Human induced pluripotent stem cell (iPSC) lines were generated from peripheral blood mononuclear cells (PBMCs) isolated from two related patients diagnosed with either idiopathic ventricular fibrillation or catecholaminergic polymorphic ventricular tachycardia, carrying an unknown variant in the RYR2 gene, c.14201A>G (p.Y4734C) and one healthy related individual. Reprogramming was done using a commercially available Epi5 Reprogramming Kit. The pluripotency of the iPSC lines was verified by the expression of pluripotency markers and by their capacity to differentiate into all three embryonic germ layers in vitro. These iPSC lines are available for functional analysis and in vitro studies of RYR2 channelopathy.
- MeSH
- buněčná diferenciace MeSH
- buněčné linie MeSH
- dospělí MeSH
- fibrilace komor * genetika MeSH
- indukované pluripotentní kmenové buňky * metabolismus MeSH
- komorová tachykardie * genetika metabolismus MeSH
- lidé MeSH
- ryanodinový receptor vápníkového kanálu * genetika metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there is limited data on the outcomes of ICD use in children. OBJECTIVE: The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without an ICD. METHODS: We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic CPVT patients with and without an ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope. RESULTS: The study included 235 patients, 73 with an ICD (31.1%) and 162 without an ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications. CONCLUSION: SCD events occurred only in patients without an ICD and mostly in those not on optimal medical therapy. Patients with an ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered.
- MeSH
- defibrilátory implantabilní * MeSH
- dítě MeSH
- komorová tachykardie * terapie patofyziologie MeSH
- lidé MeSH
- mladiství MeSH
- náhlá srdeční smrt * prevence a kontrola etiologie MeSH
- následné studie MeSH
- předškolní dítě MeSH
- retrospektivní studie MeSH
- ryanodinový receptor vápníkového kanálu genetika MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
BACKGROUND: To assess whether hypoxia, as can be found in obstructive sleep apnea syndrome, is causally associated with the development of heart failure through a direct effect on calcium leakage from the sarcoplasmic reticulum. METHODS: The impact of hypoxia on sarcoplasmic reticulum calcium leakage and expres- sion of RyR2 (ryanodine receptor2) and SERC2a (sarcoplasmic reticulum Ca2+ATPase 2a) was investigated together with the outcomes of JTV-519 and S107 treatment. HL-1 car- diomyocytes were cultured for 7 days on gas-permeable cultureware under control (12% O2) or hypoxic (1% O2) conditions with or without JTV-519 or S107. SRCL was assessed using a Fluo-5N probe. Gene and protein expression was analyzed using qPCR and western blotting. RESULTS: Hypoxic exposure increased sarcoplasmic reticulum calcium leakage by 39% and reduced RyR2 gene expression by 52%. No effect on RyR2 protein expression was observed. Treatment with 1μM JTV-519 reduced sarcoplasmic reticulum calcium leakage by 52% and 35% under control and hypoxic conditions, respectively. Administration of 1 μM JTV-519 increased RyR2 gene expression by 89% in control conditions. No effect on SRCL, RyR2, or SERC2a gene, or protein expression was observed with S107 treatment. CONCLUSION: Hypoxia increased sarcoplasmic reticulum calcium leakage which was ame- liorated by JTV-519 treatment independently of gene or protein expression. JTV-519 rep- resents a possible treatment for obstructive sleep apnea-associated HF.
- MeSH
- lidé MeSH
- maligní hypertermie * terapie MeSH
- mutace MeSH
- ryanodinový receptor vápníkového kanálu genetika MeSH
- vápníkové kanály - typ L MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- Geografické názvy
- Česká republika MeSH
- Slovenská republika MeSH
Kongenitálne myopatie predstavujú výrazne heterogénnu skupinu geneticky podmienených neuromuskulárnych ochorení s variabilným fenotypom a charakteristickým histopatologickým obrazom. V klinickom obraze pacientov dominuje svalová slabosť a hypotónia, ktorá sa často prezentuje už pri narodení (obraz tzv. floppy baby syndróm). Ochorenie má skôr neprogresívny alebo pomaly progresívny charakter. V minulosti sa diagnostika kongenitálnych myopatií zakladala predovšetkým na bioptickom vyšetrení svalov, ktoré v súčasnosti nahradili metódy molekulovej genetiky. V našej kazuistike prezentujeme prípad 15-ročného chlapca s manifestáciou hypotonického syndrómu v novorodeneckom období nasledovaného postupným rozvojom ťažkostí s chôdzou až úplnou stratou samostatnej hybnosti.
