patch
Dotaz
Zobrazit nápovědu
PURPOSE: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND. METHODS: We describe 19 patients with congenital CACNA1G-variants, including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants, including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity. RESULTS: We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics and an increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity. CONCLUSION: This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia.
- MeSH
- dítě MeSH
- fenotyp * MeSH
- genetické asociační studie MeSH
- heterozygot MeSH
- kojenec MeSH
- lidé MeSH
- missense mutace * genetika MeSH
- mladiství MeSH
- neurovývojové poruchy * genetika patologie MeSH
- předškolní dítě MeSH
- vápníkové kanály - typ T * genetika metabolismus MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Spinal cord injury (SCI) results in paralysis, driven partly by widespread glutamate-induced secondary excitotoxic neuronal cell death in and around the injury site. While there is no curative treatment, the standard of care often requires interventive decompression surgery and repair of the damaged dura mater close to the injury locus using dural substitutes. Such intervention provides an opportunity for early and local delivery of therapeutics directly to the injured cord via a drug-loaded synthetic dural substitute for localized pharmacological therapy. Riluzole, a glutamate-release inhibitor, has shown neuroprotective potential in patients with traumatic SCI, and therefore, this study aimed to develop an electrospun riluzole-loaded synthetic dural substitute patch suitable for the treatment of glutamate-induced injury in neurons. A glutamate-induced excitotoxicity was optimized in SH-SY5Y cells by exploring the effect of glutamate concentration and exposure duration. The most effective timing for administering riluzole was found to be at the onset of glutamate release as this helped to limit extended periods of glutamate-induced excitotoxic cell death. Riluzole-loaded patches were prepared by using blend electrospinning. Physicochemical characterization of the patches showed the successful encapsulation of riluzole within polycaprolactone fibers. A drug release study showed an initial burst release of riluzole within the first 24 h, followed by a sustained release of the drug over 52 days to up to approximately 400 μg released for the highest loading of riluzole within fiber patches. Finally, riluzole eluted from electrospun fibers remained pharmacologically active and was capable of counteracting glutamate-induced excitotoxicity in SH-SY5Y cells, suggesting the clinical potential of riluzole-loaded dural substitutes in counteracting the effects of secondary injury in the injured spinal cord.
- MeSH
- implantované léky MeSH
- kyselina glutamová metabolismus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- neurony účinky léků MeSH
- neuroprotektivní látky * aplikace a dávkování chemie farmakologie MeSH
- polyestery chemie MeSH
- poranění míchy * farmakoterapie MeSH
- riluzol * aplikace a dávkování chemie farmakologie MeSH
- uvolňování léčiv MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Tato kazuistika popisuje příběh 25letého muže s diabetes mellitus 1. typu od sedmi let věku s již rozvinutými komplikacemi. Po nasazení patch pumpy s hybridním uzavřeným okruhem došlo k výraznému zlepšení kompenzace, a hlavně kvality pacientova života
This case report describes the case of a 25-year-old man suffering from type 1 diabetes mel- litus since 7 years old, with advanced complications. After the initiation of treatment with hybrid closed-loop patch pump, significant improvement was observed in diabetes control as well as the patient’s quality of life.
The utilization of 3D printing- digital light processing (DLP) technique, for the direct fabrication of microneedles encounters the problem of drug solubility in printing resin, especially if it is predominantly composed of water. The possible solution how to ensure ideal belonging of drug and water-based printing resin is its pre-formulation in nanosuspension such as nanocrystals. This study investigates the feasibility of this approach on a resin containing nanocrystals of imiquimod (IMQ), an active used in (pre)cancerous skin conditions, well known for its problematic solubility and bioavailability. The resin blend of polyethylene glycol diacrylate and N-vinylpyrrolidone, and lithium phenyl-2,4,6-trimethylbenzoylphosphinate as a photoinitiator, was used, mixed with IMQ nanocrystals in water. The final microneedle-patches had 36 cylindrical microneedles arranged in a square grid, measuring approximately 600 μm in height and 500 μm in diameter. They contained 5wt% IMQ, which is equivalent to a commercially available cream. The homogeneity of IMQ distribution in the matrix was higher for nanocrystals compared to usual crystalline form. The release of IMQ from the patches was determined ex vivo in natural skin and revealed a 48% increase in efficacy for nanocrystal formulations compared to the crystalline form of IMQ.
