Microvascular dysfunction as a link between obesity, insulin resistance and hypertension

Impaired microvascular dilatation from any cause and impaired insulin-mediated capillary recruitment in particular result in suboptimal delivery of glucose and insulin to skeletal muscle, and subsequently impairment of glucose disposal (insulin resistance). In addition, microvascular dysfunction, through functional and/or structural arteriolar and capillary drop-out, and arteriolar constriction, increases peripheral resistance and thus blood pressure. Microvascular dysfunction may thus constitute a pathway that links insulin resistance and hypertension. Overweight and obesity may be an important cause of microvascular dysfunction. Mechanisms linking overweight and obesity to microvascular dysfunction include changes in the secretion of adipokines leading to increased levels of free fatty acids and inflammatory mediators, and decreased levels of adiponectin all of which may impair endothelial insulin signaling. Microvascular dysfunction may thus constitute a new treatment target in the prevention of type 2 diabetes mellitus and hypertension

Microvascular Dysfunction Is Associated With a Higher Incidence of Type 2 Diabetes Mellitus A Systematic Review and Meta-Analysis

Objective-Recent data support the hypothesis that microvascular dysfunction may be a potential mechanism in the development of insulin resistance. We examined the association of microvascular dysfunction with incident type 2 diabetes mellitus (T2DM) and impaired glucose metabolism by reviewing the literature and conducting a meta-analysis of longitudinal studies on this topic. Methods and Results-We searched Medline and Embase for articles published up to October 2011. Prospective cohort studies that focused on microvascular measurements in participants free of T2DM a baseline were included. Pooled relative risks were calculated using random effects models. Thirteen studies met the inclusion criteria for this meta-analysis. These studies focused on T2DM or impaired fasting glucose, not on impaired glucose tolerance. The pooled relative risks for incident T2DM (3846 cases) was 1.25 (95% confidence interval, 1.15; 1.36) per 1 SD greater microvascular dysfunction when all estimates of microvascular dysfunction were combined. In analyses of single estimates of microvascular dysfunction, the pooled relative risks for incident T2DM was 1.49 (1.36; 1.64) per 1 SD higher plasma soluble E-selectin levels; 1.21(1.11; 1.31) per 1 SD higher plasma soluble intercellular adhesion molecule-1 levels; 1.48 (1.03; 2.12) per 1 SD lower response to acetylcholine-mediated peripheral vascular reactivity; 1.18 (1.08; 1.29) per 1 SD lower retinal arteriole-to-venule ratio; and 1.43 (1.33; 1.54) per 1 logarithmically transformed unit higher albumin-to-creatinine ratio. In addition, the pooled relative risks for incident impaired fasting glucose (409 cases) was 1.15 (1.01-1.31) per 1 SD greater retinal venular diameters. Conclusion-These data indicate that various estimates of microvascular dysfunction were associated with incident T2DM and, possibly, impaired fasting glucose, suggesting a role for the microcirculation in the pathogenesis of T2DM. (Arterioscler Thromb Vasc Biol. 2012;32:3082-3094.

Line Defects in Molybdenum Disulfide Layers

Layered molecular materials and especially MoS2 are already accepted as promising candidates for nanoelectronics. In contrast to the bulk material, the observed electron mobility in single-layer MoS2 is unexpectedly low. Here we reveal the occurrence of intrinsic defects in MoS2 layers, known as inversion domains, where the layer changes its direction through a line defect. The line defects are observed experimentally by atomic resolution TEM. The structures were modeled and the stability and electronic properties of the defects were calculated using quantum-mechanical calculations based on the Density-Functional Tight-Binding method. The results of these calculations indicate the occurrence of new states within the band gap of the semiconducting MoS2. The most stable non-stoichiometric defect structures are observed experimentally, one of which contains metallic Mo-Mo bonds and another one bridging S atoms

Differences in renal hemodynamics and renin secretion between patients with unifocal and multifocal fibromuscular dysplasia

Objective: Fibromuscular dysplasia (FMD) can be classified in a multifocal and a unifocal subtype. As unifocal FMD generally leads to more severe hypertension at younger age, we hypothesized that renal hemodynamics are more disturbed in unifocal renal artery FMD as compared with multifocal FMD, leading to increased renin secretion. Methods: We measured renal blood flow ((133)Xenon washout method), renin secretion, and glomerular filtration rate per kidney in 101 patients with FMD (26 unifocal and 75 multifocal), all off medication and prior to balloon angioplasty. Results: We found that renal blood flow and glomerular filtration were substantially lower in kidneys with unifocal FMD as compared with multifocal FMD. In the affected kidney from patients with unilateral FMD for example, mean renal blood flow was 173 +/- 77 in unifocal vs. 244 +/- 79 ml/100 g kidney/min in multifocal FMD (P=0.013). Moreover, lateralization in renin secretion was only observed in a subset of patients with unifocal FMD, but not in any of the patients with multifocal FMD. Conclusion: These findings suggest that the impact of unifocal FMD lesions on the kidney is more severe, resulting in a classical pattern of renovascular hypertension. In multifocal FMD, however, renal blood flow is more preserved, local renin secretion is not increased, and the association between renin levels and blood pressure is inverse. These differences may explain the often more severe clinical presentation and higher success rate of revascularization in unifocal FMD, but also suggest that the pathophysiological mechanisms leading to hypertension may differ between these two disease entities

Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models

Background The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements. Methods 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specifi c intervention scenarios, which included screening for symptoms, active case fi nding, and preventive therapy. Findings Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31–62%) and a 72% reduction in mortality (range 64–82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis. Interpretation Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specifi c tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level

Prediabetes Is Associated With Structural Brain Abnormalities:The Maastricht Study

OBJECTIVE Structural brain abnormalities are key risk factors for brain diseases, such as dementia, stroke, and depression, in type 2 diabetes. It is unknown whether structural brain abnormalities already occur in prediabetes. Therefore, we investigated whether both prediabetes and type 2 diabetes are associated with lacunar infarcts (LIs), white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and brain atrophy. RESEARCH DESIGN and METHODS We used data from 2,228 participants (1,373 with normal glucose metabolism [NGM], 347 with prediabetes, and 508 with type 2 diabetes (oversampled); mean age 59.2 6 8.2 years; 48.3% women) of the Maastricht Study, a population-based cohort study. Diabetes status was determined with an oral glucose tolerance test. Brain imaging was performed with 3 Tesla MRI. Results were analyzed with multivariable logistic and linear regression analyses. RESULTS Prediabetes and type 2 diabetes were associated with the presence of LIs (odds ratio 1.61 [95% CI 0.98-2.63] and 1.67 [1.04-2.68], respectively; P trend = 0.027), larger WMH (b 0.07 log10-transformed mL [log-mL] [95% CI 0.00-0.15] and 0.21 log-mL [0.14-0.28], respectively; P trend <0.001), and smaller white matter volumes (b 24.0 mL [27.3 to 20.6] and 27.2 mL [210.4 to 24.0], respectively; P trend <0.001) compared with NGM. Prediabetes was not associated with gray matter volumes or the presence of CMBs. CONCLUSIONS Prediabetes is associated with structural brain abnormalities, with further deterioration in type 2 diabetes. These results indicate that, in middle-aged populations, structural brain abnormalities already occur in prediabetes, which may suggest that the treatment of early dysglycemia may contribute to the prevention of brain diseases

Genetic, Maternal and Placental Factors in the Association between Birth Weight and Physical Fitness: A Longitudinal Twin Study

Background Adult cardiorespiratory fitness and muscle strength are related to all-cause and cardiovascular mortality. Both are possibly related to birth weight, but it is unclear what the importance is of genetic, maternal and placental factors in these associations. Design Peak oxygen uptake and measures of strength, flexibility and balance were obtained yearly during adolescence (10–18 years) in 114 twin pairs in the Leuven Longitudinal Twin Study. Their birth weights had been collected prospectively within the East Flanders Prospective Twin Survey. Results We identified linear associations between birth weight and adolescent vertical jump (b = 1.96 cm per kg birth weight, P = 0.02), arm pull (b = 1.85 kg per kg birth weight P = 0.03) and flamingo balance (b = −1.82 attempts to stand one minute per kg birth weight, P = 0.03). Maximum oxygen uptake appeared to have a U-shaped association with birth weight (the smallest and largest children had the lowest uptake, P = 0.01), but this association was no longer significant after adjustment for parental BMI. Using the individual twin’s deviation from his own twin pair’s average birth weight, we found positive associations between birth weight and adolescent vertical jump (b = 3.49, P = 0.0007) and arm pull (b = 3.44, P = 0.02). Δ scores were calculated within the twin pairs as first born twin minus second born twin. Δ birth weight was associated with Δ vertical jump within MZ twin pairs only (b = 2.63, P = 0.009), which indicates importance of placental factors. Conclusions We found evidence for an association between adolescent physical performance (strength, balance and possibly peak oxygen uptake) and birth weight. The associations with vertical jump and arm pull were likely based on individual, more specifically placental (in the case of vertical jump) factors. Our results should be viewed as hypothesis-generating and need confirmation, but potentially support preventive strategies to optimize birth weight, for example via placental function, to target later fitness and health

Endoscopic Resection Without Subsequent Ablation Therapy for Early Barrett's Neoplasia:Endoscopic Findings and Long-Term Mortality

INTRODUCTION: After endoscopic resection (ER) of neoplasia in Barrett's esophagus (BE), it is recommended to ablate the remaining BE to minimize the risk for metachronous disease. However, we report long-term outcomes for a nationwide cohort of all patients who did not undergo ablation of the remaining BE after ER for early BE neoplasia, due to clinical reasons or performance status. METHODS: Endoscopic therapy for BE neoplasia in the Netherlands is centralized in 8 expert centers with specifically trained endoscopists and pathologists. Uniformity is ensured by a joint protocol and regular group meetings. We report all patients who underwent ER for a neoplastic lesion between 2008 and 2018, without further ablation therapy. Outcomes include progression during endoscopic FU and all-cause mortality. RESULTS: Ninety-four patients were included with mean age 74 (± 10) years. ER was performed for low-grade dysplasia (LGD) (10%), high-grade dysplasia (HGD) (25%), or low-risk esophageal adenocarcinoma (EAC) (65%). No additional ablation was performed for several reasons; in 73 patients (78%), the main argument was expected limited life expectancy. Median C2M5 BE persisted after ER, and during median 21 months (IQR 11-51) with 4 endoscopies per patient, no patient progressed to advanced cancer. Seventeen patients (18%) developed HGD/EAC: all were curatively treated endoscopically. In total, 29/73 patients (40%) with expected limited life expectancy died due to unrelated causes during FU, none of EAC. CONCLUSION: In selected patients, ER monotherapy with endoscopic surveillance of the residual BE is a valid alternative to eradication therapy with ablation