Hepatitis C as a risk factor for diabetes type 2: lack of evidence in a hospital in central-west Brazil.

In order to assess the importance of HCV infection as a possible risk factor for type 2 diabetes mellitus, a case-control study was conducted, comparing the prevalence of HCV infection among diabetic and non-diabetic patients. Diabetic outpatients attending to a University Hospital in Central-West Brazil were evaluated between April and October 2005. A control group composed by patients from the same institution was matched by gender and age. Candidates to control group were included only if fasting glucose measures were under 100 mg/dL. Diabetics and controls had blood samples taken in order to test for antibodies against HCV (anti-HCV) by enzyme-immunoassay. Polymerase chain reaction and immunoblot were performed to confirm the anti-HCV status. Each group included 206 participants. Despite of the groups were in general comparable. The diabetics had a greater body mass average and smaller family income. The prevalence of confirmed anti-HCV in the diabetic group was of 1.4%, which was similar to the controls (1%). Finding statistical difference may have been hampered by the low frequency of HCV infection in both groups. It was not possible to demonstrate a role of HCV as an etiologic factor in type 2 diabetes, since HCV infected patients represented a small portion of the overall diabetes cases. This finding does not allow to recommend regular screening for HCV infection in type 2 diabetics in this region.     

Whole genome sequence and phenotypic characterization of a Cbm+ serotype e strain of Streptococcus mutans

We report the whole genome sequence of the serotype e Cbm⁺ strain LAR01 of Streptococcus mutans, a dental pathogen frequently associated with extra‐oral infections. The LAR01 genome is a single circular chromosome of 2.1 Mb with a GC content of 36.96%. The genome contains 15 phosphotransferase system gene clusters, seven cell wall‐anchored (LPxTG) proteins, all genes required for the development of natural competence and genes coding for mutacins VI and K8. Interestingly, the cbm gene is genetically linked to a putative type VII secretion system that has been found in Mycobacteria and few other Gram‐positive bacteria. When compared with the UA159 type strain, phenotypic characterization of LAR01 revealed increased biofilm formation in the presence of either glucose or sucrose but similar abilities to withstand acid and oxidative stresses. LAR01 was unable to inhibit the growth of Strpetococcus gordonii, which is consistent with the genomic data that indicate absence of mutacins that can kill mitis streptococci. On the other hand, LAR01 effectively inhibited growth of other S. mutans strains, suggesting that it may be specialized to outcompete strains from its own species. In vitro and in vivo studies using mutational and heterologous expression approaches revealed that Cbm is a virulence factor of S. mutans by mediating binding to extracellular matrix proteins and intracellular invasion. Collectively, the whole genome sequence analysis and phenotypic characterization of LAR01 provides new insights on the virulence properties of S. mutans and grants further opportunities to understand the genomic fluidity of this important human pathogen.     

Molecular activation of PPARgamma by angiotensin II type 1-receptor antagonists

OBJECTIVE AND DESIGN: Elevated blood pressure and insulin resistance are strongly associated in patients. We explored the potential for the anti-hypertensive angiotensin II type 1-receptor (ATR(1)) antagonists to improve insulin sensitivity through modulation of the nuclear receptor PPARgamma, in vitro and in vivo compared to the potent insulin sensitizer, rosiglitazone. METHODS: PPARgamma modulation by ATR(1) antagonists was measured first by direct recruitment of PGC-1, followed by trans-activation reporter assays in cells, and promotion of adipogenesis in fibroblast and pre-adipocyte cell lines. Improvement of insulin sensitivity was measured as changes in levels of glucose, insulin, and adiponectin in ob/ob mice. RESULTS: Telmisartan, candesartan, irbesartan, and losartan (but not valsartan or olmesartan) each served as bona fide PPARgamma ligands in vitro, with EC(50) values between 3 and 5 micro mol/l. However, only telmisartan, and to a lesser extent candesartan, resulted in significant PPARgamma agonism in cells. In vivo, although rosiglitazone significantly lowered both glucose (33%, p<0.01) and insulin (61%, p<0.01) levels and increased expression of adiponectin (74%, p<0.001), sartan treatment had no effect. CONCLUSIONS: Many members of the sartan family of ATR(1) antagonists are PPARgamma ligands in cell-free assays but their modulation of PPARgamma in cells is relatively weak. Furthermore, none appear to improve insulin sensitivity in a rodent model under conditions where other insulin sensitizers, including rosiglitazone, do. These results question whether reported effects of sartans on insulin sensitivity may be through other means, and should guide further efforts to develop dual agents to treat hypertension and insulin resistance.     

