Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanism of Improvement in Glucose Metabolism After Chronic Glyburide Therapy

The effect of glyburide on glucose metabolism was examined in 10 non-insulin-dependent diabetic subjects (NIDDM) and 7 young, control subjects. After 3 mo of glyburide treatment in NIDDM, fasting plasma glucose declined from 198 to 141 mg/dl (P < 0.01) without change in fasting insulin levels. Basal hepatic glucose production (HGP) was slightly elevated in NIDDM versus controls (2.35 versus 2.18 mg/kg · min, P = NS) and was positively correlated with the fasting glucose concentration (r = 0.93, P < 0.001). With chronic glyburide therapy, HGP declined to 1.72 mg/kg · min (P < 0.01 versus preglyburide) and remained highly correlated with the fasting glucose concentration (r = 0.85, P < 0.005). Basal glucose clearance in NIDDM was reduced by 48% compared with age-matched controls (1.22 versus 2.32 ml/kg · min, P < 0.001) and was unchanged after 3 mo of glyburide. Thus, the most important factor responsible for the decline in fasting plasma glucose concentration was an inhibition of hepatic glucose output. The decrease in basal hepatic glucose production and fasting plasma glucose concentration occurred without any change in fasting plasma insulin or C-peptide concentration. Insulin-mediated glucose metabolism (insulin clamp technique) was reduced by 55% in NIDDM (2.91 versus 6.39 mg/kg · min, P < 0.001). After glyburide, insulin-mediated glucose metabolism increased by 26% to 3.67 mg/kg · min (P < 0.01). This increase in tissue sensitivity to insulin was unassociated with any change in insulin binding to monocytes. Beta cell secretion of insulin (hyperglycemie clamp technique) was markedly impaired in NIDDM (mean plasma insulin response: 24 versus 54 μU/ml, P < 0.001). After glyburide, the plasma insulin response increased to 36 μU/ ml (P < 0.01). These results indicate that improved glucose tolerance in NIDDM after glyburide results from both enhanced tissue sensitivity to insulin and increased insulin secretion. Glyburide administration to young, healthy, control subjects also increased insulin-mediated glucose metabolism (from 6.45 to 7.61 mg/kg · min, P < 0.05) without any change in insulin binding to monocytes. Insulin secretion, however, was unaltered. Thus, the primary mechanism responsible for the improvement in glucose metabolism in young controls was enhanced tissue sensitivity tO insulin.
Clinical features in affected individuals from 21 pedigrees with dominant optic atrophy.

OBJECTIVE To assess phenotypic variation of affected individuals from British families with autosomal dominant optic atrophy. DESIGN Eighty-seven patients from 21 families showing evidence of linkage to chromosome 3q were identified via the Genetic Clinic of Moorfields Eye Hospital, London, England. Genetic linkage analysis was carried out with markers from chromosome 3q28-qter. Patients underwent clinical examination and psychophysical and electrophysiological testing. RESULTS Best-corrected visual acuity ranged from 20/20 (6/6 m) to light perception. Although visual acuity was not significantly worse in older patients in the group (chi2=3.20, df=4, P>.50), it did deteriorate with age in one third of the families. Subtle or temporal pallor of the optic disc occurred in 96 (55%) of 174 eyes and total atrophy in 76 (44%). Tritanopia was found in 6 (7.5%) of 80 patients; 65 (81.2%) had a mixed color deficit. A cecocentral scotoma was found in the vast majority. Peripheral motion detection threshold was elevated in areas of visual field with raised mean surround sensitivity but not elsewhere. Pattern visual evoked potentials were of reduced amplitude and delayed. Pattern electroretinograms showed a reduced N95 component in keeping with primary ganglion cell dysfunction. CONCLUSIONS There is wide intrafamilial and interfamilial phenotypic variation in autosomal dominant optic atrophy, with visual function in some, but not all, families deteriorating with age. There is evidence of degeneration of the ganglion cell layer predominantly from central retina, but this is not the exclusive result of either parvocellular or magnocellular cell loss.
Effect of acute exercise on upper-limb volume in breast cancer survivors: a pilot study.

PURPOSE Strenuous upper-extremity activity and/or exercise have traditionally been prescribed for breast cancer survivors with or at risk of developing lymphedema. The purpose of this study was to assess the effect of an acute bout of exercise on upper-limb volume and symptoms in breast cancer survivors, with the intent to provide pilot data to guide a subsequent larger study. METHODS Twenty-three women who regularly participated in dragon-boat racing took part in the study. A single exercise bout was performed at a moderate intensity (rating of perceived exertion: 13-14) for 20 continuous minutes on an arm ergometer. The difference between affected and unaffected limb volume was assessed pre- and post-exercise via measurements of limb circumference at five time points. RESULTS Although limb volume increased following exercise in both limbs, the difference between the limbs remained stable at each measurement point. Only one participant was found to have an increase in arm-volume difference of >100 ml post intervention, and only four participants reported symptoms of tension and/or heaviness in the affected limb. CONCLUSION The results suggest that limb volume in breast cancer survivors increases after an acute bout of upper-limb exercise but that, for the majority of women, the response is not different between affected and unaffected limbs. Future research using a larger sample and more sensitive measurement methods are recommended.
Longitudinal incidence and prevalence of adverse outcomes of diabetes mellitus in elderly patients.

