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Byline: Deepak. Amalnath, Rajeshwari. Lingala, D. S Subrahmanyam Sir, Histiocytosis-lymphadenopathy plus syndrome (OMIM#602782) is the term used to represent four distinct groups of disorders with overlapping phenotypes: H syndrome, Faisalabad [...]

Background Although Escherichia coli is the most frequently isolated microorganism in acute biliary tract infections with bacteremia, data regarding its virulence are limited. Results Information on cases of bacteremia in acute biliary tract infection in a retrospective study was collected from 2013 to 2015 at a tertiary care hospital in Japan. Factors related to the severity of infection were investigated, including patient background, phylogenetic typing, and virulence factors of E. coli, such as adhesion, invasion, toxins, and iron acquisition. In total, 72 E. coli strains were identified in 71 cases, most of which primarily belonged to the B2 phylogroup (68.1%). The presence of the iutA gene (77.3% in the non-severe group, 46.4% in the severe group, P = 0.011) and the ibeA gene (9.1% in the non-severe group, and 35.7% in the severe group, P = 0.012) was significantly associated with the severity of infection. Among the patient characteristics, diabetes mellitus with organ involvement and alkaline phosphatase were different in the severe and non-severe groups. Conclusions We showed that bacteremic E. coli strains from acute biliary tract infections belonged to the virulent (B2) phylogroup. The prevalence of the iutA and ibeA genes between the two groups of bacteremia severity was significantly different. Keywords: Extraintestinal pathogenic Escherichia coli, Biliary tract infection, Bacteremia, Severity, Virulence factors, iutA, ibeA, Author(s): Mahoko Ikeda[sup.1,2], Tatsuya Kobayashi[sup.2], Fumie Fujimoto[sup.1], Yuta Okada[sup.2], Yoshimi Higurashi[sup.1], Keita Tatsuno[sup.2], Shu Okugawa[sup.2] and Kyoji Moriya[sup.1,2] Background Escherichia coli is the most frequently isolated microorganism in acute biliary [...]

Malformations of the kidney and lower urinary tract are the most frequent cause of end-stage renal disease in children. Mutations in HNF1B and PAX2 commonly cause syndromic urinary tract malformation. We searched for mutations in HNF1B and PAX2 in North American children with renal aplasia and hypodysplasia (RHD) enrolled in the Chronic Kidney Disease in Children Cohort Study (CKiD). We identified seven mutations in this multiethnic cohort (10% of patients). In HNF1B, we identified a nonsense (p.R181X), a missense (p.S148L), and a frameshift (Y352fsX352) mutation, and one whole gene deletion. In PAX2, we identified one splice site (IVS4-1G>T), one missense (p.G24E), and one frameshift (G24fsX28) mutation. All mutations occurred in Caucasians, accounting for 14% of disease in this subgroup. The absence of mutations in other ethnicities is likely due to the limited sample size. There were no differences in clinical parameters (age, baseline eGFR, blood pressure, body mass index, progression) between patients with or without HNF1B and PAX2 mutations. A significant proportion of North American Caucasian patients with RHD carry mutations in HNF1 B or PAX2 genes. These patients should be evaluated for complications (e.g., diabetes for HNF1B mutations, colobomas for PAX2) and referred for genetic counseling. Keywords: HNF1B * PAX2 * Renal hypodysplasia * Chronic kidney disease * Children, Introduction Renal hypodysplasia (RHD), encompassing the diagnosis of renal aplasia, hypoplasia, and dysplasia, is the second leading cause of chronic renal insufficiency (eCreatinine clearance ≤ 75ml/min per 1.73 [m.sup.2]) in [...]

