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Showing papers by "Research Triangle Park published in 2003"


Journal ArticleDOI
15 Feb 2003-Proteins
TL;DR: Geometrical validation around the Cα is described, with a new Cβ measure and updated Ramachandran plot, and Favored and allowed ϕ,ψ regions are also defined for Pro, pre‐Pro, and Gly (important because Gly ϕ‐ψ angles are more permissive but less accurately determined).
Abstract: Geometrical validation around the Calpha is described, with a new Cbeta measure and updated Ramachandran plot. Deviation of the observed Cbeta atom from ideal position provides a single measure encapsulating the major structure-validation information contained in bond angle distortions. Cbeta deviation is sensitive to incompatibilities between sidechain and backbone caused by misfit conformations or inappropriate refinement restraints. A new phi,psi plot using density-dependent smoothing for 81,234 non-Gly, non-Pro, and non-prePro residues with B < 30 from 500 high-resolution proteins shows sharp boundaries at critical edges and clear delineation between large empty areas and regions that are allowed but disfavored. One such region is the gamma-turn conformation near +75 degrees,-60 degrees, counted as forbidden by common structure-validation programs; however, it occurs in well-ordered parts of good structures, it is overrepresented near functional sites, and strain is partly compensated by the gamma-turn H-bond. Favored and allowed phi,psi regions are also defined for Pro, pre-Pro, and Gly (important because Gly phi,psi angles are more permissive but less accurately determined). Details of these accurate empirical distributions are poorly predicted by previous theoretical calculations, including a region left of alpha-helix, which rates as favorable in energy yet rarely occurs. A proposed factor explaining this discrepancy is that crowding of the two-peptide NHs permits donating only a single H-bond. New calculations by Hu et al. [Proteins 2002 (this issue)] for Ala and Gly dipeptides, using mixed quantum mechanics and molecular mechanics, fit our nonrepetitive data in excellent detail. To run our geometrical evaluations on a user-uploaded file, see MOLPROBITY (http://kinemage.biochem.duke.edu) or RAMPAGE (http://www-cryst.bioc.cam.ac.uk/rampage).

3,963 citations


Journal ArticleDOI
TL;DR: GPR41 was expressed primarily in adipose tissue, whereas the highest levels of GPR43 were found in immune cells, and was activated by similar ligands but with differing specificity for carbon chain length, with pentanoate being the most potent agonist.

1,876 citations


Journal ArticleDOI
TL;DR: A set of simple guidelines for developing validated and predictive QSPR models is presented, highlighting the need to establish the domain of model applicability in the chemical space to flag molecules for which predictions may be unreliable, and some algorithms that can be used for this purpose.
Abstract: This paper emphasizes the importance of rigorous validation as a crucial, integral component of Quantitative Structure Property Relationship (QSPR) model development. We consider some examples of published QSPR models, which in spite of their high fitted accuracy for the training sets and apparent mechanistic appeal, fail rigorous validation tests, and, thus, may lack practical utility as reliable screening tools. We present a set of simple guidelines for developing validated and predictive QSPR models. To this end, we discuss several validation strategies including (1) randomization of the modelled property, also called Y-scrambling, (2) multiple leave-many-out cross-validations, and (3) external validation using rational division of a dataset into training and test sets. We also highlight the need to establish the domain of model applicability in the chemical space to flag molecules for which predictions may be unreliable, and discuss some algorithms that can be used for this purpose. We advocate the broad use of these guidelines in the development of predictive QSPR models.

1,838 citations


Journal ArticleDOI
TL;DR: In this article, the authors estimated the age-specific cumulative incidence of fibroid tumors for black and white women in the United States and found that most premenopausal women develop fibroid tumor before menopause.

