- MeSH
- Cell Division MeSH
- Keratinocytes physiology MeSH
- Keratins analysis MeSH
- Cells, Cultured MeSH
- Polymers MeSH
- Serum Albumin, Bovine MeSH
- Publication type
- Comparative Study MeSH
Recent findings suggest that specific deficits in neural synchrony and binding may underlie cognitive disturbances in schizophrenia and that key aspects of schizophrenia pathology involve discoordination and disconnection of distributed processes in multiple cortical areas associated with cognitive deficits. In the present study we aimed to investigate the underlying cortical mechanism of disturbed frontal-temporal-central-parietal connectivity in schizophrenia by examination of the synchronization patterns using wavelet phase synchronization index and coherence between all defined couples of 8 EEG signals recorded at different cortical sites in its relationship to positive and negative symptoms of schizophrenia. 31 adult schizophrenic outpatients with diagnosis of paranoid schizophrenia (mean age 27.4) were assessed in the study. The obtained results present the first quantitative evidence indicating direct relationship between wavelet phase synchronization and coherence in pairs of EEG signals recorded from frontal, temporal, central and parietal brain areas and positive and negative symptoms of schizophrenia. The performed analysis demonstrates that the level of phase synchronization and coherence in some pairs of EEG signals is inversely related to positive symptoms, negative symptoms and general psychopathology in temporal scales (frequency ranges) given by wavelet frequencies (WFs) equal to or higher than 7.56 Hz, and positively related to negative symptoms in wavelet frequencies equal to or lower than 5.35 Hz. This finding suggests that higher and lower frequencies may play a specific role in binding and connectivity and may be related to decreased or increased synchrony with specific manifestation in cognitive deficits of schizophrenia.
- MeSH
- Adult MeSH
- Electroencephalography methods MeSH
- Cortical Synchronization MeSH
- Humans MeSH
- Brain Mapping MeSH
- Young Adult MeSH
- Cerebral Cortex physiopathology MeSH
- Statistics, Nonparametric MeSH
- Schizophrenia, Paranoid physiopathology pathology MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
Hepcidin is a key regulator of iron metabolism and a mediator of anemia in inflammation. Recent in vitro studies recognized prohepcidin as a type II acute phase protein regulating via interleukin-6. The aim of the present study was to investigate the time course of plasma prohepcidin after a large cardiac surgery in relation to IL-6 and other inflammatory parameters. Patients with chronic thromboembolic hypertension (n=22, males/females 14/8, age 51.9±10.2 years) underwent pulmonary endarterectomy using cardiopulmonary bypass and deep hypothermic circulatory arrest were included into study. Arterial concentrations of prohepcidin, IL-1ß, IL-6, IL-8, tumor necrosis factor-?, and C-reactive protein were measured before/after sternotomy, after circulatory arrest, after separation from bypass, and then 12, 18, 24, 36, 48 h and 72 h after the separation from bypass. Hemodynamic parameters, hematocrit and markers of iron metabolism were followed up. Pulmonary endarterectomy induced a 48 % fall in plasma prohepcidin; minimal concentrations were detected after separation from cardiopulmonary bypass. Prohepcidin decline correlated with an extracorporeal circulation time (p<0.01), while elevated IL-6 levels were inversely associated with duration of prohepcidin decline. Postoperative prohepcidin did not correlate with markers of iron metabolism or hemoglobin concentrations within a 72-h period after separation from CPB. Prohepcidin showed itself as a negative acute phase reactant during systemic inflammatory response syndrome associated with a cardiac surgery. Results indicate that the evolution of prohepcidin in postoperative period implies the antagonism of stimulatory effect of IL-6 and contraregulatory factors inhibiting prohepcidin synthesis or increasing prohepcidin clearance.
