Miracle-dz/UniFAR-FTUs huggingface dataset:
Accentuated decrease in social interaction in rats subjected to repeated ethanol withdrawals.

BACKGROUND Previous work has shown that repeated withdrawals from chronic ethanol exposure can kindle seizures in rodents. In this article, the effects of a three-cycle model of ethanol exposure and withdrawal on the social interaction test of anxiety are summarized. METHODS Rats were exposed to ethanol (7% or 4.5%) diets over three periods of 5 days, with 2 days of withdrawal between cycles. Between 5 and 6 hr after the ethanol was removed, pairs of rats were placed in open field chambers for the assessment of social interaction behavior and locomotor activity. RESULTS After the third cycle of ethanol (7%) presentation, both male and female rats exhibited lower social interaction behavior (more anxiety) and activity than after a single cycle. Rats exposed to a similar amount of ethanol but tested while ethanol was still available did not exhibit a reduction in social interaction. The decrease in social interaction was still present for up to 24 hr but had disappeared by 48 hr after ethanol was withdrawn. When rats were allowed 8 or 16 days to recover from the effects of the three-cycle protocol, a further exposure to 5 days of 7% ethanol diet resulted in a reduction in social interaction on withdrawal similar to that seen from the three-cycle protocol. In contrast, rats exposed continuously to 7% ethanol diet for 15 consecutive days exhibited higher levels of social interaction when maintained on control diet for 8 or 16 days and then reexposed to ethanol. Rats that were exposed to the three-cycle protocol and allowed 32 days to recover before being reexposed to ethanol still had a partial deficit in social interaction. Finally, animals subjected to repeated withdrawals from 4.5% ethanol exhibited a reduction in social interaction without a change in activity after the final withdrawal from ethanol, whereas rats exposed continuously to a 4.5% ethanol diet did not exhibit a reduction in social interaction or activity. Neither blood ethanol concentrations nor changes in body weight could account for these behavioral differences. CONCLUSION Repeated withdrawal from ethanol can lead to accentuated or more persistent anxiety-like behavior in rats, as indicated by a decrease in social interaction. The withdrawal-induced decrease in locomotor activity is not accentuated by repeated withdrawals. This model of repeated withdrawals from ethanol may prove useful in defining the neurochemical basis of this accentuation.
Controlling false discoveries in genetic studies

A false discovery occurs when a researcher concludes that a marker is involved in the etiology of the disease whereas in reality it is not. In genetic studies the risk of false discoveries is very high because only few among the many markers that can be tested will have an effect on the disease. In this article, we argue that it may be best to use methods for controlling false discoveries that would introduce the same ratio of false discoveries divided by all rejected tests into the literature regardless of systematic differences between studies. After a brief discussion of traditional “multiple testing” methods, we show that methods that control the false discovery rate (FDR) may be more suitable to achieve this goal. These FDR methods are therefore discussed in more detail. Instead of merely testing for main effects, it may be important to search for gene–environment/covariate interactions, gene–gene interactions or genetic variants affecting disease subtypes. In the second section, we point out the challenges involved in controlling false discoveries in such searches. The final section discusses the role of replication studies for eliminating false discoveries and the complexities associated with the definition of what constitutes a replication and the design of these studies. © 2007 Wiley‐Liss, Inc.
Coexpression of functional P2X and P2Y nucleotide receptors in single cerebellar granule cells