Congenital myopathies are a heterogenous group of genetic neuromuscular disorders characterized by variable phenotype and characteristic histopathological picture. The clinical features of patients are muscle weakness and hypotonia, which is often present at birth and in the early months of life (floppy baby syndrome). The clinical course of disease is static or slowly progressive. In the past, diagnose of congenital myopathy was based on muscle biopsy, which has been replaced by methods of genetic testing. In our case report we presented a case of 15 years-old boy with a manifestation of hypotonic syndrome in the neonatal period, followed by difficulty walking and loss of ambulation.
- MeSH
- diagnostické techniky molekulární MeSH
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- myopatie strukturální vrozené * diagnóza genetika terapie MeSH
- nemoci novorozenců MeSH
- novorozenec MeSH
- progrese nemoci MeSH
- ryanodinový receptor vápníkového kanálu MeSH
- svalová hypotonie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- kosterní svaly patologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mezioborová komunikace MeSH
- myopatie central core * diagnóza genetika komplikace terapie MeSH
- novorozenec MeSH
- ryanodinový receptor vápníkového kanálu MeSH
- svalová slabost MeSH
- vývojová kyčelní dysplazie * diagnóza chirurgie rehabilitace MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- kazuistiky MeSH
Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. Methods and results: This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. Conclusion: This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.
- MeSH
- dědičnost MeSH
- dítě MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- genetické markery MeSH
- kalsekvestrin genetika MeSH
- komorová tachykardie diagnóza genetika mortalita patofyziologie MeSH
- konformace proteinů MeSH
- lidé MeSH
- mladiství MeSH
- molekulární modely MeSH
- mutace * MeSH
- mutační analýza DNA MeSH
- náhlá srdeční smrt epidemiologie MeSH
- prognóza MeSH
- registrace MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- rodokmen MeSH
- ryanodinový receptor vápníkového kanálu chemie genetika metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
Kofeín je xantínový alkaloid so psychostimulačným účinkom, ktorý je sprostredkovaný jeho antagonistickým pôsobením na adenozínové A2A receptory. Jeho farmakologickým cieľom sú predovšetkým striatálne A2A-D2 receptorové heteroméry. Ako neselektívny antagonista adenozínových receptorov však blokuje aj presynaptické A1 receptory, čo vedie k jeho monoamínergickému pôsobeniu. V závislosti od koncentrácie môže interagovať s GABAergickou neurotransmisiou a agonisticky pôsobiť na ryanodínové receptory. Neuropsychofarmakologickým profilom kofeínu je daný i jeho neuroprotektívny účinok, synergický účinok s antidepresívami, ale aj jeho nežiaduce a potenciálne nebezpečné účinky v kombinácii s inými psychostimulanciami.
Caffeine is a xanthine alkaloid with a psychostimulant effect mediated by its antagonistic action at adenosine A2A receptors. Its pharmacological targets are primarily striatal A2A-D2 receptor heteromers. However, as a non-selective adenosine receptor antagonist, it also blocks presynaptic A1 receptors, leading to its monoaminergic action. Depending on the concentration it may interact with GABA-ergic neurotransmission and act at ryanodine receptors as an agonist. Neuropsychopharmacological profile of caffeine also determines its neuroprotective effect, synergistic effect with antidepressants, but also its undesirable and potentially dangerous effects in combination with other psychostimulants.
- Klíčová slova
- heteromerní komplex A2A-D2,
- MeSH
- abstinenční syndrom MeSH
- agonisté dopaminu MeSH
- antagonisté purinergního receptoru P1 farmakologie klasifikace MeSH
- antidepresiva MeSH
- corpus striatum účinky léků MeSH
- GABAergní neurony účinky léků MeSH
- káva MeSH
- kofein * farmakologie škodlivé účinky toxicita MeSH
- lékové interakce MeSH
- lidé MeSH
- neuroprotektivní látky MeSH
- Parkinsonova nemoc farmakoterapie patologie MeSH
- poruchy spojené s užíváním psychoaktivních látek MeSH
- psychotropní léky MeSH
- purinergní receptory P1 klasifikace účinky léků MeSH
- receptory dopaminové MeSH
- ryanodinový receptor vápníkového kanálu účinky léků MeSH
- synergismus léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Maligní hypertermie (MH) je vzácná, ale velmi obávaná a potencionálně fatální komplikace celkové anestezie. Manifestuje se na základě autozomálně dominantně podmíněné dispozice po kontaktu se spouštěčem. Spouštěči reakce jsou především všechna volatilní anestetika a sukcinylcholin. Její příčinou je porucha regulace kalciového metabolismu ve svalové buňce, způsobené abnormálním ryanodinovým receptorem RYR1. Následkem toho je extrémní svalová kontrakce bez následné relaxace vedoucí k nekontrolovatelné hypermetabolické reakci organismu. Diagnózu MH dispozice je možné potvrdit svalovým in vitro kontrakčním testem, resp. molekulárně genetickým vyšetřením. „Podezřelé“ jedince lze vytipovat pečlivým předoperačním vyšetřením, zejména důkladnou anamnézou. U jedinců s MH dispozicí je nutné vést anestezii odpovídající pravidlům pro anestezii u MH rizikových pacientů. Mortalita této komplikace dnes dosahuje cca 5–10 % (oproti 70–80 % v 70. letech 20. století). Významnému zvýšení přežívání pacientů pomohlo zlepšení perioperačního monitorování, informovanosti zdravotnického personálu a zejména zavedení dantrolenu jako kauzálního léku.
