Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found an association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 (P = 2.6 × 10−11 for rs4733781; P = 1.0 × 10−10 for rs10956514). Dendritic cells (DCs) showed high ASAP1 expression that was reduced after Mycobacterium tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in M. tuberculosis–infected DCs may lead to their impaired migration, suggesting a potential mechanism of predisposition to TB

Network modelling for road-based Faecal Sludge Management

Improvements in the collection and treatment of sewage are critical to reduce health and environmental hazards in rapidly-urbanising informal settlements. Where sewerage infrastructure is not available, road-based Fecal Sludge Management options are often the only alternative. However, the costs of fecal sludge transportation are often a barrier to their implementation and operation and thus it is desirable to optimise travel time from source to treatment to reduce costs. This paper presents a novel technique, employing spatial network analysis, to optimise the spatio-topological configuration of a road-based fecal sludge transportation network on the basis of travel time. Using crowd-sourced spatial data for the Kibera settlement and the surrounding city, Nairobi, a proof-of-concept network model was created simulating the transport of waste from the 158 public toilets within Kibera. The toilets are serviced by vacuum pump trucks which move fecal sludge to a transfer station from where a tanker transports waste to a treatment plant. The model was used to evaluate the efficiency of different network configurations, based on transportation time. The results show that the location of the transfer station is a critical factor in network optimisation, demonstrating the utility of network analysis as part of the sanitation planning process

Variant G57E of Mannose Binding Lectin Associated with Protection against Tuberculosis Caused by Mycobacterium africanum but not by M. tuberculosis

Structural variants of the Mannose Binding Lectin (MBL) cause quantitative and qualitative functional deficiencies, which are associated with various patterns of susceptibility to infectious diseases and other disorders. We determined genetic MBL variants in 2010 Ghanaian patients with pulmonary tuberculosis (TB) and 2346 controls and characterized the mycobacterial isolates of the patients. Assuming a recessive mode of inheritance, we found a protective association between TB and the MBL2 G57E variant (odds ratio 0.60, confidence interval 0.4–0.9, P 0.008) and the corresponding LYQC haplotype (Pcorrected 0.007) which applied, however, only to TB caused by M. africanum but not to TB caused by M. tuberculosis. In vitro, M. africanum isolates bound recombinant human MBL more efficiently than did isolates of M. tuberculosis. We conclude that MBL binding may facilitate the uptake of M. africanum by macrophages, thereby promoting infection and that selection by TB may have favoured the spread of functional MBL deficiencies in regions endemic for M. africanum

An SNP selection strategy identified IL-22 associating with susceptibility to tuberculosis in Chinese

Recent studies showed that IL-22 plays a protective role in the host defense. However, the contribution of polymorphisms of the IL-22 gene to human TB susceptibility remains untested. We have designed a computational approach to select functional SNPs in the IL-22 gene and genotyped them in a two-stage case-control study in Chinese (479 cases and 358 controls). We found that rs2227473, an SNP in the promoter region of IL-22, is associated with TB susceptibility at both stages of our study. The SNP shows associations with p-values of 0.028 and 0.034 respectively, and a combined p-value of 0.0086, with odds ratio at 0.65 (95% confidence interval 0.45–0.90). We further validated the association with an independent cohort (413 cases and 241 controls in Chinese). Our functional studies showed that patients with A allele have significantly higher IL-22 expression than those without A allele under both non-specific and specific stimulations

The association between diabetes mellitus, glucose, and chronic musculoskeletal complaints. Results from the Nord-Trøndelag Health Study

<p>Abstract</p> <p>Background</p> <p>The relationship between diabetes mellitus (DM) and chronic musculoskeletal complaints (MSCs) is unclear. The aim of this study was to investigate the association between DM, non-fasting glucose and chronic MSCs defined as pain and/or stiffness ≥ 3 months during the past year in the general adult population.</p> <p>Methods</p> <p>The results were based on cross-sectional data from 64,785 men and women (aged ≥ 20 years) who participated in the Nord-Trøndelag Health Survey, which included 1,940 individuals with known DM. Associations were assessed using multiple logistic regression, estimating prevalence odds ratio (OR) with 95% confidence intervals (CIs).</p> <p>Results</p> <p>High non-fasting glucose was associated with a lower prevalence of chronic MSCs compared to a low glucose level. DM was associated with higher prevalence of chronic MSCs, in particular chronic widespread MSCs. In the multivariate analysis, adjusting for glucose level, BMI, age, gender and physical activity, chronic widespread MSCs was 1.6 times more likely (OR = 1.6, 95% CI 1.2–2.2) among individuals < 60 years of age with DM than among those without DM. The association between chronic widespread MSCs and DM was most evident among the group of individuals aged < 60 years with either type 2 DM or unclassified DM (OR = 1.8, 95% CI 1.3–2.5).</p> <p>Conclusion</p> <p>In this cross-sectional study a high non-fasting glucose was associated with lower prevalence of chronic MSCs. Among individuals with known DM chronic widespread MSCs were more likely.</p

CCL2/MCP-I Genotype-Phenotype Relationship in Latent Tuberculosis Infection

Among the known biomarkers, chemokines, secreted by activated macrophages and T cells, attract groups of immune cells to the site of infection and may determine the clinical outcome. Association studies of CCL-2/MCP-1 -2518 A/G functional SNP linked to high and low phenotypes with tuberculosis disease susceptibility have shown conflicting results in tuberculosis. Some of these differences could be due the variability of latent infection and recent exposure in the control groups. We have therefore carried out a detailed analysis of CCL-2 genotype SNP -2518 (A/G transition) with plasma CCL-2 levels and related these levels to tuberculin skin test positivity in asymptomatic community controls with no known exposure to tuberculosis and in recently exposed household contacts of pulmonary tuberculosis patients. TST positivity was linked to higher concentrations of plasma CCL2 (Mann Whitney U test; p = 0.004) and was more marked when the G allele was present in TST+ asymptomatic controls (A/G; p = 0.01). Recent exposure also had a significant effect on CCL-2 levels and was linked to the G allele (p = 0.007). Therefore association studies for susceptibility or protection from disease should take into consideration the PPD status as well as recent exposure of the controls group used for comparison. Our results also suggest a role for CCL-2 in maintaining the integrity of granuloma in asymptomatic individuals with latent infection in high TB burden settings. Therefore additional studies into the role of CCL-2 in disease reactivation and progression are warranted

Interaction, Emotion, and Collective Identities

[Excerpt] This chapter poses the question: How do emotional aspects of social interaction affect the emergence and salience of collective identities? I assume that social interaction inherently involves an implicit or explicit joint task—namely to accomplish some result that can only be produced with others. The most fundamental “task” of social interaction can be construed as the coordination and alignment of behavior, such that actors successfully conclude the interact ion episode. Essential to this task is a working consensus about definitions of self and other in the social situation, i.e., consensual self-other identities. A central component of my argument is that social interaction has emotional effects that vary with the success of actors at accomplishing this fundamental task. This paper theorizes the conditions under which emotional effects of social interaction promote collective identities that bridge or transcend self-other role identities