1,712 citations


Journal ArticleDOI
12 Mar 2003-JAMA
TL;DR: The goal of this article is to articulate the 4 central challenges facing clinical research at present--public participation, information systems, workforce training, and funding; to make recommendations about how they might be addressed by particular stakeholders; and to invite a broader, participatory dialogue with a view to improving the overall performance of the US clinical research enterprise.
Abstract: Medical scientists and public health policy makers are increasingly concerned that the scientific discoveries of the past generation are failing to be translated efficiently into tangible human benefit. This concern has generated several initiatives, including the Clinical Research Roundtable at the Institute of Medicine, which first convened in June 2000. Representatives from a diverse group of stakeholders in the nation’s clinical research enterprise have collaborated to address the issues it faces. The context of clinical research is increasingly encumbered by high costs, slow results, lack of funding, regulatory burdens, fragmented infrastructure, incompatible databases, and a shortage of qualified investigators and willing participants. These factors have contributed to 2 major obstacles, or translational blocks: impeding the translation of basic science discoveries into clinical studies and of clinical studies into medical practice and health decision making in systems of care. Considering data from across the entire health care system, it has become clear that these 2 translational blocks can be removed only by the collaborative efforts of multiple system stakeholders. The goal of this article is to articulate the 4 central challenges facing clinical research at present—public participation, information systems, workforce training, and funding; to make recommendations about how they might be addressed by particular stakeholders; and to invite a broader, participatory dialogue with a viewtoimprovingtheoverallperformanceoftheUSclinicalresearchenterprise.

1,142 citations


Journal ArticleDOI
TL;DR: The authors used a regression framework and nationally representative data to compute aggregate overweight- and obesity-attributable medical spending for the United States and for select payers, and found that such expenditures accounted for 9.1 percent of total annual U.S. medical expenditures in 1998 and may have been as high as dollar 78.5 billion (dollar 92.6 billion in 2002 dollars).
Abstract: We use a regression framework and nationally representative data to compute aggregate overweight- and obesity-attributable medical spending for the United States and for select payers. Combined, such expenditures accounted for 9.1 percent of total annual U.S. medical expenditures in 1998 and may have been as high as dollar 78.5 billion (dollar 92.6 billion in 2002 dollars). Medicare and Medicaid finance approximately half of these costs.

1,118 citations


Journal ArticleDOI
TL;DR: expression analysis by quantitative reverse transcription-PCR showed that GPR40 was specifically expressed in brain and Pancreas, with expression in rodent pancreas being localized to insulin-producing β-cells.

1,043 citations


Journal ArticleDOI
TL;DR: The IRT model estimated for a 'pool' of items from widely used measures of headache impact was useful in constructing an efficient, reliable, and valid 'static' short form (HIT-6) for use in screening and monitoring patient outcomes.
Abstract: Background: Migraine and other severe headaches can cause suffering and reduce functioning and productivity. Patients are the best source of information about such impact. Objective: To develop a new short form (HIT-6) for assessing the impact of headaches that has broad content coverage but is brief as well as reliable and valid enough to use in screening and monitoring patients in clinical research and practice. Methods: HIT-6 items were selected from an existing item pool of 54 items and from 35 items suggested by clinicians. Items were selected and modified based on content validity, item response theory (IRT) information functions, item internal consistency, distributions of scores, clinical validity, and linguistic analyses. The HIT-6 was evaluated in an Internet-based survey of headache sufferers (n = 1103) who were members of America Online (AOL). After 14 days, 540 participated in a follow-up survey. Results: HIT-6 covers six content categories represented in widely used surveys of headache impact. Internal consistency, alternate forms, and test–retest reliability estimates of HIT-6 were 0.89, 0.90, and 0.80, respectively. Individual patient score confidence intervals (95%) of app. ±5 were observed for 88% of all respondents. In tests of validity in discriminating across diagnostic and headache severity groups, relative validity (RV) coefficients of 0.82 and 1.00 were observed for HIT-6, in comparison with the Total Score. Patient-level classifications based in HIT-6 were accurate 88.7% of the time at the recommended cut-off score for a probability of migraine diagnosis. HIT-6 was responsive to self-reported changes in headache impact. Conclusions: The IRT model estimated for a 'pool' of items from widely used measures of headache impact was useful in constructing an efficient, reliable, and valid 'static' short form (HIT-6) for use in screening and monitoring patient outcomes.

