Miracle-dz/UniFAR-FTUs huggingface dataset:
Prediction of fraction metabolized via CYP3A in humans utilizing cryopreserved human hepatocytes from a set of 12 single donors

Abstract 1. It has previously been demonstrated that metabolism of drugs via a single enzymatic pathway, particularly CYP3A4, is associated with increased risk for drug-drug interactions (DDI). Quantitative experimental systems as well as integrated prediction models to assess such risk during the preclinical phase are highly warranted. 2. The present study was designed to systematically investigate the performance of human cryopreserved hepatocytes in suspension to predict fraction metabolized via CYP3A (fmCYP3A) by assessing the ketoconazole sensitive intrinsic clearance (CLint) for five prototypical CYP3A substrates with varying degree of CYP3A dependent CLint in twelve individual hepatocyte batches. 3. We demonstrate that in contrast to well predicted mean hepatic metabolic clearance (CLH) and mean fmCYP3A data, the variability in CYP3A contribution for compounds having multiple metabolic pathways cannot be predicted from inhibition experiments using ketoconazole as inhibitor. Instead, data in the present paper indicate that the variability is larger after inhibition of CYP3A for compounds having multiple metabolic pathways. 4. It is therefore recommended to estimate the average CLint and fmCYP3A for a given test compound in a series (n = 10) of individual human hepatocyte batches.
Respective role of uraemic toxins and myeloperoxidase in the uraemic state.

BACKGROUND In haemodialysis (HD) patients, advanced oxidation protein products (AOPP) were previously ascribed to oxidized plasma proteins, resulting mainly from increased myeloperoxidase (MPO) activity. The aim of the present study was to assess the mechanisms leading to the generation of AOPP during the course of chronic kidney disease including end-stage renal disease, with particular focus on AOPP and MPO characterization in the plasma at decreasing levels of kidney function. METHODS Phagocyte activation was evaluated by whole blood NADPH oxidase and MPO activities. In plasma, MPO protein concentration was quantified by ELISA and catalytic activity assayed by the spectrophotometric detection of phenol and 4-aminoantipyrine (AAP) co-oxidation in the presence of hydrogen peroxide (H(2)O(2)). RESULTS In HD patients, plasma AOPP concentration was linked to neutrophil oxidative activity. Such an association was not found in control subjects or predialysis patients, suggesting that in the latter, AOPP generation did not mainly result from MPO released by activated neutrophils. Similarly, plasma AOPP correlated with plasma MPO protein concentration in HD patients, but not in control subjects or predialysis patients, suggesting that in the latter AOPP did not predominantly result from MPO activity. This interpretation was supported by the observation of a greater degree of co-oxidation of phenol and AAP in the absence of H(2)O(2) in predialysis patients than in HD patients or control subjects. The contribution of MPO dramatically differed between predialysis and HD patients (2+/-5 vs 46+/-6%; P<0.001). CONCLUSION Our observations suggest that AOPP generation in predialysis patients mainly results from MPO-independent oxidation mechanisms.
Natural Foxp3+ regulatory T cells inhibit Th2 polarization but are biased toward suppression of Th17‐driven lung inflammation

nTregs prevent autoimmunity and modulate immune and inflammatory responses to foreign antigens. CD4+Foxp3+ nTregs from DO11.10 mice were expanded ex vivo, and their effectiveness in suppressing the development of lung inflammatory responses, elicited by differentiated CD4+ T cells following antigen inhalation, was examined. Effector DO11.10 CD4+ Th2 cells, when adoptively transferred into BALB/c mice that subsequently inhaled OVA, elicited a pronounced pulmonary, eosinophilic inflammation. Surprisingly, the cotransfer of expanded nTregs failed to suppress the Th2‐mediated airway inflammation. Nevertheless, expanded OVA‐specific CD4+Foxp3+ nTregs were highly effective at inhibiting the polarization of naïve CD4+ T cells into a Th2 phenotype. This suppression was reversed by an antibody to GITR but was not affected by the presence of the soluble OX40L. Further analysis revealed that although nTregs also failed to inhibit the lung neutrophilic inflammation induced by effector CD4+ Th1 cells, they markedly suppressed pulmonary inflammation elicited by CD4+ Th17 cells but not AHR. The suppression of the Th17‐mediated response was evident from a striking reduction in the proportion of OVA‐specific T cells expressing IL‐17 and the numbers of neutrophils present in the airways of Th17 recipient mice. Collectively, these results demonstrate that expanded nTregs clearly limit the Th2 polarization process and that Th17‐mediated inflammatory responses are particularly prone to the immunoregulatory properties of nTregs. These findings thus indicate that expanded nTregs are restrictive in their ability to suppress airway inflammatory processes and AHR.
Preventive effects of selected probiotic strains on the development of asthma and allergic rhinitis in childhood. The Panda study

