Morphological analysis of the hagfish heart. II. The venous pole and the pericardium

The morphological characteristics of the venous pole and pericardium of the heart were examined in three hagfish species, Myxine glutinosa, Eptatretus stoutii, and Eptatretus cirrhatus. In these species, the atrioventricular (AV) canal is long, funnel‐shaped and contains small amounts of myocardium. The AV valve is formed by two pocket‐like leaflets that lack a papillary system. The atrial wall is formed by interconnected muscle trabeculae and a well‐defined collagenous system. The sinus venosus (SV) shows a collagenous wall and is connected to the left side of the atrium. An abrupt collagen‐muscle boundary marks the SV‐atrium transition. It is hypothesized that the SV is not homologous to that of other vertebrates which could have important implications for understanding heart evolution. In M. glutinosa and E. stoutii, the pericardium is a closed bag that hangs from the tissues dorsal to the heart and encloses both the heart and the ventral aorta. In contrast, the pericardium is continuous with the loose periaortic tissue in E. cirrhatus. In all three species, the pericardium ends at the level of the SV excluding most of the atrium from the pericardial cavity. In M. glutinosa and E. stoutii, connective bridges extend between the base of the aorta and the ventricular wall. In E. cirrhatus, the connections between the periaortic tissue and the ventricle may carry blood vessels that reach the ventricular base. A further difference specific to E. cirrhatus is that the adipose tissue associated with the pericardium contains thyroid follicles. J. Morphol. 277:853–865, 2016. © 2016 Wiley Periodicals, Inc.     

Human embryonic stem cell-derived cardiomyocytes as an in vitro model to study cardiac insulin resistance

Patients with type 2 diabetes (T2D) and/or insulin resistance (IR) have an increased risk for the development of heart failure (HF). Evidence indicates that this increased risk is linked to an altered cardiac substrate preference of the insulin resistant heart, which shifts from a balanced utilization of glucose and long-chain fatty acids (FAs) towards an almost complete reliance on FAs as main fuel source. This shift leads to a loss of endosomal proton pump activity and increased cardiac fat accumulation, which eventually triggers cardiac dysfunction. In this review, we describe the advantages and disadvantages of currently used in vitro models to study the underlying mechanism of IR-induced HF and provide insight into a human in vitro model: human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Using functional metabolic assays we demonstrate that, similar to rodent studies, hESC-CMs subjected to 16 h of high palmitate (HP) treatment develop the main features of IR, i.e., decreased insulin-stimulated glucose and FA uptake, as well as loss of endosomal acidification and insulin signaling. Taken together, these data propose that HP-treated hESC-CMs are a promising in vitro model of lipid overload-induced IR for further research into the underlying mechanism of cardiac IR and for identifying new pharmacological agents and therapeutic strategies. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.     

Discovery of tetrahydroindazoles as a novel class of potent and in vivo efficacious gamma secretase modulators

The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ((R)-42) was demonstrated to be centrally efficacious in rats at a 30?mg/kg oral dose.     

An SAR study of hydroxy-trifluoromethylpyrazolines as inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader assay

The proteins Orai1 and STIM1 control store-operated Ca²⁺ entry (SOCE) into cells. SOCE is important for migration, invasion and metastasis of MDA-MB-231 human triple negative breast cancer (TNBC) cells and has been proposed as a target for cancer drug discovery. Two hit compounds from a medium throughput screen, displayed encouraging inhibition of SOCE in MDA-MB-231 cells, as measured by a Fluorescence Imaging Plate Reader (FLIPR) Ca²⁺ assay. Following NMR spectroscopic analysis of these hits and reassignment of their structures as 5-hydroxy-5-trifluoromethylpyrazolines, a series of analogues was prepared via thermal condensation reactions between substituted acylhydrazones and trifluoromethyl 1,3-dicarbonyl arenes. Structure-activity relationship (SAR) studies showed that small lipophilic substituents at the 2- and 3-positions of the RHS and 2-, 3- and 4-postions of the LHS terminal benzene rings improved activity, resulting in a novel class of potent and selective inhibitors of SOCE.     

降低胸膜腔内压促进冠脉血流的研究

临床上用调控呼吸的训练方法可使冠心病患者的症状明显减轻,心功能增强,这可能是主要通过过低胸膜腔内压,促进了冠脉血流,改善了心肌缺血来实现的,本实验为验证此设想的真实性,对８只狗从胸膜腔反复抽气推气,造成胸内压的较大变化,以模拟深吸气动作所致的胸内压变化。     

Effects of using the unloaded configuration in predicting the in vivo diastolic properties of the heart

Computational models are increasingly being used to investigate the mechanical properties of cardiac tissue. While much insight has been gained from these studies, one important limitation associated with computational modeling arises when using in vivo images of the heart to generate the reference state of the model. An unloaded reference configuration is needed to accurately represent the deformation of the heart. However, it is rare for a beating heart to actually reach a zero-pressure state during the cardiac cycle. To overcome this, a computational technique was adapted to determine the unloaded configuration of an in vivo porcine left ventricle (LV). In the current study, in vivo measurements were acquired using magnetic resonance images (MRI) and synchronous pressure catheterization in the LV (N = 5). The overall goal was to quantify the effects of using early–diastolic filling as the reference configuration (common assumption used in modeling) versus using the unloaded reference configuration for predicting the in vivo properties of LV myocardium. This was accomplished by using optimization to minimize the difference between MRI measured and finite element predicted strains and cavity volumes. The results show that when using the unloaded reference configuration, the computational method predicts material properties for LV myocardium that are softer and less anisotropic than when using the early-diastolic filling reference configuration. This indicates that the choice of reference configuration could have a significant impact on capturing the realistic mechanical response of the heart.     

