MTP -493G/T gene polymorphism is associated with steatosis in hepatitis C-infected patients

The reduction of hepatic microsomal transfer protein (MTP) activity results in fatty liver, worsening hepatic steatosis and fibrosis in chronic hepatitis C (CHC). The G allele of the MTP gene promoter, -493G/T, has been associated with lower transcriptional activity than the T allele. We investigated this association with metabolic and histological variables in patients with CHC. A total of 174 untreated patients with CHC were genotyped for MTP -493G/T by direct sequencing using PCR. All patients were negative for markers of Wilson’s disease, hemochromatosis and autoimmune diseases and had current and past daily alcohol intake lower than 100 g/week. The sample distribution was in Hardy-Weinberg equilibrium. Among subjects with genotype 1, 56.8% of the patients with fibrosis grade 3+4 presented at least one G allele versus 34.3% of the patients with fibrosis grade 1+2 (OR = 1.8; 95%CI = 1.3-2.3). Logistic regression analysis with steatosis as the dependent variable identified genotypes GG+GT as independent protective factors against steatosis (OR = 0.4, 95%CI = 0.2-0.8; P = 0.01). The results suggest that the presence of the G allele of MTP -493G/T associated with lower hepatic MTP expression protects against steatosis in our CHC patients

Association Of Single Nucleotide Polymorphisms In The Gene Encoding Glut1 And Diabetic Nephropathy In Brazilian Patients With Type 1 Diabetes Mellitus

