Inorganic Arsenic Concentration in Fish Governed by Trophic Level and Size, not Water Concentration: Implications for Human Health Water Quality Criteria.

In 2019, the Idaho Department of Environmental Quality implemented a paired surface water and fish tissue data collection program to derive a state-specific bioaccumulation factor (BAF) for inorganic arsenic (iAs) as part of the development of new human health water quality criteria (HHWQC). No statistically significant relationship was found between total arsenic (tAs) or iAs in surface water and fish tissue. Fish body weight was the only parameter with a statistically significant effect on iAs concentration in fish tissue. The ratio of iAs to tAs in fish tissue declined significantly with both increasing trophic level and increasing body weight. The decrease in iAs concentration in fish tissue with increasing size and trophic level as well as the decrease in the proportion of tAs that is iAs with increasing trophic level are likely the result of metabolic transformation of iAs to organic As by organisms in each level of the aquatic food web. Although the linear regression-based BAF using the Idaho paired fish and water data best predicted observed iAs fish tissue concentrations compared to several alternative BAFs, it was not statistically significant (p < 0.05) and was a poor predictor (R2 = 0.01) of iAs concentrations in fish tissue. These results illustrate that iAs, and possibly other metals, in the natural environment do not conform with commonly used bioaccumulation models and the paradigm used by the US Environmental Protection Agency for determining HHWQC. These results indicate that modifications to the paradigm are necessary, such as a fish tissue criterion as Idaho has proposed, to assure that public health is protected. Environ Toxicol Chem 2023;42:1542-1552. © 2023 SETAC.

Estimating Sustainable Fish Production: Effect on Fish Consumption Rates Used to Develop Remediation Goals at Contaminated Sediment Sites.

The long-term fish consumption rate (also referred to as the "usual fish consumption rate" [UFCR]) is a critical assumption in the derivation of human health remedial goals for contaminated sediments. At many sites, remedial goals are established using fish consumption rates based on information available from surveys of the general population or of specific highly exposed populations. To be protective of human health, remedial goals are often established using those high-end fish consumption rates. However, high-end fish consumption rates may overestimate the amount of fish that can be sustainably harvested and consumed and, thus, lead to remedial goals that may not be representative of long-term consumption from the contaminated portion of a water body. This paper presents a methodology to estimate the amount of edible fish that can be harvested sustainably from a contaminated sediment site. The methodology requires 1) estimating the total fish productivity of the area of contaminated sediments, 2) estimating the portion of total productivity that can be harvested sustainably, and 3) determining the portion of the sustainable harvest that is edible fish tissue. Estimates of total fish production rate (TFPR) and the proportion of such harvest that can be harvested sustainably rely primarily on available compilations of TFPR and harvest measurements across a range of water bodies throughout the world. Estimates of the fraction of whole fresh fish that is consumed rely on information available from the United States Environmental Protection Agency (USEPA). The methodology is used to develop sustainable UFCRs for 4 hypothetical water bodies with distinct characteristics and to compare the UFCRs to commonly used default fish consumption rates. Estimates of sustainable production provide risk managers valuable perspective about the benefits realized by cleanup of contaminated sediment sites. Integr Environ Assess Manag 2021;17:584-596. © 2020 SETAC.

A urinary microRNA signature can predict the presence of bladder urothelial carcinoma in patients undergoing surveillance.

BACKGROUND: The objective of this study was to determine whether microRNA (miRNA) profiling of urine could identify the presence of urothelial carcinoma of the bladder (UCB) and to compare its performance characteristics to that of cystoscopy. METHODS: In the discovery cohort we screened 81 patients, which included 21 benign controls, 30 non-recurrers and 30 patients with active cancer (recurrers), using a panel of 12 miRNAs. Data analysis was performed using a machine learning approach of a Support Vector Machine classifier with a Student's t-test feature selection procedure. This was trained using a three-fold cross validation approach and performance was measured using the area under the receiver operator characteristic curve (AUC). The miRNA signature was validated in an independent cohort of a further 50 patients. RESULTS: The best predictor to distinguish patients with UCB from non-recurrers was achieved using a combination of six miRNAs (AUC=0.85). This validated in an independent cohort (AUC=0.74) and detected UCB with a high sensitivity (88%) and sufficient specificity (48%) with all significant cancers identified. The performance of the classifier was best in detecting clinically significant disease such as presence of T1 Stage disease (AUC=0.92) and high-volume disease (AUC=0.81). Cystoscopy rates in the validation cohort would have been reduced by 30%. CONCLUSIONS: Urinary profiling using this panel of miRNAs shows promise for detection of tumour recurrence in the surveillance of UCB. Such a panel may be useful in reducing the morbidity and costs associated with cystoscopic surveillance, and now merits prospective evaluation.