- MeSH
- 3D tisk * MeSH
- aplikace kožní MeSH
- imichimod * chemie aplikace a dávkování MeSH
- jehly * MeSH
- kožní absorpce MeSH
- kůže metabolismus MeSH
- lékové transportní systémy přístrojové vybavení MeSH
- mikroinjekce přístrojové vybavení MeSH
- nanočástice * chemie aplikace a dávkování MeSH
- polyethylenglykoly chemie aplikace a dávkování MeSH
- povidon chemie MeSH
- rozpustnost * MeSH
- uvolňování léčiv MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Diabetes mellitus (DM) causes myocardial electrical remodeling and promotes ventricular tachycardia and/or fibrillation (VT/VF). However, experimental studies have been frequently unsuccessful in developing a DM model with the expected high level of arrhythmic outcomes. The present study aims at evaluating cardiac electrophysiological properties in the rats with different Type 1 DM (T1DM) durations and identifying an electrophysiological phenotype associated with the high incidence of VT/VF. METHODS: The experiments were performed in 109 male Wistar rats (6-10 weeks old), subdivided into the groups of control, 4-weeks and 8-weeks T1DM (streptozotocin model). The animals were studied with epicardial electrophysiological mapping, whole-cell patch-clamp and histological examination. The VT/VF susceptibility was tested in ischemia/reperfusion induced in the anesthetized animals. RESULTS: In the 4-weeks T1DM group, we observed the increase in the incidence of reperfusion VT/VF, collagen deposition and dispersion of repolarization, slowed longitudinal and transverse conduction velocity, prolonged action potential duration, increased INa and ICaL currents, nonchanged Ito and IK1 currents. In the 8-weeks T1DM group, the VT/VF incidence, dispersion of repolarization, INa and Ito currents decreased. Other parameters persisted unchanged as compared to the 4-weeks T1DM group. CONCLUSIONS: Relatively early (4 weeks) diabetic electrical remodeling was proarrhythmic and included augmentation of sodium and calcium currents in the presence of fibrosis and slowed conduction and increased dispersion of repolarization. An unexpected finding was that diabetic arrhythmogenesis was associated with the increase in depolarizing transmembrane currents. Further research is warranted to elucidate molecular mechanisms and test the potential for the control of observed changes.
- MeSH
- diabetes mellitus 1. typu * komplikace patofyziologie MeSH
- experimentální diabetes mellitus patofyziologie komplikace MeSH
- fibrilace komor patofyziologie MeSH
- komorová tachykardie patofyziologie etiologie MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- potkani Wistar * MeSH
- remodelace komor MeSH
- srdeční arytmie patofyziologie etiologie MeSH
- srdeční komory patofyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The central nervous system is a well-known steroidogenic tissue producing, among others, cholesterol metabolites such as neuroactive steroids, oxysterols and steroid hormones. It is well known that these endogenous molecules affect several receptor classes, including ionotropic GABAergic and NMDA glutamatergic receptors in neurons. It has been shown that also ionotropic purinergic (P2X) receptors are cholesterol metabolites' targets. Among P2X receptors, purinergic P2X4 and P2X7 receptors are expressed in microglia, the innate immune cells involved in the brain inflammatory response. In this study, we explore the ionotropic purinergic receptors modulation by cholesterol metabolites in microglia. Patch-clamp experiments were performed in BV2 cells, a murine microglia cell line, to evaluate effects of cholesterol metabolites using micro- and nanomolar concentrations. About P2X4 receptor, we found that testosterone butyrate (20 μM and 200 nM) and allopregnanolone (10 μM and 100 nM) both potentiated its current, while neither 25-hydroxycholesterol (10 μM and 100 nM) nor 17β-estradiol (1 μM) showed any effects. On the other hand, P2X7 receptor current was potentiated by allopregnanolone (10 μM) and 25-hydroxycholesterol (10 μM and 100 nM). Taken together, our data show that modulation of either P2X4 and P2X7 current is affected differently by cholesterol metabolites, suggesting a structure-activity relationship among these players. Identifying the possible link between purinergic transmission, microglia and cholesterol metabolites will allow to define new targets for drug development to treat neuroinflammation.
- MeSH
- buněčné linie MeSH
- mikroglie * metabolismus MeSH
- pregnanolon * metabolismus MeSH
- purinergní receptory P2X4 * metabolismus MeSH
- testosteron * metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Extracellular potassium concentration might modify electrophysiological properties in the border zone of ischemic myocardium. We evaluated the depolarization and repolarization characteristics across the ischemic-normal border under [K+] variation. Sixty-four-lead epicardial mapping was performed in 26 rats ([K+] 2.3-6.4 mM) in a model of acute ischemia/reperfusion. The animals with [K+] < 4.7 mM (low-normal potassium) had an ischemic zone with ST-segment elevation and activation delay, a border zone with ST-segment elevation and no activation delay, and a normal zone without electrophysiological abnormalities. The animals with [K+] >4.7 mM (normal-high potassium) had only the ischemic and normal zones and no transitional area. Activation-repolarization intervals and local conduction velocities were inversely associated with [K+] in linear regression analysis with adjustment for the zone of myocardium. The reperfusion extrasystolic burden (ESB) was greater in the low-normal as compared to normal-high potassium animals. Ventricular tachycardia/fibrillation incidence did not differ between the groups. In patch-clamp experiments, hypoxia shortened action potential duration at 5.4 mM but not at 1.3 mM of [K+]. IK(ATP) current was lower at 1.3 mM than at 5.4 mM of [K+]. We conclude that the border zone formation in low-normal [K+] was associated with attenuation of IK(ATP) response to hypoxia and increased reperfusion ESB.