Mesangial cells subject to high extracellular glucose concentrations, as occur in hyperglycaemic states, are unable to down regulate glucose influx, resulting in intracellular activation of deleterious biochemical pathways. A high expression of GLUT1 participates in the development of diabetic glomerulopathy. Variants in the gene encoding GLUT1 (. SLC2A1) have been associated to this diabetic complication. The aim of this study was to test whether polymorphisms in SLC2A1 confer susceptibility to diabetic nephropathy (DN) in Brazilian type 1 diabetes patients. Four polymorphisms (rs3820589, rs1385129, rs841847 and rs841848) were genotyped in a Brazilian cohort comprised of 452 patients. A prospective analysis was performed in 155 patients. Mean duration of follow-up was 5.6. ±. 2.4. years and the incidence of renal events was 18.0%. The rs3820589 presented an inverse association with the prevalence of incipient DN (OR: 0.36, 95% CI: 0.16 - 0.80, p=. 0.01) and with progression to renal events (HR: 0.20; 95% CI: 0.03 - 0.70; p=. 0.009). AGGT and AGAC haplotypes were associated with the prevalence of incipient DN and the AGAC haplotype was also associated with the prevalence of established/advanced DN. In conclusion, rs3820589 in the SLC2A1 gene modulates the risk to DN in Brazilian patients with inadequate type 1 diabetes control.444170175Nishikawa, T., Edelstein, D., Brownlee, M., The missing link: a single unifying mechanism for diabetic complications (2000) Kidney Int Suppl, 77, pp. S26-S30Ayo, S.H., Radnik, R.A., Glass, W.F., Increased extracellular matrix synthesis and mRNA in mesangial cells grown in high-glucose medium (1991) Am J Physiol, 260, pp. F185-F191Sesso Rde, C., Lopes, A.A., Thome, F.S., Lugon, J.R., Watanabe, Y., Santos, D.R., Chronic dialysis in Brazil: report of the Brazilian dialysis census, 2011 (2012) J Bras Nefrol Orgao Oficial Soc Bras Lat Am Nefrol, 34, pp. 272-277Mauer, S.M., Steffes, M.W., Ellis, E.N., Sutherland, D.E., Brown, D.M., Goetz, F.C., Structural-functional relationships in diabetic nephropathy (1984) J Clin Invest, 74, pp. 1143-1155D'Agord Schaan, B., Lacchini, S., Bertoluci, M.C., Irigoyen, M.C., Machado, U.F., Schmid, H., Increased renal GLUT1 abundance and urinary TGF-beta 1 in streptozotocin-induced diabetic rats: implications for the development of nephropathy complicating diabetes (2001) Horm Metab Res Horm Stoffwechselforschung Horm Metab, 33, pp. 664-669Heilig, C.W., Liu, Y., England, R.L., D-glucose stimulates mesangial cell GLUT1 expression and basal and IGF-I-sensitive glucose uptake in rat mesangial cells: implications for diabetic nephropathy (1997) Diabetes, 46, pp. 1030-1039Henry, D.N., Busik, J.V., Brosius, F.C., Heilig, C.W., Glucose transporters control gene expression of aldose reductase, PKCalpha, and GLUT1 in mesangial cells in vitro (1999) Am J Physiol, 277, pp. F97-F104Weigert, C., Brodbeck, K., Brosius, F.C., Evidence for a novel TGF-beta1-independent mechanism of fibronectin production in mesangial cells overexpressing glucose transporters (2003) Diabetes, 52, pp. 527-535Seaquist, E.R., Goetz, F.C., Rich, S., Barbosa, J., Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy (1989) N Engl J Med, 320, pp. 1161-1165Gross, J.L., de Azevedo, M.J., Silveiro, S.P., Canani, L.H., Caramori, M.L., Zelmanovitz, T., Diabetic nephropathy: diagnosis, prevention, and treatment (2005) Diabetes Care, 28, pp. 164-176Zintzaras, E., Stefanidis, I., Association between the GLUT1 gene polymorphism and the risk of diabetic nephropathy: a meta-analysis (2005) J Hum Genet, 50, pp. 84-91Cui, W., Du, B., Zhou, W., Relationship between five GLUT1 gene single nucleotide polymorphisms and diabetic nephropathy: a systematic review and meta-analysis (2012) Mol Biol Rep, 39, pp. 8551-8558Pimenta, J.R., Zuccherato, L.W., Debes, A.A., Color and genomic ancestry in Brazilians: a study with forensic microsatellites (2006) Hum Hered, 62, pp. 190-195Levey, A.S., Stevens, L.A., Schmid, C.H., A new equation to estimate glomerular filtration rate (2009) Ann Intern Med, 150, pp. 604-612Mohammedi, K., Maimaitiming, S., Emery, N., Allelic variations in superoxide dismutase-1 (SOD1) gene are associated with increased risk of diabetic nephropathy in type 1 diabetic subjects (2011) Mol Genet Metab, 104, pp. 654-660Kohner, E.M., The lesions and natural history of diabetic retinopathy (1991) Text Book of Diabetes, pp. 575-588. , editor, Oxford, Scientific BNyholt, D.R., A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other (2004) Am J Hum Genet, 74, pp. 765-769Team, R.C., (2013) R: a language and environment for statistical computingTregouet, D.A., Garelle, V., A new JAVA interface implementation of THESIAS: testing haplotype effects in association studies (2007) Bioinformatics, 23, pp. 1038-1039Ng, D.P., Canani, L., Araki, S., Minor effect of GLUT1 polymorphisms on susceptibility to diabetic nephropathy in type 1 diabetes (2002) Diabetes, 51, pp. 2264-2269Murakami, T., Nishiyama, T., Shirotani, T., Identification of two enhancer elements in the gene encoding the type 1 glucose transporter from the mouse which are responsive to serum, growth factor, and oncogenes (1992) J Biol Chem, 267, pp. 9300-9306Heilig, C.W., Brosius, F.C., Cunningham, C., Role for GLUT1 in diabetic glomerulosclerosis (2006) Expert Rev Mol Med, 8, pp. 1-18Zeggini, E., Rayner, W., Morris, A.P., An evaluation of HapMap sample size and tagging SNP performance in large-scale empirical and simulated data sets (2005) Nat Genet, 37, pp. 1320-132

Modulation of hepatic microsomal triglyceride transfer protein (MTP) induced by S-nitroso-N-acetylcysteine in ob/ob mice

We evaluated the effects of a potent NO donor, S-nitroso-N-acetylcysteine (SNAC), on microsomal triglyceride transfer protein (MTP) expression in ob/ob mice. NAFLD was induced in male ob/ob mice using a methionine-choline deficient diet (MCD) concomitantly with oral SNAC fed solution (n = 5) or vehicle (control; n = 5) by gavage daily for 4 weeks. Livers were collected for histology and for assessing MTP by RT-qPCR, Western blot, immunohistochemistry and immunogold electron microscopy analyses. Histological analysis showed diffuse macro and microvesicular steatosis, moderate hepatocellular ballooning and moderate inflammatory infiltrate in ob/ob mice fed the MCD diet. With SNAC, mice showed a marked reduction in liver steatosis (p < 0.01), in parenchymal inflammation (p = 0.02) and in MTP protein immunoexpression in zone III (p = 0.05). Moreover, SNAC caused reduction of MTP protein in Western blot analysis (p < 0.05). In contrast, MTP mRNA content was significantly higher (p < 0.05) in mice receiving SNAC. Immuno-electron microscopy showed MTP localized in the rough endoplasmic reticulum of hepatocytes in both treated and untreated groups. However with SNAC treatment, MTP was also observed surrounding fat globules. Histological improvement mediated by a nitric oxide donor is associated with significantly altered expression and distribution of MTP in this animal model of fatty liver disease. Further studies are in progress to examine possible mechanisms and to develop SNAC as a possible therapy for human fatty liver disease. © 2007 Elsevier Inc. All rights reserved