Streamlining the assessment of haematuria: 3-year outcomes of a dedicated haematuria clinic.

BACKGROUND: Urgent assessment of haematuria is critical to exclude malignancy. The objective of this study is to report the outcomes of the first 3 years of a dedicated haematuria clinic at the Royal Melbourne Hospital, a Victorian tertiary hospital. METHODS: All patients assessed in the haematuria clinic from April 2010 to April 2013 were included in the analysis. Outcomes were recorded prospectively and analysed retrospectively. RESULTS: A total of 643 patients were seen in the haematuria clinic with non-visible (170, 26%) and visible haematuria (463, 72%) during this time period, all within 28 days of referral being triaged. Sixty-five (10%) patients were diagnosed with urothelial carcinoma, 63 with lower tract disease and two with upper tract urothelial carcinoma and another five (1%) patients with other tumours. Thirty out of 63 (48%) of the bladder urothelial carcinomas were invasive or high-grade. Two hundred and sixty-seven (42%) patients were discharged from the clinic after a single point of contact. One hundred and fifty-three (24%) patients were referred for further definitive management of suspected pathology. Two hundred and twenty-three (34%) patients were referred to outpatients clinic for further investigations. Urothelial carcinoma was diagnosed more often in males, older patients and patients with visible haematuria. CONCLUSION: The Royal Melbourne Hospital haematuria clinic has served as an effective tool for rapid, streamlined assessment of patients presenting with haematuria. Follow-up of investigations by nurses and moving towards a 'one-stop' approach are helping to further decrease the number of patients requiring a second clinic visit.

Molecular biomarkers for predicting outcomes in urothelial carcinoma of the bladder.

Molecular biomarkers are used routinely in the clinical management of several tumours such as prostate, colon, ovarian and pancreatic cancer but management decisions in bladder cancer remain dependent on clinical and pathological criteria, which are limited in their ability to predict outcomes. Molecular markers are urgently needed in detection, surveillance and prognostication of bladder cancer as well as to predict treatment response to intravesical and systemic therapies. Advances in cancer genomics and platforms for biomarker profiling have led to a plethora of biomarkers, which must now be rigorously validated in the clinical setting. Pre-clinical and clinical studies exploring the role of emerging targeted therapies to risk stratify and reduce cancer progression are also needed.

Gene-based urinary biomarkers for bladder cancer: an unfulfilled promise?

OBJECTIVE: Noninvasive biomarkers are used routinely in the clinical management of several cancers but bladder cancer detection and surveillance remains dependent on invasive procedures such as cystoscopy. No validated biomarker currently exists in routine clinical practice other than cytology. Gene-based testing has shown great promise for biomarker profiling and this review addresses the current state of biomarker research in bladder cancer. MATERIALS AND METHODS: A comprehensive review of all published literature on urinary biomarkers from 1970 - 2012 was conducted in PubMed. Keywords used alone or in combination were bladder cancer, diagnosis, surveillance, urinary biomarker, molecular biomarkers, methylation, gene expression, single nucleotide polymorphism and microRNA. The cited references of the manuscripts included in the review were also screened. RESULTS: We have reviewed various strategies currently used for gene-based biomarker profiling of bladder cancer. We have comprehensively summarized the performance of several biomarkers in the diagnosis and surveillance of bladder cancer. Finally we have identified biomarkers that have shown potential and now deserve the opportunity to be validated in the clinical setting. CONCLUSION: Several gene-based urinary biomarkers have demonstrated promise in initial studies, which now need to be rigorously validated in the clinical setting for them to be translated into clinically useful tests in diagnosis, surveillance or risk-stratification of bladder cancer.