Malignant hyperthermia (MH) is a rare but very dangerous and potentionally fatal complication of general anesthesia. It occurson the basis of an autosomal dominant condition following contact with the trigger. The triggers are volatile anesthetics andsuccinylcholine. The cause of MH is the disorder of calcium metabolism regulation in the muscle cell caused by the abnormalryanodin receptor RYR1. As a result, extreme muscle contraction without relaxation leads to a huge hypermetabolic reaction.Diagnosis of MH disposition can be confirmed by a muscle contraction test in vitro, molecular genetic examination respectively.„Suspicious“ individuals can be identified by careful preoperative examinations and medical history. In patients with MH disposition,if anesthesia is necessary, it is essential to choose special anesthetic procedures without the use of triggers with currentcareful perioperative monitoring with the option of intensive care. Mortality today is about 5–10% (compared to 70–80% in the1970s). Significant increases in patient survival have helped to improve perioperative monitoring, awareness of medical staff and,in particular, the introduction of dantrolene as a causal drug.
- MeSH
- anestetika inhalační * škodlivé účinky MeSH
- celková anestezie * škodlivé účinky MeSH
- dantrolen terapeutické užití MeSH
- dítě MeSH
- kritický stav MeSH
- lidé MeSH
- maligní hypertermie * diagnóza genetika patofyziologie terapie MeSH
- mutace MeSH
- péče o pacienty v kritickém stavu MeSH
- ryanodinový receptor vápníkového kanálu fyziologie genetika MeSH
- sukcinylcholin škodlivé účinky MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
UNLABELLED: Crayfish spermatophores are deposited on the body surface of the female during mating and remain there for a period of time before fertilization ensues. Post-mating changes in protein expression level in the noble crayfish Astacus astacus spermatophore were quantified. In-gel digestion and high resolution mass spectrometry were used for label-free protein quantification. One hundred twelve proteins were identified in the spermatophore of noble crayfish. After 7 days of storage on the body of the female, 6 proteins were identified in the post-mating spermatophore that showed significant up-regulation and 4 significant down-regulations (p < 0.05, fold change ≥ 2). The highest rate of up-regulation was observed in sodium/hydrogen exchanger, which may indicate the importance of intracellular pH adjustment for final maturation of the crayfish spermatozoon. The highest rate of down-regulation was observed in histone H2A. This may increase chromatin flexibility and facilitate its transfer into the oocyte during fertilization. The vitellogenin protein was identified in the crayfish spermatophore and its level changed during storage on the body surface of female. Extensive proteomic modification of male gametes during storage on the body surface of the female suggests post-mating final maturation of the crayfish spermatozoon. BIOLOGICAL SIGNIFICANCE: Freshwater crayfish comprise a large and diverse group of ecologically and commercially important animals. Molecular studies of gametes in the crayfish can provide insight into the complex process of reproduction in this diverse group of animals. The results of such studies can be used for development of new techniques for artificial reproduction of these economically important species.
- MeSH
- alfa-makroglobuliny metabolismus MeSH
- chromatografie kapalinová MeSH
- hemokyanin metabolismus MeSH
- histony metabolismus MeSH
- hmotnostní spektrometrie MeSH
- kapacitace spermií MeSH
- Na(+)-H(+) antiport metabolismus MeSH
- proteomika metody MeSH
- ryanodinový receptor vápníkového kanálu metabolismus MeSH
- severní raci fyziologie MeSH
- sexuální faktory MeSH
- spermatogonie fyziologie MeSH
- spermie fyziologie MeSH
- upregulace MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
