Based on the seminal observation by Cannon and Nedergaard 1 that human PET scans sometimes depicted a symmetric cold induced uptake of FDG-glucose, three independent studies, published in April 2009, demonstrated metabolically highly active brown adipose tissue (BAT) in adult humans [2][3][4] . Subsequent investigations demonstrated an inverse association of obesity and type 2 diabetes mellitus and the presence of active BAT [5][6][7] . A unique characteristic of BAT is the expression of uncoupling protein 1 (UCP1, also known as thermogenin). Activation of this transmembrane protein by fatty acids in response to adrenergic signaling short-circuits the inner mitochondrial membrane's proton gradient thereby uncoupling oxidative phosphorylation from ATP synthesis. Hence, chemical energy stored in the gradient is dissipated as heat allowing for efficient direct thermogenesis without shivering 8 . This adaptive defense against cold has been examined extensively in rodents and many aspects of BAT development and function have been elucidated. In rodents it is evident 3 that not only the distinct thermogenic BAT organ located in the interscapular region (iBAT) consists of brown adipocytes, but that a second type of brown adipocytes, so-called beige or brite cells can appear in white adipose tissue (WAT) depots in response to cold or 3-adrenergic stimuli 9,10 . Recently, lineage tracing experiments revealed that the two cell types have a different developmental origin 11 . While classical brown adipocytes and skeletal muscle cells arise from precursors in the dermomyotome 12 , beige/brite cells seem to originate from endothelial and perivascular cells within WAT depots [13][14][15] . A recent study by Wu et al suggests that the previously described depots of human BAT are of the beige/brite type and raises the question whether humans altogether lack classical brown adipocytes 16 , this has also been the topic of a recent review 17 . Histomorphological studies performed in the 1970s indicated the existence of brown adipocytes within the interscapular region in human infants and that these disappeared with age 18 . Using a combination of high resolution imaging techniques and morphological and biochemical analyses, we tested the hypothesis that human infants, like small mammals, possess an anatomically distinguishable iBAT depot consisting of classical brown adipocytes, a cell type so far not proven to exist in humans.In an attempt to visualize potential iBAT in humans we performed post mortem MR imaging of eight human infants. Using the fat fraction method 19 we did not only identify BAT depots in the supraclavicular region, but importantly also a fat depot in the interscapular region presenting with an intermediate fat fraction as opposed to the high fat fraction of the surrounding subcutaneous WAT (Supplementary Fig. 1). Using a three dimensional reconstruction we were able to compute the volume of the tissue depot with an average (±SD) volume of 3.6±2.4 ml. Figure 1 displays a representative reconstruction of the iBAT...

Ninety percent of patients with minor head injury (MHI) who have cranial computed tomography (CCT) under the present clinical decision rules have normal scans. Serum concentrations of the astroglial protein S-100B were recently found to provide useful information, but these studies were too small to provide a statistically safe basis for changing the present rule. We have investigated whether S-100B concentrations in patients with MHI can provide additional information to improve indication of the need for an initial CCT scan. One thousand three hundred nine patients with MHI were enrolled in this prospective, multicenter study. All had a CCT scan to confirm diagnosis in accordance with the present clinical decision rules. S-100B was measured in serum samples obtained upon admission. Data were analyzed using contingency table and receiver operating characteristic curve and compared with those for healthy donors (n = 540) and with those for patients with moderate to severe head injury (n = 55). Of the 1309 patients studied, 93 exhibited trauma-relevant intracerebral lesions on the CCT scan (CCT+). With a cutoff limit of 0.10-microg/L S-100B (95th percentile of values in healthy volunteers), CCT+ patients were identified with a sensitivity level of 99% (95% confidence interval, 96% - 100%) and a specificity level of 30% (95% confidence interval, 29% - 31%). Adding the measurement of S-100B concentration to the clinical decision rules for a CCT scan in patients with MHI could allow a 30% reduction in scans. A prospective study of the clinical value of S-100B measurement in such patients is now under way.

Mitochondrial Ca2+ (mCa2+) uptake mediated by the mitochondrial calcium uniporter (MCU) plays a critical role in signal transduction, bioenergetics, and cell death, and its dysregulation is linked to several human diseases. In this study, we report a new ruthenium complex Ru265 that is cell-permeable, minimally toxic, and highly potent with respect to MCU inhibition. Cells treated with Ru265 show inhibited MCU activity without any effect on cytosolic Ca2+ dynamics and mitochondrial membrane potential (ΔΨm). Dose-dependent studies reveal that Ru265 is more potent than the currently employed MCU inhibitor Ru360. Site-directed mutagenesis of Cys97 in the N-terminal domain of human MCU ablates the inhibitory activity of Ru265, suggesting that this matrix-residing domain is its target site. Additionally, Ru265 prevented hypoxia/reoxygenation injury and subsequent mitochondrial dysfunction, demonstrating that this new inhibitor is a valuable tool for studying the functional role of the MCU in intact biological models.

BackgroundThe IL23R gene has been identified as a susceptibility gene for inflammatory bowel disease (IBD) in the North American population. The aim of our study was to test this association in a large German IBD cohort and to elucidate potential interactions with other IBD genes as well as phenotypic consequences of IL23R variants.MethodsGenomic DNA from 2670 Caucasian individuals including 833 patients with Crohn's disease (CD), 456 patients with ulcerative colitis (UC), and 1381 healthy unrelated controls was analyzed for 10 IL23R SNPs. Genotyping included the NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C→T) and SLC22A5/OCTN2 (–207 G→C).ResultsAll IL23R gene variants analyzed displayed highly significant associations with CD. The strongest association was found for the SNP rs1004819 [P = 1.92×10−11; OR 1.56; 95 % CI (1.37–1.78)]. 93.2% of the rs1004819 TT homozygous carriers as compared to 78% of CC wildtype carriers had ileal involvement [P = 0.004; OR 4.24; CI (1.46–12.34)]. The coding SNP rs11209026 (p.Arg381Gln) was protective for CD [P = 8.04×10−8; OR 0.43; CI (0.31–0.59)]. Similar, but weaker associations were found in UC. There was no evidence for epistasis between the IL23R gene and the CD susceptibility genes CARD15 and SLC22A4/5.Conclusion IL23R is an IBD susceptibility gene, but has no epistatic interaction with CARD15 and SLC22A4/5. rs1004819 is the major IL23R variant associated with CD in the German population, while the p.Arg381Gln IL23R variant is a protective marker for CD and UC.

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ATG16L1 is a CD susceptibility gene without epistatic interaction with other CD susceptibility genes and is not upregulated in intestinal inflammation.

Persistent postoperative hypoaldosteronism with hyperkalemia occurs in 5% of adrenalectomized PA patients through prolonged ZG insufficiency, requiring long-term fludrocortisone treatment. Potassium levels after adrenalectomy must be monitored to avoid life-threatening hyperkalemia.