An adaptive, comprehensive monitoring strategy for chemicals of emerging concern (CECs) in California's Aquatic Ecosystems.

A scientific advisory panel was convened by the State of California to recommend monitoring for chemicals of emerging concern (CECs) in aquatic systems that receive discharge of municipal wastewater treatment plant (WWTP) effluent and stormwater runoff. The panel developed a risk-based screening framework that considered environmental sources and fate of CECs observed in receiving waters across the State. Using existing occurrence and risk threshold data in water, sediment, and biological tissue, the panel applied the framework to identify a priority list of CECs for initial monitoring in three representative receiving water scenarios. The initial screening list of 16 CECs identified by the panel included consumer and commercial chemicals, flame retardants, pesticides, pharmaceuticals and personal care products, and natural hormones. The panel designed an iterative, phased strategy with interpretive guidelines that direct and update management actions commensurate with potential risk identified using the risk-based framework and monitoring data. Because of the ever-changing nature of chemical use, technology, and management practices, the panel offered recommendations to improve CEC monitoring, including development of bioanalytical screening methods whose responses integrate exposure to complex mixtures and that can be linked to higher-order effects; development or refinement of models that predict the input, fate, and effects of future chemicals; and filling of key data gaps on CEC occurrence and toxicity. Finally, the panel stressed the need for adaptive management, allowing for future review of, and if warranted, modifications to the strategy to incorporate the latest science available to the water resources community.

Nurse-led flexible cystoscopy in Australia: initial experience and early results.

OBJECTIVE: • To present our initial experience implementing a nurse-led flexible cystoscopy (NLFC) service in a Victorian tertiary hospital and our initial results from that service, as NLFC has developed over the past decade with reports suggesting that adequately trained nurses can undertake FC competently. PATIENTS AND METHODS: • We describe the implementation of a NLFC service including approval, funding, nurses' training, and protocols. • Outcomes of all patients having a NLFC or subsequent interventions were recorded prospectively and analysed retrospectively. • To gauge patients' response to NLFC, an anonymous feedback questionnaire was administered to 60 consecutive participating patients in the recovery unit. • The effect of NLFC on waiting times was determined from surgical scheduling records. RESULTS: • In all, 272 patients had 720 NLFC done over a 2-year period. In all, 150 (21%) FCs had a suspected bladder cancer recurrence and were referred for a rigid cystoscopy. Of those, 83 (58%) revealed a recurrence comprising of 14 (17%) high-grade lesions, 45 (54%) low-grade lesions and 24 (29%) were diathermied without a biopsy. In all, 41 (27%) had benign pathology on biopsy and 21 (14%) had normal rigid cystoscopy. • There were two significant adverse events. • There was a 65% reduction in the waiting list for surveillance FC after introduction of the service. • Of 60 patients who completed the feedback questionnaire, 95% reported that they were given enough information by the nurses, 92% had all their questions answered satisfactorily and 97% had enough confidence and trust in the nurse. In all, 90% had a positive perception of the service overall and 93% were happy to have a FC performed by a nurse rather than a doctor. CONCLUSIONS: • Results from our NLFC audit compare favourably with other published reports. NLFC is a safe and feasible option when established alongside strong departmental support, comprehensive nurses' training according to established guidelines, service supervision by a designated consultant and regular audits. • NLFC clinics can provide an efficient service and excellent continuity of care for patients with non-muscle-invasive bladder cancer.

Endocrine disruption due to estrogens derived from humans predicted to be low in the majority of U.S. surface waters.

