Miracle-dz/UniFAR-FTUs huggingface dataset:
Omeprazole as a CYP2C19 Marker in Chinese Subjects: Assessment of Its Gene‐Dose Effect and Intrasubject Variability

The objective of this study was to determine the reliability of omeprazole as a marker for CYP2C19 activity in Chinese subjects. In 27 healthy male Chinese subjects, the CYP2C19 phenotype was first determined with the standard mephenytoin hydroxylation index (HI) method. Subsequently, the subjects were randomized in a three‐way crossover manner to receive an oral 40‐mg dose from each of three omeprazole formulations (as part of a bioequivalence study). Multiple blood samples were obtained over 12 hours, and plasma concentrations of omeprazole, 5‐hydroxyomeprazole, and omeprazole sulfone were determined by a high‐performance liquid chromatography (HPLC) method. Individual CYP2C19 genotype was determined by the polymerase chain reaction/restriction fragment length polymorphism method. To assess the specificity for CYP2C19 activity, the hydroxylation metabolic ratio (MR) of omeprazole (AUComeprazole/AUC5‐hydroxyomeprazole) was compared to mephenytoin HI and related to CYP2C19 genotype status. The inter‐ and intrasubject variabilities of MR were also calculated, and their magnitudes were compared. The intersubject MR varied more than 20 fold. Among the subjects, there was a gene‐dose effect, and the mean MR was 1.76, 3.45, and 33.08, respectively, in the homozygous extensive metabolizers (wt/wt, n = 9), heterozygous extensive metabolizers (wt/m1 or wt/m2, n = 10), and poor metabolizers (m1/m1 or m1/m2, n = 7). However, the coefficients of variation for intrasubject MR only ranged from 4.5% to 33.7% over the three periods with the three formulations. The phenotype based on MR was concordant with HI. In view of the clear gene‐dose effect, concordance with mephenytoin HI, and low intrasubject variability, omeprazole MR following a 40‐mg oral dose can be considered as a specific and sensitive marker for CYP2C19 activity in Chinese subjects
Common mental disorders among civil aviation pilots.

INTRODUCTION The purpose of this study was to estimate the prevalence of suspected cases of common mental disorders (CMD) on Brazilian civil aviation pilots and to investigate associations between CMD, demographics, and labor variables. METHODS A quantitative cross-sectional study was conducted on 807 working pilots between October 2009 and October 2010 using a self-administered questionnaire to obtain sociodemographic data and information about workload. CMD prevalence was estimated with the Self-Reporting Questionnaire-20 items (SRQ-20). Multiple logistic regression was used in statistical data analyses. RESULTS The overall prevalence of CMD was 6.7% with the cutoff point of 8 used in this study, i.e., scores greater than or equal to 8 in SRQ-20 define positive cases. Using alternative cutoffs, the prevalence was 9.2% (cut off point 7) or 12% (cutoff point 6). Among the individuals who did not exercise, 10.2% presented suspected CMD. Among those with a heavy workload, 23.7% presented scores indicating suspected CMD. Only variables relating to workload and the practice of physical activity were significantly correlated with the estimate of CMD after multivariate analysis. Regular physical exercise afforded a possible protective effect against suspected cases of CMD, while there was a higher prevalence of suspected cases among subjects with heavy workloads. DISCUSSION The inclusion of the topic of mental health among the targets and priorities of civil aviation in Brazil is imperative. Addressing issues such as the regular practice of physical activity and workload can contribute to achieving a better balance between flight safety and productivity.
Fermentation pH Influences the Physiological-State Dynamics of Lactobacillus bulgaricus CFL1 during pH-Controlled Culture

