The objective of this study was to elucidate the pharmacokinetics and metabolite formation of newly developed non-selective AChE/BChE 7-MEOTA-donepezil-like inhibitors for potential therapeutic use in Alzheimer's disease (AD) patients. The chemical structures of metabolites were defined during incubation with human liver microsomes, and subsequently, the metabolization was verified in in vivo study. In vitro metabolic profiling revealed the formation of nine major metabolites in the case of PC-37 and eight metabolites of PC-48. Hydroxylation and the enzymatic hydrolysis of bonds close to the piperazine ring appeared to be the principal metabolic pathways in vitro. Of these metabolites, M1-M7 of PC-37 and M1-M6 of PC-48 were confirmed under in vivo conditions. Pilot pharmacokinetic experiments in rats were focused on the absorption, distribution and elimination of these compounds. Absorption after i.m. application was relatively fast; the bioavailability expressed as AUCtotal was 28179 ± 4691 min.ng/mL for PC-37 and 23374 ± 4045 min.ng/mL for PC-48. Both compounds showed ability to target the central nervous system, with brain concentrations exceeding those in plasma. The maximal brain concentrations are approximately two times higher than the plasma concentrations. The relatively high brain concentrations persisted throughout the experiment until 24 hr after application. Elimination via the kidneys (urine) significantly exceeded elimination via the liver (bile). All these characteristics are crucial for new candidates intended for AD treatment. The principle metabolic pathways that were verified in the in vivo study do not show any evidence for formation of extremely toxic metabolites, but this needs to be confirmed by further studies.

• MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• biologická dostupnost MeSH
• cholinesterasové inhibitory chemická syntéza   metabolismus   farmakokinetika   terapeutické užití   MeSH
• hydrolýza MeSH
• hydroxylace MeSH
• jaterní mikrozomy metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• metabolické sítě a dráhy MeSH
• mozek účinky léků   MeSH
• pilotní projekty MeSH
• piperaziny chemická syntéza   metabolismus   farmakokinetika   terapeutické užití   MeSH
• potkani Wistar MeSH
• takrin analogy a deriváty   chemická syntéza   metabolismus   farmakokinetika   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

A simple, rapid and sensitive method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and validated for the quantitative determination in rat plasma of a new candidate for AD treatment, namely PC 48 (a 7-MEOTA-donepezil like compound) in rat plasma. Sample preparation involved pH adjustment with sodium hydroxide followed by solvent extraction with ethyl acetate:dichloromethane (80:20, v/v). The chromatographic separation was achieved on an Ascentis Express RP-Amide column (75 mm × 2.1mm, 2.7 μm) with a gradient mobile phase consisting of 0.05 M aqueous formic acid and acetonitrile. Detection was carried out using positive-ion electrospray tandem mass spectrometry on an LTQ XL system using the MS/MS CID (collision-induced dissociation) mode. The method was linear in the range 0.1-1000 ng/ml (r(2)=0.999) with a lower limit of quantitation of 0.1 ng/mL. Extraction recovery was in the range 63.5-72.1% for PC 48 and 70.5% for reserpine (internal standard, IS). Intra- and inter-day precisions measured as relative standard deviation were below 10.8% and accuracy was from -7.2% to 7.4%. The method was successfully applied to a pharmacokinetic study involving intramuscular application of 3.86 mg/kg PC 48 to rats for the first time. Pharmacokinetic parameters for PC 48 include Cmax 39.09 ± 4.45 ng/mL,Tmax 5.00 ± 3.08 min, AUC0-t 23374 ± 4045 min ng/mL and t1/2 1065 ± 246 min.

• MeSH
• Alzheimerova nemoc MeSH
• cholinesterasové inhibitory krev   MeSH
• indany krev   chemie   farmakokinetika   MeSH
• krysa rodu rattus MeSH
• lineární modely MeSH
• piperidiny krev   chemie   farmakokinetika   MeSH
• potkani Wistar MeSH
• reprodukovatelnost výsledků MeSH
• senzitivita a specificita MeSH
• takrin analogy a deriváty   krev   chemie   farmakokinetika   MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• Frequency XC, PC Hydrogel,
• MeSH
• hydrogely terapeutické užití   MeSH
• lidé MeSH
• měkké kontaktní čočky klasifikace   škodlivé účinky   využití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• srovnávací studie MeSH

• MeSH
• ischemická choroba srdeční diagnóza   chirurgie   MeSH
• koronární angiografie MeSH
• koronární angioplastika metody   MeSH
• lidé MeSH
• senioři MeSH
• stabilní angina pectoris * diagnóza   farmakoterapie   chirurgie   patofyziologie   MeSH
• trimetazidin aplikace a dávkování   farmakologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• kazuistiky MeSH

