Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy

INTRODUCTION Hypertrophic cardiomyopathy (HCM) is a heart disorder caused by autosomal dominant alterations affecting both sarcomeric genes and other nonsarcomeric loci in a minority of cases. However, in some patients, the occurrence of the causal pathogenic variant or variants in homozygosity, compound heterozygosity, or double heterozygosity has also been described. Most of the HCM pathogenic variants are missense and unique, but truncating mutations of the MYBPC3 gene have been reported as founder pathogenic variants in populations from Finland, France, Japan, Iceland, Italy, and the Netherlands. OBJECTIVES This study aimed to assess the genetic background of HCM in a cohort of Polish patients. PATIENTS AND METHODS Twenty–nine Polish patients were analyzed by a next–generation sequencing panel including 404 cardiovascular genes. RESULTS Pathogenic variants were found in 41% of the patients, with ultra–rare MYBPC3 c.2541C>G (p.Tyr847Ter) mutation standing for a variant hotspot and correlating with a lower age at HCM diagnosis. Among the nonsarcomeric genes, the CSRP3 mutation was found in a single case carrying the novel c.364C>T (p.Arg122Ter) variant in homozygosity. With this finding, the total number of known HCM cases with human CSRP3 knockout cases has reached 3

Четыре клеточно-автоматных алгоритма пермутаций матриц

Numerical calculation uses to describe the operation of matrix permutation algorithms based on cyclic shifts of rows and columns. This choice of discrete transformation algorithms justified by the convenience of the cellular automaton (CA) formulation, which is used. Obtained Empirical formulas for the permutation period and for the last algorithm, which period formula is recurrent. For a base scheme period has the asymptotics:  for a matrix  with pairwise different elements. Despite the complexity of the scheme, the other two modifications only give a polynomial growth of period, no higher than 3. Fourth scheme has a non-trivial period dependence, but no higher than the exponential. In some cases algorithms make special permutations: rotate, reflect, and rearrange blocks for the matrix . These formulas are closely related to individual cells paths. And paths connected with the influence of the boundaries that gives branching the matrix order by subtraction class modulo 3,4 or 12. Visualizations of these paths make in the extended CA-field. Two "mixing metrics" analyze as a parameter of CA dynamics on matrix permutations (compared to the initial). For all schemes and most branches, the behavior of these metrics shows in graphs and histograms (conditional density distribution) showing how often the permutation period occurs with the specified interval of metrics. The practical aim of this work is in the field of pseudorandom number generation and cryptography.С помощью численного расчета описывается работа алгоритмов пермутаций матриц, основанных на циклических сдвигах строк и столбцов. Такой выбор алгоритмов дискретного преобразования обоснован удобством клеточно-автоматных формулировок, которые и приводятся. Получены эмпирические формулы для периода пермутаций; для последнего алгоритма формула периода носит рекуррентный характер. Для базовой и наиболее простой схемы период N(n) имеет асимптотику exp(2n)/n для матрицы nxn с попарно различными элементами. Несмотря на усложнение схемы алгоритма, две другие модификации дают лишь полиномиальный рост степени не выше 3. Четвертая схема имеет нетривиальную зависимость периода, но не выше экспоненциальной. В ряде случаев алгоритмы порождают особые пермутации: поворот, отражение и перестановку блоков для матрицы 2kx2k. Эти формулы тесно связаны с индивидуальными траекториями элементов, а они – с влиянием границ, что дает ветвление порядка матрицы по классу вычета по модулю 3,4 или 12. Визуализации этих траекторий приводятся в расширенном поле КА. В качестве параметра динамики КА анализируются две «метрики перемешанности» на пермутациях матрицы (по сравнению с начальной). Для всех схем и большинства ветвей поведение этих метрик представлено на графиках и гистограммах (условно: плотности распределения), показывающих, как часто встречаются по периоду пермутации с заданным интервалом значений метрик. Практическое значение работы состоит в оценке применения КА в областях генерации псевдослучайных чисел и криптографии

Differences between familial and sporadic dilated cardiomyopathy: ESC EORP Cardiomyopathy & Myocarditis registry

