INTRODUCTION: The maternal part of the rodent placenta harbors a circadian clock which robustly responds to glucocorticoids, however, its sensitivity to other hormones has not been elucidated. In this study, we tested five selected hormones (dopamine, melatonin, insulin, leptin and ghrelin) for their effectiveness to affect the clock in decidual region of mouse placenta in vitro. METHODS: We administered the hormones or corresponding vehicles at various time points over 24 h to organotypic placental explants of mPer2Luc mice containing the decidua basalis (DB) region and monitored their effects on amplitude, period, median expression level (mesor) and phase of PER2-driven bioluminescence rhythms. RESULTS: Dopamine significantly increased the amplitude, robustly dampened the mesor, and during a narrow time interval (corresponding to daytime) induced phase delays of the rhythms. In contrast, melatonin had no effect on amplitude, but induced phase advances of the rhythms at the opposite time window than dopamine (corresponding to nighttime). Leptin and ghrelin, but not insulin, slightly increased amplitudes and moderately modulated phase delays of the clock, suggesting that the DB clock, in contrast to other peripheral clocks, is rather resilient to abrupt changes in levels of feeding- and metabolism-related hormones. DISCUSSION: The results demonstrate for the first time that dopamine and melatonin exhibit delicate yet specific effects on parameters of the DB clock and may thus potentially contribute to fine-tuning of its phase under in vivo conditions. It also implies that dysregulation of their levels, which accompany various pathologies, may account for malfunction of the clock in DB.

• MeSH
• cirkadiánní hodiny * MeSH
• cirkadiánní rytmus * MeSH
• dopamin fyziologie   MeSH
• hormony fyziologie   MeSH
• myši MeSH
• placenta metabolismus   MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Determination of RNA structural-dynamic properties is challenging for experimental methods. Thus, atomistic molecular dynamics (MD) simulations represent a helpful technique complementary to experiments. However, contemporary MD methods still suffer from limitations of force fields (ffs), including imbalances in the nonbonded ff terms. We have recently demonstrated that some improvement of state-of-the-art AMBER RNA ff can be achieved by adding a new term for H-bonding called gHBfix, which increases tuning flexibility and reduces risk of side-effects. Still, the first gHBfix version did not fully correct simulations of short RNA tetranucleotides (TNs). TNs are key benchmark systems due to availability of unique NMR data, although giving too much weight on improving TN simulations can easily lead to overfitting to A-form RNA. Here we combine the gHBfix version with another term called tHBfix, which separately treats H-bond interactions formed by terminal nucleotides. This allows to refine simulations of RNA TNs without affecting simulations of other RNAs. The approach is in line with adopted strategy of current RNA ffs, where the terminal nucleotides possess different parameters for terminal atoms than the internal nucleotides. Combination of gHBfix with tHBfix significantly improves the behavior of RNA TNs during well-converged enhanced-sampling simulations using replica exchange with solute tempering. TNs mostly populate canonical A-form like states while spurious intercalated structures are largely suppressed. Still, simulations of r(AAAA) and r(UUUU) TNs show some residual discrepancies with primary NMR data which suggests that future tuning of some other ff terms might be useful. Nevertheless, the tHBfix has a clear potential to improve modeling of key biochemical processes, where interactions of RNA single stranded ends are involved.

• MeSH
• konformace nukleové kyseliny MeSH
• lidé MeSH
• nukleotidy chemie   MeSH
• RNA chemie   MeSH
• simulace molekulární dynamiky normy   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: The aim of this study was to develop a simple and reliable method for the objective assessment of visual acuity by optimizing the stimulus used in commercially available systems and by improving the methods of evaluation using a nonlinear function, the modified Ricker model. METHODS: Subjective visual acuity in the normal subjects was measured with Snellen targets, best-corrected, and in some cases also uncorrected and with plus lenses (+ 1 D, + 2 D, + 3 D). In patients, subjective visual acuity was measured best-corrected using the Freiburg Visual Acuity Test. Sweep VEP recordings to 11 spatial frequencies, with check sizes in logarithmically equidistant steps (0.6, 0.9, 1.4, 2.1, 3.3, 4.9, 7.3, 10.4, 18.2, 24.4, and 36.5 cpd), were obtained from 56 healthy subjects aged between 17 and 69 years (mean 42.5 ± 15.3 SD years) and 20 patients with diseases of the lens (n = 6), retina (n = 8) or optic nerve (n = 6). The results were fit by a multiple linear regression (2nd-order polynomial) or a nonlinear regression (modified Ricker model) and parameters compared (limiting spatial frequency (sflimiting) and the spatial frequency of the vertex (sfvertex) of the parabola for the 2nd-order polynomial fitting, and the maximal spatial frequency (sfmax), and the spatial frequency where the amplitude is 2 dB higher than the level of noise (sfthreshold) for the modified Ricker model. RESULTS: Recording with 11 spatial frequencies allows a more accurate determination of acuities above 1.0 logMAR. Tuning curves fitted to the results show that compared to the normal 2nd-order polynomial analysis, the modified Ricker model is able to describe closely the amplitudes of the sweep VEP in relation to the spatial frequencies of the presented checkerboards. In patients with a visual acuity better than about 0.5 (decimal), the predicted acuities based on the different parameters show a good match of the predicted visual acuities based on the models established in healthy volunteers to the subjective visual acuities. However, for lower visual acuities, both models tend to overestimate the visual acuity (up to ~ 0.4 logMAR), especially in patients suffering from AMD. CONCLUSIONS: Both models, the 2nd-order polynomial and the modified Ricker model performed equally well in the prediction of the visual acuity based on the amplitudes recorded using the sweep VEP. However, the modified Ricker model does not require the exclusion of data points from the fit, as necessary when fitting the 2nd-order polynomial model making it more reliable and robust against outliers, and, in addition, provides a measure for the noise of the recorded results.