Endothelial death is critical in diabetic vascular diseases, but regulating factors have been only partially elucidated. Phosphatases play important regulatory roles in cell metabolism, but have not previously been implicated in hyperglycemia-induced cell death. We investigated the role of the phosphatase, type 2A protein phosphatase (PP2A), in hyperglycemia-induced changes in signaling and death in bovine aortic endothelial cells (BAEC). We explored also the influence of benfotiamine on this phosphatase. Activation of PP2A was assessed in BAEC by the extent of methylation and measurement of activity, and the enzyme was inhibited using selective pharmacological (okadaic acid, sodium fostriecin) and molecular (small interfering RNA) approaches. BAECs cultured in 30 mM glucose significantly increased PP2A methylation and activity, and PP2A inhibitors blocked these abnormalities. PP2A activity was increased also in aorta and retina from diabetic rats. NF-[kappa]B activity and cell death in BAEC were significantly increased in 30 mM glucose and inhibited by PP2A inhibition. NF-[kappa]B played a role in the hyperglycemia-induced death of BAEC, since blocking its translocation with SN50 also inhibited cell death. Inhibition of PP2A blocked the hyperglycemia-induced dephosphorylation of NF-[kappa]B and Bad, thus favoring cell survival. Incubation of benfotiamine with BAEC inhibited the high glucose-induced activation of PP2A and NF-[kappa]B and cell death, as well as several other metabolic defects, which likewise were inhibited by inhibitors of PP2A. Activation of PP2A contributes to endothelial cell death in high glucose, and beneficial actions of benfotiamine are due, at least in part, to inhibition of PP2A activation. cell death; endothelium; hyperglycemia; diabetes; phosphatase doi: 10.1152/ajpregu.00676.2009

A hallmark of diabetes is an absolute or relative reduction in the number of functional [beta] cells. Therapies that could increase the number of endogenous [beta] cells under diabetic conditions would be desirable. Prevalent gene targeting mouse models for assessing [beta]-cell proliferation and diabetes pathogenesis only address whether deletion of a gene prevents the development of diabetes. Models testing whether acute excision of a single gene can ameliorate or reverse preexisting hyperglycemia in established diabetes remain to be explored, which could directly validate the effect of gene excision on treating diabetes. Here, we report that acute and temporally controlled excision of the Men1 gene, which encodes menin, ameliorated preexisting hyperglycemia in streptozotocin-treated mice. Moreover, Men1 excision also improved the preexisting hyperglycemia and glucose intolerance in genetic db/db diabetic mice. Furthermore, acute Men1 excision reversed preexisting glucose intolerance in high-fat diet-fed mice. Men1 excision improved glucose metabolism at least partly through increasing proliferation of endogenous [beta] cells and islet size. Acute Men1 excision up-regulated a group of proproliferative genes in pancreatic islets. Together, these findings demonstrate that established hyperglycemia can be reversed through repression of a single gene, Men1, in diabetic conditions, and suggest that menin is a vital regulator in pathogenesis of diabetes. cell proliferation | db/db | high-fat diet | type 2 diabetes doi/ 10.1073/pnas.1012257107

Cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing was performed to detect recurrent 1.4 Mb deletions at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD). The data provide insight into recurrent deletion of 17q12, pathogenic CNV that confers a very high risk for ASD and schizophrenia and significance of one or more of the 1S dosage sensitive genes in the deleted interval for normal brain development and function.

CD147 is a highly glycosylated transmembrane protein that is known to play a role in regulation of many protein families. It has the unique ability to maintain functional activity in both the membrane bound state and in the soluble form. CD147 is known to play a role in regulation of matrix metalloproteinase (MMP) expression, but whether its expression is affected by the diabetic milieu is not known, and its role in regulation of monocyte MMPs in this environment has not been investigated. Therefore, in this study we investigated the effect of advanced glycation end products (AGEs) and high glucose (HG; 25 mM), on monocyte CD147 expression. Culture of THP-1 monocytes in the presence of AGEs or HG significantly increased CD147 at the gene and protein level. THP-1 cell results were confirmed using freshly isolated monocytes from human volunteers. The effect of AGEs and HG on CD147 expression was also mimicked by addition of proinflammatory cytokines. Addition of AGEs or HG also increased expression of monocyte MMP-1 and MMP-9 but not MMP-2. This increase in MMPs was significantly attenuated by inhibition of CD147 using either a small interfering RNA or an anti-CD147 antibody. Inhibition of NF-[kappa]B or addition of antibodies to either TNF-[alpha] or the receptor for AGE (RAGE) each significantly prevented in a dose-dependent manner the induction of CD147 gene and protein by AGE and also decreased MMP-1 and MMP-9. This novel result shows that AGEs can induce monocyte CD147 expression, an effect mediated by inflammatory pathways and RAGE. Because MMPs play a role in monocyte migration, inhibition of their regulator CD147 may assist in the prevention of diabetic complications, particularly those where monocyte infiltration is an early initiating event. matrix metalloproteinase doi: 10.1152/ajpcell.00228.2010.