In an effort to assess the combined risk estrone (E1), 17ß-estradiol (E2), 17α-ethinyl estradiol (EE2), and estriol (E3) pose to aquatic wildlife across United States watersheds, two sets of predicted-no-effect concentrations (PNECs) for significant reproductive effects in fish were compared to predicted environmental concentrations (PECs). One set of PNECs was developed for evaluation of effects following long-term exposures. A second set was derived for short-term exposures. Both sets of PNECs are expressed as a 17ß-estradiol equivalent (E2-eq), with 2 and 5 ng/L being considered the most likely levels above which fish reproduction may be harmed following long-term and short-term exposures, respectively. A geographic information system-based water quality model, Pharmaceutical Assessment and Transport Evaluation (PhATE™), was used to compare these PNECs to mean and low flow concentrations of the steroid estrogens across 12 U.S. watersheds. These watersheds represent approximately 19% of the surface area of the 48 North American states, contain 40 million people, and include over 44,000 kilometers of rivers. This analysis determined that only 0.8% of the segments (less than 1.1% of kilometers) of these watersheds would have a mean flow E2-eq concentration exceeding the long-term PNEC of 2.0 ng/L; only 0.5% of the segments (less than 0.8% of kilometers) would have a critical low flow E2-eq exceeding the short-term PNEC of 5 ng/L. Those few river segments where the PNECs were exceeded were effluent dominated, being either headwater streams with a publicly owned treatment works (POTW), or flowing through a highly urbanized environment with one or several POTWs. These results suggest that aquatic species in most U.S. surface waters are not at risk from steroid estrogens that may be present as a result of human releases.

Predicted-no-effect concentrations for the steroid estrogens estrone, 17ß-estradiol, estriol, and 17α-ethinylestradiol.

The authors derive predicted-no-effect concentrations (PNECs) for the steroid estrogens (estrone [E1], 17ß-estradiol [E2], estriol [E3], and 17α-ethinylestradiol [EE2]) appropriate for use in risk assessment of aquatic organisms. In a previous study, they developed a PNEC of 0.35 ng/L for EE2 from a species sensitivity distribution (SSD) based on all available chronic aquatic toxicity data. The present study updates that PNEC using recently published data to derive a PNEC of 0.1 ng/L for EE2. For E2, fish were the most sensitive taxa, and chronic reproductive effects were the most sensitive endpoint. Using the SSD methodology, we derived a PNEC of 2 ng/L for E2. Insufficient data were available to construct an SSD for E1 or E3. Therefore, the authors used in vivo vitellogenin (VTG) induction studies to determine the relative potency of the steroid estrogens to induce VTG. Based on the relative differences between in vivo VTG induction, they derive PNECs of 6 and 60 ng/L for E1 and E3, respectively. Thus, for long-term exposures to steroid estrogens in surface water (i.e., >60 d), the PNECs are 6, 2, 60, and 0.1 ng/L for E1, E2, E3, and EE2, respectively. Higher PNECs are recommended for short-term (i.e., a few days or weeks) exposures.

Predicting concentrations of trace organic compounds in municipal wastewater treatment plant sludge and biosolids using the PhATE™ model.

This article presents the capability expansion of the PhATE™ (pharmaceutical assessment and transport evaluation) model to predict concentrations of trace organics in sludges and biosolids from municipal wastewater treatment plants (WWTPs). PhATE was originally developed as an empirical model to estimate potential concentrations of active pharmaceutical ingredients (APIs) in US surface and drinking waters that could result from patient use of medicines. However, many compounds, including pharmaceuticals, are not completely transformed in WWTPs and remain in biosolids that may be applied to land as a soil amendment. This practice leads to concerns about potential exposures of people who may come into contact with amended soils and also about potential effects to plants and animals living in or contacting such soils. The model estimates the mass of API in WWTP influent based on the population served, the API per capita use, and the potential loss of the compound associated with human use (e.g., metabolism). The mass of API on the treated biosolids is then estimated based on partitioning to primary and secondary solids, potential loss due to biodegradation in secondary treatment (e.g., activated sludge), and potential loss during sludge treatment (e.g., aerobic digestion, anaerobic digestion, composting). Simulations using 2 surrogate compounds show that predicted environmental concentrations (PECs) generated by PhATE are in very good agreement with measured concentrations, i.e., well within 1 order of magnitude. Model simulations were then carried out for 18 APIs representing a broad range of chemical and use characteristics. These simulations yielded 4 categories of results: 1) PECs are in good agreement with measured data for 9 compounds with high analytical detection frequencies, 2) PECs are greater than measured data for 3 compounds with high analytical detection frequencies, possibly as a result of as yet unidentified depletion mechanisms, 3) PECs are less than analytical reporting limits for 5 compounds with low analytical detection frequencies, and 4) the PEC is greater than the analytical method reporting limit for 1 compound with a low analytical detection frequency, possibly again as a result of insufficient depletion data. Overall, these results demonstrate that PhATE has the potential to be a very useful tool in the evaluation of APIs in biosolids. Possible applications include: prioritizing APIs for assessment even in the absence of analytical methods; evaluating sludge processing scenarios to explore potential mitigation approaches; using in risk assessments; and developing realistic nationwide concentrations, because PECs can be represented as a cumulative probability distribution. Finally, comparison of PECs to measured concentrations can also be used to identify the need for fate studies of compounds of interest in biosolids.