The present study describes the presence and expression of functional nucleotide receptors, both ionotropic and metabotropic, in highly purified cultures of cerebellar granule neurons. Microfluorimetric experiments have been carried out to record specific [Ca2+]i transients in individual granule neurons after challenge with diverse nucleotides. Although great heterogeneity was found in nucleotide responses in single cells, these responses all became modified during the course of granule cell differentiation, not only at the level of the number of responding cells, but also in the magnitude of the response to nucleotides. These in vitro developmental changes were more significant in metabotropic responses to pyrimidine nucleotides, UTP and UDP, which were down‐ and upregulated, respectively, during the time in culture. At least two types of ADP‐specific receptors seem expressed in different granule cell subpopulations responding to 2MeSADP, as the specific P2Y1 antagonist MRS‐2179 inhibited Ca2+ responses in only one of these populations. The great diversity of metabotropic responses observed was confirmed by the RT‐PCR expression of different types of P2Y receptors in granule cell cultures: P2Y1, P2Y4, P2Y6, and P2Y12. Similarly, ionotropic nucleotide responses were confirmed by the presence of specific messengers for different P2X subunits, and by immunolabeling studies (P2X1, P2X2, P2X3, P2X4 and P2X7). Immunolabeling reflected great variety in the P2X subunit distribution along the granule neuron cytoarchitecture, with P2X2, P2X3 and P2X4 present at somatodendritic locations, and P2X1, P2X7, and P2X3, located at the axodendritic prolongations. The punctuated labeling pattern obtained for P2X3 and P2X7 subunits is particularly notable, as it presents a high degree of colocalization with synaptophysin, a specific marker of synaptic vesicles, suggesting specialized localization and function in granule neurons. © 2003 Wiley‐Liss, Inc.
Chromatin‐associated sphingomyelin: metabolism in relation to cell function

After the first histochemical demonstration by Chayen and Gahan of the presence of phospholipids and especially of sphingomyelin in chromatin, this became the object of long debate and of contradictory results. The general conclusion was that the presence of phospholipids may due to contamination during the isolation of chromatin. More recently the existence of a phospholipid chromatin fraction was confirmed by demonstrating that isolated hepatocyte nuclei, labelled by saturated and unsaturated radioiodination method, showed the presence of radioactivity only in the membrane and not in the isolated chromatin. The phospholipid composition showed an enrichment in sphingomyelin which increased during hepatocyte maturation or erythroleukemic cell differentiation induced by DMSO. A decrease in sphingomyelin was observed at the beginning of the S‐phase in regenerating liver or in cultured proliferating cells. These changes were due to the presence of sphingomyelinase and sphingomyelin synthase in the chromatin, the activity of which paralleled the variation in sphingomyelin content. The sphingomyelin was co‐localized with RNA as shown by biochemical and electron microscopy methods. Using bromo‐uridine it was demonstrated that labelled RNA and sphingomyelin were present in actively transcribing nuclear regions. Isolated nuclear complexes after DNase and RNase digestion contained not only protein, but also RNA and sphingomyelin. After hydrolysis of sphingomyelin the RNAse‐resistant RNA becomes RNAse sensitive. It can therefore be concluded that sphingomyelin and the related enzymes are present in the chromatin; sphingomyelin may have a role in RNA transcription protecting RNA by RNAse digestion before its transfer to the cytoplasm. Copyright © 2003 John Wiley & Sons, Ltd.
Is robot-assisted radical prostatectomy safe in men with high-risk prostate cancer? Assessment of perioperative outcomes, positive surgical margins, and use of additional cancer treatments.

INTRODUCTION Despite a rapid dissemination of robot-assisted radical prostatectomy (RARP) over open radical prostatectomy (ORP), to date no study has compared perioperative outcomes between the two approaches in patients with high-risk prostate cancer (PCa). The aim of our study was to evaluate the safety and feasibility of RARP in this setting. PATIENTS AND METHODS Overall, 1,512 patients with high-risk PCa within the Surveillance, Epidemiology, and End RESULTS (SEER) Medicare-linked database diagnosed between 2008 and 2009 were abstracted. Patients were treated with RARP or ORP. Postoperative complications, blood transfusions, prolonged length of stay (pLOS), positive surgical margins, and additional cancer therapy rates were compared. Propensity-score matched analyses and logistic regression models fitted with generalized estimating equations for clustering among hospitals were performed. RESULTS Overall, 706 (46.7%) and 806 (53.3%) patients underwent ORP and RARP, respectively. Following propensity-matched analyses, 706 patients remained. No differences were observed in complications (P=0.6), positive surgical margins (P=0.4), or additional therapy after surgery (P=0.2) between patients treated with RARP and ORP; however, RARP was associated with lower rates of transfusions and shorter hospitalization (all P<0.001). In multivariable analyses, patients undergoing RARP were less likely to receive a blood transfusion (P=0.002) or to experience pLOS (P<0.001) compared with men treated with ORP. CONCLUSIONS RARP and ORP have comparable complications, positive surgical margins, and additional cancer therapy rates in high-risk PCa. RARP is associated with lower rates of blood transfusions and shorter hospital stays. These findings suggest that RARP is safe and feasible even in this clinical scenario.
Simple Differential Detection of Entamoeba histolyticaand Entamoeba dispar in Fresh Stool Specimens by Sodium Acetate- Acetic Acid-Formalin Concentration and PCR

