Variations in Helicobacter pylori lipopolysaccharide to evade the innate immune component surfactant protein D

Helicobacter pylori is a common and persistent human pathogen of the gastric mucosa. Surfactant protein D (SP-D), a component of innate immunity, is expressed in the human gastric mucosa and is capable of aggregating H. pylori. Wide variation in the SP-D binding affinity to H. pylori has been observed in clinical isolates and laboratory-adapted strains. The aim of this study was to reveal potential mechanisms responsible for evading SP-D binding and establishing persistent infection. An escape variant, J178V, was generated in vitro, and the lipopolysaccharide (LPS) structure of the variant was compared to that of the parental strain, J178. The genetic basis for structural variation was explored by sequencing LPS biosynthesis genes. SP-D binding to clinical isolates was demonstrated by fluorescence-activated cell sorter analyses. Here, we show that H. pylori evades SP-D binding through phase variation in lipopolysaccharide. This phenomenon is linked to changes in the fucosylation of the O chain, which was concomitant with slipped-strand mispairing in a poly(C) tract of the fucosyltransferase A (fucT1) gene. SP-D binding organisms are predominant in mucus in vivo (P = 0.02), suggesting that SP-D facilitates physical elimination. Phase variation to evade SP-D contributes to the persistence of this common gastric pathogen.     

Relationship between Serum 25(OH)D and Depression: Causal Evidence from a Bi-Directional Mendelian Randomization Study

The relationship between depression and vitamin D deficiency is complex, with evidence mostly from studies affected by confounding and reverse causality. We examined the causality and direction of the relationship between 25-hydroxyvitamin D (25(OH)D) and depression in bi-directional Mendelian randomization (MR) analyses using information from up to 307,618 white British participants from the UK Biobank and summary results from the SUNLIGHT (n = 79,366) and Psychiatric Genomics consortia (PGC 113,154 cases and 218,523 controls). In observational analysis, the odds of depression decreased with higher 25(OH)D concentrations (adjusted odds ratio (OR) per 50% increase 0.95, 95%CI 0.94–0.96). In MR inverse variance weighted (IVW) using the UK Biobank, there was no association between genetically determined serum 25(OH)D and depression (OR per 50% higher 0.97, 95%CI 0.90–1.05) with consistent null association across all MR approaches and in data from PGC consortium. In contrast, genetic liability to depression was associated with lower 25(OH)D concentrations (MR IVW −3.26%, −4.94%–−1.55%), with the estimates remaining generally consistent after meta-analysing with the consortia. In conclusion, we found genetic evidence for a causal effect of depression on lower 25(OH)D concentrations, however we could not confirm a beneficial effect of nutritional vitamin D status on depression risk.     

IFN‐γ against the 38‐kDa antigen of Mycobacterium tuberculosis discriminates pulmonary tuberculosis from infection and infection from exposure: evidence from a study of human population in a high endemic setting

Mycobacterium tuberculosis (Mtb) 38‐kDa antigen is an immunogenic lipoprotein that induces strong T‐cell responses in experimental animals. However, there is limited information on the role of this antigen in human population. In this article, we present the dynamics of pro‐inflammatory (IFN‐γ and TNF‐α) and anti‐inflammatory cytokine (IL‐10) against the 38 kDa in cohorts of pulmonary TB (PTB) patients, household contacts (HHCs), and community controls (CCs) in a high endemic setting. Whole blood assay was used to determine the levels of cytokines in 149 patients, 149 HHCs, and 68 CCs at baseline, 6 months, and 12 months. At baseline, the level of IFN‐γ was significantly (p < 0.0001) higher in CCs and HHCs than in untreated patients. CCs had significantly (p < 0.05) higher level of IFN‐γ than HHCs. There was no significant difference between treated and untreated patients, and there was no significant change in HHCs over 12 months. At baseline, the levels of IL‐10 and TNF‐α were significantly (p < 0.0001) higher in patients than in HHCs and CCs. No significant change was observed between treated patients and untreated patients and HHCs over time. The study shows that IFN‐γ against the 38 kDa discriminates clinical TB from infection and infection from exposure, suggesting its potential for immune protection and diagnosis.     

