MARCKS mediates vascular contractility through regulating interactions between voltage-gated Ca2+ channels and PIP2.

Phosphatidylinositol 4,5-bisphosphate (PIP2) acts as substrate and unmodified ligand for Gq-protein-coupled receptor signalling in vascular smooth muscle cells (VSMCs) that is central for initiating contractility. The present work investigated how PIP2 might perform these two potentially conflicting roles by studying the effect of myristoylated alanine-rich C kinase substrate (MARCKS), a PIP2-binding protein, on vascular contractility in rat and mouse mesenteric arteries. Using wire myography, MANS peptide (MANS), a MARCKS inhibitor, produced robust contractions with a pharmacological profile suggesting a predominantly role for L-type (CaV1.2) voltage-gated Ca2+ channels (VGCC). Knockdown of MARCKS using morpholino oligonucleotides reduced contractions induced by MANS and stimulation of α1-adrenoceptors and thromboxane receptors with methoxamine (MO) and U46619 respectively. Immunocytochemistry and proximity ligation assays demonstrated that MARCKS and CaV1.2 proteins co-localise at the plasma membrane in unstimulated tissue, and that MANS and MO reduced these interactions and induced translocation of MARCKS from the plasma membrane to the cytosol. Dot-blots revealed greater PIP2 binding to MARCKS than CaV1.2 in unstimulated tissue, with this binding profile reversed following stimulation by MANS and MO. MANS evoked an increase in peak amplitude and shifted the activation curve to more negative membrane potentials of whole-cell voltage-gated Ca2+ currents, which were prevented by depleting PIP2 levels with wortmannin. This present study indicates for the first time that MARCKS is important regulating vascular contractility and suggests that disinhibition of MARCKS by MANS or vasoconstrictors may induce contraction through releasing PIP2 into the local environment where it increases voltage-gated Ca2+ channel activity

Characterization and modeling of sintering of polymer particles

An experimental study of simultaneous sintering of several particles has been carried out using spherical polymer grains. Considering rotational molding condition, coalescence of several grains in contact, happens simultaneously on internal surface of the mould. Theoretical model based on the effect of surface tension and viscosity can accurately predict the coalescence of a pairs of grains. However, it was observed in this study that coalescence rate changes with presence of neighboring grains and their position and the theoretical model proposed for two grains, is not able to predict the coalescence rate of mutli-grains. Based on this finding, we have modified this model with taking into account the effect of neighboring particles in the sintering rate of multi-grains. Obtained modified model is capable of predicting the multi-grains sintering rate observed in this study

Coronary artery calcification on routine CT has prognostic and treatment implications for all ages

Aims: Guidelines have recommended reporting coronary artery calcification (CAC) if present on chest CT imaging regardless of indication. This study assessed CAC prevalence, prognosis and the potential clinical impact of its reporting. Methods: We performed a single-centre retrospective analysis (January-December 2015) of 1400 chest CTs (200 consecutive within each age group: &lt;40, 40-49, 50-59, 60-69, 70-79, 80-89, ≥90). CTs were re-reviewed for CAC presence and severity and excluded if prior coronary intervention. Comorbidities, statin prescription and clinical outcomes (myocardial infarction [MI], stroke, all-cause mortality) were recorded. The impact of reporting CAC was assessed against pre-existing statin prescriptions. Results: 1343 patients were included (mean age 63±20 years, 56% female). Inter- and intra-observer variability for CAC presence at re-review was almost perfect (κ 0.89, p &lt; 0.001; κ 0.90, p &lt; 0.001) and for CAC grading was substantial and almost perfect (κ 0.68, p &lt; 0.001; κ 0.91, p &lt; 0.001). CAC was observed in 729/1343 (54%), more frequently in males (p &lt; 0.001) and rising age (p &lt; 0.001). A high proportion of patients with CAC in all age groups had no prior statin prescription (range: 42% [80-89] to 100% [&lt;40]). The ‘number needed to report’ CAC presence to potentially impact management across all ages was 2. 689 (51%) patients died (median follow-up 74-months). CAC presence was associated with risk of MI, stroke and all-cause mortality (p &lt; 0.001). After adjusting for confounders, severe calcification predicted risk of all-cause mortality (HR 1.8 [1.2-2.5], p = 0.002). Conclusion: Grading of CAC was reproducible, and although prevalence rose with age, prognostic and treatment implications were maintained in all ages.</p

Pressure-induced oxidative activation of PKG enables vasoregulation by Ca2+ sparks and BK channels

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Study of Bonding Formation between the Filaments of PLA in FFF Process

Fused filament fabrication (FFF) is an additive manufacturing (AM) process that provides physical objects commonly used for modeling, prototyping and production applications. The major drawback of this process is poor mechanical property due to the porous structure of final parts. This process requires careful management of coalescence phenomenon. In this paper, the major influencing factors during the FFF processing of poly(lactic acid) (PLA) were investigated experimentally and with a numerical model. It has been shown that the polymer temperature has a significant effect on the rheological behavior of PLA, especially on the adhesion of the filaments. An experimental set-up has been placed in the machine to have the cyclic temperature of the filament. A variation of the polymer temperature influences process parameters such as feed rate, temperature of the nozzle and temperature of the platform. The results showed that the amount of polymeric coalescence (neck growth) rises when increasing the feed rate, the nozzle temperature, and the platform temperature. A model to predict the neck growth is proposed. It predicts a lower amount of neck growth value than obtained experimentally. This difference has been explained as the effect of other phenomena, such as polymer relaxation time, pressure of the nozzle and especially cyclic temperature which is not taken into account in the model