ABSTRACT This study aims at better understanding the effects of fermentation pH and harvesting time on Lactobacillus bulgaricus CFL1 cellular state in order to improve knowledge of the dynamics of the physiological state and to better manage starter production. The Cinac system and multiparametric flow cytometry were used to characterize and compare the progress of the physiological events that occurred during pH 6 and pH 5 controlled cultures. Acidification activity, membrane damage, enzymatic activity, cellular depolarization, intracellular pH, and pH gradient were determined and compared during growing conditions. Strong differences in the time course of viability, membrane integrity, and acidification activity were displayed between pH 6 and pH 5 cultures. As a main result, the pH 5 control during fermentation allowed the cells to maintain a more robust physiological state, with high viability and stable acidification activity throughout growth, in opposition to a viability decrease and fluctuation of activity at pH 6. This result was mainly explained by differences in lactate concentration in the culture medium and in pH gradient value. The elevated content of the ionic lactate form at high pH values damaged membrane integrity that led to a viability decrease. In contrast, the high pH gradient observed throughout pH 5 cultures was associated with an increased energetic level that helped the cells maintain their physiological state. Such results may benefit industrial starter producers and fermented-product manufacturers by allowing them to better control the quality of their starters, before freezing or before using them for food fermentation.
Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma.

BACKGROUND The addition of cytokines to chemotherapy (CT) has obtained encouraging but contradictory results in metastatic melanoma. In this phase III trial, we compared the effects of CT [cisplatin, vindesine and dacarbazine (CVD)] with those of concurrent biochemotherapy (bioCT) consisting of CVD plus interleukin-2 and interferon-alpha2b. PATIENTS AND METHODS A total of 151 untreated metastatic melanoma patients were randomized, 75 on arm A (cisplatin 30 mg/m2 on days 1-3, vindesine 2.5 mg/m2 on day 1 and dacarbazine 250 mg/m2 on days 1-3), and 76 on arm B (same CVD scheme plus interferon-alpha2b on days 1-5 and interleukin-2 on days 1-5 and 8-15, both administered subcutaneously), either recycled every 3 weeks. Response was assessed every two cycles. RESULTS Ten percent of the patients were alive at a median of 52 months from start of therapy. We observed a response rate (RR) of 21% on arm A versus 33% on arm B; three patients (4%) given bioCT had complete responses (CRs). Median time to progression (TTP) was identical; median overall survival (OS) time was 12 months on arm A and 11 months on arm B. CONCLUSIONS BioCT is not better than CT alone; the trend in favor of the bioCT in terms of RR did not translate into better TTP or OS. Therefore, bioCT cannot be recommended as standard first-line therapy for metastatic melanoma.
A Cross Cultural Study on the Organizational Context of Process Redesign Initiatives: U.S. vs. Taiwan

Abstract In this study, we seek to better understand the organizational context of BPR in two different cultures: U.S. and Taiwan. The results showed remarkable consistency between the two countries and the differences may be interpreted by cultural differences. In both cultures, it was found that while factors related to IT competence may facilitate the decision to reengineer, they are not critical to project success. On the other hand, factors having significant relationships beyond the initial decision include variables pertaining to innovative capacity of the organization and Strategy-IS alignment. It appears that, to a large extent, the principles and mechanisms of organizations underlying modern business enterprises transcend cultural differences. If an organizational characteristic such as a higher level of interdepartmental integration is conducive to reengineering initiatives, it is so universally, regardless of certain differences in people's value systems in different national cultures.
KASH 'n Karry: The KASH domain family of cargo‐specific cytoskeletal adaptor proteins

A diverse family of proteins has been discovered with a small C‐terminal KASH domain in common. KASH domain proteins are localized uniquely to the outer nuclear envelope, enabling their cytoplasmic extensions to tether the nucleus to actin filaments or microtubules. KASH domains are targeted to the outer nuclear envelope by SUN domains of inner nuclear envelope proteins. Several KASH protein genes were discovered as mutant alleles in model organisms with defects in developmentally regulated nuclear positioning. Recently, KASH‐less isoforms have been found that connect the cytoskeleton to organelles other than the nucleus. A widened view of these proteins is now emerging, where KASH proteins and their KASH‐less counterparts are cargo‐specific adaptors that not only link organelles to the cytoskeleton but also regulate developmentally specific organelle movements. BioEssays 27:1136–1146, 2005. © 2005 Wiley Periodicals, Inc.
The impact of hypotension due to the trigeminocardiac reflex on auditory function in vestibular schwannoma surgery.

