Alcohol reversibly disrupts TNF-α/TACE interactions in the cell membrane

BACKGROUND: Alcohol abuse has long been known to adversely affect innate and adaptive immune responses and pre-dispose to infections. One cellular mechanism responsible for this effect is alcohol-induced suppression of TNF-α (TNF) by mononuclear phagocytes. We have previously shown that alcohol in part inhibits TNF-α processing by TNF converting enzyme (TACE) in human monocytes. We hypothesized that the chain length of the alcohol is critical for post-transcriptional suppression of TNF secretion. METHODS: Due to the complex transcriptional and post-transcriptional regulation of TNF in macrophages, to specifically study TNF processing at the cell membrane we performed transient transfections of A549 cells with the TNF cDNA driven by the heterologous CMV promoter. TNF/TACE interactions at the cell surface were assessed using fluorescent resonance energy transfer (FRET) microscopy. RESULTS: The single carbon alcohol, methanol suppressed neither TNF secretion nor FRET efficiency between TNF and TACE. However, 2, 3, and 4 carbon alcohols were potent suppressors of TNF processing and FRET efficiency. The effect of ethanol, a 2-carbon alcohol was reversible. CONCLUSION: These data show that inhibition of TNF-α processing by acute ethanol is a direct affect of ethanol on the cell membrane and is reversible upon cessation or metabolism

Vaccination against Heterologous R5 Clade C SHIV: Prevention of Infection and Correlates of Protection

A safe, efficacious vaccine is required to stop the AIDS pandemic. Disappointing results from the STEP trial implied a need to include humoral anti-HIV-1 responses, a notion supported by RV144 trial data even though correlates of protection are unknown. We vaccinated rhesus macaques with recombinant simian immunodeficiency virus (SIV) Gag-Pol particles, HIV-1 Tat and trimeric clade C (HIV-C) gp160, which induced cross-neutralizing antibodies (nAbs) and robust cellular immune responses. After five low-dose mucosal challenges with a simian-human immunodeficiency virus (SHIV) that encoded a heterologous R5 HIV-C envelope (22.1% divergence from the gp160 immunogen), 94% of controls became viremic, whereas one third of vaccinees remained virus-free. Upon high-dose SHIV rechallenge, all controls became infected, whereas some vaccinees remained aviremic. Peak viremia was inversely correlated with both cellular immunity (p<0.001) and cross-nAb titers (p<0.001). These data simultaneously linked cellular as well as humoral immune responses with the degree of protection for the first time

Regional research priorities in brain and nervous system disorders

The characteristics of neurological, psychiatric, developmental and substance-use disorders in low-and middle-income countries are unique and the burden that they have will be different from country to country. Many of the differences are explained by the wide variation in population demographics and size, poverty, conflict, culture, land area and quality, and genetics. Neurological, psychiatric, developmental and substance-use disorders that result from, or are worsened by, a lack of adequate nutrition and infectious disease still afflict much of sub-Saharan Africa, although disorders related to increasing longevity, such as stroke, are on the rise. In the Middle East and North Africa, major depressive disorders and post-traumatic stress disorder are a primary concern because of the conflict-ridden environment. Consanguinity is a serious concern that leads to the high prevalence of recessive disorders in the Middle East and North Africa and possibly other regions. The burden of these disorders in Latin American and Asian countries largely surrounds stroke and vascular disease, dementia and lifestyle factors that are influenced by genetics. Although much knowledge has been gained over the past 10 years, the epidemiology of the conditions in low-and middle-income countries still needs more research. Prevention and treatments could be better informed with more longitudinal studies of risk factors. Challenges and opportunities for ameliorating nervous-system disorders can benefit from both local and regional research collaborations. The lack of resources and infrastructure for health-care and related research, both in terms of personnel and equipment, along with the stigma associated with the physical or behavioural manifestations of some disorders have hampered progress in understanding the disease burden and improving brain health. Individual countries, and regions within countries, have specific needs in terms of research priorities.Fil: Ravindranath, Vijayalakshmi. Indian Institute of Science; IndiaFil: Dang, Hoang Minh. Vietnam National University; VietnamFil: Goya, Rodolfo Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata ; ArgentinaFil: Mansour, Hader. University of Pittsburgh; Estados Unidos. Mansoura University; EgiptoFil: Nimgaonkar, Vishwajit L.. University of Pittsburgh; Estados UnidosFil: Russell, Vivienne Ann. University of Cape Town; SudáfricaFil: Xin, Yu. Peking University; Chin

