tbuckley/cabot-search huggingface dataset:
Effects of environmental antiandrogens on reproductive development in experimental animals
Authors: L.E. Gray, J. Ostby, J. Furr, C.J. Wolf, C. Lambright, L. Parks, D.N. Veeramachaneni, V. Wilson, M. Price, A. Hotchkiss, E. Orlando, L. Guillette
Journal: Human Reproduction Update (2001)

Chemicals that act as androgen receptor (AR) agonists and antagonists or inhibit fetal steroidogenesis can induce reproductive malformations in humans and laboratory animals. Several environmental chemicals disrupt development in rats and/or rabbits at fetal concentrations at, or near, exposure levels seen in some segments of the human population. In rats, fetal tissues concentrations of 10–20 p.p.m. of the DDT metabolite, p,p′-DDE, are correlated with reproductive abnormalities in male offspring. These concentrations are similar to those measured in first-trimester human fetal tissues in the late 1960s. The pesticides vinclozolin, procymidone, linuron and DDT are AR antagonists. They reduce male rat anogenital distance, and induce areolas at relatively low dosages. Hypospadias, agenesis of the sex accessory tissues and retained nipples are seen in the middle dosages, while undescended testes and epididymal agenesis are seen in the highest doses. Phthalate esters (PE) inhibit testosterone synthesis during fetal life, but do not appear to be AR antagonists. Prenatal administration of a single low dose of dioxin (50–1000 ng TCDD/kg) alters the differentiation of androgen-dependent tissues at p.p.t. concentrations, but the mechanism of action likely involves interaction with a hormone-like nuclear transcription factor, the hormone-like receptor AhR, rather than AR. p,p′-DDT and p,p′-DDE, vinclozolin and di-n-butyl phthalate affect reproductive function in rabbits when administered during prenatal and/or neonatal life. Cryptorchidism and carcinoma in situ-like (CIS) testicular lesions were seen in male rabbits treated during development with p,p′-DDT or p,p′-DDE. Extrapolation of effects from rodents to humans would be enhanced if future studies incorporate determination of tissue concentrations of the active metabolites. Knowledge of the tissue concentrations of the active toxicants also would provide an important link to in-vitro studies, which provide more useful mechanistic information when they are executed at relevant concentrations.
Stepwise Approach for Nerve Sparing Without Countertraction During Robot-Assisted Radical Prostatectomy: Technique and Outcomes
Authors: Keith J. Kowalczyk, Andy C. Huang, Nathanael D. Hevelone, Stuart R. Lipsitz, Hua-yin Yu, William D. Ulmer, Joshua R. Kaplan, Sunil Patel, Paul L. Nguyen, Jim C. Hu
Journal: European Urology (2011)
P444 PREDICTION OF ESOPHAGEAL VARICES USING ACOUSTIC RADIATION FORCE IMPULSE ELASTOGRAPHY IN CIRRHOTIC PATIENTS: DEVELOPMENT AND VALIDATION OF A NOVEL PREDICTIVE MODEL (KOREAN MULTI-CENTER STUDY)
Authors: Y. Park, S.U. Kim, S.Y. Park, B.K. Kim, J.Y. Park, D.Y. Kim, S.H. Ahn, W.Y. Tak, Y.O. Kweon, K.-H. Han
Journal: Journal of Hepatology (2014)
One Hundred Years of Drug Regulation: Where Do We Go from Here?
Authors: Raymond L. Woosley
Journal: The Annual Review of Pharmacology and Toxicology (2012)

The first 100 years of drug regulation by the US Food and Drug Administration (FDA) have been sculpted by a series of tragedies and the consequent broadening of the FDA's authority by Congress. The distinguishing feature of the FDA's execution of its mission is that it has routinely turned to science as the primary basis for decision making, and for this reason, it is one of the world's most respected regulatory agencies. Regulatory science, currently defined by the FDA as the science that underpins its decisions, has been the foundation for the FDA's success since its inception. This review focuses on the role of science as the basis for FDA decision making. It examines how regulatory science has made the FDA's past successes possible and concludes with an overview of how the FDA might augment its science-based regulation in the future and what new policy alternatives might be necessary.
Surprising complexity of the ancestral apoptosis network
Authors: Christian M Zmasek, Qing Zhang, Yuzhen Ye, Adam Godzik
Journal: Genome biology (2007)