Prostate-specific membrane antigen (PSMA) is a well-characterized tumor marker associated with prostate cancer and neovasculature of most solid tumors. PSMA-specific ligands are thus being developed to deliver imaging or therapeutic agents to cancer cells. Here, we report on a crystal structure of human PSMA in complex with A9g, a 43-bp PSMA-specific RNA aptamer, that was determined to the 2.2 Å resolution limit. The analysis of the PSMA/aptamer interface allows for identification of key interactions critical for nanomolar binding affinity and high selectivity of A9g for human PSMA. Combined with in silico modeling, site-directed mutagenesis, inhibition experiments and cell-based assays, the structure also provides an insight into structural changes of the aptamer and PSMA upon complex formation, mechanistic explanation for inhibition of the PSMA enzymatic activity by A9g as well as its ligand-selective competition with small molecules targeting the internal pocket of the enzyme. Additionally, comparison with published protein-RNA aptamer structures pointed toward more general features governing protein-aptamer interactions. Finally, our findings can be exploited for the structure-assisted design of future A9g-based derivatives with improved binding and stability characteristics.

• MeSH
• antigeny povrchové chemie   MeSH
• aptamery nukleotidové chemie   MeSH
• buňky PC-3 MeSH
• glutamátkarboxypeptidasa II chemie   MeSH
• HEK293 buňky MeSH
• interakční proteinové domény a motivy MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• nádorové biomarkery chemie   MeSH
• nádory prostaty metabolismus   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: We hypothesized that cannulation strategy in venoarterial extracorporeal membrane oxygenation (VA-ECMO) could play a crucial role in the perioperative survival of patients affected by postcardiotomy shock. METHODS: Between January 2010 and March 2018, 781 adult patients receiving VA-ECMO for postcardiotomy shock at 19 cardiac surgical centers were retrieved from the Postcardiotomy Veno-arterial Extracorporeal Membrane Oxygenation study registry. A parallel systematic review and meta-analysis (PubMed/MEDLINE, Embase, and Cochrane Library) through December 2018 was also accomplished. RESULTS: Central and peripheral VA-ECMO cannulation were performed in 245 (31.4%) and 536 (68.6%) patients, respectively. Main indications for the institution VA-ECMO were failure to wean from cardiopulmonary bypass (38%) and heart failure following cardiopulmonary bypass weaning (48%). The doubly robust analysis after inverse probability treatment weighting by propensity score demonstrated that central VA-ECMO was associated with greater hospital mortality (odds ratio 1.54; 95% confidence interval, 1.09-2.18), reoperation for bleeding/tamponade (odds ratio, 1.96; 95% confidence interval, 1.37-2.81), and transfusion of more than 9 RBC units (odds ratio, 2.42; 95% confidence interval, 1.59-3.67). The systematic review provided a total of 2491 individuals with postcardiotomy shock treated with VA-ECMO. Pooled prevalence of in-hospital/30-day mortality in overall patient population was 66.6% (95% confidence interval, 64.7-68.4%), and pooled unadjusted risk ratio analysis confirmed that patients undergoing peripheral VA-ECMO had a lower in-hospital/30-day mortality than patients undergoing central cannulation (risk ratio, 0.92; 95% confidence interval, 0.87-0.98). Adjustments for important confounders did not alter our results. CONCLUSIONS: In patients with postcardiotomy shock treated with VA-ECMO, central cannulation was associated with greater in-hospital mortality than peripheral cannulation.

• MeSH
• dospělí MeSH
• kardiochirurgické výkony škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mimotělní membránová oxygenace * škodlivé účinky   metody   mortalita   MeSH
• pooperační komplikace chirurgie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• šok chirurgie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH

Shrnutí stavu, záměrů a postupů při vytváření možností užití informačních technologií v rozsáhlém nemocničním celku.

• MeSH
• bezpečnost MeSH
• multimédia MeSH
• nemocnice fakultní MeSH
• nemocniční informační systémy MeSH
• uživatelské rozhraní počítače MeSH

THE OBJECTIVE: The main objective of the research was to find out the effectivity of the combined therapy suitable for patients after ischemic stroke (promoting social adaptability). The therapy itself is then focused on robotic, psychomotor and cognitive therapy. The research indicators were divided into three categories of psychological, social and cognitive indicators. PROBAND SAMPLE: We have a 58 probands diagnosed with a stroke participated on the research (ischemic type I60-I69; ICD-10; the 10th revision of the International Statistical Classification of Diseases and Related Health Problem), out of which 49 were male patients ages between 48-55 and women between the age of 45-51. The data collection was then done during 2018. Indicators were evaluated and tested firstly after the initiation of the combined therapy, then after 10 weeks of intensive therapy, which took place 3 times a week 45 minutes for each patient participating in the research. RESULTS: The results of the research point to the fact, that combined therapy of robotic, psychomotor and cognitive can have positive effect on, and be suitable as a treatment for patients after ischemic stroke, regarding their productive age. Positive results have been therefore overt among all tested areas. CONCLUSION: The results of the research point to the fact, that combined therapy of robotic, psychomotor and cognitive can have positive effect on, and be suitable as a treatment for patients after ischemic stroke, regarding their productive age. Positive results have been therefore overt among all tested areas.