Amoebiasis is caused by two distinct species, a pathogenic form (Entamoeba histolytica) and a nonpathogenic form (Entamoeba dispar), which are morphologically identical. Although the distinction between these two species is of great clinical importance, the methods developed for this purpose either are very time-consuming or involve laborious procedures for isolation of the DNA. We report here a simple PCR method starting with fresh stool specimen that allows for the sensitive and reliable distinction between E. histolytica and E. dispar. After initial concentration by the sodium acetate-acetic acid-formalin (SAF) method and digestion with proteinase K, a 0.88-kb sequence of the multicopy 16S rRNA gene served as a target for PCR amplification. The method starting with unpreserved specimens proved to be very sensitive and was not influenced by the quick exposure to SAF fixative during the initial concentration step. However, storage in SAF fixative prior to testing resulted in a decreased sensitivity within 2 days. The detection limit of the method was as low as one copy of the 16S rRNA gene. No cross-reactivity was observed with other common intestinal protozoa. Mixed infections involving both E. histolytica and E. dispar could easily be detected at a ratio of 1:10,000 by agarose gel electrophoresis or a DNA hybridization immunoassay.
A longitudinal study of T1 hypointense lesions in relapsing MS

Background: T1 hypointense lesions (T1 black holes) are focal areas of relatively severe CNS tissue damage detected by MRI in patients with MS. Objective: To determine the natural history of T1 hypointense lesions in relapsing MS and the utility of T1 hypointense lesions as outcome measures in MS clinical trials. Methods: MR studies were from the Multiple Sclerosis Collaborative Research Group trial. Longitudinal results are reported in 80 placebo- and 80 interferon β-1a (IFNβ-1a)–treated patients with mild to moderate disability relapsing-remitting MS. Results: There was a small but significant correlation between T1 hypointense lesion volume and disability at baseline and on trial (r = 0.22, r = 0.28). In placebo patients there was a 29.2% increase in the mean volume of T1 hypointense lesions (median 124.5 mm3) over 2 years (p < 0.001 for change from baseline), as compared to an 11.8% increase (median 40 mm3) in the IFNβ-1a–treated patients (change from baseline not significant). These treatment group comparisons did not quite reach significance. The most significant contributor to change in T1 hypointense lesions was the baseline number of enhancing lesions (model r2 = 0.554). Placebo patients with more active disease, defined by enhancing lesions at baseline, were the only group to show a significant increase in T1 hypointense lesion volume from baseline. Conclusion: The development of T1 hypointense lesions is strongly influenced by prior inflammatory disease activity, as indicated by enhancing lesions. These results suggest that treatment with once weekly IM IFNβ-1a (30 mcg) slows the 2-year accumulation of these lesions in the brain.
Estimating Parameterized Scalable Models from the Best Linear Approximation of Nonlinear Systems for Accurate High-Level Simulations

This paper describes a technique to retrieve the best linear approximation for nonlinear MIMO systems. It also describes the extraction of pole/zero trajectories depending on the input power. The proposed algorithms show excellent results on simulations of a two-stage 5 GHz wireless-LAN power amplifier and on measurements of a 5 GHz wireless-LAN variable-gain amplifier. The pole/zero trajectories were found to be smooth functions of the input power. We therefore recommend the proposed algorithms to extract scalable high-level models from simulations or measurements
Functional status and patient satisfaction a comparison of ischemic heart disease, obstructive lung disease, and diabetes mellitus