Our objective was to investigate whether the direct bilateral infusion of the monounsaturated fatty acid (MUFA) oleic acid (OA) within the mediobasal hypothalamus (MBH) is sufficient to reproduce the effect of administration of OA (30 nmol) in the third cerebral ventricle, which inhibits glucose production (GP) in rats. We used the pancreatic basal insulin clamp technique (plasma insulin ~20 mU/ml) in combination with tracer dilution methodology to compare the effect of MBH OA on GP to that of a saturated fatty acid (SFA), palmitic acid (PA), and a polyunsaturated fatty acid (PUFA), linoleic acid (LA). The MBH infusion of 200 but not 40 pmol of OA was sufficient to markedly inhibit GP (by 61% from 12.6 [+ or -] 0.6 to 5.1 [+ or -] 1.6 mg x [kg.sup.-1] x [min.sup.-1]) such that exogenous glucose had to be infused at the rate of 6.0 [+ or -] 1.2 mg x [kg.sup.-1] x [min.sup.-1] to prevent hypoglycemia. MBH infusion of PA also caused a significant decrease in GP, but only at a total dose of 4 nmol (GP 5.8 [+ or -] 1.6 mg x [kg.sup.-1] x [min.sup.-1]). Finally, MBH LA at a total dose of 0.2 and 4 nmol failed to modify GP compared with rats receiving MBH vehicle. Increased availability of OA within the MBH is sufficient to markedly inhibit GP. LA does not share the effect of OA, whereas PA can reproduce the potent effect of OA on GP, but only at a higher dose. It remains to be determined whether SFAs need to be converted to MUFAs to exert this effect or whether they activate a separate signaling pathway to inhibit GP. nutrient sensing; diabetes; obesity; central nervous system doi: 10.1152/ajpendo.00190.2010.

ABSTRACT Aim of the study: The aim of present study was to investigate the effects of ethanolic extracts of red propolis (EERP) on adipogenesis and evaluate the molecular basis for [...]

There is strong genetic association between type 1A diabetes (TID) and autoimmune thyroid disease (AITD). TID and AITD frequently occur together in the same individual, a condition classified as a variant of the autoimmune polyglandular syndrome type 3 (APS3). Because TID and AITD are individually strongly associated with different HLA class II sequences, we asked which HLA class II pocket sequence and structure confer joint susceptibility to both T1 D and AITD in the same individual (APS3v). We sequenced the HLA-DR gene in 105 APS3v patients and 153 controls, and identified a pocket amino acid signature, DR[beta]-Tyr-26, DR[beta]-Leu-67, DR[beta]-Lys-71, and DR[beta]-Arg-74, that was strongly associated with APS3v (P = 5.4 x [10.sup.-14], odds ratio = 8.38). Logistic regression analysis demonstrated that DR[beta]-Leu-67 (P = 9.4 x [10.sup.-13]) and DR[beta]-Arg-74 (P = 1.21 x [10.sup.-13]) gave strong independent effects on disease susceptibility. Structural modeling studies demonstrated that pocket 4 was critical for the development of T1 D+AITD; all disease-associated amino acids were linked to areas of the pocket that interact directly with the peptide and, therefore, influence peptide binding. The disease-susceptible HLA-DR pocket was more positively charged (Lys-71, Arg-74) compared with the protective pocket (Ala-71, Gin-74). We conclude that a specific pocket amino acid signature confers joint susceptibility to TID+AITD in the same individual by causing significant structural changes in the MHC II peptide binding pocket and influencing peptide binding and presentation. Moreover, Arg-74 is a major amino acid position for the development of several autoimmune diseases. These findings suggest that blocking the critical Arg-74 pocket might offer a method for treating certain autoimmune conditions. autoimmunity | gene | structure doi/ 10.1073/pnas.1009511107