Effect of a thrombin receptor (protease-activated receptor 1, PAR-1) gene polymorphism in chronic hepatitis C liver fibrosis

Background and Aim:  Tissue injury leads to activation of coagulation and generation of thrombin. Inhibition of thrombin receptor protease-activated receptor 1 (PAR-1) has been shown to reduce liver fibrosis in animals. This study aimed to evaluate the effect of PAR-1 gene polymorphism on rate of liver fibrosis (RF) in chronic hepatitis C.
Methods:  Polymorphisms studied: C > T transition 1426 bp upstream of translation start site (-1426C/T), 13 bp repeat of preceding -506 5'-CGGCCGCGGGAAG-3' sequence (-506I/D), and A > T transversion in intervening sequence (IVS) 14 bp upstream of exon-2 start site (IVS-14A/T). A total of 287 European and 90 Brazilian patients were studied.
Results:  1426C/T polymorphism: There was a trend to higher RF in patients with the TT genotype ( P  = 0.06) and an association between genotype CC and slow fibrosis ( P  = 0.03) in Europeans. In males, RF was significantly higher in those with the TT genotype compared to CT ( P  = 0.003) and CC ( P  = 0.007). There was a significant association between TT and fast fibrosis ( P  = 0.04). This was confirmed in an independent cohort of Brazilians where RF was higher in TT than in CC ( P  = 0.03). Analysis of -506I/D showed no difference in RF and distribution of slow/fast fibrosis among different genotypes in both populations. Analysis of IVS-14A/T showed no difference between genotypes.
Conclusion:  In conclusion, these findings suggest that PAR-1 receptor polymorphisms influence the progression of liver fibrosis.     

The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition of Mycobacterium tuberculosis viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against M. tuberculosis in vitro, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition of M. tuberculosis growth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistant M. tuberculosis strains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target against M. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development.     

Antibiogram of E. coli serotypes isolated from children aged under five with acute diarrhea in Bahir Dar town

Background

Diarrheal disease and its complications remain a major cause of morbidity and mortality in children. The prevalence and antibiogram of E. coli as causative agents of diarrhea vary from region to region, and even within countries in the same geographical area.

Objectives

To determine the serotype and antimicrobial susceptibility of E. coli in children under-five years of age.

Methods

A cross-sectional study was conducted among 422 children with diarrhea from December 2011 to February 2012. Identification of E. coli and antimicrobial susceptibility testing were done following standard procedures.

Results

The overall isolation rate of E. coli was 48.3%. Poly 2 sero-groups, poly 3 sero-groups, poly 4 sero-groups and E. coli O157:H7 accounted for 80 (39.2%), 40 (19.6%), 25 (12.3%), and 59 (28.9%) of the isolates, respectively. Poly 2 sero-groups, constituting isolates belonging to enteropathogenic E. coli were the most commonly isolated serotypes. E. coli exhibited high levels of antimicrobial resistance to ampicillin (86.8%), tetracycline (76%) and cotrimoxazole (76%). Low levels of resistance to ciprofloxacin (6.9%) and norfloxacin (9.3%) were documented.

Conclusion

High prevalence of diarrheagenic E. coli compounded by alarming antimicrobial resistances is a serious public health problem. Regular determination of antibiogram and public education are recommended.     

Longitudinal control of blood pressure among a cohort of Ghanaians with hypertension: A multicenter,hospital‐based study

There are limited data on factors associated with longitudinal control of blood pressure (BP) among Ghanaians on antihypertensive treatment. We sought to evaluate associations between prospective BP control and 24 putative factors within socio‐demographic, biological, and organizational domains. This is a cohort study involving 1867 (65%) adults with hypertension and 1006 (35%) with both hypertension and diabetes mellitus at five public hospitals. Clinic BP was measured every 2 months for 18 months of follow‐up. A multivariate logistic regression analysis was fitted via generalized linear mixed models to identify factors associated with clinic BP ≥ 140/90 mm Hg at each clinic visit during follow‐up. Mean age of study participants was 58.9 ± 16.6 years and 76.8% were females. Proportions with controlled BP increased from 46.3% at baseline to 59.8% at month 18, P < .0001. Eight factors with adjusted OR (95% CI) associated prospectively with uncontrolled BP were male gender: 1.37 (1.09‐1.72), secondary education: 1.32 (1.00‐1.74), non‐adherence to antihypertensive treatment: 1.03 (1.00‐1.06), fruit intake: 0.94 (0.89‐1.00), duration of hypertension diagnosis: 1.01 (1.00‐1.02), hypertension with diabetes mellitus: 2.05 (1.72‐2.46), number of antihypertensive medications: 1.63 (1.49‐1.79), and estimated glomerular filtration rate (mL/min rise): 0.82 (0.76‐0.89). Interventions aimed at addressing modifiable factors associated with poorly controlled BP would be critical in prevention of cardiovascular diseases among Ghanaians.