EVALUATION OF THE PROTECTIVE EFFECT OF NIGELLA SATIVA (BLACK CUMIN) OIL AGAINST VANCOMYCIN-INDUCED NEPHROTOXICITY IN RATS

Objective: The study was designed to investigate a possible protective effect of Nigella sativa (NS) against vancomycin (VAN)-induced nephrotoxicity in rats. Methods: Twenty-eight adult male Albino rats were randomly divided into four groups; seven rats in each. Group I (control): The animals were treated with normal saline (2 ml/kg/day) given orally and intraperitoneally (IP); Group II: VAN was given at a dose of 400 mg/kg/day for 7 days IP and normal saline orally; Group III: NS oil was given at a dose of 2 ml/kg/day for seven days orally and normal saline IP; and Group IV: VAN 400 mg/kg/day IP in combination with NS oil 2 ml/kg/day orally for 7 days. Twenty-four hours after the last dose, the animals were sacrificed, and serum was collected to estimate urea and creatinine. Then, both kidneys were excised, one for homogenate preparation to estimate renal tissue malondialdehyde (MDA), glutathione (GSH) and neutrophil gelatinase-associated lipocalin (NGAL) and the other for histopathological examination. Results: NS significantly decreased serum urea and creatinine compared to VAN treated group, p<0.001. NS significantly increased renal tissue GSH compared to VAN treated group p<0.001. NS lowered MDA and NGAL levels in the homogenate of renal tissues compared to their elevated levels in rats treated with VAN, but this did not achieve statistical significance. NS also ameliorated renal histopathological changes induced by VAN. Conclusion: NS has a protective effect against VAN-induced nephrotoxicity

Enteric infection coupled with chronic Notch pathway inhibition alters colonic mucus composition leading to dysbiosis, barrier disruption and colitis

Intestinal mucus layer disruption and gut microflora modification in conjunction with tight junction (TJ) changes can increase colonic permeability that allows bacterial dissemination and intestinal and systemic disease. We showed previously that Citrobacter rodentium (CR)-induced colonic crypt hyperplasia and/or colitis is regulated by a functional cross-talk between the Notch and Wnt/β-catenin pathways. In the current study, mucus analysis in the colons of CR-infected (108 CFUs) and Notch blocker Dibenzazepine (DBZ, i.p.; 10μmol/Kg b.w.)-treated mice revealed significant alterations in the composition of trace O-glycans and complex type and hybrid N-glycans, compared to CR-infected mice alone that preceded/ accompanied alterations in 16S rDNA microbial community structure and elevated EUB338 staining. While mucin-degrading bacterium, Akkermansia muciniphila (A. muciniphila) along with Enterobacteriaceae belonging to Proteobacteria phyla increased in the feces, antimicrobial peptides Angiogenin-4, Intelectin-1 and Intelectin-2, and ISC marker Dclk1, exhibited dramatic decreases in the colons of CR-infected/DBZ-treated mice. Also evident was a loss of TJ and adherens junction protein immuno-staining within the colonic crypts that negatively impacted paracellular barrier. These changes coincided with the loss of Notch signaling and exacerbation of mucosal injury. In response to a cocktail of antibiotics (Metronidazole/ ciprofloxacin) for 10 days, there was increased survival that coincided with: i) decreased levels of Proteobacteria, ii) elevated Dclk1 levels in the crypt and, iii) reduced paracellular permeability. Thus, enteric infections that interfere with Notch activity may promote mucosal dysbiosis that is preceded by changes in mucus composition. Controlled use of antibiotics seems to alleviate gut dysbiosis but may be insufficient to promote colonic crypt regeneration.R01-CA18532

Economic burden of livestock disease and drought in Northern Tanzania

Livestock-dependent communities face considerable livestock disease and drought risk, which can impact herd value, income and consumption. This paper summarizes economic data collected from 404 households in Arusha and Manyara regions of Northern Tanzania in 2016. They provide estimates for (i) herd loss due to disease and drought as a fraction of herd value and income, (ii) the relative risk of disease and drought in small versus large ruminants and (iii) the relationship between livestock disease outcomes and household expenditures. We find that disease and drought losses comprise 10 to 4% of sheep, cattle and goat herd value, and amount to an estimated 62.1% of household income. The drought and disease risk ratios for small versus large ruminants indicate that small stock face higher disease risk, while large ruminants are affected more by drought. Furthermore, cattle abortions are negatively related to schooling expenditure and positively associated with increases in off-farm food expenditure related to livestock management, presumably through increased investments in prevention and therapy. These results suggest that climatic variability and livestock diseases are an important source of economic vulnerability and reducing this burden may help alleviate poverty in livestock-dependent communities