Preventive effects of selected probiotic strains on the development of asthma and allergic rhinitis in childhood. The Panda study D. M. W. Gorissen, N. B. M. M. Rutten, C. M. J. Oostermeijer, L. E. M. Niers, M. O. Hoekstra, G. T. Rijkers and C. K. van der Ent Department of Pediatric Pulmonology and Allergology, Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, The Netherlands, Department of Pediatrics, Sint Antonius Hospital, Nieuwegein, The Netherlands, Department of Pediatrics, Deventer Ziekenhuis, Deventer, The Netherlands, Department of Pediatrics, Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, The Netherlands, Department of Pediatrics, University Medical Centre, Groningen, The Netherlands, Department of Sciences, University College Roosevelt Academy, Middelburg, The Netherlands and Department of Medical Microbiology and Immunology, St Antonius Hospital, Nieuwegein, The Netherlands
Biological characteristics of embryonic epicardial cells in vitro correlate with embryonic day

The epicardial cell (EpiC) culture system plays an important role in investigating the specific mechanisms and signaling molecules that are involved in the development of EpiCs. From this early formation until adulthood, EpiCs undergo dynamic changes in the expression of embryonic genes that correlate with changes in the embryonic EpiC properties. The differences of embryonic EpiC properties may affect the related results of experiments in which EpiC culture system is used; however, these differences have not been explored. Therefore, in this study we examined the differences in the biological characteristics of EpiCs on different embryonic days in vitro. EpiCs were isolated from embryonic ventricle explants on embryonic day (E) 11.5, E13.5, and E15.5. The differences in the migration, proliferation and differentiation were studied in EpiCs of different embryonic day by scratch assay, cell cycle analysis and platelet derived growth factor-bb (PDGF-BB) treatment. The results showed that EpiCs were successfully cultured from E11.5, E13.5, and E15.5 embryonic ventricle explants. The time windows of E11.5, E13.5, and E15.5 EpiC isolation out of the explants were different. The migration abilities of E11.5, E13.5, and E15.5 EpiCs decreased during embryonic development. Smooth muscle cell differentiation potential of early stage EpiCs was better than that of the later stage EpiCs. Although the proliferation ability of E11.5 EpiCs was significantly weaker than those of E13.5 and E15.5 EpiCs, the proliferation abilities of E13.5 and E15.5 EpiCs did not differ. These results suggest that the biological characteristics of EpiCs correlate with the timing of embryonic development, and different embryonic stage of ventricle should be properly chosen for culturing EpiCs depending on the purposes of the specific experiments.
Direct observation of extension and retraction of type IV pili

Type IV pili are thin filaments that extend from the poles of a diverse group of bacteria, enabling them to move at speeds of a few tenths of a micrometer per second. They are required for twitching motility, e.g., in Pseudomonas aeruginosa and Neisseria gonorrhoeae, and for social gliding motility in Myxococcus xanthus. Here we report direct observation of extension and retraction of type IV pili in P. aeruginosa. Cells without flagellar filaments were labeled with an amino-specific Cy3 fluorescent dye and were visualized on a quartz slide by total internal reflection microscopy. When pili were attached to a cell and their distal ends were free, they extended or retracted at rates of about 0.5 μm s−1 (29°C). They also flexed by Brownian motion, exhibiting a persistence length of about 5 μm. Frequently, the distal tip of a filament adsorbed to the substratum and the filament was pulled taut. From the absence of lateral deflections of such filaments, we estimate tensions of at least 10 pN. Occasionally, cell bodies came free and were pulled forward by pilus retraction. Thus, type IV pili are linear actuators that extend, attach at their distal tips, exert substantial force, and retract.
Finite Element Methods for the Simulation of Waves in Composite Saturated Poroviscoelastic Media

