Characteristics of hospitalizations due to acute stroke in the Silesian Province,Poland, between 2009 and 2015

Introduction

The available data on acute stroke (AS) in Poland come mainly from non-representative cohorts or are outdated. Therefore, the current study was done to access the most recent data on AS in the industrial region that covers 12% (4.6 mln) of the country's population.

Elevated lipoprotein(a) as a new risk factor of cerebral venous sinus thrombosis: association with fibrin clot properties

Journal of Thrombosis and Thrombolysis - Elevated lipoprotein(a) [Lp(a)] has been reported to be associated with prothrombotic clot phenotype. We hypothesized that increased Lp(a) contributes to...     

A mechanism for sudden infant death syndrome (SIDS): stress-induced leak via ryanodine receptors.

BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality in the United States. Mutations in the RyR2-encoded cardiac ryanodine receptor cause the highly lethal catecholaminergic polymorphic ventricular tachycardia (CPVT1) in the young. OBJECTIVE: The purpose of this study was to determine the spectrum and prevalence of RyR2 mutations in a large cohort of SIDS cases. METHODS: Using polymerase chain reaction, denaturing high performance liquid chromatography, and direct DNA sequencing, a targeted mutational analysis of RyR2 was performed on genomic DNA isolated from frozen necropsy tissue on 134 unrelated cases of SIDS (57 females, 77 males; 83 white, 50 black, 1 Hispanic; average age = 2.7 months). RyR2 mutations were engineered by site-directed mutagenesis, heterologously expressed in HEK293 cells, and functionally characterized using single-channel recordings in planar lipid bilayers. RESULTS: Overall, two distinct and novel RyR2 mutations were identified in two cases of SIDS. A 6-month-old black female hosted an R2267H missense mutation, and a 4-week-old white female infant harbored a S4565R mutation. Both nonconservative amino acid substitutions were absent in 400 reference alleles, involved conserved residues, and were localized to key functionally significant domains. Under conditions that simulate stress [Protein Kinase A (PKA) phosphorylation] during diastole (low activating [Ca2+]), SIDS-associated RyR2 mutant channels displayed a significant gain-of-function phenotype consistent with the functional effect of previously characterized CPVT-associated RyR2 mutations. CONCLUSIONS: Here we report a novel pathogenic mechanism for SIDS, whereby SIDS-linked RyR2 mutations alter the response of the channels to sympathetic nervous system stimulation such that during stress the channels become "leaky" and thus potentially trigger fatal cardiac arrhythmias.     

Enhanced oxidative stress in hypertrophic cardiomyopathy

Elevated plasma levels of inflammation and endothelial dysfunction markers have been reported in patients with hypertrophic cardiomyopathy (HCM). The aim of the current study was to determine whether HCM is associated with enhanced oxidative stress. We enrolled 54HCMpatients with sinus rhythm, including 21 subjects with a left ventricular outflow tract (LVOT) obstruction (gradient ≥ 30 mmHg), and 54 age- and sex-matched controls without cardiovascular diseases. Serum levels of 8-isoprostaglandin F_2α (8-iso-PGF_2α), a stable marker of oxidative stress, were determined.Serum 8-iso-PGF_2α levels were elevated in HCM patients compared with controls (35.4 ± 10.2 vs. 29.9 ± 9.9 pg/ml, p < 0.001). Patients with obstructiveHCMdisplayed higher 8-iso-PGF_2α levels compared with the non-obstructiveHCMsubgroup (41.6 ± 12.7 vs. 31.4 ± 5.4 pg/ml, p < 0.0001). Both anatomic (mitral-septal distance) and hemodynamic (subaortic gradient) indexes of LVOT obstruction, but not other echocardiographic variables, correlated with 8-iso-PGF_2α levels (r = –0.43; p < 0.05 and r = 0.39; p < 0.05, respectively).This study is the first to show that HCM is characterized by enhanced oxidative stress as evidenced by higher 8-iso-PGF_2α, which achieves its highest values in the presence of LVOT obstruction in HCM patients.     

Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice

The Ca2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and is also present in the brain. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated RyR2 mutations result in "leaky" RyR2 channels due to the decreased binding of the calstabin2 (FKBP12.6) subunit, which stabilizes the closed state of the channel. We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with a novel RyR2-specific compound (S107) that enhances the binding of calstabin2 to the mutant Ryr2-R2474S channel inhibited the channel leak and prevented cardiac arrhythmias and raised the seizure threshold. Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exercise-induced sudden cardiac death.     

Nɛ–homocysteinyl–lysine Isopeptide is Associated with Progression of Peripheral Artery Disease in Patients Treated with Folic Acid

ObjectiveFolic acid (FA) administration can reduce plasma total homocysteine (tHcy); however, it fails to decrease cardiovascular events and progression of peripheral artery disease (PAD). N?–homocysteinyl–lysine isopeptide (N?–Hcy–Lys) is formed during catabolism of homocysteinylated proteins. We sought to investigate factors that determine the presence of N?–Hcy–Lys in PAD patients with hyperhomocysteinemia receiving FA.Patients and methodsWe studied 131 consecutive PAD patients with tHcy > 15 μmol l^?1 taking FA 0.4 mg d^?1 for 12 months. Serum N?–Hcy–Lys was determined by high-performance liquid chromatography (HPLC). We also measured interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), asymmetric dimethylarginine (ADMA) and 8-iso-prostaglandin F_2α (8-iso-PGF_2α).ResultsFA administration resulted in a 70.5% decrease in tHcy (p < 0.0001). However, serum N?–Hcy–Lys was detectable in 28 (21.4%) patients on FA who were more frequently current smokers and survivors of ischaemic stroke (p < 0.001). They had higher tHcy by 46.0%, PAI-1 by 51.7%, 8-iso-PGF_2α by 59.1% and ADMA by 26.4% (all, p < 0.0001). The presence of N?–Hcy–Lys was associated with lower ankle-brachial index (ABI) values (p < 0.001) and higher prevalence of cardiovascular events (p < 0.001) following therapy.ConclusionThe presence of N?–Hcy–Lys in one-fifth of hyperhomocysteinemic individuals with PAD despite FA treatment is associated with progression of PAD and with increased ADMA formation, oxidative stress and hypofibrinolysis.     

What are the roles of microRNAs at the mammalian synapse?

The modification of neuronal connections in response to stimuli is believed to be the basis of long-term memory formation. It is currently accepted that local protein synthesis critically contributes to site-restricted modulation of individual synapses. Here, we summarize recent evidence implicating miRNAs in this process, leading to altered dendrite morphogenesis and synaptic plasticity. Second, we discuss findings in non-neuronal systems about how RNA-binding proteins can modulate miRNA–mRNA interactions, and how these mechanisms might apply to neurons. Finally, we review recent findings that P-bodies may be important sites for miRNA action at the synapse.