In morbid obese patients, NASH, particularly lobular inflammation and advanced fibrosis, associates with mild decreases in eGFR, suggesting a common inflammatory link between liver and renal lesion.

Aims/hypothesis Non-alcoholic fatty liver disease (NAFLD) is associated with insulin resistance and characterised by different degrees of hepatic lesion. Its pathogenesis and correlation with apoptosis and insulin resistance in insulin target tissues remains incompletely understood. We investigated how insulin signalling, caspase activation and apoptosis correlate with different NAFLD stages in liver, muscle and visceral adipose tissues. Methods Liver, muscle and adipose tissue biopsies from 26 morbidly obese patients undergoing bariatric surgery were grouped according to the Kleiner-Brunt scoring system into simple steatosis, and less severe and more severe nonalcoholic steatohepatitis (NASH). Apoptosis was assessed by DNA fragmentation, and caspase-2 and -3 activation. Insulin signalling and c-Jun NH 2 -terminal kinase (JNK) proteins were evaluated by western blot. Results Caspase-3 and -2 activation, and DNA fragmentation were markedly increased in the liver of patients with severe NASH vs in that of those with simple steatosis (p<0.01). Muscle tissue, and to a lesser extent the liver, had decreased tyrosine phosphorylated insulin receptor and insulin receptor substrate in patients with severe NASH, compared with those with simple steatosis (p < 0.01 muscle; p < 0.05 liver). Concomitantly, Akt phosphorylation decreased in muscle, liver and visceral adipose tissues in patients with severe NASH (at least p< 0.05). Finally, JNK phosphorylation was significantly increased in muscle (p< 0.01) and liver (p<0.05) from NASH patients, compared with tissue from those with simple steatosis. Conclusions/interpretation Our results demonstrate a link between apoptosis, insulin resistance and different NAFLD stages, where JNK and caspase-2 may play a key regulatory role.

An imbalance in adiponectin, leptin, and ghrelin seems to be associated with more severe NAFLD. A formula combining the three cytokines showed good accuracy for NASH.

Identifying factors, including human papillomavirus (HPV) genotypes, associated with abnormal anal cytology in HIV-infected women have implications for anal squamous cell cancer (SCC) prevention in HIV-infected women. Anal and cervical samples were collected for cytology, and tested for high-(HR-HPV) and low-risk HPV (LR-HPV) genotypes in a cross-sectional analysis of the IPEC Women's HIV Cohort (Rio de Janeiro, Brazil). Multivariate log-binomial regression models estimated prevalence ratios for factors associated with abnormal anal cytology [ ‡ atypical squamous cells of undetermined significance, (ASC-US)]. Characteristics of the 863 participants included: median age 42 years, 57% non-white, 79% current CD4 + T-cell count > 350 cells/mm 3 , 53% HIV-1 viral load < 50 copies/mL, median ART duration 5.8 years. Fifty-one percent of anal specimens contained ‡ 1 HR-HPV genotype; 31% had abnormal anal cytology [14% ASC-US, 11% low-grade squamous intra-epithelial lesion, (LSIL); 2% atypical squamous cells-cannot exclude high-grade SIL (ASC-H); 4% high-grade SIL/cancer (HSIL + )]. In multivariate analysis, cervical LSIL + , nadir CD4 + T-cell count £ 50 cells/mm 3 , HIV-1 viral load ‡ 50 copies/mL, and anal HPV 6,11,16,18,33, 45, 52, 56, and 58 were associated with ‡ anal ASC-US ( p < 0.05). Abnormal anal cytology and HR-HPV prevalences were high. HIVinfected women with cervical LSIL + , low nadir CD4 + counts, or detectable HIV-1 viral loads should be a particular focus for enhanced anal SCC screening efforts.

