BackgroundGenetic variants at the vitamin D receptor (VDR) locus are associated with asthma and atopy. We hypothesized that polymorphisms in other genes of the vitamin D pathway are associated with asthma or atopy.MethodsEleven candidate genes were chosen for this study, five of which code for proteins in the vitamin D metabolism pathway (CYP27A1, CYP27B1, CYP2R1, CYP24A1, GC) and six that are known to be transcriptionally regulated by vitamin D (IL10, IL1RL1, CD28, CD86, IL8, SKIIP). For each gene, we selected a maximally informative set of common SNPs (tagSNPs) using the European-derived (CEU) HapMap dataset. A total of 87 SNPs were genotyped in a French-Canadian family sample ascertained through asthmatic probands (388 nuclear families, 1064 individuals) and evaluated using the Family Based Association Test (FBAT) program. We then sought to replicate the positive findings in four independent samples: two from Western Canada, one from Australia and one from the USA (CAMP).ResultsA number of SNPs in the IL10, CYP24A1, CYP2R1, IL1RL1 and CD86 genes were modestly associated with asthma and atopy (p < 0.05). Two-gene models testing for both main effects and the interaction were then performed using conditional logistic regression. Two-gene models implicating functional variants in the IL10 and VDR genes as well as in the IL10 and IL1RL1 genes were associated with asthma (p < 0.0002). In the replicate samples, SNPs in the IL10 and CYP24A1 genes were again modestly associated with asthma and atopy (p < 0.05). However, the SNPs or the orientation of the risk alleles were different between populations. A two-gene model involving IL10 and VDR was replicated in CAMP, but not in the other populations.ConclusionA number of genes involved in the vitamin D pathway demonstrate modest levels of association with asthma and atopy. Multilocus models testing genes in the same pathway are potentially more effective to evaluate the risk of asthma, but the effects are not uniform across populations.

Abstract-Coxsackievirus (CV)B3 is the primary cause of viral myocarditis. We previously observed CXC chemokine ligand 10 (CXCL10) upregulation in the myocardium early in infection. However, the impact of CXCL10 in CVB3-induced myocarditis is unknown. Using isolated primary mouse cardiomyocytes we demonstrated for the first time that cardiomyocytes can express CXCL10 on interferon-␥ stimulation. To explore the role of CXCL10 in CVB3-induced myocarditis, both CXCL10 transgenic and knockout mice were used. Following CVB3 challenges, the viral titer in the hearts inversely correlated with the levels of CXCL10 at early phase of infection before visible immune infiltration. Furthermore, as compared with the control mice, the decreased virus titers in the CXCL10 transgenic mouse hearts led to less cardiac damage and better cardiac function and vice verse in the knockout mice. This antiviral ability of CXCL10 might be through recruitment of natural killer (NK) cells to the heart and increased interferon-␥ expression early in infection. At day 7 postinfection, with massive influx of mononuclear cells the expression of CXCL10 enhanced the infiltration of CXCR3 ϩ cells, CD4ϩ , and CD8 ϩ T cells, as well as the expression of associated inflammatory cytokines. However, the augmented accumulation of these immune cells and associated cytokines failed to alter the viral clearance and mice survival. These results suggest the protective role of CXCL10 during the early course of CVB3 infection, which is attributed to the recruitment of NK cells. Nonetheless, CXCL10-directed chemoattractant effect is not sufficient for host to clear the virus in the heart. (Circ Res. 2009;104:628-638.) Key Words: cardiomyocytes Ⅲ chemokine CXCL 10 Ⅲ coxsackievirus Ⅲ myocarditis Ⅲ natural killer cells C oxsackievirus (CV)B3 has been recognized as the predominant cause of viral myocarditis in humans. 1 This disease is composed of three distinct stages including viremic injury, immune infiltration, and reclamation. 2 Earlier studies have suggested that mechanisms of viral myocarditis include direct myocyte injury by CVB3 and subsequent immune-mediated damage of the heart. 3,4 The essential role of the immune response in combating viral myocarditis has been demonstrated by recent studies using a series of knockout (KO) mice. Conversely, others have argued that the robust protective response can also be deleterious to host tissue to some extent. For instance, mice lacking T cells or T cell subsets developed less severe disease following CVB3 inoculation. 5 However, general immunosuppressive therapy did not benefit patients with myocarditis, 6 raising the need for better understanding the role of major immune mediators in disease cascade of CVB-induced myocarditis.During the process of leukocyte trafficking, it is well known that chemokines are the principle chemotactic factors to mediate leukocyte migration to the site of infection. 7 CXC chemokines, including interferon (IFN)-inducible protein 10 (IP10/CXCL10), monokine induced by IFN-␥ (Mig/CXCL9), an...

The high prevalence of diabetes mellitus (DM) among multidrug resistant tuberculosis (MDR-TB) patients is a serious cause for concern. We conducted a meta-analysis to determine whether DM is an independent risk factor for MDR-TB. Electronic literature searches of the PubMed, Web of Science and EMBASE databases up to July 12, 2016 were conducted. The pooled adjusted odds ratio (OR) and 95% confidence intervals (CIs) were calculated using the random effects model with STATA 12.0 software. In total 13 studies, including 9289 individuals with TB, were included in this meta-analysis. Significant association between DM and MDR-TB (OR = 1.71; 95% CI = 1.32, 2.22) was identified. Subgroup analyses showed that: 1) Pooled OR was 1.25 (95% CI: 0.82–1.91) for cross-sectional studies, and was 2.14 (95% CI: 1.51–3.02) for longitudinal studies; 2) The pooled OR was 1.69 (95% CI:1.09–2.62) for primary MDR-TB, 1.94 (95% CI:1.42–2.65) for any MDR-TB, and 0.85 for secondary MDR-TB (95% CI: 0.29–2.54); 3) DM was significantly associated with MDR-TB in both Caucasian (OR = 2.26, 95% CI: 1.66–3.07) and Asian (OR = 1.40, 95% CI: 1.01–1.95) subgroups. No evidence of publication bias was identified. In conclusion, the pooling analysis indicated that DM was an independent risk factor for MDR-TB, especially for primary MDR-TB.

Understanding the composition of the microbial populations in the intestines of liver transplant patients is important to preventing postoperative infection. We investigated the relationship between the risk of postoperative infection and variation in the predominant fecal microbial composition during the perioperative period. We prospectively analyzed the predominant intestinal microbiome of five asymptomatic adult carriers of hepatitis B virus (as controls without any antibiotics) at four weekly follow-up visits and 12 patients before operation and at three weekly postoperative follow-up visits within the first month. Analysis was by denaturing gradient gel electrophoresis (DGGE) and sequencing with digital processing of DGGE profiles using BioNumerics software. Our results showed that the predominant intestinal microbial diversity decreased substantially in eight patients during the perioperative period. Among these, five patients experienced infection with a postoperative hospital stay of more than 30 days. The rest of the four patients who experienced shorter postoperative hospital stays showed only slight variation in predominant intestinal bacterial composition and temporal stability similar to asymptomatic controls. Postoperative fecal DGGE profiles showed mostly bands assigned to Bacteroides and Firmicutes. We conclude that an empiric prophylaxis strategy that destructs gut microecological balance will not be effective in reducing the risk of postoperative infection. Instead, the destruction of intestinal microbiota might result in the appearance of opportunistic pathogens such as Bifidobacterium dentium which rarely appears in the intestinal DGGE profiles of normal humans. Cognizance of the variation of intestinal microbial profiles during the perioperative period is a critical aspect of caring for liver transplant recipients.