984 citations


Journal ArticleDOI
TL;DR: In this article, an initial evaluation of the Models-3 Community Multiscale Air Quality (CMAQ) model aerosol component reveals CMAQ's varying ability to simulate observed visibility indices and aerosol species concentrations.
Abstract: [1] An initial evaluation of the Models-3 Community Multiscale Air Quality (CMAQ) model aerosol component reveals CMAQ's varying ability to simulate observed visibility indices and aerosol species concentrations. The visibility evaluation, using National Weather Service observations from 139 airports for 11–15 July 1995, shows that CMAQ reasonably captured the general spatial and temporal patterns of visibility degradation, including major gradients, maxima and minima. However, CMAQ's two visibility prediction methods, Mie theory approximation and mass reconstruction, both underpredict visibility degradation (i.e., overpredict visibility). The mean bias, normalized mean bias (NMB), mean error and normalized mean error (NME) for the Mie calculations are −5.9 dv, −21.7%, 7.0 dv and 25.4%, respectively. For the reconstruction simulations, these statistics are −9.8 dv, −35.5%, 10.0 dv and 36.2%, respectively. Most simulated values (∼90% Mie and ∼85% reconstruction) fall within a factor of two of the observations, although r2 = 0.25 (Mie) and r2 = 0.24 (reconstruction). The speciated aerosol evaluation uses observations of sulfate, nitrate, PM2.5, PM10 and organic carbon obtained from 18 stations of the Interagency Monitoring of Protected Visual Environments (IMPROVE) network in June 1995. This evaluation reveals that, with the exception of sulfate (mean bias: 0.15 μg/m3, NMB: 3.1%), the model consistently underpredicts aerosol concentrations of nitrate (−0.10 μg/m3, −33.1%), PM2.5 (−3.9 μg/m3, −30.1%), PM10 (−5.66 μg/m3, −29.2%) and organic carbon (−0.78 μg/m3, −33.7%). Sulfate was simulated best by the model (r2 = 0.63, mean error = 1.75 μg/m3, NME = 36.2%), followed by PM2.5 (0.55, 5.00 μg/m3, 38.5%), organic carbon (0.25, 0.94 μg/m3, 40.6%), PM10 (0.13, 9.85 μg/m3, 50.8%) and nitrate (0.01, 0.33 μg/m3, 104.3%). Except for nitrate, 75–80% of simulated concentrations fall within a factor of two of the IMPROVE observations.

802 citations


Journal ArticleDOI
TL;DR: It is demonstrated that lamivudine treatment for up to 6 years has an excellent safety profile in patients with HBeAg-positive compensated liver disease, but patients with long-standing lamivUDine-resistant mutations may experience worsening liver disease.

758 citations


Journal ArticleDOI
TL;DR: Three years of lamivudine therapy reduces necroinflammatory activity and reverses fibrosis (including cirrhosis) in most patients, therefore, extended-duration YMDD variants may require additional therapies to maintain the histological benefit of treatment.