The crystal structure of Z‐(Aib)10‐OH at 0.65 Å resolution: three complete turns of 310‐helix

The synthetic peptide Z‐(Aib)₁₀‐OH was crystallized from hot methanol by slow evaporation. The crystal used for data collection reflected synchrotron radiation to sub‐atomic resolution, where the bonding electron density becomes visible between the non‐hydrogen atoms. Crystals belong to the centrosymmetric space group P . Both molecules in the asymmetric unit form regular 3₁₀‐helices. All residues in each molecule possess the same handedness, which is in contrast to all other crystal structure determined to date of longer Aib‐homopeptides. These other peptides are C‐terminal protected by OtBu or OMe. In these cases, because of the missing ability of the C‐terminal protection group to form a hydrogen bond to the residue i‐3, the sense of the helix is reversed in the last residue. Here, the C‐terminal OH‐groups form hydrogen bonds to the residues i‐3, in part mediated by water molecules. This makes Z‐(Aib)₁₀‐OH an Aib‐homopeptide with three complete 3₁₀‐helical turns in spite of the shorter length it has compared with Z‐(Aib)₁₁‐OtBu, the only homopeptide to date with three complete turns.     

无创正压通气序贯治疗急性左心衰合并呼吸衰竭患者的时机选择

目的:探讨无创正压通气序贯治疗急性左心衰合并呼吸衰竭患者的时机选择。方法:选择2013年6月-2015年8月我院收治的120例先行气管插管有创通气治疗的急性左心衰合并呼吸衰竭患者作为研究对象,病情得到控制后,按照拔管时间的长短分为A、B、C 3组,各40例,其中A组在进行自主呼吸30 min后拔管,B组在进行自主呼吸2 h后拔管,C组在进行自主呼吸24 h后拔管,拔管后全部患者均进行无创正压通气序贯治疗,比较3组患者治疗后血气分析结果、呼吸机相关肺炎发生率及脱机成功率。结果:13组患者无创正压通气治疗后的呼吸频率、心率、氧合指数、氧分压、二氧化碳分压及ph值均无明显差异(t1=1.402,t2=1.338,t1=0.738,t2=1.201,t1=0.969,t1=0.857,均P0.05);2A组患者的脱机成功率为7.50%,显著低于B组的77.50%与C组的82.50%,差异具有统计学意义(P0.05);A组患者的再插管率为92.50%,显著高于B组的22.50%与C组的17.50%,比较差异具有统计学意义(P0.05);A组患者的呼吸机相关肺炎发生率为45.00%,显著高于B组的12.50%与C组的10.00%,比较差异具有统计学意义(P0.05)。结论:急性左心衰合并呼吸衰竭患者在自主呼吸超过2 h后拔管,进行无创正压通气序贯治疗,可明显提高脱机成功率,降低再插管率和呼吸机相关肺炎发生率,值得临床推广。     

清栓酶治疗冠心病人左心功能的评价

1988至1990年期间,我们采用SV、CO、SI、CI、HI、TPR六项心功能指标测定了清栓酶对45例冠心病治疗前后左心功能的变化,结合临床症状和心电图的观察,45例冠心病患者的心功能改善率为73.3％。因而提示我们清栓酶在纠正心肌缺血,改善左心功能,防治心力衰竭等方面具有较好的效果,为治疗冠心病提供了一个新的药物。     

心脏收缩时间间期与冠状动脉狭窄程度或范围的相关性研究

心脏收缩时间间期(STI)通过单笔心电图机叠加记录ECG、心音图和颈动脉图后测得。对83例患者进行了STI均值与选择性冠状动脉造影(CAG)及左室造影的相关研究。患者除陈旧性心肌梗塞及室壁瘤外,根据冠状动脉(CA)狭窄程度而分组。STI随CA狭窄程度及范围的增加而显著异常,提示心功能随心肌缺血程度加重而进行性恶化。左室射血分数(LVEF)的降低也支持这一点。CA狭窄程度、范围与射血前时间/左室射血时间(PEP/LVET)呈正相关。在决定左室功能的异常方面,PEP/LVET和LVEF的临床意义完全相同。提示STI在评价冠心病心功能上是有用的。排除影响STI的某些因素后,PEP/LVET≥0.38可作为判断冠心病左心功能减退的标志。但轻度CA狭窄患者的STI可正常,这可能与静息时尚有足够的CA贮备力有关。