Incidence and survival for oropharynx and non-oropharynx head and neck cancers among veterans living with HIV

BACKGROUND: People living with HIV/AIDS (PLWH) have an excess risk for head and neck squamous cell carcinoma (HNSCC) compared to the general U.S. population, but little is known about HIV-specific risk factors associated with the incidence and outcomes HNSCC. We aim to identify clinical and HIV-specific risk factors associated with oropharyngeal and non-oropharyngeal HNSCC incidence and outcomes separately. METHODS: We constructed a retrospective cohort study of 45,052 PLWH aged 18 or above from the national Veteran Affairs (VA) Corporate Data from 1999 to 2015. We extracted demographic data and risk factor information, including history of alcohol abuse, smoking, CD4 count (cells/μl), and percent of follow-up time with undetectable HIV viral load as time-updated variables. We calculated the age-standardized incidence rates of oropharyngeal and non-oropharyngeal HNSCC and estimated adjusted hazard ratios (HR). We also examined overall survival using Kaplan-Meier curves and adjusted HR. RESULTS: The standardized incidence rate of oropharyngeal and non-oropharyngeal HNSCC in this veteran cohort of PLWH is 23.0 (95% confidence intervals (CIs): 17.1-28.9) and 55.4 (95% CI: 46.5-64.3) per 100,000 person-years, respectively. Nadir CD4 count ≤200 was associated with an increased risk of non-oropharyngeal HNSCC (HR: 1.78; 95% CI: 1.31-2.30 vs \u3e200). Five-year overall survival of OPSCC (37.0%) was significantly lower than non-oropharyngeal HNSCC (49.1%). CONCLUSIONS: PLWH who receive care in the VA had higher age-adjusted HNSCC incidence rates than reported in the general population, suggesting that HIV and immunosuppression play a role. Additional studies should be conducted to study the interaction between HPV and HIV

Maternal deaths in Pakistan : intersection of gender, class and social exclusion.

Background: A key aim of countries with high maternal mortality rates is to increase availability of competent maternal health care during pregnancy and childbirth. Yet, despite significant investment, countries with the highest burdens have not reduced their rates to the expected levels. We argue, taking Pakistan as a case study, that improving physical availability of services is necessary but not sufficient for reducing maternal mortality because gender inequities interact with caste and poverty to socially exclude certain groups of women from health services that are otherwise physically available. Methods: Using a critical ethnographic approach, two case studies of women who died during childbirth were pieced together from information gathered during the first six months of fieldwork in a village in Northern Punjab, Pakistan. Findings: Shida did not receive the necessary medical care because her heavily indebted family could not afford it. Zainab, a victim of domestic violence, did not receive any medical care because her martial family could not afford it, nor did they think she deserved it. Both women belonged to lower caste households, which are materially poor households and socially constructed as inferior. Conclusions: The stories of Shida and Zainab illustrate how a rigidly structured caste hierarchy, the gendered devaluing of females, and the reinforced lack of control that many impoverished women experience conspire to keep women from lifesaving health services that are physically available and should be at their disposal

Does the Hematopoietic Cell Transplantation Specific Comorbidity Index Predict Transplant Outcomes? A Validation Study in a Large Cohort of Umbilical Cord Blood and Matched Related Donor Transplants

