tiny displacement of feed point with respect to the geometrical center of the spiral plasmonic antenna, the direction of the radiation can be steered at considerably high angles. Simulation results show that steering angles of 8°, 17° and 34° are obtainable for a displacement of 50 nm, 100 nm and 200 nm, respectively. Benefiting from the reduced device size and the shorter SPP wavelength, the beam steering sensitivity of the beam steering is improved by 10-fold compared with the case reported previously. This miniature plasmonic beam steering device may find many potential applications in quantum optical information processing and integrated photonic circuits. PMID:25091405

  13. Parkinson's Disease Research at NIH | NIH MedlinePlus the Magazine

    MedlinePlus

    ... turn JavaScript on. Feature: Parkinson's Disease Parkinson's Disease Research at NIH Past Issues / Winter 2014 Table of ... Disorders/All-Disorders/Parkinsons-Disease-Information-Page What Research Is Being Done? The National Institute of Neurological ...

  14. Hepatotoxicity due to red bush tea consumption: a case report.

    PubMed

    Reddy, Shamantha; Mishra, Pragnyadipta; Qureshi, Sana; Nair, Singh; Straker, Tracey

    2016-12-01

    Many conventional drugs used today, including isoniazid, dapsone, and acetaminophen, are well recognized culprits of hepatotoxicity. With increasing use of complementary and alternative medical therapies, several herbal medicines, such as Ma-Huang, kava, and chaparral leaf, have been implicated as hepatotoxins. Hepatotoxicity may be the most frequent adverse reaction to these herbal remedies when taken in excessive quantities. A myriad of liver dysfunctions may occur including transient liver enzyme abnormalities due to acute and chronic hepatitis. These herbal products are often overlooked as the causal etiologic agent during the evaluation of a patient with elevated liver function tests. We describe a case of hepatotoxicity due to ingestion of red bush tea diagnosed during preoperative assessment of a patient scheduled for laparoscopic appendectomy. Elevated liver enzymes and thrombocytopenia detected in the patient's laboratory work up confounded the initial diagnosis of acute appendicitis and additional investigations were required to rule out cholecystitis and other causes of hepatitis. Open appendectomy was done uneventfully under spinal anesthesia without any further deterioration of hepatic function. Copyright © 2016. Published by Elsevier Inc.

  15. 21 CFR 812.30 - FDA action on applications.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false FDA action on applications. 812.30 Section 812.30...) MEDICAL DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Application and Administrative Action § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the date...

  16. 21 CFR 812.30 - FDA action on applications.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false FDA action on applications. 812.30 Section 812.30...) MEDICAL DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Application and Administrative Action § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the date...

  17. 21 CFR 812.30 - FDA action on applications.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false FDA action on applications. 812.30 Section 812.30...) MEDICAL DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Application and Administrative Action § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the date...

  18. 21 CFR 812.30 - FDA action on applications.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false FDA action on applications. 812.30 Section 812.30...) MEDICAL DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Application and Administrative Action § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the date...

  19. 21 CFR 812.30 - FDA action on applications.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false FDA action on applications. 812.30 Section 812.30...) MEDICAL DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Application and Administrative Action § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the date...

  20. 46 CFR 169.623 - Power-driven steering systems.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Power-driven steering systems. 169.623 Section 169.623 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Machinery and Electrical Steering Systems § 169.623 Power-driven steering systems. (a) Power-driven steering...

  1. 46 CFR 169.623 - Power-driven steering systems.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 7 2011-10-01 2011-10-01 false Power-driven steering systems. 169.623 Section 169.623 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Machinery and Electrical Steering Systems § 169.623 Power-driven steering systems. (a) Power-driven steering...

  2. Predicting Drug-induced Hepatotoxicity Using QSAR and Toxicogenomics Approaches

    PubMed Central

    Low, Yen; Uehara, Takeki; Minowa, Yohsuke; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro; Sedykh, Alexander; Muratov, Eugene; Fourches, Denis; Zhu, Hao; Rusyn, Ivan; Tropsha, Alexander

    2014-01-01

    Quantitative Structure-Activity Relationship (QSAR) modeling and toxicogenomics are used independently as predictive tools in toxicology. In this study, we evaluated the power of several statistical models for predicting drug hepatotoxicity in rats using different descriptors of drug molecules, namely their chemical descriptors and toxicogenomic profiles. The records were taken from the Toxicogenomics Project rat liver microarray database containing information on 127 drugs (http://toxico.nibio.go.jp/datalist.html). The model endpoint was hepatotoxicity in the rat following 28 days of exposure, established by liver histopathology and serum chemistry. First, we developed multiple conventional QSAR classification models using a comprehensive set of chemical descriptors and several classification methods (k nearest neighbor, support vector machines, random forests, and distance weighted discrimination). With chemical descriptors alone, external predictivity (Correct Classification Rate, CCR) from 5-fold external cross-validation was 61%. Next, the same classification methods were employed to build models using only toxicogenomic data (24h after a single exposure) treated as biological descriptors. The optimized models used only 85 selected toxicogenomic descriptors and had CCR as high as 76%. Finally, hybrid models combining both chemical descriptors and transcripts were developed; their CCRs were between 68 and 77%. Although the accuracy of hybrid models did not exceed that of the models based on toxicogenomic data alone, the use of both chemical and biological descriptors enriched the interpretation of the models. In addition to finding 85 transcripts that were predictive and highly relevant to the mechanisms of drug-induced liver injury, chemical structural alerts for hepatotoxicity were also identified. These results suggest that concurrent exploration of the chemical features and acute treatment-induced changes in transcript levels will both enrich the

  3. Exacerbation of Acetaminophen Hepatotoxicity by the Anthelmentic Drug Fenbendazole

    PubMed Central

    Gardner, Carol R.; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2012-01-01

    Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8–12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole. PMID

  4. Exacerbation of acetaminophen hepatotoxicity by the anthelmentic drug fenbendazole.

    PubMed

    Gardner, Carol R; Mishin, Vladimir; Laskin, Jeffrey D; Laskin, Debra L

    2012-02-01

    Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8-12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole.

  5. In silico models for the prediction of dose-dependent human hepatotoxicity

    NASA Astrophysics Data System (ADS)

    Cheng, Ailan; Dixon, Steven L.

    2003-12-01

    The liver is extremely vulnerable to the effects of xenobiotics due to its critical role in metabolism. Drug-induced hepatotoxicity may involve any number of different liver injuries, some of which lead to organ failure and, ultimately, patient death. Understandably, liver toxicity is one of the most important dose-limiting considerations in the drug development cycle, yet there remains a serious shortage of methods to predict hepatotoxicity from chemical structure. We discuss our latest findings in this area and present a new, fully general in silico model which is able to predict the occurrence of dose-dependent human hepatotoxicity with greater than 80% accuracy. Utilizing an ensemble recursive partitioning approach, the model classifies compounds as toxic or non-toxic and provides a confidence level to indicate which predictions are most likely to be correct. Only 2D structural information is required and predictions can be made quite rapidly, so this approach is entirely appropriate for data mining applications and for profiling large synthetic and/or virtual libraries.

  6. Dr. Francis Collins Is New NIH Director

    MedlinePlus

    ... Current Issue Past Issues Dr. Francis Collins Is New NIH Director Past Issues / Summer 2009 Table of ... of this page please turn Javascript on. The new NIH Director, Dr. Francis Collins, served as Director ...

  7. 21 CFR 812.42 - FDA and IRB approval.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false FDA and IRB approval. 812.42 Section 812.42 Food... DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Responsibilities of Sponsors § 812.42 FDA and IRB approval. A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both...

  8. 21 CFR 812.42 - FDA and IRB approval.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false FDA and IRB approval. 812.42 Section 812.42 Food... DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Responsibilities of Sponsors § 812.42 FDA and IRB approval. A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both...

  9. 21 CFR 60.10 - FDA assistance on eligibility.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FDA assistance on eligibility. 60.10 Section 60.10... TERM RESTORATION Eligibility Assistance § 60.10 FDA assistance on eligibility. (a) Upon written request from the U.S. Patent and Trademark Office, FDA will assist the U.S. Patent and Trademark Office in...

  10. 21 CFR 60.10 - FDA assistance on eligibility.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FDA assistance on eligibility. 60.10 Section 60.10... TERM RESTORATION Eligibility Assistance § 60.10 FDA assistance on eligibility. (a) Upon written request from the U.S. Patent and Trademark Office, FDA will assist the U.S. Patent and Trademark Office in...

  11. 21 CFR 812.42 - FDA and IRB approval.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false FDA and IRB approval. 812.42 Section 812.42 Food... DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Responsibilities of Sponsors § 812.42 FDA and IRB approval. A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both...

  12. 21 CFR 60.10 - FDA assistance on eligibility.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FDA assistance on eligibility. 60.10 Section 60.10... TERM RESTORATION Eligibility Assistance § 60.10 FDA assistance on eligibility. (a) Upon written request from the U.S. Patent and Trademark Office, FDA will assist the U.S. Patent and Trademark Office in...

  13. 21 CFR 812.42 - FDA and IRB approval.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false FDA and IRB approval. 812.42 Section 812.42 Food... DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Responsibilities of Sponsors § 812.42 FDA and IRB approval. A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both...

  14. 21 CFR 812.42 - FDA and IRB approval.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false FDA and IRB approval. 812.42 Section 812.42 Food... DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Responsibilities of Sponsors § 812.42 FDA and IRB approval. A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both...

  15. 21 CFR 60.10 - FDA assistance on eligibility.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FDA assistance on eligibility. 60.10 Section 60.10... TERM RESTORATION Eligibility Assistance § 60.10 FDA assistance on eligibility. (a) Upon written request from the U.S. Patent and Trademark Office, FDA will assist the U.S. Patent and Trademark Office in...

  16. [Nevirapine related hepatotoxicity: the prevalence and risk factors in a cohort of ART naive Han Chinese with AIDS].

    PubMed

    Gao, Shi-cheng; Gui, Xi-en; Deng, Li-ping; Zhang, Yong-xi; Yan, Ya-jun; Rong, Yu-ping; Liang, Ke; Yang, Rong-rong

    2010-09-01

    To investigate the incidence of hepatotoxicity in acquired immunodeficiency syndrome (AIDS) patients on combined anti-retroviral therapy (cART) containing nevirapine (NVP) and to assess the risk factors and its impact on cART. 330 AIDS patients from March 2003 to June 2008 at local county were enrolled and a retrospective study using Kaplan-meier survival and Multivariate logistic regression modeling was conducted. 267 out of 330 patients received NVP based cART and 63 cases received EFV-based cART. The deference of prevalences of hepatotoxicity between the two groups is statistically significant (Chi2 = 6.691, P = 0.01). 133 out of 267 (49.8%) patients on NVP based cART had at least one episode of ALT elevation during a median 21 months (interquartile ranges, IQR 6, 37) follow-up time, amounts for 28.5 cases per 100 person-years. Baseline ALT elevation (OR = 14.368, P = 0.017)and HCV co-infection (OR = 3.009, P = 0.000) were risk factors for cART related hepatotoxicity, while greatly increased CD4+ T(CD4) cell count was protective against hepatotoxicity development (OR = 0.996, P = 0.000). Patients co-infected with HCV received NVP-based cART had the higher probability of hepatotoxicity than those without HCV co-infection (Log rank: Chi2 = 16.764, P = 0.000). 23 out of the 133 subjects (17.3%) with NVP related hepatotoxicity discontinued cART temporarily or shifted NVP to efavirenz. NVP related hepatotoxicity was common among ARV naive HIV infected subjects in our cohort. Baseline ALT elevation and HCV co-infection were associated statistically with the development of hepatotoxicity. Hepatotoxicity led to discontinuing cART temporarily or switching to other regimens in some subjects. It suggested that NVP should be used with caution in patients co-infected with HCV among whom anti-HCV therapy before cART initiation may contribute to minimizing the probability of NVP associated hepatotoxicity.

  17. 46 CFR 108.641 - Instructions for changing steering gear.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 4 2010-10-01 2010-10-01 false Instructions for changing steering gear. 108.641 Section... steering gear. Instructions stating, in order, the different steps to be taken for changing to emergency and secondary steering gear must be posted in the steering gear room and at each secondary steering...

  18. How to Submit | Center for Cancer Research

    Cancer.gov

    be submitted by a current NIH or FDA fellow. The work does not need to have been done at the NIH/FDA. However, the submitter must be an author on the document and be in compliance with the intended journal's authorship guidelines or general good authorship practices. 

  19. 21 CFR 806.30 - FDA access to records.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false FDA access to records. 806.30 Section 806.30 Food... DEVICES MEDICAL DEVICES; REPORTS OF CORRECTIONS AND REMOVALS Reports and Records § 806.30 FDA access to... designated by FDA and under section 704(e) of the act, permit such officer or employee at all reasonable...

  20. 21 CFR 806.30 - FDA access to records.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false FDA access to records. 806.30 Section 806.30 Food... DEVICES MEDICAL DEVICES; REPORTS OF CORRECTIONS AND REMOVALS Reports and Records § 806.30 FDA access to... designated by FDA and under section 704(e) of the act, permit such officer or employee at all reasonable...

  1. 21 CFR 806.30 - FDA access to records.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false FDA access to records. 806.30 Section 806.30 Food... DEVICES MEDICAL DEVICES; REPORTS OF CORRECTIONS AND REMOVALS Reports and Records § 806.30 FDA access to... designated by FDA and under section 704(e) of the act, permit such officer or employee at all reasonable...

  2. 21 CFR 806.30 - FDA access to records.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false FDA access to records. 806.30 Section 806.30 Food... DEVICES MEDICAL DEVICES; REPORTS OF CORRECTIONS AND REMOVALS Reports and Records § 806.30 FDA access to... designated by FDA and under section 704(e) of the act, permit such officer or employee at all reasonable...

  3. 21 CFR 806.30 - FDA access to records.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false FDA access to records. 806.30 Section 806.30 Food... DEVICES MEDICAL DEVICES; REPORTS OF CORRECTIONS AND REMOVALS Reports and Records § 806.30 FDA access to... designated by FDA and under section 704(e) of the act, permit such officer or employee at all reasonable...

  4. Experimental models of hepatotoxicity related to acute liver failure

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Maes, Michaël; Vinken, Mathieu, E-mail: mvinken@vub.ac.be; Jaeschke, Hartmut

    Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposuremore » or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure. - Highlights: • The murine APAP model is very close to what is observed in patients. • The Gal/ET model is useful to study TNFα-mediated apoptotic signaling mechanisms. • Fas receptor activation is an effective model of apoptosis and secondary necrosis. • The ConA model is a relevant model of auto-immune hepatitis and viral hepatitis. • Multiple time point evaluation needed in experimental models of acute liver injury.« less

  5. Access to F.D.A. Information.

    ERIC Educational Resources Information Center

    Sinovic, Dianna

    Prior to the enactment of the Freedom of Information Act (FOIA), little of the data collected by the Food and Drug Administration (FDA) was made public or could be obtained from the agency. Although the FDA files are now open, information is considered exempt from public disclosure when it involves regulatory procedures, program guidelines, work…

  6. NIH disease funding levels and burden of disease.

    PubMed

    Gillum, Leslie A; Gouveia, Christopher; Dorsey, E Ray; Pletcher, Mark; Mathers, Colin D; McCulloch, Charles E; Johnston, S Claiborne

    2011-02-24

    An analysis of NIH funding in 1996 found that the strongest predictor of funding, disability-adjusted life-years (DALYs), explained only 39% of the variance in funding. In 1998, Congress requested that the Institute of Medicine (IOM) evaluate priority-setting criteria for NIH funding; the IOM recommended greater consideration of disease burden. We examined whether the association between current burden and funding has changed since that time. We analyzed public data on 2006 NIH funding for 29 common conditions. Measures of US disease burden in 2004 were obtained from the World Health Organization's Global Burden of Disease study and national databases. We assessed the relationship between disease burden and NIH funding dollars in univariate and multivariable log-linear models that evaluated all measures of disease burden. Sensitivity analyses examined associations with future US burden, current and future measures of world disease burden, and a newly standardized NIH accounting method. In univariate and multivariable analyses, disease-specific NIH funding levels increased with burden of disease measured in DALYs (p = 0.001), which accounted for 33% of funding level variation. No other factor predicted funding in multivariable models. Conditions receiving the most funding greater than expected based on disease burden were AIDS ($2474 M), diabetes mellitus ($390 M), and perinatal conditions ($297 M). Depression ($719 M), injuries ($691 M), and chronic obstructive pulmonary disease ($613 M) were the most underfunded. Results were similar using estimates of future US burden, current and future world disease burden, and alternate NIH accounting methods. Current levels of NIH disease-specific research funding correlate modestly with US disease burden, and correlation has not improved in the last decade.

  7. Real-World Evidence, Public Participation, and the FDA.

    PubMed

    Schwartz, Jason L

    2017-11-01

    For observers of pharmaceutical regulation and the Food and Drug Administration, these are uncertain times. Events in late 2016 raised concerns that the FDA's evidentiary standards were being weakened, compromising the agency's ability to adequately perform its regulatory and public health responsibilities. Two developments most directly contributed to these fears-the approval of eteplirsen, a treatment for Duchenne muscular dystrophy, against the recommendations of both FDA staff and an advisory committee and the December 2016 signing of the 21st Century Cures Act, which encouraged greater use by the FDA of "real-world" evidence not obtained through randomized controlled trials. The arrival of the Trump administration-with its deregulatory, industry-friendly approach-has only amplified concerns over the future of the FDA. It is too early to know whether the recent developments are truly harbingers of an FDA less likely to prevent unsafe or ineffective products from reaching the market. But elements in the two events-the role of patient narratives in deliberations regarding eteplirsen and the enthusiasm for real-world evidence in the 21st Century Cures Act-raise critical issues for the future of evidence in the FDA's work. The rigorous, inclusive approach under way to consider issues related to real-world evidence provides a model for a similarly needed inquiry regarding public participation in FDA decision-making. © 2017 The Hastings Center.

  8. Method of Controlling Steering of a Ground Vehicle

    NASA Technical Reports Server (NTRS)

    Guo, Raymond (Inventor); Atluri, Venkata Prasad (Inventor); Bluethmann, William J. (Inventor); Lee, Chunhao J. (Inventor); Vitale, Robert L. (Inventor); Dawson, Andrew D. (Inventor)

    2016-01-01

    A method of controlling steering of a vehicle through setting wheel angles of a plurality of modular electronic corner assemblies (eModules) is provided. The method includes receiving a driving mode selected from a mode selection menu. A position of a steering input device is determined in a master controller. A velocity of the vehicle is determined, in the master controller, when the determined position of the steering input device is near center. A drive mode request corresponding to the selected driving mode to the plurality of steering controllers is transmitted to the master controller. A required steering angle of each of the plurality of eModules is determined, in the master controller, as a function of the determined position of the steering input device, the determined velocity of the vehicle, and the selected first driving mode. The eModules are set to the respective determined steering angles.

  9. Gender differences in successful NIH grant funding in otolaryngology.

    PubMed

    Eloy, Jean Anderson; Svider, Peter F; Kovalerchik, Olga; Baredes, Soly; Kalyoussef, Evelyne; Chandrasekhar, Sujana S

    2013-07-01

    To evaluate gender differences in NIH funding among faculty in otolaryngology departments and discuss potential reasons for these differences. Analysis of NIH funding data available on the online NIH RePORTER system. Fiscal year 2011 and 2012 NIH funding awards to principal investigators (PIs) in otolaryngology departments were obtained and used to examine faculty listings from otolaryngology departments for academic rank and gender. The Scopus database was used to determine publication range of these faculty members. Individual mean NIH awards to men ($362,946 ± $21,247 standard error of mean) were higher than those to women ($287,188 ± $38,029). Male PIs were found to have higher mean NIH funding totals (aggregating grants for PIs with multiple awards) than female PIs ($498,593 vs $359,276). Upon organization by academic rank and years active, men had significantly higher funding levels at both the level of assistant professor and at 10 to 20 years of experience. Of all NIH grants awarded, men had a higher percentage of the more prestigious R-series grants (76.2%) than did women (63.4%). Male faculty members have higher NIH funding levels than their female colleagues, a disparity that exists separate from career longevity, as it is true both at the rank of assistant professor and for those with 10 to 20 years of research experience. The larger proportion of R-series NIH grants awarded to male faculty may contribute to this finding. This discrepancy in percentage and dollars of funding exists despite the increasing percentages of women in higher ranks.

  10. Herbal hepatotoxicity: suspected cases assessed for alternative causes.

    PubMed

    Teschke, Rolf; Schulze, Johannes; Schwarzenboeck, Alexander; Eickhoff, Axel; Frenzel, Christian

    2013-09-01

    Alternative explanations are common in suspected drug-induced liver injury (DILI) and account for up to 47.1% of analyzed cases. This raised the question of whether a similar frequency may prevail in cases of assumed herb-induced liver injury (HILI). We searched the Medline database for the following terms: herbs, herbal drugs, herbal dietary supplements, hepatotoxic herbs, herbal hepatotoxicity, and herb-induced liver injury. Additional terms specifically addressed single herbs and herbal products: black cohosh, Greater Celandine, green tea, Herbalife products, Hydroxycut, kava, and Pelargonium sidoides. We retrieved 23 published case series and regulatory assessments related to hepatotoxicity by herbs and herbal dietary supplements with alternative causes. The 23 publications comprised 573 cases of initially suspected HILI; alternative causes were evident in 278/573 cases (48.5%). Among them were hepatitis by various viruses (9.7%), autoimmune diseases (10.4%), nonalcoholic and alcoholic liver diseases (5.4%), liver injury by comedication (DILI and other HILI) (43.9%), and liver involvement in infectious diseases (4.7%). Biliary and pancreatic diseases were frequent alternative diagnoses (11.5%), raising therapeutic problems if specific treatment is withheld; pre-existing liver diseases including cirrhosis (9.7%) were additional confounding variables. Other diagnoses were rare, but possibly relevant for the individual patient. In 573 cases of initially assumed HILI, 48.5% showed alternative causes unrelated to the initially incriminated herb, herbal drug, or herbal dietary supplement, calling for thorough clinical evaluations and appropriate causality assessments in future cases of suspected HILI.

  11. FDA's perspectives on cardiovascular devices.

    PubMed

    Chen, Eric A; Patel-Raman, Sonna M; O'Callaghan, Kathryn; Hillebrenner, Matthew G

    2009-06-01

    The Food and Drug Administration (FDA) decision process for approving or clearing medical devices is often determined by a review of robust clinical data and extensive preclinical testing of the device. The mission statement for the Center for Devices and Radiological Health (CDRH) is to review the information provided by manufacturers so that it can promote and protect the health of the public by ensuring the safety and effectiveness of medical devices deemed appropriate for human use (Food, Drug & Cosmetic Act, Section 903(b)(1, 2(C)), December 31, 2004; accessed December 17, 2008 http://www.fda.gov/opacom/laws/fdcact/fdctoc.htm). For high-risk devices, such as ventricular assist devices (VADs), mechanical heart valves, stents, cardiac resynchronization therapy (CRT) devices, pacemakers, and defibrillators, the determination is based on FDA's review of extensive preclinical bench and animal testing followed by use of the device in a clinical trial in humans. These clinical trials allow the manufacturer to evaluate a device in the intended use population. FDA reviews the data from the clinical trial to determine if the device performed as predicted and the clinical benefits outweigh the risks. This article reviews the regulatory framework for different marketing applications related to cardiovascular devices and describes the process of obtaining approval to study a cardiovascular device in a U.S. clinical trial.

  12. FDA's Approach to Regulating Biosimilars.

    PubMed

    Lemery, Steven J; Ricci, M Stacey; Keegan, Patricia; McKee, Amy E; Pazdur, Richard

    2017-04-15

    The Biologics Price Competition and Innovation (BPCI) Act, enacted as part of the Affordable Care Act, created a new licensure pathway for biological products demonstrated to be biosimilar with or interchangeable with an FDA-licensed biological product (the "reference product"). The FDA's approach to the regulation of biosimilars is based on the requirements set forth in the BPCI Act. A biosimilar product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between products in terms of safety, purity, and potency. The foundation of a biosimilar development program is an analytic similarity assessment that directly compares the structural/physiochemical and functional properties of the proposed biosimilar with the reference product. Data from clinical studies, which include an assessment of immunogenicity and pharmacokinetics/pharmacodynamics, are used to assess for clinically meaningful differences and not to independently establish the safety and effectiveness of the biosimilar. Like all products that the FDA regulates, the FDA requires that biosimilar products meet the agency's rigorous standards of safety and efficacy for approval. That means patients and health care professionals are able to rely upon the safety and effectiveness of biosimilar products in the same manner as for the reference product. Clin Cancer Res; 23(8); 1882-5. ©2016 AACR . ©2016 American Association for Cancer Research.

  13. Establishment of a methodology for investigating protectants against ethanol-induced hepatotoxicity.

    PubMed

    Ruan, Xueqing; Shen, Chong; Meng, Qin

    2010-05-01

    Ethanol-induced liver injury has been extensively reported in clinic, but still lacks an efficient in vitro platform for investigating its hepatotoxicity and protectants. This study aimed to establish a methodology on the culture conditions regarding the sealability against evaporation of ethanol, culture medium and 2D/3D culture of hepatocytes. Based on the experimental findings, it was indicated that the ethanol evaporation from culture plates was a severe problem reducing its toxicity in hepatocyte. According to the detected ethanol toxic response marked by reduced cell viability, 3D cultured hepatocytes in gel entrapment were suggested to be better than 2D hepatocyte in monolayer, but the cultures in either William's Medium E or DMEM exhibited comparable sensitivity to ethanol toxicity. Subsequently, 3D cultured hepatocytes with Parafilm sealing were systematically illustrated to well reflect the ethanol-induced lipid accumulation, reactive oxygen species/malondialdehyde generation, glutathione depletion and cytochrome 2E1 induction. Finally, such hepatocyte models were proposed as a platform for screening of herbal component against ethanol hepatotoxicity. Nano-silibinin, for the first time, found to perform significant protection against ethanol-induced hepatotoxicity while silibinin in normal particles could not inhibit such toxicity. This protection of nano-silibinin might relate to its improved bioavailability compared to normal insoluble silibinin and could act as an anti-oxidative and anti-steatosis agent against ethanol-induced hepatotoxicity. Copyright (c) 2010. Published by Elsevier Ltd.

  14. Improved specific energy Ni-H2 cell

    NASA Astrophysics Data System (ADS)

    Miller, L.

    1985-07-01

    Design optimization activities which have evolved and validated the necessary technology to produce Ni-H2 battery cells exhibiting a specific energy of 75-80 Whr/Kg (energy density approximately 73 Whr/L are summarized. Final design validation is currently underway with the production of battery cells for qualification and life testing. The INTELSAT type Ni-H2 battery cell design has been chosen for expository purposes. However, it should be recognized portions of the improved technology could be applied to the Air Force type Ni-H2 battery cell design with equal benefit.

  15. Improved Specific Energy Ni-h2 Cell

    NASA Technical Reports Server (NTRS)

    Miller, L.

    1985-01-01

    Design optimization activities which have evolved and validated the necessary technology to produce Ni-H2 battery cells exhibiting a specific energy of 75-80 Whr/Kg (energy density approximately 73 Whr/L are summarized. Final design validation is currently underway with the production of battery cells for qualification and life testing. The INTELSAT type Ni-H2 battery cell design has been chosen for expository purposes. However, it should be recognized portions of the improved technology could be applied to the Air Force type Ni-H2 battery cell design with equal benefit.

  16. NIH Research: Advances in Parkinson's Disease Research

    MedlinePlus

    ... of this page please turn JavaScript on. NIH Research: Advances in Parkinson's Disease Research Past Issues / Winter 2014 Table of Contents Story ... Photo courtesy of NIH Advances in Parkinson's Disease Research Story Landis, Ph.D., has been Director of ...

  17. The NIH Undiagnosed Diseases Program | NIH MedlinePlus the Magazine

    MedlinePlus

    ... to discover and understand rare diseases,” says Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute ( ... interdisciplinary approach,” says NIH Director Francis S. Collins, M.D., Ph.D. “The disorder had long-evaded conventional ...

  18. Comparison of manual steering and steering via joystick of a flexible rhino endoscope.

    PubMed

    Eckl, R; Gumprecht, J J; Strauss, G; Hofer, M; Dietz, A; Lueth, T C

    2010-01-01

    Flexible endoscopes are used in ENT surgery for examination tasks in cases wherever rigid endoscopes are unsuitable to reach certain positions in the nasal cavity. Until today they are steered by hand and no robotized system has been put into clinical practice. One qualification a robot manipulator system has to fulfill to be accepted is not to create new disadvantages compared to the conventional method in surgery. An important factor is the time needed to steer the new system compared to the time needed to steer the conventional system. In this article a robot manipulator system and an experiment are presented to compare the particular times test persons need to perform a certain task. This approach offers the possibility to benchmark the developed robot manipulator system and future systems for flexible rhino endoscopes.

  19. Effects of ebselen on radiocontrast media-induced hepatotoxicity in rats.

    PubMed

    Basarslan, Fatmagul; Yilmaz, Nigar; Davarci, Isil; Akin, Mustafa; Ozgur, Mustafa; Yilmaz, Cahide; Ulutas, Kemal Turker

    2013-09-01

    Oxidative stress is accepted as a potential responsible mechanism in the pathogenesis of radiocontrast media (RCM)-induced hepatotoxicity. Therefore, we aimed to investigate the protective effects of ebselen against RCM-induced hepatotoxicity by measuring tissue oxidant/antioxidant parameters and histological changes in rats. Wistar albino rats were randomly separated into four groups consisting of eight rats per group. Normal saline was given to the rats in control group (group 1). RCM was given to the rats in group 2, and both RCM and ebselen were given to the rats in group 3. Only ebselen was given to the rats in group 4. Liver sections of the killed animals were analyzed to measure the levels of malondialdehyde (MDA) and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), as well as histopathological changes. In RCM group, SOD and CAT levels were found increased. In RCM-ebselen group, MDA, SOD and CAT levels were found decreased. In RCM-ebselen group, however, GSH-Px activities of liver tissue increased. All these results indicated that ebselen produced a protective mechanism against RCM-induced hepatotoxicity and took part in oxidative stress.

  20. Diesel Technology: Steering and Suspension.

    ERIC Educational Resources Information Center

    Miller, Roger; Scarberry, Terry; Tesch, Carl; Kellum, Mary

    Competency-based teacher and student materials on steering and suspension are provided for a diesel technology curriculum. Eleven units of instruction cover the following topics: chassis, tires, and wheels; steering; and suspension. The materials are based on the curriculum-alignment concept of first stating the objectives, then developing…

  1. 46 CFR 61.20-1 - Steering gear.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Steering gear. 61.20-1 Section 61.20-1 Shipping COAST... Periodic Tests of Machinery and Equipment § 61.20-1 Steering gear. (a) The marine inspector must inspect the steering gear at each inspection for certification for vessels whose Certificate of Inspections...

  2. Toxicogenomic analysis identifies the apoptotic pathway as the main cause of hepatotoxicity induced by tributyltin.

    PubMed

    Zhou, Mi; Feng, Mei; Fu, Ling-Ling; Ji, Lin-Dan; Zhao, Jin-Shun; Xu, Jin

    2016-11-01

    Tributyltin (TBT) is one of the most widely used organotin biocides, which has severe endocrine-disrupting effects on marine species and mammals. Given that TBT accumulates at higher levels in the liver than in any other organ, and it acts mainly as a hepatotoxic agent, it is important to clearly delineate the hepatotoxicity of TBT. However, most of the available studies on TBT have focused on observations at the cellular level, while studies at the level of genes and proteins are limited; therefore, the molecular mechanisms of TBT-induced hepatotoxicity remains largely unclear. In the present study, we applied a toxicogenomic approach to investigate the effects of TBT on gene expression in the human normal liver cell line HL7702. Gene expression profiling identified the apoptotic pathway as the major cause of hepatotoxicity induced by TBT. Flow cytometry assays confirmed that medium- and high-dose TBT treatments significantly increased the number of apoptotic cells, and more cells underwent late apoptosis in the high-dose TBT group. The genes encoding heat shock proteins (HSPs), kinases and tumor necrosis factor receptors mediated TBT-induced apoptosis. These findings revealed novel molecular mechanisms of TBT-induced hepatotoxicity, and the current microarray data may also provide clues for future studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Side Effects of HIV Medicines: HIV and Hepatotoxicity

    MedlinePlus

    ... provider tells you to. How is hepatotoxicity detected? Liver function tests (LFTs) are a group of blood tests ... Laboratory Testing From the Department of Veterans Affairs: Primary Care of Veterans with HIV: Liver Disease and Cirrhosis From the National Institutes of ...