BackgroundSexually transmitted diseases (STD) are frequently asymptomatic and increase the likelihood of transmitting and acquiring HIV. In Brazil, the guidelines for STDs diagnosis and treatment are based on the syndromic approach. Nucleic acid amplification tests (NAAT) has been recommended as routine STDs screening in some countries, especially for men who have sex with men (MSM). Limited data are available about how to best define target groups for routine screening by NAATs within this population. We aimed to assess the prevalence of rectal and urethral Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections and syphilis, and the factors associated with having at least one STD among HIV-infected and uninfected MSM in Rio de Janeiro, Brazil.MethodsFrom August 2010 to June 2012, 391 MSM were enrolled into the Evandro Chagas National Institute of Infectious Diseases-INI-Fiocruz cohort, and 292 MSM (HIV-infected:211 and HIV-uninfected:81) were included in this study. NAATs were performed on the rectal swabs and urine for CT and NG. The rapid plasma reagin test and microhemagglutination assay for Treponema pallidum were performed for syphilis diagnosis.ResultsThe overall prevalence of STD was 20.0 % (95%CI:15.7-25.1): 10 % anorectal chlamydia; syphilis 9.9 %; anorectal gonorrheae 2.5 %; and urethral chlamydia 2.2 %; no case of urethral gonorrheae was detected. The proportion of HIV-positive MSM who had at least one STD was nearly two times that of HIV-negative MSM (22.6 % vs 13.2 %; P = 0.09). The frequency of each STD, except for anorectal NG (1.5 % vs.5.2 %), was higher among HIV-positive than HIV-negative individuals. Among the 211 asymptomatic participants, 17.5 % (n = 37) were identified as having at least one STD; 10.4 % (n = 22/211) tested positive for anorectal chlamydia. Sixty five percent of HIV-positive MSM were asymptomatic at the time of the STD diagnosis, while 100.0 % of the HIV-negative MSM. Age (APR = 0.78; 95%CI:0.60-1.00 for each additional ten years) and a positive-HIV serostatus (APR = 2.05; 95%CI:1.03-4.08) were significantly associated with STD diagnosis.ConclusionAn overall high STD-prevalence rate was observed, especially among HIV-infected and in younger individuals, and the majority of STDs were asymptomatic. STD screening using NAATs among asymptomatic MSM is a potentially cost-effective intervention for the prevention of HIV infection among MSM.

IntroductionNonalcoholic fatty liver disease (NAFLD) can be seen as a manifestation of overnutrition. The muscle is a central player in the adaptation to energy overload, and there is an association between fatty-muscle and -liver. We aimed to correlate muscle morphology, mitochondrial function and insulin signaling with NAFLD severity in morbid obese patients.MethodsLiver and deltoid muscle biopsies were collected during bariatric surgery in NAFLD patients. NAFLD Activity Score and Younossi's classification for nonalcoholic steatohepatitis (NASH) were applied to liver histology. Muscle evaluation included morphology studies, respiratory chain complex I to IV enzyme assays, and analysis of the insulin signaling cascade. A healthy lean control group was included for muscle morphology and mitochondrial function analyses.ResultsFifty one NAFLD patients were included of whom 43% had NASH. Intramyocellular lipids (IMCL) were associated with the presence of NASH (OR 12.5, p<0.001), progressive hepatic inflammation (p = 0.029) and fibrosis severity (p = 0.010). There was a trend to an association between IMCL and decreased Akt phosphorylation (p = 0.059), despite no association with insulin resistance. In turn, hepatic steatosis (p = 0.015) and inflammation (p = 0.013) were associated with decreased Akt phosphoryation. Citrate synthase activity was lower in obese patients (p = 0.047) whereas complex I (p = 0.040) and III (p = 0.036) activities were higher, compared with controls. Finally, in obese patients, complex I activity increased with progressive steatosis (p = 0.049) and with a trend with fibrosis severity (p = 0.056).ConclusionsIn morbid obese patients, presence of IMCL associates with NASH and advanced fibrosis. Muscle mitochondrial dysfunction does not appear to be a major driving force contributing to muscle fat accumulation, insulin resistance or liver disease. Importantly, insulin resistance in muscle might occur at a late point in the insulin signaling cascade and be associated with IMCL and NAFLD severity.

Objective The aim of the current study was to evaluate secretory leukocyte protease inhibitor (SLPI) expression in anal biopsies from HIV-positive (HIV+) individuals, and compare that to anal intraepithelial neoplasia (AIN) diagnoses and human papillomavirus (HPV) status. Design This is a cross-sectional study of a cohort of 54 HIV+ (31 males and 23 females) from an AIDS clinic in Rio de Janeiro, Brazil. Methods The study material consisted of anorectal tissue biopsies obtained from HIV+ subjects, which were used to construct tissue microarray paraffin blocks for immunohistochemical analysis of SLPI expression. Biopsies were evaluated by an expert pathologist and classified as low-grade anal intraepithelial neoplasia (AIN1), high-grade anal intraepithelial neoplasia (AIN2/3), or normal squamous epithelium. Additionally, DNA from the biopsies was extracted and analyzed for the presence of low- or high-risk HPV DNA. Results Histologically normal squamous epithelium from the anorectal region showed strong positive SLPI staining in 17/20 (85%) samples. In comparison, 9/17 (53%) dysplastic squamous epithelial samples from AIN1 patients showed strong SLPI staining, and only 5/17 (29%) samples from AIN2-3 patients exhibited strong SPLI staining, which both were significantly fewer than those from normal tissue (p=0.005). Furthermore, there was a significantly higher proportion of samples in which oncogenic high-risk HPV genotypes were detected in low SLPI expressing tissues than that in tissues with high SLPI expression (p=0.040). Conclusion Taken together these results suggest that low SLPI expression is associated with high-risk HPV infections in the development of AIN.

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