This work presents and analyzes a collection of finite element procedures for the simulation of wave propagation in a porous medium composed of two weakly coupled solids saturated by a single-phase fluid. The equations of motion, formulated in the space-frequency domain, include dissipation due to viscous interaction between the fluid and solid phases with a correction factor in the high-frequency range and intrinsic anelasticity of the solids modeled using linear viscoelasticity. This formulation leads to the solution of a Helmholtz-type boundary value problem for each temporal frequency. For the spatial discretization, nonconforming finite element spaces are employed for the solid phases, while for the fluid phase the vector part of the Raviart-Thomas-Nedelec mixed finite element space is used. Optimal a priori error estimates for global standard and hybridized Galerkin finite element procedures are derived. An iterative nonoverlapping domain decomposition procedure is also presented and convergence results are derived. Numerical experiments showing the application of the numerical procedures to simulate wave propagation in partially frozen porous media are presented.
Re-evaluating the treatment of nongonococcal urethritis: emphasizing emerging pathogens--a randomized clinical trial.

BACKGROUND Nongonococcal urethritis (NGU) is a common chlamydia-associated syndrome in men; however, Trichomonas vaginalis and Mycoplasma genitalium are associated with its etiology and should be considered in approaches to therapy. We sought to determine whether the addition of tinidazole, an anti-trichomonal agent, to the treatment regimen would result in higher cure rates than those achieved with treatment with doxycycline or azithromycin alone. A secondary aim was to compare the efficacy of doxycycline therapy and with that of azithromycin therapy. METHODS Randomized, controlled, double-blinded phase IIB trial of men with NGU. Participants were randomized to receive doxycycline plus or minus tinidazole or azithromycin plus or minus tinidazole and were observed for up to 45 days. RESULTS The prevalences of Chlamydia trachomatis, M. genitalium, and T. vaginalis were 43%, 31%, and 13%, respectively. No pathogens were identified in 29% of participants. Clinical cure rates at the first follow-up visit were 74.5% (111 of 149 patients) for doxycycline-containing regimens and 68.6% (107 of 156 patients) for azithromycin-containing regimens. By the final visit, cure rates were 49% (73 of 149 patients) for doxycycline-containing regimens and 43.6% (68 of 156 patients) for azithromycin-containing regimens. There were no significant differences in clinical response rates among the treatment arms. However, the chlamydia clearance rate was 94.8% (55 of 58 patients) for the doxycycline arm and 77.4% (41 of 53 patients) for the azithromycin arm (P = .011), and the M. genitalium clearance rate was 30.8% (12 of 39 patients) for the doxycycline arm and 66.7% (30 of 45 patients) for the azithromycin arm (P = .002). CONCLUSIONS Addition of tinidazole to the treatment regimen did not result in higher cure rates but effectively eradicated trichomonas. Clinical cure rates were not significantly different between patients treated with doxycycline and those treated with azithromycin; however, doxycycline had significantly better efficacy against Chlamydia, whereas azithromycin was superior to doxycycline for the treatment of M. genitalium.
When to use drugs to help sleep

Paediatric sleep medicine is a relatively new but important and rapidly growing field. It is increasingly recognised that many “adult” sleep disorders begin in childhood where the consequences of missed diagnoses can be devastating. Adequate training of all health care professionals and careful eliciting of symptoms remains the first step in ensuring accurate and timely diagnoses. Although behavioural approaches play a huge role in paediatric sleep medicine, at times severe sleep disorders also require pharmacological treatments. However, the evidence base for these is weak, and currently treatments of conditions including insomnia, narcolepsy and restless legs syndrome in childhood still rely on hopeful extrapolation from adult data. A growth in randomised controlled trials over the last 5 years is encouraging; trial methodologies are also improving. International working groups and multicentre trials will increasingly be needed to evaluate the new technologies and pharmacological treatments that are emerging.
Impact of Closed-suction Drain in Preperitoneal Space on the Incidence of Seroma Formation After Laparoscopic Total Extraperitoneal Inguinal Hernia Repair

