Functional Redundancy of SWI/SNF Catalytic Subunits in Maintaining Vascular Endothelial Cells in the Adult Heart

Rationale: Mating type switching/sucrose non-fermenting (SWI/SNF) chromatin-remodeling complexes utilize either BRG1 or BRM as a catalytic subunit to alter nucleosome position and regulate gene expression. BRG1 is required for vascular endothelial cell (VEC) development and embryonic survival, whereas BRM is dispensable. Objective: To circumvent embryonic lethality and study Brg1 function in adult tissues, we used conditional gene targeting. To evaluate possible Brg1-Brm redundancy, we analyzed Brg1 mutant mice on wild-type and Brm-deficient backgrounds. Methods and Results: The inducible Mx1-Cre driver was used to mutate Brg1 in adult mice. These conditional-null mutants exhibited a tissue-specific phenotype and unanticipated functional compensation between Brg1 and Brm. Brg1 single mutants were healthy and had a normal lifespan, whereas Brg1/Brm double mutants exhibited cardiovascular defects and died within 1 month. BRG1 and BRM were required for the viability of VECs but not other cell types where both genes were also knocked out. The VEC phenotype was most evident in the heart, particularly in the microvasculature of the outer myocardium, and was recapitulated in primary cells ex vivo. VEC death resulted in vascular leakage, cardiac hemorrhage, secondary death of cardiomyocytes due to ischemia, and ventricular dissections. Conclusions: BRG1-catalyzed SWI/SNF complexes are particularly important in cardiovascular tissues. However, in contrast to embryonic development, in which Brm does not compensate, Brg1 is required in adult VECs only when Brm is also mutated. These results demonstrate for the first time that Brm functionally compensates for Brg1 in vivo and that there are significant changes in the relative importance of BRG1- and BRM-catalyzed SWI/SNF complexes during the development of an essential cell lineage.     

Improvdent: Improving dentures for patient benefit. A crossover randomised clinical trial comparing impression materials for complete dentures

ABSTRACT: BACKGROUND: According to the UK Adult Dental Health Survey (2009) 15% of adults aged 65-74, 30% aged 75-84 and 47% aged >85 years are edentulous and require complete dentures. Patients' quality of life and nutrition status are affected by poor dentures. The quality of the dental impression is the most important issue for improving the fit and comfort of new dentures. There is paucity of RCT evidence for which impression material is best for complete dentures construction. This study aims to compare two impression materials for effectiveness and cost effectiveness. METHODS: IMPROVDENT is a double-blind crossover trial comparing the use of alginate and silicone, two commonly used denture impression materials, in terms of patient preference and cost-effectiveness. Eighty five edentulous patients will be recruited and provided with two sets of dentures, similar in all aspects except for the impression material used (alginate or silicone). Patients will try both sets of dentures for a two-week period, unadjusted, to become accustomed to the feel of the new dentures (habituation period). Patients will then wear each set of dentures for a period of 8 weeks (in random order) during which time the dentures will be adjusted for optimum comfort. Finally, patients will be given both sets of dentures for a further two weeks to wear whichever denture they prefer (confirmation period). Patients will be asked about quality of life and to rate dentures on function and comfort at the end of each trial period and asked which set they prefer at the end of the habituation period (unadjusted denture preference) and confirmation period (adjusted denture preference). A health economic evaluation will estimate incremental cost-effectiveness ratios of producing dentures from the two materials. A qualitative study will investigate the impact of dentures on behaviour and quality of life. Funding: IMPROVDENT is funded by NIHR RfPB (PB-PG-0408-16300). DISCUSSION: This trial aims to provide evidence on the costs and quality of dentures cast from two different commonly used impression materials; the intention is to significantly impact on the quality of denture production within NHS dentistry. Trial Registration ISRCTN Register: ISRCTN01528038 UKCRN Portfolio ID: 8305.     

Stem cell-based treatments for Type 1 diabetes mellitus: bone marrow, embryonic, hepatic, pancreatic and induced pluripotent stem cells

Type 1 diabetes mellitus--characterized by the permanent destruction of insulin-secreting β-cells--is responsive to cell-based treatments that replace lost β-cell populations. The current gold standard of pancreas transplantation provides only temporary independence from exogenous insulin and is fraught with complications, including increased mortality. Stem cells offer a number of theoretical advantages over current therapies. Our review will focus on the development of treatments involving tissue stem cells from bone marrow, liver and pancreatic cells, as well as the potential use of embryonic and induced pluripotent stem cells for Type 1 diabetes therapy. While the body of research involving stem cells is at once promising and inconsistent, bone marrow-derived mesenchymal stem cell transplantation seems to offer the most compelling evidence of efficacy. These cells have been demonstrated to increase endogenous insulin production, while partially mitigating the autoimmune destruction of newly formed β-cells. However, recently successful experiments involving induced pluripotent stem cells could quickly move them into the foreground of therapeutic research. We address the limitations encountered by present research and look toward the future of stem cell treatments for Type 1 diabetes.     

