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.     

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.     

How Helicobacter pylori urease may affect external pH and influence growth and motility in the mucus environment: evidence from in-vitro studies

BACKGROUND: Survival of Helicobacter pylori is dependent upon urease in the cytoplasm and at the bacterial surface. We have sought to clarify how alkaline ammonium salts, released from urea by this enzyme, might alter mucus pH and so affect growth and motility of the bacterium in the gastric mucus environment. METHODS: Experiments were conducted in vitro to determine how the growth and motility of H. pylori are affected by changes in external pH, and how the bacterium, by hydrolysing urea, alters the pH of the bicarbonate buffer that occurs at the gastric mucosal surface. These data were fitted into experimental models that describe how pH varies within the mucus layer in the acid-secreting stomach. RESULTS: H. pylori was motile between pH 5 and 8, with optimal motility at pH 5. It grew between pH 6 and 8, with optimal growth at pH 6. The bacterium had urease activity between pH 2.7 and 7.4, as evidenced by pH rises in bicarbonate-buffered solutions of urea. Changes in buffer pH were dependent upon initial pH and urea concentration, with the greatest rate of pH change occurring at pH 3. Modelling experiments utilizing these data indicated that (1) in the absence of urease, H. pylori growth and motility in the mucus layer would be restricted severely by low mucus pH in the acid-secreting stomach, and (2) urease will sometimes inhibit H. pylori growth and motility in the mucus layer by elevating the pH of the mucus environment above pH 8. CONCLUSIONS: Urease is essential to the growth and motility of H. pylori in the mucus layer in the acid-secreting stomach, but, paradoxically, sometimes it might suppress colonization by raising the mucus pH above 8. This latter effect may protect the bacteria from the adverse consequences of overpopulation.     

Evaluation of antiretroviral treatment in two private medical centers in Addis, Ethiopia

Ethiopia is one of the countries affected severely by the HIV/AIDS epidemic in sub-Saharan Africa. The disease is gradually fatal without antiretroviral therapy (ARV). The experience with antiretroviral therapy is limited in this country. This study is the first of its kind that has evaluated the status and implication of the clinical use of ARV drugs in Ethiopia. The guidelines for the initiation of treatment, the strengths and weaknesses of such treatment and the implications of similar intervention in a wider scale were assessed. Clinical records of 33 patients under follow-up and treatment with ARV in Hayat Hospital and Bethezatha Medical Center were identified. Data were collected from the medical records using a tool designed for the purpose. All 33 patients were receiving ARV for a mean duration of about 4 months. Twenty- three (69.7%) were males and 10 (30.3%) were females and the mean age was 38 years. Fifteen (45.5%) were married, fourteen (40.7%) were single, one (3%) divorced and there was no record for three (9.1%). Fifteen (45.5%) were businessmen, seven (21.2%) were private employees, four (12.1%) civil servants and in the remaining seven (21.2%) their occupation was not recorded. The decision to initiate ARV therapy was entirely based on the presence of symptomatic HIV disease. CD4+ lymphocyte count was done in 24 (72.7%) and basic hematological tests were done for all. However, biochemical investigations were incomplete in all of them. Triple therapy was started for all patients and the cost of the drugs was covered by their family in eleven (33.3%), by the patients in twenty-two (66.7%). Side effects of the drugs were noted in ten (30.3%) that resulted in change of the regimen in two and drug interruption in one. Response to treatment was entirely based on clinical parameters only. Twenty-three patients (69.7%) were noted to improve while nine (27.3%) remained the same and death occurred in one (3%). Standard triple therapy was used in all patients in this study and symptomatic HIV disease was the reason for the initiation of treatment. The improvement observed was not substantiated by immunological or virological parameters. Thus, the impacts of ARVs cannot be measured and the response documented in this study can be due to the effective treatment of opportunistic infections. Hence a standard protocol should be developed based on the minimum set-up required for the initiation of ARV therapy.     

Inhibition of acetylcholine muscarinic M(1) receptor function by the M(1)-selective ligand muscarinic toxin 7 (MT-7)

MT-7 (1 - 30 nM), a peptide toxin isolated from the venom of the green mamba Dendroaspis angusticeps and previously found to bind selectively to the muscarinic M(1) receptor, inhibited the acetylcholine (ACh)-stimulated [(35)S]-guanosine-5'-O-(3-thio)triphosphate ([(35)S]-GTPgammaS) binding to membranes of Chinese hamster ovary (CHO) cells stably expressing the cloned human muscarinic M(1) receptor subtype. MT-7 failed to affect the ACh-stimulated [(35)S]-GTPgammaS binding in membranes of CHO cells expressing either the M(2), M(3) or M(4) receptor subtype. In N1E-115 neuroblastoma cells endogenously expressing the M(1) and M(4) receptor subtypes, MT-7 (0.3 - 3.0 nM) inhibited the carbachol (CCh)-stimulated inositol phosphates accumulation, but failed to affect the CCh-induced inhibition of pituitary adenylate cyclase activating polypeptide (PACAP) 38-stimulated cyclic AMP accumulation. In both CHO/M(1) and N1E-115 cells the MT-7 inhibition consisted in a decrease of the maximal agonist effect with minimal changes in the agonist EC(50) value. In CHO/M(1) cell membranes, MT-7 (0.05 - 25 nM) reduced the specific binding of 0.05, 1.0 and 15 nM [(3)H]-N-methylscopolamine ([(3)H]-NMS) in a concentration-dependent manner, but failed to cause a complete displacement of the radioligand. Moreover, MT-7 (3 nM) decreased the dissociation rate of [(3)H]-NMS by about 5 fold. CHO/M(1) cell membranes preincubated with MT-7 (10 nM) and washed by centrifugation and resuspension did not recover control [(3)H]-NMS binding for at least 8 h at 30 degrees C. It is concluded that MT-7 acts as a selective noncompetitive antagonist of the muscarinic M(1) receptors by binding stably to an allosteric site.