OBJECT Surgical manipulation of the fifth cranial nerve during its intra- or extracranial course may lead to bradycardia or even asystole as well as arterial hypotension, a phenomenon described as the trigeminocardiac reflex (TCR). The authors studied the impact of this reflex on postoperative auditory function in patients undergoing vestibular schwannoma (VS) surgery. METHODS One hundred patients scheduled for VS surgery were studied prospectively for parameters influencing the postoperative auditory function. The evaluation included sex, age, pre- and postoperative auditory function, preoperative mean arterial blood pressure, preoperative medical diseases or medication (for example, antiarrhythmia drugs), tumor size and localization, and the intraoperative occurrence of the TCR. The TCR, which occurred in 11% of the patients, influenced the postoperative hearing function in the patients with Hannover Class T3 and T4 VSs. With an overall hearing preservation of 47%, 11.1% of the patients in the TCR group and 51.4% of those in the non-TCR group experienced preserved hearing function postoperatively. In cases involving larger tumors (Hannover Class T3 and T4), an intraoperative TCR was associated with a significantly worse postoperative hearing function during VS surgery (p = 0.005). CONCLUSIONS The hypotension following TCR is a negative prognostic factor for hearing preservation in patients undergoing VS surgery. Patients' knowledge of this can be increased pre- and postoperatively. Further study of this phenomenon will advance the understanding of the underlying mechanisms and may help to improve hearing preservation by controlling the occurrence of the TCR.
The role of plasma lipid transfer proteins in lipoprotein metabolism and atherogenesis D.M. is supported by a grant from the Philippe Foundation. Published, JLR Papers in Press, November 20, 2008.

The plasma lipid transfer proteins promote the exchange of neutral lipids and phospholipids between the plasma lipoproteins. Cholesteryl ester transfer protein (CETP) facilitates the removal of cholesteryl esters from HDL and thus reduces HDL levels, while phospholipid transfer protein (PLTP) promotes the transfer of phospholipids from triglyceride-rich lipoproteins into HDL and increases HDL levels. Studies in transgenic mouse models and in humans with rare genetic deficiencies (CETP) or common genetic variants (CETP and PLTP) highlight the central role of these molecules in regulating HDL levels. Human CETP deficiency is associated with dramatic elevations of HDL cholesterol and apolipoprotein A-I levels, while PLTP variants with increased expression are associated with higher HDL levels. A recent meta-analysis suggests that common CETP alleles causing reduced CETP and increased HDL levels are associated with reduced coronary heart disease. The failure of a clinical trial with the CETP inhibitor torcetrapib may have been related in part to off-target toxicity. Ongoing phase 3 clinical trials with other CETP inhibitors may help to clarify if this strategy can ultimately be successful in the treatment of atherosclerosis.
Comparison of different kits in the detection of autoantibodies to cardiolipin and beta2glycoprotein 1.

OBJECTIVE To estimate the performance characteristics of 10 commercial kits and one in-house kit for the detection and quantification of anticardiolipin (aCL) (six kits) and anti-beta2glycoprotein 1 (anti-beta2GP1) (five kits) antibodies, and to evaluate the degree of variability between these different kits. METHODS We determined the presence of aCL and anti-beta2GP1 IgG and IgM antibodies in 67 sera from 62 patients and reviewed the data separately. Each serum sample was tested with six commercial aCL determination kits and with four commercial and one in-house anti-beta2GP1 determination kit. We then analysed the operating characteristics of each kit (sensitivity, specificity, positive and negative predictive values) and we analysed the absolute and 2 x 2 agreements. RESULTS The 62 patients included had primary antiphospholipid syndrome (APS) in 10 cases, secondary APS for eight, systemic lupus (SLE) for 23 and other diagnoses for the remaining 21. Operating characteristics differed from one kit to another. Good agreement was found using sensitive aCL determination kit and specific anti-beta2GP1 determination kit. Agreement between kits was medium for IgG aCL. 2 x 2 concordance studies showed a group of three aCL kits which were quite homogenous and showed that all anti-beta2GP1 kits formed quite a homogenous group. CONCLUSION A high degree of variability still persists for aCL antibody determination posing the question of the qualification of commercial or in-house kits and the question of standardization of results. A better concordance is found for high positive results. Good agreement exists for anti-beta2GP1 kits. aCL determination is still needed and should be complemented by anti-beta2GP1 determination.
Direct Role for Proliferating Cell Nuclear Antigen in Substrate Recognition by the E3 Ubiquitin Ligase CRL4Cdt2*