Aims: Dilated cardiomyopathy (DCM) is a complex disease where genetics interplay with extrinsic factors. This study aims to compare the phenotype, management, and outcome of familial DCM (FDCM) and non‐familial (sporadic) DCM (SDCM) across Europe. / Methods and results: Patients with DCM that were enrolled in the prospective ESC EORP Cardiomyopathy & Myocarditis Registry were included. Baseline characteristics, genetic testing, genetic yield, and outcome were analysed comparing FDCM and SDCM; 1260 adult patients were studied (238 FDCM, 707 SDCM, and 315 not disclosed). Patients with FDCM were younger (P < 0.01), had less severe disease phenotype at presentation (P < 0.02), more favourable baseline cardiovascular risk profiles (P ≤ 0.007), and less medication use (P ≤ 0.042). Outcome at 1 year was similar and predicted by NYHA class (HR 0.45; 95% CI [0.25–0.81]) and LVEF per % decrease (HR 1.05; 95% CI [1.02–1.08]. Throughout Europe, patients with FDCM received more genetic testing (47% vs. 8%, P < 0.01) and had higher genetic yield (55% vs. 22%, P < 0.01). / Conclusions: We observed that FDCM and SDCM have significant differences at baseline but similar short‐term prognosis. Whether modification of associated cardiovascular risk factors provide opportunities for treatment remains to be investigated. Our results also show a prevalent role of genetics in FDCM and a non‐marginal yield in SDCM although genetic testing is largely neglected in SDCM. Limited genetic testing and heterogeneity in panels provides a scaffold for improvement of guideline adherence

Blood pressure and metabolic effects of acetyl-L-carnitine in type 2 diabetes: DIABASI randomized controlled trial

Context: Acetyl-L-carnitine (ALC), a mitochondrial carrier involved in lipid oxidation and glucose metabolism, decreased systolic blood pressure (SBP), and ameliorated insulin sensitivity in hypertensive nondiabetic subjects at high cardiovascular risk. Objective: To assess the effects of ALC on SBP and glycemic and lipid control in patients with hypertension, type 2 diabetes mellitus (T2D), and dyslipidemia on background statin therapy. Design: After 4-week run-in period and stratification according to previous statin therapy, patients were randomized to 6-month, double-blind treatment with ALC or placebo added-on simvastatin. Setting: Five diabetology units and one clinical research center in Italy. Patients: Two hundred twenty-nine patients with hypertension and dyslipidemic T2D &gt; 40 years with stable background antihypertensive, hypoglycemic, and statin therapy and serum creatinine &lt; 1.5 mg/ dL. Interventions: Oral ALC 1000 mg or placebo twice daily on top of stable simvastatin therapy. Outcome and Measures: Primary outcome was SBP. Secondary outcomes included lipid and glycemic profiles. Total-body glucose disposal rate and glomerular filtration rate were measured in subgroups by hyperinsulinemic-euglycemic clamp and iohexol plasma clearance, respectively. Results: SBP did not significantly change after 6-month treatment with ALC compared with placebo (-2.09mmHg vs-3.57mmHg, P = 0.9539). Serum cholesterol, triglycerides, and lipoprotein(a), as well as blood glucose, glycated hemoglobin, fasting insulin levels, homeostatic model assessment of insulin resistance index, glucose disposal rate, and glomerular filtration rate did not significantly differ between treatments. Adverse events were comparable between groups. Conclusions: Six-month oral ALC supplementation did not affect blood pressure, lipid and glycemic control, insulin sensitivity and kidney function in hypertensive normoalbuminuric and microalbuminuric T2D patients on background statin therapy

Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort

Four Cellular Automata Algorithms for Matrix Permutation

Numerical calculation uses to describe the operation of matrix permutation algorithms based on cyclic shifts of rows and columns. This choice of discrete transformation algorithms justified by the convenience of the cellular automaton (CA) formulation, which is used. Obtained Empirical formulas for the permutation period and for the last algorithm, which period formula is recurrent. For a base scheme period has the asymptotics:  for a matrix  with pairwise different elements. Despite the complexity of the scheme, the other two modifications only give a polynomial growth of period, no higher than 3. Fourth scheme has a non-trivial period dependence, but no higher than the exponential. In some cases algorithms make special permutations: rotate, reflect, and rearrange blocks for the matrix . These formulas are closely related to individual cells paths. And paths connected with the influence of the boundaries that gives branching the matrix order by subtraction class modulo 3,4 or 12. Visualizations of these paths make in the extended CA-field. Two "mixing metrics" analyze as a parameter of CA dynamics on matrix permutations (compared to the initial). For all schemes and most branches, the behavior of these metrics shows in graphs and histograms (conditional density distribution) showing how often the permutation period occurs with the specified interval of metrics. The practical aim of this work is in the field of pseudorandom number generation and cryptography