Impact of a hospital-wide multifaceted programme for reducing carbapenem-resistant Enterobacteriaceae infections in a large teaching hospital in northern Italy

AbstractWe performed a quasi-experimental study of a multifaceted infection control programme for reducing carbapenem-resistant Enterobacteriaceae (CRE) transmission and bloodstream infections (BSIs) in a 1420-bed university-affiliated teaching hospital during 2010–2014, with 30 months of follow-up. The programme consisted of the following: (a) rectal swab cultures were performed in all patients admitted to high-risk units (intensive-care units, transplantation, and haematology) to screen for CRE carriage, or for any room-mates of CRE-positive patients in other units; (b) cohorting of carriers, managed with strict contact precautions; (c) intensification of education, cleaning and hand-washing programmes; and (d) promotion of an antibiotic stewardship programme carbapenem-sparing regimen. The 30-month incidence rates of CRE-positive rectal cultures and BSIs were analysed with Poisson regression. Following the intervention, the incidence rate of CRE BSI (risk reduction 0.96, 95% CI 0.92–0.99, p 0.03) and CRE colonization (risk reduction 0.96, 95% CI 0.95–0.97, p <0.0001) significantly decreased over a period of 30 months. After accounting for changes in monthly census and percentage of externally acquired cases (positive at ≤72 h), the average institutional monthly rate of compliance with CRE screening procedures was the only independent variable associated with a declining monthly incidence of CRE colonization (p 0.002). The monthly incidence of CRE carriage was predictive of BSI (p 0.01). Targeted screening and cohorting of CRE carriers and infections, combined with cleaning, education, and antimicrobial stewardship measures, significantly decreased the institutional incidence of CRE BSI and colonization, despite endemically high CRE carriage rates in the region

Catalase Activity, Allelic Variations In The Catalase Gene And Risk Of Kidney Complications In Patients With Type 1 Diabetes