  4. 21 CFR 830.100 - FDA accreditation of an issuing agency.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false FDA accreditation of an issuing agency. 830.100... (CONTINUED) MEDICAL DEVICES UNIQUE DEVICE IDENTIFICATION FDA Accreditation of an Issuing Agency § 830.100 FDA... issuing agency. (b) Accreditation criteria. FDA may accredit an organization as an issuing agency, if the...

  5. Relative entropy of steering: on its definition and properties

    NASA Astrophysics Data System (ADS)

    Kaur, Eneet; Wilde, Mark M.

    2017-11-01

    In Gallego and Aolita (2015 Phys. Rev. X 5 041008), the authors proposed a definition for the relative entropy of steering and showed that the resulting quantity is a convex steering monotone. Here we advocate for a different definition for relative entropy of steering, based on well grounded concerns coming from quantum Shannon theory. We prove that this modified relative entropy of steering is a convex steering monotone. Furthermore, we establish that it is uniformly continuous and faithful, in both cases giving quantitative bounds that should be useful in applications. We also consider a restricted relative entropy of steering which is relevant for the case in which the free operations in the resource theory of steering have a more restricted form (the restricted operations could be more relevant in practical scenarios). The restricted relative entropy of steering is convex, monotone with respect to these restricted operations, uniformly continuous, and faithful.

  6. Agenda: EDRN FDA Education Workshop — EDRN Public Portal

    Cancer.gov

    The purpose of this workshop was to open dialogue between FDA staff that provide oversight for review of in vitro diagnostic applications and EDRN scientists currently performing clinical validation studies on cancer biomarkers. Issues related to FDA review of diagnostic tests were presented by FDA personnel. Representatives from EDRN provided details on supporting data of their validation studies and the resources developed within EDRN to facilitate such research for FDA compliance. The agenda provided here provides links to the presentations by each speaker.

  7. Ginger for Prevention of Antituberculosis-induced Gastrointestinal Adverse Reactions Including Hepatotoxicity: A Randomized Pilot Clinical Trial.

    PubMed

    Emrani, Zahra; Shojaei, Esphandiar; Khalili, Hossein

    2016-06-01

    In this study, the potential benefits of ginger in preventing antituberculosis drug-induced gastrointestinal adverse reactions including hepatotoxicity have been evaluated in patients with tuberculosis. Patients in the ginger and placebo groups (30 patients in each group) received either 500 mg ginger (Zintoma)(®) or placebo one-half hour before each daily dose of antituberculosis drugs for 4 weeks. Patients' gastrointestinal complaints (nausea, vomiting, dyspepsia, and abdominal pain) and antituberculosis drug-induced hepatotoxicity were recorded during the study period. In this cohort, nausea was the most common antituberculosis drug-induced gastrointestinal adverse reactions. Forty eight (80%) patients experienced nausea. Nausea was more common in the placebo than the ginger group [27 (90%) vs 21 (70%), respectively, p = 0.05]. During the study period, 16 (26.7%) patients experienced antituberculosis drug-induced hepatotoxicity. Patients in the ginger group experienced less, but not statistically significant, antituberculosis drug-induced hepatotoxicity than the placebo group (16.7% vs 36.7%, respectively, p = 0.07). In conclusion, ginger may be a potential option for prevention of antituberculosis drug-induced gastrointestinal adverse reactions including hepatotoxicity. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  8. Predicting hepatotoxicity using ToxCast in vitro bioactivity and ...

    EPA Pesticide Factsheets

    Background: The U.S. EPA ToxCastTM program is screening thousands of environmental chemicals for bioactivity using hundreds of high-throughput in vitro assays to build predictive models of toxicity. We represented chemicals based on bioactivity and chemical structure descriptors then used supervised machine learning to predict their hepatotoxic effects.Results: A set of 677 chemicals were represented by 711 in vitro bioactivity descriptors (from ToxCast assays), 4,376 chemical structure descriptors (from QikProp, OpenBabel, PADEL, and PubChem), and three hepatotoxicity categories (from animal studies). Hepatotoxicants were defined by rat liver histopathology observed after chronic chemical testing and grouped into hypertrophy (161), injury (101) and proliferative lesions (99). Classifiers were built using six machine learning algorithms: linear discriminant analysis (LDA), Naïve Bayes (NB), support vector classification (SVM), classification and regression trees (CART), k-nearest neighbors (KNN) and an ensemble of classifiers (ENSMB). Classifiers of hepatotoxicity were built using chemical structure, ToxCast bioactivity, and a hybrid representation. Predictive performance was evaluated using 10-fold cross-validation testing and in-loop, filter-based, feature subset selection. Hybrid classifiers had the best balanced accuracy for predicting hypertrophy (0.78±0.08), injury (0.73±0.10) and proliferative lesions (0.72±0.09). Though chemical and bioactivity class

  9. p-Aminophenol-induced hepatotoxicity in hamsters: role of glutathione.

    PubMed

    Fu, Xin; Chen, Theresa S; Ray, Mukunda B; Nagasawa, Herbert T; Williams, Walter M

    2004-01-01

    p-Aminophenol (PAP) is a widely used industrial chemical and a known nephrotoxin. Recently, it was found to also cause hepatotoxicity and glutathione (GSH) depletion in mice. The exact mechanism of liver toxicity is not known. The aims of this study were to determine whether PAP can cause acute hepatotoxicity in hamsters and to further investigate the role of GSH in PAP-induced toxicity. PAP was administered ip to hamsters in doses of 200-800 mg/kg. Liver damage at 24 h after PAP administration was assessed by elevations in plasma enzyme activities and histopathologic examination. GSH and cysteine (Cys) levels in liver at 4 h were determined by HPLC. PAP decreased hepatic GSH concentration to 8% and Cys to 30% of vehicle control values. It increased plasma glutamic pyruvic transaminase (GPT) activity by 47-fold and sorbitol dehydrogenase (SDH) activity by 113-fold. PAP also caused severe centrilobular hepatocellular necrosis. 2(RS)-n-Propylthiazolidine-4(R)-carboxylic acid (PTCA), a Cys precursor, attenuated the PAP-induced decreases in hepatic sulfhydryl levels; GSH and Cys were 39% and 78% of vehicle controls, respectively. PTCA also attenuated the PAP-induced elevations in plasma enzyme activities and hepatic necrosis. It was concluded that PAP hepatotoxicity is associated with depletion of hepatic GSH and can be prevented by PTCA. Copyright 2004 Wiley Periodicals, Inc.

  10. Investigation of the Hepatotoxic and Immunotoxic Effects of the Peroxisome Proliferator Perfluorodecanoic Acid

    DTIC Science & Technology

    1991-04-30

    np. A #127 6Investigation of the Hepatotoxic and OHIO Immunotoxic Effects of the Peroxisome AJE Proliferator Perfluorodecanoic Acid Donald E. Frazier...Investigation of the Hepatotoxic and Immunotoxic Effects G-AFOSR 90-0371 of the Peroxisome Proliferator Perfluorodecanoic Acid TA - 2312/A5 L AUTMOS) Donald E...involved evaluation of the immunotoxic and toxic effects of perfluorodecanoic acid (PFDA). Eight day exposure to PFDA caused thymic atrophy with marked

  11. New approaches to enhance active steering system functionalities: preliminary results

    NASA Astrophysics Data System (ADS)

    Serarslan, Benan

    2014-09-01

    An important development of the steering systems in general is active steering systems like active front steering and steer-by-wire systems. In this paper the current functional possibilities in application of active steering systems are explored. A new approach and additional functionalities are presented that can be implemented to the active steering systems without additional hardware such as new sensors and electronic control units. Commercial active steering systems are controlling the steering angle depending on the driving situation only. This paper introduce methods for enhancing active steering system functionalities depending not only on the driving situation but also vehicle parameters like vehicle mass, tyre and road condition. In this regard, adaptation of the steering ratio as a function of above mentioned vehicle parameters is presented with examples. With some selected vehicle parameter changes, the reduction of the undesired influences on vehicle dynamics of these parameter changes has been demonstrated theoretically with simulations and with real-time driving measurements.

  12. Steering system for a train of rail-less vehicles

    DOEpatents

    Voight, Edward T.

    1983-01-01

    A steering system for use with a multiple vehicle train permits tracking without rails of one vehicle after another. This system is particularly useful for moving conveyor systems into and out of curved paths of room and pillar underground mine installations. The steering system features an elongated steering bar pivotally connected to each of adjacent vehicles at end portions of the bar permitting angular orientation of each vehicle in respect to the steering bar and other vehicles. Each end portion of the steering bar is linked to the near pair of vehicle wheels through wheel yoke pivot arms about king pin type pivots. Movement of the steering bar about its pivotal connection provides proportional turning of the wheels to effect steering and tracking of one vehicle following another in both forward and reverse directions.

  13. Static Force-Deflection Properties of Automobile Steering Components

    DOT National Transportation Integrated Search

    1987-06-01

    This report provides the static force-deflection test results for 28 steering columns and 24 steering wheels used in domestic and import passener cars from model year 1975 to 1985. The steering columns and wheels tested include approzimately 90 perce...

  14. Protective effect of the edible brown alga Ecklonia stolonifera on doxorubicin-induced hepatotoxicity in primary rat hepatocytes.

    PubMed

    Jung, Hyun Ah; Kim, Jae-I; Choung, Se Young; Choi, Jae Sue

    2014-08-01

    As part of our efforts to isolate anti-hepatotoxic agents from marine natural products, we screened the ability of 14 edible varieties of Korean seaweed to protect against doxorubicin-induced hepatotoxicity in primary rat hepatocytes. Among the crude extracts of two Chlorophyta (Codium fragile and Capsosiphon fulvescens), seven Phaeophyta (Undaria pinnatifida, Sargassum thunbergii, Pelvetia siliquosa, Ishige okamurae, Ecklonia cava, Ecklonia stolonifera and Eisenia bicyclis), five Rhodophyta (Chondrus ocellatus, Gelidium amansii, Gracilaria verrucosa, Symphycladia latiuscula and Porphyra tenera), and the extracts of Ecklonia stolonifera, Ecklonia cava, Eisenia bicyclis and Pelvetia siliquosa exhibited significant protective effects on doxorubicin-induced hepatotoxicity, with half maximal effective concentration (EC50) values of 2.0, 2.5, 3.0 and 15.0 μg/ml, respectively. Since Ecklonia stolonifera exhibits a significant protective potential and is frequently used as foodstuff, we isolated six phlorotannins, including phloroglucinol (1), dioxinodehydroeckol (2), eckol (3), phlorofucofuroeckol A (4), dieckol (5) and triphloroethol-A (6). Phlorotannins 2 ∼ 6 exhibited potential protective effects on doxorubicin-induced hepatotoxicity, with corresponding EC50 values of 3.4, 8.3, 4.4, 5.5 and 11.5 μg/ml, respectively. The results clearly demonstrated that the anti-hepatotoxic effects of Ecklonia stolonifera and its isolated phlorotannins are useful for further exploration and development of therapeutic modalities for treatment of hepatotoxicity. © 2014 Royal Pharmaceutical Society.

  15. Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests.

    PubMed

    Teschke, Rolf; Frenzel, Christian; Schulze, Johannes; Schwarzenboeck, Alexander; Eickhoff, Axel

    2013-07-27

    To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase (ALT) < 5 upper limit of normal (N) before reexposure, with N as the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding

  16. Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests

    PubMed Central

    Teschke, Rolf; Frenzel, Christian; Schulze, Johannes; Schwarzenboeck, Alexander; Eickhoff, Axel

    2013-01-01

    AIM: To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. METHODS: We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase (ALT) < 5 upper limit of normal (N) before reexposure, with N as the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. RESULTS: Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n

  17. Systemic Integration and Macro Steering

    ERIC Educational Resources Information Center

    Bleiklie, Ivar

    2007-01-01

    The article deals with the development of national higher education systems and the emergence of macro steering in Europe and to some extent in the USA. It is based on the assumption that this process of integration of higher education systems through macro steering will increasingly be felt as a forceful influence on higher education. Integration…

  18. 21 CFR 316.34 - FDA recognition of exclusive approval.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false FDA recognition of exclusive approval. 316.34... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.34 FDA recognition of exclusive approval. (a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely...

  19. 21 CFR 316.34 - FDA recognition of exclusive approval.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false FDA recognition of exclusive approval. 316.34... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.34 FDA recognition of exclusive approval. (a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely...

  20. 21 CFR 316.34 - FDA recognition of exclusive approval.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 5 2013-04-01 2013-04-01 false FDA recognition of exclusive approval. 316.34... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.34 FDA recognition of exclusive approval. (a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely...

  1. 21 CFR 316.34 - FDA recognition of exclusive approval.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 5 2014-04-01 2014-04-01 false FDA recognition of exclusive approval. 316.34... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.34 FDA recognition of exclusive approval. (a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely...

  2. 21 CFR 316.34 - FDA recognition of exclusive approval.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false FDA recognition of exclusive approval. 316.34... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.34 FDA recognition of exclusive approval. (a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely...

  3. 46 CFR 131.845 - Instructions for shift of steering gear.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... alternative steering stations must be on water-resistant material and posted at each steering station and in... gear or steering stations. (d) Each clutch, gear, wheel, lever, valve, or switch used during any shift of steering gear or steering stations must be numbered or lettered on a metal plate or painted so...

  4. Micromachined actuators/sensors for intratubular positioning/steering

    DOEpatents

    Lee, Abraham P.; Krulevitch, Peter A.; Northrup, M. Allen; Trevino, Jimmy C.

    1998-01-01

    Micromachined thin film cantilever actuators having means for individually controlling the deflection of the cantilevers, valve members, and rudders for steering same through blood vessels, or positioning same within a blood vessel, for example. Such cantilever actuators include tactile sensor arrays mounted on a catheter or guide wire tip for navigation and tissues identification, shape-memory alloy film based catheter/guide wire steering mechanisms, and rudder-based steering devices that allow the selective actuation of rudders that use the flowing blood itself to help direct the catheter direction through the blood vessel. While particularly adapted for medical applications, these cantilever actuators can be used for steering through piping and tubing systems.

  5. Combating HIV/AIDS | NIH MedlinePlus the Magazine

    MedlinePlus

    Skip to main content NIH MedlinePlus the Magazine NIH MedlinePlus Salud Download the Current Issue PDF [3.1 mb] Trusted Health Information from the National Institutes of Health Home Current Issue ...

  6. Acetaminophen hepatotoxicity and sterile inflammation: The mechanism of protection of Chlorogenic acid.

    PubMed

    Jaeschke, Hartmut

    2016-01-05

    Acetaminophen hepatotoxicity is characterized by extensive necrotic cell death and a sterile inflammatory response. A recent report suggested that a therapeutic intervention with chlorogenic acid, a dietary polyphenolic compound, protects against acetaminophen-induced liver injury by inhibiting the inflammatory injury. The purpose of this letter is to discuss a number of reasons why the protective mechanism of chlorogenic acid against acetaminophen hepatotoxicity does not involve an anti-inflammatory effect and provides an alternative explanation for the observed protection. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Advancing Predictive Hepatotoxicity at the Intersection of Experimental, in Silico, and Artificial Intelligence Technologies.

    PubMed

    Fraser, Keith; Bruckner, Dylan M; Dordick, Jonathan S

    2018-06-18

    Adverse drug reactions, particularly those that result in drug-induced liver injury (DILI), are a major cause of drug failure in clinical trials and drug withdrawals. Hepatotoxicity-mediated drug attrition occurs despite substantial investments of time and money in developing cellular assays, animal models, and computational models to predict its occurrence in humans. Underperformance in predicting hepatotoxicity associated with drugs and drug candidates has been attributed to existing gaps in our understanding of the mechanisms involved in driving hepatic injury after these compounds perfuse and are metabolized by the liver. Herein we assess in vitro, in vivo (animal), and in silico strategies used to develop predictive DILI models. We address the effectiveness of several two- and three-dimensional in vitro cellular methods that are frequently employed in hepatotoxicity screens and how they can be used to predict DILI in humans. We also explore how humanized animal models can recapitulate human drug metabolic profiles and associated liver injury. Finally, we highlight the maturation of computational methods for predicting hepatotoxicity, the untapped potential of artificial intelligence for improving in silico DILI screens, and how knowledge acquired from these predictions can shape the refinement of experimental methods.

  8. The protective role of quercetin and arginine on gold nanoparticles induced hepatotoxicity in rats.

    PubMed

    Abdelhalim, Mohamed Anwar K; Moussa, Sherif A Abdelmottaleb; Qaid, Huda Abdo Yahya

    2018-01-01

    The aim of the study was to confirm the hepatotoxicity induced by small-sized gold nanoparticles (GNPs) and evaluate the role of quercetin (Qur) and arginine (Arg) against hepatotoxicity caused by GNPs. Twenty-five healthy male Wistar-Kyoto rats were used. GNPs were administered intraperitoneally to these rats at the dose of 50 μL for seven consecutive days. The role of Qur and Arg antioxidants against toxicity induced by GNPs was detected through the measurement of serum liver function and oxidative stress biomarkers in the liver tissues. Coadministration of Qur and Arg along with GNPs significantly induced dramatic alterations in the biochemical parameters. Levels of malondialdehyde, gamma-glutamyl transferase, alanine aminotransferase, alkaline phosphatase, and total protein increased significantly in the GNPs injected group than in the control group, while reduced glutathione was greatly reduced in the GNPs group than in the control group. It also significantly decreased liver enzymes and the oxidative stress, therefore improving the liver damage and hepatotoxicity induced by GNPs. This study demonstrated that Qur and Arg antioxidants effectively improved the hepatic oxidative damage induced by GNPs. It also substantiates the application of Qur and Arg as protecting stand-in against GNPs' hepatotoxicity.

  9. Acute hepatotoxicity after ingestion of Morinda citrifolia (Noni Berry) juice in a 14-year-old boy.

    PubMed

    Yu, Elizabeth L; Sivagnanam, Mamata; Ellis, Linda; Huang, Jeannie S

    2011-02-01

    We present a case of a 14-year-old previously healthy boy with acute hepatotoxicity after noni berry juice consumption. As the popularity of noni berry consumption continues to increase, heightened awareness of the relation between noni berry consumption and acute hepatotoxicity is important.

  10. Holographic memory using beam steering

    NASA Technical Reports Server (NTRS)

    Chao, Tien-Hsin (Inventor); Hanan, Jay C. (Inventor); Reyes, George F. (Inventor); Zhou, Hanying (Inventor)

    2007-01-01

    A method, apparatus, and system provide the ability for storing holograms at high speed. A single laser diode emits a collimated laser beam to both write to and read from a photorefractice crystal. One or more liquid crystal beam steering spatial light modulators (BSSLMs) steer a reference beam, split from the collimated laser beam, at high speed to the photorefractive crystal.

  11. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps.

    PubMed

    Teschke, Rolf; Eickhoff, Axel

    2015-01-01

    Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI) with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although, herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences) scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM) are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality.

  12. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps

    PubMed Central

    Teschke, Rolf; Eickhoff, Axel

    2015-01-01

    Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI) with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although, herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences) scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM) are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality. PMID:25954198

  13. The Children's Inn at NIH turns 25 | NIH MedlinePlus the Magazine

    MedlinePlus

    ... Children's Inn at NIH turns 25 Past Issues / Summer 2014 Table of Contents "A place like home …" ... volunteers help in every area of operations, too. Summer 2014 Issue: Volume 9 Number 2 Page 24

  14. Micromachined actuators/sensors for intratubular positioning/steering

    DOEpatents

    Lee, A.P.; Krulevitch, P.A.; Northrup, M.A.; Trevino, J.C.

    1998-06-30

    Micromachined thin film cantilever actuators having means for individually controlling the deflection of the cantilevers, valve members, and rudders for steering same through blood vessels, or positioning same within a blood vessel, for example. Such cantilever actuators include tactile sensor arrays mounted on a catheter or guide wire tip for navigation and tissues identification, shape-memory alloy film based catheter/guide wire steering mechanisms, and rudder-based steering devices that allow the selective actuation of rudders that use the flowing blood itself to help direct the catheter direction through the blood vessel. While particularly adapted for medical applications, these cantilever actuators can be used for steering through piping and tubing systems. 14 figs.

  15. Focused Ultrasound Steering for Harmonic Motion Imaging.

    PubMed

    Han, Yang; Payen, Thomas; Wang, Shutao; Konofagou, Elisa

    2018-02-01

    Harmonic motion imaging (HMI) is a radiation-force-based ultrasound elasticity imaging technique, which is designed for both tissue relative stiffness imaging and reliable high-intensity focused ultrasound treatment monitoring. The objective of this letter is to develop and demonstrate the feasibility of 2-D focused ultrasound (FUS) beam steering for HMI using a 93-element, FUS phased array. HMI with steered FUS beam was acquired in tissue-mimicking phantoms. The HMI displacement was imaged within the steering range of ±1.7 mm laterally and ±2 mm axially. Using the steered FUS beam, HMI can be used to image a larger tissue volume with higher efficiency and without requiring mechanical movement of the transducer.

  16. Multipartite Gaussian steering: Monogamy constraints and quantum cryptography applications

    NASA Astrophysics Data System (ADS)

    Xiang, Yu; Kogias, Ioannis; Adesso, Gerardo; He, Qiongyi

    2017-01-01

    We derive laws for the distribution of quantum steering among different parties in multipartite Gaussian states under Gaussian measurements. We prove that a monogamy relation akin to the generalized Coffman-Kundu-Wootters inequality holds quantitatively for a recently introduced measure of Gaussian steering. We then define the residual Gaussian steering, stemming from the monogamy inequality, as an indicator of collective steering-type correlations. For pure three-mode Gaussian states, the residual acts as a quantifier of genuine multipartite steering, and is interpreted operationally in terms of the guaranteed key rate in the task of secure quantum secret sharing. Optimal resource states for the latter protocol are identified, and their possible experimental implementation discussed. Our results pin down the role of multipartite steering for quantum communication.

  17. Optimization Under Uncertainty for Wake Steering Strategies

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Quick, Julian; Annoni, Jennifer; King, Ryan N.

    Here, wind turbines in a wind power plant experience significant power losses because of aerodynamic interactions between turbines. One control strategy to reduce these losses is known as 'wake steering,' in which upstream turbines are yawed to direct wakes away from downstream turbines. Previous wake steering research has assumed perfect information, however, there can be significant uncertainty in many aspects of the problem, including wind inflow and various turbine measurements. Uncertainty has significant implications for performance of wake steering strategies. Consequently, the authors formulate and solve an optimization under uncertainty (OUU) problem for finding optimal wake steering strategies in themore » presence of yaw angle uncertainty. The OUU wake steering strategy is demonstrated on a two-turbine test case and on the utility-scale, offshore Princess Amalia Wind Farm. When we accounted for yaw angle uncertainty in the Princess Amalia Wind Farm case, inflow-direction-specific OUU solutions produced between 0% and 1.4% more power than the deterministically optimized steering strategies, resulting in an overall annual average improvement of 0.2%. More importantly, the deterministic optimization is expected to perform worse and with more downside risk than the OUU result when realistic uncertainty is taken into account. Additionally, the OUU solution produces fewer extreme yaw situations than the deterministic solution.« less

  18. Optimization Under Uncertainty for Wake Steering Strategies

    NASA Astrophysics Data System (ADS)

    Quick, Julian; Annoni, Jennifer; King, Ryan; Dykes, Katherine; Fleming, Paul; Ning, Andrew

    2017-05-01

    Wind turbines in a wind power plant experience significant power losses because of aerodynamic interactions between turbines. One control strategy to reduce these losses is known as “wake steering,” in which upstream turbines are yawed to direct wakes away from downstream turbines. Previous wake steering research has assumed perfect information, however, there can be significant uncertainty in many aspects of the problem, including wind inflow and various turbine measurements. Uncertainty has significant implications for performance of wake steering strategies. Consequently, the authors formulate and solve an optimization under uncertainty (OUU) problem for finding optimal wake steering strategies in the presence of yaw angle uncertainty. The OUU wake steering strategy is demonstrated on a two-turbine test case and on the utility-scale, offshore Princess Amalia Wind Farm. When we accounted for yaw angle uncertainty in the Princess Amalia Wind Farm case, inflow-direction-specific OUU solutions produced between 0% and 1.4% more power than the deterministically optimized steering strategies, resulting in an overall annual average improvement of 0.2%. More importantly, the deterministic optimization is expected to perform worse and with more downside risk than the OUU result when realistic uncertainty is taken into account. Additionally, the OUU solution produces fewer extreme yaw situations than the deterministic solution.

  19. Optimization Under Uncertainty for Wake Steering Strategies

    DOE PAGES

    Quick, Julian; Annoni, Jennifer; King, Ryan N.; ...

    2017-06-13

    Here, wind turbines in a wind power plant experience significant power losses because of aerodynamic interactions between turbines. One control strategy to reduce these losses is known as 'wake steering,' in which upstream turbines are yawed to direct wakes away from downstream turbines. Previous wake steering research has assumed perfect information, however, there can be significant uncertainty in many aspects of the problem, including wind inflow and various turbine measurements. Uncertainty has significant implications for performance of wake steering strategies. Consequently, the authors formulate and solve an optimization under uncertainty (OUU) problem for finding optimal wake steering strategies in themore » presence of yaw angle uncertainty. The OUU wake steering strategy is demonstrated on a two-turbine test case and on the utility-scale, offshore Princess Amalia Wind Farm. When we accounted for yaw angle uncertainty in the Princess Amalia Wind Farm case, inflow-direction-specific OUU solutions produced between 0% and 1.4% more power than the deterministically optimized steering strategies, resulting in an overall annual average improvement of 0.2%. More importantly, the deterministic optimization is expected to perform worse and with more downside risk than the OUU result when realistic uncertainty is taken into account. Additionally, the OUU solution produces fewer extreme yaw situations than the deterministic solution.« less

  20. Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type

    PubMed Central

    Kane, Alice E.; Mitchell, Sarah J.; Mach, John; Huizer-Pajkos, Aniko; McKenzie, Catriona; Jones, Brett; Cogger, Victoria; Le Couteur, David G.; de Cabo, Rafael; Hilmer, Sarah N.

    2018-01-01

    Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice. PMID:26615879

  1. Dose Matters: FDA's Guidance on Children's X-rays

    MedlinePlus

    ... Consumers Home For Consumers Consumer Updates Dose Matters: FDA's Guidance on Children's X-rays Share Tweet Linkedin ... extra care to “child size” the radiation dose. FDA’s Role The FDA's Center for Devices and Radiological ...

  2. Upgrading cytochrome P450 activity in HepG2 cells co-transfected with adenoviral vectors for drug hepatotoxicity assessment.

    PubMed

    Tolosa, Laia; Donato, M Teresa; Pérez-Cataldo, Gabriela; Castell, José Vicente; Gómez-Lechón, M José

    2012-12-01

    In a number of adverse drug reactions leading to hepatotoxicity, drug metabolism is thought to be involved by the generation of reactive metabolites from non-toxic drugs. The use of hepatoma cell lines, such as HepG2 cell line, for the evaluation of drug-induced hepatotoxicity is hampered by their low cytochrome P450 expression which makes impossible the study of the toxicity produced by bioactivable compounds. Genetically manipulated cells constitute promising tools for hepatotoxicity applications. HepG2 cells were simultaneously transfected with recombinant adenoviruses encoding CYP1A2, CYP2C9 and CYP3A4 to confer them drug-metabolic competence. Upgraded cells (Adv-HepG2) were highly able to metabolize the toxin studied in contrast to the reduced metabolic capacity of HepG2 cells. Aflatoxin B1-induced hepatotoxicity was studied as a proof of concept in metabolically competent and non-competent HepG2 cells by using high content screening technology. Significant differences in mitochondrial membrane potential, intracellular calcium concentration, nuclear morphology and cell viability after treatment with aflatoxin B1 were observed in Adv-HepG2 when compared to HepG2 cells. Rotenone (non bioactivable) and citrate (non hepatotoxic) were analysed as negative controls. This cell model showed to be a suitable hepatic model to test hepatotoxicity of bioactivable drugs and constitutes a valuable alternative for hepatotoxicity testing. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. FDA 101: Dietary Supplements

    MedlinePlus

    ... too good to be true, it probably is. Report Problems Adverse effects with dietary supplements should be ... immediately. Both of you are then encouraged to report this problem to FDA. For information on how ...

  4. All-Versus-Nothing Proof of Einstein-Podolsky-Rosen Steering

    PubMed Central

    Chen, Jing-Ling; Ye, Xiang-Jun; Wu, Chunfeng; Su, Hong-Yi; Cabello, Adán; Kwek, L. C.; Oh, C. H.

    2013-01-01

    Einstein-Podolsky-Rosen steering is a form of quantum nonlocality intermediate between entanglement and Bell nonlocality. Although Schrödinger already mooted the idea in 1935, steering still defies a complete understanding. In analogy to “all-versus-nothing” proofs of Bell nonlocality, here we present a proof of steering without inequalities rendering the detection of correlations leading to a violation of steering inequalities unnecessary. We show that, given any two-qubit entangled state, the existence of certain projective measurement by Alice so that Bob's normalized conditional states can be regarded as two different pure states provides a criterion for Alice-to-Bob steerability. A steering inequality equivalent to the all-versus-nothing proof is also obtained. Our result clearly demonstrates that there exist many quantum states which do not violate any previously known steering inequality but are indeed steerable. Our method offers advantages over the existing methods for experimentally testing steerability, and sheds new light on the asymmetric steering problem. PMID:23828242

  5. Research on Performance of Wire-controlled Hydraulic Steering System Based on Four-wheel Steering

    NASA Astrophysics Data System (ADS)

    Tao, P.; Jin, X. H.

    2018-05-01

    In this paper, the steering stability and control strategy of forklift are put forward. Drive based on yawing moment distribution of rotary torque coordination control method, through analyzing the linear two degree of freedom model of forklift truck, forklift yawing angular velocity and mass center side-slip Angle of expectations, as the control target parameters system, using fuzzy controller output driving forklift steering the yawing moment, to drive rotary torque distribution, make the forklift truck to drive horizontal pendulum angular velocity and side-slip Angle tracking reference model very well. In this paper, the lateral stability control system were designed, the joint simulation in MATLAB/Simulink, the simulation results show that under the different partial load, the control system can effectively to control side forklift lateral stability, enhanced the forklift driving safety, for the side forklift steering stability study provides a theoretical basis.

  6. Rofecoxib-induced hepatotoxicity: A forgotten complication of the coxibs

    PubMed Central

    Yan, Brian; Leung, Yvette; Urbanski, Stefan J; Myers, Robert P

    2006-01-01

    Rofecoxib is a member of the coxib family of nonsteroidal anti-inflammatory drugs that selectively inhibit cyclooxygenase-2. Although the coxibs are generally well-tolerated, rofecoxib was recently withdrawn from the market due to concerns regarding cardiovascular safety. Rare cases of hepatic injury attributable to the coxibs have been reported. In the present study, two additional cases of severe hepatotoxicity are described in patients with cholestatic symptoms and abnormal liver biochemistry, shortly following the initiation of rofecoxib for arthritic complaints. In both cases, liver histology was compatible with drug-induced hepatotoxicity, and rapid clinical and biochemical improvements were observed following rofecoxib discontinuation. With new coxibs and expanding indications on the horizon, physicians in all areas of practice must be aware of this disorder and consider it in any patient who develops hepatic dysfunction after taking a coxib. PMID:16691302

  7. Amplitude steered array

    NASA Technical Reports Server (NTRS)

    Dietrich, F. J.; Koloboff, G. J.; Martel, R. J.; Johnson, C. C. (Inventor)

    1974-01-01

    A spin stabilized satellite has an electronically despun antenna array comprising a multiplicity of peripheral antenna elements. A high gain energy beam is established by connecting a suitable fraction or array of the elements in phase. The beam is steered or caused to scan by switching elements in sequence into one end of the array as elements at the other end of the array are switched out. The switching transients normally associated with such steering are avoided by an amplitude control system. Instead of abruptly switching from one element to the next, a fixed value of power is gradually transferred from the element at the trailing edge of the array to the element next to the leading edge.