OBJECTIVE: To determine the extent to which chronic illness and disease severity affect patient satisfaction with their primary care provider in general internal medicine clinics.DESIGN: Cross-sectional mailed questionnaire study.SETTING: Primary care clinics at 7 Veterans Affairs medical centers.PATIENTS/PARTICIPANTS: Of 62,487 patients participating in the Ambulatory Care Quality Improvement Project, 35,383 (57%) returned an initial screening questionnaire and were subsequently sent a satisfaction questionnaire. Patients (N=21,689; 61%) who returned the Seattle Outpatient Satisfaction Survey (SOSQ) were included in the final analysis, representing 34% of the original sample.MEASUREMENTS AND MAIN RESULTS: The organizational score of the SOSQ measures satisfaction with health care services in the internal medicine clinic, and the humanistic scale measures patient satisfaction with the communication skills and humanistic qualities of the primary care physician. For ischemic heart disease (IHD), chronic obstructive pulmonary disease (COPD), and diabetes, patient ability to cope with their disease was more strongly associated with patient satisfaction than disease severity. Among IHD patients, improvement in ability to cope emotionally with their angina was associated with higher SOSQ organizational sores (standardized β=0.18; P<.001) but self-reported physical limitation due to angina was not (β=0.01; P=.65). Similarly, in COPD, improved ability to cope with dyspnea was associated with greater organizational scores (β=0.11; P<.001) but physical function was not (β=−0.03; P=.27). For diabetes, increased education was associated with improved organizational scores (β=0.31; P<.001) but improvement in symptom burden was not (β=0.03; P=.14). Similar results were seen with prediction of SOSQ humanistic scores.CONCLUSIONS: Patient education and ability to cope with chronic conditions are more strongly associated with satisfaction with their primary care provider than disease severity. Further improvements in patient education and self-management may lead to improved satisfaction and quality of care.
Effects of a Cognitive‐Behavioural Internet Program on Depression, Vulnerability to Depression and Stigma in Adolescent Males: A School‐Based Controlled Trial

This study evaluated the effectiveness of a cognitive behaviour therapy Internet program (MoodGYM) for depressive symptoms, attributional style, self‐esteem and beliefs about depression, and on depression and depression‐vulnerable status in male youth. A total of 78 boys age 15 and 16 years were allocated to either undertake MoodGYM or to standard personal development activities. Outcomes were measured before commencement, post‐program and 16 weeks post‐program. There were no significant between‐group differences in change scores pre‐ to post‐ or pre‐ to follow‐up using the intention to treat sample or for participants with post‐ and/or follow‐up data. For boys completing 3 or more modules there were small relative benefits of MoodGYM for depressive symptoms (Effect Size, ES = 0.34), attributional style (ES = 0.17) and self‐esteem (ES = 0.16) at post‐program, although only the effect for self‐esteem was sustained at follow‐up. Both groups showed improvement in their beliefs about depression at follow‐up, with the control group showing a moderate relative benefit (ES = 0.40). While the numbers are small, there was a reduction in the risk of being depressed in the MoodGYM group of 9% at post‐treatment compared with a slightly increased risk for the control group. The risk of being classified as vulnerable to depression reduced by 17% in the MoodGYM group at post‐treatment compared with no change in risk for the control group. These reductions in risk for the MoodGYM group were not sustained at follow‐up. The limitations of the study highlight several important challenges for MoodGYM and other self‐directed Internet cognitive behaviour therapy programs. These include how to ensure enough of the program is received and that people who could potentially benefit access the program and continue to remain engaged with it, and how to enhance the sustainability of any benefits.
Relationship between serum cartilage oligomeric matrix protein levels and disease progression in osteoarthritis of the knee joint.