• MeSH
• dospělí MeSH
• elektroretinografie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoci oční čočky patofyziologie   MeSH
• nemoci retiny patofyziologie   MeSH
• nemoci zrakového nervu patofyziologie   MeSH
• senioři MeSH
• statistické modely MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• zraková ostrost fyziologie   MeSH
• zrakové evokované potenciály fyziologie   MeSH
• zrakové testy metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The European Influenza Surveillance Scheme is a collaboration with 18 member countries (2001/02) which monitors the activity and impact of influenza by collecting morbidity and virological data in primary care facilities throughout the winter season each year. Despite being in principle similar in the surveillance concept, the indicators used and observations made are very different. Different healthcare systems and organisational needs (eg a certificate of illness for the employer) influence the consultation behaviour. Furthermore, and partly as a result of differences in the healthcare systems, the definitions used for the numerator and denominator when calculating morbidity rates are different. Thus comparative interpretation of participating countries' morbidity data is extremely difficult. Reporting 'harmonisation' by using equivalent numerators and denominators is one option but is difficult to achieve in the short term. Moreover, several additional issues would need to be considered, for example, the need for continuity of surveillance and whether such steps would indeed result in direct comparability etc. A simple index was tested, through which the impact of influenza morbidity in any one year is compared with what is considered a 'usual' epidemic in that country. The index in principle describes numerically the extent to which the influenza-attributable excess morbidity in the current epidemic in each country is within, exceeds, or is less than a range typical for an influenza epidemic. In this pilot study, the usefulness of such an index is explored with the example of eight countries for the seasons 1999/2000 and 2000/01. A fine tuning of the methods has not yet been performed.

• MeSH
• časoprostorové shlukování MeSH
• chřipka lidská epidemiologie   MeSH
• epidemický výskyt choroby statistika a číselné údaje   MeSH
• lidé MeSH
• morbidita trendy   MeSH
• pilotní projekty MeSH
• statistické modely MeSH
• surveillance populace metody   MeSH
• virus chřipky A klasifikace   izolace a purifikace   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• srovnávací studie MeSH
• Geografické názvy
• Anglie MeSH
• Belgie MeSH
• Česká republika MeSH
• Francie MeSH
• Německo MeSH
• Nizozemsko MeSH
• Švýcarsko MeSH

Recent advances in polarizable force fields have revealed that major reparameterization is necessary when the polarization energy is treated explicitly. This study is focused on the torsional parameters, which are crucial for the accurate description of conformational equilibria in biomolecules. In particular, attention is paid to the influence of polarization on the (i) transferability of dihedral terms between molecules, (ii) transferability between different environments, and (iii) additivity of dihedral energies. To this end, three polarizable force fields based on the induced point dipole model designed for use in AMBER are tested, including two recent ff02 reparameterizations. Attention is paid to the contributions due to short range interactions (1-2, 1-3, and 1-4) within the four atoms defining the dihedral angle. The results show that when short range 1-2 and 1-3 polarization interactions are omitted, as for instance in ff02, the 1-4 polarization contribution is rather small and unlikely to improve the description of the torsional energy. Conversely, when screened 1-2 and 1-3 interactions are included, the polarization contribution is sizeable and shows potential to improve the transferability of parameters between different molecules and environments as well as the additivity of dihedral terms. However, to reproduce intramolecular polarization effects accurately, further fine-tuning of the short range damping of polarization is necessary.