  8. Protective effect of rutin in comparison to silymarin against induced hepatotoxicity in rats.

    PubMed

    Reddy, M Kasi; Reddy, A Gopala; Kumar, B Kala; Madhuri, D; Boobalan, G; Reddy, M Anudeep

    2017-01-01

    The aim of this study is to evaluate the hepatoprotective effect of rutin (RTN) in comparison to silymarin (SLM) against acetaminophen (APAP)-induced hepatotoxicity in rats. Male Wistar albino rats (n=24) of 3 months age were equally divided into four groups. Group 1 served as normal control. Hepatotoxicity was induced in the remaining three groups with administration of 500 mg/kg po APAP from day 1-3. Groups 2, 3, and 4 were subsequently administered orally with distilled water, 25 mg/kg of SLM, and 20 mg/kg of RTN, respectively, for 11 days. The mean body weights and biomarkers of hepatotoxicity were estimated on day 0, 4 (confirmation of toxicity), and 15 (at the end of treatment). Hematological parameters were evaluated on day 4 and 15. Antioxidant profile and adenosine triphosphatases (ATPases) were assessed at the end of the experiment. Liver tissues were subjected to histopathology and transmission electron microscopy after the sacrifice on day 15. Antioxidant profile, ATPases, and hematological and sero-biochemical parameters were significantly altered, and histopathological changes were noticed in the liver of toxic control group. These changes were reversed in groups 3 and 4 that were administered with SLM and RTN, respectively. The results of the present investigation enunciated that SLM has potent hepatoprotective activity though the RTN was found superior in restoring the pathological alterations in paracetamol-induced hepatotoxicity in Wistar albino rats.

  9. The Relationship Between OREF Grants and Future NIH Funding Success.

    PubMed

    Hegde, Vishal; Johansen, Daniel; Park, Howard Y; Zoller, Stephen D; Hamad, Christopher; Bernthal, Nicholas M

    2017-08-16

    The Orthopaedic Research and Education Foundation (OREF) is the leading specialty-specific nongovernmental organization providing orthopaedic funding in the United States. As extramural research funding has become increasingly difficult to acquire, one mission of the OREF is to support investigators to generate data needed to secure larger extramural funding from agencies such as the National Institutes of Health (NIH). The objectives of this study were to evaluate the rate of translating OREF faculty-level grants into subsequent NIH funding and to determine if there are identifiable factors that increase the rate of converting an OREF grant into NIH funding. This is a retrospective review of OREF grants awarded to full-time faculty orthopaedic surgeons between 1994 and 2014. Grants were analyzed on the basis of award type and were categorized as basic science, clinical, or epidemiological. Sex, individual scholarly productivity, and publication experience were evaluated. All awardees were assessed for subsequent NIH funding using the NIH RePORTER web site. One hundred and twenty-six faculty-level OREF grants were awarded to 121 individuals. Twenty-seven OREF grant awardees (22%) received NIH funding at a mean of 6.3 years after OREF funding. Nineteen (46%) of 41 Career Development Grant winners later received NIH funding compared with 10 (12%) of 85 other award winners. OREF grants for basic science projects were awarded more often (58%) and were more than 4 times as likely to result in NIH funding than non-basic science projects (odds ratio, 4.70 [95% confidence interval, 1.66 to 13.33]; p = 0.0036). Faculty who later received NIH funding had higher scholarly productivity and publication experience (p < 0.05). The OREF grant awardee conversion rate of 22% and, particularly, the 46% for Career Development Grant winners compares favorably with the overall NIH funding success rate (18% in 2014). Faculty-level OREF grants appear to achieve their purpose of

  10. Quantum Steering Beyond Instrumental Causal Networks

    NASA Astrophysics Data System (ADS)

    Nery, R. V.; Taddei, M. M.; Chaves, R.; Aolita, L.

    2018-04-01

    We theoretically predict, and experimentally verify with entangled photons, that outcome communication is not enough for hidden-state models to reproduce quantum steering. Hidden-state models with outcome communication correspond, in turn, to the well-known instrumental processes of causal inference but in the one-sided device-independent scenario of one black-box measurement device and one well-characterized quantum apparatus. We introduce one-sided device-independent instrumental inequalities to test against these models, with the appealing feature of detecting entanglement even when communication of the black box's measurement outcome is allowed. We find that, remarkably, these inequalities can also be violated solely with steering, i.e., without outcome communication. In fact, an efficiently computable formal quantifier—the robustness of noninstrumentality—naturally arises, and we prove that steering alone is enough to maximize it. Our findings imply that quantum theory admits a stronger form of steering than known until now, with fundamental as well as practical potential implications.

  11. 21 CFR 14.15 - Committees working under a contract with FDA.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Committees working under a contract with FDA. 14... under a contract with FDA. (a) FDA may enter into contracts with independent scientific or technical... contract initially executed with FDA after July 1, 1975, but which is determined not to be an advisory...

  12. 21 CFR 14.15 - Committees working under a contract with FDA.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Committees working under a contract with FDA. 14... under a contract with FDA. (a) FDA may enter into contracts with independent scientific or technical... contract initially executed with FDA after July 1, 1975, but which is determined not to be an advisory...

  13. 21 CFR 14.15 - Committees working under a contract with FDA.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Committees working under a contract with FDA. 14... under a contract with FDA. (a) FDA may enter into contracts with independent scientific or technical... contract initially executed with FDA after July 1, 1975, but which is determined not to be an advisory...

  14. 21 CFR 14.15 - Committees working under a contract with FDA.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Committees working under a contract with FDA. 14... under a contract with FDA. (a) FDA may enter into contracts with independent scientific or technical... contract initially executed with FDA after July 1, 1975, but which is determined not to be an advisory...

  15. 21 CFR 14.15 - Committees working under a contract with FDA.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false Committees working under a contract with FDA. 14... under a contract with FDA. (a) FDA may enter into contracts with independent scientific or technical... contract initially executed with FDA after July 1, 1975, but which is determined not to be an advisory...

  16. The NIH's Funding to US Dental Institutions from 2005 to 2014.

    PubMed

    Ferland, C L; O'Hayre, M; Knosp, W M; Fox, C H; Horsford, D J

    2017-01-01

    This study examines funding from the National Institutes of Health (NIH) to US dental institutions between 2005 and 2014 based on publicly available data from the NIH Research Portfolio Online Reporting Tools. Over the 10-y span, 56 US dental institutions received approximately $2.2 billion from 20 Institutes, Centers, and Offices at the NIH. The National Institute of Dental and Craniofacial Research (NIDCR) is the largest NIH supporter of dental institutions, having invested 70% of the NIH total, about $1.5 billion. The NIDCR is also the primary supporter of research training and career development, as it has invested $177 million, which represents 92% of the total NIH investment of $192 million. Over the past 10 y, about half of the NIDCR's extramural award dollars have gone to dental schools, while the NIH has invested about 1%. There has been an approximately 10% net decrease in extramural dollars awarded to dental institutions over the past decade; however, given the year-to-year variability in support to dental institutions, it is unclear if this net decline reflects a long-term trend. In addition, there was an overall reduction in the extramural dollars awarded by the NIDCR and by the NIH. For example, from 2005 to 2014, the total NIDCR budget for extramural research decreased by roughly 4%, which represents a decrease of $20 million to dental institutions. After adjusting for inflation, the decline in funding to dental institutions from the NIDCR and NIH was approximately 30%. Although the NIDCR and NIH continue to invest in dental institutions, if the current decline were to continue, it could negatively affect the research conducted at dental institutions. Therefore, we discuss opportunities for dental institutions to increase NIDCR and NIH support and improve their capacity for research, research training, and career development.

  17. NIH Funding within Otolaryngology: 2005-2014.

    PubMed

    Lennon, Christen J; Hunter, Jacob B; Mistry, Akshitkumar M; Espahbodi, Mana; Deasey, Matthew; Niesner, K J; Labadie, Robert F

    2017-11-01

    Objective Analyze grants awarded between 2005 and 2014 to otolaryngology departments that appear in the National Institutes of Health (NIH) RePORTER database, summarize characteristics of grant recipients associated with otolaryngology departments as listed in the RePORTER between 2005 and 2014, and identify trends in otolaryngology NIH funding between 2005 and 2014 by topic. Study Design Case series. Setting NIH database inquiry. Subjects Grant recipients. Methods The RePORTER was queried for all grants awarded to otolaryngology departments between 2005 and 2014. All grants classified as new, renewal, or revision were included while duplicates were excluded. Results In total, 475 grants to 51 institutions were categorized by topic and subtopic. Internet searches were conducted for characteristics of 352 principal investigators. Sixty-seven percent of awardees had a PhD, 22% had an MD, and 11% had an MD/PhD. Sex ratios varied by degrees held. Although 31% of all grant recipients were women, this ratio was not seen when recipients were classified by degree type, with 78% of women holding a PhD compared with 55% of men ( P = .0013). Of the award types, 39% were R01s, 15% were R21s, and 10% were R03s. The top 3 represented topics were otology/neurotology (52%), audiology (25%), and head and neck surgery (14%). The mean annual award amount, after adjusting for inflation to 2014 dollars, was $226,495.76, with 72.8% awarded by the National Institute of Deafness and Communication Disorders. Twenty percent of awardees received multiple grants. Conclusion NIH funding in otolaryngology tends to be awarded to those with PhDs studying the hearing sciences, with 1 in 5 having multiple awards. As in other areas of NIH funding, women are underrepresented overall.

  18. Multipartite steering inequalities based on entropic uncertainty relations

    NASA Astrophysics Data System (ADS)

    Riccardi, Alberto; Macchiavello, Chiara; Maccone, Lorenzo

    2018-05-01

    We investigate quantum steering for multipartite systems by using entropic uncertainty relations. We introduce entropic steering inequalities whose violation certifies the presence of different classes of multipartite steering. These inequalities witness both steerable states and genuine multipartite steerable states. Furthermore, we study their detection power for several classes of states of a three-qubit system.

  19. Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity.

    PubMed

    McEneny-King, Alanna; Osman, Wesseem; Edginton, Andrea N; Rao, Praveen P N

    2017-06-01

    The 1,2,3,4-tetrahydroacridine derivative tacrine was the first drug approved to treat Alzheimer's disease (AD). It is known to act as a potent cholinesterase inhibitor. However, tacrine was removed from the market due to its hepatotoxicity concerns as it undergoes metabolism to toxic quinonemethide species through the cytochrome P450 enzyme CYP1A2. Despite these challenges, tacrine serves as a useful template in the development of novel multi-targeting anti-AD agents. In this regard, we sought to evaluate the risk of hepatotoxicity in a series of C9 substituted tacrine derivatives that exhibit cholinesterase inhibition properties. The hepatotoxic potential of tacrine derivatives was evaluated using recombinant cytochrome (CYP) P450 CYP1A2 and CYP3A4 enzymes. Molecular docking studies were conducted to predict their binding modes and potential risk of forming hepatotoxic metabolites. Tacrine derivatives compound 1 (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) and 2 (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) which possess a C9 3,4-dimethoxybenzylamino substituent exhibited weak binding to CYP1A2 enzyme (1, IC 50 =33.0µM; 2, IC 50 =8.5µM) compared to tacrine (CYP1A2 IC 50 =1.5µM). Modeling studies show that the presence of a bulky 3,4-dimethoxybenzylamino C9 substituent prevents the orientation of the 1,2,3,4-tetrahydroacridine ring close to the heme-iron center of CYP1A2 thereby reducing the risk of forming hepatotoxic species. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  20. Hepatotoxicity induced by acute and chronic paracetamol overdose in children: Where do we stand?

    PubMed

    Tong, Hoi Yan; Medrano, Nicolás; Borobia, Alberto Manuel; Ruiz, José Antonio; Martínez, Ana María; Martín, Julia; Quintana, Manuel; García, Santos; Carcas, Antonio José; Ramírez, Elena

    2017-02-01

    There are few data on hepatotoxicity induced by acute or chronic paracetamol poisoning in the pediatric population. Paracetamol poisoning data can reveal the weaknesses of paracetamol poisoning management guidelines. We retrospectively studied the patients of less than 18 years old with measurable paracetamol levels, who were brought to the emergency department (ED) of La Paz University Hospital, Madrid, Spain, for suspected paracetamol overdoses between 2005 and 2010. Ninety-two patients with suspected paracetamol poisoning were identified. In 2007, the incidence of paracetamol poisoning in the pediatric population was 0.8 [Poisson-95% confidence interval (CI): 0.03-3.69] per 10 000 inhabitants aged less than 18 years. The incidence in the same year was 1.53 (Poisson-95% CI: 0.24-5.57) per 10 000 patients in the pediatric ED. The most common cause of poisoning was attempted suicide (47.8%) in teenagers with a median age of 15 years, followed by accidental poisoning (42.2%) in babies with a median age of 2.65 years. Difference was seen in the frequency of hepatotoxicity between acute and chronic poisoning cases. Only 1 of 49 patients with acute poisoning showed hepatotoxicity [acute liver failure (ALF)], whereas 7 of 8 patients with chronic poisoning showed hepatotoxicity (3 cases of ALF). The average time to medical care was 6.83 hours for acute poisoning and 52.3 hours for chronic poisoning (P<0.001). Chronic paracetamol poisoning is a potential risk factor for hepatotoxicity and acute liver failure. Delays in seeking medical help might be a contributing factor. Clinicians should have a higher index of clinical suspicion for this entity.

  1. Emotion assessment using the NIH Toolbox

    PubMed Central

    Butt, Zeeshan; Pilkonis, Paul A.; Cyranowski, Jill M.; Zill, Nicholas; Hendrie, Hugh C.; Kupst, Mary Jo; Kelly, Morgen A. R.; Bode, Rita K.; Choi, Seung W.; Lai, Jin-Shei; Griffith, James W.; Stoney, Catherine M.; Brouwers, Pim; Knox, Sarah S.; Cella, David

    2013-01-01

    One of the goals of the NIH Toolbox for Assessment of Neurological and Behavioral Function was to identify or develop brief measures of emotion for use in prospective epidemiologic and clinical research. Emotional health has significant links to physical health and exerts a powerful effect on perceptions of life quality. Based on an extensive literature review and expert input, the Emotion team identified 4 central subdomains: Negative Affect, Psychological Well-Being, Stress and Self-Efficacy, and Social Relationships. A subsequent psychometric review identified several existing self-report and proxy measures of these subdomains with measurement characteristics that met the NIH Toolbox criteria. In cases where adequate measures did not exist, robust item banks were developed to assess concepts of interest. A population-weighted sample was recruited by an online survey panel to provide initial item calibration and measure validation data. Participants aged 8 to 85 years completed self-report measures whereas parents/guardians responded for children aged 3 to 12 years. Data were analyzed using a combination of classic test theory and item response theory methods, yielding efficient measures of emotional health concepts. An overview of the development of the NIH Toolbox Emotion battery is presented along with preliminary results. Norming activities led to further refinement of the battery, thus enhancing the robustness of emotional health measurement for researchers using the NIH Toolbox. PMID:23479549

  2. Identifying cognitive distraction using steering wheel reversal rates.

    PubMed

    Kountouriotis, Georgios K; Spyridakos, Panagiotis; Carsten, Oliver M J; Merat, Natasha

    2016-11-01

    The influence of driver distraction on driving performance is not yet well understood, but it can have detrimental effects on road safety. In this study, we examined the effects of visual and non-visual distractions during driving, using a high-fidelity driving simulator. The visual task was presented either at an offset angle on an in-vehicle screen, or on the back of a moving lead vehicle. Similar to results from previous studies in this area, non-visual (cognitive) distraction resulted in improved lane keeping performance and increased gaze concentration towards the centre of the road, compared to baseline driving, and further examination of the steering control metrics indicated an increase in steering wheel reversal rates, steering wheel acceleration, and steering entropy. We show, for the first time, that when the visual task is presented centrally, drivers' lane deviation reduces (similar to non-visual distraction), whilst measures of steering control, overall, indicated more steering activity, compared to baseline. When using a visual task that required the diversion of gaze to an in-vehicle display, but without a manual element, lane keeping performance was similar to baseline driving. Steering wheel reversal rates were found to adequately tease apart the effects of non-visual distraction (increase of 0.5° reversals) and visual distraction with offset gaze direction (increase of 2.5° reversals). These findings are discussed in terms of steering control during different types of in-vehicle distraction, and the possible role of manual interference by distracting secondary tasks. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Holographic memory using beam steering

    NASA Technical Reports Server (NTRS)

    Chao, Tien-Hsin (Inventor); Hanan, Jay C. (Inventor); Reyes, George F. (Inventor); Zhou, Hanying (Inventor)

    2006-01-01

    A method, apparatus, and system provide the ability for storing holograms at high speed. A single laser diode emits a collimated laser beam to both write to and read from a photorefractice crystal. One or more liquid crystal beam steering spatial light modulators (BSSLMs) or Micro-Electro-Mechanical Systems (MEMS) mirrors steer a reference beam, split from the collimated laser beam, at high speed to the photorefractive crystal.

  4. 46 CFR 58.25-80 - Automatic pilots and ancillary steering gear.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... AND AUXILIARY MACHINERY AND RELATED SYSTEMS Steering Gear § 58.25-80 Automatic pilots and ancillary steering gear. (a) Automatic pilots and ancillary steering gear, and steering-gear control systems, must be arranged to allow immediate resumption of manual operation of the steering-gear control system required in...

  5. 46 CFR 58.25-80 - Automatic pilots and ancillary steering gear.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... AND AUXILIARY MACHINERY AND RELATED SYSTEMS Steering Gear § 58.25-80 Automatic pilots and ancillary steering gear. (a) Automatic pilots and ancillary steering gear, and steering-gear control systems, must be arranged to allow immediate resumption of manual operation of the steering-gear control system required in...

  6. Do AAO-HNSF CORE Grants Predict Future NIH Funding Success?

    PubMed

    Eloy, Jean Anderson; Svider, Peter F; Kanumuri, Vivek V; Folbe, Adam J; Setzen, Michael; Baredes, Soly

    2014-08-01

    To determine (1) whether academic otolaryngologists who have received an American Academy of Otolaryngology- Head and Neck Surgery Foundation (AAO-HNSF) Centralized Otolaryngology Research Efforts (CORE) grant are more likely to procure future National Institutes of Health (NIH) funding; (2) whether CORE grants or NIH Career Development (K) awards have a stronger association with scholarly impact. Historical cohort. Scholarly impact, as measured by the h-index, publication experience, and prior grant history, were determined for CORE-funded and non-CORE-funded academic otolaryngologists. All individuals were assessed for NIH funding history. Of 192 academic otolaryngologists with a CORE funding history, 39.6% had active or prior NIH awards versus 15.1% of 1002 non-CORE-funded faculty (P < .0001). Higher proportions of CORE-funded otolaryngologists have received K-series and R-series grants from the NIH (P-values < .05). K-grant recipients had higher h-indices than CORE recipients (12.6 vs 7.1, P < .01). Upon controlling for rank and experience, this difference remained significant among junior faculty. A higher proportion of academic otolaryngologists with prior AAO-HNSF CORE funding have received NIH funding relative to their non-CORE-funded peers, suggesting that the CORE program may be successful in its stated goals of preparing individuals for the NIH peer review process, although further prospective study is needed to evaluate a "cause and effect" relationship. Individuals with current or prior NIH K-grants had greater research productivity than those with CORE funding history. Both cohorts had higher scholarly impact values than previously published figures among academic otolaryngologists, highlighting that both CORE grants and NIH K-grants awards are effective career development resources. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.

  7. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How will NIH evaluate applications? 52a.5 Section 52a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers the...

  8. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How will NIH evaluate applications? 52a.5 Section 52a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers the...

  9. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How will NIH evaluate applications? 52a.5 Section 52a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers the...

  10. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How will NIH evaluate applications? 52a.5 Section 52a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers the...

  11. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How will NIH evaluate applications? 52a.5 Section 52a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers the...

  12. Gaussian quantum steering and its asymmetry in curved spacetime

    NASA Astrophysics Data System (ADS)

    Wang, Jieci; Cao, Haixin; Jing, Jiliang; Fan, Heng

    2016-06-01

    We study Gaussian quantum steering and its asymmetry in the background of a Schwarzschild black hole. We present a Gaussian channel description of quantum state evolution under the influence of Hawking radiation. We find that thermal noise introduced by the Hawking effect will destroy the steerability between an inertial observer Alice and an accelerated observer Bob who hovers outside the event horizon, while it generates steerability between Bob and a hypothetical observer anti-Bob inside the event horizon. Unlike entanglement behaviors in curved spacetime, here the steering from Alice to Bob suffers from a "sudden death" and the steering from anti-Bob to Bob experiences a "sudden birth" with increasing Hawking temperature. We also find that the Gaussian steering is always asymmetric and the maximum steering asymmetry cannot exceed ln 2 , which means the state never evolves to an extremal asymmetry state. Furthermore, we obtain the parameter settings that maximize steering asymmetry and find that (i) s =arccosh cosh/2r 1 -sinh2r is the critical point of steering asymmetry and (ii) the attainment of maximal steering asymmetry indicates the transition between one-way steerability and both-way steerability for the two-mode Gaussian state under the influence of Hawking radiation.

  13. 10 CFR 35.7 - FDA, other Federal, and State requirements.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 1 2011-01-01 2011-01-01 false FDA, other Federal, and State requirements. 35.7 Section....7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee from complying with applicable FDA, other Federal, and State requirements governing radioactive drugs or devices. ...

  14. 10 CFR 35.7 - FDA, other Federal, and State requirements.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false FDA, other Federal, and State requirements. 35.7 Section....7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee from complying with applicable FDA, other Federal, and State requirements governing radioactive drugs or devices. ...

  15. 10 CFR 35.7 - FDA, other Federal, and State requirements.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 1 2012-01-01 2012-01-01 false FDA, other Federal, and State requirements. 35.7 Section....7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee from complying with applicable FDA, other Federal, and State requirements governing radioactive drugs or devices. ...

  16. 10 CFR 35.7 - FDA, other Federal, and State requirements.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 1 2014-01-01 2014-01-01 false FDA, other Federal, and State requirements. 35.7 Section....7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee from complying with applicable FDA, other Federal, and State requirements governing radioactive drugs or devices. ...

  17. 10 CFR 35.7 - FDA, other Federal, and State requirements.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 1 2013-01-01 2013-01-01 false FDA, other Federal, and State requirements. 35.7 Section....7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee from complying with applicable FDA, other Federal, and State requirements governing radioactive drugs or devices. ...

  18. Be an NIH Reviewer: Contribute to Multidisciplinary Research.

    PubMed

    Jenkins, Melinda L

    2018-03-01

    One of the best ways to contribute to multidisciplinary research and to improve your own knowledge of the review process at the National Institutes of Health (NIH) is to serve as a peer reviewer for research, traineeship, and small business innovation research proposals. Proactive targeted outreach to Scientific Review Officers (SROs) at NIH will increase your chances to become a reviewer. Reviewers with nursing expertise are especially welcome as multidisciplinary research is becoming more prevalent. Steps to identify a likely study section, contact the correct SRO, and review responsibly are described in this article, written by an experienced NIH review officer.

  19. Vehicle Steering control: A model of learning

    NASA Technical Reports Server (NTRS)

    Smiley, A.; Reid, L.; Fraser, M.

    1978-01-01

    A hierarchy of strategies were postulated to describe the process of learning steering control. Vehicle motion and steering control data were recorded for twelve novices who drove an instrumented car twice a week during and after a driver training course. Car-driver describing functions were calculated, the probable control structure determined, and the driver-alone transfer function modelled. The data suggested that the largest changes in steering control with learning were in the way the driver used the lateral position cue.

  20. Subarray-based FDA radar to counteract deceptive ECM signals

    NASA Astrophysics Data System (ADS)

    Abdalla, Ahmed; Wang, Wen-Qin; Yuan, Zhao; Mohamed, Suhad; Bin, Tang

    2016-12-01

    In recent years, the frequency diverse array (FDA) radar concept has attracted extensive attention, as it may benefit from a small frequency increment, compared to the carrier frequency across the array elements and thereby achieve an array factor that is a function of the angle, the time, and the range which is superior to the conventional phase array radar (PAR). However, limited effort on the subject of FDA in electronic countermeasure scenarios, especially in the presence of mainbeam deceptive jamming, has been published. Basic FDA is not desirable for anti-jamming applications, due to the range-angle coupling response of targets. In this paper, a novel method based on subarrayed FDA signal processing is proposed to counteract deceptive ECM signals. We divide the FDA array into multiple subarrays, each of which employs a distinct frequency increment. As a result, in the subarray-based FDA, the desired target can be distinguished at subarray level in joint range-angle-Doppler domain by utilizing the fact that the jammer generates false targets with the same ranges to each subarray without reparations. The performance assessment shows that the proposed solution is effective for deceptive ECM targets suppression. The effectiveness is verified by simulation results.

  1. Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts

    PubMed Central

    Burel, Sebastien A.; Hart, Christopher E.; Cauntay, Patrick; Hsiao, Jill; Machemer, Todd; Katz, Melanie; Watt, Andy; Bui, Huynh-hoa; Younis, Husam; Sabripour, Mahyar; Freier, Susan M.; Hung, Gene; Dan, Amy; Prakash, T.P.; Seth, Punit P.; Swayze, Eric E.; Bennett, C. Frank; Crooke, Stanley T.; Henry, Scott P.

    2016-01-01

    High affinity antisense oligonucleotides (ASOs) containing bicylic modifications (BNA) such as locked nucleic acid (LNA) designed to induce target RNA cleavage have been shown to have enhanced potency along with a higher propensity to cause hepatotoxicity. In order to understand the mechanism of this hepatotoxicity, transcriptional profiles were collected from the livers of mice treated with a panel of highly efficacious hepatotoxic or non-hepatotoxic LNA ASOs. We observed highly selective transcript knockdown in mice treated with non-hepatotoxic LNA ASOs, while the levels of many unintended transcripts were reduced in mice treated with hepatotoxic LNA ASOs. This transcriptional signature was concurrent with on-target RNA reduction and preceded transaminitis. Remarkably, the mRNA transcripts commonly reduced by toxic LNA ASOs were generally not strongly associated with any particular biological process, cellular component or functional group. However, they tended to have much longer pre-mRNA transcripts. We also demonstrate that the off-target RNA knockdown and hepatotoxicity is attenuated by RNase H1 knockdown, and that this effect can be generalized to high affinity modifications beyond LNA. This suggests that for a certain set of ASOs containing high affinity modifications such as LNA, hepatotoxicity can occur as a result of unintended off-target RNase H1 dependent RNA degradation. PMID:26553810

  2. Long-enduring primary hepatocyte-based co-cultures improve prediction of hepatotoxicity.

    PubMed

    Novik, Eric I; Dwyer, Jacquelyn; Morelli, James K; Parekh, Amit; Cho, Cheul; Pludwinski, Eitan; Shrirao, Anil; Freedman, Robert M; MacDonald, James S; Jayyosi, Zaid

    2017-12-01

    The failure of drug candidates during clinical trials and post-marketing withdrawal due to Drug Induced Liver Injury (DILI), results in significant late-stage attrition in the pharmaceutical industry. Animal studies have proven insufficient to definitively predict DILI in the clinic, therefore a variety of in vitro models are being tested in an effort to improve prediction of human hepatotoxicity. The model system described here consists of cryopreserved primary rat, dog or human hepatocytes co-cultured together with a fibroblast cell line, which aids in the hepatocytes' maintenance of more in vivo-like characteristics compared to traditional hepatic mono-cultures, including long term viability and retention of activity of cytochrome P450 isozymes. Cell viability was assessed by measurement of ATP following treatment with 29 compounds having known hepatotoxic liabilities. Hμrelrat™, Hμreldog™, and Hμrelhuman™ hepatic co-cultures were treated for 24h, or under repeat-dosing for 7 or 13days, and compared to rat and human hepatic mono-cultures following single-dose exposure for 24h. The results allowed for a comparison of cytotoxicity, species-specific responses and the effect of repeat compound exposure on the prediction of hepatotoxic potential in each model. Results show that the co-culture model had greater sensitivity compared to that of the hepatic mono-cultures. In addition, "time-based ratios" were determined by dividing the compounds' 24-hour TC 50 /C max values by TC 50 /C max values measured after dosing for either 7 or 13days. The results suggest that this approach may serve as a useful adjunct to traditional measurements of hepatotoxicity, improving the predictive value of early screening studies. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Henninger, Christian; Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf; Huelsenbeck, Johannes

    2012-05-15

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by anmore » attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  4. Multicenter study of trimethoprim/sulfamethoxazole-related hepatotoxicity: incidence and associated factors among HIV-infected patients treated for Pneumocystis jirovecii pneumonia.

    PubMed

    Yang, Jen-Jia; Huang, Chung-Hao; Liu, Chun-Eng; Tang, Hung-Jen; Yang, Chia-Jui; Lee, Yi-Chien; Lee, Kuan-Yeh; Tsai, Mao-Song; Lin, Shu-Wen; Chen, Yen-Hsu; Lu, Po-Liang; Hung, Chien-Ching

    2014-01-01

    The incidence of hepatotoxicity related to trimethoprim/sulfamethoxazole (TMP/SMX) administered at a therapeutic dose may vary among study populations of different ethnicities and hepatotoxic metabolites of TMP/SMX may be decreased by drug-drug interaction with fluconazole. We aimed to investigate the incidence of hepatotoxicity and the role of concomitant use of fluconazole in HIV-infected patients receiving TMP/SMX for Pneumocystis jirovecii pneumonia. We reviewed medical records to collect clinical characteristics and laboratory data of HIV-infected patients who received TMP/SMX for treatment of P. jirovecii pneumonia at 6 hospitals around Taiwan between September 2009 and February 2013. Hepatotoxicity was defined as 2-fold or greater increase of aminotransferase or total bilirubin level from baselines. Roussel UCLAF Causality Assessment Method (RUCAM) was used to analyze the causality of drug-induced liver injuries. NAT1 and NAT2 acetylator types were determined with the use of polymerase-chain-reaction (PCR) restriction fragment length polymorphism to differentiate common single-nucleotide polymorphisms (SNPs) predictive of the acetylator phenotypes in a subgroup of patients. During the study period, 286 courses of TMP/SMX treatment administered to 284 patients were analyzed. One hundred and fifty-two patients (53.1%) developed hepatotoxicity, and TMP/SMX was considered causative in 47 (16.4%) who had a RUCAM score of 6 or greater. In multivariate analysis, concomitant use of fluconazole for candidiasis was the only factor associated with reduced risk for hepatotoxicity (adjusted odds ratio, 0.372; 95% confidence interval, 0.145-0.957), while serostatus of hepatitis B or C virus, NAT1 and NAT2 acetylator types, or receipt of combination antiretroviral therapy was not. The incidence of hepatotoxicity decreased with an increasing daily dose of fluconazole up to 4.0 mg/kg. We conclude that the incidence of TMP/SMX-related hepatotoxicity was 16.4% in HIV

  5. Potential protective effect of honey against paracetamol-induced hepatotoxicity.

    PubMed

    Galal, Reem M; Zaki, Hala F; Seif El-Nasr, Mona M; Agha, Azza M

    2012-11-01

    Paracetamol overdose causes severe hepatotoxicity that leads to liver failure in both humans and experimental animals. The present study investigates the protective effect of honey against paracetamol-induced hepatotoxicity in Wistar albino rats. We have used silymarin as a standard reference hepatoprotective drug. Hepatoprotective activity was assessed by measuring biochemical parameters such as the liver function enzymes, serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST). Equally, comparative effects of honey on oxidative stress biomarkers such as malondialdyhyde (MDA), reduced glutathione (GSH) and glutathione peroxidase (GPx) were also evaluated in the rat liver homogenates.  We estimated the effect of honey on serum levels and hepatic content of interleukin-1beta (IL-1β) because the initial event in paracetamol-induced hepatotoxicity has been shown to be a toxic-metabolic injury that leads to hepatocyte death, activation of the innate immune response and upregulation of inflammatory cytokines. Paracetamol caused marked liver damage as noted by significant increased activities of serum AST and ALT as well as the level of Il-1β. Paracetamol also resulted in a significant decrease in liver GSH content and GPx activity which paralleled an increase in Il-1β and MDA levels. Pretreatment with honey and silymarin prior to the administration of paracetamol significantly prevented the increase in the serum levels of hepatic enzyme markers, and reduced both oxidative stress and inflammatory cytokines. Histopathological evaluation of the livers also revealed that honey reduced the incidence of paracetamol-induced liver lesions. Honey can be used as an effective hepatoprotective agent against paracetamol-induced liver damage.