Apoptosis, one of the main types of programmed cell death, is regulated and performed by a complex protein network. Studies in model organisms, mostly in the nematode Caenorhabditis elegans, identified a relatively simple apoptotic network consisting of only a few proteins. However, analysis of several recently sequenced invertebrate genomes, ranging from the cnidarian sea anemone Nematostella vectensis, representing one of the morphologically simplest metazoans, to the deuterostomes sea urchin and amphioxus, contradicts the current paradigm of a simple ancestral network that expanded in vertebrates.Here we show that the apoptosome-forming CED-4/Apaf-1 protein, present in single copy in vertebrate, nematode, and insect genomes, had multiple paralogs in the cnidarian-bilaterian ancestor. Different members of this ancestral Apaf-1 family led to the extant proteins in nematodes/insects and in deuterostomes, explaining significant functional differences between proteins that until now were believed to be orthologous. Similarly, the evolution of the Bcl-2 and caspase protein families appears surprisingly complex and apparently included significant gene loss in nematodes and insects and expansions in deuterostomes.The emerging picture of the evolution of the apoptosis network is one of a succession of lineage-specific expansions and losses, which combined with the limited number of 'apoptotic' protein families, resulted in apparent similarities between networks in different organisms that mask an underlying complex evolutionary history. Similar results are beginning to surface for other regulatory networks, contradicting the intuitive notion that regulatory networks evolved in a linear way, from simple to complex.
Improved Pharmacokinetic and Pharmacodynamic Profile of Rapid-Acting Insulin Using Needle-Free Jet Injection Technology
Authors: Elsemiek E.C. Engwerda, Evertine J. Abbink, Cees J. Tack, Bastiaan E. de Galan
Journal: Diabetes Care (2011)

Insulin administered by jet injectors is dispensed over a larger subcutaneous area than insulin injected with a syringe, which may facilitate a more rapid absorption. This study compared the pharmacologic profile of administration of insulin aspart by jet injection to that by conventional insulin pen.Euglycemic glucose clamp tests were performed in 18 healthy volunteers after subcutaneous administration of 0.2 units/kg body wt of aspart, either administered by jet injection or by conventional pen, using a randomized, double-blind, double-dummy, cross over study design. Pharmacodynamic and pharmacokinetic profiles were derived from the glucose infusion rate (GIR) needed to maintain euglycemia and from plasma insulin levels, respectively.The time to maximal GIR was significantly shorter when insulin was injected with the jet injector compared with conventional pen administration (51 ± 3 vs. 105 ± 11 min, P < 0.0001). The time to peak insulin concentration was similarly reduced (31 ± 3 vs. 64 ± 6 min, P < 0.0001) and peak insulin concentrations were increased (108 ± 13 vs. 79 ± 7 mU/L, P = 0.01) when insulin was injected by jet injection compared with conventional pen injection. Jet injector insulin administration reduced the time to 50% glucose disposal by ∼40 min (P < 0.0001). There were no differences in maximal GIR, total insulin absorption, or total insulin action between the two devices.Administration of insulin aspart by jet injection enhances insulin absorption and reduces the duration of glucose-lowering action. This profile resembles more closely the pattern of endogenous insulin secretion and may help to achieve better meal insulin coverage and correction of postprandial glucose excursions.
Variation in rates of caesarean section among English NHS trusts after accounting for maternal and clinical risk: cross sectional study
Authors: F. Bragg, D. A. Cromwell, L. C. Edozien, I. Gurol-Urganci, T. A. Mahmood, A. Templeton, J. H. van der Meulen
Journal: BMJ (2010)

<b>Objective</b> To determine whether the variation in unadjusted rates of caesarean section derived from routine data in NHS trusts in England can be explained by maternal characteristics and clinical risk factors. <b>Design</b> A cross sectional analysis using routinely collected hospital episode statistics was performed. A multiple logistic regression model was used to estimate the likelihood of women having a caesarean section given their maternal characteristics (age, ethnicity, parity, and socioeconomic deprivation) and clinical risk factors (previous caesarean section, breech presentation, and fetal distress). Adjusted rates of caesarean section for each NHS trust were produced from this model. <b>Setting</b> 146 English NHS trusts. <b>Population</b> Women aged between 15 and 44 years with a singleton birth between 1 January and 31 December 2008. <b>Main outcome measure</b> Rate of caesarean sections per 100 births (live or stillborn). <b>Results</b> Among 620 604 singleton births, 147 726 (23.8%) were delivered by caesarean section. Women were more likely to have a caesarean section if they had had one previously (70.8%) or had a baby with breech presentation (89.8%). Unadjusted rates of caesarean section among the NHS trusts ranged from 13.6% to 31.9%. Trusts differed in their patient populations, but adjusted rates still ranged from 14.9% to 32.1%. Rates of emergency caesarean section varied between trusts more than rates of elective caesarean section. <b>Conclusion</b> Characteristics of women delivering at NHS trusts differ, and comparing unadjusted rates of caesarean section should be avoided. Adjusted rates of caesarean section still vary considerably and attempts to reduce this variation should examine issues linked to emergency caesarean section.
Current value of preimplantation genetic aneuploidy screening in IVF
Authors: P. Donoso, C. Staessen, B.C.J.M. Fauser, P. Devroey
Journal: Human Reproduction Update (2006)