Background: CRL4Cdt2 requires that a substrate bind to proliferating cell nuclear antigen (PCNA) on DNA prior to ligase recruitment, but the precise role of PCNA is unclear. Results: A specific PCNA residue is required for destruction of CRL4Cdt2 substrates. Conclusion: CRL4Cdt2 recognizes a composite surface composed of PCNA and substrate residues. Significance: This is the first ubiquitin ligase whose substrate recognition requires creation of a bipartite substrate surface. The E3 ubiquitin ligase Cullin-ring ligase 4-Cdt2 (CRL4Cdt2) is emerging as an important cell cycle regulator that targets numerous proteins for destruction in S phase and after DNA damage, including Cdt1, p21, and Set8. CRL4Cdt2 substrates contain a “PIP degron,” which consists of a canonical proliferating cell nuclear antigen (PCNA) interaction motif (PIP box) and an adjacent basic amino acid. Substrates use their PIP box to form a binary complex with PCNA on chromatin and the basic residue to recruit CRL4Cdt2 for substrate ubiquitylation. Using Xenopus egg extracts, we identify an acidic residue in PCNA that is essential to support destruction of all CRL4Cdt2 substrates. This PCNA residue, which adjoins the basic amino acid of the bound PIP degron, is dispensable for substrate binding to PCNA but essential for CRL4Cdt2 recruitment to chromatin. Our data show that the interaction of CRL4Cdt2 with substrates requires molecular determinants not only in the substrate degron but also on PCNA. The results illustrate a potentially general mechanism by which E3 ligases can couple ubiquitylation to the formation of protein-protein interactions.
Role of cytokines as a double-edged sword in sepsis.

BACKGROUND Sepsis is a deadly immunological disorder and its pathophysiology is still poorly understood. We aimed to determine if specific pro-inflammatory and anti-inflammatory cytokines can be used as diagnostic and therapeutic targets for sepsis. MATERIALS AND METHODS Recent publications in the MEDLINE database were searched for articles regarding the clinical significance of inflammatory cytokines in sepsis. RESULTS In response to pathogen infection, pro-inflammatory cytokines [interleukin-6 (IL-6), IL-8, IL-18 and tumor necrosis factor-α (TNF-α)] and anti-inflammatory cytokine (IL-10) increased in patients with sepsis. Importantly, a decrease in IL-6 was associated with a better prognosis and overproduction of IL-10 was found to be the main predictor of severity and fatal outcome. CONCLUSION Both pro-inflammatory and anti-inflammatory cytokines constitute a double-edged sword in sepsis; on one hand they are critical to eliminate the infection while on the other, excessive production can cause tissue and organ damage. Increase in cytokines such as IL-6, Il-8, IL-10, IL-18 and TNF-α may have implications in diagnosis and treatment of sepsis.
Enzyme-linked immunosorbent assay and indirect immunofluorescence assay for Lyme disease.

The sensitivity and specificity of an indirect immunofluorescence assay (IFA) and ELISA for Lyme disease were estimated. Sera from patients with Lyme disease, patients with other infections, and healthy individuals were examined. Significant cross-reactivity occurred only with sera from patients with syphilis, yaws, and pinta . All tested sera from patients with Lyme disease, however, gave negative results in the rapid reagin screening test and the microhemagglutination assay for antibodies to Treponema pallidum confirmatory for syphilis. When sera from patients with treponemal diseases were excluded from the analysis, the IFA and ELISA were highly specific, having 97% and 100% reliability, respectively. Sensitivity of both tests varied with the stage of disease but was 100% for both tests during complicated Lyme disease. The results indicate that both tests are highly specific and sensitive for complicated Lyme disease but relatively insensitive for patients with erythema chronicum migrans alone.
Molecular Mechanism of Altered Ezetimibe Disposition in Nonalcoholic Steatohepatitis

