Despite the availability of new drugs on the clinics in recent years, drug-resistant epilepsy remains an unresolved challenge for healthcare, and one-third of epilepsy patients remain refractory to anti-seizure medications. Gene therapy in experimental models has emerged as effective treatment targeting specific neuronal populations in the epileptogenic focus. When combined with an external chemical activator using chemogenetics, it also becomes an "on-demand" treatment. Here, we evaluate a targeted and specific chemogenetic therapy, the PSAM/PSEM system, which holds promise as a potential candidate for clinical application in treating drug-resistant epilepsy. We show that the inert ligand uPSEM817, which selectively activates the chloride-permeable channel PSAM4-GlyR, effectively reduces the number of depolarization-induced action potentials in vitro. This effect is likely due to the shunting of depolarizing currents, as evidenced by decreased membrane resistance in these cells. In organotypic slices, uPSEM817 decreased the number of bursts and peak amplitude of events of spontaneous epileptiform activity. Although administration of uPSEM817 in vivo did not significantly alter electrographic seizures in a male mouse model of temporal lobe epilepsy, it did demonstrate a strong trend toward reducing the frequency of interictal epileptiform discharges. These findings indicate that PSAM4-GlyR-based chemogenetics holds potential as an anti-seizure strategy, although further refinement is necessary to enhance its efficacy.

• MeSH
• Action Potentials drug effects   MeSH
• Epilepsy physiopathology   genetics   drug therapy   therapy   metabolism   MeSH
• Genetic Therapy methods   MeSH
• Hippocampus * metabolism   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Problematika trombotických mikroangiopatií (TMA) představuje, nejen v porodnictví, velmi závažný patologický stav, který je spojen s tvorbou trombóz na úrovni kapilár i arteriol v důsledku poškození endotelu a aktivace komplementu. Je pro- vázen mikroangiopatickou hemolytickou anémií (MAHA), trombocytopenií a dysfunkcí různých orgánů. Relativně často je navíc spojen se sekundárními systémovými změnami srážlivosti. TMA zahrnují velmi nesourodou skupinu syndromů a sta- vů, kdy ke konečné diagnóze docházíme postupným vylučováním jednotlivých příčin („per exclusionem“). V porodnické praxi se nejčastěji setkáváme s tím, že těhotné/rodičky/nedělky se prezentují pod obrazem preeklampsie/HELLP syndromu (hemolysis, elevated liver enzymes, low platelets). Tento všem porodníkům jinak dobře známý stav zahrnuje obraz MAHA (dynamické snižování hladiny hemoglobinu, zvyšování hladiny bilirubinu, snížení haptoglobinu, přítomnost schistocytů v periferním nátěru krve), periportální ischémie jater (elevace transamináz) a trombocytopenie v důsledku vyšší agregace trombocytů v poškozené periferní mikrocirkulaci. HELLP syndrom se řadí mezi TMA také, měl by však spontánně odezní- vat přibližně do 48-72 hodin po porodu. Pakliže se tak nestane, je velmi důležité pomýšlet na jiné příčiny TMA, které často představují ještě vážnější ohrožení života než HELLP syndrom. Důkladná znalost diferenciální diagnostiky je proto velmi důležitá. Problematiku tedy musí dobře ovládat každý poskytovatel zdravotní péče těhotným ženám, a proto ji kolektiv autorů předkládá ve formě tohoto doporučeného postupu.

The issue of thrombotic microangiopathy (TMA) represents, not only in obstetrics, a serious pathological condition that is associated with the formation of thromboses at the level of capillaries and arterioles due to endothelial damage and complement activation. It is accompanied by microangiopathic haemolytic anaemia (MAHA), thrombocytopenia and dysfunction of various organs. In addition, it is relatively often associated with secondary systemic changes in coagulation. TMAs comprise a very heterogeneous group of syndromes and conditions, where the final diagnosis is reached by sequential exclusion of the individual causes (‚per exclusionem‘). In obstetric practice, we most often encounter pregnant/parturient/ pregnant women presenting with a picture of pre-eclampsia/HELLP syndrome (haemolysis, elevated liver enzymes, low platelets). This condition, otherwise well known to all obstetricians, includes the picture of MAHA (dynamic decrease in hemoglobin, increase in bilirubin, decrease in haptoglobin, presence of schistocytes in the peripheral blood smear), periportal hepatic ischemia (elevation of transaminases) and thrombocytopenia due to increased platelet aggregation in the damaged peripheral microcirculation. HELLP syndrome is also classified as a TMA, but should resolve spontaneously within approximately 48-72 hours after delivery. If this does not happen, it is very important to think about other causes of TMA, which often represent an even more serious threat to life than HELLP syndrome. A thorough knowledge of differential diagnosis is therefore very important. The issue therefore needs to be well understood by every provider of health care to pregnant women, which is why the team of authors presents it in the form of this recommended practice.