Journal ArticleDOI
TL;DR: It is demonstrated that FXR directly regulates expression of fibroblast growth factor-19 (FGF-19), a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase, which defines a novel mechanism for feedback repression of bile acid biosynthesis.
Abstract: The catabolism of cholesterol to bile acids represents a major pathway for the elimination of this potentially pathogenic sterol fromthe body. Bile acids subserve a number of important physiological functions, including the solubilization of cholesterol, fat soluble vitamins, and other lipids in the intestine (Vlahcevic et al. 1994, 1996). In addition, bile acids contribute to the generation of bile flow and promote the secretion of lipids, notably phosphatidylcholine and cholesterol, fromthe canalicular membrane into the bile canaliculus. However, because of their intrinsic toxicity, intracellular levels of bile acids must be tightly regulated, which is largely accomplished by transcriptional regulation of genes encoding proteins involved in bile acid biosynthesis, transport, and metabolism. The conversion of cholesterol to the primary bile acids, cholic acid and chenodeoxycholic acid (CDCA), involves at least 14 distinct enzymes and is accomplished via 2 pathways (Bjorkhem 1985; Russell and Setchell 1992). The first and rate-limiting step in the neutral (classic) pathway of bile acid biosynthesis is catalyzed by cholesterol 7 α-hydroxylase (CYP7A1; Bjorkhem 1985; Russell and Setchell 1992; Chiang 1998). Expression of the gene encoding CYP7A1 is known to be suppressed by a number of factors including insulin, protein kinase C activators, cytokines such as tumor necrosis factor α (TNF-α), steroid hormones, and, importantly, bile acids (for review, see Chiang 1998). The bile acid-dependent feedback repression of CYP7A1 is important in preventing a potentially harmful expansion of the bile acid pool. A number of studies have focused on characterizing the molecular mechanisms by which bile acids suppress CYP7A1 expression, and it is now apparent that multiple, redundant pathways exist (Stravitz et al. 1995; Antes et al. 2000; Goodwin et al. 2000; Lu et al. 2000; Miyake et al. 2000; De Fabiani et al. 2001; Kerr et al. 2002; Wang et al. 2002). Notably, these signaling cascades converge on a common bile acid responsive element (BARE) in the CYP7A1 promoter (Chiang and Stroup 1994; Stroup et al. 1997). This element is highly conserved across species and is a well-documented binding site for members of the nuclear receptor superfamily of ligand activated transcription factors, including liver receptor homolog-1 (LRH-1, NR5A2) and hepatocyte nuclear factor 4α (HNF-4α, NR2A1; Crestani et al. 1998; Nitta et al. 1999; Lu et al. 2000; Stroup and Chiang 2000; De Fabiani et al. 2001; Chiang 2002). The farnesoid X receptor (FXR; NR1H4) is a bile acid-activated transcription factor that also belongs to the nuclear receptor family (Makishima et al. 1999; Parks et al. 1999; Wang et al. 1999). FXR binds DNA as an obligate heterodimer with the retinoid X receptors (RXRs; Forman et al. 1995; Seol et al. 1995). The FXR/RXR heterodimer typically binds to an inverted repeat of the hexanucleotide motif AGG/TTCA separated by a single nucleotide, a so-called IR-1 (Forman et al. 1995; Seol et al. 1995). FXR is known to be expressed in tissues that are exposed to bile acids, including liver, intestine, gallbladder (C. Housset, pers. comm.), kidney, and adrenal gland (Forman et al. 1995; Seol et al. 1995). In liver, the biological consequences of FXR activation have recently become increasingly clear. Upon activation, FXR initiates transcription of a cohort of genes that function to decrease the concentration of bile acids within the hepatocyte. Specifically, FXR induces the expression of ATP-binding cassette (ABC) transporters bile salt export pump (BSEP; ABCB11; Sinal et al. 2000; Ananthanarayanan et al. 2001; Plass et al. 2002), multidrug resistance protein 3 (MDR3, ABCB4; B. Goodwin and S.A. Jones, unpubl.), and multidrug resistance-associated protein 2 (MRP2; ABCC2; Kast et al. 2002). These transporters function to transport bile acids and bile constituents fromthe hepatocytes into the bile. In addition, activation of FXR by both naturally occurring (CDCA) and synthetic ligands leads to the repression of two important genes in the bile acid biosynthetic pathway, namely CYP7A1 and CYP8B1, which encodes oxysterol 12α hydroxylase (Goodwin et al. 2000; Lu et al. 2000; Sinal et al. 2000; del Castillo-Olivares and Gil 2001; Zhang and Chiang 2001). The FXR-dependent suppression of CYP7A1 is mediated by the transcriptional repressor short heterodimer partner-1 (SHP; NR0B2), an atypical nuclear receptor that lacks a DNA-binding domain (Goodwin et al. 2000; Lu et al. 2000). Thus, activation of FXR results in increased expression of the SHP gene. In turn, SHP interacts with LRH-1, a known positive regulator of CYP7A1 (discussed above) and represses its transcriptional activity. Elegant studies performed in mice harboring a disrupted SHP gene confirmthe importance of the FXR–SHP–LRH-1 cascade in suppression of CYP7A1, however, they also demonstrate the existence of additional SHP-independent pathways, possibly involving the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (Kerr et al. 2002; Wang et al. 2002). In this study, we describe the discovery of a novel FXR-dependent signaling cascade for the suppression of CYP7A1. We show that FXR directly regulates expression of FGF-19, a member of the fibroblast growth factor (FGF) family of signaling molecules (Nishimura et al. 1999; Xie et al. 1999). The FGFs bind the extracellular domain of their cognate cell surface receptor (FGFR) and induce receptor dimerization and tyrosine kinase phosphorylation, which, in turn, leads to the activation of a number of intracellular pathways (Goldfarb 2001; Ornitz and Itoh 2001). For many years, it has been understood that the FGFs regulate cell growth, differentiation, and morphogenesis, however, it is now apparent that some of these proteins are also important components of specific homeostatic pathways (Yu et al. 2000; Shimada et al. 2001; Tomlinson et al. 2002). We demonstrate that FGF-19, acting as an FXR-induced signaling molecule, represses expression of the CYP7A1 gene. Our findings define a novel regulatory pathway for the suppression of bile acid biosynthesis.

