Physiological role for nitrate-reducing oral bacteria in blood pressure control

AbstractCirculating nitrate (NO3−), derived from dietary sources or endogenous nitric oxide production, is extracted from blood by the salivary glands, accumulates in saliva, and is then reduced to nitrite (NO2−) by the oral microflora. This process has historically been viewed as harmful, because nitrite can promote formation of potentially carcinogenic N-nitrosamines. More recent research, however, suggests that nitrite can also serve as a precursor for systemic generation of vasodilatory nitric oxide, and exogenous administration of nitrate reduces blood pressure in humans. However, whether oral nitrate-reducing bacteria participate in “setting” blood pressure is unknown. We investigated whether suppression of the oral microflora affects systemic nitrite levels and hence blood pressure in healthy individuals. We measured blood pressure (clinic, home, and 24-h ambulatory) in 19 healthy volunteers during an initial 7-day control period followed by a 7-day treatment period with a chlorhexidine-based antiseptic mouthwash. Oral nitrate-reducing capacity and nitrite levels were measured after each study period. Antiseptic mouthwash treatment reduced oral nitrite production by 90% (p < 0.001) and plasma nitrite levels by 25% (p = 0.001) compared to the control period. Systolic and diastolic blood pressure increased by 2–3 .5mmHg, increases correlated to a decrease in circulating nitrite concentrations (r2 = 0.56, p = 0.002). The blood pressure effect appeared within 1 day of disruption of the oral microflora and was sustained during the 7-day mouthwash intervention. These results suggest that the recycling of endogenous nitrate by oral bacteria plays an important role in determination of plasma nitrite levels and thereby in the physiological control of blood pressure

Kapsula

Selections from the 14th Annual York University Art History Graduate Student Symposiu

Mendelian Randomisation and Causal Inference in Observational Epidemiology

Nuala Sheehan and colleagues describe how Mendelian randomization provides an alternative way of dealing with the problems of observational studies, especially confounding

The dietary management of calcium and phosphate in children with CKD stages 2-5 and on dialysis-clinical practice recommendation from the Pediatric Renal Nutrition Taskforce

In children with chronic kidney disease (CKD), optimal control of bone and mineral homeostasis is essential, not only for the prevention of debilitating skeletal complications and achieving adequate growth but also for preventing vascular calcification and cardiovascular disease. Complications of mineral bone disease (MBD) are common and contribute to the high morbidity and mortality seen in children with CKD. Although several studies describe the prevalence of abnormal calcium, phosphate, parathyroid hormone, and vitamin D levels as well as associated clinical and radiological complications and their medical management, little is known about the dietary requirements and management of calcium (Ca) and phosphate (P) in children with CKD. The Pediatric Renal Nutrition Taskforce (PRNT) is an international team of pediatric renal dietitians and pediatric nephrologists, who develop clinical practice recommendations (CPRs) for the nutritional management of various aspects of renal disease management in children. We present CPRs for the dietary intake of Ca and P in children with CKD stages 2-5 and on dialysis (CKD2-5D), describing the common Ca- and P-containing foods, the assessment of dietary Ca and P intake, requirements for Ca and P in healthy children and necessary modifications for children with CKD2-5D, and dietary management of hypo- and hypercalcemia and hyperphosphatemia. The statements have been graded, and statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs based on the clinical judgment of the treating physician and dietitian. These CPRs will be regularly audited and updated by the PRNT.Peer reviewe

High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington\u27s disease CAG knock-in mice across multiple genetic backgrounds.

Huntington\u27s disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, molecular and cellular phenotypes in the striatum of six distinct knock-in mouse models of the HD mutation. We studied the effects of the HttQ111 allele on the C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds, and of two additional alleles, HttQ92 and HttQ50, on the C57BL/6J background. We describe the emergence of a transcriptomic signature in HttQ111/+  mice involving hundreds of differentially expressed genes and changes in diverse molecular pathways. We also show that this time course spanned the onset of mutant huntingtin nuclear localization phenotypes and somatic CAG-length instability in the striatum. Genetic background strongly influenced the magnitude and age at onset of these effects. This work provides a foundation for understanding the earliest transcriptional and molecular changes contributing to HD pathogenesis

Improving the robustness and efficiency of covariate-adjusted linear instrumental variable estimators

Two‐stage least squares estimators and variants thereof are widely used to infer the effect of an exposure on an outcome using instrumental variables (IVs). Two‐stage least squares estimators enjoy greater robustness to model misspecification than other two‐stage estimators but can be inefficient when the exposure is non‐linearly related to the IV (or covariates). Locally efficient double‐robust estimators overcome this concern. These make use of a possibly non‐linear model for the exposure to increase efficiency but remain consistent when that model is misspecified, so long as either a model for the IV or for the outcome model is correctly specified. However, their finite sample performance can be poor when the models for the IV, exposure, and/or outcome are misspecified. We therefore develop double‐robust procedures with improved efficiency and robustness properties under misspecification of some or even all working models. Simulation studies and a data analysis demonstrate remarkable improvements

Transcriptional regulatory networks underlying gene expression changes in Huntington's disease

Abstract Transcriptional changes occur presymptomatically and throughout Huntington's disease (HD), motivating the study of transcriptional regulatory networks (TRNs) in HD. We reconstructed a genome‐scale model for the target genes of 718 transcription factors (TFs) in the mouse striatum by integrating a model of genomic binding sites with transcriptome profiling of striatal tissue from HD mouse models. We identified 48 differentially expressed TF‐target gene modules associated with age‐ and CAG repeat length‐dependent gene expression changes in Htt CAG knock‐in mouse striatum and replicated many of these associations in independent transcriptomic and proteomic datasets. Thirteen of 48 of these predicted TF‐target gene modules were also differentially expressed in striatal tissue from human disease. We experimentally validated a specific model prediction that SMAD3 regulates HD‐related gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP‐seq) of mouse striatum. We found CAG repeat length‐dependent changes in the genomic occupancy of SMAD3 and confirmed our model's prediction that many SMAD3 target genes are downregulated early in HD

HIV disease progression among women following seroconversion during a tenofovir-based HIV prevention trial.

CAPRISA, 2017.Abstract available in pdf