Accumulating evidence suggests that manganese oxide nanoparticles (NPs) show multiple enzyme-mimicking antioxidant activities, which supports their potential in redox-targeting therapeutic strategies for diseases with impaired redox signaling. However, the systemic administration of any NP requires thorough hemocompatibility testing. In this study, we assessed the hemocompatibility of synthesized Mn3O4 NPs, identifying their ability to induce spontaneous hemolysis and eryptosis or impair osmotic fragility. Concentrations of up to 20 mg/L were found to be safe for erythrocytes. Eryptosis assays were shown to be more sensitive than hemolysis and osmotic fragility as markers of hemocompatibility for Mn3O4 NP testing. Flow cytometry- and confocal microscopy-based studies revealed that eryptosis induced by Mn3O4 NPs was accompanied by Ca2+ overload, altered redox homeostasis verified by enhanced intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS), and a decrease in the lipid order of cell membranes. Furthermore, Mn3O4 NP-induced eryptosis was calpain- and caspase-dependent.

• MeSH
• Cell Membrane * metabolism   drug effects   MeSH
• Eryptosis * drug effects   MeSH
• Erythrocytes drug effects   metabolism   MeSH
• Hemolysis drug effects   MeSH
• Calpain * metabolism   MeSH
• Caspases * metabolism   MeSH
• Humans MeSH
• Nanoparticles * chemistry   MeSH
• Oxides * pharmacology   chemistry   MeSH
• Reactive Nitrogen Species * metabolism   MeSH
• Reactive Oxygen Species * metabolism   MeSH
• Manganese Compounds * pharmacology   chemistry   MeSH
• Calcium * metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

A20/Tnfaip3, an early NF-κB response gene and key negative regulator of NF-κB signaling, suppresses proinflammatory responses. Its ubiquitinase and deubiquitinase activities mediate proteasomal degradation within the NF-κB pathway. This study investigated the involvement of A20 signaling alterations in podocytes in the development of kidney injury. The phenotypes of A20Δpodocyte (podocyte-specific knockout of A20) mice were compared with those of control mice at 6 months of age to identify spontaneous changes in kidney function. A20Δpodocyte mice presented elevated serum urea nitrogen and creatinine levels, along with increased accumulation of inflammatory cells-neutrophils and macrophages-within the glomeruli. Additionally, A20Δpodocyte mice displayed significant podocyte loss. Ultrastructural analysis of A20 podocyte-knockout mouse glomeruli revealed hypocellularity of the glomerular tuft, expansion of the extracellular matrix, podocytopenia associated with foot process effacement, karyopyknosis, micronuclei, and podocyte detachment. In addition to podocyte death, we also observed damage to intracapillary endothelial cells with vacuolation of the cytoplasm and condensation of nuclear chromatin. A20 expression downregulation and CRISPR-Cas9 genome editing targeting A20 in a podocyte cell line confirmed these findings in vitro, highlighting the significant contribution of A20 activity in podocytes to glomerular injury pathogenesis. Finally, we analyzed TNFAIP3 transcription levels alongside genes involved in apoptosis, anoikis, NF-κB regulation, and cell attachment in glomerular and tubular compartments of kidney biopsies of patients with various renal diseases.

• MeSH
• Cytoskeleton * metabolism   MeSH
• Glomerulonephritis * pathology   metabolism   genetics   MeSH
• Kidney Glomerulus pathology   metabolism   MeSH
• Humans MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout * MeSH
• Mice MeSH
• NF-kappa B metabolism   MeSH
• Podocytes * metabolism   pathology   MeSH
• Signal Transduction MeSH
• Tumor Necrosis Factor alpha-Induced Protein 3 * metabolism   genetics   MeSH
• Inflammation * pathology   genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: The epidemiology of pediatric cardiac arrest in Europe is largely unknown. We aimed to characterize pediatric cardiac arrest registries and obtain the first survival outcome data on pediatric cardiac arrest in Europe. DESIGN: This is a prospective multinational survey. SETTING: We surveyed all 53 countries in Europe asking about: the existence registries for pediatric out-of-hospital cardiac arrest (pOHCA) and/or in-hospital cardiac arrest (pIHCA)), the data collected, and the structure of the registries. Subsequently, we investigated outcomes (number of pOHCA/pIHCA since start of the registry, return of spontaneous circulation (ROSC), survival to hospital discharge/30-day survival) from the countries with active registries. PATIENTS AND INTERVENTIONS: We obtained information from 33 countries including 25 of the 27 European Union states. MEASUREMENTS AND MAIN RESULTS: Thirteen countries (39%) have an ongoing pediatric cardiac arrest registry (pOHCA: 11 countries, pIHCA: 8 countries). All use the Utstein template for data collection. Five countries (15%) collect data about CPR quality. Eleven countries (33%) expressed interest in European collaboration on registry data. Overall, 13 countries reported data on outcomes from a total of 17,708 pOHCAs and 2,743 pIHCAs. The ROSC rate after pOHCA ranges from 10% to 72% as compared to 60% to 72% after pIHCA. Survival to hospital discharge ranges from 16% to 39% after pOHCA as compared to 32% to 57% after pIHCA. CONCLUSIONS: Less than 40% of the European countries have a pOHCA and/or pIHCA registry, reporting a wide variety in survival rates, especially after pOHCA. More systematic data collection is needed to identify the real incidence and outcomes from pediatric cardiac arrest, ideally through a joint European registry.