Purpose To study the effect of closed suction drain in preperitoneal space on seroma formation after laparoscopic total extraperitoneal repair (TEP). Methods A closed suction drain-12G was put through the midline 5 mm port incision and removed with in 24 hours of operation in TEP repair. The results were compared with a group with TEP without any drain. Results In 929 patients (1753 hernias), drain was put in 849 patients (1607 hernias) and no drain was put in 80 patients (146 hernias). Follow-up ranged from 9 to 45 months. Seroma formation was significantly lower in the drain group (12/1607; 0.75%) compared with the nondrain group (22/146; 15.1%) (P<0.0001). Both the groups were comparable in pain scores, conversion to open, hospital stay, and days taken to return to normal activity and recurrence rates. There was no infection in either group Conclusions Drain after TEP significantly reduces the incidence of seroma formation without increasing the risk of infection or recurrence.
The 15q24/25 susceptibility variant for lung cancer and chronic obstructive pulmonary disease is associated with emphysema.

RATIONALE Genome-wide association studies have identified genetic variants in the nicotinic acetylcholine receptor (nAChR) on chromosome 15q24/25 as a risk for nicotine dependence, lung cancer, and chronic obstructive pulmonary disease (COPD). Assessment of bronchial obstruction by spirometry, typically used for diagnosing COPD, fails, however, to detect emphysema. OBJECTIVES To determine the association of the 15q24/25 locus with emphysema. METHODS The rs1051730 variant on 15q24/25 was genotyped in two independent white cohorts of 661 and 456 heavy smokers. Participants underwent pulmonary function tests and computed tomography (CT) of the chest, and took questionnaires assessing smoking behavior and health status. MEASUREMENTS AND MAIN RESULTS The rs1051730 A-allele correlated with reduced FEV(1) and with increased susceptibility for bronchial obstruction with a pooled odds ratio (OR) of 1.33 (95% confidence interval [CI] = 1.11-1.61; P = 0.0026). In both studies a correlation between the rs1051730 A-allele and lung diffusing capacity (Dl(CO)) and diffusing capacity per unit alveolar volume (Kco) was observed. Consistently, the rs1051730 A-allele conferred increased risk for emphysema as assessed by CT (P = 0.0097 and P = 0.019), with a pooled OR of 1.39 (CI = 1.15-1.68; P = 0.00051). Visual emphysema scores and scores based on densities quantified on CT were more pronounced in A-allele carriers, indicating that rs1051730 correlates with the severity of emphysema. CONCLUSIONS The 15q24/25 locus in nAChR is associated with the presence and severity of emphysema. This association was independent of pack-years smoking, suggesting that nAChR is causally involved in alveolar destruction as a potentially shared pathogenic mechanism in lung cancer and COPD.
Glial cell-derived neurotrophic factor independent ureteric bud outgrowth from the Wolffian duct.

The kidney collecting duct system and the ureter derive from the ureteric bud, an outgrowth of the Wolffian duct. It is generally believed that glial cell–derived neurotrophic factor (GDNF) plays a critical role in this earliest stage of kidney development, but 30 to 50% of knockout mice that lack
Design and analysis of non‐inferiority mortality trials in oncology

