Prevodu prvih petih knjig Livijevega dela, ki je ostal v zapuščini Primoža Simonitija in je lani izšel pri Slovenski matici, bo letos sledil izid druge peterke v prevodu Aleša Mavra. Kot pri prvi ...peterki so opombe tudi tu povzete po izdaji Hansa Jürgena Hillena za Sammlung Tusculum.
Izhodišče prispevka je domneva, da nad precejšnjim delom Salustijevega historiografskega opusa lebdi senca izkušnje dolge državljanske vojne v Rimu v času njegovega življenja. To je razvidno iz ...zgodovinarjevega prikaza surovega obračuna nobilitete z bratoma Grakh in iz njegove upodobitve Sule in njegove vladavine kot vira moralnega kaosa v desetletju po njegovem zavzetju Rima. Ko razmišlja o vzrokih krize rimske republike v šestdesetih letih pr. Kr. in v času nastanka svojih spisov, se Salustij sicer skuša predstaviti kot nepristranski opazovalec, ki občasno biča napake političnih voditeljev obeh sprtih taborov, aristokracije in ljudstva. Vendar zgodovinar gotovo ne deli Ciceronovega mnenja o slogi med osrednjima skupinama vladajočega sloja kot zadostnem zdravilu za rimske težave. Preveč resno je jemal družbene korenine krize. Pri tem je nedvomno pripisoval odgovornost za krizo vladajočemu sloju. Zato si po Salustijevem mnenju pozornost zaslužijo celo neverodostojni glasniki sprememb, kakršen je bil Katilina. Po eni strani se Salustij ni odmaknil od uničujočega Ciceronovega prikaza voditelja zarote in ga je še dodatno prikazal kot demagoga, ki se, kadar mu to koristi, predstavlja za tipičnega člana nobilitete. Toda po drugi strani slika njegov razmislek o položaju v Rimu kot verodostojen, zlasti ko gre za Katilinov goreč napad na vodilno elito.
Determining the genetic contribution of susceptibility to severe SARS-CoV-2 infection outcomes is important for public health measures and individualized treatment. Through intense research on this ...topic, several hundred genes have been implicated as possibly contributing to the severe infection phenotype(s); however, the findings are complex and appear to be population-dependent. We aimed to determine the contribution of human rare genetic variants associated with a severe outcome of SARS-CoV-2 infections and their burden in the Slovenian population. A panel of 517 genes associated with severe SARS-CoV-2 infection were obtained by combining an extensive review of the literature, target genes identified by the COVID-19 Host Genetic Initiative, and the curated Research COVID-19 associated genes from PanelApp, England Genomics. Whole genome sequencing was performed using PCR-free WGS on DNA from 60 patients hospitalized due to severe COVID-19 disease, and the identified rare genomic variants were analyzed and classified according to the ACMG criteria. Background prevalence in the general Slovenian population was determined by comparison with sequencing data from 8025 individuals included in the Slovenian genomic database (SGDB). Results show that several rare pathogenic/likely pathogenic genomic variants in genes CFTR, MASP2, MEFV, TNFRSF13B, and RNASEL likely contribute to the severe infection outcomes in our patient cohort. These results represent an insight into the Slovenian genomic diversity associated with a severe COVID-19 outcome.
Epigenetic mechanisms, especially DNA methylation, are suggested to play a role in the age-of-onset in Huntington's disease (HD) based on studies on patient brains, and cellular and animal models. ...Methylation is tissue-specific and it is not clear how HD specific methylation in the brain correlates with the blood compartment, which represents a much more clinically accessible sample. Therefore, we explored the presence of HD specific DNA methylation patterns in whole blood on a cohort of HDM and healthy controls from Slovenia. We compared CpG site-specific DNA methylation in whole blood of 11 symptomatic and 9 pre-symptomatic HDM (HDM), and 15 healthy controls, by using bisulfite converted DNA on the Infinium® Human Methylation27 BeadChip microarray (Illumina) covering 27,578 CpG sites and 14,495 genes. Of the examined 14,495 genes, 437 were differentially methylated (
< 0.01) in pre-symptomatic HDM compared to controls, with three genes (
) retaining statistical significance after the correction for multiple testing (false discovery rate, FDR < 0.05). Comparisons between symptomatic HDM and controls, and the comparison of symptomatic and pre-symptomatic HDM further identified 260 and 198 differentially methylated genes (
< 0.01), respectively, whereas the comparison of all HDM (symptomatic and pre-symptomatic) and healthy controls identified 326 differentially methylated genes (
< 0.01), however, none of these changes retained significance (FDR < 0.05) after the correction for multiple testing. The results of our study suggest that methylation signatures in the blood compartment are not robust enough to prove as valuable biomarkers for predicting HD progression, but recognizable changes in methylation deserve further research.
Population-based estimates of pathogenic variation burden in gynecologic cancer predisposition genes are a prerequisite for the development of effective precision public health strategies. This study ...aims to reveal the burden of pathogenic variants in a comprehensive set of clinically relevant breast, ovarian, and endometrial cancer genes in a large population-based study. We performed a rigorous manual classification procedure to identify pathogenic variants in a panel of 17 gynecologic cancer predisposition genes in a cohort of 7091 individuals, representing 0.35% of the general population. The population burden of pathogenic variants in hereditary gynecologic cancer-related genes in our study was 2.14%. Pathogenic variants in genes ATM, BRCA1, and CDH1 are significantly enriched and the burden of pathogenic variants in CHEK2 is decreased in our population compared to the control population. We have identified a high burden of pathogenic variants in several gynecologic cancer-related genes in the Slovenian population, most importantly in the BRCA1 gene.
Objective
Voltage‐gated sodium (Na+) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the ...genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore‐forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit β1, are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of 4 patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in 2 cases, p.Pro1333Leu, and p.Val1769Ala).
Methods
All patients presented with treatment‐resistant epilepsy in the first year of life, severe to profound intellectual disability, and in 2 cases (both with the variant p.Ile875Thr), diffuse polymicrogyria.
Results
Electrophysiological recordings of mutant channels revealed prominent gain of channel function, with a markedly increased amplitude of the slowly inactivating current component, and for 2 of 3 mutants (p.Ile875Thr and p.Pro1333Leu), a leftward shift in the voltage dependence of activation to more hyperpolarized potentials. Gain of function was not observed for Nav1.3 variants known or presumed to be inherited (p.Arg1642Cys and p.Lys1799Gln). The antiseizure medications phenytoin and lacosamide selectively blocked slowly inactivating over transient current in wild‐type and mutant Nav1.3 channels.
Interpretation
These findings establish SCN3A as a new gene for infantile epileptic encephalopathy and suggest a potential pharmacologic intervention. These findings also reinforce the role of Nav1.3 as an important regulator of neuronal excitability in the developing brain, while providing additional insight into mechanisms of slow inactivation of Nav1.3. Ann Neurol 2018;83:703–717
According to a rough estimate, one in fifteen people worldwide is affected by a rare disease. Rare diseases are therefore common in clinical practice; however, timely diagnosis of rare diseases is ...still challenging. Introduction of novel methods based on next-generation sequencing (NGS) technology offers a successful diagnosis of genetically heterogeneous disorders, even in case of unclear clinical diagnostic hypothesis. However, the application of novel technology differs among the centres and health systems significantly. Our goal is to discuss the impact of the implementation of NGS in the diagnosis of rare diseases and present advantages along with challenges of diagnostic approach. Systematic implementation of NGS in health systems can significantly improve the access of patients with rare diseases to diagnosis and reduce the dependence of national health systems for cross-border collaboration.
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