• Publication type
• Journal Article MeSH

Sympathetic hyperactivity and relative NO deficiency are characteristic alterations in both genetic and salt hypertension. The contribution of these abnormalities to blood pressure (BP) maintenance can be determined in conscious rats using a consecutive blockade of particular vasoactive systems. Thus, the contribution of pressor effects of angiotensin II to the maintenance of high BP is usually small, but the role of renin-angiotensin system in the development of hypertension mediated by central and peripheral effects of angiotensin II on sympathetic activity is highly important. This is even true in angiotensin-dependent hypertension of heterozygous Ren-2 transgenic rats in which sympathetic hyperactivity is increasing with age. Central sympathoexcitation in this hypertensive model can be inhibited by lower losartan doses than peripheral angiotensin II-dependent vasoconstriction. This experimental model also yielded important knowledge on nephroprotective effects of new therapeutic drugs - endothelin receptor type A blockers. A considerable part of sympathetic vasoconstriction is dependent on the interaction of Ca2+ sensitization (RhoA/Rho kinase pathway) and Ca2+ influx (through L-VDCC). The blockade of these pathways prevents a major part of sympathetic vasoconstriction. Ca2+ sensitization seems to be attenuated in genetic hypertension in order to compensate increased Ca2+ influx. In contrast, enhanced Ca2+ sensitization is a hallmark of salt sensitivity in Dahl rats in which salt hypertension is dependent on increased Ca2+ influx. The attention should also be paid to the impairment of arterial baroreflex sensitivity which permits enhanced BP responses to pressor or depressor stimuli. Some abnormalities can be studied in blood vessels isolated from hypertensive rats but neither conduit arteries nor mesenteric resistance arteries represent the vascular beds decisive for the increased peripheral resistance and high BP. Keywords: Sympathetic vasoconstriction, NO-dependent vasodilatation, Calcium sensitization, Calcium influx, Arterial baroreflex, Spontaneously hypertensive rats, Salt hypertensive Dahl rats, Ren-2 transgenic rats, RAS blockade, SNS blockade, NOS inhibition, Endothelin, Vascular contraction and relaxation, Isolated conduit and resistance arteries, EDCF, PGI2, BKCa channels.

• MeSH
• Hypertension * physiopathology   metabolism   MeSH
• Blood Pressure drug effects   physiology   MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Renin-Angiotensin System drug effects   physiology   MeSH
• Sympathetic Nervous System physiopathology   drug effects   MeSH
• Vasodilation drug effects   physiology   MeSH
• Vasoconstriction * drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Spontaneous tumor regression is a recognized phenomenon across various cancer types. Recent research emphasizes the alterations in autoantibodies against carbonic anhydrase I (CA I) (anti-CA I) levels as potential prognostic markers for various malignancies. Particularly, autoantibodies targeting CA I and II appear to induce cellular damage by inhibiting their respective protein's catalytic functions. Our study illuminates the profound impact of anti-CA I autoantibodies from patient serum on the esterase activity of human CA I, exhibiting inhibitory effects akin to the acetazolamide inhibitor. Concurrently, our newly synthesized mouse monoclonal IgG antibody, mAb 2B8, against human CA I showcased a potent inhibitory action. An in-depth exploration into mAb 2B8's binding dynamics with its target enzyme was undertaken. Leveraging epitope extraction and phage display library techniques, we identified the amino acid sequence DFWTYP (positions 191-196 of CA I) as crucial for mAb 2B8's interaction. In 3-D structural analysis, this sequence is spatially adjacent to a previously identified epitope (DFWTYP) that interacts with patient-derived autoantibodies. Critically, mAb 2B8 demonstrated an ability to infiltrate eukaryotic cells, engaging specifically with its intracytoplasmic target. This positions mAb 2B8 as a promising model for future studies aimed at tumor cell eradication.