- MeSH
- akční potenciály * fyziologie MeSH
- draslík * krev metabolismus MeSH
- ischemická choroba srdeční * patofyziologie krev metabolismus MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- reperfuzní poškození myokardu krev patofyziologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Aminophylline, a bronchodilator mainly used to treat severe asthma attacks, may induce arrhythmias. Unfortunately, the underlying mechanism is not well understood. We have recently described a significant, on average inhibitory effect of aminophylline on inward rectifier potassium current IK1, known to substantially contribute to arrhythmogenesis, in rat ventricular myocytes at room temperature. This study was aimed to examine whether a similar effect may be observed under clinically relevant conditions. Experiments were performed using the whole cell patch clamp technique at 37°C on enzymatically isolated healthy porcine and failing human ventricular myocytes. The effect of clinically relevant concentrations of aminophylline (10-100 μM) on IK1 did not significantly differ in healthy porcine and failing human ventricular myocytes. IK1 was reversibly inhibited by ∼20 and 30 % in the presence of 30 and 100 μM aminophylline, respectively, at -110 mV; an analogical effect was observed at -50 mV. To separate the impact of IK1 changes on AP configuration, potentially interfering ionic currents were blocked (L-type calcium and delayed rectifier potassium currents). A significant prolongation of AP duration was observed in the presence of 100 μM aminophylline in porcine cardiomyocytes which well agreed with the effect of a specific IK1 inhibitor Ba2+ (10 μM) and with the result of simulations using a porcine ventricular cell model. We conclude that the observed effect of aminophylline on healthy porcine and failing human IK1 might be involved in its proarrhythmic action. To fully understand the underlying mechanism, potential aminophylline impact on other ionic currents should be explored.
- MeSH
- akční potenciály účinky léků MeSH
- aminofylin * farmakologie MeSH
- draslíkové kanály dovnitř usměrňující * metabolismus MeSH
- kardiomyocyty * účinky léků metabolismus MeSH
- lidé MeSH
- metoda terčíkového zámku MeSH
- prasata MeSH
- srdeční komory účinky léků metabolismus MeSH
- srdeční selhání metabolismus farmakoterapie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Spontánní intrakraniální hypotenze je charakterizovaná ortostaticky vázanými bolestmi hlavy vznikajícími při samovolném úniku mozkomíšního moku do extradurálního prostoru. Magnetická rezonance má zásadní význam v diagnostice díky řadě typických znaků vyskytujících se u tohoto onemocnění u převážné většiny pacientů. Druhým krokem je identifikace místa úniku mozkomíšního moku, což vyžaduje již speciální diagnostické zobrazovací metody a techniku vyšetření. Spontánní intrakraniální hypotenze může i samovolně vymizet. Její léčba je především konzervativní a spočívá v klidovém režimu, objemové terapii a podávání analgetik. Na pomezí konzervativního a invazivního postupu je aplikace epidurální krevní zátky. Pokud tyto postupy nejsou úspěšné a je jasně identifikované místo úniku mozkomíšního moku, je indikována chirurgická terapie. V případě longitudinální durální trhliny její identifikace a uzávěr, u meningeálního divertiklu jeho ošetření s případnou plastikou u větší durální ektázie, přerušení likvoro-venózní fistuly, popřípadě lumbální durální rekonstrukční operace.
Spontaneous intracranial hypotension is characterized by postural headaches arising from leakage of cerebrospinal fluid without any previous insult into the extradural space. Magnetic resonance is of fundamental importance in the diagnosis of the disease due to a number of typical signs occurring in this disease in the vast majority of patients. The second step is the identification of the location of the cerebrospinal fluid leak, which requires special diagnostic imaging methods and examination techniques. Spontaneous intracranial hypotension can also disappear spontaneously. Its treatment is primarily conservative and consists of rest, volume therapy and administration of analgesics. The application of an epidural blood patch is on the border between conservative and invasive treatments. If these procedures are not successful and the site of cerebrospinal fluid leakage is clearly identified, the surgical treatment is indicated. In the case of a longitudinal dural tear, its identification and closure is performed, in the case of a meningeal diverticulum, its closure with possible duraplasty in patients with a larger dural ectasia is made, cutting off a CSF-venous fistula, or lumbar dural reconstruction surgery.
- Klíčová slova
- epidurální krevní zátka,
- MeSH
- bolesti hlavy etiologie MeSH
- intrakraniální hypotenze * chirurgie etiologie MeSH
- konzervativní terapie MeSH
- laminektomie metody MeSH
- laminoplastika metody MeSH
- lidé MeSH
- ligace metody MeSH
- magnetická rezonanční tomografie metody MeSH
- únik mozkomíšního moku chirurgie etiologie komplikace MeSH
- Check Tag
- lidé MeSH