AbstractThe hematopoietic cell transplantation specific comorbidity index (HCT-CI) has been recently proposed to predict the probability of nonrelapse mortality (NRM) and overall survival (OS) in allogeneic HCT recipients while taking into account any pretransplant comorbidity. We tested the validity of the HCT-CI in a cohort of 373 adult HCT recipients (184 matched-related donor and 189 unrelated umbilical cord blood) who received a myeloablative (N = 150) or nonmyeloablative (N = 223) conditioning regimen. HCT-CI scores of 0, 1, 2, and ≥3 were present in 58 (16%), 56 (15%), 64 (17%), and 195 (52%) patients, respectively. Pulmonary conditions were the most common comorbidity. Cumulative incidence of NRM at 2 years was 10%, 20%, 24%, and 28% for HCT-CI scores of 0, 1, 2, and ≥3, respectively (P = .01). The corresponding probability of OS at 2 years was 72%, 67%, 51%, and 48%, respectively (P < .01). On multivariate analyses adjusted for recipient age, disease risk, donor source, and conditioning regimen intensity, the relative risks for NRM for HCT-CI scores of 1, 2, and ≥3 (compared to a score of 0) were 2.0 (95% confidence intervals, 0.8–5.3), 2.6 (1.0–6.7), and 3.2 (1.4-7.4), respectively. The risks for overall mortality were 1.2 (0.6-2.1), 2.0 (1.1-3.4), and 2.1 (1.3-3.3), respectively. In subgroup analyses, the HCT-CI score did not consistently predict NRM and OS among different donor sources and conditioning regimens. The HCT-CI, although a useful tool for capturing pretransplant comorbidity and risk-assessment, needs to be further validated prior to adopting it for routine clinical use

Pressure-induced oxidative activation of PKG enables vasoregulation by Ca2+ sparks and BK channels

K

Assessment of animal hosts of pathogenic Leptospira in northern Tanzania

Funding: This work was supported by the Wellcome Trust (grant number 096400/Z/11/Z; https://wellcome.ac.uk/). JEBH, VPM, JAC, and SC received support from the Research Councils UK, UK Department for International Development, and UK Biotechnology and Biological Sciences Research Council (BBSRC) (grant numbers BB/J010367/1, BB/L018926, BB/L017679, BB/L018845; http://www.bbsrc.ac.uk/). JAC and VPM also received support from the US National Institutes of Health (NIH)-National Science Foundation (NSF) Ecology and Evolution of Infectious Disease program (R01TW009237; https://www.fic.nih.gov/programs/pages/ecology-infectious-diseases.aspx). MM received support from the BBSRC East of Scotland Bioscience Doctoral Training Partnership (http://www.eastscotbiodtp.ac.uk/). MJM received support from a University of Otago Frances G. Cotter Scholarship and a University of Otago MacGibbon PhD Travel Fellowship (http://www.otago.ac.nz/). VPM and JAC received support from the US National Institutes of Health National Institute for Allergy and Infectious (grant number R01 AI121378; https://www.niaid.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability: Datasets supporting this manuscript are available through: http://dx.doi.org/10.5525/gla.researchdata.582. Unique sequences generated through this study are available through GenBank (accession numbers MF955862 to MF955882).Peer reviewedPublisher PD

Genetic deletion of hepatic NCOR1 protects from atherosclerosis by promoting alternative bile acid-metabolism and sterol excretion

BACKGROUND The nuclear receptor corepressor 1 (NCOR1) plays an important role in the regulation of gene expression in immunometabolic conditions by connecting chromatin-modifying enzymes, coregulators and transcription factors. NCOR1 has been shown to be involved in cardiometabolic diseases. Recently, we demonstrated that the deletion of macrophage NCOR1 aggravates atherosclerosis by promoting CD36-triggered foam cell formation via PPARG derepression. PURPOSE Since NCOR1 modulates the function of several key regulators involved in hepatic lipid and bile acid metabolism, we hypothesized that its deletion in hepatocytes alters lipid metabolism and atherogenesis. METHODS To test this hypothesis, we generated hepatocyte-specific Ncor1 knockout mice on a Ldlr-/- background. Besides assessing the progression of the disease in thoracoabdominal aortae en face, we analyzed hepatic cholesterol and bile acid metabolism at expression and functional levels. RESULTS Our data demonstrate that liver-specific Ncor1 knockout mice on an atherosclerosis-prone background develop less atherosclerotic lesions than controls. Interestingly, under chow diet, plasma cholesterol levels of liver-specific Ncor1 knockout mice were slightly higher compared to control, but strongly reduced compared to control mice after feeding them an atherogenic diet for 12 weeks. Moreover, the hepatic cholesterol content was decreased in liver-specific Ncor1 knockout compared to control mice. Our mechanistic data revealed that NCOR1 reprograms the synthesis of bile acids towards the alternative pathway, which in turn reduce bile hydrophobicity and enhances fecal cholesterol excretion. CONCLUSIONS Our data suggest that hepatic Ncor1 deletion in mice decreases atherosclerosis development by reprograming bile acid metabolism and enhancing fecal cholesterol excretion