  6. 21 CFR 807.100 - FDA action on a premarket notification.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false FDA action on a premarket notification. 807.100... IMPORTERS OF DEVICES Premarket Notification Procedures § 807.100 FDA action on a premarket notification. (a) After review of a premarket notification, FDA will: (1) Issue an order declaring the device to be...

  7. 21 CFR 807.100 - FDA action on a premarket notification.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false FDA action on a premarket notification. 807.100... IMPORTERS OF DEVICES Premarket Notification Procedures § 807.100 FDA action on a premarket notification. (a) After review of a premarket notification, FDA will: (1) Issue an order declaring the device to be...

  8. 21 CFR 807.100 - FDA action on a premarket notification.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false FDA action on a premarket notification. 807.100... IMPORTERS OF DEVICES Premarket Notification Procedures § 807.100 FDA action on a premarket notification. (a) After review of a premarket notification, FDA will: (1) Issue an order declaring the device to be...

  9. 21 CFR 807.100 - FDA action on a premarket notification.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false FDA action on a premarket notification. 807.100... IMPORTERS OF DEVICES Premarket Notification Procedures § 807.100 FDA action on a premarket notification. (a) After review of a premarket notification, FDA will: (1) Issue an order declaring the device to be...

  10. 21 CFR 807.100 - FDA action on a premarket notification.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false FDA action on a premarket notification. 807.100... IMPORTERS OF DEVICES Premarket Notification Procedures § 807.100 FDA action on a premarket notification. (a) After review of a premarket notification, FDA will: (1) Issue an order declaring the device to be...

  11. FDA Approval for Imiquimod

    Cancer.gov

    On July 15, 2004, the U.S. Food and Drug Administration (FDA) announced the approval of a new indication for Aldara® (imiquimod) topical cream for the treatment of superficial basal cell carcinoma (sBCC), a type of skin cancer.

  12. 46 CFR 58.25-10 - Main and auxiliary steering gear.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Main and auxiliary steering gear. 58.25-10 Section 58.25... AUXILIARY MACHINERY AND RELATED SYSTEMS Steering Gear § 58.25-10 Main and auxiliary steering gear. (a) Power-operated main and auxiliary steering gear must be separate systems that are independent throughout their...

  13. 46 CFR 196.37-33 - Instructions for changing steering gear.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Instructions for changing steering gear. 196.37-33... steering gear. (a) Instructions in at least 1/2 inch letters and figures shall be posted in the steering engineroom, relating in order, the different steps to be taken in changing to the emergency steering gear...

  14. Hepatoprotective and antioxidant effects of Cuscuta chinensis against acetaminophen-induced hepatotoxicity in rats.

    PubMed

    Yen, Feng-Lin; Wu, Tzu-Hui; Lin, Liang-Tzung; Lin, Chun-Ching

    2007-04-20

    Tu-Si-Zi, the seeds of Cuscuta chinensis Lam. (Convolvulaceae), is a traditional Chinese medicine that is commonly used to nourish and improve the liver and kidney conditions in China and other Asian countries. As oxidative stress promotes the development of acetaminophen (APAP)-induced hepatotoxicity, the aim of the present study was to evaluate and compare the hepatoprotective effect and antioxidant activities of the aqueous and ethanolic extracts of C chinensis on APAP-induced hepatotoxicity in rats. The C chinensis ethanolic extract at an oral dose of both 125 and 250mg/kg showed a significant hepatoprotective effect relatively to the same extent (P<0.05) by reducing levels of glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), and alkaline phosphatase (ALP). In addition, the same ethanolic extract prevented the hepatotoxicity induced by APAP-intoxicated treatment as observed when assessing the liver histopathology. Regarding the antioxidant activity, C chinensis ethanolic extract exhibited a significant effect (P<0.05) by increasing levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and by reducing malondialdehyde (MDA) levels. In contrast, the same doses of the aqueous extract of C chinensis did not present any hepatoprotective effect as seen in the ethanolic extract, and resulted in further liver deterioration. In conclusion, these data suggest that the ethanolic extract of Cuscuta chinensis can prevent hepatic injuries from APAP-induced hepatotoxicity in rats and this is likely mediated through its antioxidant activities.

  15. Helping others hear better | NIH MedlinePlus the Magazine

    MedlinePlus

    Skip to main content NIH MedlinePlus the Magazine NIH MedlinePlus Salud Download the Current Issue PDF [2.68 mb] Trusted Health Information from the National Institutes of Health Home Current Issue ...

  16. Integrated phased array for wide-angle beam steering.

    PubMed

    Yaacobi, Ami; Sun, Jie; Moresco, Michele; Leake, Gerald; Coolbaugh, Douglas; Watts, Michael R

    2014-08-01

    We demonstrate an on-chip optical phased array fabricated in a CMOS compatible process with continuous, fast (100 kHz), wide-angle (51°) beam-steering suitable for applications such as low-cost LIDAR systems. The device demonstrates the largest (51°) beam-steering and beam-spacing to date while providing the ability to steer continuously over the entire range. Continuous steering is enabled by a cascaded phase shifting architecture utilizing, low power and small footprint, thermo-optic phase shifters. We demonstrate these results in the telecom C-band, but the same design can easily be adjusted for any wavelength between 1.2 and 3.5 μm.

  17. Bee sting therapy-induced hepatotoxicity: A case report.

    PubMed

    Alqutub, Adel Nazmi; Masoodi, Ibrahim; Alsayari, Khalid; Alomair, Ahmed

    2011-10-27

    The use of bee venom as a therapeutic agent for the relief of joint pains dates back to Hippocrates, and references to the treatment can be found in ancient Egyptian and Greek medical writings as well. Also known as apitherapy, the technique is widely used in Eastern Europe, Asia, and South America. The beneficial effects of bee stings can be attributed to mellitinin, an anti-inflammatory agent, known to be hundred times stronger than cortisone. Unfortunately, certain substances in the bee venom trigger allergic reactions which can be life threatening in a sensitized individual. Multiple stings are known to cause hemolysis, kidney injury, hepatotoxicity and myocardial infarction. The toxicity can be immediate or can manifest itself only weeks after the exposure. We describe hepatotoxicity in a 35-year-old female, following bee sting therapy for multiple sclerosis. She presented to our clinic 3 wk after therapy with a history of progressive jaundice. The patient subsequently improved, and has been attending our clinic now for the last 9 mo.

  18. Bee sting therapy-induced hepatotoxicity: A case report

    PubMed Central

    Alqutub, Adel Nazmi; Masoodi, Ibrahim; Alsayari, Khalid; Alomair, Ahmed

    2011-01-01

    The use of bee venom as a therapeutic agent for the relief of joint pains dates back to Hippocrates, and references to the treatment can be found in ancient Egyptian and Greek medical writings as well. Also known as apitherapy, the technique is widely used in Eastern Europe, Asia, and South America. The beneficial effects of bee stings can be attributed to mellitinin, an anti-inflammatory agent, known to be hundred times stronger than cortisone. Unfortunately, certain substances in the bee venom trigger allergic reactions which can be life threatening in a sensitized individual. Multiple stings are known to cause hemolysis, kidney injury, hepatotoxicity and myocardial infarction. The toxicity can be immediate or can manifest itself only weeks after the exposure. We describe hepatotoxicity in a 35-year-old female, following bee sting therapy for multiple sclerosis. She presented to our clinic 3 wk after therapy with a history of progressive jaundice. The patient subsequently improved, and has been attending our clinic now for the last 9 mo. PMID:22059110

  19. Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats.

    PubMed

    Khoza, Star; Moyo, Ishmael; Ncube, Denver

    2017-01-01

    Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels ( p = 0.0017) and AST levels ( p = 0.0008) than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment ( p < 0.0001). The liver enzyme levels suggested that ketoconazole had the highest risk in causing liver injury followed by itraconazole, fluconazole, terbinafine, and griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

  20. Regulating nanomedicine - can the FDA handle it?

    PubMed

    Bawa, Raj

    2011-05-01

    There is enormous excitement and expectation surrounding the multidisciplinary field of nanomedicine - the application of nanotechnology to healthcare - which is already influencing the pharmaceutical industry. This is especially true in the design, formulation and delivery of therapeutics. Currently, nanomedicine is poised at a critical stage. However, regulatory guidance in this area is generally lacking and critically needed to provide clarity and legal certainty to manufacturers, policymakers, healthcare providers as well as public. There are hundreds, if not thousands, of nanoproducts on the market for human use but little is known of their health risks, safety data and toxicity profiles. Less is known of nanoproducts that are released into the environment and that come in contact with humans. These nanoproducts, whether they are a drug, device, biologic or combination of any of these, are creating challenges for the Food and Drug Administration (FDA), as regulators struggle to accumulate data and formulate testing criteria to ensure development of safe and efficacious nanoproducts (products incorporating nanoscale technologies). Evidence continues to mount that many nanoproducts inherently posses novel size-based properties and toxicity profiles. Yet, this scientific fact has been generally ignored by the FDA and the agency continues to adopt a precautionary approach to the issue in hopes of countering future potential negative public opinion. As a result, the FDA has simply maintained the status quo with regard to its regulatory policies pertaining to nanomedicine. Therefore, there are no specific laws or mechanisms in place for oversight of nanomedicine and the FDA continues to treat nanoproducts as substantially equivalent ("bioequivalent") to their bulk counterparts. So, for now nanoproducts submitted for FDA review will continue to be subjected to an uncertain regulatory pathway. Such regulatory uncertainty could negatively impact venture funding, stifle

  1. Severe hepatotoxic reaction with progression to cirrhosis after use of a novel retinoid (acitretin).

    PubMed

    van Ditzhuijsen, T J; van Haelst, U J; van Dooren-Greebe, R J; van de Kerkhof, P C; Yap, S H

    1990-09-01

    We report the case of a 50-year-old female who suffered from severe palmar and plantar pustulosis. During treatment with acitretin, a novel oral retinoid, which is the main derivative of etretinate, the patient developed a severe hepatotoxic reaction. Subsequent histological studies strongly suggested the development of liver cirrhosis. Reversible elevation of serum aminotransferase values during treatment with acitretin has been reported. However, the present observation indicates that severe hepatotoxic injury may also follow treatment with this agent.

  2. Quantum steering: a review with focus on semidefinite programming.

    PubMed

    Cavalcanti, D; Skrzypczyk, P

    2017-02-01

    Quantum steering refers to the non-classical correlations that can be observed between the outcomes of measurements applied on half of an entangled state and the resulting post-measured states that are left with the other party. From an operational point of view, a steering test can be seen as an entanglement test where one of the parties performs uncharacterised measurements. Thus, quantum steering is a form of quantum inseparability that lies in between the well-known notions of Bell nonlocality and entanglement. Moreover, quantum steering is also related to several asymmetric quantum information protocols where some of the parties are considered untrusted. Because of these facts, quantum steering has received a lot of attention both theoretically and experimentally. The main goal of this review is to give an overview of how to characterise quantum steering through semidefinite programming. This characterisation provides efficient numerical methods to address a number of problems, including steering detection, quantification, and applications. We also give a brief overview of some important results that are not directly related to semidefinite programming. Finally, we make available a collection of semidefinite programming codes that can be used to study the topics discussed in this article.

  3. Altered Protein S-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

    PubMed Central

    McGarry, David J.; Chakravarty, Probir; Wolf, C. Roland

    2015-01-01

    Acetaminophen (APAP) is the most commonly used over-the-counter analgesic. However, hepatotoxicity induced by APAP is a major clinical issue, and the factors that define sensitivity to APAP remain unclear. We have previously demonstrated that mice nulled for glutathione S-transferase Pi (GSTP) are resistant to APAP-induced hepatotoxicity. This study aims to exploit this difference to delineate pathways of importance in APAP toxicity. We used mice nulled for GSTP and heme oxygenase-1 oxidative stress reporter mice, together with a novel nanoflow liquid chromatography–tandem mass spectrometry methodology to investigate the role of oxidative stress, cell signaling, and protein S-glutathionylation in APAP hepatotoxicity. We provide evidence that the sensitivity difference between wild-type and Gstp1/2−/− mice is unrelated to the ability of APAP to induce oxidative stress, despite observing significant increases in c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation in wild-type mice. The major difference in response to APAP was in the levels of protein S-glutathionylation: Gstp1/2−/− mice exhibited a significant increase in the number of S-glutathionylated proteins compared with wild-type animals. Remarkably, these S-glutathionylated proteins are involved in oxidative phosphorylation, respiratory complexes, drug metabolism, and mitochondrial apoptosis. Furthermore, we found that S-glutathionylation of the rate-limiting glutathione-synthesizing enzyme, glutamate cysteine ligase, was markedly increased in Gstp1/2−/− mice in response to APAP. The data demonstrate that S-glutathionylation provides an adaptive response to APAP and, as a consequence, suggest that this is an important determinant in APAP hepatotoxicity. This work identifies potential novel avenues associated with cell survival for the treatment of chemical-induced hepatotoxicity. PMID:26311813

  4. Role of the Sympathetic Nervous System in Carbon Tetrachloride-Induced Hepatotoxicity and Systemic Inflammation

    PubMed Central

    Lin, Jung-Chun; Peng, Yi-Jen; Wang, Shih-Yu; Young, Ton-Ho; Salter, Donald M.; Lee, Herng-Sheng

    2015-01-01

    Carbon tetrachloride (CCl4) is widely used as an animal model of hepatotoxicity and the mechanisms have been arduously studied, however, the contribution of the sympathetic nervous system (SNS) in CCl4-induced acute hepatotoxicity remains controversial. It is also known that either CCl4 or SNS can affect systemic inflammatory responses. The aim of this study was to establish the effect of chemical sympathectomy with 6-hydroxydopamine (6-OHDA) in a mouse model of CCl4-induced acute hepatotoxicity and systemic inflammatory response. Mice exposed to CCl4 or vehicle were pretreated with 6-OHDA or saline. The serum levels of aminotransferases and alkaline phosphatase in the CCl4-poisoning mice with sympathetic denervation were significantly lower than those without sympathetic denervation. With sympathetic denervation, hepatocellular necrosis and fat infiltration induced by CCl4 were greatly decreased. Sympathetic denervation significantly attenuated CCl4-induced lipid peroxidation in liver and serum. Acute CCl4 intoxication showed increased expression of inflammatory cytokines/chemokines [eotaxin-2/CCL24, Fas ligand, interleukin (IL)-1α, IL-6, IL-12p40p70, monocyte chemoattractant protein-1 (MCP-1/CCL2), and tumor necrosis factor-α (TNF-α)], as well as decreased expression of granulocyte colony-stimulating factor and keratinocyte-derived chemokine. The overexpressed levels of IL-1α, IL-6, IL-12p40p70, MCP-1/CCL2, and TNF-α were attenuated by sympathetic denervation. Pretreatment with dexamethasone significantly reduced CCl4-induced hepatic injury. Collectively, this study demonstrates that the SNS plays an important role in CCl4-induced acute hepatotoxicity and systemic inflammation and the effect may be connected with chemical- or drug-induced hepatotoxicity and circulating immune response. PMID:25799095

  5. 21 CFR 516.34 - FDA recognition of exclusive marketing rights.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false FDA recognition of exclusive marketing rights. 516... SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive marketing rights. (a) FDA will send the sponsor (or the permanent-resident U.S. agent, if applicable) timely...

  6. 21 CFR 516.34 - FDA recognition of exclusive marketing rights.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false FDA recognition of exclusive marketing rights. 516... SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive marketing rights. (a) FDA will send the sponsor (or the permanent-resident U.S. agent, if applicable) timely...

  7. 21 CFR 516.34 - FDA recognition of exclusive marketing rights.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false FDA recognition of exclusive marketing rights. 516... SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive marketing rights. (a) FDA will send the sponsor (or the permanent-resident U.S. agent, if applicable) timely...

  8. 21 CFR 516.34 - FDA recognition of exclusive marketing rights.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false FDA recognition of exclusive marketing rights. 516... SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive marketing rights. (a) FDA will send the sponsor (or the permanent-resident U.S. agent, if applicable) timely...

  9. 21 CFR 516.34 - FDA recognition of exclusive marketing rights.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false FDA recognition of exclusive marketing rights. 516... SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive marketing rights. (a) FDA will send the sponsor (or the permanent-resident U.S. agent, if applicable) timely...

  10. Motor assessment using the NIH Toolbox

    PubMed Central

    Magasi, Susan; McCreath, Heather E.; Bohannon, Richard W.; Wang, Ying-Chih; Bubela, Deborah J.; Rymer, William Z.; Beaumont, Jennifer; Rine, Rose Marie; Lai, Jin-Shei; Gershon, Richard C.

    2013-01-01

    Motor function involves complex physiologic processes and requires the integration of multiple systems, including neuromuscular, musculoskeletal, and cardiopulmonary, and neural motor and sensory-perceptual systems. Motor-functional status is indicative of current physical health status, burden of disease, and long-term health outcomes, and is integrally related to daily functioning and quality of life. Given its importance to overall neurologic health and function, motor function was identified as a key domain for inclusion in the NIH Toolbox for Assessment of Neurological and Behavioral Function (NIH Toolbox). We engaged in a 3-stage developmental process to: 1) identify key subdomains and candidate measures for inclusion in the NIH Toolbox, 2) pretest candidate measures for feasibility across the age span of people aged 3 to 85 years, and 3) validate candidate measures against criterion measures in a sample of healthy individuals aged 3 to 85 years (n = 340). Based on extensive literature review and input from content experts, the 5 subdomains of dexterity, strength, balance, locomotion, and endurance were recommended for inclusion in the NIH Toolbox motor battery. Based on our validation testing, valid and reliable measures that are simultaneously low-cost and portable have been recommended to assess each subdomain, including the 9-hole peg board for dexterity, grip dynamometry for upper-extremity strength, standing balance test, 4-m walk test for gait speed, and a 2-minute walk test for endurance. PMID:23479547

  11. Factors associated with anti-TB drug-induced hepatotoxicity and genetic polymorphisms in indigenous and non-indigenous populations in Brazil.

    PubMed

    Heinrich, Melissa M; Zembrzuski, Verônica M; Ota, Marcos M; Sacchi, Flavia P; Teixeira, Raquel L F; Cabello Acero, Pedro H; Cunha, Geraldo Marcelo; Souza-Santos, Reinaldo; Croda, Julio; Basta, Paulo C

    2016-12-01

    Anti-tuberculosis (TB) drugs are responsible for the occurrence of several adverse drug reactions (ADRs), including hepatotoxicity. The aim was to estimate the incidence of hepatotoxicity and its association with genetic polymorphisms and clinical-epidemiological factors by comparing indigenous and non-indigenous TB patients. We investigated clinical-epidemiological variables, serum levels of liver enzymes and NAT2, CYP2E1 and GSTM1 polymorphisms. A non-conditional logistic regression was used to identify the factors associated with hepatotoxicity. Odds ratios were used as the association measures. The incidence of hepatotoxicity was 19.7% for all patients. The risk of hepatotoxicity was almost four times higher in indigenous patients, comparing to non-indigenous. We identified a new nonsynonymous single nucleotide polymorphism of NAT2 in indigenous patients. In total, 54.6% of the patients expressed a slow acetylation phenotype profile. The frequency of the null genotype of GSTM1 was higher in non-indigenous patients (p = 0.002), whereas no significant differences in relation to polymorphisms of CYP2E1 were observed between the groups. Hepatotoxicity was associated with patients older than 60 and indigenous (OR = 26.0; 95%CI:3.1-217.6; OR = 3.8; 95%CI:1.3-11.1, respectively). Furthermore, hepatotoxicity was associated with a slow acetylation profile in indigenous patients (OR = 10.7; 95%CI:1.2-97.2). Our findings suggest that there are distinct acetylation profiles in the Brazilian population, emphasizing the importance of pharmacogenetic analyses for achieving personalized therapeutic schemes and better outcomes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. 76 FR 1180 - FDA Transparency Initiative: Improving Transparency to Regulated Industry

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-07

    ...] FDA Transparency Initiative: Improving Transparency to Regulated Industry AGENCY: Food and Drug... the Transparency Initiative, the Food and Drug Administration (FDA) is announcing the availability of a report entitled ``FDA Transparency Initiative: Improving Transparency to Regulated Industry.'' The...

  13. Monsanto may bypass NIH in microbe test.

    PubMed

    Sun, Marjorie

    1985-01-11

    The Monsanto Company is planning to ask the Environmental Protection Agency for clearance to field test a genetically engineered microbial pesticide, bypassing the traditional approval process of the National Institutes of Health. Although only federally funded institutions are required to obtain NIH approval for genetic engineering tests, Monsanto is the first company to bypass the NIH regulatory process, which has become mired in a lawsuit brought by Jeremy Rifkin.

  14. NIH MedlinePlus the Magazine: Health, Medical & Wellness Articles

    MedlinePlus

    ... to the Web site for NIH MedlinePlus, the magazine. Our purpose is to present you with the ... sponsorship and other charitable donations for NIH MedlinePlus magazine's publication and distribution, many more thousands of Americans ...

  15. New technology in electrophysiology: FDA process and perspective.

    PubMed

    Selzman, Kimberly A; Fellman, Mark; Farb, Andrew; de Del Castillo, Sergio; Zuckerman, Bram

    2016-10-01

    The Food and Drug Administration (FDA) is a large regulatory agency that monitors everything from food, tobacco, and veterinary medicine to pharmaceutical drugs and medical devices. The Mission statement of the CDRH, one of the Centers of the FDA, in its most succinct form is to protect and promote public health. This is accomplished through timely and continued access to safe, effective, and high quality medical devices. This paper aims to review the overarching principles of the Agency's review process for cardiac devices as well as highlight some of the newer programs that FDA has engaged in to facilitate innovation, device development, research, and timely market approval.

  16. Observation of one-way Einstein-Podolsky-Rosen steering

    NASA Astrophysics Data System (ADS)

    Händchen, Vitus; Eberle, Tobias; Steinlechner, Sebastian; Samblowski, Aiko; Franz, Torsten; Werner, Reinhard F.; Schnabel, Roman

    2012-09-01

    The distinctive non-classical features of quantum physics were first discussed in the seminal paper by A. Einstein, B. Podolsky and N. Rosen (EPR) in 1935. In his immediate response, E. Schrödinger introduced the notion of entanglement, now seen as the essential resource in quantum information as well as in quantum metrology. Furthermore, he showed that at the core of the EPR argument is a phenomenon that he called steering. In contrast to entanglement and violations of Bell's inequalities, steering implies a direction between the parties involved. Recent theoretical works have precisely defined this property, but the question arose as to whether there are bipartite states showing steering only in one direction. Here, we present an experimental realization of two entangled Gaussian modes of light that in fact shows the steering effect in one direction but not in the other. The generated one-way steering gives a new insight into quantum physics and may open a new field of applications in quantum information.

  17. 21 CFR 5.1110 - FDA public information offices.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FDA public information offices. 5.1110 Section 5.1110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ORGANIZATION Organization § 5.1110 FDA public information offices. (a) Division of Dockets Management. The...

  18. 21 CFR 5.1110 - FDA public information offices.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FDA public information offices. 5.1110 Section 5.1110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ORGANIZATION Organization § 5.1110 FDA public information offices. (a) Division of Dockets Management. The...

  19. 21 CFR 5.1110 - FDA public information offices.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FDA public information offices. 5.1110 Section 5.1110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ORGANIZATION Organization § 5.1110 FDA public information offices. (a) Division of Dockets Management. The...

  20. 21 CFR 5.1110 - FDA public information offices.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FDA public information offices. 5.1110 Section 5.1110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ORGANIZATION Organization § 5.1110 FDA public information offices. (a) Division of Dockets Management. The...

  1. 21 CFR 5.1110 - FDA public information offices.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FDA public information offices. 5.1110 Section 5.1110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ORGANIZATION Organization § 5.1110 FDA public information offices. (a) Division of Dockets Management. The...

  2. Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cosgrove, Benjamin D.; Cell Decision Processes Center, Massachusetts Institute of Technology, Cambridge, MA; Biotechnology Process Engineering Center, Massachusetts Institute of Technology, Cambridge, MA

    Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF,more » IFN{gamma}, IL-1{alpha}, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1{alpha}, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.« less

  3. FDA recognition of consensus standards in the premarket notification program.

    PubMed

    Marlowe, D E; Phillips, P J

    1998-01-01

    "The FDA has long advocated the use of standards as a significant contributor to safety and effectiveness of medical devices," Center for Devices and Radiological Health's (CDRH) Donald E. Marlowe and Philip J. Phillips note in the following article, highlighting the latest U.S. Food and Drug Administration (FDA) plans for use of standards. They note that the important role standards can play has been reinforced as part of FDA reengineering efforts undertaken in anticipation of an increased regulatory work-load and declining agency resources. As part of its restructuring effort, the FDA announced last spring that it would recognize some consensus standards for use in the device approval process. Under the new 510(k) paradigm--the FDA's proposal to streamline premarket review, which includes incorporating the use of standards in the review of 510(k) submissions--the FDA will accept proof of compliance with standards as evidence of device safety and effectiveness. Manufacturers may submit declarations of conformity to standards instead of following the traditional review process. The International Electrotechnical Commission (IEC) 60601 series of consensus standards, which deals with many safety issues common to electrical medical devices, was the first to be chosen for regulatory review. Other standards developed by nationally or internationally recognized standards development organizations, such as AAMI, may be eligible for use to ensure review requirements. In the following article, Marlowe and Phillips describe the FDA's plans to use standards in the device review process. The article focuses on the use of standards for medical device review, the development of the standards recognition process for reviewing devices, and the anticipated benefits of using standards to review devices. One important development has been the recent implementation of the FDA Modernization Act of 1997 (FDAMA), which advocates the use of standards in the device review process. In

  4. A novel estimating method for steering efficiency of the driver with electromyography signals

    NASA Astrophysics Data System (ADS)

    Liu, Yahui; Ji, Xuewu; Hayama, Ryouhei; Mizuno, Takahiro

    2014-05-01

    The existing research of steering efficiency mainly focuses on the mechanism efficiency of steering system, aiming at designing and optimizing the mechanism of steering system. In the development of assist steering system especially the evaluation of its comfort, the steering efficiency of driver physiological output usually are not considered, because this physiological output is difficult to measure or to estimate, and the objective evaluation of steering comfort therefore cannot be conducted with movement efficiency perspective. In order to take a further step to the objective evaluation of steering comfort, an estimating method for the steering efficiency of the driver was developed based on the research of the relationship between the steering force and muscle activity. First, the steering forces in the steering wheel plane and the electromyography (EMG) signals of the primary muscles were measured. These primary muscles are the muscles in shoulder and upper arm which mainly produced the steering torque, and their functions in steering maneuver were identified previously. Next, based on the multiple regressions of the steering force and EMG signals, both the effective steering force and the total force capacity of driver in steering maneuver were calculated. Finally, the steering efficiency of driver was estimated by means of the estimated effective force and the total force capacity, which represented the information of driver physiological output of the primary muscles. This research develops a novel estimating method for driver steering efficiency of driver physiological output, including the estimation of both steering force and the force capacity of primary muscles with EMG signals, and will benefit to evaluate the steering comfort with an objective perspective.

  5. Chaos in quantum steering in high-dimensional systems

    NASA Astrophysics Data System (ADS)

    He, Guang Ping

    2018-04-01

    Quantum steering means that in some bipartite quantum systems the local measurements on one side can determine the state of the other side. Here we show that in high-dimensional systems there exists a specific entangled state which can display a kind of chaos effect when being adopted for steering. That is, a subtle difference in the measurement results on one side can steer the other side into completely orthogonal states. Moreover, by expanding the result to infinite-dimensional systems, we find two sets of states for which, contrary to common belief, even though their density matrices approach being identical, the steering between them is impossible. This property makes them very useful for quantum cryptography.

  6. Refractive waveguide non-mechanical beam steering (NMBS) in the MWIR

    NASA Astrophysics Data System (ADS)

    Myers, Jason D.; Frantz, Jesse A.; Spillmann, Christopher M.; Bekele, Robel Y.; Kolacz, Jakub; Gotjen, Henry; Naciri, Jawad; Shaw, Brandon; Sanghera, Jas S.

    2018-02-01

    Beam steering is a crucial technology for a number of applications, including chemical sensing/mapping and light detection and ranging (LIDAR). Traditional beam steering approaches rely on mechanical movement, such as the realignment of mirrors in gimbal mounts. The mechanical approach to steering has several drawbacks, including large size, weight and power usage (SWAP), and frequent mechanical failures. Recently, alternative non-mechanical approaches have been proposed and developed, but these technologies do not meet the demanding requirements for many beam steering applications. Here, we highlight the development efforts into a particular non-mechanical beam steering (NMBS) approach, refractive waveguides, for application in the MWIR. These waveguides are based on an Ulrich-coupled slab waveguide with a liquid crystal (LC) top cladding; by selectively applying an electric field across the liquid crystal through a prismatic electrode, steering is achieved by creating refraction at prismatic interfaces as light propagates through the device. For applications in the MWIR, we describe a versatile waveguide architecture based on chalcogenide glasses that have a wide range of refractive indices, transmission windows, and dispersion properties. We have further developed robust shadow-masking methods to taper the subcladding layers in the coupling region. We have demonstrated devices with >10° of steering in the MWIR and a number of advantageous properties for beam steering applications, including low-power operation, compact size, and fast point-to-point steering.

  7. Modern Control Aspects of Automatically Steered Vehicles

    DOT National Transportation Integrated Search

    1971-12-01

    In the study of automatically steered rubber tired vehicles, little emphasis in the past has been placed on the steering control laws. The report examines the control law problem from the state variable point of view and it is shown that, except for ...

  8. New FDA draft guidance on immunogenicity.

    PubMed

    Parenky, Ashwin; Myler, Heather; Amaravadi, Lakshmi; Bechtold-Peters, Karoline; Rosenberg, Amy; Kirshner, Susan; Quarmby, Valerie

    2014-05-01

    A "Late Breaking" session was held on May 20 at the 2013 American Association of Pharmaceutical Scientists-National Biotech Conference (AAPS-NBC) to discuss the US Food and Drug Administration's (FDA) 2013 draft guidance on Immunogenicity Assessment for Therapeutic Protein Products. The session was initiated by a presentation from the FDA which highlighted several key aspects of the 2013 draft guidance pertaining to immunogenicity risk, the potential impact on patient safety and product efficacy, and risk mitigation. This was followed by an open discussion on the draft guidance which enabled delegates from biopharmaceutical companies to engage the FDA on topics that had emerged from their review of the draft guidance. The multidisciplinary audience fostered an environment that was conducive to scientific discussion on a broad range of topics such as clinical impact, immune mitigation strategies, immune prediction and the role of formulation, excipients, aggregates, and degradation products in immunogenicity. This meeting report highlights several key aspects of the 2013 draft guidance together with related dialog from the session.

  9. Optimization Under Uncertainty for Wake Steering Strategies: Preprint

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Quick, Julian; Annoni, Jennifer; King, Ryan N

    Wind turbines in a wind power plant experience significant power losses because of aerodynamic interactions between turbines. One control strategy to reduce these losses is known as 'wake steering,' in which upstream turbines are yawed to direct wakes away from downstream turbines. Previous wake steering research has assumed perfect information, however, there can be significant uncertainty in many aspects of the problem, including wind inflow and various turbine measurements. Uncertainty has significant implications for performance of wake steering strategies. Consequently, the authors formulate and solve an optimization under uncertainty (OUU) problem for finding optimal wake steering strategies in the presencemore » of yaw angle uncertainty. The OUU wake steering strategy is demonstrated on a two-turbine test case and on the utility-scale, offshore Princess Amalia Wind Farm. When we accounted for yaw angle uncertainty in the Princess Amalia Wind Farm case, inflow-direction-specific OUU solutions produced between 0% and 1.4% more power than the deterministically optimized steering strategies, resulting in an overall annual average improvement of 0.2%. More importantly, the deterministic optimization is expected to perform worse and with more downside risk than the OUU result when realistic uncertainty is taken into account. Additionally, the OUU solution produces fewer extreme yaw situations than the deterministic solution.« less

  10. Bulling among yearling feedlot steers.

    PubMed

    Pierson, R E; Jensen, R; Braddy, P M; Horton, D P; Christie, R M

    1976-09-01

    In a survey to determine the cause of illness and deaths among yearling feedlot cattle, bulling was found to be one of the major problems. During the years 1971-1974, 54,913 (2.88%) steers became bullers and represented an annual loss of around +325,000. Some of the causes of bulling were found to be hormones, either as implants or in the feed. In 1974, from 1,988 necropsies, it was determined that 83 steers died from riding injuries.