Preimplantation genetic aneuploidy screening (PGS) has been performed during the last decade as a way of enhancing embryo selection in patients with an increased incidence of embryonic numerical chromosome abnormalities (advanced maternal age, recurrent miscarriage and recurrent implantation failure). It has been proposed that the replacement of euploid embryos in these patients would result in a higher implantation and pregnancy rate and a reduced miscarriage rate. Additionally, the transfer of fewer embryos could reduce the chances for multiple pregnancies in all IVF patients. Although, to date, multiple studies have addressed this issue, contradictory results have been encountered. As a result, the effectiveness of aneuploidy screening remains to be established. Moreover, child outcome studies documenting the safety of this procedure are needed. The aim of this review is to summarize the available evidence concerning the use of PGS to determine the current value of the technique.
Assessment of Plasma DNA Levels, Allelic Imbalance, and CA 125 as Diagnostic Tests for Cancer
Authors: Hsueh Wei Chang, Shing M. Lee, Steven N. Goodman, Gad Singer, Sarah K.R. Cho, Lori J. Sokoll, Frederick J. Montz, Richard Roden, Zheng Zhang, Daniel W. Chan, Robert J. Kurman, Ie Ming Shih
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Allelic imbalance (AI), the loss or gain of chromosomal regions, is found in many cancers. AI can be detected in genomic tumor DNA released into the blood after necrosis or apoptosis. We evaluated plasma DNA concentration, allelic status in plasma DNA, and serum CA 125 level as screening tests for ovarian and other cancers. Methods: Plasma samples were obtained from 330 women (44 normal healthy control individuals, 122 patients with various cancers, and 164 control patients with non-neoplastic diseases). Plasma DNA concentration was determined in all samples. Allelic status was determined by digital single nucleotide polymorphism (SNP) analysis with eight SNP markers in plasma DNA from 54 patients with ovarian cancer and 31 control patients. CA 125 was determined in 63 samples. Receiver-operating characteristic (ROC) curves were plotted, and the areas under the ROC curves—a measure of the overall ability of a diagnostic test with multiple cutoffs to distinguish between diseased and nondiseased individuals—were determined. Results: The area under the ROC curve for plasma DNA concentration was 0.90 for patients with neoplastic disease versus healthy control individuals and 0.74 for patients with neoplastic diseases versus control patients with non-neoplastic diseases. For control subjects given a specificity of 100% (95% confidence interval [CI] = 92% to 100%), the highest sensitivity achieved was 57% (95% CI = 49% to 67%). AI in at least one SNP was found in 87% (95% CI = 60% to 98%) of patients with stage I/II ovarian cancer and 95% (95% CI = 83% to 99%) of patients with stage III/IV ovarian cancer, but AI was not found in 31 patients with non-neoplastic diseases (specificity = 100%, 95% CI = 89% to 100%). The area under the ROC curve assessing AI was 0.95. Combining the serum CA 125 level with the plasma DNA concentration increased the area under the ROC curve from 0.78 (CA 125 alone) to 0.84. Conclusion: Plasma DNA concentration may not be sensitive or specific enough for cancer screening or diagnosis, even when combined with CA 125. AI was detected with high specificity in plasma DNA from patients with ovarian cancer and should be studied further as a screening tool.
Effect of bariatric surgery on asthma control, lung function and bronchial and systemic inflammation in morbidly obese subjects with asthma
Authors: A. van Huisstede, A. Rudolphus, M. Castro Cabezas, L. U. Biter, G.-J. van de Geijn, C. Taube, P. S. Hiemstra, G.-J. Braunstahl, A. van Schadewijk
Journal: Thorax (2015)

