Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene

<p>Abstract</p> <p>Background</p> <p>Mutations in <it>MYBPC3 </it>encoding myosin binding protein C belong to the most frequent causes of hypertrophic cardiomyopathy (HCM) and may also lead to dilated cardiomyopathy (DCM). <it>MYBPC3 </it>mutations initially were considered to cause a benign form of HCM. The aim of this study was to examine the clinical outcome of patients and their relatives with 18 different <it>MYBPC3 </it>mutations.</p> <p>Methods</p> <p>87 patients with HCM and 71 patients with DCM were screened for <it>MYBPC3 </it>mutations by denaturing gradient gel electrophoresis and sequencing. Close relatives of mutation carriers were genotyped for the respective mutation. Relatives with mutation were then evaluated by echocardiography and magnetic resonance imaging. A detailed family history regarding adverse clinical events was recorded.</p> <p>Results</p> <p>In 16 HCM (18.4%) and two DCM (2.8%) index patients a mutation was detected. Seven mutations were novel. Mutation carriers exhibited no additional mutations in genes <it>MYH7</it>, <it>TNNT2</it>, <it>TNNI3</it>, <it>ACTC </it>and <it>TPM1</it>. Including relatives of twelve families, a total number of 42 mutation carriers was identified of which eleven (26.2%) had at least one adverse event. Considering the twelve families and six single patients with mutations, 45 individuals with cardiomyopathy and nine with borderline phenotype were identified. Among the 45 patients, 23 (51.1%) suffered from an adverse event. In eleven patients of seven families an unexplained sudden death was reported at the age between 13 and 67 years. Stroke or a transient ischemic attack occurred in six patients of five families. At least one adverse event occurred in eleven of twelve families.</p> <p>Conclusion</p> <p><it>MYBPC3 </it>mutations can be associated with cardiac events such as progressive heart failure, stroke and sudden death even at younger age. Therefore, patients with <it>MYBPC3 </it>mutations require thorough clinical risk assessment.</p

Gene expression throughout a vertebrate's embryogenesis

Abstract Background Describing the patterns of gene expression during embryonic development has broadened our understanding of the processes and patterns that define morphogenesis. Yet gene expression patterns have not been described throughout vertebrate embryogenesis. This study presents statistical analyses of gene expression during all 40 developmental stages in the teleost Fundulus heteroclitus using four biological replicates per stage. Results Patterns of gene expression for 7,000 genes appear to be important as they recapitulate developmental timing. Among the 45% of genes with significant expression differences between pairs of temporally adjacent stages, significant differences in gene expression vary from as few as five to more than 660. Five adjacent stages have disproportionately more significant changes in gene expression (&gt; 200 genes) relative to other stages: four to eight and eight to sixteen cell stages, onset of circulation, pre and post-hatch, and during complete yolk absorption. The fewest differences among adjacent stages occur during gastrulation. Yet, at stage 16, (pre-mid-gastrulation) the largest number of genes has peak expression. This stage has an over representation of genes in oxidative respiration and protein expression (ribosomes, translational genes and proteases). Unexpectedly, among all ribosomal genes, both strong positive and negative correlations occur. Similar correlated patterns of expression occur among all significant genes. Conclusions These data provide statistical support for the temporal dynamics of developmental gene expression during all stages of vertebrate development

Heavy and light roles: myosin in the morphogenesis of the heart

Myosin is an essential component of cardiac muscle, from the onset of cardiogenesis through to the adult heart. Although traditionally known for its role in energy transduction and force development, recent studies suggest that both myosin heavy-chain and myosin lightchain proteins are required for a correctly formed heart. Myosins are structural proteins that are not only expressed from early stages of heart development, but when mutated in humans they may give rise to congenital heart defects. This review will discuss the roles of myosin, specifically with regards to the developing heart. The expression of each myosin protein will be described, and the effects that altering expression has on the heart in embryogenesis in different animal models will be discussed. The human molecular genetics of the myosins will also be reviewed