• MeSH
• ethylendichloridy chemie   MeSH
• halogenace MeSH
• kvantová teorie MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• rozpouštědla chemie   MeSH
• statická elektřina MeSH
• termodynamika MeSH
• voda chemie   MeSH
• Publikační typ
• časopisecké články MeSH

V roce 2009 americká FDA po zdlouhavém registračním procesu schválila nové antipsychotikum iloperidon. Iloperidon má vysokou afinitu k serotoninovým 5-HT2a a dopaminovým D2 receptorům. Dále působí jako antagonista na 5-HT2c a 5-HT6 a parciální agonista na 5-HTla receptorech, má vysokou afinitu k dopaminovým D3 a střední k D4 receptorům, vysokou vazbu kala střední k a2c adrenoreceptorům, nízkou k histaminovým Hla zanedbatelnou vazbu k muskarinovým receptorům. Antipsychotickou účinnost prokázal v krátkodobých placebem kontrolovaných studiích se schizofrenií. . V dlouhodobých studiích prevence relapsu byla jeho účinnost srovnatelná s haloperidolem. Doporučená denní účinná dávka je 12-24 mg. Nejčastěji popisovanými nežádoucími účinky byly přechodná ortostatická hypotenze, zejména v prvním týdnu léčby, prodloužení QTc intervalu, závratě, bolesti hlavy, sucho v ústech a nespavost, vše závislé na dávce. Ve srovnání s haloperidolem a risperidonem iloperidon vykazoval méně EPS a akatizie, váhový přírůstek v průběhu šesti týdnů byl obdobný jako u risperidonu, minimálně ovlivňuje biochemické parametry. Iloperidon byl testován pro genetické biomarkery Účinnosti a bezpečnosti. Vazebné studie genomu identifikovaly šest jednotlivých nukleotidových polymorfizmu (SNP) spojených s jeho ucmnosti a šest SNP definujících genotypy s nízkým a vysokým rizikem prodloužení QT intervalu. Tato data je nutné dále replikovat. Iloperidon je dalším představitelem atypického antipsychotika SDA typu, přičemž jeho farmakogenetika navíc nabízí možnost individualizace terapie, cíleného podání potenciálním respondérům a minimalizaci nežádoucích účinků.

In 2009, following lengthy registration process, the US FDA approved new antipsychotic iloperidone. Iloperidone has a high affi nity to serotonin 5-HT2a and dopamine D2 receptors. It is an antagonist of 5-HT2c and 5-HT6 and partial agonist of 5-HT1a, with high affinity to dopamine D3 and moderate to D4 receptors, high affinity to α 1 and moderate to α 2c adrenoreceptors, low to histamine H1 and minimal to muscarine receptors. Antipsychotic efficacy was shown in acute placebo-controlled trials of schizophrenia. Long- term relapse prevention studies demonstrated efficacy comparable to that of haloperidol. The recommended effective daily dose is 12– 24 mg. The most frequently reported side effects were transitory orthostatic hypotension, especially during the first week of treatmen t, QTc interval prolongation, dizziness, headache, dry mouth, and insomnia, all dose-dependent. Comparing to haloperidol and risperido ne, iloperidone was associated with a low risk of EPS and akathisia. Weight gain in six weeks was similar to that observed in rispe ridone, it has minimal adverse impact on biochemical parameters. Iloperidone was tested for genetic biomarkers of efficacy and safety. Whole- genome association studies identified six single nucleotide polymorphisms (SNP) associated with its antipsychotic effects and s ix SNP that defined genotypes with low and high risk of QT interval prolongation. This data has to be further replicated. Iloperidone represents another SDA-like atypical antipsychotic; nevertheless, its pharmacogenetics may be an opportunity for individualized treatment, tailored administration to potential responders and minimization of side effects.

• MeSH
• antipsychotika farmakologie   škodlivé účinky   terapeutické užití   MeSH
• farmakogenetika MeSH
• financování organizované MeSH
• hodnocení léčiv MeSH
• isoxazoly farmakokinetika   farmakologie   terapeutické užití   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• piperidiny farmakokinetika   farmakologie   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• schizofrenie farmakoterapie   MeSH
• syndrom dlouhého QT chemicky indukované   MeSH
• Check Tag
• lidé MeSH

Srdeční resynchronizační terapie (CRT) se stala velkou nadějí pro pacienty a efektivní léčbou srdečního selhání. Nicméně ne všichni pacienti na resynchronizační terapii dobře zareagují. Nutno definovat, jak tyto pacienty odlišíme a označíme je za nonrespondéry CRT. U nonrespondérů CRT musíme zejména zajistit adekvátní množství levokomorové stimulace, dále pak vyladění technických parametrů CRT, jako je např. velmi diskutované nastavení optimálního atrioventrikulárního zpoždění. Každopádně do managementu nonrespondérů CRT zahrnujeme také nastavení optimální medikamentózní terapie srdečního selhání a v indikovaných případech přistoupení k provedení srdeční transplantace.