<h3>Background</h3> The pathogenesis of asthma in obese subjects is poorly understood and has been described as a specific phenotype in these patients. Weight loss improves asthma control and lung function. Whether this improvement is the result of better mechanical properties of the airways or decreased systemic and bronchial inflammation remains unclear. <h3>Methods</h3> A longitudinal study in obese patients with asthma (bariatric surgery and asthma group (BS+A), n=27) and obese control (bariatric surgery without asthma group (BS−A), n=39) subjects undergoing bariatric surgery, and obese patients with asthma without intervention (no bariatric surgery and asthma group (NBS+A), n=12). Lung function, asthma control, cellular infiltrates in bronchial biopsies and circulating markers of systemic inflammation were measured during follow up at 3, 6 and 12 months. <h3>Results</h3> Bariatric surgery resulted in a profound weight loss at 12 months. In the BS+A group as well as the BS−A group FEV<sub>1</sub>, functional residual capacity, total lung capacity improved, whereas FEV<sub>1</sub>/FVC only improved in the BS−A group. In addition, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire, inhaled corticosteroid use and PD<sub>20</sub> improved in BS+A, whereas in the NBS+A group only ACQ improved. Small airway function R<sub>5</sub>–R<sub>20</sub> improved in both surgery groups, however the change in the BS+A group was greater, resulting in a comparable R<sub>5</sub>–R<sub>20</sub> between BS+A and BS−A at 12-month follow-up. Besides improvement of systemic inflammation (high sensitivity C-reactive protein, adiponectin and leptin) after BS, only a decrease in mast cell numbers was detectable in the BS+A group. <h3>Conclusions</h3> Bariatric surgery improved small airway function, decreased systemic inflammation and number of mast cells in the airways. These effects could explain the improvement of asthma control, quality of life and lung function. Therefore bariatric surgery, in addition to all other positive effects, also improves asthma in subjects with morbid obesity. <h3>Trial registration number</h3> 3204.
Effect of maximal exercise on the short-term kinetics of zinc metabolism in sedentary men
Authors: Stella Lucia Volpe, Nicola M Lowe, Leslie R Woodhouse, Janet C King
Journal: British Journal of Sports Medicine (2006)

Objective: To examine the effect of acute exhaustive exercise versus rest on short-term zinc kinetics in men. Design: Crossover design, wherein all subjects were their own control. Setting: University setting, where subjects were free living. Participants: 12 healthy, sedentary men, 25–35 years of age. Interventions: 70 Zn was infused 10 min after exercise or at rest. Plasma zinc concentrations were measured at baseline and 2, 5, 10, 15, 30, 45, 60, 75, 90 and 120 min after exercise or rest. Haematocrit was measured before and after exercise to assess changes in plasma volume. Main outcome measurements: Plasma zinc (primary), serum creatine kinase and serum cortisol concentrations (secondary). Results: Plasma zinc concentrations decreased (p&lt;0.05) after exercise, with a mean (SD) nadir of 13.9% (4.1%) observed at 70 min after exercise. There were increases in the size of the rapidly exchangeable plasma zinc pool (Qa; from 3.1 (0.2) to 3.6 (0.2) mg; p&lt;0.05) and the liver zinc pool (Qb; from 10.2 (0.6) to 11.4 (0.8) mg; p = 0.12). Conclusion: Exercise seems to cause a shift of plasma zinc into the interstitial fluid and liver after exercise, which may reflect the acute stress response of strenuous exercise.
A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes
Authors: Sunita Sharma, Xiaobo Zhou, Derek M. Thibault, Blanca E. Himes, Andy Liu, Stanley J. Szefler, Robert Strunk, Mario Castro, Nadia N. Hansel, Gregory B. Diette, Becky M. Vonakis, N. Franklin Adkinson, Lydiana Avila, Manuel Soto-Quiros, Albino Barraza-Villareal, Robert F. Lemanske, Julian Solway, Jerry Krishnan, Steven R. White, Chris Cheadle, Alan E. Berger, Jinshui Fan, Meher Preethi Boorgula, Dan Nicolae, Frank Gilliland, Kathleen Barnes, Stephanie J. London, Fernando Martinez, Carole Ober, Juan C. Celedón, Vincent J. Carey, Scott T. Weiss, Benjamin A. Raby
Journal: Journal of Allergy and Clinical Immunology (2014)
Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone.
Authors: M Bianchi, O Bloom, T Raabe, P S Cohen, J Chesney, B Sherry, H Schmidtmayerova, T Calandra, X Zhang, M Bukrinsky, P Ulrich, A Cerami, K J Tracey
Journal: The Journal of Experimental Medicine (1996)