BLOOD COAGULATION PROBLEMS AND THROMBOEMBOLIC COMPLICATIONS IN THE ACUTE STAGE OF STROKE

Background: High prevalence of stroke and constant mortality which is related to thromboembolic complications in one fourth of patients make it necessary to continue evaluation of clinically precise and technologically feasible methods of adequate control of coagulation and anticoagulation systems and predicting of venous thromboses and embolism. Aim: To improve diagnostics and treatment of patients with acute stroke of various types through assessment of haemostasis system and pathophysiological mechanisms of venous thromboembolism (VTE). Materials and methods: One hundred and forty five (145) patients with acute cerebral stroke (mean age, 69±13.2 years; 75 male and 70  female) were included into the study. All patients were admitted to the neuroresuscitation unit within 6 to 24 hours from manifestation; the diagnosis was verified by multiaxial computerized tomography. One hundred and four (104) (71.7%) of patients had ischemic stroke, 41 (28.3%) of patients had hemorrhagic stroke. At admittance, all patients had a  certain level of consciousness derangement. All patients were monitored by means of computerized tomography, general and neurological assessment, functional assessment, chest X-ray, ultrasound examination of extremities and assessment of haemostasis (screening and direct thrombodynamics test). Results: In 95%  of cases, VTE risk factors were found; VTE developed in 40  (27.6%) of patients. The most frequent complication was pulmonary embolism (90%  of all VTE and 24.8%  of 145  patients). In-hospital mortality was 44.1%  (n=64) and correlated with VTE (r=0.384; р&lt;0.01). Outcomes of ischemic stroke depended mainly on VTE (at autopsy, they were found in 58.5%  of patients with ischemic stroke and in 26.1%  of those with hemorrhagic stroke) and other complications. Outcomes of hemorrhagic insult depended on the size of the lesion that correlated with severity of clinical symptoms. Screening coagulation parameters were not informative enough for the assessment of haemostasis. Development of VTE correlated with some hypercoagulation in the first days after stroke that were quickly transformed into hypocoagulation. This process could be reliably assessed by the thrombodynamics test. Conclusion: Taking into account high incidence of VTE in patients with severe stroke and low informative value of coagulation screening, it is reasonable to use direct methods of haemostasis assessment and individualized approached to preventive and therapeutic anticoagulation

CONTEMPORARY APPROACH TO THE CORRECTION OF COGNITIVE DISORDERS IN PATIENTS WITH VASCULAR COMORBIDITY

Various aspects of the therapy of patients with cognitive impairments and vascular comorbidity, including cerebral stroke and chronic brain ischemia associated with cardiac and endocrine diseases are discussed. Influence of vascular cognitive and psycho-emotional disorders on the social and everyday activity is demonstrated. Clinical studies of efficacy and safety of vinpocetine treatment in these patients are presented

CARDIOVASCULAR PATHOLOGY IN ACUTE STROKE (ISSUES ON PREVALENCE, PREVENTION AND TREATMENT)

The article concerns on the problems of vascular comorbidity epidemiology and pathophysiological aspects of heart disease, which became a leading etiopathologic factor of cerebral infarctions and hemorrhages. The relationship between coronary artery disease (CAD), atrial fibrillation, hypertension and cerebral infarction types is emphasized.Aim. To analyze the role of comorbidity, attributable to cardio-vascular pathology in the initiation, course, clinical features and outcomes of cerebral infarction.Material and methods. We performed a prospective study, including 1072 patients with stroke, attributable to various cardiovascular pathology, evaluated the influence of vascular comorbidity of variable degree on the course and outcomes at an inpatient stage and at follow-up.Results. We demonstrated a negative influence of CAD, atrial fibrillation and postinfarction cardiosclerosis on the incidence of cerebral infarction, unfavorable course of the disease and functional outcomes at inpatient stage. The combination of vascular comorbidity resulted in an increased mortality in post-stroke period during 6 years of follow-up.Conclusion. Epidemiology of vascular comorbidity, its role in cerebrovascular accidents in patients with cardiac pathology justifies the need of active realization of contemporary multidisciplinary prevention programs, prolonged instrumental monitoring and implementation of energy deficiency correction therapy in comprehensive treatment programs