Abnormal Remodeling of Subcutaneous Small Arteries Is Associated With Early Diastolic Impairment in Metabolic Syndrome

Background Small artery pathophysiology is frequently invoked as a cause of obesity‐related diastolic heart failure. However, evidence to support this hypothesis is scant, particularly in humans. Methods and Results To address this, we studied human small artery structure and function in obesity and looked for correlations between vascular parameters and diastolic function. Seventeen obese patients with metabolic syndrome and 5 control participants underwent echocardiography and subcutaneous gluteal fat biopsy. Small arteries were isolated from the biopsy and pressure myography was used to study endothelial function and wall structure. In comparison with the control group, small arteries from obese participants exhibited significant endothelial dysfunction, assessed as the vasodilatory response to acetylcholine and also pathological growth of the wall. For the obese participants, multiple regression analysis revealed an association between left atrial volume and both the small artery wall thickness (β=0.718, P =0.02) and wall‐to‐lumen ratio (β=0.605, P =0.02). Furthermore, the E:E′ ratio was associated with wall‐to‐lumen ratio (β=0.596, P =0.02) and inversely associated with interleukin‐6 (β=−0.868, P =0.03). By contrast, endothelial function did not correlate with any of the echocardiographic parameters studied. Conclusions Although the small arteries studied were not cardiac in origin, our results support a role for small artery remodeling in the development of diastolic dysfunction in humans. Further direct examination of the structure and function of the myocardial resistance vasculature is now warranted, to elucidate the temporal association between metabolic risk factors, small artery injury, and diastolic impairment. </jats:sec

Preoperative Hematocrit Concentration and the Risk of Stroke in Patients Undergoing Isolated Coronary-Artery Bypass Grafting

Background. Identification and management of risk factors for stroke following isolated coronary artery bypass grafting (CABG) could potentially lower the risk of such serious morbidity. Methods. We retrieved data for 30-day stroke incidence and perioperative variables for patients undergoing isolated CABG and used multivariate logistic regression to assess the adjusted effect of preoperative hematocrit concentration on stroke incidence. Results. In 2,313 patients (mean age 65.9 years, 73.6% men), 43 (1.9%, 95% CI: 1.4-2.5) developed stroke within 30 days following CABG (74.4% within 6 days). After adjustment for a priori defined potential confounders, each 1% drop in preoperative hematocrit concentration was associated with 1.07 (95% CI: 1.01-1.13) increased odds for stroke (men, OR: 1.08, 95% CI: 1.01-1.16; women, OR: 1.02, 95% CI: 0.91-1.16). The predicted probability of stroke for descending preoperative hematocrit concentration exceeded 2% for values &lt;37% (&lt;37% for men (adjusted OR: 2.39, 95% CI: 1.08-5.26) and &lt;38% for women (adjusted OR: 2.52, 95% CI: 0.53-11.98), with a steeper probability increase noted in men). The association between lower preoperative hematocrit concentration and stroke was evident irrespective of intraoperative transfusion use. Conclusion. Screening and management of patients with low preoperative hematocrit concentration may alter postoperative stroke risk in patients undergoing isolated CABG

Diabetic cardiomyopathy

Diabetic cardiomyopathy is a distinct primary disease process, independent of coronary artery disease, which leads to heart failure in diabetic patients. Epidemiological and clinical trial data have confirmed the greater incidence and prevalence of heart failure in diabetes. Novel echocardiographic and MR (magnetic resonance) techniques have enabled a more accurate means of phenotyping diabetic cardiomyopathy. Experimental models of diabetes have provided a range of novel molecular targets for this condition, but none have been substantiated in humans. Similarly, although ultrastructural pathology of the microvessels and cardiomyocytes is well described in animal models, studies in humans are small and limited to light microscopy. With regard to treatment, recent data with thiazoledinediones has generated much controversy in terms of the cardiac safety of both these and other drugs currently in use and under development. Clinical trials are urgently required to establish the efficacy of currently available agents for heart failure, as well as novel therapies in patients specifically with diabetic cardiomyopathy

What the radiologist needs to know about the diabetic patient

Diabetes mellitus (DM) is recognised as a major health problem. Ninety-nine percent of diabetics suffer from type 2 DM and 10% from type 1 and other types of DM. The number of diabetic patients worldwide is expected to reach 380 millions over the next 15 years. The duration of diabetes is an important factor in the pathogenesis of complications, but other factors frequently coexisting with type 2 DM, such as hypertension, obesity and dyslipidaemia, also contribute to the development of diabetic angiopathy. Microvascular complications include retinopathy, nephropathy and neuropathy. Macroangiopathy mainly affects coronary arteries, carotid arteries and arteries of the lower extremities. Eighty percent of deaths in the diabetic population result from cardiovascular incidents. DM is considered an equivalent of coronary heart disease (CHD). Stroke and peripheral artery disease (PAD) are other main manifestations of diabetic macroangiopathy. Diabetic cardiomyopathy (DC) represents another chronic complication that occurs independently of CHD and hypertension. The greater susceptibility of diabetic patients to infections completes the spectrum of the main consequences of DM. The serious complications of DM make it essential for physicians to be aware of the screening guidelines, allowing for earlier patient diagnosis and treatment