Perfluorooctanoic acid exposure triggers oxidative stress in the mouse pancreas

• PFOA triggers focal ductal hyperplasia following 7 day exposure. • PFOA exposure increases 8-iso-PGF2α levels in the pancreas. • Antioxidant gene expression is upregulated in the pancreas following PFOA exposure. , Perfluorooctanoic acid (PFOA) is used in the manufacture of many industrial and commercial products. PFOA does not readily decompose in the environment, and is biologically persistent. Human epidemiologic and animal studies suggest that PFOA exposure elicits adverse effects on the pancreas. While multiple animal studies have examined PFOA-mediated toxicity in the liver, little is known about the potential adverse effects of PFOA on the pancreas. To address this, we treated C57Bl/6 mice with vehicle, or PFOA at doses of 0.5, 2.5 or 5.0 mg/kg BW/day for 7 days. Significant accumulation of PFOA was found in the serum, liver and pancreas of PFOA-treated animals. Histopathologic examination of the pancreas revealed focal ductal hyperplasia in mice treated with 2.5 and 5.0 mg/kg BW/day PFOA, while inflammation was observed only in the high dose group. Elevated serum levels of amylase and lipase were observed in the 2.5 mg/kg BW/day PFOA treatment group. In addition, PFOA exposure resulted in a dose-dependent increase in the level of the lipid peroxidation product 8-iso-PGF2α and induction of the antioxidant response genes Sod1, Sod2, Gpx2 and Nqo1. Our findings provide additional evidence that the pancreas is a target organ for PFOA-mediated toxicity and suggest that oxidative stress may be a mechanism through which PFOA induces histopathological changes in the pancreas

Neurofibromin Deficient Myeloid Cells are Critical Mediators of Aneurysm Formation In Vivo

Background Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity in circulating hematopoietic and vascular wall cells, which are critical for maintaining vessel wall homeostasis. NF1 patients have evidence of chronic inflammation resulting in development of premature cardiovascular disease, including arterial aneurysms, which may manifest as sudden death. However, the molecular pathogenesis of NF1 aneurysm formation is unknown. Method and Results Utilizing an angiotensin II-induced aneurysm model, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/−) enhanced aneurysm formation with myeloid cell infiltration and increased oxidative stress in the vessel wall. Using lineage-restricted transgenic mice, we show loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/− aneurysm phenotype in vivo. Finally, oral administration of simvastatin or the antioxidant apocynin, reduced aneurysm formation in Nf1+/− mice. Conclusion These data provide genetic and pharmacologic evidence that Nf1+/− myeloid cells are the cellular triggers for aneurysm formation in a novel model of NF1 vasculopathy and provide a potential therapeutic target

IL-10R Blockade during Chronic Schistosomiasis Mansoni Results in the Loss of B Cells from the Liver and the Development of Severe Pulmonary Disease

In schistosomiasis patients, parasite eggs trapped in hepatic sinusoids become foci for CD4+ T cell-orchestrated granulomatous cellular infiltrates. Since the immune response is unable to clear the infection, the liver is subjected to ongoing cycles of focal inflammation and healing that lead to vascular obstruction and tissue fibrosis. This is mitigated by regulatory mechanisms that develop over time and which minimize the inflammatory response to newly deposited eggs. Exploring changes in the hepatic inflammatory infiltrate over time in infected mice, we found an accumulation of schistosome egg antigen-specific IgG1-secreting plasma cells during chronic infection. This population was significantly diminished by blockade of the receptor for IL-10, a cytokine implicated in plasma cell development. Strikingly, IL-10R blockade precipitated the development of portal hypertension and the accumulation of parasite eggs in the lungs and heart. This did not reflect more aggressive Th2 cell responsiveness, increased hepatic fibrosis, or the emergence of Th1 or Th17 responses. Rather, a role for antibody in the prevention of severe disease was suggested by the finding that pulmonary involvement was also apparent in mice unable to secrete class switched antibody. A major effect of anti-IL-10R treatment was the loss of a myeloid population that stained positively for surface IgG1, and which exhibited characteristics of regulatory/anti-inflammatory macrophages. This finding suggests that antibody may promote protective effects within the liver through local interactions with macrophages. In summary, our data describe a role for IL-10-dependent B cell responses in the regulation of tissue damage during a chronic helminth infection

A randomized, controlled trial of the effect of rilpivirine versus efavirenz on cardiovascular risk in healthy volunteers.