The value of serum cartilage oligomeric matrix protein (COMP) as a marker of disease progression was investigated in 81 hospital out-patients with clinical knee osteoarthritis (OA). Progressing patients were defined by a decrease of > or = 2 mm in joint space on X-ray or requiring knee surgery during the 5 yr of follow-up. Of the 57 patients for whom full data were available, 20 progressed and 37 did not progress. Serum COMP levels increased during the first year in those who progressed (mean 6.42 micrograms/ml) (S.D. 6.64) compared to those who did not progress [mean 0.07 microgram/ml (S.D. 4.99); P < 0.001]. Changes in COMP during the first year were related to baseline COMP (r = -0.672, P < 0.001) and weight-to-height ratio (r = 0.272, P = 0.47). After allowing for these variables, serum COMP increased during the first year in progressive patients by 5.04 micrograms/ml [95% confidence interval (CI): (2.61, 7.46)] more than in non-progressive patients. Discriminant analysis gave a sensitivity of 70% and specificity of 78% at a cut-off value of 3.17 micrograms/ml. Baseline serum COMP levels did not differ between the groups but were related to late phase scintigraphy scan abnormalities. These observations suggest that the changes in serum COMP may have prognostic significance and are consistent with a model of OA in which early signs of episodic clinical progression can be found in the cartilage as well as in subchondral bone.
Real-life experience with first generation HCV protease inhibitor therapy in Germany: The prospective, non-interventional PAN cohort

Abstract Background and Aims: The efficacy and safety of peginterferon alfa-2a (PEG-IFN) plus ribavirin (RBV) and either boceprevir (BOC) or telaprevir (TVR), and physician adherence to treatment algorithms were evaluated in patients included in an ongoing non-interventional study (PAN) enrolling adults with chronic hepatitis C virus (HCV) infection managed in German office-based practices. Methods: The analysis included HCV genotype 1-infected, treatment-naïve and treatment-experienced patients treated with BOC or TVR. Demographic, treatment history, virological response, safety, and patient management data were collected. Results: Of a total 1087 patients, 58.1 % achieved sustained virological responses (SVR). Response rates were higher in treatment-naïve (BOC 55 %; TVR 63.4 %) and prior relapse patients (BOC 63.2 %; TVR 74.5 %) versus previous null-responders (BOC 14.3 %; TVR 25 %). The most commonly reported adverse event overall was fatigue (60.6 %); 45.8 % patients experienced hemoglobin < 10 g/dL. Patients with cirrhosis had lower rates of SVR versus those without (42.9 % vs. 60.7 %, respectively), and had a higher incidence of serious adverse events (SAEs) (16.7 % vs. 8.6 %, respectively) and treatment discontinuation (44.6 % vs. 25.2 %, respectively). According to recommended response-guided treatment algorithms, about 70 % of patients were managed appropriately, 11/10 % (BOC/TVR) received unnecessarily extended therapy, and 19/7 % (BOC/TVR) received inappropriately shortened therapy. Conclusions: The efficacy and safety of BOC- and TVR-based triple therapy in this large, “real-world” cohort were largely comparable to that reported in pivotal clinical trials, although SVR rates were lower overall. Recommended futility or treatment extension rules were violated in a substantial proportion of patients with potential implications for response, adverse events and costs.
A liquid chromatography tandem mass spectrometric method for in vivo dose monitoring of diepoxybutane, a metabolite of butadiene.

1,3-Butadiene, a common air pollutant formed in the combustion of organic matter, has been assessed by the U.S. EPA to be a strongly carcinogenic compound. This risk assessment is very uncertain because of the lack of information on the dose of the powerful carcinogenic metabolite diepoxybutane (DEB). This report presents an analytical method for in vivo dose monitoring of a unique marker for DEB. For a large number of alkylating agents in vivo doses are monitored by measurement by gas chromatography/mass spectrometry (GC/MS) of adducts to N-terminal valine in hemoglobin (Hb), using a modified Edman degradation method. This method is applicable to monofunctional epoxides from butadiene. However, in reaction with N-terminal valine, DEB forms an adduct which is ring-closed to a pyrrolidine, N,N-(2,3-dihydroxy-1,4-butadiyl)valine, with a tertiary amino group that prevents detachment of the alkylated valine by the Edman reagent. Therefore a method has been developed based on the analysis by liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) of the N-modified N-terminal peptides enriched after trypsin digestion of globin. In this study Hb samples from mice injected intraperitoneally with (+/-)-DEB were examined qualitatively and quantitatively with regard to the ring-closed adduct. The N-terminal pyrrolidine-heptapeptide was identified in treated mice. The highest adduct levels were obtained in samples from animals given the highest dose of DEB and the adduct levels were below the detection level in control mice.