The neurogenic bladder: medical treatment

Neurogenic bladder sphincter dysfunction (NBSD) can cause severe and irreversible renal damage and bladder-wall destruction years before incontinence becomes an issue. Therefore, the first step in adequate management is to recognize early the bladder at risk for upper- and lower-tract deterioration and to start adequate medical treatment proactively. Clean intermittent catheterization combined with anticholinergics (oral or intravesical) is the standard therapy for NBSD. Early institution of such treatment can prevent both renal damage and secondary bladder-wall changes, thereby potentially improving long-term outcomes. In children with severe side effects or with insufficient suppression of detrusor overactivity despite maximal dosage of oral oxybutynin, intravesical instillation is an effective alternative. Intravesical instillation eliminates systemic side effects by reducing the first-pass metabolism and, compared with oral oxybutynin, intravesical oxybutynin is a more potent and long-acting detrusor suppressor. There is growing evidence that with early adequate treatment, kidneys are saved and normal bladder growth can be achieved in children so they will no longer need surgical bladder augmentation to achieve safe urinary continence in adolescence and adulthood

Constitutive Activation of PrfA Tilts the Balance of Listeria monocytogenes Fitness Towards Life within the Host versus Environmental Survival

PrfA is a key regulator of Listeria monocytogenes pathogenesis and induces the expression of multiple virulence factors within the infected host. PrfA is post-translationally regulated such that the protein becomes activated upon bacterial entry into the cell cytosol. The signal that triggers PrfA activation remains unknown, however mutations have been identified (prfA* mutations) that lock the protein into a high activity state. In this report we examine the consequences of constitutive PrfA activation on L. monocytogenes fitness both in vitro and in vivo. Whereas prfA* mutants were hyper-virulent during animal infection, the mutants were compromised for fitness in broth culture and under conditions of stress. Broth culture prfA*-associated fitness defects were alleviated when glycerol was provided as the principal carbon source; under these conditions prfA* mutants exhibited a competitive advantage over wild type strains. Glycerol and other three carbon sugars have been reported to serve as primary carbon sources for L. monocytogenes during cytosolic growth, thus prfA* mutants are metabolically-primed for replication within eukaryotic cells. These results indicate the critical need for environment-appropriate regulation of PrfA activity to enable L. monocytogenes to optimize bacterial fitness inside and outside of host cells

Genome-wide positioning of bivalent mononucleosomes

BACKGROUND: Bivalent chromatin refers to overlapping regions containing activating histone H3 Lys4 trimethylation (H3K4me3) and inactivating H3K27me3 marks. Existence of such bivalent marks on the same nucleosome has only recently been suggested. Previous genome-wide efforts to characterize bivalent chromatin have focused primarily on individual marks to define overlapping zones of bivalency rather than mapping positions of truly bivalent mononucleosomes. RESULTS: Here, we developed an efficacious sequential ChIP technique for examining global positioning of individual bivalent nucleosomes. Using next generation sequencing approaches we show that although individual H3K4me3 and H3K27me3 marks overlap in broad zones, bivalent nucleosomes are focally enriched in the vicinity of the transcription start site (TSS). These seem to occupy the H2A.Z nucleosome positions previously described as salt-labile nucleosomes, and are correlated with low gene expression. Although the enrichment profiles of bivalent nucleosomes show a clear dependency on CpG island content, they demonstrate a stark anti-correlation with methylation status. CONCLUSIONS: We show that regional overlap of H3K4me3 and H3K27me3 chromatin tend to be upstream to the TSS, while bivalent nucleosomes with both marks are mainly promoter proximal near the TSS of CpG island-containing genes with poised/low expression. We discuss the implications of the focal enrichment of bivalent nucleosomes around the TSS on the poised chromatin state of promoters in stem cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12920-016-0221-6) contains supplementary material, which is available to authorized users

Nicotinamide's Ups and Downs:Consequences for Fertility, Development, Longevity and Diseases of Poverty and Affluence

Aims and Scope: To further explore the role of dietary nicotinamide in both brain development and diseases, particularly those of ageing. Articles cover neurodegenerative disease and cancer. Also discussed are the effects of nicotinamide, contained in meat and supplements and derived from symbionts, on the major transitions of disease and fertility from ancient times up to the present day. A key role for the tryptophan – NAD ‘de novo’ and immune tolerance pathway are discussed at length in the context of fertility and longevity and the transitions from immune paresis to Treg-mediated immune tolerance and then finally to intolerance and their associated diseases. Abstract: Nicotinamide in human evolution increased cognitive power in a positive feedback loop originally involving hunting. As the precursor to metabolic master molecule NAD it is, as vitamin B3, vital for health. Paradoxically, a lower dose on a diverse plant then cereal-based diet fuelled population booms from the Mesolithic onwards, by upping immune tolerance of the foetus. Increased tolerance of risky symbionts, whether in the gut or TB, that excrete nicotinamide co-evolved as buffers for when diet was inadequate. High biological fertility, despite disease trade-offs, avoided the extinction of Homo sapiens and heralded the dawn of a conscious, creative, and pro-fertility culture. Nicotinamide equity now would stabilise populations and prevent NAD-based diseases of poverty and affluence