Adverse Events in a Cohort of HIV Infected Pregnant and Non-Pregnant Women Treated with Nevirapine versus Non-Nevirapine Antiretroviral Medication

BACKGROUND: Predictors of adverse events (AE) associated with nevirapine use are needed to better understand reports of severe rash or liver enzyme elevation (LEE) in HIV+ women. METHODOLOGY: AE rates following ART initiation were retrospectively assessed in a multi-site cohort of 612 women. Predictors of onset of rash or LEE were determined using univariate and multivariate analyses. PRINCIPAL FINDINGS: Of 612 subjects, 152 (24.8%) initiated NVP-based regimens with 86 (56.6%) pregnant; 460 (75.2%) initiated non-NVP regimens with 67 (14.6%) pregnant. LEE: No significant difference was found between regimens in the development of new grade ≥2 LEE (p  =  0.885). Multivariate logistic regression demonstrated an increased likelihood of LEE with HCV co-infection (OR 2.502, 95% CI: 1.04 to 6, p =  0.040); pregnancy, NVP-based regimen, and baseline CD4 >250 cells/mm(3) were not associated with this toxicity. RASH: NVP initiation was associated with rash after controlling for CD4 and pregnancy (OR 2.78; 95%CI: 1.14-6.76), as was baseline CD4 >250 cells/mm(3) when controlling for pregnancy and type of regimen (OR 2.68; 95% CI: 1.19-6.02 p  =  0.017). CONCLUSIONS: CD4 at initiation of therapy was a predictor of rash but not LEE with NVP use in HIV+ women. Pregnancy was not an independent risk factor for the development of AEs assessed. The findings from this study have significant implications for women of child-bearing age initiating NVP-based ART particularly in resource limited settings. This study sheds more confidence on the lack of LEE risk and the need to monitor rash with the use of this medication

Epithelial-immune cell interplay in primary Sjogren syndrome salivary gland pathogenesis

In primary Sjogren syndrome (pSS), the function of the salivary glands is often considerably reduced. Multiple innate immune pathways are likely dysregulated in the salivary gland epithelium in pSS, including the nuclear factor-kappa B pathway, the inflammasome and interferon signalling. The ductal cells of the salivary gland in pSS are characteristically surrounded by a CD4(+) T cell-rich and B cell-rich infiltrate, implying a degree of communication between epithelial cells and immune cells. B cell infiltrates within the ducts can initiate the development of lymphoepithelial lesions, including basal ductal cell hyperplasia. Vice versa, the epithelium provides chronic activation signals to the glandular B cell fraction. This continuous stimulation might ultimately drive the development of mucosa-associated lymphoid tissue lymphoma. This Review discusses changes in the cells of the salivary gland epithelium in pSS (including acinar, ductal and progenitor cells), and the proposed interplay of these cells with environmental stimuli and the immune system. Current therapeutic options are insufficient to address both lymphocytic infiltration and salivary gland dysfunction. Successful rescue of salivary gland function in pSS will probably demand a multimodal therapeutic approach and an appreciation of the complicity of the salivary gland epithelium in the development of pSS. Salivary gland dysfunction is an important characteristic of primary Sjogren syndrome (pSS). In this Review, the authors discuss various epithelial abnormalities in pSS and the mechanisms by which epithelial cell-immune cell interactions contribute to disease development and progression

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Survival, growth and metabolic parameters of silver catfish, Rhamdia quelen, juveniles exposed to different waterborne nitrite levels

High nitrite (NO2-) levels may develop in aquaculture systems due to high fish density, but studies of lethal concentration values and the effect of NO2- on metabolic parameters and growth are scarce. Consequently, in this study was verified the lethal concentration at 96 h (LC50-96h) for (NO2-) in juvenile silver catfish, Rhamdia quelen and the effect of four waterborne NO2- concentrations (0.06, 0.46, 1.19, and 1.52 mg.L-1) on growth, and hepatic and muscular lactate, glucose, glycogen and protein. Nitrite LC50-96h was 20.46 (confidence interval: 16.10-23.68) mg.L-1. In the growth experiment, exposure to NO2- did not affect weight, length or specific growth rate, but due to mortality (66.7% and 100% after 20 and 40 days, respectively), biomass of juveniles exposed to 1.52 mg.L-1 NO2- was significantly lower than the biomass of juveniles exposed to other treatments. Therefore, the safe level of nitrite for growth of silver catfish juveniles is below 1.19 mg.L-1 (2% of LC50-96h). Exposure of silver catfish to NO2- for 40 days reduced lactate levels in muscle, but lactate levels increased in liver tissue of fish maintained at 1.19 mg.L-1 NO2-. In addition, glucose levels in muscle and liver tissues were significantly lower in silver catfish exposed to the highest NO2- level. These results indicate that chronic NO2- exposure causes anaerobic substrate oxidation to meet energy demand.<br>Altos níveis de nitrito (NO2-) podem ocorrer em sistemas de cultivo com alta densidade de estocagem, mas análises sobre os valores de concentração letal e o efeito do NO2- em parâmetros metabólicos e no crescimento são escassos. Neste estudo foi analisada a concentração letal em 96 h (CL50-96h) para nitrito (NO2-) em juvenis de jundiá, Rhamdia quelen, e o efeito de quatro níveis de nitrito (0,06; 0,46; 1,19 e 1,52 mg.L-1) no crescimento e no lactato, glicose, glicogênio e proteína hepática e muscular. A CL50-96h para NO2- foi 20,46 (intervalo de confiança: 16,10-23,68) mg.L-1. No experimento de crescimento, a exposição ao NO2- não afetou o peso, comprimento ou taxa de crescimento específico, mas devido à mortalidade (66,7% e 100% após 20 e 40 dias, respectivamente), a biomassa dos juvenis expostos a 1,52 mg.L-1. NO2- foi significativamente mais baixa que a biomassa dos juvenis expostos aos outros tratamentos. Deste modo, o nível seguro de NO2- para o crescimento do jundiá é abaixo de 1,19 mg.L-1 (2% da CL50-96h). A exposição do jundiá ao NO2- por 40 dias diminuiu os níveis de lactato no músculo, mas esses níveis aumentaram nos exemplares mantidos em 1,19 mg.L-1 NO2-. Além disso, os níveis de glicose no músculo e fígado foram significativamente mais baixos nos jundiás expostos à concentração mais elevada de NO2-. Estes resultados indicam que a exposição crônica ao NO2- provoca uma oxidação anaeróbica do substrato para obtenção de energia

The effect of interspecific oocytes on demethylation of sperm DNA

none12noneBEAUJEAN N; TAYLOR JE; MCGARRY M; GARDNER JO; WILMUT I; LOI P; PTAK G; GALLI C.; LAZZARI G; BIRD A; YOUNG LE; MEEHAN RRBEAUJEAN N; TAYLOR JE; MCGARRY M; GARDNER JO; WILMUT I; LOI P; PTAK G; GALLI C.; LAZZARI G; BIRD A; YOUNG LE; MEEHAN R