Journal ArticleDOI
TL;DR: Patients with YMDD variants losing clinical response with a significant increase in the HBV DNA and ALT levels may require additional therapy.
Abstract: YMDD variants of hepatitis B virus (HBV) emerge in some patients with chronic hepatitis B who receive lamivudine. YMDD variants were examined in 794 patients in 4 controlled studies of 1 year's duration. The long-term effects of YMDD variants were examined in a subset of patients treated up to 4 years. YMDD variants were detected by polymerase chain reaction (PCR) and restriction fragment-length polymorphism assays. After 1 year, YMDD variants were detected in 81 (24%) of 335 patients. In these patients, the median serum HBV DNA concentration at 1 year was <20% of the baseline level, and serum alanine transaminase (ALT) levels and liver histologic findings had significantly improved. In patients with YMDD variants who were treated for up to 4 years, median HBV DNA and ALT levels showed improvements. Sex, baseline body mass index, and HBV DNA level were associated with emergence of YMDD variants. Patients with YMDD variants losing clinical response with a significant increase in the HBV DNA and ALT levels may require additional therapy.


Journal ArticleDOI
TL;DR: These results provide the first unequivocal link between mammalian meiotic aneuploidy and an accidental environmental exposure and suggest that the oocyte and its meiotic spindle will provide a sensitive assay system for the study of reproductive toxins.

Journal ArticleDOI
TL;DR: In this article, the clinical efficacy and safety of cognitive-behavioral therapy (CBT) against education (EDU) and desipramine (DES) against placebo (PLA) in female patients with moderate to severe functional bowel disorders (irritable bowel syndrome, functional abdominal pain, painful constipation, and unspecified FBD).

Journal ArticleDOI
TL;DR: It is indicated that in utero exposure to PFOS severely compromised postnatal survival of neonatal rats and mice, and caused delays in growth and development that were accompanied by hypothyroxinemia in the surviving rat pups.

Journal ArticleDOI
TL;DR: The identification of the G protein-coupled receptor HM74 as a low affinity receptor for nicotinic acid and the subsequent identification of HM74A in follow-up bioinformatics searches and demonstrate that it acts as a high affinity receptors for Nicotinic Acid and other compounds with related pharmacology.

Journal ArticleDOI
TL;DR: The results suggest that BOS1 mediates responses to signals, possibly mediated by reactive oxygen intermediates from both biotic and abiotic stress agents, and suggests a common host response strategy against these pathogens.
Abstract: The molecular and cellular mechanisms involved in plant resistance to the necrotrophic fungal pathogen Botrytis cinerea and their genetic control are poorly understood. Botrytis causes severe disease in a wide range of plant species, both in the field and in postharvest situations, resulting in significant economic losses. We have isolated the BOS1 (BOTRYTIS-SUSCEPTIBLE1) gene of Arabidopsis based on a T-DNA insertion allele that resulted in increased susceptibility to Botrytis infection. The BOS1 gene is required to restrict the spread of another necrotrophic pathogen, Alternaria brassicicola, suggesting a common host response strategy against these pathogens. In the case of the biotrophic pathogens Pseudomonas syringae pv tomato and the oomycete parasite Peronospora parasitica, bos1 exhibits enhanced disease symptoms, but pathogen growth is similar in bos1 and wild-type plants. Strikingly, bos1 plants have impaired tolerance to water deficit, increased salinity, and oxidative stress. Botrytis infection induces the expression of the BOS1 gene. This increased expression is severely impaired in the coi1 mutant, suggesting an interaction of BOS1 with the jasmonate signaling pathway. BOS1 encodes an R2R3MYB transcription factor protein, and our results suggest that it mediates responses to signals, possibly mediated by reactive oxygen intermediates from both biotic and abiotic stress agents.

Journal ArticleDOI
01 Nov 2003
TL;DR: This paper considers computational systems whose material realizations utilize electrons and energy barriers to represent and manipulate their binary representations of state.
Abstract: In this paper we consider device scaling and speed limitations on irreversible von Neumann computing that are derived from the requirement of "least energy computation." We consider computational systems whose material realizations utilize electrons and energy barriers to represent and manipulate their binary representations of state.

Journal ArticleDOI
TL;DR: The proposed technique enables the implementation of high-efficiency high-power-density fully regulated fully regulated CEET systems suitable for applications with a wide input and load range.
Abstract: A high-performance contactless electrical energy transmission (CEET) technique which employs the inductive energy transmission principle is described. The proposed technique enables the implementation of high-efficiency high-power-density fully regulated CEET systems suitable for applications with a wide input and load range. A high efficiency of the system is achieved by recovering the energy stored in the leakage inductances of the transformer by incorporating them in the operation of the circuit, and by employing high-frequency-inverter and controlled-rectifier topologies that allow a controlled bidirectional power flow through the transformer. In addition, a feedforward variable-switching-frequency control of the inverter is used to maintain approximately constant power transfer through the transformer with the input voltage changes, whereas the output-side rectifier employs a local pulsewidth-modulation control to achieve a tight regulation of the output in the presence of load variations. Specifically, the described CEET system is suitable for use in universal-input battery chargers.