Aims/hypothesis: Oxidative stress is involved in the pathogenesis of diabetic nephropathy. The antioxidant enzyme catalase plays a key role in redox regulation in the kidney. We investigated associations of catalase gene (CAT) polymorphisms and plasma catalase activity with diabetic nephropathy in type 1 diabetic patients. Methods: We genotyped nine single nucleotide polymorphisms (SNPs) in the CAT region in participants from the Survival Genetic Nephropathy (SURGENE) (340 French participants, 10 year follow-up) and the Génétique de la Néphropathie Diabétique (GENEDIAB) (444 Belgian and French participants, 8 year follow-up) study cohorts. Replication was performed in a Brazilian cross-sectional cohort (n = 451). Baseline plasma catalase activity was measured in SURGENE (n = 120) and GENEDIAB (n = 391) participants. Results: The A allele of rs7947841 was associated with the prevalence of incipient (OR 2.79, 95% CI 1.21, 6.24, p = 0.01) and established or advanced nephropathy (OR 5.72, 95% CI 1.62, 22.03, p = 0.007), and with the incidence of renal events, which were defined as new cases of microalbuminuria or progression to a more severe stage of nephropathy during follow-up (HR 1.82, 95% CI 1.13, 2.81, p = 0.01) in SURGENE participants. The same risk allele was associated with incipient nephropathy (OR 3.13, 95% CI 1.42, 7.24, p = 0.004) and with the incidence of end-stage renal disease (ESRD) (HR 2.11, 95% CI 1.23, 3.60, p = 0.008) in GENEDIAB participants. In both cohorts, the risk allele was associated with lower catalase activity. Associations with incipient and established or advanced nephropathy were confirmed in the replication cohort. Conclusions/interpretation: CAT variants were associated with the prevalence and incidence of diabetic nephropathy and ESRD in type 1 diabetic patients. Our results confirm the protective role of catalase against oxidative stress in the kidney. © 2013 Springer-Verlag Berlin Heidelberg.561227332742Jones, C.A., Krolewski, A.S., Rogus, J., Xue, J.L., Collins, A., Warram, J.H., Epidemic of end-stage renal disease in people with diabetes in the United States population: Do we know the cause? 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1:CAS:528:DC%2BD3cXos1ejsLY%3DCoughlan, M.T., Mibus, A.L., Forbes, J.M., Oxidative stress and advanced glycation in diabetic nephropathy (2008) Ann N y Acad Sci, 1126, pp. 190-193. , 18448815 10.1196/annals.1433.018 1:CAS:528:DC%2BD1cXmtFynsr4%3DForbes, J.M., Coughlan, M.T., Cooper, M.E., Oxidative stress as a major culprit in kidney disease in diabetes (2008) Diabetes, 57, pp. 1446-1454. , 18511445 10.2337/db08-0057 1:CAS:528:DC%2BD1cXnsF2jurs%3DMates, J.M., Perez-Gomez, C., Nunez De Castro, I., Antioxidant enzymes and human diseases (1999) Clin Biochem, 32, pp. 595-603. , 10638941 10.1016/S0009-9120(99)00075-2 1:CAS:528:DC%2BD3cXos12jsQ%3D%3DDeisseroth, A., Dounce, A.L., Catalase: Physical and chemical properties, mechanism of catalysis, and physiological role (1970) Physiol Rev, 50, pp. 319-375. , 4912904 1:CAS:528:DyaE3cXkvVeqtbw%3DBrezniceanu, M.L., Liu, F., Wei, C.C., Catalase overexpression attenuates angiotensinogen expression and apoptosis in diabetic mice (2007) Kidney Int, 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of the human catalase gene influences transcription factor binding, reporter gene transcription and is correlated to blood catalase levels (2001) Free Radic Biol Med, 30, pp. 500-505. , 11182520 10.1016/S0891-5849(00)00487-1 1:CAS:528:DC%2BD3MXht1Oqu7s%3DHadjadj, S., Belloum, R., Bouhanick, B., Prognostic value of angiotensin-I converting enzyme I/D polymorphism for nephropathy in type 1 diabetes mellitus: A prospective study (2001) J Am Soc Nephrol, 12, pp. 541-549. , 11181802 1:CAS:528:DC%2BD3MXitV2ktro%3DVieira, S.M., Monteiro, M.B., Marques, T., Association of genetic variants in the promoter region of genes encoding p22phox (CYBA) and glutamate cysteine ligase catalytic subunit (GCLC) and renal disease in patients with type 1 diabetes mellitus (2011) BMC Med Genet, 12, p. 129. , 21962117 10.1186/1471-2350-12-129 1:CAS:528:DC%2BC3MXhtl2lsr%2FKPimenta, J.R., Zuccherato, L.W., Debes, A.A., Color and genomic ancestry in Brazilians: A study with forensic microsatellites (2006) Hum 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Impact of a hospital-wide multifaceted programme for reducing carbapenem-resistant Enterobacteriaceae infections in a large teaching hospital in northern Italy

We performed a quasi-experimental study of a multifaceted infection control programme for reducing carbapenem-resistant Enterobacteriaceae (CRE) transmission and bloodstream infections (BSIs) in a 1420-bed university-affiliated teaching hospital during 2010-2014, with 30 months of follow-up. The programme consisted of the following: (a) rectal swab cultures were performed in all patients admitted to high-risk units (intensive-care units, transplantation, and haematology) to screen for CRE carriage, or for any room-mates of CRE-positive patients in other units; (b) cohorting of carriers, managed with strict contact precautions; (c) intensification of education, cleaning and hand-washing programmes; and (d) promotion of an antibiotic stewardship programme carbapenem-sparing regimen. The 30-month incidence rates of CRE-positive rectal cultures and BSIs were analysed with Poisson regression. Following the intervention, the incidence rate of CRE BSI (risk reduction 0.96, 95% CI 0.92-0.99, p 0.03) and CRE colonization (risk reduction 0.96, 95% CI 0.95-0.97, p <0.0001) significantly decreased over a period of 30 months. After accounting for changes in monthly census and percentage of externally acquired cases (positive at 6472h), the average institutional monthly rate of compliance with CRE screening procedures was the only independent variable associated with a declining monthly incidence of CRE colonization (p 0.002). The monthly incidence of CRE carriage was predictive of BSI (p 0.01). Targeted screening and cohorting of CRE carriers and infections, combined with cleaning, education, and antimicrobial stewardship measures, significantly decreased the institutional incidence of CRE BSI and colonization, despite endemically high CRE carriage rates in the region