Ezetimibe (EZE) lowers serum lipid levels by blocking cholesterol uptake in the intestine. Disposition of EZE and its pharmacologically active glucuronide metabolite (EZE-GLUC) to the intestine is dependent on hepatobiliary efflux. Previous studies suggested that hepatic transporter expression and function may be altered during nonalcoholic steatohepatitis (NASH). The purpose of the current study was to determine whether NASH-induced changes in the expression and function of hepatic transporters result in altered disposition of EZE and EZE-GLUC. Rats fed a methionine- and choline-deficient (MCD) diet for 8 weeks were administered 10 mg/kg EZE either by intravenous bolus or oral gavage. Plasma and bile samples were collected over 2 h followed by terminal urine and tissue collection. EZE and EZE-GLUC concentrations were determined by liquid chromatography-tandem mass spectrometry. The sinusoidal transporter Abcc3 was induced in MCD rats, which correlated with increased plasma concentrations of EZE-GLUC, regardless of dosing method. Hepatic expression of the biliary transporters Abcc2 and Abcb1 was also increased in MCD animals, but the biliary efflux of EZE-GLUC was slightly diminished, whereas biliary bile acid concentrations were unaltered. The cellular localization of Abcc2 and Abcb1 appeared to be internalized away from the canalicular membrane in MCD livers, providing a mechanism for the shift to plasma drug efflux. The combination of induced expression and altered localization of efflux transporters in NASH shifts the disposition profile of EZE-GLUC toward plasma retention away from the site of action. This increased plasma retention of drugs in NASH may have implications for the pharmacological effect and safety of numerous drugs.
Advanced Dementia Research in the Nursing Home: The CASCADE Study

Despite the growing number of persons with advanced dementia, and the need to improve their end-of-life care, few studies have addressed this important topic. The objectives of this report are to present the methodology established in the CASCADE (Choices, Attitudes, and Strategies for Care of Advanced Dementia at the End-of-Life) study, and to describe how challenges specific to this research were met. The CASCADE study is an ongoing, federally funded, 5-year prospective cohort study of nursing [nursing home (NH)] residents with advanced dementia and their health care proxies (HCPs) initiated in February 2003. Subjects were recruited from 15 facilities around Boston. The recruitment and data collection protocols are described. The demographic features, ownership, staffing, and quality of care of participant facilities are presented and compared to NHs nationwide. To date, 189 resident/HCP dyads have been enrolled. Baseline data are presented, demonstrating the success of the protocol in recruiting and repeatedly assessing NH residents with advanced dementia and their HCPs. Factors challenging and enabling implementation of the protocol are described. The CASCADE experience establishes the feasibility of conducting rigorous, multisite dementia NH research, and the described methodology serves as a detailed reference for subsequent CASCADE publications as results from the study emerge.
A Worksite Diabetes Prevention Program

The purpose of this study was to determine the 2-year impact of a worksite-based diabetes prevention program. Thirty-seven pre-diabetic and previously undiagnosed diabetic employees participating in a 12-month worksite diabetes prevention program were included. Weight, body mass index, waist circumference, oral glucose tolerance testing, fasting insulin, blood lipids, and aerobic fitness had improved significantly after 6 months. Much of this improvement continued through 12 months. One year following the intervention, oral glucose tolerance and aerobic fitness had improved significantly. Of the 22 employees remaining in the study through 24 months, more than half had normal results on glucose tolerance testing. Worksite diabetes prevention programs may reduce blood glucose below pre-diabetic and diabetic levels. Improvements in diabetes risk factors persisted for at least 2 years in most of these employees.
Early Experience of New Oral Anticoagulants for Stroke Prevention in Octogenarian Patients with Atrial Fibrillation

Background and Objectives: The safety of new oral anticoagulants (NOACs) depends largely on renal function. As renal function deteriorates with aging, the safety of NOACs is clinically important for very old cardiac patients. This study analyzed the efficacy and safety of NOACs prescribed to an octogenarian population in a university hospital. Subject and Methods: A total of 158 consecutive patients aged ≥80 years and who had been prescribed NOACs for non-valvular atrial fibrillation (54 patients on dabigatran, 104 patients on rivaroxaban) were included. Demographic features, laboratory findings, and clinical follow-up results were retrospectively reviewed. Results: Reduced doses were prescribed in 105 (66.2%) patients. The estimated GFR curve in octogenarian patients shifted left compared to that of patients aged <80 years. There were two strokes or systemic embolic events during the follow-up period of 276 days. Major bleeding occurred in 13 patients, where gastrointestinal bleeding and anemia of unknown origin were the major causes. Conclusion: NOACs seem to be highly effective for the prevention of stroke or systemic embolism in octogenarian populations. Bleeding events occurred in a considerable number of the study patients. Further studies on optimum dose ranges are required for very old subjects.