A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Melanocortin receptor accessory proteins in adrenal gland physiology and beyond

The melanocortin receptor (MCR) family consists of five G-protein-coupled receptors (MC1R–MC5R) with diverse physiological roles. MC1R controls pigmentation, MC2R is a critical component of the hypothalamic–pituitary–adrenal axis, MC3R and MC4R have a vital role in energy homeostasis and MC5R is involved in exocrine function. The melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are small single-pass transmembrane proteins that have been shown to regulate MCR expression and function. In the adrenal gland, MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency, where inactivating MRAP mutations account for ∼20% of cases. MRAP is highly expressed in both the zona fasciculata and the undifferentiated zone. Expression in the undifferentiated zone suggests that MRAP could also be important in adrenal cell differentiation and/or maintenance. In contrast, the role of adrenal MRAP2, which is highly expressed in the foetal gland, is unclear. The expression of MRAPs outside the adrenal gland is suggestive of a wider physiological purpose, beyond MC2R-mediated adrenal steroidogenesis. In vitro, MRAPs have been shown to reduce surface expression and signalling of all the other MCRs (MC1,3,4,5R). MRAP2 is predominantly expressed in the hypothalamus, a site that also expresses a high level of MC3R and MC4R. This raises the intriguing possibility of a CNS role for the MRAPs

A specific inhibitor of protein kinase CK2 delays gamma-H2Ax foci removal and reduces clonogenic survival of irradiated mammalian cells

<p>Abstract</p> <p>Background</p> <p>The protein kinase CK2 sustains multiple pro-survival functions in cellular DNA damage response and its level is tightly regulated in normal cells but elevated in cancers. Because CK2 is thus considered as potential therapeutic target, DNA double-strand break (DSB) formation and rejoining, apoptosis induction and clonogenic survival was assessed in irradiated mammalian cells upon chemical inhibition of CK2.</p> <p>Methods</p> <p>MRC5 human fibroblasts and WIDR human colon carcinoma cells were incubated with highly specific CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB), or mock-treated, 2 hours prior to irradiation. DSB was measured by pulsed-field electrophoresis (PFGE) as well as gamma-H2AX foci formation and removal. Apoptosis induction was tested by DAPI staining and sub-G1 flow cytometry, survival was quantified by clonogenic assay.</p> <p>Results</p> <p>TBB treatment did not affect initial DNA fragmention (PFGE; up to 80 Gy) or foci formation (1 Gy). While DNA fragment rejoining (PFGE) was not inhibited by the drug, TBB clearly delayed gamma-H2AX foci disappearence during postirradiation incubation. No apoptosis induction could be detected for up to 38 hours for both cell lines and exposure conditions (monotherapies or combination), but TBB treatment at this moderately toxic concentration of 20 μM (about 40% survival) enhanced radiation-induced cell killing in the clonogenic assay.</p> <p>Conclusions</p> <p>The data imply a role of CK2 in gamma-H2AX dephosporylation, most likely through its known ability to stimulate PP2A phosphatase, rather than DSB rejoining. The slight but definite clonogenic radiosensitization by TBB does apparently not result from interference with an apoptosis suppression function of CK2 in these cells but could reflect inhibitor-induced uncoupling of DNA damage response decay from break ligation.</p

Serosurveillance for Livestock Pathogens in Free-Ranging Mule Deer (Odocoileus hemionus)

Routine disease surveillance has been conducted for decades in mule deer (Odocoileus hemionus) in California for pathogens shared between wildlife and domestic ruminants that may have implications for the animal production industry and wildlife health. Deer sampled from 1990 to 2007 (n = 2,619) were tested for exposure to six pathogens: bluetongue virus (BTV), epizootic hemorrhagic disease virus (EHDV), bovine viral diarrhea virus (BVDV), Leptospira spp., Anaplasma spp. and Brucella spp. We evaluated the relationship between exposure to these pathogens and demographic risk factors to identify broad patterns in seroprevalence across a large temporal and spatial scale. The overall seroprevalence for the entire study period was 13.4% for BTV, 16.8% for EHDV, 17.1% for BVDV, 6.5% for Leptospira spp., 0.2% for Brucella spp., and 17% for Anaplasma spp. Antibodies against BTV and EHDV were most prevalent in the deer populations of southern California. Antibodies against Leptospira spp. and Anaplasma spp. were most prevalent in coastal and central northern California whereas antibodies against BVDV were most prevalent in central-eastern and northeastern California. The overall seroprevalence for Anaplasma spp. was slightly lower than detected in previous studies. North and central eastern California contains large tracts of federal land grazed by livestock; therefore, possible contact between deer and livestock could explain the high BVDV seroprevalence found in these areas. Findings from this study will help to establish baseline values for future comparisons of pathogen exposure in deer, inform on long-term trends in deer population health and provide relevant information on the distribution of diseases that are shared between wildlife and livestock