• MeSH
• Autoantibodies * immunology   metabolism   MeSH
• Epitopes immunology   chemistry   MeSH
• Carbonic Anhydrase I * metabolism   antagonists & inhibitors   MeSH
• Humans MeSH
• Antibodies, Monoclonal * immunology   MeSH
• Mice MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Spontaneously fluctuating brain activity patterns that emerge at rest have been linked to the brain's health and cognition. Despite detailed descriptions of the spatio-temporal brain patterns, our understanding of their generative mechanism is still incomplete. Using a combination of computational modeling and dynamical systems analysis we provide a mechanistic description of the formation of a resting state manifold via the network connectivity. We demonstrate that the symmetry breaking by the connectivity creates a characteristic flow on the manifold, which produces the major data features across scales and imaging modalities. These include spontaneous high-amplitude co-activations, neuronal cascades, spectral cortical gradients, multistability, and characteristic functional connectivity dynamics. When aggregated across cortical hierarchies, these match the profiles from empirical data. The understanding of the brain's resting state manifold is fundamental for the construction of task-specific flows and manifolds used in theories of brain function. In addition, it shifts the focus from the single recordings towards the brain's capacity to generate certain dynamics characteristic of health and pathology.

• MeSH
• Adult MeSH
• Humans MeSH
• Magnetic Resonance Imaging methods   MeSH
• Brain Mapping methods   MeSH
• Models, Neurological * MeSH
• Brain * physiology   diagnostic imaging   MeSH
• Nerve Net physiology   MeSH
• Rest * physiology   MeSH
• Computer Simulation MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Introduction: Volunteer activities during emergencies occur both formally and informally. In developed countries, emergencies are managed by professionals and formal volunteers. Spontaneous (informal) volunteers often respond at any stage, and this is known as convergent response. While these volunteers help prevent loss of life and property, their lack of organization and emergency knowledge poses risks, such as safety and responsibility issues. This leads professional responders to hesitate in using them. The implementation of effective integration strategies can significantly aid in emergencies. Objective: This work focuses on volunteering in ensuring hospital crisis preparedness. The aim is to assess volunteering and identify applicable activities during emergencies, especially in hospitals. A methodical procedure for selecting suitable volunteers was developed using multi-criteria evaluation methods. Methods: A systematic procedure for selecting volunteers was developed based on the implementation of multi-criteria evaluation methods. The implementation of multi-criteria decision-making methods offers an objective selection tool. Sequential steps are directed towards the selection of volunteers who will be competent in performing selected activities of healthcare personnel in hospitals during crisis preparedness. A step-by-step, organized, and targeted process is elaborated in individual, interconnected steps. Results: The study defines a criteria model for selecting hospital volunteers during emergencies, including Professional Qualification, Length of Practice in Healthcare Fields, Volunteering Costs, and Driver's License Category B.

• MeSH
• Voluntary Health Agencies statistics & numerical data   MeSH
• Hospital Volunteers * statistics & numerical data   MeSH
• Humans MeSH
• Emergencies * classification   MeSH
• Personnel Management methods   MeSH
• Disaster Planning methods   MeSH
• Personnel Selection methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Toto sdělení je zaměřeno na historii turistiky na Šumavě a Šumavském podhůří, které jsou nejrozsáhlejším horským celkem v České republice. Z hlediska časového se jedná o poměrně dlouhé období od 80. let 19. století do obsazení československého pohraničí na podzim 1938. Ve většině částí tohoto území mělo až do konce II. světové války výraznou převahu obyvatelstvo německé národnosti. Navzdory tomu zde ale nevznikla velký německý specifický turistický spolek, a tak po vzniku Československa v roce 1918, zde došlo k výraznému vlivovému průniku Klubu československých turistů. Toto sdělení je zaměřeno na organizovanou i spontánní pěší turistiku, na popis turistických cílů, turistické infrastruktury a na činnost turistických spolků. Text je doplněn celkem 19 obrázky složenými většinou z dobových pohlednic.

This study focuses on the history of tourism in the Bohemian Forest (Šumava) and its Foothills, which constitute the largest mountain range in the Czech Republic. In terms of time, it covers a relatively long period from the 1880s to the occupation of the Czechoslovak borderlands in the autumn of 1938. In most parts of this region, until the end of World War II, the German population predominated. Nevertheless, there was no significant German-specific tourist association established here. After the formation of Czechoslovakia in 1918, there was a significant influence from the Czechoslovak Tourist Club. This message focuses on organized and spontaneous hiking tourism, describing tourist destinations, tourist infrastructure, and the activities of tourist associations. The text is supplemented by a total of 19 images, mostly composed of vintage postcards.

• Keywords
• Šumava,
• MeSH
• History, 19th Century MeSH
• History, 20th Century MeSH
• Humans MeSH
• Recreation history   MeSH
• Tourism MeSH
• Check Tag
• History, 19th Century MeSH
• History, 20th Century MeSH
• Humans MeSH
• Publication type
• Historical Article MeSH
• Geographicals
• Czechoslovakia MeSH