  11. 21 CFR 830.220 - Termination of FDA service as an issuing agency.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Termination of FDA service as an issuing agency... SERVICES (CONTINUED) MEDICAL DEVICES UNIQUE DEVICE IDENTIFICATION FDA as an Issuing Agency § 830.220 Termination of FDA service as an issuing agency. (a) FDA may end our services as an issuing agency if we...

  12. Aeroelastic Tailoring via Tow Steered Composites

    NASA Technical Reports Server (NTRS)

    Stanford, Bret K.; Jutte, Christine V.

    2014-01-01

    The use of tow steered composites, where fibers follow prescribed curvilinear paths within a laminate, can improve upon existing capabilities related to aeroelastic tailoring of wing structures, though this tailoring method has received relatively little attention in the literature. This paper demonstrates the technique for both a simple cantilevered plate in low-speed flow, as well as the wing box of a full-scale high aspect ratio transport configuration. Static aeroelastic stresses and dynamic flutter boundaries are obtained for both cases. The impact of various tailoring choices upon the aeroelastic performance is quantified: curvilinear fiber steering versus straight fiber steering, certifiable versus noncertifiable stacking sequences, a single uniform laminate per wing skin versus multiple laminates, and identical upper and lower wing skins structures versus individual tailoring.

  13. Mechanistic Biomarkers in Acetaminophen-induced Hepatotoxicity and Acute Liver Failure: From Preclinical Models to Patients

    PubMed Central

    McGill, Mitchell R.; Jaeschke, Hartmut

    2015-01-01

    SUMMARY Introduction Drug hepatotoxicity is a major clinical issue. Acetaminophen (APAP) overdose is especially common. Serum biomarkers used to follow patient progress reflect either liver injury or function, but focus on biomarkers that can provide insight into the basic mechanisms of hepatotoxicity is increasing and enabling us to translate mechanisms of toxicity from animal models to humans. Areas covered We review recent advances in mechanistic serum biomarker research in drug hepatotoxicity. Specifically, biomarkers for reactive drug intermdiates, mitochondrial dysfunction, nuclear DNA damage, mode of cell death and inflammation are discussed, as well as microRNAs. Emphasis is placed on APAP-induced liver injury. Expert Opinion Several serum biomarkers of reactive drug intermediates, mitochondrial damage, nuclear DNA damage, apoptosis and necrosis, and inflammation have been described. These studies have provided evidence that mitochondrial damage is critical in APAP hepatotoxicity in humans, while apoptosis has only a minor role, and inflammation is important for recovery and regeneration after APAP overdose. Additionally, mechanistic serum biomarkers have been shown to predict outcome as well as, or better than, some clinical scores. In the future, such biomarkers will help determine the need for liver transplantation and, with improved understanding of the human pathophysiology, identify novel therapeutic targets. PMID:24836926

  14. Collective multipartite Einstein-Podolsky-Rosen steering: more secure optical networks.

    PubMed

    Wang, Meng; Gong, Qihuang; He, Qiongyi

    2014-12-01

    Collective multipartite Einstein-Podolsky-Rosen (EPR) steering is a type of quantum correlation shared among N parties, where the EPR paradox of one party can only be realized by performing local measurements on all the remaining N-1 parties. We formalize the collective tripartite steering in terms of local hidden state model and give the steering inequalities that act as signatures and suggest how to optimize collective tripartite steering in specific optical schemes. The special entangled states with property of collective multipartite steering may have potential applications in ultra-secure multiuser communication networks where the issue of trust is critical.

  15. 9 CFR 78.6 - Steers and spayed heifers.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... AGRICULTURE INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS BRUCELLOSIS Restrictions on Interstate Movement of Cattle Because of Brucellosis § 78.6 Steers and spayed heifers. Steers...

  16. 9 CFR 78.6 - Steers and spayed heifers.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... AGRICULTURE INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS BRUCELLOSIS Restrictions on Interstate Movement of Cattle Because of Brucellosis § 78.6 Steers and spayed heifers. Steers...

  17. 9 CFR 78.6 - Steers and spayed heifers.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AGRICULTURE INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS BRUCELLOSIS Restrictions on Interstate Movement of Cattle Because of Brucellosis § 78.6 Steers and spayed heifers. Steers...

  18. 9 CFR 78.6 - Steers and spayed heifers.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AGRICULTURE INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS BRUCELLOSIS Restrictions on Interstate Movement of Cattle Because of Brucellosis § 78.6 Steers and spayed heifers. Steers...

  19. 9 CFR 78.6 - Steers and spayed heifers.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... AGRICULTURE INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS BRUCELLOSIS Restrictions on Interstate Movement of Cattle Because of Brucellosis § 78.6 Steers and spayed heifers. Steers...

  20. Directional control-response compatibility of joystick steered shuttle cars.

    PubMed

    Burgess-Limerick, Robin; Zupanc, Christine M; Wallis, Guy

    2012-01-01

    Shuttle cars are an unusual class of vehicle operated in underground coal mines, sometimes in close proximity to pedestrians and steering errors may have very serious consequences. A directional control-response incompatibility has previously been described in shuttle cars which are controlled using a steering wheel oriented perpendicular to the direction of travel. Some other shuttle car operators are seated perpendicular to the direction of travel and steer the car via a seat mounted joystick. A virtual simulation was utilised to determine whether the steering arrangement in these vehicles maintains directional control-response compatibility. Twenty-four participants were randomly assigned to either a condition corresponding to this design (consistent direction), or a condition in which the directional steering response was reversed while driving in-bye (visual field compatible). Significantly less accurate steering performance was exhibited by the consistent direction group during the in-bye trials only. Shuttle cars which provide the joystick steering mechanism described here require operators to accommodate alternating compatible and incompatible directional control-response relationships with each change of car direction. A virtual simulation of an underground coal shuttle car demonstrates that the design incorporates a directional control-response incompatibility when driving the vehicle in one direction. This design increases the probability of operator error, with potential adverse safety and productivity consequences.

  1. Low-Absorption Liquid Crystals for Infrared Beam Steering

    DTIC Science & Technology

    2015-09-30

    liquid crystals for infrared laser beam steering applications. To suppress the optical loss in MW1R and LW1R, we have investigated following...dielectric anisotropy, and low optical loss nematic liquid crystals for infrared laser beam steering applications. To suppress the optical loss in MWIR and...modulators. 1. Objective The main objective of this program is to develop low-loss liquid crystals for electronic laser beam steering in the infrared

  2. Cost of Einstein-Podolsky-Rosen steering in the context of extremal boxes

    NASA Astrophysics Data System (ADS)

    Das, Debarshi; Datta, Shounak; Jebaratnam, C.; Majumdar, A. S.

    2018-02-01

    Einstein-Podolsky-Rosen steering is a form of quantum nonlocality, which is weaker than Bell nonlocality, but stronger than entanglement. Here we present a method to check Einstein-Podolsky-Rosen steering in the scenario where the steering party performs two black-box measurements and the trusted party performs projective qubit measurements corresponding to two arbitrary mutually unbiased bases. This method is based on decomposing the measurement correlations in terms of extremal boxes of the steering scenario. In this context, we propose a measure of steerability called steering cost. We show that our steering cost is a convex steering monotone. We illustrate our method to check steerability with two families of measurement correlations and find out their steering cost.

  3. Steering and Suspension Systems. Auto Mechanics Curriculum Guide. Module 5. Instructor's Guide.

    ERIC Educational Resources Information Center

    Rains, Larry

    This module is the fifth of nine modules in the competency-based Missouri Auto Mechanics Curriculum Guide. Seventeen units cover: steering system design; diagnosing steering systems problems; inspecting and replacing steering linkage components; manual and power steering gear service; manual and power rack and pinion steering gear service; power…

  4. Drug induced hepatotoxicity: data from the Serbian pharmacovigilance database.

    PubMed

    Petronijevic, Marija; Ilic, Katarina; Suzuki, Ayako

    2011-04-01

    The main aim of this study was to determine the most frequently reported drugs to the Serbian Pharmacovigilance Database (SPD) with suspected induced hepatotoxicity. Additionally, reasons for the low reporting rate of adverse drug reactions (ADRs) in Serbia were identified. Retrospective observational study of spontaneously reported ADRs recorded in the SPD from January 1995 to December 2008 was performed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify cases of hepatobiliary disorders (HD). Drugs were classified using the Anatomical Therapeutic Chemical (ATC) classification. Medline and WHO-UMC databases were used to address specific queries suggested by our results. The questionnaire was used to investigate the health care professionals' knowledge and practice related to spontaneous reporting. Among the 1804 reports of ADRs recorded in the SPD between 1995 and 2008, 70 (3.9%) cases of HD were identified. Drugs most frequently associated with hepatotoxicity were anti-infectives for systemic use, drugs affecting the nervous system, herbal products, hypolipemics, and anticoagulant drugs (26.83, 24.39, 12.20, 9.76, and 8.54% cases, respectively). Four cases (5.71%) of liver injury resulted in death, which accounted for 10.26% of all ADR fatalities reported to the SPD. The main reasons for not reporting ADRs were lack of reporting knowledge (30.26%), well-known ADRs (29.89%), and insecurity about causality relationship (15.50%). Anti-infectives, nervous system drugs, and herbal products were the most common drug classes reported for hepatotoxicity in Serbia. There is a need for additional education about ADRs, and enhanced reporting by health care professionals. Copyright © 2011 John Wiley & Sons, Ltd.

  5. Herbal hepatotoxicity: Challenges and pitfalls of causality assessment methods

    PubMed Central

    Teschke, Rolf; Frenzel, Christian; Schulze, Johannes; Eickhoff, Axel

    2013-01-01

    The diagnosis of herbal hepatotoxicity or herb induced liver injury (HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation. At the day HILI is suspected in a patient, physicians should start assessing the quality of the used herbal product, optimizing the clinical data for completeness, and applying the Council for International Organizations of Medical Sciences (CIOMS) scale for initial causality assessment. This scale is structured, quantitative, liver specific, and validated for hepatotoxicity cases. Its items provide individual scores, which together yield causality levels of highly probable, probable, possible, unlikely, and excluded. After completion by additional information including raw data, this scale with all items should be reported to regulatory agencies and manufacturers for further evaluation. The CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases, compared to numerous other causality assessment methods, which are inferior on various grounds. Among these disputed methods are the Maria and Victorino scale, an insufficiently qualified, shortened version of the CIOMS scale, as well as various liver unspecific methods such as the ad hoc causality approach, the Naranjo scale, the World Health Organization (WHO) method, and the Karch and Lasagna method. An expert panel is required for the Drug Induced Liver Injury Network method, the WHO method, and other approaches based on expert opinion, which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the physician. In conclusion, HILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale, avoiding pitfalls commonly observed with other approaches. PMID:23704820

  6. BEAMLINE-CONTROLLED STEERING OF SOURCE-POINT ANGLE AT THE ADVANCED PHOTON SOURCE

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Emery, L.; Fystro, G.; Shang, H.

    An EPICS-based steering software system has been implemented for beamline personnel to directly steer the angle of the synchrotron radiation sources at the Advanced Photon Source. A script running on a workstation monitors "start steering" beamline EPICS records, and effects a steering given by the value of the "angle request" EPICS record. The new system makes the steering process much faster than before, although the older steering protocols can still be used. The robustness features of the original steering remain. Feedback messages are provided to the beamlines and the accelerator operators. Underpinning this new steering protocol is the recent refinementmore » of the global orbit feedback process whereby feedforward of dipole corrector set points and orbit set points are used to create a local steering bump in a rapid and seamless way.« less

  7. NiH2 Battery Reconditioning for LEO Applications

    NASA Technical Reports Server (NTRS)

    Armantrout, J. D.; Hafen, D. P.

    1997-01-01

    This paper summarizes reasons for and benefits of reconditioning nickel-hydrogen (NiH2) batteries used for Low Earth Orbit (LEO) applications. NiH2 battery cells do not have the classic discharge voltage problems more commonly associated with nickel-cadmium (NiCd) cells. This is due, in part, to use of hydrogen electrodes in place of cadmium electrodes. The nickel electrode, however, does have a similar discharge voltage signature for both cell designs. This can have an impact on LEO applications where peak loads at higher relative depths of discharge can impact operations. Periodic reconditioning provides information which can be used for analyzing long term performance trends to predict usable capacity to a specified voltage level. The reconditioning process described herein involves discharging NiH2 batteries at C/20 rates or less, to an average cell voltage of 1.0 volts or less. Recharge is performed at nominal C/5 rates to specified voltage/temperature (V/T) charge levels selected to restore required capacity with minimal overcharge. Reconditioning is a process of restoring reserve capacity lost on cycling, which is commonly called the memory effect in NiCd cells. This effect is characterized by decreases in the discharge voltage curve with operational life and cycling. The end effect of reconditioning NiH2 cells may be hidden in the versatility, of that design over the NiCd cell design and its associated negative electrode fading problem. The process of deep discharge at lower rates by way of reconditioning tends to redistribute electrolyte and water in the NiH2 cell electrode stack, while improving utilization and charge efficiency. NiH2 battery reconditioning effects on life are considered beneficial and may, in fact. extend life based on NiCd experience. In any case, usable capacity data obtained from reconditioning is required for performance evaluation and trend analysis. Characterization and life tests have provided the historical data base used to

  8. 21 CFR 830.120 - Responsibilities of an FDA-accredited issuing agency.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Responsibilities of an FDA-accredited issuing... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES UNIQUE DEVICE IDENTIFICATION FDA Accreditation of an Issuing Agency § 830.120 Responsibilities of an FDA-accredited issuing agency. To maintain its accreditation, an...

  9. Interview with Janet Woodcock: progress on the FDA's critical path initiative.

    PubMed

    Woodcock, Janet

    2009-12-01

    Janet Woodcock is the Director of the US FDA's Center for Drug Evaluation and Research. Dr Woodcock has held various positions within the FDA's Office of the Commissioner from October 2003 until 1 April, 2008, as Deputy Commissioner and Chief Medical Officer, Deputy Commissioner for Operations and Chief Operating Officer and Director of the Critical Path Programs. She oversaw scientific and medical regulatory operations for the FDA. Dr Woodcock served as Director of the Center for Drug Evaluation and Research at the FDA from 1994 to 2005. She previously served in other positions at the FDA including Director of the Office of Therapeutics Research and Review and Acting Deputy Director of the Center for Biologics Evaluation and Research. Dr Woodcock received her MD from Northwestern Medical School (IL, USA), and completed further training and held teaching appointments at the Pennsylvania State University (PA, USA)and the University of California in San Francisco (CA, USA). She joined the FDA in 1986.

  10. The Impact of NIH Postdoctoral Training Grants on Scientific Productivity.

    PubMed

    Jacob, Brian A; Lefgren, Lars

    2011-07-01

    In this paper, we estimate the impact of receiving an NIH postdoctoral training grant on subsequent publications and citations. Our sample consists of all applications for NIH postdoctoral training grants (unsuccessful as well as successful) from 1980 to 2000. Both ordinary least squares and regression discontinuity estimates show that receipt of an NIH postdoctoral fellowship leads to about one additional publication over the next five years, which reflects a 20 percent increase in research productivity.

  11. Report raises questions about drug companies advertising budgets.

    PubMed

    1999-08-06

    A report by AIDS Action cites that data, indicates the pharmaceutical industry is spending more resources on marketing and advertising than on research and development (R&D). The pharmaceutical industry blames the high cost of AIDS drugs on R&D information compiled from annual reports and industry publications show excessive marketing as the source. A spokesman for the Pharmaceutical Research and Manufacturers of America (PhRMA) disputes the information in the AIDS Action report as misleading. According to PhRMA, research spending has been steadily increasing, and at a greater rate than any other industry. In addition, PhRMA noted that pharmaceutical companies have already dedicated money to fund initiatives in developing countries. Solutions proposed by AIDS Action include lowering drug prices or transferring funds from marketing to research, and reestablishing the "reasonable pricing clause" between National Institutes of Health and those companies seeking tax breaks for R&D.

  12. Contribution of NIH funding to new drug approvals 2010-2016.

    PubMed

    Galkina Cleary, Ekaterina; Beierlein, Jennifer M; Khanuja, Navleen Surjit; McNamee, Laura M; Ledley, Fred D

    2018-03-06

    This work examines the contribution of NIH funding to published research associated with 210 new molecular entities (NMEs) approved by the Food and Drug Administration from 2010-2016. We identified >2 million publications in PubMed related to the 210 NMEs ( n = 131,092) or their 151 known biological targets ( n = 1,966,281). Of these, >600,000 (29%) were associated with NIH-funded projects in RePORTER. This funding included >200,000 fiscal years of NIH project support (1985-2016) and project costs >$100 billion (2000-2016), representing ∼20% of the NIH budget over this period. NIH funding contributed to every one of the NMEs approved from 2010-2016 and was focused primarily on the drug targets rather than on the NMEs themselves. There were 84 first-in-class products approved in this interval, associated with >$64 billion of NIH-funded projects. The percentage of fiscal years of project funding identified through target searches, but not drug searches, was greater for NMEs discovered through targeted screening than through phenotypic methods (95% versus 82%). For targeted NMEs, funding related to targets preceded funding related to the NMEs, consistent with the expectation that basic research provides validated targets for targeted screening. This analysis, which captures basic research on biological targets as well as applied research on NMEs, suggests that the NIH contribution to research associated with new drug approvals is greater than previously appreciated and highlights the risk of reducing federal funding for basic biomedical research. Copyright © 2018 the Author(s). Published by PNAS.

  13. Acute Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCIPP) Causes Hepatic Inflammation and Leads to Hepatotoxicity in Zebrafish

    NASA Astrophysics Data System (ADS)

    Liu, Chunsheng; Su, Guanyong; Giesy, John P.; Letcher, Robert J.; Li, Guangyu; Agrawal, Ira; Li, Jing; Yu, Liqin; Wang, Jianghua; Gong, Zhiyuan

    2016-01-01

    Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been frequently detected in environmental media and has adverse health effect on wildlife and humans. It has been implicated to have hepatotoxicity, but its molecular mechanisms remain unclear. In the present study, adult male zebrafish were exposed to TDCIPP and global hepatic gene expression was examined by RNA-Seq and RT-qPCR in order to understand the molecular mechanisms of TDCIPP-induced hepatotoxicity. Our results indicated that TDCIPP exposure significantly up-regulated the expression of genes involved in endoplasmic reticulum stress and Toll-like receptor (TLR) pathway, implying an inflammatory response, which was supported by up-regulation of inflammation-related biomaker genes. Hepatic inflammation was further confirmed by histological observation of increase of infiltrated neutrophils and direct observation of liver recruitment of neutrophils labeled with Ds-Red fluorescent protein of Tg(lysC:DsRed) zebrafish upon TDCIPP exposure. To further characterize the hepatotoxicity of TDCIPP, the expression of hepatotoxicity biomarker genes, liver histopathology and morphology were examined. The exposure to TDCIPP significantly up-regulated the expression of several biomarker genes for hepatotoxicity (gck, gsr and nqo1) and caused hepatic vacuolization and apoptosis as well as increase of the liver size. Collectively, our results suggest that exposure to TDCIPP induces hepatic inflammation and leads to hepatotoxicity in zebrafish.

  14. 21 CFR 60.20 - FDA action on regulatory review period determinations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

  15. 21 CFR 60.20 - FDA action on regulatory review period determinations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

  16. 21 CFR 60.20 - FDA action on regulatory review period determinations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

  17. 21 CFR 60.20 - FDA action on regulatory review period determinations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

  18. 21 CFR 60.20 - FDA action on regulatory review period determinations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

  19. Reflections on the US FDA's Warning on Direct-to-Consumer Genetic Testing.

    PubMed

    Yim, Seon-Hee; Chung, Yeun-Jun

    2014-12-01

    In November 2013, the US Food and Drug Administration (FDA) sent a warning letter to 23andMe, Inc. and ordered the company to discontinue marketing of the 23andMe Personal Genome Service (PGS) until it receives FDA marketing authorization for the device. The FDA considers the PGS as an unclassified medical device, which requires premarket approval or de novo classification. Opponents of the FDA's action expressed their concerns, saying that the FDA is overcautious and paternalistic, which violates consumers' rights and might stifle the consumer genomics field itself, and insisted that the agency should not restrict direct-to-consumer (DTC) genomic testing without empirical evidence of harm. Proponents support the agency's action as protection of consumers from potentially invalid and almost useless information. This action was also significant, since it reflected the FDA's attitude towards medical application of next-generation sequencing techniques. In this review, we followed up on the FDA-23andMe incident and evaluated the problems and prospects for DTC genetic testing.

  20. The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nishiya, Takayoshi; Mori, Kazuhiko; Hattori, Chiharu

    2008-10-15

    To investigate the hepatotoxic potential of tienilic acid in vivo, we administered a single oral dose of tienilic acid to Sprague-Dawley rats and performed general clinicopathological examinations and hepatic gene expression analysis using Affymetrix microarrays. No change in the serum transaminases was noted at up to 1000 mg/kg, although slight elevation of the serum bile acid and bilirubin, and very mild hepatotoxic changes in morphology were observed. In contrast to the marginal clinicopathological changes, marked upregulation of the genes involved in glutathione biosynthesis [glutathione synthetase and glutamate-cysteine ligase (Gcl)], oxidative stress response [heme oxygenase-1 and NAD(P)H dehydrogenase quinone 1] andmore » phase II drug metabolism (glutathione S-transferase and UDP glycosyltransferase 1A6) were noted after 3 or 6 h post-dosing. The hepatic reduced glutathione level decreased at 3-6 h, and then increased at 24 or 48 h, indicating that the upregulation of NF-E2-related factor 2 (Nrf2)-regulated gene and the late increase in hepatic glutathione are protective responses against the oxidative and/or electrophilic stresses caused by tienilic acid. In a subsequent experiment, tienilic acid in combination with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of Gcl caused marked elevation of serum alanine aminotransferase (ALT) with extensive centrilobular hepatocyte necrosis, whereas BSO alone showed no hepatotoxicity. The elevation of ALT by this combination was observed at the same dose levels of tienilic acid as the upregulation of the Nrf2-regulated genes by tienilic acid alone. In conclusion, these results suggest that the impairment of glutathione biosynthesis may play a critical role in the development of tienilic acid hepatotoxicity through extensive oxidative and/or electrophilic stresses.« less

  1. Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study

    PubMed Central

    Wang, Meng-Ting; Lee, Wan-Ju; Huang, Tien-Yu; Chu, Che-Li; Hsieh, Chang-Hsun

    2014-01-01

    Aims The evidence of hepatotoxicity of antithyroid drugs (ATDs) is limited to case reports or spontaneous reporting. This study aimed to quantify the incidence and comparative risks of hepatotoxicity for methimazole (MMI)/carbimazole (CBM) vs. propylthiouracil (PTU) in a population-based manner. Methods We conducted a cohort study of hyperthyroidism patients initially receiving MMI/CBM or PTU between 1 January 2004 and 31 December 2008 using the Taiwan National Health Insurance Research Database. The examined hepatotoxicity consisted of cholestasis, non-infectious hepatitis, acute liver failure and liver transplant, with the incidences and relative risks being quantified by Poisson exact methods and Cox proportional hazard models, respectively. Results The study cohort comprised 71 379 ATD initiators, with a median follow-up of 196 days. MMI/CBM vs. PTU users had a higher hepatitis incidence rate (3.17/1000 vs. 1.19/1000 person-years) but a lower incidence of acute liver failure (0.32/1000 vs. 0.68/1000 person-years). The relative risk analysis indicated that any use of MMI/CBM was associated with a 2.89-fold (95% CI 1.81, 4.60) increased hepatitis risk compared with PTU, with the risk increasing to 5.08-fold for high dose MMI/CBM (95% CI 3.15, 8.18). However, any MMI/CBM use vs. PTU was not related to an increased risk of cholestasis (adjusted hazard ratio [HR] 1.14, 95% CI 0.40, 3.72) or acute liver failure (adjusted HR 0.54, 95% CI 0.24, 1.22). Conclusions MMI/CBM and PTU exert dissimilar incidence rates of hepatotoxicity. Compared to PTU, MMI/CBM are associated in a dose-dependent manner with an increased risk for hepatitis while the risks are similar for acute liver failure and cholestasis. PMID:25279406

  2. Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi

    PubMed Central

    Henderson, Colin J.; Wolf, C. Roland; Kitteringham, Neil; Powell, Helen; Otto, Diana; Park, B. Kevin

    2000-01-01

    Overdose of acetaminophen, a widely used analgesic drug, can result in severe hepatotoxicity and is often fatal. This toxic reaction is associated with metabolic activation by the P450 system to form a quinoneimine metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which covalently binds to proteins and other macromolecules to cause cellular damage. At low doses, NAPQI is efficiently detoxified, principally by conjugation with glutathione, a reaction catalyzed in part by the glutathione S-transferases (GST), such as GST Pi. To assess the role of GST in acetaminophen hepatotoxicity, we examined acetaminophen metabolism and liver damage in mice nulled for GstP (GstP1/P2(−/−)). Contrary to our expectations, instead of being more sensitive, GstP null mice were highly resistant to the hepatotoxic effects of this compound. No significant differences between wild-type (GstP1/P2(+/+)) mice and GstP1/P2(−/−) nulls in either the rate or route of metabolism, particularly to glutathione conjugates, or in the levels of covalent binding of acetaminophen-reactive metabolites to cellular protein were observed. However, although a similar rapid depletion of hepatic reduced glutathione (GSH) was found in both GstP1/P2(+/+) and GstP1/P2(−/−) mice, GSH levels only recovered in the GstP1/P2(−/−) mice. These data demonstrate that GstP does not contribute in vivo to the formation of glutathione conjugates of acetaminophen but plays a novel and unexpected role in the toxicity of this compound. This study identifies new ways in which GST can modulate cellular sensitivity to toxic effects and suggests that the level of GST Pi may be an important and contributing factor in the sensitivity of patients with acetaminophen-induced hepatotoxicity. PMID:11058152

  3. Laser-phased-array beam steering based on crystal fiber

    NASA Astrophysics Data System (ADS)

    Yang, Deng-cai; Zhao, Si-si; Wang, Da-yong; Wang, Zhi-yong; Zhang, Xiao-fei

    2011-06-01

    Laser-phased-array system provides an elegant means for achieving the inertial-free, high-resolution, rapid and random beam steering. In laser-phased-array system, phase controlling is the most important factor that impacts the system performance. A novel scheme is provided in this paper, the beam steering is accomplished by using crystal fiber array, the difference length between adjacent fiber is fixed. The phase difference between adjacent fiber decides the direction of the output beam. When the wavelength of the input fiber laser is tuned, the phase difference between the adjacent elements has changed. Therefore, the laser beam direction has changed and the beam steering has been accomplished. In this article, based on the proposed scheme, the steering angle of the laser beam is calculated and analyzed theoretically. Moreover, the far-field steering beam quality is discussed.

  4. LABORATORY MEASUREMENTS OF NiH BY FOURIER TRANSFORM DISPERSED FLUORESCENCE

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Vallon, Raphael; Richard, Cyril; Crozet, Patrick

    2009-05-01

    Red and orange bands of laser-induced fluorescence in NiH have been recorded on a Fourier transform interferometer at Doppler resolution. The spectra show strong transitions to low-lying vibronic states which are not thermally populated in a laboratory source, and therefore do not appear in laser excitation spectra, but which would be expected to contribute significantly to any stellar spectrum. The strongest bands belong to the G[{omega}' 5/2]-X {sub 2} {sup 2}{delta}{sub 3/2}, I[{omega}' 3/2]-X {sub 2}, and {sup 2}{delta}{sub 3/2} I[{omega}' 3/2]-W {sub 1} {sup 2}{pi}{sub 3/2} systems. Measurements are reported for {sup 58}NiH, {sup 60}NiH, and {sup 62}NiH.

  5. Congress OKs $2 Billion Boost for the NIH.

    PubMed

    2017-07-01

    President Donald Trump last week signed a $1.1 trillion spending bill for fiscal year 2017, including a welcome $2 billion boost for the NIH that will support former Vice President Joe Biden's Cancer Moonshot initiative, among other priorities. However, researchers who rely heavily on NIH grant funding remain concerned about proposed cuts for 2018. ©2017 American Association for Cancer Research.

  6. The Impact of NIH Postdoctoral Training Grants on Scientific Productivity

    PubMed Central

    Jacob, Brian A.; Lefgren, Lars

    2011-01-01

    In this paper, we estimate the impact of receiving an NIH postdoctoral training grant on subsequent publications and citations. Our sample consists of all applications for NIH postdoctoral training grants (unsuccessful as well as successful) from 1980 to 2000. Both ordinary least squares and regression discontinuity estimates show that receipt of an NIH postdoctoral fellowship leads to about one additional publication over the next five years, which reflects a 20 percent increase in research productivity. PMID:21860538

  7. Crossbred steer temperament as yearlings and whole genome association of steer temperament as yearlings and calf temperament post-weaning.

    PubMed

    Riley, D G; Gill, C A; Boldt, C R; Funkhouser, R R; Herring, A D; Riggs, P K; Sawyer, J E; Lunt, D K; Sanders, J O

    2016-04-01

    cattle often have the reputation for a poor or dangerous temperament. Identification of genomic regions that associate with temperament of such cattle may be useful for genetic improvement strategies. The objectives of this study were to evaluate subjective temperament scores (1 to 9; higher scores indicated more unfavorable temperament) for aggressiveness, nervousness, flightiness, gregariousness, and overall temperament of one-half steers in feedlot conditions at 1 yr of age and compare those scores of those steers when evaluated approximately 1 mo postweaning, and conduct whole genome association analyses using SNP markers and the temperament traits of those steers at 1 yr of age and for temperament traits of all calves at weaning. Contemporary groups ( < 0.001) were steers born in the same year and season, and fed in the same feedlot pen. Aggressiveness of steers at 1 yr of age was not associated with aggressiveness at weaning (linear regression coefficient did not differ from 0; = 0.96), but regressions of all other yearling scores of steers on the scores at weaning were positive (coefficients ranged from 0.26 ± 0.04 to 0.32 ± 0.04; < 0.001). Estimates of Pearson correlation coefficients (using unadjusted values and residual values) of the different traits measured at 1 yr of age were large ( > 0.63; < 0.008) except for aggressiveness with nervousness, flightiness, or gregariousness, which did not differ from 0 ( > 0.1). Five SNP on BTA 1, 24, and 29 had suggestive associations (0.17 < [adjusted for FDR] < 0.24) with aggressiveness, nervousness, or flightiness at evaluation postweaning and 13 SNP on 11 chromosomes had suggestive associations (0.07 < [adjusted for FDR] < 0.24) with aggressiveness, nervousness, flightiness, or overall temperament score of steers at 1 yr of age. Genes close to these loci with roles in neural systems of various organisms included synaptotagmin 4 (BTA 24), FAT atypical cadhedrin 3 (BTA 29), tubulin tyrosine ligase-like 1 (BTA 5

  8. Quercetin attenuates toosendanin-induced hepatotoxicity through inducing the Nrf2/GCL/GSH antioxidant signaling pathway.