An assessment of potential exposure and risk from estrogens in drinking water.

BACKGROUND: Detection of estrogens in the environment has raised concerns in recent years because of their potential to affect both wildlife and humans. OBJECTIVES: We compared exposures to prescribed and naturally occurring estrogens in drinking water to exposures to naturally occurring background levels of estrogens in the diet of children and adults and to four independently derived acceptable daily intakes (ADIs) to determine whether drinking water intakes are larger or smaller than dietary intake or ADIs. METHODS: We used the Pharmaceutical Assessment and Transport Evaluation (PhATE) model to predict concentrations of estrogens potentially present in drinking water. Predicted drinking water concentrations were combined with default water intake rates to estimate drinking water exposures. Predicted drinking water intakes were compared to dietary intakes and also to ADIs. We present comparisons for individual estrogens as well as combined estrogens. RESULTS: In the analysis we estimated that a child's exposures to individual prescribed estrogens in drinking water are 730-480,000 times lower (depending upon estrogen type) than exposure to background levels of naturally occurring estrogens in milk. A child's exposure to total estrogens in drinking water (prescribed and naturally occurring) is about 150 times lower than exposure from milk. Adult margins of exposure (MOEs) based on total dietary exposure are about 2 times smaller than those for children. Margins of safety (MOSs) for an adult's exposure to total prescribed estrogens in drinking water vary from about 135 to > 17,000, depending on ADI. MOSs for exposure to total estrogens in drinking water are about 2 times lower than MOSs for prescribed estrogens. Depending on the ADI that is used, MOSs for young children range from 28 to 5,120 for total estrogens (including both prescribed and naturally occurring sources) in drinking water. CONCLUSIONS: The consistently large MOEs and MOSs strongly suggest that prescribed and total estrogens that may potentially be present in drinking water in the United States are not causing adverse effects in U.S. residents, including sensitive subpopulations.

Experimental endotoxemia induces adipose inflammation and insulin resistance in humans.

OBJECTIVE: An emerging model of metabolic syndrome and type 2 diabetes is of adipose dysfunction with leukocyte recruitment into adipose leading to chronic inflammation and insulin resistance (IR). This study sought to explore potential mechanisms of inflammatory-induced IR in humans with a focus on adipose tissue. RESEARCH DESIGN AND METHODS: We performed a 60-h endotoxemia protocol (3 ng/kg intravenous bolus) in healthy adults (n = 20, 50% male, 80% Caucasian, aged 27.3 +/- 4.8 years). Before and after endotoxin, whole-blood sampling, subcutaneous adipose biopsies, and frequently sampled intravenous glucose tolerance (FSIGT) testing were performed. The primary outcome was the FSIGT insulin sensitivity index (S(i)). Secondary measures included inflammatory and metabolic markers and whole-blood and adipose mRNA and protein expression. RESULTS: Endotoxemia induced systemic IR as demonstrated by a 35% decrease in S(i) (3.17 +/- 1.66 to 2.06 +/- 0.73 x 10(-4) [microU * ml(-1) * min(-1)], P < 0.005), while there was no effect on pancreatic beta-cell function. In adipose, endotoxemia suppressed insulin receptor substrate-1 and markedly induced suppressor of cytokine signaling proteins (1 and 3) coincident with local activation of innate (interleukin-6, tumor necrosis factor) and adaptive (monocyte chemoattractant protein-1 and CXCL10 chemokines) inflammation. These changes are known to attenuate insulin receptor signaling in model systems. CONCLUSIONS: We demonstrate, for the first time in humans, that acute inflammation induces systemic IR following modulation of specific adipose inflammatory and insulin signaling pathways. It also provides a rationale for focused mechanistic studies and a model for human proof-of-concept trials of novel therapeutics targeting adipose inflammation in IR and related consequences in humans.