An overproduction of proinflammatory cytokines by activated macrophages/monocytes mediates the injurious sequelae of inflammation, septic shock, tissue injury, and cachexia. We recently synthesized a tetravalent guanylhydrazone compound (CNI-1493) that inhibits cytokine-inducible arginine transport and nitric oxide (NO) production in macrophages, and protects mice against lethal endotoxemia and carrageenan-induced inflammation. During these investigations we noticed that CNI-1493 effectively prevented lipopolysaccharide (LPS)-induced NO production, even when added in concentrations 10-fold less than required to competitively inhibit L-arginine uptake, suggesting that the suppressive effects of this guanylhydrazone compound might extend to other LPS-induced responses. Here, we report that CNI-1493 suppressed the LPS-stimulated production of proinflammatory cytokines (tumor necrosis factor [TNF], interleukins 1beta and 6, macrophage inflammatory proteins 1alpha and 1beta) from human peripheral blood mononuclear cells. Cytokine suppression was specific, in that CNI-1493 did not inhibit either the constitutive synthesis of transforming growth factor beta or the upregulation of major histocompatibility complex class II by interferon gamma (IFN-gamma). In contrast to the macrophage suppressive actions of dexamethasone, which are overridden in the presence of IFN-gamma, CNI-1493 retained its suppressive effects even in the presence of IFN-gamma. The mechanism of cytokine-suppressive action by CNI-1493 was independent of extracellular L-arginine content and NO production and is not restricted to induction by LPS. As a selective inhibitor of macrophage activation that prevents TNF production, this tetravalent guanylhydrazone could be useful in the development of cytokine-suppressive agents for the treatment of diseases mediated by overproduction of cytokines.
Post-Approval Drug Safety Surveillance
Authors: Robert D. Gibbons, Anup K. Amatya, C. Hendricks Brown, Kwan Hur, Sue M. Marcus, Dulal K. Bhaumik, J. John Mann
Journal: Annual Review of Public Health (2010)

Following the drug-approval process, concerns remain regarding the safety of new drugs that are introduced into the marketplace. In the case of rare adverse events, the number of subjects that are treated in randomized controlled trials is invariably inadequate to determine the safety of the new pharmaceutical. Identifying safety signals for new and/or existing drugs is a major priority in the protection of public health. Unfortunately, design, analysis, and available data are often quite limited for detecting in a timely fashion any potentially harmful effects of drugs. In this review, we examine a variety of approaches for determining the possibility of adverse drug reactions. Our review includes spontaneous reports, meta-analysis of randomized controlled clinical trials, ecological studies, and analysis of medical claims data. We consider both experimental design and analytic problems as well as potential solutions. Many of these methodologies are then illustrated through application to data on the possible relationship between taking antidepressants and increased risk of suicidality.
New methods of treatment in an experimental murine model of systemic lupus erythematosus induced by idiotypic manipulation
Authors: Y. Shoenfeld, I. Krause, M. Blank
Journal: Annals of the Rheumatic Diseases (1997)

In this article we have presented our experiences and those of others with various experimental and novel treatments in an experimental model of murine SLE, induced by immunisation with pathogenic anti-DNA antibody (fig 4). Many of the treatments (summarised in the table) were highly effective in ameliorating clinical, serological, and histological manifestations of the disease. According to our results, it seems that hormonal treatments--such as testosterone metabolites, anti-oestrogens, or bromocriptine--as well as immunomodulation with IVIG or anti-CD4 antibodies, hold the most promising potential for application in lupus patients. We believe, therefore, that these types of treatment should receive high priority in human trials. It should be emphasised, however, that the timing of treatment may be critical, since several treatments were effective when used before or during the induction of the disease. This limitation may pose difficulty for human application, since the aetiology of SLE is still obscure and is probably multifactorial38; therefore it is not yet possible to identify patients at risk of developing SLE. Nevertheless, those treatments which proved to be effective might be used early in the course of the disease in lupus patients and hence influence the outcome of the disease, or may even induce partial or complete remission.
Quantitative angiography parameters fail to accurately predict stent expansion
Authors: J. Botas, J. Elizaga, E. Garcia, J. Bermejo, M. Faddoul, J. Soriano, M. Abaytua, R. Lopez-Palop, F. Sarnago, G. Migliaro, J.L. Delcán
Journal: Journal of the American College of Cardiology (1998)