Objectives: The HIV NNRTI rilpivirine is being evaluated as a possible agent for HIV pre-exposure prophylaxis. We have recently shown that the NNRTI efavirenz may impair endothelial function assessed as flow-mediated dilation (FMD), but whether this impairment is also found with rilpivirine is unknown. We sought to compare cardiovascular risk profiles between efavirenz and rilpivirine in healthy volunteers. Methods: We performed a prospective, randomized, open-label trial in 40 HIV-uninfected healthy volunteers who were randomized 1: 1 to either efavirenz or rilpivirine. Vascular indices, metabolic parameters, inflammatory biomarkers and oxidative stress were measured before and after 4 weeks of treatment. This study is registered at ClinicalTrials.gov (NCT01585038). Results: There were no significant differences in 4 week mean (SD) changes in FMD between efavirenz and rilpivirine [0.089 (3.65)% versus 0.63 (2.42)%; P = 0.77]. There were also no significant differences in 4 week changes in high-sensitivity C-reactive protein

Measuring Biophysical and Psychological Stress Levels Following Visitation to Three Locations with Differing Levels of Nature

Visitation to natural environments has been linked to psychological stress reduction. Although most stress-related research has relied on self-report formats, a growing number of studies now incorporate biological stress-related hormones and catalysts, such as cortisol and α-amylase, to measure levels of stress. Presented here is a protocol to examine the effects on levels of biophysical and psychological stress following visitation to three different locations with differing levels of nature. Biophysical and self-reported psychological stress levels are measured immediately upon entering the selected locations and just prior to the visitors leaving the site. Using a "drool" method, the biophysical measure consists of 1-2 mL samples of saliva provided by study subjects upon entry to one of three study locations. As prescribed by extant literature, the saliva is collected within a 45 minute time frame following the end of the visitor’s engagement at the location. Following saliva collection, the samples are labeled and transported to a biological lab. Cortisol is the biophysical variable of interest in this study and measured using an ELISA process with a TECAN plate reader. To measure self-reported stress, the Perceived Stress Questionnaire (PSQ), which reports levels of worry, tension, joy, and perceived demands. Data are collected at all three sites in the late afternoon through early evening. When compared across all three settings, stress levels, as measured by both the biological markers and self-reports, are significantly lower after visitation to the most natural setting

Short-term changes after a weight reduction intervention in advanced diabetic nephropathy

BACKGROUND AND OBJECTIVES: Obesity precedes and is strongly linked to the development of type 2 diabetic nephropathy in most patients, yet little is known about the effects of weight reduction on this disease. This study aimed to establish proof of concept for the hypothesis that weight reduction ameliorates diabetic nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Six obese individuals with advanced diabetic nephropathy (estimated GFR 30 mg/d) currently taking a renin-aldosterone axis inhibitor underwent a 12-week very low calorie ketogenic weight reduction diet with encouragement of exercise between March and September 2012. Albuminuria and other parameters of kidney health were the main outcome measures. RESULTS: There was a 12% reduction in weight (median 118.5 versus 104.3 kg, P=0.03). The intervention was associated with a 36% reduction in albuminuria that did not reach statistical significance (2124 versus 1366 mg/24 h, P=0.08) and significant reductions in the filtration markers serum creatinine (3.54 versus 3.13 mg/dl, P<0.05) and cystatin C (2.79 versus 2.46 mg/l, P<0.05). Improvements were also noted for the diabetes markers fasting glucose (166 versus 131 mg/dl, P<0.05), fasting insulin (26.9 versus 10.4 μU/ml, P<0.05), and insulin resistance (9.6 versus 4.2, P=0.03). Physical function, general health, and the number of diabetes medications also showed statistically significant signs of improvement. CONCLUSIONS: After a short-term intensive weight reduction intervention in patients with advanced diabetic nephropathy, improvements were observed in markers of glomerular filtration, diabetes status, and risk factors for kidney disease progression, as well as other general indicators of health and well-being