    PubMed

    Jin, Yao; Huang, Zhen-Lin; Li, Li; Yang, Yang; Wang, Chang-Hong; Wang, Zheng-Tao; Ji, Li-Li

    2018-06-19

    Toosendanin (TSN) is the main active compound in Toosendan Fructus and Meliae Cortex, two commonly used traditional Chinese medicines. TSN has been reported to induce hepatotoxicity, but its mechanism remains unclear. In this study, we demonstrated the critical role of nuclear factor erythroid 2-related factor 2 (Nrf2) in protecting against TSN-induced hepatotoxicity in mice and human normal liver L-02 cells. In mice, administration of TSN (10 mg/kg)-induced acute liver injury evidenced by increased serum alanine/aspartate aminotransferase (ALT/AST) and alkaline phosphatase (ALP) activities, and total bilirubin (TBiL) content as well as the histological changes. Furthermore, TSN markedly increased liver reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and decreased liver glutathione (GSH) content and Nrf2 expression. In L-02 cells, TSN (2 μM) time-dependently reduced glutamate-cysteine ligase (GCL) activity and cellular expression of the catalytic/modify subunit of GCL (GCLC/GCLM). Moreover, TSN reduced cellular GSH content and the increased ROS formation, and time-dependently decreased Nrf2 expression and increased the expression of the Nrf2 inhibitor protein kelch-like ECH-associated protein-1 (Keap1). Pre-administration of quercetin (40, 80 mg/kg) effectively inhibited TSN-induced liver oxidative injury and reversed the decreased expression of Nrf2 and GCLC/GCLM in vivo and in vitro. In addition, the quercetin-provided protection against TSN-induced hepatotoxicity was diminished in Nrf2 knock-out mice. In conclusion, TSN decreases cellular GSH content by reducing Nrf2-mediated GCLC/GCLM expression via decreasing Nrf2 expression. Quercetin attenuates TSN-induced hepatotoxicity by inducing the Nrf2/GCL/GSH antioxidant signaling pathway. This study implies that inducing Nrf2 activation may be an effective strategy to prevent TSN-induced hepatotoxicity.

  9. 46 CFR 169.623 - Power-driven steering systems.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... systems must have means to be brought into operation from a dead ship condition, without external aid. The... steering systems from the main steering control location must include, as applicable— (1) Control of any...

  10. 46 CFR 169.623 - Power-driven steering systems.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... systems must have means to be brought into operation from a dead ship condition, without external aid. The... steering systems from the main steering control location must include, as applicable— (1) Control of any...

  11. 46 CFR 169.623 - Power-driven steering systems.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... systems must have means to be brought into operation from a dead ship condition, without external aid. The... steering systems from the main steering control location must include, as applicable— (1) Control of any...

  12. Hepatotoxicity of Microcystin-LR in Fed and Fasted Rats

    DTIC Science & Technology

    1990-04-20

    a free radical scavenger, silymarin , prot’cted mice against MCYST-LR (MEREISH et al., 1989). One of the more dramatic changes in liver after exposure...Microcystin-LR hepatotoxicity by silymarin in mice and rats. The FASEB J. 3, A1190. MERILUOTO, J. A. 0., SANDSTROM, A., ERIKSSON, J. E., REMAUD, G

  13. Off the roadmap? Family medicine's grant funding and committee representation at NIH.

    PubMed

    Lucan, Sean C; Phillips, Robert L; Bazemore, Andrew W

    2008-01-01

    Family medicine is challenged to develop its own research infrastructure and to inform and contribute to a national translational-research agenda. Toward these ends, understanding family medicine's engagement with the National Institutes of Health (NIH) is important. We descriptively analyzed NIH grants to family medicine from 2002 through 2006 and the current NIH advisory committee memberships. Grants (and dollars) awarded to departments of family medicine increased from 89 ($25.6 million) in 2002, to 154 ($44.6 million) in 2006. These values represented only 0.20% (0.15% for dollars) and 0.33% (0.22% for dollars), respectively, of total NIH awards. Nearly 75% of family medicine grants came from just 6 of NIH's grant-funding 24 institutes and centers. Although having disproportionately fewer grant continuations (62% vs 72%) and R awards (68% vs 74%)-particularly R01 awards (53% vs 84%)-relative to NIH grantees overall, family medicine earned proportionately more new (28% vs 21%) and K awards (25% vs 9%) and had more physician principal investigators (52% vs 15%). Ten of the nation's 132 departments of family medicine (7.6%) earned almost 50% of all family medicine awards. Representatives from family medicine were on 6.4% of NIH advisory committees (0.38% of all members); family physicians were on 2.7% (0.16% of members). Departments of family medicine, and family physicians in particular, receive a miniscule proportion of NIH grant funding and have correspondingly minimal representation on standing NIH advisory committees. Family medicine's engagement at the NIH remains near well-documented historic lows, undermining family medicine's potential for translating medical knowledge into community practice, and advancing knowledge to improve health care and health for the US population as a whole.

  14. Characteristics of NIH- and industry-sponsored head and neck cancer clinical trials.

    PubMed

    Devaiah, Anand; Murchison, Charles

    2016-09-01

    Compare U.S. clinical trials sponsored by the National Institutes of Health (NIH) and industry, especially with regard to trial design, interventions studied, and results reporting rates. U.S. head and neck cancer clinical trials. We used information from ClinicalTrials.gov to compare NIH- and industry-sponsored head and neck cancer clinical trials, specifically analyzing differences in trial design and interventions studied. We examined publication rates and positive results rates using PubMed.gov. About 50% of NIH- and industry-sponsored clinical trials have their results reported in peer-reviewed literature. Industry-sponsored trials had higher rates of positive results than NIH-sponsored trials. NIH- and industry-sponsored clinical trials had similar trial designs, although industry-sponsored trials had significantly lower rates of randomization. Industry trials utilized radiation in 19% of trials and surgery in 2% of trials. NIH trials also had low utilization of both radiation and surgery (27% and 12% of trials, respectively). NIH- and industry-sponsored trials published their results in journals with comparable impact factors. There is significant underreporting of results in U.S. head and neck cancer clinical trials, whether sponsored by NIH or industry. Industry trials have significantly higher rates of positive results, although it is unclear what contributes to this. Both NIH- and industry-sponsored trials underutilize surgery and radiation as treatment modalities, despite the fact that these are standard-of-care therapies for head and neck cancer. We recommend that the NIH and industry report all results from clinical trials and use surgery and radiation as treatment arms in order to arrive at more balanced therapeutic recommendations. N/A. Laryngoscope, 126:E300-E303, 2016. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

  15. Agile wide-angle beam steering with electrowetting microprisms

    NASA Astrophysics Data System (ADS)

    Smith, Neil R.; Abeysinghe, Don C.; Haus, Joseph W.; Heikenfeld, Jason

    2006-07-01

    A novel basis for beam steering with electrowetting microprisms (EMPs) is reported. EMPs utilize electrowetting modulation of liquid contact angle in order to mimic the refractive behavior for various classical prism geometries. Continuous beam steering through an angle of 14° (±7°) has been demonstrated with a liquid index of n=1.359. Experimental results are well-matched to theoretical behavior up to the point of electrowetting contact-angle saturation. Projections show that use of higher index liquids (n~1.6) will result in steering through ~30° (±15°). Fundamental factors defining achievable deflection range, and issues for Ladar use, are reviewed. This approach is capable of good switching speed (~ms), polarization independent operation, modulation of beam field-of-view (lensing), and high steering efficiency that is independent of deflection angle.

  16. Advances in Patient-Reported Outcomes: The NIH PROMIS® Measures

    PubMed Central

    Broderick, Joan E.; DeWitt, Esi Morgan; Rothrock, Nan; Crane, Paul K.; Forrest, Christopher B.

    2013-01-01

    Patient-reported outcomes (PRO) are questionnaire measures of patients’ symptoms, functioning, and health-related quality of life. They are designed to provide important clinical information that generally cannot be captured with objective medical testing. In 2004, the National Institutes of Health launched a research initiative to improve the clinical research enterprise by developing state-of-the-art PROs. The NIH Patient-Reported Outcomes Measurement System (PROMIS) and Assessment Center are the products of that initiative. Adult, pediatric, and parent-proxy item banks have been developed by using contemporary psychometric methods, yielding rapid, accurate measurements. PROMIS currently provides tools for assessing physical, mental, and social health using short-form and computer-adaptive testing methods. The PROMIS tools are being adopted for use in clinical trials and translational research. They are also being introduced in clinical medicine to assess a broad range of disease outcomes. Recent legislative developments in the United States support greater efforts to include patients’ reports of health experience in order to evaluate treatment outcomes, engage in shared decision-making, and prioritize the focus of treatment. PROs have garnered increased attention by the Food and Drug Administration (FDA) for evaluating drugs and medical devices. Recent calls for comparative effectiveness research favor inclusion of PROs. PROs could also potentially improve quality of care and disease outcomes, provide patient-centered assessment for comparative effectiveness research, and enable a common metric for tracking outcomes across providers and medical systems. PMID:25848562

  17. Comparison of mouse strains for susceptibility to styrene-induced hepatotoxicity and pneumotoxicity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Carlson, G.P.

    1997-10-01

    Styrene is known to cause both hepatotoxicity and pneumotoxicity in mice. Strain differences have been reported by other investigators suggesting that Swiss mice are less susceptible than non-Swiss mice to styrene-induced liver damage. In this study, All and C57BL16 mice were found to be similar to non-Swiss albino (NSA) mice in susceptibility whereas CD-1 (Swiss) mice were more resistant to hepatotoxicity as assessed by serum sorbitol dehydrogenase levels and pneumotoxicity as determined by gamma-glutamyltranspeptidase and lactate dehydrogenase measurements in bronchoalveolar ravage fluid. Styrene was hepatotoxic in CD-1 mice treated with pyridine to induce CYP2E1. CYP2E1 apoprotein levels and p-nitrophenol hydroxylasemore » activities in control and pyridine-induced mice were similar in the two strains. Hepatic and pulmonary microsomal preparations from both strains metabolized styrene to styrene oxide at similar rates. CD-1 mice were as susceptible as the NSA mice to the effects of styrene oxide. The data suggest that there are no differences in the bioactivation of styrene to styrene oxide or innate susceptibility to the active metabolite that would account for the differences between the CD-1 and NSA mice. 26 refs., 6 tabs.« less

  18. The liver-gut microbiota axis modulates hepatotoxicity of tacrine in the rat.

    PubMed

    Yip, Lian Yee; Aw, Chiu Cheong; Lee, Sze Han; Hong, Yi Shuen; Ku, Han Chen; Xu, Winston Hecheng; Chan, Jessalyn Mei Xuan; Cheong, Eleanor Jing Yi; Chng, Kern Rei; Ng, Amanda Hui Qi; Nagarajan, Niranjan; Mahendran, Ratha; Lee, Yuan Kun; Browne, Edward R; Chan, Eric Chun Yong

    2018-01-01

    The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses is poorly understood. In this study, we investigated the role of the liver-gut microbiota axis in underpinning the hepatotoxicity of tacrine. We employed an integrated strategy combining pharmacokinetics, toxicology, metabonomics, genomics, and metagenomics to elucidate and validate the mechanism of tacrine-induced hepatotoxicity in Lister hooded rats. Pharmacokinetic studies in rats demonstrated 3.3-fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealing enhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup, not attributable to variation in hepatic disposition gene expression. Metabonomic studies implicated variations in gut microbial activities that mapped onto tacrine-induced transaminitis. Metagenomics delineated greater deglucuronidation capabilities in strong responders, based on differential gut microbial composition (e.g., Lactobacillus, Bacteroides, and Enterobacteriaceae) and approximately 9% higher β-glucuronidase gene abundance compared with nonresponders. In the validation study, coadministration with oral β-glucuronidase derived from Escherichia coli and pretreatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine-induced transaminitis in vivo. This study establishes pertinent gut microbial influences in modifying the hepatotoxicity of tacrine, providing insights for personalized medicine initiatives. (Hepatology 2018;67:282-295). © 2017 by the American Association for the Study of Liver Diseases.

  19. A channel-based framework for steering, non-locality and beyond

    NASA Astrophysics Data System (ADS)

    Hoban, Matty J.; Belén Sainz, Ana

    2018-05-01

    Non-locality and steering are both non-classical phenomena witnessed in nature as a result of quantum entanglement. It is now well-established that one can study non-locality independently of the formalism of quantum mechanics, in the so-called device-independent framework. With regards to steering, although one cannot study it completely independently of the quantum formalism, ‘post-quantum steering’ has been described, which is steering that cannot be reproduced by measurements on entangled states but does not lead to superluminal signalling. In this work we present a framework based on the study of quantum channels in which one can study steering (and non-locality) in quantum theory and beyond. In this framework, we show that kinds of steering, whether quantum or post-quantum, are directly related to particular families of quantum channels that have been previously introduced by Beckman et al (2001 Phys. Rev. A 64 052309). Utilizing this connection we also demonstrate new analytical examples of post-quantum steering, give a quantum channel interpretation of almost quantum non-locality and steering, easily recover and generalize the celebrated Gisin–Hughston–Jozsa–Wootters theorem, and initiate the study of post-quantum Buscemi non-locality and non-classical teleportation. In this way, we see post-quantum non-locality and steering as just two aspects of a more general phenomenon.

  20. Exploring the Celiac Disease Mystery | NIH MedlinePlus the Magazine

    MedlinePlus

    Skip to main content NIH MedlinePlus the Magazine NIH MedlinePlus Salud Download the Current Issue PDF [2.68 mb] Trusted Health Information from the National Institutes of Health Home Current Issue ...

  1. Examining the FDA's oversight of direct-to-consumer advertising.

    PubMed

    Gahart, Martin T; Duhamel, Louise M; Dievler, Anne; Price, Roseanne

    2003-01-01

    Our analysis examined the effects of the Food and Drug Administration's (FDA's) 1997 draft guidance regarding advertisements for prescription drugs broadcast directly to consumers. We found that although direct-to-consumer (DTC) advertising spending by pharmaceutical companies has increased, more than 80 percent of their promotional spending is directed to physicians. DTC advertising appears to increase the use of prescription drugs among consumers. The FDA's oversight has not prevented companies from making misleading claims in subsequent advertisements, and a recent policy change has lengthened the FDA's review process, raising the possibility that some misleading campaigns could run their course before review.

  2. 21 CFR 1271.27 - Will FDA assign me a registration number?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

  3. 21 CFR 1271.27 - Will FDA assign me a registration number?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

  4. 21 CFR 1271.27 - Will FDA assign me a registration number?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

  5. 21 CFR 1271.27 - Will FDA assign me a registration number?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

  6. 21 CFR 1271.27 - Will FDA assign me a registration number?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

  7. Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity.

    PubMed

    Hayashi, Paul H; Fontana, Robert J; Chalasani, Naga P; Stolz, Andrew A; Talwalkar, Jay A; Navarro, Victor J; Lee, William M; Davern, Timothy J; Kleiner, David E; Gu, Jiezhun; Hoofnagle, Jay H

    2015-09-01

    Isoniazid is a leading cause of liver injury but it is not clear how many cases are reported or how many clinicians and patients adhere to American Thoracic Society (ATS) guidelines. We collected data on cases of isoniazid hepatotoxicity and assessed adherence to ATS guidelines and reports to the Centers for Disease Control's (CDC) isoniazid severe adverse events program. We analyzed Drug-Induced Liver Injury Network (DILIN) cases considered definite, highly likely, or probable for isoniazid injury from 2004 through 2013. We assessed the delays in isoniazid discontinuance according to ATS criteria and hepatotoxicity severity by Severity Index Score. We checked reporting to the CDC by matching cases based on age, latency, indication, reporting period, and comorbidities. Isoniazid was the second most commonly reported agent in the DILIN, with 69 cases; 60 of these met inclusion criteria. The median age of cases was 49 years (range, 4-68 y), 70% were female, 97% had latent tuberculosis, and 62% were hospitalized. Patients took a median of 9 days to stop taking isoniazid (range, 0-99 days). Thirty-three cases (55%) continued taking isoniazid for more than 7 days after the ATS criteria for stopping were met. Twenty-four cases (40%) continued isoniazid for more than 14 days after meeting criteria for stopping. A delay in stopping was associated with more severe injury (P < .05). Of 13 patients who died or underwent liver transplantation, 9 (70%) continued taking isoniazid for more than 7 days after meeting criteria for stopping. Only 1 of 25 cases of isoniazid hepatotoxicity eligible for reporting to the CDC was reported. Poor adherence to ATS guidelines is common in cases of hepatotoxicity and is associated with more severe outcomes including hospitalization, death, and liver transplantation. Isoniazid continues to be a leading cause of DILI in the United States, and its hepatotoxicity is under-reported significantly. Copyright © 2015 AGA Institute. Published by

  8. [Hepatotoxicity of emodin based on UGT1A1 enzyme-mediated bilirubin in liver microsomes].

    PubMed

    Wang, Qi; Dai, Zhong; Zhang, Yu-Jie; Ma, Shuang-Cheng

    2016-12-01

    To study the hepatotoxicity of emodin based on bilirubin metabolism mediated by glucuronidation of UGT1A1 enzyme. In this study, three different incubation systems were established by using RLM, HLM, and rUGT1A1, with bilirubin as the substrate. Different concentrations of bilirubin and emodin were added in the incubation systems. The double reciprocal Michaelis equation was drawn based on the total amount of bilirubin glucuronidation. The apparent inhibition constant Ki was then calculated with the slope curve to predict the hepatotoxicity. The results indicated that emodin had a significant inhibition to the UGT1A1 enzyme in all of the three systems, with Ki=5.400±0.956(P<0.05) in HLM system, Ki =10.020±0.611(P<0.05) in RLM system, Ki=4.850±0.528(P<0.05) in rUGT1A1 system. Meanwhile, emodin had no significant difference between rat and human in terms of inhibition of UGT1A1 enzyme. Emodin had a potential risk of the hepatotoxicity by inhibiting the UGT1A1 enzyme activity. And the method established in this study provides a new thought and new method to evaluate hepatotoxicity and safety of traditional Chinese medicines. Copyright© by the Chinese Pharmaceutical Association.

  9. Surgeon Scientists Are Disproportionately Affected by Declining NIH Funding Rates.

    PubMed

    Narahari, Adishesh K; Mehaffey, J Hunter; Hawkins, Robert B; Charles, Eric J; Baderdinni, Pranav K; Chandrabhatla, Anirudha S; Kocan, Joseph W; Jones, R Scott; Upchurch, Gilbert R; Kron, Irving L; Kern, John A; Ailawadi, Gorav

    2018-04-01

    Obtaining National Institutes of Health (NIH) funding over the last 10 years has become increasingly difficult due to a decrease in the number of research grants funded and an increase in the number of NIH applications. National Institutes of Health funding amounts and success rates were compared for all disciplines using data from NIH, Federation of American Societies for Experimental Biology (FASEB), and Blue Ridge Medical Institute. Next, all NIH grants (2006 to 2016) with surgeons as principal investigators were identified using the National Institutes of Health Research Portfolio Online Reporting Tools Expenditures and Results (NIH RePORTER), and a grant impact score was calculated for each grant based on the publication's impact factor per funding amount. Linear regression and one-way ANOVA were used for analysis. The number of NIH grant applications has increased by 18.7% (p = 0.0009), while the numbers of funded grants (p < 0.0001) and R01s (p < 0.0001) across the NIH have decreased by 6.7% and 17.0%, respectively. The mean success rate of funded grants with surgeons as principal investigators (16.4%) has been significantly lower than the mean NIH funding rate (19.2%) (p = 0.011). Despite receiving only 831 R01s during this time period, surgeon scientists were highly productive, with an average grant impact score of 4.9 per $100,000, which increased over the last 10 years (0.15 ± 0.05/year, p = 0.02). Additionally, the rate of conversion of surgeon scientist-mentored K awards to R01s from 2007 to 2012 was 46%. Despite declining funding over the last 10 years, surgeon scientists have demonstrated increasing productivity as measured by impactful publications and higher success rates in converting early investigator awards to R01s. Copyright © 2018 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

  10. Estimating the NIH efficient frontier.

    PubMed

    Bisias, Dimitrios; Lo, Andrew W; Watkins, James F

    2012-01-01

    The National Institutes of Health (NIH) is among the world's largest investors in biomedical research, with a mandate to: "…lengthen life, and reduce the burdens of illness and disability." Its funding decisions have been criticized as insufficiently focused on disease burden. We hypothesize that modern portfolio theory can create a closer link between basic research and outcome, and offer insight into basic-science related improvements in public health. We propose portfolio theory as a systematic framework for making biomedical funding allocation decisions-one that is directly tied to the risk/reward trade-off of burden-of-disease outcomes. Using data from 1965 to 2007, we provide estimates of the NIH "efficient frontier", the set of funding allocations across 7 groups of disease-oriented NIH institutes that yield the greatest expected return on investment for a given level of risk, where return on investment is measured by subsequent impact on U.S. years of life lost (YLL). The results suggest that NIH may be actively managing its research risk, given that the volatility of its current allocation is 17% less than that of an equal-allocation portfolio with similar expected returns. The estimated efficient frontier suggests that further improvements in expected return (89% to 119% vs. current) or reduction in risk (22% to 35% vs. current) are available holding risk or expected return, respectively, constant, and that 28% to 89% greater decrease in average years-of-life-lost per unit risk may be achievable. However, these results also reflect the imprecision of YLL as a measure of disease burden, the noisy statistical link between basic research and YLL, and other known limitations of portfolio theory itself. Our analysis is intended to serve as a proof-of-concept and starting point for applying quantitative methods to allocating biomedical research funding that are objective, systematic, transparent, repeatable, and expressly designed to reduce the burden of

  11. Lost in Translation: NIH Funding for Family Medicine Research Remains Limited.

    PubMed

    Cameron, Brianna J; Bazemore, Andrew W; Morley, Christopher P

    2016-01-01

    Departments of Family Medicine (DFMs) in the United States consistently received around 0.2% of total research funding dollars and 0.3% of all awards awarded by the National Institutes of Health (NIH) across the years 2002 to 2014. We used the NIH Reporter tool to quantify the amount of funding and the number of grants received by DFMs from the NIH from 2002 to 2014, using criteria similar to those applied by previous researchers. NIH funding to DFMs as remained fairly consistent across the time period, at roughly 0.2% of total NIH funding and 0.3% of total grants awarded. Changing these proportions will likely require considerable effort to build research capacity within DFMs and their frontline practice research networks, and to shift policymaker and funder perceptions of the value of the FM research enterprise. © Copyright 2016 by the American Board of Family Medicine.

  12. NIH/NIAID Radiation/Nuclear Medical Countermeasures Development Program

    DTIC Science & Technology

    2011-06-15

    NIH/NIAID Radiation/Nuclear Medical Countermeasures Development Program Bert W. Maidment, Ph.D. Associate Director for Product Development Division...REPORT TYPE 3. DATES COVERED 00-00-2011 to 00-00-2011 4. TITLE AND SUBTITLE NIH/NIAID Radiation/Nuclear Medical Countermeasures Development...unclassified c. THIS PAGE unclassified Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 NIAID Radiation/Nuclear Medical Countermeasures

  13. Memory and Forgetfulness: NIH Research

    MedlinePlus

    ... please turn Javascript on. Feature: Memory & Forgetfulness NIH Research Past Issues / Summer 2013 Table of Contents The ... life, is also the primary federal agency for research on Alzheimer's disease and related memory research. An ...

  14. Cognition assessment using the NIH Toolbox

    PubMed Central

    Dikmen, Sureyya S.; Heaton, Robert K.; Tulsky, David S.; Zelazo, Philip D.; Bauer, Patricia J.; Carlozzi, Noelle E.; Slotkin, Jerry; Blitz, David; Wallner-Allen, Kathleen; Fox, Nathan A.; Beaumont, Jennifer L.; Mungas, Dan; Nowinski, Cindy J.; Richler, Jennifer; Deocampo, Joanne A.; Anderson, Jacob E.; Manly, Jennifer J.; Borosh, Beth; Havlik, Richard; Conway, Kevin; Edwards, Emmeline; Freund, Lisa; King, Jonathan W.; Moy, Claudia; Witt, Ellen; Gershon, Richard C.

    2013-01-01

    Cognition is 1 of 4 domains measured by the NIH Toolbox for the Assessment of Neurological and Behavioral Function (NIH-TB), and complements modules testing motor function, sensation, and emotion. On the basis of expert panels, the cognition subdomains identified as most important for health, success in school and work, and independence in daily functioning were Executive Function, Episodic Memory, Language, Processing Speed, Working Memory, and Attention. Seven measures were designed to tap constructs within these subdomains. The instruments were validated in English, in a sample of 476 participants ranging in age from 3 to 85 years, with representation from both sexes, 3 racial/ethnic categories, and 3 levels of education. This report describes the development of the Cognition Battery and presents results on test-retest reliability, age effects on performance, and convergent and discriminant construct validity. The NIH-TB Cognition Battery is intended to serve as a brief, convenient set of measures to supplement other outcome measures in epidemiologic and longitudinal research and clinical trials. With a computerized format and national standardization, this battery will provide a “common currency” among researchers for comparisons across a wide range of studies and populations. PMID:23479546

  15. Creation of quantum steering by interaction with a common bath

    NASA Astrophysics Data System (ADS)

    Sun, Zhe; Xu, Xiao-Qiang; Liu, Bo

    2018-05-01

    By applying the hierarchy equation method, we computationally study the creation of quantum steering in a two-qubit system interacting with a common bosonic bath. The calculation does not adopt conventional approximate approaches, such as the Born, Markov, rotating-wave, and other perturbative approximations. Three kinds of quantum steering, i.e., Einstein-Podolsky-Rosen steering (EPRS), temporal steering (TS), and spatiotemporal steering (STS), are considered. Since the initial state of the two qubits is chosen as a product state, there does not exist EPRS at the beginning. During the evolution, we find that STS as well as EPRS are generated at the same time. An inversion relationship between STS and TS is revealed. By varying the system-bath coupling strength from weak to ultrastrong regimes, we find the nonmonotonic dependence of STS, TS, and EPRS on the coupling strength. It is interesting to study the dynamics of the three kinds of quantum steering by using an exactly numerical method, which is not considered in previous researches.

  16. 6-gingerol, an active ingredient of ginger, protects acetaminophen-induced hepatotoxicity in mice.

    PubMed

    Sabina, Evan Prince; Pragasam, Samuel Joshua; Kumar, Suresh; Rasool, Mahaboobkhan

    2011-11-01

    To investigate the hepatoprotective efficacy of 6-gingerol against acetaminophen-induced hepatotoxicity in mice. Mice were injected with a single dose of acetaminophen (900 mg/kg) to induce hepatotoxicity, while 6-gingerol (30 mg/kg) or the standard drug silymarin (25 mg/kg) was given 30 min after the acetaminophen administration. The mice were sacrificed 4 h after acetaminophen injection to determine the activities of liver marker enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), total bilirubin in serum, and lipid peroxidation and antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione transferase and glutathione) in liver homogenate. The treatment of 6-gingerol and silymarin to acetaminophen-induced hepatotoxicity showed significant hepatoprotective effect by lowering the hepatic marker enzymes (AST, ALT, and ALP) and total bilirubin in serum (P<0.05). In addition, 6-gingerol and silymarin treatment prevented the elevation of hepatic malondialdehyde formation and the depletion of antioxidant status in the liver of acetaminophen-intoxicated mice (P<0.05). The results evidently demonstrate that 6-gingerol has promising hepatoprotective effect which is comparable to the standard drug silymarin.

  17. The Future of Personalized Medicine | NIH MedlinePlus the Magazine

    MedlinePlus

    ... please turn Javascript on. The Future of Personalized Medicine, From NIH Director Dr. Francis S. Collins Past Issues / ... five priorities for NIH is to advance personalized medicine. What does this mean for the average American? ...

  18. Optimized detection of steering via linear criteria for arbitrary-dimensional states

    NASA Astrophysics Data System (ADS)

    Zheng, Yu-Lin; Zhen, Yi-Zheng; Cao, Wen-Fei; Li, Li; Chen, Zeng-Bing; Liu, Nai-Le; Chen, Kai

    2017-03-01

    Einstein-Podolsky-Rosen (EPR) steering, as a new form of nonlocality, stands between entanglement and Bell nonlocality, implying promising applications for quantum information tasks. The problem of detecting EPR steering plays an important role in characterization of quantum nonlocality. Despite some significant progress, one still faces a practical issue: how to detect EPR steering in an experimentally friendly fashion. Resorting to an EPR steering inequality, one is required to apply a strategy as efficiently as possible for any selected measurement settings on the two subsystems, one of which may not be trusted. Inspired by the recent powerful linear criteria proposed by Saunders et al. [D. J. Saunders, S. J. Jones, H. M. Wiseman, and G. J. Pryde, Nat. Phys. 6, 845 (2010)., 10.1038/nphys1766], we present an optimized method of certifying steering for an arbitrary-dimensional state in a cost-effective manner. We provide a practical way to signify steering via only a few settings to optimally violate the steering inequality. Our method leads to steering detections in a highly efficient way, and can be performed with any number of settings, for an arbitrary bipartite mixed state, which can reduce experimental overheads significantly.

  19. A theoretical model of speed-dependent steering torque for rolling tyres

    NASA Astrophysics Data System (ADS)

    Wei, Yintao; Oertel, Christian; Liu, Yahui; Li, Xuebing

    2016-04-01

    It is well known that the tyre steering torque is highly dependent on the tyre rolling speed. In limited cases, i.e. parking manoeuvre, the steering torque approaches the maximum. With the increasing tyre speed, the steering torque decreased rapidly. Accurate modelling of the speed-dependent behaviour for the tyre steering torque is a key factor to calibrate the electric power steering (EPS) system and tune the handling performance of vehicles. However, no satisfactory theoretical model can be found in the existing literature to explain this phenomenon. This paper proposes a new theoretical framework to model this important tyre behaviour, which includes three key factors: (1) tyre three-dimensional transient rolling kinematics with turn-slip; (2) dynamical force and moment generation; and (3) the mixed Lagrange-Euler method for contact deformation solving. A nonlinear finite-element code has been developed to implement the proposed approach. It can be found that the main mechanism for the speed-dependent steering torque is due to turn-slip-related kinematics. This paper provides a theory to explain the complex mechanism of the tyre steering torque generation, which helps to understand the speed-dependent tyre steering torque, tyre road feeling and EPS calibration.

  20. A single acute hepatotoxic dose of CCl4 causes oxidative stress in the rat brain.

    PubMed

    Ritesh, K R; Suganya, A; Dileepkumar, H V; Rajashekar, Y; Shivanandappa, T

    2015-01-01

    Carbon tetrachloride (CCl 4 ), a hepatotoxic agent is widely used to study the toxic mechanisms in experimental animals. We have investigated whether oxidative stress is induced in the brain at a single hepatotoxic dosage (1 ml/kg bw) of CCl 4 . Increased lipid peroxidation (LPO), protein carbonyls (PC) content and glutathione (GSH) depletion were observed in the brain regions of rats treated with CCl 4 which was higher than that of liver. A drastic reduction in the activity of glutathione- S -transferase (GST) was seen in the brain regions which was higher than that of liver. Similarly, activities of glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), NADH- and NADPH-dehydrogenase were reduced in the brain regions similar to that of liver. Higher induction of oxidative stress in the brain compared to that of liver implies vulnerability of the brain for CCl 4 neurotoxicity. Our study shows that a single hepatotoxic dose of CCl 4 is equally neurotoxic to rats.

  1. Characteristics of FDA drug recalls: A 30-month analysis.

    PubMed

    Hall, Kelsey; Stewart, Tyler; Chang, Jongwha; Freeman, Maisha Kelly

    2016-02-15

    The characteristics of drug recalls issued over 30 months by the Food and Drug Administration (FDA) were analyzed. All FDA-issued recalls for drugs (prescription and nonprescription, including dietary supplements) and biological products issued from June 20, 2012, to December 31, 2014, were included in this retrospective analysis. Data for all drug recalls were downloaded and sorted by the inclusion criteria from weekly FDA enforcement reports. The following data were analyzed: product type, recall firm, type of recall firm (compounding or noncompounding), country, voluntary or involuntary recall, method of communication of recall, recall number, FDA recall classification (class I, II, or III), product availability (prescription or nonprescription), reason for recall, recall initiation date, and recall report date. A total of 21,120 products were recalled during the 30-month study period. Of these, 3,045 drug products (14.4%) met the inclusion criteria and were analyzed. A total of 348 total manufacturers were associated with recalled drug products. The 5 firms most frequently involved in recalls accounted for 299, 273, 212, 118, and 112 recalls. The most common reasons for recalls were contamination, mislabeling, adverse reaction, defective product, and incorrect potency. There was a significant association between FDA recall classification and the following outcomes: reasons for recall, product availability, type of recall firm, and form of communication. An investigation of FDA drug recalls revealed that the five most common recall reasons were contamination, mislabeling, adverse reaction, defective product, and incorrect potency. Compounding firms were associated more frequently with contamination than were noncompounding firms. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  2. Evaluation of efficacy of heartworm preventive products at the FDA.