Journal ArticleDOI
TL;DR: This study illustrates that the BCF/BAF criteria, as currently applied, are inappropriate for the hazard identification and classification of metals, as values are highest at low exposure concentrations and are lowest at high exposure concentrations, where impacts are likely.
Abstract: The bioconcentration factor (BCF) and bioaccumulation factor (BAF) are used as the criteria for bioaccumulation in the context of identifying and classifying substances that are hazardous to the aquatic environment. The BCF/BAF criteria, while developed as surrogates for chronic toxicity and/or biomagnification of anthropogenic organic substances, are applied to all substances including metals. This work examines the theoretical and experimental basis for the use of BCF/BAF in the hazard assessment of Zn, Cd, Cu, Pb, Ni, and Ag. As well, BCF/BAFs for Hg (methyl and inorganic forms) and hexachlorobenzene (HCB) were evaluated. The BCF/BAF data for Zn, Cd, Cu, Pb, Ni, and Ag were characterized by extreme variability in mean BCF/BAF values and a clear inverse relationship between BCF/BAF and aqueous exposure. The high variability persisted when even when data were limited to an exposure range where chronic toxicity would be expected. Mean BCF/BAF values for Hg were also variable, but the inverse relationship was equivocal, in contrast with HCB, which conformed to the BCF model. This study illustrates that the BCF/BAF criteria, as currently applied, are inappropriate for the hazard identification and classification of metals. Furthermore, using BCF and BAF data leads to conclusions that are inconsistent with the toxicological data, as values are highest (indicating hazard) at low exposure concentrations and are lowest (indicating no hazard) at high exposure concentrations, where impacts are likely. Bioconcentration and bioaccumulation factors do not distinguish between essential mineral nutrient, normal background metal bioaccumulation, the adaptive capabilities of animals to vary uptake and elimination within the spectrum of exposure regimes, nor the specific ability to sequester, detoxify, and store internalized metal from metal uptake that results in adverse effect. An alternative to BCF, the accumulation factor (ACF), for metals was assessed and, while providing an improvement, it did not provide a complete solution. A bioaccumulation criterion for the hazard identification of metals is required, and work directed at linking chronic toxicity and bioaccumulation may provide some solutions.

Journal ArticleDOI
TL;DR: Evidence is provided that viewing smoking in movies promotes smoking initiation among adolescents, and the effect of exposure to movie smoking was stronger in adolescents with non-smoking parents than in those whose parent smoked.

Journal ArticleDOI
TL;DR: The results support the use of enterococci in marine water at U.S. Environmental Protection Agency guideline levels and the ability of new, more rapid and specific microbial methods to predict health effects, and estimating the risks of recreational water exposure among susceptible persons.
Abstract: Despite numerous studies, uncertainty remains about how water quality indicators can best be used in the regulation of recreational water. We conducted a systematic review of this topic with the goal of quantifying the association between microbial indicators of recreational water quality and gastrointestinal (GI) illness. A secondary goal was to evaluate the potential for GI illness below current guidelines. We screened 976 potentially relevant studies and from these identified 27 studies. From the latter, we determined summary relative risks for GI illness in relation to water quality indicator density. Our results support the use of enterococci in marine water at U.S. Environmental Protection Agency guideline levels. In fresh water, (Italic)Escherichia(/Italic) coli was a more consistent predictor of GI illness than are enterococci and other bacterial indicators. A log (base 10) unit increase in enterococci was associated with a 1.34 [95% confidence intervals (CI), 1.00-1.75] increase in relative risk in marine waters, and a log (base 10) unit increase in E. coli was associated with a 2.12 (95% CI, 0.925-4.85) increase in relative risk in fresh water. Indicators of viral contamination were strong predictors of GI illness in both fresh and marine environments. Significant heterogeneity was noted among the studies. In our analysis of heterogeneity, studies that used a nonswimming control group, studies that focused on children, and studies of athletic or other recreational events found elevated relative risks. Future studies should focus on the ability of new, more rapid and specific microbial methods to predict health effects, and estimating the risks of recreational water exposure among susceptible persons.