The recent revision of the Declaration of Helsinki and the existence of many new therapies that affect survival or serious morbidity, and that therefore cannot be denied patients, have generated increased interest in active‐control trials, particularly those intended to show equivalence or non‐inferiority to the active‐control. A non‐inferiority hypothesis has historically been formulated in terms of a fixed margin. This margin was historically designed to exclude a ‘clinically meaningful difference’, but has become recognized that the margin must also be no larger than the assured effect of the control in the new study. Depending on how this ‘assured effect’ is determined or estimated, the selected margin may be very small, leading to very large sample sizes, especially when there is an added requirement that a loss of some specified fraction of the assured effect must be ruled out. In cases where it is appropriate, this paper proposes non‐inferiority analyses that do not involve a fixed margin, but can be described as a two confidence interval procedure that compares the 95 per cent two‐sided CI for the difference between the treatment and the control to a confidence interval for the control effect (based on a meta‐analysis of historical data comparing the control to placebo) that is chosen to preserve a study‐wide type I error rate of about 0.025 (similar to the usual standard for a superiority trial) for testing for retention of a prespecified fraction of the control effect. The approach assumes that the estimate of the historical active‐control effect size is applicable in the current study. If there is reason to believe that this effect size is diminished (for example, improved concomitant therapies) the estimate of this historical effect could be reduced appropriately. The statistical methodology for testing this non‐inferiority hypothesis is developed for a hazard ratio (rather than an absolute difference between treatments, because a hazard ratio seems likely to be less population dependent than the absolute difference). In the case of oncology, the hazard ratio is the usual way of comparing treatments with respect to time to event (time to progression or survival) endpoints. The proportional hazards assumption is regarded as reasonable (approximately holding). The testing procedures proposed are conditionally equivalent to two confidence interval procedures that relax the conservatism of two 95 per cent confidence interval testing procedures and preserve the type I error rate at a one‐sided 0.025 level. An application of this methodology to Xeloda, a recently approved drug for the treatment of metastatic colorectal cancers, is illustrated. Other methodologies are also described and assessed – including a point estimate procedure, a Bayesian procedure and two delta‐method confidence interval procedures. Published in 2003 by John Wiley & Sons, Ltd.
Lateral infraclavicular plexus block vs. axillary block for hand and forearm surgery

Background: In the last few years infraclavicular plexus block has become a method of increasing interest. However, this block has been associated with high complication incidences and without advantage in the quality of blockade over the axillary approach. We prospectively studied 40 patients (ASA I–III) undergoing surgery of the forearm and hand, and investigated the performance of the lateral infraclavicular plexus block against an axillary paravascular block to evaluate the success rate as well as the extent and quality of blockade.
Production of Serum-free and Total Prostate-specific Antigen Due to Prostatic Intraepithelial Neoplasia

Objective: High serum total prostate-specific antigen (PSA) levels have proven to be predictive of concurrent cancer but the role of prostatic intraepithelial neoplasia (PIN) in the production of total (t) and free (f) PSA is still the subject of research. In this study we wanted to discover whether variations in serum fPSA and tPSA levels are caused by PIN. Material and Methods: We reviewed the medical records of 87 patients: in 32 of them the diagnosis of isolated PIN was made from surgical samples (simple prostatectomy, n = 19; radical cystectomy, n = 13); in 30 patients a diagnosis of benign prostatic hyperplasia (BPH) without PIN or prostatic carcinoma was made after simple prostatectomy ( n = 20) or radical cystectomy ( n = 10); and in 25 patients a clinically significant prostatic cancer was diagnosed and these patients underwent radical prostatectomy. All patients underwent a standard preoperative evaluation, including serum fPSA and tPSA determinations and PSA density. Results: The frequency of isolated PIN in simple prostatectomy specimens was 6.3%. The mean f/t PSA ratios were 17.66% in the 32 patients with PIN, 19.2% in the 8 patients with low-grade PIN, 17.6% in the 24 patients with high-grade PIN, 24.2% in patients with BPH and 13% in patients who underwent radical prostatectomy. Conclusions: We believe that to make a definitive diagnosis of isolated PIN without carcinoma, study of the whole prostate gland is necessary, in order to definitively exclude the presence of concurrent neoplastic foci. Our data show that PIN does not contribute to tPSA levels and density; however, it may be responsible for a slight reduction in the f/t PSA ratio, with a significant reduction in cases with high-grade PIN (17.6%) compared to those with BPH (24.2%).