PROBLEMS AND PROSPECTS OF INTERMEDIARY METABOLISM CORRECTION IN PATIENTS WITH VASCULAR COMORBIDITY

Disorders of intermediary metabolism in the glycolysis cycles and fatty acids oxidation play a major role in heart and brain lesions of vascular origin. Features of the free-radical processes in various forms of vascular disease are presented. Differences within the free-radical processes reflecting the severity of tissue energy deficit are shown in stroke patients with concomitant ischemic heart disease, atrial fibrillation, and diabetes mellitus. Various aspects of the treatment of patients with vascular comorbidity are presented with the focus on correction of intermediary metabolism disorders. Complex energy correcting therapy including beta-oxidation blocker (meldonium) is discussed

PROBLEMS AND PROSPECTS OF INTERMEDIARY METABOLISM CORRECTION IN PATIENTS WITH VASCULAR COMORBIDITY

Disorders of intermediary metabolism in the glycolysis cycles and fatty acids oxidation play a major role in heart and brain lesions of vascular origin. Features of the free-radical processes in various forms of vascular disease are presented. Differences within the free-radical processes reflecting the severity of tissue energy deficit are shown in stroke patients with concomitant ischemic heart disease, atrial fibrillation, and diabetes mellitus. Various aspects of the treatment of patients with vascular comorbidity are presented with the focus on correction of intermediary metabolism disorders. Complex energy correcting therapy including beta-oxidation blocker (meldonium) is discussed

АТФ-деградирующая активность мембран легочной ткани: исследование особенностей гидролиза, клеточной специфичности и локализации

Peculiarities of ATP and ADP degradation by lung membranes were studed. It was shown that AMP is the final product of ATP hydrolysis. AMP is formed from ATP by sequential release of terminal phosphate according to the scheme: ATP─ ─→ADP─ ─→AMP, and not by pyrophosphatase activity.Inhibitory analysis using adenine nucleotides, their nonhydrolysible analogs, phosphate and pyrophosphate and also determination of kinetic values (Kni and Vmax) for the ATP-ase and ADP-ase reactions indicates on a coordinated hydrolysis of ATP and ADP.ATP-degradating activity is discovered in membranes of cells formed a blood vessels (endothelial and smooth-muscle), but not in membranes of Type II alveolar cells, which secrete surfactant.This nucleotide hydrolising activity is preferentially localised on a luminal surfase of plasma membrane, since addition of a pore-forming antibiotic alameticine to a confluent endothelial monolayer does not significantly increase the ATP hydrolysis.Исследованы особенности деградации АТФ и АДФ под действием мембран легких. Показано, что гидролиз АТФ протекает с образованием конечного продукта реакции АМФ. Образование АМФ из АТФ происходит за счет последовательного отщепления терминального фосфата согласно схеме: АТФ ─ ─→АДФ ─ ─→АМФ, а не за счет пирофосфатазной активности.Ингибиторный анализ с использованием адениловых нуклеотидов, их негидролизуемых аналогов, фосфата и пирофосфата, а также определение кинетических параметров АТФ-азной и АДФ-азной реакций указывает на согласованное протекание стадий гидролиза АТФ.АТФ-деградирующая активность обнаружена в мембранах клеток, формирующих сосуды (эндотелиальных и гладкомышечных) и не обнаружена в мембранах альвеолоцитов II порядка — клетках альвеол, секретирующих сурфактант.Данная нуклеотид-гидролизующая активность локализована преимущественно на внешней стороне плазматической мембраны клетки, поскольку добавление порообразующего антибиотика аламетицина к нативному монослою эндотелия незначительно увеличивало скорость гидролиза АТФ