The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy

Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies results from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca2+ desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis. Methods and Findings: We ablated Tnnt2 to produce heterozygous Tnnt2+/ mice, and crossbreeding produced homozygous null Tnnt2-/-embryos. We also generated transgenic mice overexpressing wildtype (TGWT) or DCM mutant (TGK210Δ) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2+/-/TGWT) or mutant (Tnnt2+/-/TGK210Δ) transgenes. Tnnt2+/-mice relative to wildtype had significantly reduced transcript (0.82 ± 0.06 [SD] vs. 1.00 ± 0.12 arbitrary units; p = 0.025), but not protein (1.01 ± 0.20 vs. 1.00 ± 0.13 arbitrary units; p = 0.44). Tnnt2+/-mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2+/-/ TGK210Δ mice had severe DCM, TGK210Δ mice had only mild DCM (FS 18 ± 4 vs. 29 ± 7%; p < 0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2+/-/TGK210Δ relative to TGK210Δ mice (2.42±0.08, p = 0.03). Tnnt2+/-/TGK210Δ muscle showed Ca2+ desensitization (pCa50 = 5.34 ± 0.08 vs. 5.58 ± 0.03 at sarcomere length 1.9 μm. p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2-/-embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres. Conclusions: Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca2+ desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity. © 2008 Ahmad et al

HOW DOES COALESCENCE OF DENDRITE ARMS OR GRAINS INFLUENCE HOT TEARING ?

Hot tearing, a severe defect occurring during solidification, is the conjunction of tensile stresses which are transmitted to the mushy zone by the coherent solid underneath and of an insufficient liquid feeding to compensate for the volumetric change. In most recent hot tearing criteria, one of the critical issues is the definition of a coherency point which, in low-concentration alloys, corresponds to the bridging or coalescence of the primary phase. A coalescence model has been developed recently using the concept of the disruptive pressure in thin liquid films.[1] It has been shown that large-misorientation grain boundaries, which are characterized by an interfacial energy, γgb, larger than twice the solid-liquid interfacial energy, γsl, solidify at an undercooling ΔTb = (γgb - 2γsl)/(Δsfδ), where Δsf is the entropy of fusion and δ the thickness of the diffuse interface. When γgb < 2γsl (e.g., low-angle grain boundaries), dendrite arms coalesce as soon as they impinge on each other. Using such concepts and a back-diffusion model, the percolation of equiaxed, randomly oriented grains has been studied in 2D : it is shown that the grain structure gradually evolves from isolated grains separated by a continuous interdendritic liquid film, to a fully coherent solid with a few remaining wet boundaries. The implication of such findings for the hot cracking tendency of aluminum alloys are discussed

Coronary endothelial dysfunction in patients with acute-onset idiopathic dilated cardiomyopathy

AbstractObjectives. This study sought to determine whether coronary endothelial dysfunction exists in patients with acute-onset idiopathic dilated cardiomyopathy (DCM) and to explore its relation to recovery of left ventricular systolic function in this patient population.Background. Coronary endothelial dysfunction exists in chronic DCM, but its importance in the development and progression of ventricular dysfunction is not known. To address this issue we studied coronary endothelial function in patients with idiopathic DCM <6 months in duration and explored the relation between coronary endothelial function and subsequent changes in left ventricular ejection fraction (LVEF).Methods. Ten patients with acute-onset idiopathic DCM (duration of heart failure symptoms 2.0 ± 0.4 months [mean ± SEM]) and 11 control patients with normal left ventricular function underwent assessment of coronary endothelial function during intracoronary administration of the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator adenosine. Coronary cross-sectional area (CSA) was determined by quantitative coronary angiography and coronary blood flow (CBF) by the product of coronary CSA and CBF velocity measured by an intracoronary Doppler catheter. Patients with DCM underwent assessment of left ventricular function before and several months after the study.Results. Acetylcholine infusion produced no change in coronary CSA in control patients but significant epicardial constriction in patients with DCM (−36 ± 11%, p < 0.01). These changes were associated with increases in CBF in control patients (+118 ± 49%, p < 0.01) but no change in patients with DCM. Infusion of adenosine produced increases in coronary caliber and blood flow in both groups. Follow-up assessment of left ventricular function was obtained in nine patients with DCM 7.0 ± 1.7 months after initial study, at which time LVEF had improved by ≥0.10 in four patients. Multiple linear regression revealed a positive correlation between both the coronary CSA (r2 = 0.57, p < 0.05) and CBF (r2 = 0.68, p < 0.01) response to acetylcholine and the subsequent improvement in LVEF.Conclusions. Coronary endothelial dysfunction exists at both the microvascular and the epicardial level in patients with acute-onset idiopathic DCM. The preservation of coronary endothelial function in this population is associated with subsequent improvement in left ventricular function

Current status and perspectives of interventional clinical trials for glioblastoma - analysis of ClinicalTrials.gov

The records of 208.777 (100%) clinical trials registered at ClinicalTrials.gov were downloaded on the 19th of February 2016. Phase II and III trials including patients with glioblastoma were selected for further classification and analysis. Based on the disease settings, trials were classified into three groups: newly diagnosed glioblastoma, recurrent disease and trials with no differentiation according to disease setting. Furthermore, we categorized trials according to the experimental interventions, the primary sponsor, the source of financial support and trial design elements. Trends were evaluated using the autoregressive integrated moving average model. Two hundred sixteen (0.1%) trials were selected for further analysis. Academic centers (investigator initiated trials) were recorded as primary sponsors in 56.9% of trials, followed by industry 25.9%. Industry was the leading source of monetary support for the selected trials in 44.4%, followed by 25% of trials with primarily academic financial support. The number of newly initiated trials between 2005 and 2015 shows a positive trend, mainly through an increase in phase II trials, whereas phase III trials show a negative trend. The vast majority of trials evaluate forms of different systemic treatments (91.2%). In total, one hundred different molecular entities or biologicals were identified. Of those, 60% were involving drugs specifically designed for central nervous system malignancies. Trials that specifically address radiotherapy, surgery, imaging and other therapeutic or diagnostic methods appear to be rare. Current research in glioblastoma is mainly driven or sponsored by industry, academic medical oncologists and neuro-oncologists, with the majority of trials evaluating forms of systemic therapies. Few trials reach phase III. Imaging, radiation therapy and surgical procedures are underrepresented in current trials portfolios. Optimization in research portfolio for glioblastoma is needed

Effects of iron-rich intermetallics and grain structure on semisolid tensile properties of Al-Cu 206 cast alloys near solidus temperature

The effects of iron-rich intermetallics and grain size on the semisolid tensile properties of Al-Cu 206 cast alloys near the solidus were evaluated in relation to the mush microstructure. Analyses of the stress–displacement curves showed that the damage expanded faster in the mush structure dominated by plate-like β-Fe compared to the mush structure dominated by Chinese script-like α-Fe. While there was no evidence of void formation on the β-Fe intermetallics, they blocked the interdendritic liquid channels and thus hindered liquid flow and feeding during semisolid deformation. In contrast, the interdendritic liquid flows more freely within the mush structure containing α-Fe. The tensile properties of the alloy containing α-Fe are generally higher than those containing β-Fe over the crucial liquid fraction range of ~0.6 to 2.8 pct, indicating that the latter alloy may be more susceptible to stress-related casting defects such as hot tearing. A comparison of the semisolid tensile properties of the alloy containing α-Fe with different grain sizes showed that the maximum stress and elongation of the alloy with finer grains were moderately higher for the liquid fractions of ~2.2 to 3.6 pct. The application of semisolid tensile properties for the evaluation of the hot tearing susceptibility of experimental alloys is discussed