Serum Calcium Concentrations, Chronic Inflammation and Glucose Metabolism: A Cross-Sectional Analysis in the Andhra Pradesh Children and Parents Study (APCaPS).

BACKGROUND: Evidence suggests a role for elevated serum calcium in dysregulated glucose metabolism, linked through low-level chronic inflammation. OBJECTIVES: We investigated the association of elevated serum calcium concentrations (corrected for albumin) with markers of dysregulated glucose metabolism and type II diabetes and tested if these associations were accounted for by chronic inflammation in a rural Indian population. METHODS: A cross-sectional analysis of participants aged 40-84 y from the Andhra Pradesh Children and Parents Study (APCaPS; n = 2699, 52.2% women) was conducted. Comprehensive information on household, sociodemographic, and lifestyle factors; medical and family history; physical measurements; blood measurements including fasting plasma glucose (FPG), fasting insulin (FI), serum calcium, albumin, phosphorous, vitamin D (in a subset), and creatinine were analyzed. Additionally, in a random sample of healthy participants (n = 1000), inflammatory biomarkers (interleukins 6 and 18, soluble intercellular adhesion molecule 1, adiponectin, and high-sensitivity C-reactive protein) were measured and an inflammatory score (IScore) calculated. RESULTS: After adjustments for sociodemographics, lifestyle factors, and anthropometry the highest calcium quartile (Q4 compared with Q1) was associated with FI (β = 1.4 µU/ml; 95% CI: 1.2, 1.5 µU/ml; P-trend < 0.001), the homeostasis model assessment for insulin resistance (HOMA-IR) (β = 1.4; 95% CI: 1.2, 1.5; P-trend < 0.001), and was modestly associated with FPG (β = 2.1 mg/dL; 95% CI: -0.9, 5.2 mg/dL; P-trend = 0.058) and prevalent type II diabetes (OR = 1.6; 95% CI: 1.0, 2.6; P-trend= 0.020). In the healthy subgroup, the association of the highest calcium quartile was similar for FI and HOMA-IR. Additional adjustment with IScore did not alter the associations. Further, in a subset, all these associations were independent of endogenous regulators of calcium metabolism (serum vitamin D, phosphorus, and creatinine). Independently, after accounting for potential confounders, the highest IScore quartile (Q4 compared with Q1) was positively associated with FPG, FI, HOMA-IR, and prevalent prediabetes, and also with serum calcium concentrations in men. CONCLUSIONS: Elevated serum calcium was positively associated with markers of dysregulated glucose metabolism and prevalent type II diabetes in a rural Indian population. Chronic inflammation did not mediate this association but was independently associated with markers of dysregulated glucose metabolism. Inflammation might be responsible for elevated serum calcium concentrations in men

The influence of obesity and body mass index on the outcome of laparoscopic colorectal surgery: a systematic literature review

AIM: The relationship between obesity, body-mass index (BMI) and laparoscopic colorectal resection is unclear. Our object was to assess systematically the available evidence to establish the influence of obesity and BMI on the outcome of laparoscopic colorectal resection. METHOD: A search of PubMed/Medline databases was performed in May 2015 to identify all studies investigating the impact of BMI and obesity on elective laparoscopic colorectal resection performed for benign or malignant bowel disease. Clinical end points examined included operation time, conversion rate to open surgery, post-operative complications including anastomotic leakage, length of hospital stay, readmission rate, reoperation rate and mortality. For patients who underwent an operation for cancer, the harvested number of lymph nodes and long-term oncological data were also examined. RESULTS: 45 studies were analysed, the majority of which were Level IV with only four level III case-controlled studies. Thirty comparative studies containing 23649 patients including 17895 non-obese and 5754 obese showed no significant differences between the two groups with respect to intraoperative blood loss, overall postoperative morbidity, anastomotic leakage, reoperation rate, mortality and the number of retrieved lymph nodes in patients operated on for malignancy. Most studies, including 15 non-comparative studies, reported a longer operation time in patients who underwent a laparoscopic procedure with the BMI being an independent predictor in multivariate analyses for the operation time. CONCLUSION: Laparoscopic colorectal resection is safe and technically and oncologically feasible in obese patients. These results, however, may be different outside high volume centres of expertise. This article is protected by copyright. All rights reserved

Long Term Stabilization of Expanding Aortic Aneurysms by a Short Course of Cyclosporine A through Transforming Growth Factor-Beta Induction

Abdominal aortic aneurysms (AAAs) expand as a consequence of extracellular matrix destruction, and vascular smooth muscle cell (VSMC) depletion. Transforming growth factor (TGF)-beta 1 overexpression stabilizes expanding AAAs in rat. Cyclosporine A (CsA) promotes tissue accumulation and induces TGF -beta1 and, could thereby exert beneficial effects on AAA remodelling and expansion. In this study, we assessed whether a short administration of CsA could durably stabilize AAAs through TGF-beta induction. We showed that CsA induced TGF-beta1 and decreased MMP-9 expression dose-dependently in fragments of human AAAs in vitro, and in animal models of AAA in vivo. CsA prevented AAA formation at 14 days in the rat elastase (diameter increase: CsA: 131.9±44.2%; vehicle: 225.9±57.0%, P = 0.003) and calcium chloride mouse models (diameters: CsA: 0.72±0.14 mm; vehicle: 1.10±0.11 mm, P = .008), preserved elastic fiber network and VSMC content, and decreased inflammation. A seven day administration of CsA stabilized formed AAAs in rats seven weeks after drug withdrawal (diameter increase: CsA: 14.2±15.1%; vehicle: 45.2±13.7%, P = .017), down-regulated wall inflammation, and increased αSMA-positive cell content. Co-administration of a blocking anti-TGF-beta antibody abrogated CsA impact on inflammation, αSMA-positive cell accumulation and diameter control in expanding AAAs. Our study demonstrates that pharmacological induction of TGF-beta1 by a short course of CsA administration represents a new approach to induce aneurysm stabilization by shifting the degradation/repair balance towards healing