Use of negative pressure wound therapy in the management of infected abdominal wounds containing mesh: an analysis of outcomes

The purpose of this study was to examine the clinical outcomes of negative pressure wound therapy (NPWT) using reticulated open-cell foam (ROCF) in the adjunctive management of abdominal wounds with exposed and known infected synthetic mesh. A non randomised, retrospective review of medical records for 21 consecutive patients with infected abdominal wounds treated with NPWT was conducted. All abdominal wounds contained exposed synthetic mesh [composite, polypropylene (PP), or knitted polyglactin 910 (PG) mesh]. Demographic and bacteriological data, wound history, pre-NPWT and comparative post-NPWT, operative procedures and complications, hospital length of stay (LOS) and wound healing outcomes were all analysed. Primary endpoints measured were (1) hospital LOS prior to initiation of NPWT, (2) total time on NPWT, (3) hospital LOS from NPWT initiation to discharge and (4) wound closure status at discharge. A total of 21 patients with abdominal wounds with exposed, infected mesh were treated with NPWT. Aetiology of the wounds was ventral hernia repair (n = 11) and acute abdominal wall defect (n = 10). Prior to NPWT initiation, the mean hospital LOS for the composite, PP and PG meshes were 76 days (range: 21-171 days), 51 days (range: 32-62 days) and 19 days (range: 12-39 days), respectively. The mean hospital LOS following initiation of NPWT for wounds with exposed composite, PP and PG mesh were 28, 31 and 32 days, respectively. Eighteen of the 21 wounds (86%) reached full closure after a mean time of 26 days of NPWT and a mean hospital LOS of 30 days postinitiation of NPWT. Three wounds, all with composite mesh left in situ, did not reach full closure, although all exhibited decreased wound dimensions, granulating beds and decreased surface area exposure of mesh. During NPWT/ROCF, one hypoalbuminemic patient with exposed PP mesh developed an enterocutaneous fistula over a prior enterotomy site. This patient subsequently underwent total mesh extraction, takedown of the fistula and PP mesh replacement followed by reinstitution of NPWT and flap closure. In addition to appropriate systemic antibiotics and nutritional optimisation, the adjunctive use of NPWT resulted in successful closure of 86% of infected abdominal wounds with exposed prosthetic mesh. Patient hospital LOS (except those with PG mesh), operative procedures and readmissions were decreased during NPWT compared with treatment prior to NPWT. Future multi-site prospective, controlled studies would provide a strong evidence base from which treatment decisions could be made in the management of these challenging and costly cases.     

A randomised study of the effect of danoprevir/ritonavir or ritonavir on substrates of cytochrome P450 (CYP) 3A and 2C9 in chronic hepatitis C patients using a drug cocktail

Purpose

The aim of this study was to evaluate the effects of danoprevir in combination with low-dose ritonavir (danoprevir/r) and placebo plus low-dose ritonavir on the pharmacokinetics of probe drugs for cytochrome P450 (CYP) 3A and CYP2C9, in patients with chronic hepatitis C.

Methods

A total of 54 patients infected with hepatitis C virus genotype 1 received an oral drug cocktail (2 mg midazolam, 10 mg warfarin and 10 mg vitamin K) before and after 14 days of dosing with either danoprevir/r or placebo plus low-dose ritonavir (placebo/r). Serial pharmacokinetic samples were collected up to 24 (midazolam) and 72 (S-warfarin) h post-dose. Plasma concentrations of midazolam, α-hydroxymidazolam and S-warfarin were measured using validated assays. Pharmacokinetic parameters were estimated using non-compartmental analysis, and geometric mean ratios (GMRs) and 90 % confidence intervals (CIs) for the differences between baseline and post-dosing values were calculated.

Results

Danoprevir/r and placebo/r significantly increased midazolam area under the time–concentration curve (AUC_0–∞) and reduced the midazolam metabolic ratio while S-warfarin AUC_0–∞ was modestly decreased. When danoprevir data were pooled across doses, the midazolam GMR (90 % CI) AUC_0–∞ was 9.41 (8.11, 10.9) and 11.14 (9.42, 13.2) following danoprevir/r and placebo/r dosing, respectively, and the S-warfarin GMR (90 % CI) AUC_0–∞ was 0.72 (0.68, 0.76) and 0.76 (0.69, 0.85), respectively. The effects of danoprevir/r and placebo/r appeared to be qualitatively similar.

Conclusions

Substantial inhibition of CYP3A- and modest induction of CYP2C9- activity were observed with danoprevir/r and low-dose ritonavir.     

Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes

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