Cardiac resynchronization therapy (CRT) has become a big hope and an effective treatment option for patients with heart failure. Nevertheless, not all of them respond well to CRT. It is necessary to define this group of patients and identify them as non‑responders. For CRT non‑responders it is primarily necessary to arrange for adequate left ventricular stimulation as well as CRT technical parameter tuning, such as the much‑discussed atrioventricular delay optimization. Either way, the management of CRT non‑responders also includes optimal medical therapy of heart failure and, in some indicated cases, also heart transplant.

• MeSH
• kardiostimulace umělá * MeSH
• lidé MeSH
• neúspěšná terapie MeSH
• srdeční resynchronizační terapie * metody   MeSH
• výsledek terapie * MeSH
• Check Tag
• lidé MeSH

Inhalation is used for local therapy of the lungs and as an alternative route for systemic drug delivery. Modern powder inhalation systems try to target the required site of action/absorption in the respiratory tract. Large porous particles (LPPs) with a size >5 μm and a low mass density (usually measured as bulk or tapped) of <0.4 g/cm3 can avoid protective lung mechanisms. Their suitable aerodynamic properties make them perspective formulations for deep lung deposition. This experiment studied the effect of spray-drying process parameters on LPP properties. An experimental design of twelve experiments with a central point was realized using the Box-Behnken method. Three process parameters (drying temperature, pump speed, and air speed) were combined on three levels. Particles were formed from a D-mannitol solution, representing a perspective material for lung microparticles. The microparticles were characterized in terms of physical size (laser diffraction), aerodynamic diameter (aerodynamic particle sizer), morphology (SEM), and densities. The novelty and main goal of this research were to describe how the complex parameters of the spray-drying process affect the properties of mannitol LPPs. New findings can provide valuable data to other researchers, leading to the easy tuning of the properties of spray-dried particles by changing the process setup.

• Publikační typ
• časopisecké články MeSH

For most patients, the HIV viral load can be made undetectable by highly active antiretroviral treatments highly active antiretroviral therapy: the virus, however, cannot be eradicated. Thus, the major problem is to try to reduce the side effects of the treatment that patients have to take during their life time. We tackle the problem of monitoring the treatment dose, with the aim of giving the minimum dose that yields an undetectable viral load. The approach is based on mechanistic models of the interaction between virus and the immune system. It is shown that the "activated cells model," allows making good predictions of the effect of dose changes and, thus, could be a good basis for treatment monitoring. Then, we use the fact that in dynamical models, there is a nontrivial equilibrium point, that is with a virus load larger than zero, only if the reproductive number R(0) is larger than one. For reducing side effects, we may give a dose just above the critical dose corresponding to R(0) equal to 1. A prior distribution of the parameters of the model can be taken as the posterior arising from the analysis of previous clinical trials. Then the observations for a given patient can be used to dynamically tune the dose so that there is a high probability that the reproductive number is below one. The advantage of the approach is that it does not depend on a cost function, weighing side effects and efficiency of the drug. It is shown that it is possible to approach the critical dose if the model is correct. A sensitivity analysis assesses the robustness of the approach.

• MeSH
• algoritmy MeSH
• biologické modely MeSH
• biometrie MeSH
• CD4-pozitivní T-lymfocyty účinky léků   imunologie   virologie   MeSH
• HIV infekce farmakoterapie   imunologie   virologie   MeSH
• klinické zkoušky jako téma statistika a číselné údaje   MeSH
• látky proti HIV aplikace a dávkování   škodlivé účinky   MeSH
• lidé MeSH
• modely imunologické MeSH
• monitorování léčiv statistika a číselné údaje   MeSH
• statistické modely * MeSH
• virová nálož účinky léků   MeSH
• vysoce aktivní antiretrovirová terapie * škodlivé účinky   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Detection of grapes in real-life images is a serious task solved by researchers dealing with precision viticulture. In the case of white wine varieties, grape detectors based on SVMs classifiers, in combination with a HOG descriptor, have proven to be very efficient. Simplified versions of the detectors seem to be the best solution for practical applications. They offer the best known performance versus time-complexity ratio. As our research showed, a conversion of RGB images to grayscale format, which is implemented at an image preprocessing level, is ideal means for further improvement of performance of the detectors. In order to enhance the ratio, we explored relevance of the conversion in a context of a detector potential sensitivity to a rotation of berries. For this purpose, we proposed a modification of the conversion, and we designed an appropriate method for a tuning of such modified detectors. To evaluate the effect of the new parameter space on their performance, we developed a specialized visualization method. In order to provide accurate results, we formed new datasets for both tuning and evaluation of the detectors. Our effort resulted in a robust grape detector which is less sensitive to image distortion.

• MeSH
• rotace MeSH
• support vector machine * MeSH
• víno analýza   MeSH
• Vitis * MeSH
• Publikační typ
• časopisecké články MeSH