- MeSH
- Pulmonary Artery surgery MeSH
- Biomarkers blood MeSH
- Time Factors MeSH
- Surgical Procedures, Operative adverse effects MeSH
- Adult MeSH
- Down-Regulation MeSH
- Endarterectomy adverse effects MeSH
- Financing, Organized MeSH
- Interleukin-6 blood MeSH
- Cardiopulmonary Bypass adverse effects MeSH
- Antimicrobial Cationic Peptides blood MeSH
- Middle Aged MeSH
- Humans MeSH
- Inflammation Mediators blood MeSH
- Hypertension, Pulmonary etiology surgery blood MeSH
- Protein Precursors blood MeSH
- Acute-Phase Proteins MeSH
- Sternum surgery MeSH
- Systemic Inflammatory Response Syndrome etiology blood MeSH
- Thromboembolism surgery complications blood MeSH
- Treatment Outcome MeSH
- Circulatory Arrest, Deep Hypothermia Induced adverse effects MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
Východisko. U pacientů v akutní fázi srdečního infarktu byly sérové koncentrace proteinů akutní fáze a koncentrace mědi významně vyšší u nemocných se srdečním selháním než u pacientů s nekomplikovaným průběhem infarktu myokardu a korelovaly s parametry systolické funkce levé komory. Cílem práce bylo zjistit, zda koncentrace proteinů akutní fáze a koncentrace mědi korelují s echokardiograficky stanovenými parametry systolické a diastolické funkce levé komory u pacientů s chronickým srdečním selháním mimo akutní fázi infarktu myokardu. Metody a výsledky.Autoři hodnotili vztah koncentrací proteinů akutní fáze – C-reaktivního proteinu a fibrinogenu a koncentrací mědi k echokardiograficky stanoveným parametrům systolické a diastolické funkce levé komory u 38 pacientů s chronickým srdečním selháním a významnou systolickou dysfunkcí levé komory po infarktu myokardu s ejekční frakcí levé komory menší nebo rovnu 35 %. Sérové koncentrace C-reaktivního proteinu korelovaly statisticky významně s ejekční frakcí levé komory (r=-0,38, p<0,05) a časem izovolumické relaxace IRVT (r=-0,51, p<0,001) – inverzní korelace. Koncentrace C-reaktivního proteinu korelovaly statisticky významně s poměrem maximální rychlosti časného transmitrálního diastolického průtoku (vlna E) a maximální rychlosti transmitrálního průtoku při síňové kontrakci (vlna A) – E/A (r=0,43, p<0,01) a s poměrem časově rychlostních integrálů časného diastolického průtoku a průtoku při síňové kontrakci – TVIE/TVIA (r=0,45, p<0,01) – pozitivní korelace. Korelace koncentrací fibrinogenu a mědi s ejekční frakcí levé komory a s parametry diastolické funkce levé komory nejsou statisticky významné. Závěry. Koncentrace proteinu akutní fáze C-reaktivního proteinu statisticky významně korelují u nemocných s chronickým srdečním selháním a systolickou dysfunkcí levé komory po infarktu myokardu s parametry systolické a diastolické funkce levé komory, vztah koncentrací fibrinogenu a mědi k těmto parametrům není statisticky významný.
Background. Acute phase protein concentrations and serum copper levels in patients in acute phase of myocardial infarction were significantly higher in subjects with heart failure compared to patients with non-complicated course of myocardial infarction. Acute phase protein concentrations correlated with the parameters of the left ventricular systolic function in patients in acute phase of myocardial infarction. The aim of the study was to evaluate the relation of acute phase protein concentrations and serum copper levels with the parameters of left ventricular systolic and diastolic function in patients with chronic heart failure out of the acute phase post myocardial infarction. Methods and Results. Authors analysed relation between the acute phase proteins, C-reactive protein, fibrinogen, and copper concentrations and the left ventricular systolic and diastolic function assessed by echocardiography in 38 patients (26 men and 12 women, average age 68 years) with chronic heart failure and advanced left ventricular systolic dysfunction post myocardial infarction with ejection fraction lower or equal to 35 %. Serum C-reactive protein concentrations correlated significantly with the left ventricular ejection fraction (r=-0.38, p<0.05) and with isovolumic relaxation time IRVT (r=-0.51, p<0.001) – inverse correlation. C-reactive protein concentration correlated with the ratio of the maximal flow velocity of the early transmitral diastolic filling (E vave) and with the maximal transmitral flow velocity during atrial contraction (A wave) – E/A ration (r=0.43, p<0.01). C-reactive protein concentration also correlated with the ration of the time velocity integrals of the E wave and the A wave – TVIE/TVIA (r=0.45, p<0.01) – positive correlation. Correlation between the fibrinogen and copper concentrations and the left ventricular ejection, or that with parameters of the diastolic left ventricular function were not statistically significant. Conclusions. Study revealed significant correlation between C-reactive protein concentration and parameters of the left ventricular systolic and diastolic function in patients with chronic heart failure post myocardial infarction. Correlation between copper and fibrinogen levels and parameters of the left ventricular function was not significant.
Cíl práce: Analýza vztahů mezi farmakokinetikou, účinkem a nežádoucími účinky metotrexátu (MTX) v iniciální fázi systémové léčby středně těžké a těžké psoriázy. Metody: Souhrnná analýza třech prospektivních otevřených randomizovaných studií zahrnula 63 nemocných s psoriázou. Koncentrace MTX v plazmě byly stanoveny HPLC a farmakokinetické parametry byly vypočítány nekompartmentovými postupy v programu Kinetica (verze 4.0) v týdnu 1, 5 a 13. Stav postižení kůže byl hodnocen pomocí PASI skóre (Psoriasis area and severity index). Data byla testována analýzou rozptylu (ANOVA) a korelace byla hodnocena pomocí Spearmanova pořadového koeficientu. Výsledky: Terapeutický účinek se rozvíjel postupně během 120 dní a byl nejmenší po týdenní dávce 7,5 mg jednorázově a největší po týdenní dávce 15 mg podané rozděleně do 3 dávek po 12 h. Farmakokinetika MTX byla lineární v dávkovém rozmezí 2,5 mg až 15 mg. Byla nalezena vysoce signifikantní a těsná negativní korelace (rs = -0.82, p < 0.0001) mezi relativními hodnotami PASI po 13 týdnech (v % počáteční hodnoty) a hodnotami plochy pod křivkou koncentrací v intervalu 0 až 8h po podání (AUC0–8h) vyšetřenými na začátku studie. Při překročení hranice AUC0–8h = 700 nmol.h/l byla četnost dosažení PASI50 (50-procentní a větší pokles PASI) 100%, zatímco pod touto hranicí 33%. Mediány výsledků hematologických (hemoglobin, počet erytrocytů, leukocytů a trombocytů) a biochemických (ALT, AST, GMT, ALP, močovina, kreatinin) vyšetření krve se v období prvních 6 měsíců od zahájení farmakoterapie nezměnily s výjimkou koncentrace homocysteinu v plazmě (zvýšení o 35 %, p<0.005). Závěr. Úspěch iniciální fáze léčby psoriázy je závislý především na dosažení dostatečných koncentrací MTX v krvi (AUC0–8h > 700 nmol.h/l). Farmakokinetika MTX je interindividuálně variabilní, ale v průběhu terapie se nemění a intraindividuální kolísání hodnot AUC0–8h je nízké. Z těchto důvodů je indikováno terapeutické monitorování a individualizace dávky MTX podle AUC0–8h.
Aim: To evaluate the relationship between pharmacokinetics (PK) and pharmacodynamics (PD, therapeutic and adverse effects) during the initial phase of psoriasis treatment with methotrexate (MTX). Methods: Analysis of the results obtained in three prospective randomized trials enrolled 63 patients with moderate-severe and severe psoriasis. In weeks 1, 5 and 13, plasma concentrations of MTX were assayed using HPLC and pharmacokinetic parameters were evaluated using standard noncompartmental methods in the software Kinetica, version 4.0. The Psoriasis Area and Severity Index (PASI) was obtained. Data were tested using analysis of variance (ANOVA) and Spearman rank correlation. Results: Therapeutic effect developed gradually over 120 days since the start of therapy. The least effective dose was 7.5 mg as a bolus, the highest effect was observed after 15 mg given in three doses at 12h intervals. MTX pharmacokinetics were linear in the range of 2.5 mg to 15 mg. PK/PD analysis revealed a highly significant inverse relationship between the PASI at week 13 (in % of the initial value) and the area under concentration-time curve AUC0–8h at week 1 (rho = -0.82, p < 0.0001. All patients with the AUC0–8h > 700 nmol.h/l attained the PASI50 (a drop in PASI ≥ 50%), while those with lower values attained it in only 33% of cases. There were no significant changes in the results of routine hematology and clinical biochemistry tests with the exception of plasma homocysteine which increased by 35 % (p<0.005). Conclusion: The results of this study suggest that the AUC0–8h > 700 nmol.h/l is associated with a high skin-clearing effect of antipsoriatic therapy with MTX. MTX pharmacokinetics is characterized by a high interindividual variability, no changes in time and low within-subject fluctuation. Therefore, therapeutic monitoring and dose individualization at the start of therapy are strongly recommended.
- MeSH
- Analysis of Variance MeSH
- Administration, Oral MeSH
- Pharmacokinetics MeSH
- Research Support as Topic MeSH
- Hematologic Tests methods statistics & numerical data MeSH
- Homocysteine blood MeSH
- Humans MeSH
- Methotrexate administration & dosage pharmacology blood MeSH
- Prospective Studies MeSH
- Psoriasis diagnosis drug therapy pathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Randomized Controlled Trial MeSH
Výskyt paracentrických inverzí v běžné populaci není přesně stanoven, kolísá od 0,09 do 0,49 případů na 1000 jedinců. Párování homologních chromozómů při meióze bývá u těchto inverzímaximalizováno zformováníminverzní smyčky. Pokud v této smyčce dojde ke crossing-overu, může vzniknout acentrický a dicentrický chromozóm. Ve výsledných gametách tak dochází k různým duplikacím a deficiencím, které vedou k neživotaschopnosti plodu. Z tohoto pravidla existují výjimky, jednou z nich může být tzv. rekombinace U smyčkou. Jde o abnormální proces na základě chromatidových zlomů a znovuspojení, výsledkem jsou monocentrické rekombinované chromozómy. Většina paracentrických inverzí u člověka nepředstavuje větší riziko a pravděpodobnost narození dítěte s nevyváženým karyotypem je u heterozygotů – nosičů této inverze – relativně nízká. Proto je při těhotenství náhodně zachycených nosičů nabídka prenatálního vyšetření chromozómů víceméně nezávazná. Je však třeba mít na paměti, že u některých případů je velmi obtížné rozlišit paracentrickou inverzi od paracentrické inzerce – riziko inzerce je okolo 15 %. Dojde-li v plodové vodě k zachycení paracentrické inverze vzniklé de novo, to znamená, že rodiče mají karyotyp normální, je vhodné partnerům sdělit riziko postižení plodu ve výši 6,7 %, které je v podstatě platné pro všechny nově vzniklé dvouzlomové přestavby.
The incidence of paracentric inversions in the general population has not been clearly established, it ranges from 0.09 to 0.49/1,000. Homologue pairing during meiosis in a paracentric-inversion heterozygote is maximized by the formation of an inversion loop. If a crossing-over occurs within this loop, dicentric and acentric chromosomes are formed. Resulting gametes can have variety of duplications and deficiencies and give a non-viable progeny. One of the exceptions to the rule is a mutation event „U loop recombination“. FromU-loop event a monocentric recombinant chromosome can arise by an abnormal process, which involves chromatid breakage and reunion. Most of the paracentric inversions inman are harmless and the risk of heterozygotes having a child with an unbalanced karyotype is relatively low. In carriers of an accidentally discovered paracentric inversion, amniocentesis is optional. However, in some cases, it is difficult to distinguish between a paracentric inversion and paracentric insertion - the risk of the insertion is about 15 %. When a de novo inversion is detected in amniotic fluid, the overall risk for two-break rearrangements is 6.7 %.
- MeSH
- Chromosome Aberrations MeSH
- Gametogenesis physiology MeSH
- Karyotyping MeSH
- Meiosis MeSH
- Prenatal Diagnosis MeSH
- Recombination, Genetic MeSH
- Publication type
- Review MeSH
Herein, we report the stereoselective synthesis of trisubstituted benzoxazino[4,3-b][1,2,5]thiadiazepinone 6,6-dioxides from polymer-supported Fmoc-Ser(tBu)-OH and Fmoc-Thr(tBu)-OH. After the solid-phase synthesis of N-alkylated-N-sulfonylated intermediates using various 2-nitrobenzenesulfonyl chlorides and bromoketones, the target compounds were obtained via trifluoroacetic acid (TFA)-mediated cleavage from the resin, followed by cyclization of the diazepinone scaffold. Except for the threonine-based intermediates, the inclusion of triethylsilane (TES) in the cleavage cocktail yielded a specific configuration of the newly formed C3 chiral center. The final cyclization resulted in minor or no inversion of the C12a stereocenter configuration.