Exposure assessment of 17alpha-ethinylestradiol in surface waters of the United States and Europe.

An evaluation of measured and predicted concentrations of 17-ethinylestradiol in surface waters of the United States and Europe was conducted to develop expected long-term exposure concentrations for this compound. Measured environmental concentrations (MECs) in surface waters were identified from the literature. Predicted environmental concentrations (PECs) were generated for European and U.S. watersheds using the GREAT-ER and PhATE models, respectively. The majority of MECs are nondetect and generally consistent with model PECs and conservative mass balance calculations. However, the highest MECs are not consistent with concentrations derived from conservative (worst-case) mass balance estimates or model PECs. A review of analytical methods suggests that tandem or high-resolution mass spectrometry methods with extract cleanup result in lower detection limits and lower reported concentrations consistent with model predictions and bounding estimates. Based on model results using PhATE and GREAT-ER, the 90th-percentile low-flow PECs in surface water are approximately 0.2 and 0.3 ng/L for the United States and Europe, respectively. These levels represent conservative estimates of long-term exposure that can be used for risk assessment purposes. Our analysis also indicates that average concentrations are one to two orders of magnitude lower than these 90th-percentile estimates. Higher reported concentrations (e.g., greater than the 99th-percentile PEC of approximately 1 ng/L) could result from methodological problems or unusual environmental circumstances; however, such concentrations are not representative of levels generally found in the environment, warrant special scrutiny, and are not appropriate for use in risk assessments of long-term exposures.

Derivation of an aquatic predicted no-effect concentration for the synthetic hormone, 17 alpha-ethinyl estradiol.

17alpha-Ethinyl estradiol (EE2) is a synthetic estrogen widely used in combination with other steroid hormones in oral contraceptives and in the contraceptive patch. EE2 has been detected in sewage treatment plant effluents in the low nanogram -per-liter range and occasionally in surface waters in the U.S., U.K., Canada, Brazil, Germany, and elsewhere. The mode of action is receptor-mediated, and estrogen receptors exist in mammals and other vertebrates. A large number of studies on the effects of EE2 on aquatic organisms exist. One hundred English language studies published between 1994 and 2007, one as yet unpublished study, and findings published in conference proceedings (in German) were compared to published data quality criteria to identify the most relevant studies for deriving a predicted no-effect concentration (PNEC). Reproduction in fish was identified as the most sensitive end point in aquatic species. A species sensitivity distribution was constructed using no observed effect concentrations (NOECs) for reproductive effects from 39 papers in 26 species, resulting in a median hazardous concentration at which 5% of the species tested are affected (HC5,50) of 0.35 ng/L. After comparing this HC5,50 to all of the laboratory and field-derived toxicity information available for EE2, we recommend using 0.35 ng/L as the PNEC for EE2 in surface water. This PNEC is below 95% of the existing NOECs for effects on reproduction and is also below virtually all of the NOECs for vitellogenin induction in the key fish reproduction studies.

Innate immunity modulates adipokines in humans.

CONTEXT: Chronic inflammation converges in type 2 diabetes and atherosclerosis. Modulation of adipokine signaling by innate immunity in humans is of considerable interest given the role of adipokines in insulin resistance and atherosclerosis. OBJECTIVE: The aim of the study was to examine effects of low-grade endotoxemia, a model of human inflammation, on adipokines in vivo. DESIGN/SETTING: An open-label, placebo-controlled, fixed-sequence clinical study was conducted at a General Clinical Research Center. PATIENTS: There were 20 healthy male (50%) and female volunteers aged 18-40 yr. INTERVENTION: Serial blood sampling and adipose biopsies were performed for 24 h before and after iv bolus endotoxin [lipopolysaccharide (LPS), 3 ng/kg]. MAIN OUTCOME MEASURES: We measured plasma leptin, adiponectin, resistin, soluble leptin receptor, cytokines, insulin, and glucose; distribution of adiponectin among multimeric complexes; whole blood, monocyte and adipose mRNA for adipokines and their receptors. RESULTS: LPS induced fever, blood, and adipose TNF and IL-6 and increased homeostasis model assessment of insulin resistance. These were associated with increases in plasma leptin (from 4.1 +/- 1.1 to 6.1 +/- 1.9 ng/ml in men; 21.1 +/- 4.4 to 27.4 +/- 4.7 ng/ml in women; P < 0.005), doubling of the leptin:soluble leptin receptor ratio, and marked induction of whole blood resistin mRNA (13.7 +/- 7.3-fold; P < 0.001) and plasma resistin (8.5 +/- 2.75 to 43.2 +/- 15.3 ng/ml; P < 0.001). Although total adiponectin levels and low and high molecular weight adiponectin complexes were unaltered by LPS treatment, whole blood mRNA for adiponectin receptors 1 (49%; P < 0.005) and 2 (65%; P < 0.001) was suppressed. CONCLUSIONS: Modulation of adipokine signaling may contribute to the insulin resistant, atherogenic state associated with human inflammatory syndromes. Targeting of individual adipokines or their upstream regulation may prove effective in preventing acute and chronic inflammation-related metabolic complications.