No effect of epoprostenol on right ventricular diameter in patients with acute pulmonary embolism: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Right ventricular dilatation in the setting of acute pulmonary embolism is associated with an adverse prognosis. Treatment with a pulmonary vasodilator has never been studied systematically. We evaluated the effect of epoprostenol on right ventricular diameter and function in patients with acute pulmonary embolism and right ventricular dilatation.</p> <p>Methods</p> <p>In a randomized, single-blind study, 14 patients with acute pulmonary embolism received epoprostenol or placebo infusion for 24 hours on top of conventional treatment. Effects on right ventricular end-diastolic diameter, systolic pulmonary artery pressure, right ventricle fractional area changeand tricuspid annular plane systolic excursion were assessed by serial echocardiography. Furthermore Troponin T and NT-proBNP were measured serially.</p> <p>Results</p> <p>Compared to placebo, epoprostenol was associated with a relative change from baseline in right ventricular end-diastolic diameter of +2% after 2.5 hours and -8% after 24 hours. Epoprostenol did not have a significant effect on systolic pulmonary artery pressure, right ventricular fractional area change and tricuspid annular plane systolic excursion, nor on biochemical parameters.</p> <p>Conclusion</p> <p>In patients with acute pulmonary embolism and right ventricular overload, treatment with epoprostenol did not improve right ventricular dilatation or any other measured variables of right ventricular overload.</p> <p>Trial Registration</p> <p><it>Registration</it>: URL: NCT01014156</p> <p><it>Medical ethical committee</it>: Medisch-ethische toetsingscommissie (METc) from the VUmc (free university medical centre)</p

Longitudinal strain of right ventricular free wall by 2-dimensional speckle-tracking echocardiography is useful for detecting pulmonary hypertension

Aims Echocardiography is widely used for screening pulmonary hypertension (PH). More recently developed two-dimensional speckle-tracking echocardiography (2D-STE) can assess regional deformation of the myocardium and is useful for detecting left ventricular dysfunction. However, its usefulness to assess right ventricular (RV) dysfunction is not clear. Therefore, the aim of this study was to investigate the ability of peak systolic strain (PSS) and post-systolic strain index (PSI) at the RV free wall determined by 2D-STE to detect PH. Main methods Thirty-six images (27 images from PH patients, nine from patients with connective tissue disease without PH) obtained by 2D-STE were analysed. We investigated the relationship between RV hemodynamics measured by right heart catheterization and PSS, PSI and other echocardiographic parameters reflecting RV overload including RV end-diastolic diameter (RVDd) and tricuspid valve regurgitant pressure gradient (TRPG). Key findings PSS, PSI, RVDd and TRPG were all correlated with mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR). Furthermore, when PSS and MPAP were measured twice, the change in PSS was correlated with the change in MPAP (r = 0.633, p = 0.037). Multivariate logistic regression analysis identified PSS as the only independent factor associated with MPAP ? 35 mm Hg [odds ratio (OR), 1.616; 95% confidence interval (CI) 1.017-2.567; p = 0.042] and PVR ? 400 dyn・s・cm- 5(OR, 1.804; 95% CI 1.131-2.877; p = 0.013). Furthermore, the optimal PSS cut-off value to detect an elevated MPAP and PVR was - 20.75%, based on receiver operating characteristic curve analysis. Significance PSS of the RV free wall might serve as a useful non-invasive indicator of PH

Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans

Aneurysm of the abdominal aorta (AAA) is a particular, specifically localized form of atherothrombosis, providing a unique human model of this disease. The pathogenesis of AAA is characterized by a breakdown of the extracellular matrix due to an excessive proteolytic activity, leading to potential arterial wall rupture. The roles of matrix metalloproteinases and plasmin generation in progression of AAA have been demonstrated both in animal models and in clinical studies. In the present review, we highlight recent studies addressing the role of the haemoglobin-rich, intraluminal thrombus and the adventitial response in the development of human AAA. The intraluminal thrombus exerts its pathogenic effect through platelet activation, fibrin formation, binding of plasminogen and its activators, and trapping of erythrocytes and neutrophils, leading to oxidative and proteolytic injury of the arterial wall. These events occur mainly at the intraluminal thrombus–circulating blood interface, and pathological mediators are conveyed outwards, where they promote matrix degradation of the arterial wall. In response, neo-angiogenesis, phagocytosis by mononuclear cells, and a shift from innate to adaptive immunity in the adventitia are observed. Abdominal aortic aneurysm thus represents an accessible spatiotemporal model of human atherothrombotic progression towards clinical events, the study of which should allow further understanding of its pathogenesis and the translation of pathogenic biological activities into diagnostic and therapeutic applications

Impaired Vascular Contractility and Aortic Wall Degeneration in Fibulin-4 Deficient Mice: Effect of Angiotensin II Type 1 (AT1) Receptor Blockade

Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT1) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4+/R) and 4-fold (homozygous Fibulin-4R/R) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-β signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-β. Tissue levels of Ang II, a regulator of TGF-β signaling, were increased. Prenatal treatment with the AT1 receptor antagonist losartan, which blunts TGF-β signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4R/R mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT1 receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease