Mitochondrial ND5 12338T>C variant is associated with maternally inherited hypertrophic cardiomyopathy in a Chinese pedigree

Hypertrophic cardiomyopathy is a primary disorder characterized by asymmetric thickening of the septum and left ventricular wall, which affects 1 in 500 individuals in the general population. Mutations in mitochondrial DNA have been found to be one of the most important causes of hypertrophic cardiomyopathy. Here we report the clinical, genetic and molecular characterization of a Han Chinese family with a likely maternally transmitted hypertrophic cardiomyopathy. Four (2 men/2 women) of 5 matrilineal relatives in this 3-generation family exhibited the variable severity and age at onset of 44 to 79years old. Sequence analysis of the entire mitochondrial DNA in this pedigree identified the known homoplasmic ND5 12338T>C variant. This mitochondrial DNA haplogroup belongs to the Eastern Asian F2a. The 12338T>C variant, highly evolutionarily conserved, resulted in the replacement of the translation initiating methionine with a threonine, shortening the ND5 polypeptide by 2 amino acids. The occurrence of ND5 12338T>C variant exclusively in maternal members of this Chinese family suggested that the 12338T>C variant is associated with maternally inherited hypertrophic cardiomyopathy. Our findings will provide theoretical basis for genetic counseling of maternally inherited hypertrophic cardiomyopathy.     

Neurohormonal and cytokine fluctuations following transcatheter closure for an atrial septal defect

Introduction

Inflammation and neurohormonal activation are considered to be involved in the development of earlier and/or later complications in congenital heart disease patients, even after a successful repair of the lesion. It is not yet clarified what is the role of the therapeutic interventions in the occurrence of such a response and how it could be associated with possible postoperative complications.

Aim

We sought to assess the inflammatory and neurohormonal response to transcatheter closure of secundum type atrial septal defects (ASD) over a six-month follow-up period. We also evaluated the association between the respective markers and catheterization data as well as echocardiographic measurements.

Methods

Plasma concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), N-terminal-proatrial natriuretic peptide (NT-proANP) and N-terminal-probrain natriuretic peptide (NT-proBNP) were assessed and echocardiographic measurements were performed in twenty-eight patients with atrial septal defect prior to, and at the first, second and sixth months post transcatheter closure. Thirty-three age-matched healthy volunteers were also enrolled.

Results

IL-6 plasma levels, although higher preoperatively, [physical logarithm (ln) IL-6: 3.37 ± 0.66 vs 2.92 ± 0.44 pg/ml, p = 0.015], reached control levels postoperatively, at the end of the third month, whereas TNF-α and IL-10 were not influenced by the procedure. NT-proANP levels were elevated preoperatively compared to the control group (ln NT-proANP 3.78 ± 0.572 vs 3.48 ± 0.30, p = 0.031), with a further significant increase during the 1st month (ln NT-proANP 3.78 ± 0.572 vs 4.2 ± 0.42, p = 0.006), following the pattern of the left atrial volume enlargement, and remained high even 6 months after the procedure .On the other hand, the initially normal concentrations of NT-proBNP, after a transient significant increase during the first month postoperatively (ln NT-proBNP 3.56 ± 0.94 vs 4.58 ± 0.91, p < 0.0001) returned to the controls’ levels at the end of the third month. Preoperative concentrations of NT-proANP positively correlated with NT-proBNP concentrations and pulmonary to systemic flow ratio (Qp/Qs).

Conclusions

Transcatheter closure could improve, on a mid- term basis, the inflammatory process but natriuretic peptides’ secretion continues in parallel with left atrial volume increase. Further follow up is required to determine the long-term progress of the inflammatory and neurohormonal response to the procedure.     

ELV对青春期大鼠睾丸中VEGF与VEGFR2蛋白表达的影响

目的研究血管内皮生长因子(VEGF)及其受体2(VEGFR2)在实验性左侧精索静脉曲张大鼠睾丸中的表达和定位,探讨精索静脉曲张中VEGF和VEGFR2的可能作用。方法通过部分结扎左肾静脉建立大鼠实验性左侧精索静脉曲张模型,于术后2周和4周取材,采用免疫组化法检测VEGF、VEGFR2在睾丸上的表达变化。结果 ELV2周与4周组大鼠两侧睾丸中VEGF蛋白表达均上调,但ELV组间VEGF蛋白表达没有明显变化;ELV2周组大鼠睾丸中VEGFR2蛋白的表达与对照组比较增强,而4周组比对照组和2周组均显著增强。结论实验性左侧精索静脉曲张对VEGF、VEGFR2蛋白的表达有影响,说明它们与男性不育可能有一定的关系。     

Fluid–structure interaction analysis of the left coronary artery with variable angulation

The aim of this study is to elucidate the correlation between coronary artery branch angulation, local mechanical and haemodynamic forces at the vicinity of bifurcation. Using a coupled fluid–structure interaction (FSI) modelling approach, five idealized left coronary artery models with various angles ranging from 70° to 110° were developed to investigate the influence of branch angulations. In addition, one CT image-based model was reconstructed to further demonstrate the medical application potential of the proposed FSI coupling method. The results show that the angulation strongly alters its mechanical stress distribution, and the instantaneous wall shear stress distributions are substantially moderated by the arterial wall compliance. As high tensile stress is hypothesized to cause stenosis, the left circumflex side bifurcation shoulder is indicated to induce atherosclerotic changes with a high tendency for wide-angled models.     

THE EFFECT OF AEROBIC CONTINUOUS AND INTERVAL TRAINING ON LEFT VENTRICULAR STRUCTURE AND FUNCTION IN MALE NON-ATHLETES

Exercise plays an important role to improve cardiovascular performance. The aim of this study was to compare the effect of aerobic continuous and interval training on the left ventricular structure and function. Twenty untrained healthy male students (aged 18-22 years) were randomly divided into two groups: continuous (C; n = 10) and interval (I; n = 10). The training programme consisted of countryside jogging for 45 min during 8 weeks three times a week at 70% of maximum heart rate (MHR). In each session group C was jogging for 45 min and in group I jogging was performed in 5 nine-minute stages with a four-minute inactive rest between them. M-mode, 2-dimensional, colour and Doppler transthoracic echocardiography were performed, during resting conditions, before and after the training period. After 8-week training the end diastolic diameter, systolic blood pressure and diastolic blood pressure in groups C and I, and the posterior wall thickness and the end systolic diameter in group I showed no significant difference (P > 0.05). On the other hand, the percentage of ejection fraction and shortening fraction in groups C and I, the end systolic diameter and the posterior wall thickness in group C and the interventricular septum thickness in group I demonstrated a significant difference (P ≤ 0.05). Comparing the two groups, only the value of the interventricular septum thickness was significant (P ≤ 0.05). In general, eight-week aerobic continuous and interval training can affect left ventricular structure and function.     

Increased gene expression of plasminogen activators and inhibitors in left ventricular hypertrophy

In the early stages of left ventricular hypertrophy (LVH) acute adaptive changes occur in the coronary vasculature as it remodels. Plasminogen activators (PAs) and inhibitors (PAIs) have the potential effects of proteolytic degradation that is relevant to tissue remodeling and angiogenesis. Our study focused on the possible roles of PAI-1, PAI-2, uPA and tPA in myocyte hypertrophy and angiogenesis in the early and late stages of pressure overload induced left ventricular hypertrophy (LVH). We divided seventeen adult swine, weighing 24.2 ± 6.5 kg, into four groups: control, sham-operated, early LVH and late heart failure LVH group. At surgery we placed a fixed constrictor on the ascending aorta immediately above the aortic valve. This increased LV systolic pressure from 133 ± 15 to 193 ± 24 mm Hg after the surgery. We subdivided the early group into groups of 3 animals each that we euthanized at 8, 24 and 72 h after operation and obtained heart samples for analysis. In the late heart failure group individual animals were euthanized at 55, 59, 62 and 72 days after the detection of congestive heart failure. We also obtained tissue samples from the control and sham-operated swine. Sections for histologic analysis were fixed in 10% buffered formalin. We isolated RNA, size fractionated it using 1% formaldehyde-agarose gel electrophoresis and then did Northern blots. The mRNAs from both PAI-1 and PAI-2 showed a remarkable increase at 8 and 24 h after acute aortic constriction and returned to control by 72 h. Regional differences showed that most of the increases were in the endocardium. Three animals in the late heart failure LVH group were determined to be in congestive heart failure at about 2 months after the onset of aortic constriction. In these animals PAI-1 and PAI-2 were increased in both the left and right ventricles but remained low in an animal of the same elevation in aortic pressure seen by the LV who did not have congestive failure. These data suggest that PA and PAI gene expressions change before morphologic changes occur in the early stages of developing LVH. Also at the time of onset of congestive heart failure this increased expression reappears. PAs and PA inhibitors mRNA levels vary in the different regions of the heart reflecting changing wall stresses. Thus, the PAs and PA inhibitors may play an important role in angiogenesis that occurs during the early stages of LVH. The increased expression in the late stage of LVH may reflect further changes in wall stresses since these animals also showed overt clinical signs of heart failure.     

Abaristophora sachalinensis Michailovskaya (Diptera: Phoridae) representing genitalic affinities with the genus Borophaga Enderlein

Abaristophora sachalinensis Michailovskaya is reviewed based on Japanese materials. Its male genitalia are compared with those of the genus Borophaga, which is a genus in a group of the related genera, the Borophaga subgroup. A synapomorphic character of the Borophaga subgroup including Abaristophora, the left flattened arm derived from the posterodorsal margin of the hypandrium being broadened at the base, is confirmed in A. sachalinensis. Morphology of the aedeagus in A. sachalinensis is complex and extremely asymmetric, and very similar to that of species of the genus Borophaga, but the characters observed in this study are not regarded as synapomorphic for the Borophaga subgroup.     

Structural classification of αββ and ββα supersecondary structure units in proteins

We present a fully automatic structural classification of supersecondary structure units, consisting of two hydrogen-bonded β strands, preceded or followed by an α helix. The classification is performed on the spatial arrangement of the secondary structure elements, irrespective of the length and conformation of the intervening loops. The similarity of the arrangements is estimated by a structure alignment procedure that uses as similarity measure the root mean square deviation of superimposed backbone atoms. Applied to a set of 141 well-resolved nonhomologous protein structures, the classification yields 11 families of recurrent arrangements. In addition, fragments that are structurally intermediate between the families are found; they reveal the continuity of the classification. The analysis of the families shows that the α helix and β hairpin axes can adopt virtually all relative orientations, with, however, some preferable orientations; moreover, according to the orientation, preferences in the left/right handedness of the α–β connection are observed. These preferences can be explained by favorable side by side packing of the α helix and the β hairpin, local interactions in the region of the α–β connection or stabilizing environments in the parent protein. Furthermore, fold recognition procedures and structure prediction algorithms coupled to database-derived potentials suggest that the preferable nature of these arrangements does not imply their intrinsic stability. They usually accommodate a large number of sequences, of which only a subset is predicted to stabilize the motif. The motifs predicted as stable could correspond to nuclei formed at the very beginning of the folding process. Proteins 30:193–212, 1998. © 1998 Wiley-Liss, Inc.     

缺血/再灌注时豚鼠左心室流出道自律组织电活动的改变及药物干预效应

目的：研究缺血/再灌注（I/R）时豚鼠离体左心室流出道自律组织电活动的改变及其药物干预效应。方法：采用标准玻璃微电极细胞内电位记录技术,记录豚鼠离体左心室流出道标本的自发慢反应电位,观测模拟I/R时该电位的改变,以及临床上常用的抗心律失常药物灌流标本时对I/R电生理效应的干预作用。观测指标：4相自动除极速度（VDD）、自发放电频率（RPF）、最大舒张电位（MDP）、0相最大除极速度（V_max）、动作电位幅度（APA）、复极50%和90%时间（APD₅₀和APD₉₀）。结果：①与对照组相比,I 10 min组VDD和RPF明显减慢（P<0.05）,V_max加快（P<0.01）,APA增大（P<0.01）。与I 10 min组和对照组相比,R 2 min组VDD和RPF明显加快（P<0.01）,且在R至5 min过程中可出现明显节律不齐,MDP绝对值明显增大（P<0.05）,V_max与对照组相比明显加快（P<0.05）,APA与I 10 min组相比明显下降（P<0.05）,但仍显著高于对照组（P<0.05）,APD₅₀和APD₉₀显著缩短（P<0.01）。R 15 min组自发慢反应电位各项指标逐渐恢复至对照组水平。②与I 10min/R 2 min组相比,1 μmol/L利多卡因、10 μmol/L普罗帕酮、1 μmol/L胺碘酮、1 μmol/L维拉帕米、50 μmol/L腺苷和10 μmol/L硝普钠均可明显改善R过程中VDD和RPF的改变以及由此引起的节律不齐。结论：I/R可触发左心室流出道自律组织电活动异常,这种效应在应用不同的抗心律失常药物灌流时可显著恢复。     

A Cre transgene active in developing endodermal organs, heart, limb, and extra-ocular muscle

Cre-mediated recombination, a method widely used in mice for tissue-specific inactivation of endogenous genes or activation of transgenes, is critically dependent on the availability of mouse lines in which Cre recombinase functions in the tissue of interest or its progenitors. Here we describe a transgenic mouse line, Osr1-cre, in which Cre is active from embryonic day (E)11.5 in a few specific tissues. These include the endoderm of the posterior foregut, midgut, hindgut, and developing urogenital system, the heart left atrium, extra-ocular muscle progenitors, and mesenchyme in particular regions of the limb. Furthermore, starting at E12.5, Cre functions in limb interdigital mesenchyme. Within the urogenital system, recombination appears to be virtually complete in the epithelium of the bladder and urethra just posterior to it by E14.5. In males, some of these urethral cells form the prostate. The spatiotemporal pattern of Cre activity in Osr1-cre makes it a unique resource among the lines available for Cre-mediated recombination experiments.