    PubMed

    Hampshire, Victoria A

    2005-10-24

    The Center for Veterinary Medicine, U.S. Food and Drug Administration (FDA/CVM) has authority under the United States Code 21 under Section 514.80 to monitor for adverse experiences of approved animal products. Although veterinarians voluntarily report suspect drug-related events to manufacturers, firms that market FDA-approved animal products must report serious events to the FDA within 15 working days of the veterinarian or pet-owner's call to them. Under the present regulations, canine heartworm preventatives are approved for 100% efficacy after testing in laboratory and field conditions. The report of lack of efficacy against heartworm larvae is a serious adverse drug event because the resulting condition or the treatment of the condition is life threatening. Information on lack of effect that are deemed possibly, probably, or definitely drug-related available for review under generic product on the FDA/CVM website Surveillance of these reports indicates there are some failures for virtually all heartworm prevention product categories. Most failures have been reported in heartworm-endemic states. At this time, it is unclear whether these are representative of the rare occurrences of failure that have been in existence for a long time, but not reported regularly or promptly, or whether there is a true increase in complaints of ineffectiveness and real variability between products. This paper discusses methods, personnel, and procedures in place in the Division of Surveillance that will aid the FDA to better assess heartworm preventive treatment failures. It discusses scoring paradigms presently utilized by FDA/CVM to assess severity of complaints of lack of efficacy against heartworms, and welcomes audience input as to how to improve existing processes. Results suggest that more comprehensive reporting will provide FDA/CVM more accurate surveillance information regarding efficacy problems. Such practices will permit FDA/CVM to better interpret both incidence and

  3. Analysis of US Food and Drug Administration Warning Letters: False Promotional Claims Relating to Prescription and Over-the-Counter Medications.

    PubMed

    Salas, Maribel; Martin, Michelle; Pisu, Maria; McCall, Erin; Zuluaga, Alvaro; Glasser, Stephen P

    2008-03-01

    Recent studies have suggested that there has been an increase in the number of 'warning letters' issued by the US Food and Drug Administration (FDA) despite the publication of the FDA advertising guidelines. However, limited information is available on the description of warning letters. The objective of this study was to analyse the frequency and content of FDA warning letters in relation to promotional claims and discuss the influence of regulatory and industry constraints on promotion. All warning letters published by the FDA between 5 May 1995 and 11 June 2007 were reviewed. Warning letters related to promotional issues were included and analysed. Information related to the identification number, date of the warning letter, FDA division that issued the letter, drug name, manufacturer, specific warning problem, type of promotional material and requested action was extracted. Two independent investigators reviewed and classified each PDF file, any differences were discussed until a consensus was reached. Between May 1995 and June 2007 a total of 8692 warning letters were issued, of which 25% were related to drugs. Of these, 206 warning letters focused on drug promotion and were included in this study: 23% were issued in 2005, 15% in 2004 and 14% in 1998. In total, 47% of the warning letters were issued because of false or misleading unapproved doses and uses, 27% failed to disclose risks, 15% cited misleading promotion, 8% related to misleading labelling and 3% promoted false effectiveness claims. There is an important variation in the number of warning letters issued in the last decade, probably because of the increasing number of drugs approved by the FDA, drug withdrawal scandals, and the publication of the FDA and the Pharmaceutical Research and Manufacturers of America (PhRMA) guidelines. We found that benefit-related claims, such as unapproved uses or doses of drugs, and failure to disclose risks, are the main causes of FDA issued warning letters for

  4. Experimental test of single-system steering and application to quantum communication

    NASA Astrophysics Data System (ADS)

    Liu, Zhao-Di; Sun, Yong-Nan; Cheng, Ze-Di; Xu, Xiao-Ye; Zhou, Zong-Quan; Chen, Geng; Li, Chuan-Feng; Guo, Guang-Can

    2017-02-01

    Einstein-Podolsky-Rosen (EPR) steering describes the ability to steer remotely quantum states of an entangled pair by measuring locally one of its particles. Here we report on an experimental demonstration of single-system steering. The application to quantum communication is also investigated. Single-system steering refers to steering of a single d -dimensional quantum system that can be used in a unifying picture to certify the reliability of tasks employed in both quantum communication and quantum computation. In our experiment, high-dimensional quantum states are implemented by encoding polarization and orbital angular momentum of photons with dimensionality of up to 12.

  5. 42 CFR 63.9 - How may NIH terminate awards?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How may NIH terminate awards? 63.9 Section 63.9 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING TRAINEESHIPS § 63.9 How may NIH terminate awards? The Director may terminate a traineeship at any...

  6. 42 CFR 63.9 - How may NIH terminate awards?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How may NIH terminate awards? 63.9 Section 63.9 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING TRAINEESHIPS § 63.9 How may NIH terminate awards? The Director may terminate a traineeship at any...

  7. 42 CFR 63.9 - How may NIH terminate awards?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How may NIH terminate awards? 63.9 Section 63.9 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING TRAINEESHIPS § 63.9 How may NIH terminate awards? The Director may terminate a traineeship at any...

  8. 42 CFR 63.9 - How may NIH terminate awards?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How may NIH terminate awards? 63.9 Section 63.9 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING TRAINEESHIPS § 63.9 How may NIH terminate awards? The Director may terminate a traineeship at any...

  9. Electronic differential control of 2WD electric vehicle considering steering stability

    NASA Astrophysics Data System (ADS)

    Hua, Yiding; Jiang, Haobin; Geng, Guoqing

    2017-03-01

    Aiming at the steering wheel differential steering control technology of rear wheel independent driving electric wheel, considering the assisting effect of electronic differential control on vehicle steering, based on the high speed steering characteristic of electric wheel car, the electronic differential speed of auxiliary wheel steering is also studied. A yaw moment control strategy is applied to the vehicle at high speed. Based on the vehicle stability reference value, yaw rate is used to design the fuzzy controller to distribute the driving wheel torque. The simulation results show that the basic electronic differential speed function is realized based on the yaw moment control strategy, while the vehicle stability control is improved and the driving safety is enhanced. On the other hand, the torque control strategy can also assist steering of vehicle.

  10. 21 CFR 1.393 - What information must FDA include in the detention order?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false What information must FDA include in the detention... Consumption How Does Fda Order A Detention? § 1.393 What information must FDA include in the detention order? (a) FDA must issue the detention order in writing, in the form of a detention notice, signed and...

  11. 21 CFR 1.393 - What information must FDA include in the detention order?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false What information must FDA include in the detention... Consumption How Does Fda Order A Detention? § 1.393 What information must FDA include in the detention order? (a) FDA must issue the detention order in writing, in the form of a detention notice, signed and...

  12. 21 CFR 1.393 - What information must FDA include in the detention order?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false What information must FDA include in the detention... Consumption How Does Fda Order A Detention? § 1.393 What information must FDA include in the detention order? (a) FDA must issue the detention order in writing, in the form of a detention notice, signed and...

  13. 21 CFR 830.210 - Eligibility for use of FDA as an issuing agency.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Eligibility for use of FDA as an issuing agency... SERVICES (CONTINUED) MEDICAL DEVICES UNIQUE DEVICE IDENTIFICATION FDA as an Issuing Agency § 830.210 Eligibility for use of FDA as an issuing agency. When FDA acts as an issuing agency, any labeler will be...

  14. 21 CFR 1.393 - What information must FDA include in the detention order?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false What information must FDA include in the detention... Consumption How Does Fda Order A Detention? § 1.393 What information must FDA include in the detention order? (a) FDA must issue the detention order in writing, in the form of a detention notice, signed and...

  15. 21 CFR 1.393 - What information must FDA include in the detention order?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false What information must FDA include in the detention... Consumption How Does Fda Order A Detention? § 1.393 What information must FDA include in the detention order? (a) FDA must issue the detention order in writing, in the form of a detention notice, signed and...

  16. 46 CFR 78.47-55 - Instructions for changing steering gear.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 3 2010-10-01 2010-10-01 false Instructions for changing steering gear. 78.47-55... OPERATIONS Markings for Fire and Emergency Equipment, Etc. § 78.47-55 Instructions for changing steering gear..., relating in order, the different steps to be taken in changing to the emergency steering gear. Each clutch...

  17. FDA's Flexibility in Subpart H Approvals: Assessing Quantum of Effectiveness Evidence.

    PubMed

    Sasinowski, Frank J; Varond, Alexander J

    2016-08-01

    This article examines the strength of scientific and clinical evidence for FDA's nineteen non-AIDS, non-cancer Subpart H approval determinations over the Accelerated Approval program's twenty-four year existence. The authors researched the bases for FDA's determinations when an unvalidated surrogate or intermediate clinical endpoint is "reasonably likely to predict clinical benefit." The four key factors set forth in FDA's "Guidance for Industry, Expedited Programs for Serious Conditions - Drugs and Biologics" were applied to past Subpart H approvals. For the nineteen precedents, the authors found wide variances between the quantum and quality of evidence on each of the four factors, indicating that a lack of evidence on any single factor was not disqualifying in and of itself. The results of this study, therefore, show that FDA exercises extraordinarily more regulatory flexibility than either FDA's foundational statutes or even FDA' s most recent 2014 Expedited Programs Guidance explicitly express. Given recent legislative exhortations and the increasing promise of personalized medicine and translational sciences, the authors conclude that Subpart H should be further explored and utilized. The authors provide a detailed analysis of the orecedents established in the nineteen approvals.

  18. Genuine multipartite Einstein-Podolsky-Rosen steering.

    PubMed

    He, Q Y; Reid, M D

    2013-12-20

    We develop the concept of genuine N-partite Einstein-Podolsky-Rosen (EPR) steering. This nonlocality is the natural multipartite extension of the original EPR paradox. Useful properties emerge that are not guaranteed for genuine multipartite entangled states. In particular, there is a close link with the task of one-sided, device-independent quantum secret sharing. We derive inequalities to demonstrate multipartite EPR steering for Greenberger-Horne-Zeilinger and Gaussian continuous variable states in loophole-free scenarios.

  19. Genuine Multipartite Einstein-Podolsky-Rosen Steering

    NASA Astrophysics Data System (ADS)

    He, Q. Y.; Reid, M. D.

    2013-12-01

    We develop the concept of genuine N-partite Einstein-Podolsky-Rosen (EPR) steering. This nonlocality is the natural multipartite extension of the original EPR paradox. Useful properties emerge that are not guaranteed for genuine multipartite entangled states. In particular, there is a close link with the task of one-sided, device-independent quantum secret sharing. We derive inequalities to demonstrate multipartite EPR steering for Greenberger-Horne-Zeilinger and Gaussian continuous variable states in loophole-free scenarios.

  20. Accuracy of the paracetamol-aminotransferase product to predict hepatotoxicity in paracetamol overdose treated with a 2-bag acetylcysteine regimen.

    PubMed

    Wong, Anselm; Sivilotti, Marco L A; Gunja, Naren; McNulty, Richard; Graudins, Andis

    2018-03-01

    Paracetamol concentration is a highly accurate risk predictor for hepatotoxicity following overdose with known time of ingestion. However, the paracetamol-aminotransferase multiplication product can be used as a risk predictor independent of timing or ingestion type. Validated in patients treated with the traditional, "three-bag" intravenous acetylcysteine regimen, we evaluated the accuracy of the multiplication product in paracetamol overdose treated with a two-bag acetylcysteine regimen. We examined consecutive patients treated with the two-bag regimen from five emergency departments over a two-year period. We assessed the predictive accuracy of initial multiplication product for the primary outcome of hepatotoxicity (peak alanine aminotransferase ≥1000IU/L), as well as for acute liver injury (ALI), defined peak alanine aminotransferase ≥2× baseline and above 50IU/L). Of 447 paracetamol overdoses treated with the two-bag acetylcysteine regimen, 32 (7%) developed hepatotoxicity and 73 (16%) ALI. The pre-specified cut-off points of 1500 mg/L × IU/L (sensitivity 100% [95% CI 82%, 100%], specificity 62% [56%, 67%]) and 10,000 mg/L × IU/L (sensitivity 70% [47%, 87%], specificity of 97% [95%, 99%]) were highly accurate for predicting hepatotoxicity. There were few cases of hepatotoxicity irrespective of the product when acetylcysteine was administered within eight hours of overdose, when the product was largely determined by a high paracetamol concentration but normal aminotransferase. The multiplication product accurately predicts hepatotoxicity when using a two-bag acetylcysteine regimen, especially in patients treated more than eight hours post-overdose. Further studies are needed to assess the product as a method to adjust for exposure severity when testing efficacy of modified acetylcysteine regimens.

  1. Healthy public relations: the FDA's 1930s legislative campaign.

    PubMed

    Kay, G

    2001-01-01

    In this article, I argue that the Food and Drug Administration (FDA) is an oft-overlooked government agency that acts to preserve and secure the public's health. From its early years as an agency charged with enforcement of the 1906 Pure Food and Drugs Act, the FDA not only protected the public's health but also made the public aware of its mission, using methods as diverse as displays at county fairs and at the 1933 Chicago World's Fair, radio programming, and active correspondence. The agency encouraged the public to protect itself, particularly in those arenas in which the FDA had no regulatory authority. In addition, it may have overstepped its boundaries when it actively solicited public support for a bill submitted to Congress in the early 1930s. In the dark days of the Great Depression, the FDA contended not only with limited resources and its own feelings of inadequacy in terms of what could and could not be done to protect the populace, but also with "guinea pig" books that horrified and angered many readers. By 1938, when the agency prevailed and the revisions to the 1906 Act passed Congress and were signed into law by President Franklin D. Roosevelt, the FDA had done all that a responsible public health agency should do, and more.

  2. Detection of quantum steering in multipartite continuous-variable Greenberger-Horne-Zeilinger-like states

    NASA Astrophysics Data System (ADS)

    Wang, Meng; Xiang, Yu; He, Qiongyi; Gong, Qihuang

    2015-01-01

    The multipartite entangled state has drawn broad attention for both foundations of quantum mechanics and applications in quantum information processing. Here, we study the spatially separated N -partite continuous-variable Greenberger-Horne-Zeilinger-like states, which can be produced by a linear optical network with squeezed light and N -1 beamsplitters. We investigate the properties of multipartite Einstein-Podolsky-Rosen steering possessed by those states, and find that the steering of a given quantum mode is allowed when not less than half of the modes within the states take part in the steering group. This is certified by the detection of the correlation between position and momentum quadratures of the steered mode and a combination of quadratures of other modes inside the steering group. The steering is evidenced by the high correlation where the steering group can infer the quadratures of the steered mode to high precision, i.e., below the quantum limit for the position and momentum quadratures of the steered quantum mode. We also examine the influence of inefficiency on the multipartite steering, and derive the threshold of the loss tolerance. Furthermore, we discuss the collective N -partite steering induced by the asymmetric loss on beams, which exists when a given quantum mode can only be steered by all the remaining N -1 modes collaboratively. The present multipartite steering correlation may have potential applications in certain quantum information tasks where the issue of trust is important, such as one-sided device-independent quantum secret sharing.

  3. NIH Clinical Center: There’s No Other Hospital Like It | NIH MedlinePlus the Magazine

    MedlinePlus

    ... scientists. The innovative curriculum includes courses in pharmacology, principles and practice of clinical research, and bioethics. Recently, the NIH Clinical Center launched the Sabbatical in Clinical Research Management program for clinical investigators, healthcare managers and administrators, ...

  4. A control theoretic model of driver steering behavior

    NASA Technical Reports Server (NTRS)

    Donges, E.

    1977-01-01

    A quantitative description of driver steering behavior such as a mathematical model is presented. The steering task is divided into two levels: (1) the guidance level involving the perception of the instantaneous and future course of the forcing function provided by the forward view of the road, and the response to it in an anticipatory open-loop control mode; (2) the stabilization level whereby any occuring deviations from the forcing function are compensated for in a closed-loop control mode. This concept of the duality of the driver's steering activity led to a newly developed two-level model of driver steering behavior. Its parameters are identified on the basis of data measured in driving simulator experiments. The parameter estimates of both levels of the model show significant dependence on the experimental situation which can be characterized by variables such as vehicle speed and desired path curvature.

  5. 42 CFR 63.5 - How will NIH make awards?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How will NIH make awards? 63.5 Section 63.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING TRAINEESHIPS § 63.5 How will NIH make awards? Subject to the regulations of this part, the Director may award...

  6. 42 CFR 63.5 - How will NIH make awards?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How will NIH make awards? 63.5 Section 63.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING TRAINEESHIPS § 63.5 How will NIH make awards? Subject to the regulations of this part, the Director may award...

  7. 42 CFR 63.5 - How will NIH make awards?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How will NIH make awards? 63.5 Section 63.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING TRAINEESHIPS § 63.5 How will NIH make awards? Subject to the regulations of this part, the Director may award...

  8. 42 CFR 63.5 - How will NIH make awards?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How will NIH make awards? 63.5 Section 63.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING TRAINEESHIPS § 63.5 How will NIH make awards? Subject to the regulations of this part, the Director may award...

  9. 42 CFR 63.5 - How will NIH make awards?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How will NIH make awards? 63.5 Section 63.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING TRAINEESHIPS § 63.5 How will NIH make awards? Subject to the regulations of this part, the Director may award...

  10. 46 CFR 97.37-33 - Instructions for changing steering gear.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 4 2010-10-01 2010-10-01 false Instructions for changing steering gear. 97.37-33... steering gear. (a) Instructions in at least 1/2 inch letters and figures shall be posted in the steering... gear. Each clutch, gear, wheel, lever, valve, or switch which is used during the changeover shall be...

  11. 21 CFR 1.379 - How long may FDA detain an article of food?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false How long may FDA detain an article of food? 1.379... Provisions § 1.379 How long may FDA detain an article of food? (a) FDA may detain an article of food for a... institute a seizure or injunction action. The authorized FDA representative may approve the additional 10...

  12. 21 CFR 1.379 - How long may FDA detain an article of food?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false How long may FDA detain an article of food? 1.379... Provisions § 1.379 How long may FDA detain an article of food? (a) FDA may detain an article of food for a... institute a seizure or injunction action. The authorized FDA representative may approve the additional 10...

  13. 21 CFR 1.379 - How long may FDA detain an article of food?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false How long may FDA detain an article of food? 1.379... Provisions § 1.379 How long may FDA detain an article of food? (a) FDA may detain an article of food for a... institute a seizure or injunction action. The authorized FDA representative may approve the additional 10...

  14. 21 CFR 1.379 - How long may FDA detain an article of food?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false How long may FDA detain an article of food? 1.379... Provisions § 1.379 How long may FDA detain an article of food? (a) FDA may detain an article of food for a... institute a seizure or injunction action. The authorized FDA representative may approve the additional 10...

  15. 21 CFR 1.379 - How long may FDA detain an article of food?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false How long may FDA detain an article of food? 1.379... Provisions § 1.379 How long may FDA detain an article of food? (a) FDA may detain an article of food for a... institute a seizure or injunction action. The authorized FDA representative may approve the additional 10...

  16. Applications of EPR steering in quantum teleportation and NOON states

    NASA Astrophysics Data System (ADS)

    Zárate, Laura Rosales

    2018-04-01

    Einstein-Podolsky-Rosen (EPR) steering refers to the type of correlations described in the EPR paradox, where one observer seems to affect ("steer") the state of other observer by using local measurements. There have been several works regarding characterization and quantification of EPR steering. One characteristic of this non-local correlation is that it can be asymmetric, while entanglement is symmetric. This asymmetric property is relevant for potential applications of EPR steering to quantum information, in particular to quantum cryptography and quantum teleportation. This latter refers to the process where one observer sends an unknown quantum state to Bob, who is in a different location. They communicate by classical means. Here we will show that EPR steering is a necessary resource to obtain secure continuous variable teleportation. We will also consider NOON states, which is an example of an entangled state. For this state, we will present a steering signature. This contribution reviews the work derived in Refs. [1] and [2], which was presented as an invited talk in ELAF 2017.

  17. NIH Precision Medicine Initiative: Implications for Diabetes Research

    PubMed Central

    Fradkin, Judith E.; Hanlon, Mary C.; Rodgers, Griffin P.

    2016-01-01

    In his January 2015 State of the Union address, President Barack Obama announced a new Precision Medicine Initiative (PMI) to personalize approaches toward improving health and treating disease (www.whitehouse.gov/precision-medicine). He stated that the goal of such an initiative was “to bring us closer to curing diseases like cancer and diabetes, and to give all of us access to the personalized information we need to keep ourselves and our families healthier.” Since that time, the National Institutes of Health (NIH) has taken a leadership role in implementing the President’s vision related to biomedical research (www.nih.gov/precisionmedicine). Here, we discuss the NIH component of the PMI, related ongoing diabetes research, and near-term research that could position the diabetes field to take full advantage of the opportunities that stem from the PMI. PMID:27289128

  18. Monogamy inequalities for the Einstein-Podolsky-Rosen paradox and quantum steering

    NASA Astrophysics Data System (ADS)

    Reid, M. D.

    2013-12-01

    Monogamy inequalities for the way bipartite Einstein-Podolsky-Rosen (EPR) steering can be distributed among N systems are derived. One set of inequalities is based on witnesses with two measurement settings, and may be used to demonstrate correlation of outcomes between two parties, that cannot be shared with more parties. It is shown that the monogamy for steering is directional. Two parties cannot independently demonstrate steering of a third system, using the same two-setting steering witness, but it is possible for one party to steer two independent systems. This result explains the monogamy of two-setting Bell inequality violations and the sensitivity of the continuous variable (CV) EPR criterion to losses on the steering party. We generalize to m settings. A second type of monogamy relation gives the quantitative amount of sharing possible, when the number of parties is less than or equal to m, and takes a form similar to the Coffman-Kundu-Wootters relation for entanglement. The results enable characterization of the tripartite steering for CV Gaussian systems and qubit Greenberger-Horne-Zeilinger and W states.

  19. NIH Clinical Research Trials and You

    MedlinePlus

    ... Record Research & Training Medical Research Initiatives Science Highlights Science Education Research in NIH Labs & Clinics Training Opportunities Library Resources Research Resources Clinical Research Resources Safety, Regulation ...

  20. Contribution of NIH funding to new drug approvals 2010–2016

    PubMed Central

    Beierlein, Jennifer M.; Khanuja, Navleen Surjit; McNamee, Laura M.; Ledley, Fred D.

    2018-01-01

    This work examines the contribution of NIH funding to published research associated with 210 new molecular entities (NMEs) approved by the Food and Drug Administration from 2010–2016. We identified >2 million publications in PubMed related to the 210 NMEs (n = 131,092) or their 151 known biological targets (n = 1,966,281). Of these, >600,000 (29%) were associated with NIH-funded projects in RePORTER. This funding included >200,000 fiscal years of NIH project support (1985–2016) and project costs >$100 billion (2000–2016), representing ∼20% of the NIH budget over this period. NIH funding contributed to every one of the NMEs approved from 2010–2016 and was focused primarily on the drug targets rather than on the NMEs themselves. There were 84 first-in-class products approved in this interval, associated with >$64 billion of NIH-funded projects. The percentage of fiscal years of project funding identified through target searches, but not drug searches, was greater for NMEs discovered through targeted screening than through phenotypic methods (95% versus 82%). For targeted NMEs, funding related to targets preceded funding related to the NMEs, consistent with the expectation that basic research provides validated targets for targeted screening. This analysis, which captures basic research on biological targets as well as applied research on NMEs, suggests that the NIH contribution to research associated with new drug approvals is greater than previously appreciated and highlights the risk of reducing federal funding for basic biomedical research. PMID:29440428

  1. The altered liver microRNA profile in hepatotoxicity induced by rhizome Dioscorea bulbifera in mice.

    PubMed

    Yang, Rui; Bai, Qingyun; Zhang, Jiaqi; Sheng, Yuchen; Ji, Lili

    2017-08-01

    MicroRNA (miRNA) has been reported to play important roles in regulating drug-induced liver injury. Ethyl acetate extract isolated from rhizoma Dioscoreae bulbifera (EF) has been reported to induce hepatotoxicity in our previous studies. This study aims to observe the altered liver miRNA profile and its related signalling pathway involved in EF-induced hepatotoxicity. Serum alanine/aspartate aminotransferase assay showed that EF (450 mg/kg)-induced hepatotoxicity in mice. Results of miRNA chip analysis showed that the expression of eight miRNAs was up-regulated and of other nine miRNAs was down-regulated in livers from EF-treated mice. Further, the altered expression of miR-200a-3p, miR-5132-5p and miR-5130 was validated using real-time polymerase chain reaction (PCR) assay. There were total seven predicted target genes of miR-200a-3p, miR-5132-5p and miR-5130. Only one kyoto encyclopedia genes and genomes pathway was annotated using those target genes, which is protein processing in endoplasmic reticulum (ER). Furthermore, liver expression of DnaJ subfamily A member 1, a key gene involved in protein processing in ER based on the altered miRNAs, was increased in EF-treated mice. In conclusion, the results demonstrated that EF altered the expression of liver miRNA profile and its related signalling pathway, which may be involved in EF-induced hepatotoxicity.

  2. Magnetorheological fluid based automotive steer-by-wire systems

    NASA Astrophysics Data System (ADS)

    Ahmadkhanlou, Farzad; Washington, Gregory N.; Bechtel, Stephen E.; Wang, Yingru

    2006-03-01

    The idea of this paper is to design a Magnetorheological (MR) fluid based damper for steer-by-wire systems to provide sensory feedback to the driver. The advantages of using MR fluids in haptic devices stem from the increase in transparency gained from the lightweight semiactive system and controller implementation. The performance of MR fluid based steer-by wire system depends on MR fluid model and specifications, MR damper geometry, and the control algorithm. All of these factors are addressed in this study. The experimental results show the improvements in steer-by-wire by adding force feedback to the system.

  3. Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

    PubMed Central

    Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

    2017-01-01

    Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening

  4. The protective effect of vildagliptin in chronic experimental cyclosporine A-induced hepatotoxicity.

    PubMed

    El-Sherbeeny, Nagla A; Nader, Manar A

    2016-03-01

    The study examined the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor, vildagliptin, in cyclosporine (CsA)-induced hepatotoxicity. Rats were divided into 4 groups treated for 28 days: control (vehicle), vildagliptin (10 mg/kg, orally), CsA (20 mg/kg, s.c.), and CsA-vildagliptin group. Liver function was assessed by measuring serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (γGT), lactate dehydrogenase (LDH), and albumin, and histopathological changes of liver were examined. Oxidative stress markers were evaluated. Assessment of nuclear factor-kappa B (NF-κB) activity in hepatic nuclear extract, serum DPP-4, and expression of Bax and Bcl2 were also done. CsA-induced hepatotoxicity was evidenced by increase in serum levels of AST, ALT, and γGT; a decrease in serum albumin; and a significant alteration in hepatic architecture. Also, significant increase in thiobarbituric acid reactive substance (TBARS) and decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) levels, increased expression Bax proteins with deceased expression of Bcl2, and increased hepatic activity of NF-κB and serum DPP-4 level were observed upon CsA treatment. Vildagliptin significantly improved all altered parameters induced by CsA administration. Vildagliptin has the potential to protect the liver against CsA-induced hepatotoxicity by reducing oxidative stress, DPP-4 activity, apoptosis, and inflammation.

  5. Altered steering strategies for goal-directed locomotion in stroke

    PubMed Central

    2013-01-01

    Background Individuals who have sustained a stroke can manifest altered locomotor steering behaviors when exposed to optic flows expanding from different locations. Whether these alterations persist in the presence of a visible goal and whether they can be explained by the presence of a perceptuo-motor disorder remain unknown. The purpose of this study was to compare stroke participants and healthy participants on their ability to control heading while exposed to changing optic flows and target locations. Methods Ten participants with stroke (55.6 ± 9.3 yrs) and ten healthy controls (57.0 ± 11.5 yrs) participated in a mouse-driven steering task (perceptuo-motor task) while seated and in a walking steering task. In the seated steering task, participants were instructed to head or ‘walk’ toward a target in the virtual environment by using a mouse while wearing a helmet-mounted display (HMD). In the walking task, participants performed a similar steering task in the same virtual environment while walking overground at their comfortable speed. For both experiments, the target and/or the focus of expansion (FOE) of the optic flow shifted to the side (±20°) or remained centered. The main outcome measure was net heading errors (NHE). Secondary outcomes included mediolateral displacement, horizontal head orientation, and onsets of heading and head reorientation. Results In the walking steering task, the presence of FOE shifts modulated the extent and timing of mediolateral displacement and head rotation changes, as well as NHE magnitudes. Participants overshot and undershot their net heading, respectively, in response to ipsilateral and contralateral FOE and target shifts. Stroke participants made larger NHEs, especially when the FOE was shifted towards the non-paretic side. In the seated steering task, similar NHEs were observed between stroke and healthy participants. Conclusions The findings highlight the fine coordination between rotational and

  6. Hepatotoxicity and nephrotoxicity of 3-bromopyruvate in mice.

    PubMed

    Pan, Qiong; Sun, Yiming; Jin, Qili; Li, Qixiang; Wang, Qing; Liu, Hao; Zhao, Surong

    2016-11-01

    To investigate the hepatotoxicity and nephrotoxicity of 3-Bromopyruvate (3BP) in mice. Fifteen nude mice were grafted subcutaneously in the left flank with MDA-MB-231 cells, then all mice were divided into control group (PBS), 3BP group (8 mg/kg), positive group (DNR: 0.8 mg/kg) when tumor volume reached approximately 100 mm3. 28 days later, tumors, livers and kidneys were stored in 4 % formalin solution and stained with hematoxylin and eosin staining. The Kunming mice experiment included control group (PBS), 3BP group (4mg/kg; 8mg/kg; 16mg/kg), positive group (DNR: 0.8 mg/kg). 24 hours later, the blood were used for the determination of hepatic damage serum biomarkers. Livers were stored in 4 % formalin solution for the later detection. 3BP at the dose of 8mg/kg had a good effect on inhibiting tumor growth in nude mice and did not damage liver and kidney tissues. Kunming mice experiment showed 3BP at the dose of 16mg/kg did damage to liver tissues. 3-Bromopyruvate at the dose of suppressing tumor growth did not exhibit hepatotoxicity and nephrotoxicity in nude mice, and the effect on liver was confirmed in Kunming mice.