• MeSH
• afekt MeSH
• cévní mozková příhoda patofyziologie   MeSH
• činnosti denního života MeSH
• exoskeleton MeSH
• fyzická vytrvalost MeSH
• fyzioterapie (techniky) * MeSH
• ischemie mozku patofyziologie   rehabilitace   MeSH
• kognitivně behaviorální terapie * MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• rehabilitace po cévní mozkové příhodě metody   MeSH
• sociální přizpůsobení * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Cíl: Covid-19 způsobil posun směrem k technologiím orientovaným na spotřebitele, jako jsou mobilní zdravotní aplikace (mHealth). Většina aplikací mHealth však přístupný jazyk nepoužívá. Standardizované terminologie mají potenciál tento problém vyřešit, ale nebyly zjednodušeny pro spotřebitelské použití. Metodika: Použili jsme standardizovanou zdravotnickou terminologii, systém Omaha, jako rámec pro vývoj Simplified Omaha System Terms (SOST) pro použití v aplikaci mHealth, MyStrengths + MyHealth. Principy jednoduchého jazyka informovaly o vývoji SOST ve třech fázích, komunitní validační skupina umožnila zpětnou vazbu od různých koncových uživatelů, hodnocení čitelnosti poskytlo ověření požadované cílové úrovně čitelnosti. Výsledky: Věk členů v komunitní validační skupině (n = 19) byl v rozmezí od 22 do 74 let; 51 % muži, 84 % lidí jiné barvy pleti a 21 % vysokoškolsky vzdělaných. Úroveň čtení konečného SOST byla v průměru 3,86 na Coleman-Liau Index (čtvrtý stupeň). Případová studie ukázala, že v komunitní studii během pandemie covidu-19 byly vygenerovány smysluplné údaje o celkovém zdraví člověka. Závěr: Komunitní validace a hodnocení čitelnosti prokázaly přístupný jazyk pro klinickou terminologii. SOST byl úspěšně nasazen v MyStrengths + MyHealth a komunitní studii. Systém Omaha jako rámec pro SOST může umožnit integraci dat s klinickými datovými soubory. Budoucí výzkum by se měl zaměřit na validaci SOST v dalších jazycích a integraci v rámci platforem elektronického zdravotnictví.

Purpose: COVID-19 has caused a shift toward consumer-facing technology such as mobile health (mHealth) applications. However, most mHealth apps do not use accessible language. Standardized terminologies have potential to solve this problem but have not been simplified for consumer use. Methods: We used a standardized health terminology, the Omaha System, as the framework to develop the Simplified Omaha System Terms (SOST) for use within a mHealth application, MyStrengths + MyHealth. Plain language principles informed the SOST development in three phases, a community-validation focus group enabled feedback from diverse end-users, a readability assessment provide validation to the desired goal readability level. Results: The community-validation members (n = 19) ages ranged from 22 to 74; 51% male, 84% people of color, and 21% college educated. The reading level of the final SOST averaged 3.86 on the Coleman-Liau Index (fourth grade). A case study showed meaningful whole-person health data were generated in a community-led study during COVID-19. Conclusions: Community validation and readability assessment demonstrated accessible language for a clinical terminology. The SOST was deployed successfully in MyStrengths + My Health and in a community-led study. The Omaha System as a framework for the SOST may enable the data to be integrated with clinical datasets. Future research should focus on validation of SOST in additional languages and integration within electronic health platforms.

• Klíčová slova
• Omaha System,
• MeSH
• databáze jako téma MeSH
• informační systémy MeSH
• uživatelské rozhraní počítače MeSH

V lednu 1999 byl zahájen zkušební provoz virtuální multimediální knihovny Univerzity Karlovy. Jedná se o distribuovanou elektronickou knihovnu, která poskytuje všem uživatelům univerzity přímý přístup k CD titulům, zejména odborným databázím a výukovým programům.

• MeSH
• CD-ROM MeSH
• digitální knihovny MeSH
• internet využití   MeSH
• multimédia MeSH
• počítačové komunikační sítě MeSH
• studium lékařství metody   MeSH
• uživatelské rozhraní počítače MeSH