Journal ArticleDOI
TL;DR: To improve the future health and well-being of women and their children, there is a continued need for well-designed studies of substance abuse treatment programming for women.
Abstract: Recent research has shown that women and men differ in substance abuse etiology, disease progression, and access to treatment for substance abuse. Substance abuse treatment specifically designed for women has been proposed as one way to meet women's distinctive needs and reduce barriers to their receiving and remaining in treatment. However, relatively few substance abuse treatment programs offer specialized services for women, and effectiveness has not been fully evaluated. This article reviews the literature on the extent and effectiveness of substance abuse treatment programming for women and provides an overview of what is known about the components of successful treatment programs for women. Thirty-eight studies of the effect on treatment outcomes of substance abuse treatment programming for women were reviewed. Seven were randomized, controlled trials, and 31 were nonrandomized studies. In our review, six components of substance abuse treatment programming for women were examined: child care, prenatal care, women-only programs, supplemental services and workshops that address women-focused topics, mental health programming, and comprehensive programming. The studies found positive associations between these six components and treatment completion, length of stay, decreased use of substances, reduced mental health symptoms, improved birth outcomes, employment, self-reported health status, and HIV risk reduction. These findings suggest that to improve the future health and well-being of women and their children, there is a continued need for well-designed studies of substance abuse treatment programming for women.

Journal ArticleDOI
TL;DR: The results support previous evidence that religiosity is protective for a number of adolescent health-related outcomes and suggest that further work is warranted to explore the causal mechanisms by which religiosity are protective for adolescents.

Journal ArticleDOI
TL;DR: Both maternal and developmental toxicity of PFOS are demonstrated in the rat and mouse, with a host of birth defects, including cleft palate, anasarca, ventricular septal defect, and enlargement of the right atrium seen.

Journal ArticleDOI
TL;DR: It is reported that CAR and PXR activators differentially regulated the expression of several genes, demonstrating that these two nuclear receptors subserve overlapping but distinct biological functions in human hepatocytes.

Journal ArticleDOI
TL;DR: Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile Acid transport, including the phospholipid flippase MDR2.
Abstract: Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct-ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease.

Journal ArticleDOI
TL;DR: The studies indicate that 17‐β‐trenbolone is a potent androgen and reproductive toxicant in fish and further studies are warranted to assess potential ecological risk.
Abstract: Trenbolone acetate is a synthetic steroid that is extensively used in the United States as a growth promoter in beef cattle. The acetate is administered to livestock via slow-release implants; some is converted by the animal to 17-beta-trenbolone, a relatively potent androgen receptor agonist in mammalian systems. Recent studies indicate that excreted 17-beta-trenbolone is comparatively stable in animal waste, suggesting the potential for exposure to aquatic animals via direct discharge, runoff, or both. However, little is known concerning the toxicity of trenbolone to fish. Our goal was to assess the effects of 17-beta-trenbolone on reproductive endocrinology of the fathead minnow (Pimephales promelas). An in vitro competitive binding study with the fathead minnow androgen receptor demonstrated that 17-beta-trenbolone had a higher affinity for the receptor than that of the endogenous ligand, testosterone. Male and female fish were exposed for 21 d to nominal (target) concentrations of 17-beta-trenbolone ranging from 0.005 to 50 microg/L. Fecundity of the fish was significantly reduced by exposure to measured test concentrations > or = 0.027 microg/ L. The 17-beta-trenbolone was clearly androgenic in vivo at these concentrations, as evidenced by the de novo production in females of dorsal (nuptial) tubercles, structures normally present only on the heads of mature males. Plasma steroid (testosterone and beta-estradiol) and vitellogenin concentrations in the females all were significantly reduced by exposure to 17-beta-trenbolone. The 17-beta-trenbolone also altered reproductive physiology of male fathead minnows, albeit at concentrations much higher than those producing effects in females. Males exposed to 17-beta-trenbolone at 41 microg/L (measured) exhibited decreased plasma concentrations of 11-ketotestosterone and increased concentrations of beta-estradiol and vitellogenin. Overall, our studies indicate that 17-beta-trenbolone is a potent androgen and reproductive toxicant in fish. Given the widespread use of trenbolone acetate as a growth promoter, and relative stability of its metabolites in animal wastes, further studies are warranted to assess potential ecological risk.