- MeSH
- Alkylation MeSH
- Cyclic S-Oxides chemical synthesis MeSH
- Cyclization MeSH
- Small Molecule Libraries chemical synthesis MeSH
- Polymers chemistry MeSH
- Stereoisomerism MeSH
- Solid-Phase Synthesis Techniques MeSH
- Thiadiazoles chemical synthesis MeSH
- Structure-Activity Relationship MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Glucuronidation of the non-steroidal anti-inflammatory chiral drug flobufen and its major metabolite M17203 has been implicated as an important mechanism of flobufen elimination. To characterize flobufen metabolism by O-glucuronidation, new liquid chromatographic method (LC) coupled with ESI-MS was developed to detect the conjugates of flobufen and its metabolites formed in vitro in rat liver microsomes. Discovery DSC-18 LT cartridge columns were utilized for solid phase extraction (SPE) and Discovery C18 column (150 mm x 2.1 mm, 5 microm particle size) was used for LC separation. Chiral inversion of flobufen and its metabolites enantiomers was checked by special 1-allyl-(5R,8S,10R)-terguride column (150 mm x 4.6 mm). O-Glucuronidation of the S-enantiomer displayed a typical Michaelis-Menten kinetics, whereas the R-enantiomer exhibited a substrate inhibition type of kinetics. The study of glucuronidation of M17203 led to kinetics with sigmoidal characteristics.
OBJECTIVE: To analyze the meiotic segregation and an interchromosomal effect in sperm of an inv(Y) (p11.1;q11.2),t(10;15) (q25.2;q12) carrier. DESIGN: Case report. SETTING: Research institute. PATIENT(S): Man with a karyotype 46,X,inv(Y),t(10;15), normal sperm parameters, and secondary infertility. INTERVENTION(S): Multicolor fluorescence in situ hybridization using probes for chromosomes 10, 15, 8, 18, 21, X, and Y. MAIN OUTCOME MEASURE(S): Frequencies of meiotic segregation products and aneuploidy of chromosomes 8, 18, 21, X, and Y. RESULT(S): The most frequent type of meiotic segregation was the alternate (40.82%), followed by the adjacent 1 (28.09%), adjacent 2 (16.33%), and 3:1 (9.91%) segregations. Neither deviation from the expected 1:1 ratio of the X- and Y-bearing spermatozoa nor any evidence of an interchromosomal effect on aneuploidy of chromosomes X, Y, 8, 18, and 21 and diploidy was observed in the carrier compared with control donors. The disomies of chromosomes 8 and 21 were equally frequent in X- and Y-bearing spermatozoa of the carrier. CONCLUSION(S): The fluorescence in situ hybridization analysis of meiotic segregation and aneuploidy helps to personalize the reproductive risk in carriers of balanced structural chromosomal aberrations. Complete information concerning the quality of spermatogenesis is necessary in all donors (both translocation carriers and controls) implicated in interchromosomal effect studies.
- MeSH
- Sex Chromosome Aberrations MeSH
- Aneuploidy MeSH
- Chromosome Inversion MeSH
- Adult MeSH
- Heterozygote MeSH
- Karyotyping MeSH
- Humans MeSH
- Chromosomes, Human, Pair 10 MeSH
- Chromosomes, Human, Pair 15 MeSH
- Chromosomes, Human, Y genetics MeSH
- Meiosis genetics MeSH
- Young Adult MeSH
- Chromosome Segregation physiology genetics MeSH
- Spermatozoa abnormalities metabolism MeSH
- Case-Control Studies MeSH
- Translocation, Genetic MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
- Keywords
- MagNA Pure System for DNA Extraction from Whole blood, Quiagen microcolumn-based extraction system,
- MeSH
- Biomedical Research MeSH
- Chromatography methods utilization MeSH
- DNA isolation & purification blood MeSH
- Polymerase Chain Reaction standards MeSH
- Reagent Kits, Diagnostic statistics & numerical data MeSH
- Publication type
- Evaluation Study MeSH
- Geographicals
- Czech Republic MeSH
