Antigen 85C inhibition restricts Mycobacterium tuberculosis growth through disruption of cord factor biosynthesis

The antigen 85 (Ag85) protein family, consisting of Ag85A, -B, and -C, is vital for Mycobacterium tuberculosis due to its role in cell envelope biogenesis. The mycoloyl transferase activity of these proteins generates trehalose dimycolate (TDM), an envelope lipid essential for M. tuberculosis virulence, and cell wall arabinogalactan-linked mycolic acids. Inhibition of these enzymes through substrate analogs hinders growth of mycobacteria, but a link to mycolic acid synthesis has not been established. In this study, we characterized a novel inhibitor of Ag85C, 2-amino-6-propyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile (I3-AG85). I3-AG85 was isolated from a panel of four inhibitors that exhibited structure- and dose-dependent inhibition of M. tuberculosis division in broth culture. I3-AG85 also inhibited M. tuberculosis survival in infected primary macrophages. Importantly, it displayed an identical MIC against the drug-susceptible H37Rv reference strain and a panel of extensively drug-resistant/multidrug-resistant M. tuberculosis strains. Nuclear magnetic resonance analysis indicated binding of I3-AG85 to Ag85C, similar to its binding to the artificial substrate octylthioglucoside. Quantification of mycolic acid-linked lipids of the M. tuberculosis envelope showed a specific blockade of TDM synthesis. This was accompanied by accumulation of trehalose monomycolate, while the overall mycolic acid abundance remained unchanged. Inhibition of Ag85C activity also disrupted the integrity of the M. tuberculosis envelope. I3-AG85 inhibited the division of and reduced TDM synthesis in an M. tuberculosis strain deficient in Ag85C. Our results indicate that Ag85 proteins are promising targets for novel antimycobacterial drug design.     

Calibration of diffuse correlation spectroscopy with a time-resolved near-infrared technique to yield absolute cerebral blood flow measurements

A primary focus of neurointensive care is the prevention of secondary brain injury, mainly caused by ischemia. A noninvasive bedside technique for continuous monitoring of cerebral blood flow (CBF) could improve patient management by detecting ischemia before brain injury occurs. A promising technique for this purpose is diffuse correlation spectroscopy (DCS) since it can continuously monitor relative perfusion changes in deep tissue. In this study, DCS was combined with a time-resolved near-infrared technique (TR-NIR) that can directly measure CBF using indocyanine green as a flow tracer. With this combination, the TR-NIR technique can be used to convert DCS data into absolute CBF measurements. The agreement between the two techniques was assessed by concurrent measurements of CBF changes in piglets. A strong correlation between CBF changes measured by TR-NIR and changes in the scaled diffusion coefficient measured by DCS was observed (R(2) = 0.93) with a slope of 1.05 ± 0.06 and an intercept of 6.4 ± 4.3% (mean ± standard error).     

IL-2,IL-7,IL-15和IL-21在艾滋病免疫疗法中的应用前景

高效抗反转录病毒疗法可以有效地减少HIV的复制,但却不能完全恢复CD4+T细胞的数量.即使病毒血清学指标得到良好控制的病人,CD4+T细胞数也很难达到正常水平.目前研究表明:γ链细胞因子在始动、维持及调节免疫稳态和炎症反应中发挥重要作用.γ链细胞因子具有多重功能,如在健康及疾病中作为调节和效应分子发挥作用,因此,该家族...     

Portrait of socio-economic inequality in childhood morbidity and mortality over time, Québec, 1990-2005

Aim: To determine the age and cause groups contributing to absolute and relative socio‐economic inequalities in paediatric mortality, hospitalisation and tumour incidence over time. Methods: Deaths (n= 9559), hospitalisations (n= 834 932) and incident tumours (n= 4555) were obtained for five age groupings (<1, 1–4, 5–9, 10–14, 15–19 years) and four periods (1990–1993, 1994–1997, 1998–2001, 2002–2005) for Québec, Canada. Age‐ and cause‐specific morbidity and mortality rates for males and females were calculated across socio‐economic status decile based on a composite deprivation score for 89 urban communities. Absolute and relative measures of inequality were computed for each age and cause. Results: Mortality and morbidity rates tended to decrease over time, as did absolute and relative socio‐economic inequalities for most (but not all) causes and age groups, although precision was low. Socio‐economic inequalities persisted in the last period and were greater on the absolute scale for mortality and hospitalisation in early childhood, and on the relative scale for mortality in adolescents. Four causes (respiratory, digestive, infectious, genito‐urinary diseases) contributed to the majority of absolute inequality in hospitalisation (males 85%, females 98%). Inequalities were not pronounced for cause‐specific mortality and not apparent for tumour incidence. Conclusions: Socio‐economic inequalities in Québec tended to narrow for most but not all outcomes. Absolute socio‐economic inequalities persisted for children <10 years, and several causes were responsible for the majority of inequality in hospitalisation. Public health policies and prevention programs aiming to reduce socio‐economic inequalities in paediatric health should account for trends that differ across age and cause of disease.     

Unexpected Rift Valley fever outbreak, northern Mauritania

During September-October 2010, an unprecedented outbreak of Rift Valley fever was reported in the northern Sahelian region of Mauritania after exceptionally heavy rainfall. Camels probably played a central role in the local amplification of the virus. We describe the main clinical signs (hemorrhagic fever, icterus, and nervous symptoms) observed during the outbreak.     

Seroprevalence of Chikungunya virus infection on Grande Comore Island, union of the Comoros, 2005

An outbreak of Chikungunya virus (CHIKV) illness associated with high fever combined with prolonged and severe arthralgias occurred on Grande Comore Island from January through May 2005; 5,202 cases were reported. A seroprevalence study was conducted to define the extent of transmission on the island. We conducted a cross-sectional survey using a multistage sampling technique. A total of 481 households were sampled. In each household, one resident was selected randomly for interview and blood collection. We administered questionnaires and tested 331 sera for CHIKV-specific IgM and IgG antibodies by capture enzyme-linked immunosorbent assay. Infection with CHIKV infection (seropositivity) was defined as presence of IgG and/or IgM antibodies to CHIKV. A total of 331 (69%) of 481 survey participants consented to blood collection. Antibodies to CHIKV were detected in 63% of sera; IgM antibodies were found in 60% of specimens and IgG antibodies were detected in 27% of specimens. Extrapolation of the findings to the entire Grande Comore population suggested that nearly 215,000 people were infected with CHIKV during the outbreak. A total of 79% of the seropositive persons were hospitalized or stayed at home in bed for a mean of 6 days (range = 1-30 days); 52% missed work or school for a mean of 7 days (range = 1-40 days). The findings suggest that CHIKV was broadly transmitted during the outbreak with a high attack rate. Although not fatal during this outbreak, CHIKV infection caused significant morbidity and decreased economic productivity.