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

Variation in the composition of carbohydrates in the Dona Paula Bay (west of India) during May/June 1998

Suspended particulate material was analysed for particulate carbohydrate concentration and composition and for the bulk parameters: suspended particulate matter, chlorophyll a, particulate organic carbon, particulate organic nitrogen and particulate proteins. Chlorophyll a concentrations increased from May 7 to 15 due to the development of a small scale bloom of diatom Navicula sp. and decreased for the remaining period after the premonsoon rain on 16 and 17 May. Concentrations of particulate organic carbon, organic nitrogen, carbohydrates and proteins increased with the increase in chlorophyll a concentration. Together particulate protein-carbon and carbohydrate-carbon accounted for 10 to 30% of the organic carbon. Glucose contributed 26 to 81% to the total particulate carbohydrates. The decrease in glucose concentration was accompanied by the increase in mannose, galactose, xylose, arabinose, rhamnose and fucose. Chlorophyll a showed significant positive relationship with glucose and negative relationships with arabinose and xylose. Conversely, suspended particulate matter showed significant positive relationships with xylose and arabinose and negative relationships with chlorophyll a and glucose. The hexoses to pentoses ratio increased during 7 to 15 May and decreased thereafter. Relatively higher chlorophyll a, particulate protein-carbon plus carbohydrate-carbon, glucose, hexoses:pentoses ratio and lower rhamnose plus fucose suggested the presence of more fresh marine organic matter during May 8 to 15. Subsequently, chlorophyll a, contribution of particulate protein-carbon plus carbohydrates-carbon to organic carbon, hexoses to pentoses ratio, and weight percentage of glucose decreased whereas, weight percentage of rhamnose plus fucose, arabinose and xylose increased, reflecting highly degraded diagenetically altered particulate organic matter from May 16 to June 2. The carbohydrate content and composition as well as protein data suggest that the nature and source of organic matter Varied within a few days at this tropical coastal site. Such variability in the nutritional quality of organic matter may have a strong influence on the metabolic activity of filter feeding organisms.La concentration en chlorophylle a a augmenté du 7 au 15 mai (floraison de la diatomée Navicula sp.), avant de décroître après l’épisode pluvieux des 16 et 17 mai. Les concentrations de carbone et d’azote organique particulaires, ainsi que les hydrates de carbone et les protéines varient parallèlement à la chlorophylle a. Le carbone particulaire (protéines et hydrates de carbone) représente de 10 à 30% du carbone organique. Le glucose représente de 26 à 81% du total des hydrates de carbone dans le matériel particulaire. Sa décroissance est accompagnée de l’accroissement du mannose, du galactose, du xylose, de l’arabinose, du rhamnose et du fucose. La chlorophylle a présente une corrélation positive avec le glucose et négative avec l’arabinose et le xylose. La matière particulaire en suspension est positivement corrélée au xylose et à l’arabinose et négativement à la chlorophylle a et au glucose. Le rapport hexoses/pentoses s’élève du 7 au 15 mai et décroît après. Les concentrations relativement élevées en chlorophylle a, en carbone sous forme de protéines et d’hydrates de carbone, en glucose et le taux hexoses/pentoses élevé ainsi que les valeurs basses du rhamnose plus fucose suggèrent la présence de matière organique marine néoformée dans la période du 8 au 15 mai. Les tendances inverses s’observent du 16 mai au 2 juin. La teneur et la composition en hydrates de carbone, ainsi que les données de protéines suggèrent une variation de l’origine de la matière organique en peu de jours à ce site côtier tropical. Une telle variabilité de la qualité nutritive de la matière organique doit avoir une forte influence sur l’actvité métabolique des filtreurs