Human pharmaceuticals in US surface waters: a human health risk assessment.

The detection of low levels of pharmaceuticals in rivers and streams, drinking water, and groundwater has raised questions as to whether these levels may affect human health. This report presents human health risk assessments for 26 active pharmaceutical ingredients (APIs) and/or their metabolites, representing 14 different drug classes, for which environmental monitoring data are available for the United States. Acceptable daily intakes (ADIs) are derived using the considerable data that are available for APIs. The resulting ADIs are designed to protect potentially exposed populations, including sensitive sub-populations. The ADIs are then used to estimate predicted no effect concentrations (PNECs) for two sources of potential human exposure: drinking water and fish ingestion. The PNECs are compared to measured environmental concentrations (MECs) from the published literature and to maximum predicted environmental concentrations (PECs) generated using the PhATE model. The PhATE model predictions are made under conservative assumptions of low river flow and no depletion (i.e., no metabolism, no removal during wastewater or drinking water treatment, and no instream depletion). Ratios of MECs to PNECs are typically very low and consistent with PEC to PNEC ratios. For all 26 compounds, these low ratios indicate that no appreciable human health risk exists from the presence of trace concentrations of these APIs in surface water and drinking water.

Autoaugmentation gastrocystoplasty: further studies of the sheep model.

OBJECTIVE: To report our experience with autoaugmentation gastrocystoplasty (AAGC, reported to result in an inconsistent augmentation effect in children) in a sheep model, specifically addressing issues of surgical techniques and postoperative bladder drainage that may affect the augmentation result, as many factors have been implicated in the poor outcome. MATERIALS AND METHODS: Ten 6-month-old male lambs had a suprapubic catheter placed by an open laparotomy. Intraoperative urodynamics were evaluated before and after detrusorotomy for autoaugmentation and after completing AAGC. The bladder was drained with no distension for 1 week after surgery and the urodynamic evaluation repeated on control and experimental animals 6 months after surgery. The animals were then killed and the bladders evaluated for gastric flap survival and histological changes in the native bladder and augmentation segments. The results were analysed using a one-sided Student's t-test. RESULTS: The median (range) native bladder volume at leak-point pressure was 110 (40-490) mL. Intraoperative bladder volumes after completing AAGC confirmed adequate augmentation segments in all animals. The urodynamic evaluation at 6 months after AAGC showed increases in bladder volumes in nine of 10 animals (0-1336 mL), significantly greater than the increase in volume in the control sheep (median 337.5 vs 115.3 mL; P < 0.05). The bladder compliance (volume/pressure at leak capacity) 6 months after AAGC was slightly better but not significantly higher than in controls (median 17.3 vs 10.8 mL/cmH(2)O; P > 0.05). The median (range) ratio of surviving gastric flap to native bladder circumferences was 34.5 (31-53)%. Histology showed scarring of the submucosal layer in one of 10 augmentation segments and normal urothelium in all bladders. CONCLUSION: AAGC produces reliable bladder augmentation and excellent bladder compliance in a sheep model of a non-neurogenic bladder. The gastric flap survived well and there was no bladder wall separation with simple postoperative catheter drainage.