  7. Relationship between antioxidant capacity, oxidative stress, and feed efficiency in beef steers.

    PubMed

    Russell, J R; Sexten, W J; Kerley, M S; Hansen, S L

    2016-07-01

    Feed efficiency (FE) can vary between individuals but sources of variation are not well characterized. Oxidative stress is among the biological mechanisms believed to contribute to variation. The objective of this study was to evaluate the relationship between FE, antioxidant activity, and oxidative stress in feedlot steers representing phenotypic extremes for FE. Crossbred beef steers ( = 181) fed 70-d growing phase (GP) whole-shell corn-based (G-Corn) or rye baleage and soybean hull-based (G-Rough) diets in GrowSafe bunks at the University of Missouri were shipped to Iowa State University where the 12 most feed efficient (HFE) and 12 least feed efficient (LFE) steers from each diet (n = 48; 467 kg [SD 51]) were selected for evaluation. Steers received diets similar to GP diets, and 3 d after arrival, blood was sampled to evaluate antioxidant activity and oxidative stress markers for the GP following transit. Steers were transitioned to finishing phase (FP) cracked corn-based (F-Corn) or dried distillers' grains and soybean hull-based (F-Byp) diets, and on FP d 97, blood samples for the FP were collected. Data for the GP were analyzed as a 2 × 2 factorial, and data for the FP were analyzed as a 2 × 2 × 2 factorial using PROC MIXED of SAS. No GP diet × FP diet, FP diet × FE group, or 3-way interactions were noted ( ≥ 0.11) for FP measures. Steers fed the G-Rough diet had greater ( = 0.04) GP plasma protein carbonyl concentrations. During the GP, HFE steers had greater ( ≤ 0.04) protein carbonyl and ratio of oxidized:reduced blood lysate glutathione concentrations than LFE steers. There were GP diet × FE group interactions ( ≤ 0.03) during the GP and FP. During the GP, total blood lysate superoxide dismutase (SOD) activity was greater ( ≤ 0.03) in G-Rough/LFE steers than in G-Rough/HFE and G-Corn/LFE steers; G-Corn/HFE steers were intermediate. The G-Rough/LFE steers had greater ( < 0.04) glutathione peroxidase (GPX) activity than other groups and

  8. FDA pregnancy risk categories and the CPS

    PubMed Central

    Law, Ruth; Bozzo, Pina; Koren, Gideon; Einarson, Adrienne

    2010-01-01

    ABSTRACT QUESTION My patient is taking a medication for a chronic condition and has just found out that she is 6 weeks pregnant. The US Food and Drug Administration (FDA) has assigned this medication to pregnancy risk category D, and the Compendium of Pharmaceuticals and Specialties provides no additional data. How should I interpret this information, and how does the Motherisk Program evaluate the safety or risks of drug use in pregnancy? ANSWER Pregnancy safety data provided by the FDA pregnancy risk categories and the Compendium of Pharmaceuticals and Specialties are insufficient to guide clinical decisions on how to proceed with a pregnancy following exposure to a category D medication. The Motherisk Program creates peer-reviewed statements derived from the primary literature, and we examine fetal outcomes as well as the risk-benefit profile of maternal treatment when evaluating the safety of medication use in pregnancy. The FDA announced in May 2008 that it is dropping its pregnancy risk categories and adopting a method similar to the one we use at Motherisk. PMID:20228306

  9. Demonstration of Multisetting One-Way Einstein-Podolsky-Rosen Steering in Two-Qubit Systems

    NASA Astrophysics Data System (ADS)

    Xiao, Ya; Ye, Xiang-Jun; Sun, Kai; Xu, Jin-Shi; Li, Chuan-Feng; Guo, Guang-Can

    2017-04-01

    Einstein-Podolsky-Rosen (EPR) steering describes the ability of one party to remotely affect another's state through local measurements. One of the most distinguishable properties of EPR steering is its asymmetric aspect. Steering can work in one direction but fail in the opposite direction. This type of one-way steering, which is different from the symmetry concepts of entanglement and Bell nonlocality, has garnered much interest. However, an experimental demonstration of genuine one-way EPR steering in the simplest scenario, i.e., one that employs two-qubit systems, is still lacking. In this Letter, we experimentally demonstrate one-way EPR steering with multimeasurement settings for a class of two-qubit states, which are still one-way steerable even with infinite settings. The steerability is quantified by the steering radius, which represents a necessary and sufficient steering criterion. The demonstrated one-way steering in the simplest bipartite quantum system is of fundamental interest and may provide potential applications in one-way quantum information tasks.

  10. Unusual Synchronous Methimazole-Induced Agranulocytosis and Severe Hepatotoxicity in Patient with Hyperthyroidism: A Case Report and Review of the Literature

    PubMed Central

    Yang, Jun; Zhang, Jun; Xu, Qin; Sheng, Guo-ping; Weng, Wan-wen; Dong, Meng-jie

    2015-01-01

    Context. To report a patient with hyperthyroidism who developed concurrent occurrence of agranulocytosis and severe hepatotoxicity after taking methimazole (MMI). Case. A 51-year-old Chinese male was diagnosed as hyperthyroidism with normal white blood count and liver function. After 4 weeks' treatment with MMI 20 mg/d, it developed to agranulocytosis and severe cholestatic hepatotoxicity. The patient's symptoms and laboratory abnormalities disappeared after the withdrawal of MMI; his white blood count and liver function recover to normal in 2 weeks and 5 weeks, respectively. 296 MBq dose of 131I was given to the patient 3 weeks after the withdrawal of MMI and his thyroid function was back to normal in 6 months. As we know through literature review, only 5 previous cases reported the synchronous ATD-induced agranulocytosis and severe hepatotoxicity in patients with hyperthyroidism. Methods. Review of the patient's clinical course. Literature review of cases of hyperthyroidism with agranulocytosis and severe hepatotoxicity demonstrated that these complications occurred after taking antithyroid drug (ATD). Conclusions. Patient with hyperthyroidism can have synchronous ATD-induced agranulocytosis and severe hepatotoxicity. This case is extremely rare, but the adverse effects with ATDs is clinically significant. The clinicians need to be careful about this and monitor biochemical of patients who take ATDs. PMID:26060496

  11. 76 FR 20588 - FDA Food Safety Modernization Act: Focus on Preventive Controls for Facilities; Public Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-13

    .... FDA-2011-N-0251] FDA Food Safety Modernization Act: Focus on Preventive Controls for Facilities... comment. SUMMARY: The Food and Drug Administration (FDA) is announcing a public meeting entitled ``FDA... controls for facilities provisions of the recently enacted FDA Food Safety Modernization Act (FSMA). FDA is...

  12. Collision-model approach to steering of an open driven qubit

    NASA Astrophysics Data System (ADS)

    Beyer, Konstantin; Luoma, Kimmo; Strunz, Walter T.

    2018-03-01

    We investigate quantum steering of an open quantum system by measurements on its environment in the framework of collision models. As an example we consider a coherently driven qubit dissipatively coupled to a bath. We construct local nonadaptive and adaptive as well as nonlocal measurement scenarios specifying explicitly the measured observable on the environment. Our approach shows transparently how the conditional evolution of the open system depends on the type of the measurement scenario and the measured observables. These can then be optimized for steering. The nonlocal measurement scenario leads to maximal violation of the used steering inequality at zero temperature. Further, we investigate the robustness of the constructed scenarios against thermal noise. We find generally that steering becomes harder at higher temperatures. Surprisingly, the system can be steered even when bipartite entanglement between the system and individual subenvironments vanishes.

  13. Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer's Disease.

    PubMed

    Dgachi, Youssef; Bautista-Aguilera, Oscar M; Benchekroun, Mohamed; Martin, Hélène; Bonet, Alexandre; Knez, Damijan; Godyń, Justyna; Malawska, Barbara; Gobec, Stanislav; Chioua, Mourad; Janockova, Jana; Soukup, Ondrej; Chabchoub, Fakher; Marco-Contelles, José; Ismaili, Lhassane

    2016-05-14

    We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

  14. 33 CFR 164.39 - Steering gear: Foreign tankers.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Steering gear: Foreign tankers. 164.39 Section 164.39 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) PORTS AND WATERWAYS SAFETY NAVIGATION SAFETY REGULATIONS § 164.39 Steering gear: Foreign tankers...

  15. Analysis of hydraulic steering system of tracked all-terrain vehicles' articulated mechanism

    NASA Astrophysics Data System (ADS)

    Meng, Zhongliang; Zang, Hao

    2018-04-01

    As for the researches on the dynamic characteristics of tracked all-terrain vehicles' articulated mechanism, the hydraulic feature of their steering system needs researching more, apart from the study on mechanical models. According to the maximum pressure required by the steering system of tracked all-terrain vehicle and the principle of the steering system, this paper conducts an analysis of the hydraulic steering system of the articulated mechanism. Based on the structure principle of the steering gear, a simulation model of the tracked all-terrain vehicle turning left is built. When building the simulation model of the steering gear, it makes a simulation analysis, taking the tracked all-terrain vehicle turning left as an example.

  16. Growth, carcass characteristics, and profitability of organic versus conventional dairy beef steers.

    PubMed

    Bjorklund, E A; Heins, B J; Dicostanzo, A; Chester-Jones, H

    2014-03-01

    Bull calves (n=49), born at the University of Minnesota West Central Research and Outreach Center (Morris) between March and May 2011, were used to compare growth measurements and profitability of conventional and organic dairy steers. Calves were assigned to 1 of 3 replicated groups at birth: conventional (CONV; n=16), organic (pasture and concentrate; ORG; n=16), or organic grass only (GRS; n=17), and analysis of variables was on a pen basis. Breed groups of calves were Holstein (HO; n=9); Holsteins (n=11) maintained at 1964 breed average level; crossbreds (n=19) including combinations of HO, Montbéliarde, and Swedish Red; and crossbreds (n=10) including combinations of HO, Jersey, Swedish Red, and Normande. The CONV steers were fed a diet of 80% concentrate and 20% forage. The ORG steers were fed a diet of organic corn, organic corn silage, and at least 30% of their diet consisted of organic pasture during the grazing season. The GRS steers grazed pasture during the grazing season and were fed high-quality hay or hay silage during the nongrazing season. Intakes of a total mixed ration were recorded daily with herd management software. A profit function was defined to include revenues and expenses for beef value, feed intake, pasture intake, health cost, and yardage. The GRS (358.6 kg) steers had lesser total gains from birth to slaughter than ORG (429.6 kg) and CONV (534.5 kg) steers. Furthermore, the GRS (0.61 kg/d) steers had lesser average daily gain from birth compared with ORG (0.81 kg/d) and CONV (1.1 kg/d) steers. The GRS and ORG steers had smaller rib eye area (49.5 and 65.8 cm(2), respectively) compared with CONV (75.4 cm(2)) steers. For profitability, GRS steers had 43% greater profit than CONV steers due to organic beef price premiums and lower feed costs. On the other hand, ORG steers had substantially less profit than CONV steers. The higher cost of production for the ORG steers is due to the extreme high value of organic corn. The results of the

  17. 46 CFR 35.20-10 - Steering gear test-T/ALL.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 1 2012-10-01 2012-10-01 false Steering gear test-T/ALL. 35.20-10 Section 35.20-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS OPERATIONS Navigation § 35.20-10 Steering gear test—T/ALL. On all tankships making voyages of more than 48 hours' duration, the entire steering gear, the whistle, the means of...

  18. NMR-based metabonomic analysis of the hepatotoxicity induced by combined exposure to PCBs and TCDD in rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lu Chunfeng; Department of Pharmacology, Basic Medical College, Jiamusi University, Jiamusi 154007; Wang Yimei

    2010-11-01

    A metabonomic approach using {sup 1}H NMR spectroscopy was adopted to investigate the metabonomic pattern of rat urine after oral administration of environmental endocrine disruptors (EDs) polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) alone or in combination and to explore the possible hepatotoxic mechanisms of combined exposure to PCBs and TCDD. {sup 1}H NMR spectra of urines collected 24 h before and after exposure were analyzed via pattern recognition by using principal component analysis (PCA). Serum biochemistry and liver histopathology indicated significant hepatotoxicity in the rats of the combined group. The PCA scores plots of urinary {sup 1}H NMR datamore » showed that all the treatment groups could be easily distinguished from the control group, so could the PCBs or TCDD group and the combined group. The loadings plots of the PCA revealed remarkable increases in the levels of lactate, glucose, taurine, creatine, and 2-hydroxy-isovaleric acid and reductions in the levels of 2-oxoglutarate, citrate, succinate, hippurate, and trimethylamine-N-oxide in rat urine after exposure. These changes were more striking in the combined group. The changed metabolites may be considered possible biomarker for the hepatotoxicity. The present study demonstrates that combined exposure to PCBs and TCDD induced significant hepatotoxicity in rats, and mitochondrial dysfunction and fatty acid metabolism perturbations might contribute to the hepatotoxicity. There was good conformity between changes in the urine metabonomic pattern and those in serum biochemistry and liver histopathology. These results showed that the NMR-based metabonomic approach may provide a promising technique for the evaluation of the combined toxicity of EDs.« less

  19. Protective effect of ALDH2 against cyclophosphamide-induced acute hepatotoxicity via attenuating oxidative stress and reactive aldehydes.

    PubMed

    Zhai, Xiaoxuan; Zhang, Zhenxiao; Liu, Wenwen; Liu, Baoshan; Zhang, Rui; Wang, Wenjun; Zheng, Wen; Xu, Feng; Wang, Jiali; Chen, Yuguo

    2018-04-30

    Cyclophosphamide (CY) is a widely used chemotherapeutic agent that is associated with severe side effects, such as hepatotoxicity and nephrotoxicity. However, the extent, mechanisms and potential prevention and treatment strategies of CY-induced acute hepatotoxicity and nephrotoxicity are largely unknown. In this study, we determined the existence and extent of CY-induced acute hepatotoxicity and nephrotoxicity, and demonstrated the effect of ALDH2 on CY-induced acute tissue toxicity and related mechanisms. Adult male C57BL/6J (wide-type, WT) and ALDH2 -/- (KO) mice were divided into four groups: WT, WT + CY, KO + CY and WT + CY + Alda-1. Biochemical analysis showed that plasma ALT was increased by 35.8% in KO + CY group and decreased by 21.1% in WT + CY + Alda-1 group compared to WT + CY group (P < 0.05, respectively). However, there was no significant difference among WT, WT + CY and KO + CY groups regarding plasma renal marker enzymes, including blood urea nitrogen (BUN), creatinine and cystatin C (CysC). Levels of reactive oxygen species (ROS) and toxic aldehydes (acrolein, 4-hydroxynonenol and malondialdehyde) were increased significantly in KO + CY group and decreased significantly in WT + CY + Alda-1 group compared to WT + CY group (P < 0.05, respectively). These findings demonstrate that CY could induce acute hepatotoxicity without nephrotoxicity, and ALDH2 plays a protective role in CY-induced acute hepatotoxicity. The underlying mechanisms are associated with attenuating oxidative stress and detoxifying reactive aldehydes. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Workshop for Open Source Universal Picture Archiving and Communication Systems (PACS)

    DTIC Science & Technology

    2006-12-01

    Gap! Michael J. Ackerman, PhD NLM/NIH 2:00pm Triple Helix Model Conrad Clyburn TATRC 2:30pm Perspectives from FDA Alford Taylor CDRH ...Medical Robotics, BRSS, STAT- Care and Retinal Imaging) 57 An FDA Perspective Alford Taylor, Jr., CDRH /FDA Issues • CDRH mission is to protect

  1. Hesperidin protects against cyclophosphamide-induced hepatotoxicity by upregulation of PPARγ and abrogation of oxidative stress and inflammation.

    PubMed

    Mahmoud, Ayman M

    2014-09-01

    The most important reason for the non-approval and withdrawal of drugs by the Food and Drug Administration is hepatotoxicity. Therefore, this study was undertaken to evaluate the protective effects of hesperidin against cyclophosphamide (CYP)-induced hepatotoxicity in Wistar rats. The rats received a single intraperitoneal dose of CYP of 200 mg/kg body mass, followed by treatment with hesperidin, orally, at doses of 25 and 50 mg/kg for 11 consecutive days. CYP induced hepatic damage, as evidenced by the significantly elevated levels of serum pro-inflammatory cytokines, serum transaminases, liver lipid peroxidation, and nitric oxide. As a consequence, there was reduced glutathione content, and the activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, were markedly reduced. In addition, CYP administration induced a considerable downregulation of peroxisome proliferator activated receptor gamma (PPARγ) and upregulation of nuclear factor-kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) mRNA expression. Hesperidin, in a dose-dependent manner, rejuvenated the altered markers to an almost normal state. In conclusion, hesperidin showed a potent protective effect against CYP-induced oxidative stress and inflammation leading to hepatotoxicity. The study suggests that hesperidin exerts its protective effect against CYP-induced hepatotoxicity through upregulation of hepatic PPARγ expression and abrogation of inflammation and oxidative stress.

  2. Of poops and parasites: unethical FDA overregulation.

    PubMed

    Young, Kenneth A

    2014-01-01

    Therapies born out of the Hygiene Hypothesis--such as helminthic therapy and fecal bacteriotherapy--provide a compelling example of the FDA's institutional blindness. Unlike the traditional pharmaceutical model of treatment, therapies based in the Hygiene Hypothesis purport to resolve or alleviate conditions by reintroducing organisms once thought to be wholly negative. While questions of negative effects and safety remain in the former, they are largely absent in the latter. Nonetheless, the FDA has chosen to regulate the use of both helminthic therapy and fecal bacteriotherapy. Such restriction of doctor-patient autonomy in the name of efficacy is costly and unethical.

  3. Estimating the NIH Efficient Frontier

    PubMed Central

    2012-01-01

    Background The National Institutes of Health (NIH) is among the world’s largest investors in biomedical research, with a mandate to: “…lengthen life, and reduce the burdens of illness and disability.” Its funding decisions have been criticized as insufficiently focused on disease burden. We hypothesize that modern portfolio theory can create a closer link between basic research and outcome, and offer insight into basic-science related improvements in public health. We propose portfolio theory as a systematic framework for making biomedical funding allocation decisions–one that is directly tied to the risk/reward trade-off of burden-of-disease outcomes. Methods and Findings Using data from 1965 to 2007, we provide estimates of the NIH “efficient frontier”, the set of funding allocations across 7 groups of disease-oriented NIH institutes that yield the greatest expected return on investment for a given level of risk, where return on investment is measured by subsequent impact on U.S. years of life lost (YLL). The results suggest that NIH may be actively managing its research risk, given that the volatility of its current allocation is 17% less than that of an equal-allocation portfolio with similar expected returns. The estimated efficient frontier suggests that further improvements in expected return (89% to 119% vs. current) or reduction in risk (22% to 35% vs. current) are available holding risk or expected return, respectively, constant, and that 28% to 89% greater decrease in average years-of-life-lost per unit risk may be achievable. However, these results also reflect the imprecision of YLL as a measure of disease burden, the noisy statistical link between basic research and YLL, and other known limitations of portfolio theory itself. Conclusions Our analysis is intended to serve as a proof-of-concept and starting point for applying quantitative methods to allocating biomedical research funding that are objective, systematic, transparent

  4. ADHD medication use following FDA risk warnings.

    PubMed

    Barry, Colleen L; Martin, Andres; Busch, Susan H

    2012-09-01

    In 2006, the U.S. Food and Drug Administration (FDA) investigated cardiac and psychiatric risks associated with attention deficit/hyperactivity disorder (ADHD) medication use. To examine how disclosure of safety risks affected pediatric ADHD use, and to assess news media coverage of the issue to better understand trends in treatment patterns. We used the AHRQ's Medical Expenditure Panel Survey (MEPS), a nationally representative household panel survey, to calculate unadjusted rates of pediatric ADHD use from 2002 to 2008 overall and by parents' education. We examined whether children (ages 0 to 20) filled a prescription for any ADHD medication during the calendar year. Next, we used content analysis methods to analyze news coverage of the issue in 10 high-circulation newspapers, the 3 major television networks and a major cable news network in the U.S. We examined 6 measures capturing information conveyed on risk and benefits of ADHD medication use. No declines in medication use following FDA safety warnings overall or by parental education level were observed. News media coverage was relatively balanced in its portrayal of the risks and benefits of ADHD medication use by children. ADHD risk warnings were not associated with large declines in medication use, and balanced news coverage may have contributed to the treatment patterns observed. Self-reported surveys like the MEPS rely on the recall of respondents and may be subject to reporting bias. However, the validity of these data is supported by their consistency with other data on drug use from other sources. These findings are in direct contrast to the substantial declines in use observed after pediatric antidepressant risk warnings in the context of a news media environment that emphasized risks over benefits. Our findings are relevant to the ongoing discussion about improving the FDA's ability to monitor drug safety. Safety warnings occur amid ongoing concern that the agency has insufficient authority and

  5. FDA's regulation of tanning beds: how much heat?

    PubMed

    Knapp, Veronica

    2011-01-01

    This paper considers the problem of indoor tanning bed use by teenagers. The paper explores FDA's current authority to regulate tanning lamps as Class I medical devices, concluding that FDA's authority is poorly tailored to affect teenagers' repeated use of these products. An outright ban is unlikely; therefore, the best available options are to regulate access by minors and to amend the warning label requirements to reflect the current state of knowledge about the risks of tanning bed use.

  6. FDA plan for statutory compliance. Notice of availability.

    PubMed

    1998-11-24

    The Food and Drug Administration (FDA) is announcing the availability of a document entitled "FDA Plan for Statutory Compliance" (the plan). This document is the agency's response to section 406(b) of the Food and Drug Administration Modernization Act of 1997 (FDAMA), which requires the Secretary of the Department of Health and Human Services (the Secretary) to develop a plan bringing the agency into compliance with the requirements of the Federal Food, Drug, and Cosmetic Act (the act).

  7. Autonomous Shepherding Behaviors of Multiple Target Steering Robots.

    PubMed

    Lee, Wonki; Kim, DaeEun

    2017-11-25

    This paper presents a distributed coordination methodology for multi-robot systems, based on nearest-neighbor interactions. Among many interesting tasks that may be performed using swarm robots, we propose a biologically-inspired control law for a shepherding task, whereby a group of external agents drives another group of agents to a desired location. First, we generated sheep-like robots that act like a flock. We assume that each agent is capable of measuring the relative location and velocity to each of its neighbors within a limited sensing area. Then, we designed a control strategy for shepherd-like robots that have information regarding where to go and a steering ability to control the flock, according to the robots' position relative to the flock. We define several independent behavior rules; each agent calculates to what extent it will move by summarizing each rule. The flocking sheep agents detect the steering agents and try to avoid them; this tendency leads to movement of the flock. Each steering agent only needs to focus on guiding the nearest flocking agent to the desired location. Without centralized coordination, multiple steering agents produce an arc formation to control the flock effectively. In addition, we propose a new rule for collecting behavior, whereby a scattered flock or multiple flocks are consolidated. From simulation results with multiple robots, we show that each robot performs actions for the shepherding behavior, and only a few steering agents are needed to control the whole flock. The results are displayed in maps that trace the paths of the flock and steering robots. Performance is evaluated via time cost and path accuracy to demonstrate the effectiveness of this approach.

  8. Autonomous Shepherding Behaviors of Multiple Target Steering Robots

    PubMed Central

    Lee, Wonki; Kim, DaeEun

    2017-01-01

    This paper presents a distributed coordination methodology for multi-robot systems, based on nearest-neighbor interactions. Among many interesting tasks that may be performed using swarm robots, we propose a biologically-inspired control law for a shepherding task, whereby a group of external agents drives another group of agents to a desired location. First, we generated sheep-like robots that act like a flock. We assume that each agent is capable of measuring the relative location and velocity to each of its neighbors within a limited sensing area. Then, we designed a control strategy for shepherd-like robots that have information regarding where to go and a steering ability to control the flock, according to the robots’ position relative to the flock. We define several independent behavior rules; each agent calculates to what extent it will move by summarizing each rule. The flocking sheep agents detect the steering agents and try to avoid them; this tendency leads to movement of the flock. Each steering agent only needs to focus on guiding the nearest flocking agent to the desired location. Without centralized coordination, multiple steering agents produce an arc formation to control the flock effectively. In addition, we propose a new rule for collecting behavior, whereby a scattered flock or multiple flocks are consolidated. From simulation results with multiple robots, we show that each robot performs actions for the shepherding behavior, and only a few steering agents are needed to control the whole flock. The results are displayed in maps that trace the paths of the flock and steering robots. Performance is evaluated via time cost and path accuracy to demonstrate the effectiveness of this approach. PMID:29186836

  9. Association of the FDA Amendment Act with trial registration, publication, and outcome reporting.

    PubMed

    Phillips, Adam T; Desai, Nihar R; Krumholz, Harlan M; Zou, Constance X; Miller, Jennifer E; Ross, Joseph S

    2017-07-18

    Selective clinical trial publication and outcome reporting has the potential to bias the medical literature. The 2007 Food and Drug Administration (FDA) Amendment Act (FDAAA) mandated clinical trial registration and outcome reporting on ClinicalTrials.gov, a publicly accessible trial registry. Using publicly available data from ClinicalTrials.gov, FDA documents, and PubMed, we determined registration, publication, and reporting of findings for all efficacy trials supporting FDA approval of new drugs for cardiovascular disease and diabetes between 2005 and 2014, before and after the FDAAA. For published trials, we compared the published interpretation of the findings (positive, equivocal, or negative) with the FDA reviewer's interpretation. Between 2005 and 2014, the FDA approved 30 drugs for 32 indications of cardiovascular disease (n = 17) and diabetes (n = 15) on the basis of 183 trials (median per indication 5.7 (IQR, 3-8)). Compared with pre FDAAA, post-FDAAA studies were more likely to be registered (78 of 78 (100%) vs 73 of 105 (70%); p < 0.001), to be published (76 of 78 (97%) vs 93 of 105 (89%); p = 0.03), and to present findings concordant with the FDA reviewer's interpretation (74 of 76 (97%) vs 78 of 93 (84%); p = 0.004). Pre FDAAA, the FDA reviewer interpreted 80 (76%) trials as positive and 91 (98%) were published as positive. Post FDAAA, the FDA reviewer interpreted 71 (91%) trials as positive and 71 (93%) were published as positive. FDAAA was associated with increased registration, publication, and FDA-concordant outcome reporting for trials supporting FDA approval of new drugs for cardiovascular disease and diabetes.

  10. A Critical Review of Methods to Evaluate the Impact of FDA Regulatory Actions

    PubMed Central

    Briesacher, Becky A.; Soumerai, Stephen B.; Zhang, Fang; Toh, Sengwee; Andrade, Susan E.; Wagner, Joann L.; Shoaibi, Azadeh; Gurwitz, Jerry H.

    2013-01-01

    Purpose To conduct a synthesis of the literature on methods to evaluate the impacts of FDA regulatory actions, and identify best practices for future evaluations. Methods We searched MEDLINE for manuscripts published between January 1948 and August 2011 that included terms related to FDA, regulatory actions, and empirical evaluation; the review additionally included FDA-identified literature. We used a modified Delphi method to identify preferred methodologies. We included studies with explicit methods to address threats to validity, and identified designs and analytic methods with strong internal validity that have been applied to other policy evaluations. Results We included 18 studies out of 243 abstracts and papers screened. Overall, analytic rigor in prior evaluations of FDA regulatory actions varied considerably; less than a quarter of studies (22%) included control groups. Only 56% assessed changes in the use of substitute products/services, and 11% examined patient health outcomes. Among studies meeting minimal criteria of rigor, 50% found no impact or weak/modest impacts of FDA actions and 33% detected unintended consequences. Among those studies finding significant intended effects of FDA actions, all cited the importance of intensive communication efforts. There are preferred methods with strong internal validity that have yet to be applied to evaluations of FDA regulatory actions. Conclusions Rigorous evaluations of the impact of FDA regulatory actions have been limited and infrequent. Several methods with strong internal validity are available to improve trustworthiness of future evaluations of FDA policies. PMID:23847020

  11. New NIH-funded Ultrasound Technology is Changing Lives around the World | NIH MedlinePlus the Magazine

    MedlinePlus

    ... please turn Javascript on. New NIH-funded Ultrasound Technology is Changing Lives around the World Past Issues / ... to high-quality medical images. Vscan uses advanced technology to produce high-quality images of internal organs. ...

  12. Successful oral desensitization with osimertinib following osimertinib-induced fever and hepatotoxicity: a case report.

    PubMed

    Hirabayashi, Ryosuke; Fujimoto, Daichi; Satsuma, Yukari; Hirabatake, Masaki; Tomii, Keisuke

    2018-05-02

    Osimertinib is a standard second-line therapy for patients who develop EGFR Thr790Met resistance mutation after treatment with first-line epidermal growth factor receptor tyrosine kinase inhibitors. Although no other effective targeted treatment option exists for these patients, osimertinib might be permanently discontinued owing to the onset of severe drug-induced toxicities like hepatotoxicity. Herein, we report a case of successful oral desensitization with osimertinib after the patient developed osimertinib-induced fever and hepatotoxicity. In the present case report, a 62-year-old Japanese woman received osimertinib as the sixth-line therapy for non-small cell lung carcinoma harboring EGFR Thr790Met-mutation. After 15 days of treatment, she developed general malaise. Although we reduced the drug at a lower dose, she again presented with high fever and elevated serum AST/ALT levels three days after re-initiating treatment. We then attempted oral desensitization with osimertinib over a two-week period. Thereafter, the patient continued osimertinib treatment for 6 months without the recurrence of side effects. In conclusion, oral desensitization may be a useful method in treating hepatotoxicity and drug fever caused by osimertinib.

  13. Experimental EPR-steering using Bell-local states

    NASA Astrophysics Data System (ADS)

    Saunders, D. J.; Jones, S. J.; Wiseman, H. M.; Pryde, G. J.

    2010-11-01

    The concept of `steering' was introduced in 1935 by Schrödinger as a generalization of the EPR (Einstein-Podolsky-Rosen) paradox. It has recently been formalized as a quantum-information task with arbitrary bipartite states and measurements, for which the existence of entanglement is necessary but not sufficient. Previous experiments in this area have been restricted to an approach that followed the original EPR argument in considering only two different measurement settings per side. Here we demonstrate experimentally that EPR-steering occurs for mixed entangled states that are Bell local (that is, that cannot possibly demonstrate Bell non-locality). Unlike the case of Bell inequalities, increasing the number of measurement settings beyond two-we use up to six-significantly increases the robustness of the EPR-steering phenomenon to noise.

  14. Stability analysis of automobile driver steering control

    NASA Technical Reports Server (NTRS)

    Allen, R. W.

    1981-01-01

    In steering an automobile, the driver must basically control the direction of the car's trajectory (heading angle) and the lateral deviation of the car relative to a delineated pathway. A previously published linear control model of driver steering behavior which is analyzed from a stability point of view is considered. A simple approximate expression for a stability parameter, phase margin, is derived in terms of various driver and vehicle control parameters, and boundaries for stability are discussed. A field test study is reviewed that includes the measurement of driver steering control parameters. Phase margins derived for a range of vehicle characteristics are found to be generally consistent with known adaptive properties of the human operator. The implications of these results are discussed in terms of driver adaptive behavior.

  15. Tightening conflict-of-interest policies: the impact of 2005 ethics rules at the NIH.

    PubMed

    Zinner, Darren E; DesRoches, Catherine M; Bristol, Steffanie J; Clarridge, Brian; Campbell, Eric G

    2010-11-01

    To determine both the intended and unintended effects of the National Institutes of Health (NIH) 2005 ethics rules by examining changes in publishing rates and the frequency of external relationships among NIH scientists. After identifying eligible intramural scientists and administrators from institutes' Web pages and central directories, a mailed survey was administered to 900 NIH research faculty between October 2008 and January 2009 (response rate 70.1%). Eighty percent of respondents believed the NIH ethics rules were too restrictive. Whereas 45% of respondents believed the rules positively impacted the public's trust in the NIH, 77% believed the rules hindered the NIH's ability to complete its mission. Implementation of the ethics rules significantly decreased self-reported government-industry relationships among NIH faculty (from 51.8% to 33.2%, P < .01), including significant drops in consulting (33.1% to 7.8%, P < .01) and scientific advisory board membership (31.5% to 16.0%, P < .01), both of which may be allowed under the new regulations in restricted situations with increased oversight. The policy had limited impact on NIH faculty participation in nonindustrial professional service roles and had no detectable change in publishing behavior (5.29 articles per researcher per year from 2002-2005 versus 5.26 from 2005-2008, P = .88). The NIH ethics rules accomplished much of what they were intended to do, limiting relationships with industry while maintaining NIH researchers' association with external scientific and professional organizations. However, the rules negatively affected personnel morale and the perceived progress of research.

  16. 21 CFR 111.610 - What records must be made available to FDA?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 2 2011-04-01 2011-04-01 false What records must be made available to FDA? 111... records must be made available to FDA? (a) You must have all records required under this part, or copies of such records, readily available during the retention period for inspection and copying by FDA when...

  17. 21 CFR 111.610 - What records must be made available to FDA?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false What records must be made available to FDA? 111... records must be made available to FDA? (a) You must have all records required under this part, or copies of such records, readily available during the retention period for inspection and copying by FDA when...

  18. 21 CFR 111.610 - What records must be made available to FDA?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 2 2014-04-01 2014-04-01 false What records must be made available to FDA? 111... records must be made available to FDA? (a) You must have all records required under this part, or copies of such records, readily available during the retention period for inspection and copying by FDA when...

  19. 21 CFR 111.610 - What records must be made available to FDA?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 2 2012-04-01 2012-04-01 false What records must be made available to FDA? 111... records must be made available to FDA? (a) You must have all records required under this part, or copies of such records, readily available during the retention period for inspection and copying by FDA when...

  20. 21 CFR 111.610 - What records must be made available to FDA?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 2 2013-04-01 2013-04-01 false What records must be made available to FDA? 111... records must be made available to FDA? (a) You must have all records required under this part, or copies of such records, readily available during the retention period for inspection and copying by FDA when...