Default mode network activity and white matter integrity in healthy middle-aged ApoE4 carriers

Alzheimer’s disease (AD) is most commonly detected during old age, but the underlying neuropathologic changes likely appear decades earlier, especially among patients possessing genetic risk factors, such as the isoform E4 of the apolipoprotein E (ApoE4). In this study, we used magnetic resonance imaging (MRI) to assess default mode network (DMN) connectivity in 22 ApoE4 non-carriers and 14 matched ApoE4 carriers as well as white matter fractional anisotropy (FA) in 15 ApoE4 non-carriers and 11 demographically matched ApoE4 carriers. Cognitive tests were also administered. All of the participants were middle-aged adults. The analysis revealed no cognitive or white matter FA differences between carriers and non-carriers. However, in DMN regions previously implicated in AD, we did detect decreased functional connectivity. Our findings suggest that functional MRI abnormalities may be detectable well before cognitive decline or white matter changes among individuals at increased genetic risk for AD.     

Beyond the snare: technically accessible large en bloc colonic resection in the West: an animal study

Background: Endoscopic submucosal dissection (ESD) and circumferential submucosal incision endoscopic mucosal resection (CSI‐EMR) are techniques for en bloc excision of large sessile colonic lesions. Our aims were to compare the efficacy, safety and learning curve of colonic hybrid knife (HK) ESD versus CSI‐EMR for en bloc excision of 50 mm diameter hemi‐circumferential artificial lesions in a porcine model. Patients and Methods: Two separate 50 mm diameter areas of normal recto‐sigmoid mucosa were marked out in each of ten pigs. One was excised with HK‐ESD using succinylated gelatin (SG) submucosal injection. The other was isolated with CSI with the Insulated Tip Knife 2 followed by SG submucosal injection then EMR with a large snare. Euthanasia and colectomy was performed at 72 h followed by blinded histopathology assessment. Results: En bloc excision rates were: HK‐ESD 100% versus CSI‐EMR 20% (P = 0.008). The mean number of resections per lesion was HK‐ESD 1 versus CSI‐EMR 3 (P = 0.001). The mean dimensions of the largest specimen per technique were HK‐ESD 63 × 54 mm versus CSI‐EMR 49 × 41 mm (P = 0.005). Procedure duration mean was HK‐ESD 54 min versus CSI‐EMR 22 min (P < 0.001). When procedure duration was adjusted for the size of the resected en bloc specimen, a statistically significant and accelerated learning effect was noted for HK‐ESD (r = ?0.83, P = 0.003). There were no perforations and no significant bleeding. Conclusions: HK‐ESD with SG submucosal injection is superior to CSI‐EMR for en bloc excision of 50 mm diameter lesions in a porcine model. The technique is rapidly learnt. This novel approach may lower the barrier to colonic ESD for Western endoscopists.     

HIV disclosure patterns, predictors, and psychosocial correlates among HIV positive women in Zimbabwe

Disclosure of positive HIV status in Sub-Saharan Africa has been associated with safer sexual practices and better antiretroviral therapy (ART) adherence, but associations with psychosocial function are unclear. We examined patterns and psychosocial correlates of disclosure in a Zimbabwean community. Two hundred HIV positive women at different stages of initiating ART participated in a cross-sectional study examining actual disclosures, disclosure beliefs, perceived stigma, self-esteem, depression, and quality of life. Ninety-seven percent of the women disclosed to at least one person, 78% disclosed to their current husband/partner, with an average disclosure of four persons per woman. The majority (85-98%) of disclosures occurred in a positive manner and 72-95% of the individuals reacted positively. Factors significantly correlated with HIV disclosure to partners included being married, later age at menses, longer duration of HIV since diagnosis, being on ART, being more symptomatic at baseline, ever having used condoms, and greater number of partners in the last year. In multivariate analysis, being married and age at menses predicted disclosure to partners. Positive disclosure beliefs, but not the total number of disclosures, significantly correlated with lower perceived stigma (ρ = 0.44 for personalized subscale and ρ = 0.51 for public subscale, both p<0.0001), higher self-esteem (ρ = 0.15, p=0.04), and fewer depressive symptoms (ρ = -0.14, p=0.05). In conclusion, disclosure of positive HIV status among Zimbabwean women is common and is frequently met with positive reactions. Moreover, positive disclosure beliefs correlate significantly with psychosocial measures, including lower perceived stigma, higher self-esteem, and lower depression.     

Animal models of atherosclerosis

Atherosclerosis is a chronic inflammatory disorder that is the underlying cause of most cardiovascular disease. Both cells of the vessel wall and cells of the immune system participate in atherogenesis. This process is heavily influenced by plasma lipoproteins, genetics, and the hemodynamics of the blood flow in the artery. A variety of small and large animal models have been used to study the atherogenic process. No model is ideal as each has its own advantages and limitations with respect to manipulation of the atherogenic process and modeling human atherosclerosis or lipoprotein profile. Useful large animal models include pigs, rabbits, and nonhuman primates. Due in large part to the relative ease of genetic manipulation and the relatively short time frame for the development of atherosclerosis, murine models are currently the most extensively used. Although not all aspects of murine atherosclerosis are identical to humans, studies using murine models have suggested potential biological processes and interactions that underlie this process. As it becomes clear that different factors may influence different stages of lesion development, the use of mouse models with the ability to turn on or delete proteins or cells in tissue specific and temporal manner will be very valuable.