Phenotyping of hypertensive heart disease and hypertrophic cardiomyopathy using personalized 3D modelling and cardiac cine MRI

Differential diagnosis of hypertensive heart disease (HHD) and hypertrophic cardiomyopathy (HCM) is clinically challenging but important for treatment management. This study aims to phenotype HHD and HCM in 3D + time domain by using a multiparametric motion-corrected personalized modeling algorithm and cardiac magnetic resonance (CMR). 44 CMR data, including 12 healthy, 16 HHD and 16 HCM cases, were examined. Multiple CMR phenotype data consisting of geometric and dynamic variables were extracted globally and regionally from the models over a full cardiac cycle for comparison against healthy models and clinical reports. Statistical classifications were used to identify the distinctive characteristics and disease subtypes with overlapping functional data, providing insights into the challenges for differential diagnosis of both types of disease. While HCM is characterized by localized extreme hypertrophy of the LV, wall thickening/contraction/strain was found to be normal and in sync, though it was occasionally exaggerated at normotrophic/less severely hypertrophic regions during systole to preserve the overall ejection fraction (EF) and systolic functionality. Additionally, we observed that hypertrophy in HHD could also be localized, although at less extreme conditions (i.e. more concentric). While fibrosis occurs mostly in those HCM cases with aortic obstruction, only minority of HHD patients were found affected by fibrosis. We demonstrate that subgroups of HHD (i.e. preserved and reduced EF: HHDpEF & HHDrEF) have different 3D + time CMR characteristics. While HHDpEF has cardiac functions in normal range, dilation and heart failure are indicated in HHDrEF as reflected by low LV wall thickening/contraction/strain and synchrony, as well as much reduced EF.     

Characterization of the growth plate-bone interphase region using cryo-FIB SEM 3D volume imaging

The interphase region at the base of the growth plate includes blood vessels, cells and mineralized tissues. In this region, cartilage is mineralized and replaced with bone. Blood vessel extremities permeate this space providing nutrients, oxygen and signaling factors. All these different components form a complex intertwined 3D structure. Here we use cryo-FIB SEM to elaborate this 3D structure without removing the water. As it is challenging to image mineralized and unmineralized tissues in a hydrated state, we provide technical details of the parameters used. We obtained two FIB SEM image stacks that show that the blood vessels are in intimate contact not only with cells, but in some locations also with mineralized tissues. There are abundant red blood cells at the extremities of the vessels. We also documented large multinucleated cells in contact with mineralized cartilage and possibly also with bone. We observed membrane bound mineralized particles in these cells, as well as in blood serum, but not in the hypertrophic chondrocytes. We confirm that there is an open pathway from the blood vessel extremities to the mineralizing cartilage. Based on the sparsity of the mineralized particles, we conclude that mainly ions in solution are used for mineralizing cartilage and bone, but these are augmented by the supply of mineralized particles.     

不同能量CO2点阵激光对博来霉素诱导的小鼠增生性瘢痕的作用及Hedgehog信号通路的影响

目的:探讨不同能量CO_2点阵激光对博莱霉素诱导的小鼠增生性瘢痕模型的作用及其对瘢痕组织中Hedgehog信号通路的影响。方法:于雄性C57BL/6J小鼠背部皮肤注射博来霉素(1 mg/d,4周)制作增生性瘢痕模型,另取4只小鼠背部注射PBS缓冲液作为对照。造模成功之后,随机将小鼠分为瘢痕对照组(模型组),10 mj激光治疗组(10 mj组)和20 mj激光治疗组(20 mj组),每组6只小鼠。10 mj组小鼠给予10 mj激光治疗(共3次,每次间隔2周);20 mj组小鼠给予20 mj激光治疗(共3次,每次间隔2周)。治疗结束后,处死小鼠,取瘢痕全层标本进行病理组织学染色观察(HE、Masson染色)以及α-平滑肌肌动蛋白(α-SMA)、GLi1免疫荧光观察。结果:①我们成功复制出小鼠增生性瘢痕模型;②20 mj CO_2点阵激光治疗可有效修复瘢痕组织,经治疗后皮肤瘢痕程度显著减轻,同时可降低真皮层厚度和减轻瘢痕组织的纤维化程度;③免疫荧光染色结果提示,CO_2点阵激光可显著减少小鼠皮肤增生性瘢痕中α-SMA、GLi1表达。结论:于小鼠的背部皮肤注射博莱霉素可建立增生性瘢痕模型。CO_2点阵激光为治疗增生性瘢一种有效的治疗方式,其作用可能与其对Hedgehog信号通路的抑制有关。     

Hypertrophic cardiomyopathy: two homozygous cases with "typical" hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy

About 10% of cases of hypertrophic cardiomyopathy (HCM) evolve into dilated cardiomyopathy (DCM) with unknown causes. We studied 11 unrelated patients (pts) with HCM who progressed to DCM (group A) and 11 who showed "typical" HCM (group B). Mutational analysis of the beta-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), and cardiac troponin T (TNNT2) genes demonstrated eight mutations affecting MYH7 or MYBPC3 gene, five of which were new mutations. In group A-pts, the first new mutation occurred in the myosin head-rod junction and the second occurred in the light chain-binding site. The third new mutation leads to a MYBPC3 lacking titin and myosin binding sites. In group B, two pts with severe HCM carried two homozygous MYBPC3 mutations and one with moderate hypertrophy was a compound heterozygous for MYBPC3 gene. We identified five unreported mutations, potentially "malignant" defects as for the associated phenotypes, but no specific mutations of HCM/DCM.     

A molecular analysis of matrix remodeling and angiogenesis during long bone development

The replacement of cartilage by bone is the net result of genetic programs that control chondrocyte differentiation, matrix degradation, and bone formation. Disruptions in the rate, timing, or duration of chondrocyte proliferation and differentiation result in shortened, misshapen skeletal elements. In the majority of these skeletal disruptions, vascular invasion of the elements is also perturbed. Our hypothesis is that the processes involved in endochondral ossification are synchronized via the vasculature. The purpose of this study was to examine carefully the events of vascular invasion and matrix degradation in the context of chondrocyte differentiation and bone formation. Here, we have produced a ‘molecular map’ of the initial vascularization of the developing skeleton that provides a framework in which to interpret a wide range of fetal skeletal malformations, disruptions, and dysplasias.     

HyTK基因转移联合ganciclovir对瘢痕成纤维细胞的体外杀伤作用

增生性瘢痕和瘢痕疙瘩的过度增生主要是由于高度增生活性的成纤维细胞的数量异常增多及细胞外基质合成增加所致．用逆转录病毒载体介导单纯疱疹病毒胸苷激酶基因（ＨＳＶｔｋ）的转移,随后应用药物９－（１,３－二羟基－丙氧基－甲基）鸟嘌呤（ｇａｎｃｉｃｌｏｖｉｒ,ＧＣＶ）可选择性地杀死增生细胞．采用组织块贴壁法在体外原代培养成功增生性瘢痕病人的成纤维细胞（ＦＢ）．重组逆转录病毒ＧＴＫ转染ＦＢ细胞后,用ｈｙｇｒｏｍｙｃｉｎＢ筛选出阳性细胞克隆（ＦＢ／ＧＴＫ）,经ＰＣＲ方法检测证明ＨｙＴＫ基因已成功地导入ＦＢ中,但不含可复制的辅助病毒．分别用不同浓度的ＧＣＶ作用于ＦＢ／ＧＴＫ及ＦＢ,光镜下观察不同时间后细胞形态变化及ＭＴＴ法检测细胞活性．结果表明,ＧＣＶ浓度大于０．１μｍｏｌ／Ｌ时即对ＦＢ／ＧＴＫ有显著的杀伤作用,且具有强有力的“旁观者效应”     

SPECIES‐SPECIFIC DIFFERENCES IN ADAPTIVE PHENOTYPIC PLASTICITY IN AN ECOLOGICALLY RELEVANT TROPHIC TRAIT: HYPERTROPHIC LIPS IN MIDAS CICHLID FISHES

The spectacular species richness of cichlids and their diversity in morphology, coloration, and behavior have made them an ideal model for the study of speciation and adaptive evolution. Hypertrophic lips evolved repeatedly and independently in African and Neotropical cichlid radiations. Cichlids with hypertrophic lips forage predominantly in rocky crevices and it has been hypothesized that mechanical stress caused by friction could result in larger lips through phenotypic plasticity. To test the influence of the environment on the size and development of lips, we conducted a series of breeding and feeding experiments on Midas cichlids. Full‐sibs of Amphilophus labiatus (thick‐lipped) and Amphilophus citrinellus (thin‐lipped) each were split into a control group which was fed food from the water column and a treatment group whose food was fixed to substrates. We found strong evidence for phenotypic plasticity on lip area in the thick‐lipped species, but not in the thin‐lipped species. Intermediate phenotypic values were observed in hybrids from thick‐ and thin‐lipped species reared under “control” conditions. Thus, both a genetic, but also a phenotypic plastic component is involved in the development of hypertrophic lips in Neotropical cichlids. Moreover, species‐specific adaptive phenotypic plasticity was found, suggesting that plasticity is selected for in recent thick‐lipped species.     

Delayed AICD therapy and cardiac arrest resulting from undersensing of ventricular fibrillation in a subject with hypertrophic cardiomyopathy–A case report

Defibrillation testing is no longer routinely performed after automatic implantable cardioverter-defibrillator (AICD) implantation. However, certain subjects undergoing AICD implantation may be at higher risk of undersensing of ventricular arrhythmias resulting in potentially fatal outcomes. We present the case of a 30-year-old woman with hypertrophic cardiomyopathy (HCM; ‘asymmetric septal hypertophy’ morphologic variant) and prophylactic AICD who experienced an out of hospital cardiac arrest. AICD interrogation revealed undersensing as a result of intermittent high amplitude electrograms during an episode of ventricular fibrillation (VF). The subject underwent replacement and repositioning of the AICD lead along with pulse generator replacement (that utilized a different VF sensing algorithm) with appropriate sensing of VF and successful defibrillation testing. The presence of intermittent high amplitude electrograms during episodes of VF in AICDs using the AGC function should be recognized as a situation that may necessitate interventions to prevent undersensing and consequent delay in therapy.     

Dizzy Spells in a Patient with Hypertrophic Obstructive Cardiomyopathy and a Pacemaker

Pacemaker syndrome represents the clinical consequences of the haemodynamic adverse effects of atrioventricular asynchrony during pacing. Patients suffering from hypertrophic cardiomyopathy may be particularly sensitive to these effects because of the importance of atrial systolic contribution to left ventricular diastolic filling. In this case report, we describe the symptoms and cause of pacemaker syndrome in a patient with hypertrophic obstructive cardiomyopathy.