BACKGROUND The natural history of type 2 diabetes mellitus (DM) in the elderly has not been previously described in a national longitudinal sample. METHODS This national longitudinal analysis (January 1, 1991, to December 31, 2004) examines mortality and morbidity rates in a representative sample of elderly patients newly diagnosed as having DM. Medicare beneficiaries diagnosed as having DM in 1994 (n=33,772) were compared with a control group (n=25,563) regarding death, lower extremity complications, nephropathy, retinopathy, cardiovascular complications, and cerebrovascular complications. RESULTS The DM group had excess mortality of 9.2% by year 11 compared with the control group. By 2004, 91.8% of the DM group experienced an adverse complication compared with 72.0% of the control group. The DM group had a higher prevalence and incidence of microvascular and macrovascular complications at all time points compared with controls. Patients with DM were at increased risk for all lower extremity complications, particularly those requiring surgical intervention (gangrene, debridement, and amputation). Cardiovascular complications were a leading cause of morbidity, with 57.6% of the DM group diagnosed as having heart failure compared with 34.1% of the controls. CONCLUSION Elderly persons newly diagnosed as having DM experienced high rates of complications during 10-year follow-up, far in excess of elderly persons without this diagnosis, implying a substantial burden on the individual and on the health care system.
Reduced SOD activity and increased neural tube defects in embryos of the sensitive but not of the resistant Cohen diabetic rats cultured under diabetic conditions.

BACKGROUND The role of reactive oxygen species in the etiology of diabetes-induced anomalies was studied in a genetic model of nutritionally induced Type 2 diabetes mellitus: the Cohen diabetic sensitive (CDs) and resistant (CDr) rats. We have previously shown in this model that embryopathy may be induced by a combination of genetic and environmental factors. In our study we investigated the role of the antioxidant defense mechanism, genetic predisposition or environmental factors in embryos cultured under diabetic conditions. METHODS CDs, CDr and Sabra rat 11.5-day old embryos were studied after 28 hr of culture in control (low glucose), high glucose, diabetic sub-teratogenic, and diabetic teratogenic media. Embryos were monitored for growth retardation and congenital anomalies. Activity of superoxide dismutase (SOD) and catalase-like (CAT) enzymes was measured in embryonic homogenates. RESULTS In control medium, CDs embryos were significantly underdeveloped but exhibited no anomalies and SOD activity was not significantly different from that of CDr embryos. In high glucose medium, CDs embryos were smaller than CDr and Sabra embryos and smaller than CDs embryos cultured in control medium. Neural tube defects (NTD) were found predominantly in the CDs embryos starting from 14% in the high glucose medium and increasing to 29% in the sub-teratogenic medium. In the teratogenic medium, < 50% of the CDs and Sabra embryos were alive whereas all (100%) of the CDr embryos were alive. SOD activity significantly increased in CDs embryos when cultured in the high glucose medium but was significantly reduced in the sub-teratogenic medium. SOD activity was increased significantly in the Sabra embryos cultured in the sub-teratogenic medium but did not change in CDr embryos cultured in either one of the different culture media. CAT activity did not show any significant trend in either one of the rat strains or in any of the different culture conditions. CONCLUSIONS Our results suggest that genetic susceptibility plays an important role in inducing underdevelopment and NTD in cultured CDs embryos in sub-teratogenic medium and in protecting the CDr embryos under the same conditions. The combination of a sub-teratogenic environment with genetic susceptibility is sufficient to reduce the activity of SOD, hence decreasing the ability of the CDs embryos to cope with diabetic sub-teratogenic environment and prevent NTD.
Hierarchic function approximation in kd-Q-learning

Function approximation is an important issue in reinforcement learning for control problems with continuous state space. A new learning algorithm is presented that approximates the quality function with a hierarchic discretization structure called kd-tree. It learns at the beginning for each experienced state transition simultaneously on several hierarchic levels representing different spatial generalizations. As learning proceeds, state transitions get increasingly refined by a descent in the kd-tree scaling down both the spatial and temporal generalization, the latter being the natural abstraction in action space. By increasing the representational complexity within the agent, we can reduce the learning effort considerably.
Emerging treatments for hepatitis C

Introduction: About 2.35% of the world population can be infected with hepatitis C virus (HCV) responsible for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Currently available interferon-based medication is successful in up to 75% of the patients infected with HCV genotypes 1, 2 or 3 and lower efficacy in other genotypes. Unfortunately sustained virologic response (SVR) rate in genotype 1 infected non-responders to previous therapy with advanced hepatic fibrosis even after retreatment with the first generation direct acting antivirals (DAA) is about 40% only. Areas covered: The second generation DAA, which have recently been submitted for registration (Sofosbuvir and Simeprevir) still need combination with PegIFNα and RBV in patients infected with HCV genotype 1. There is a need for more effective antiviral therapy for difficult to treat patients who are interferon intolerant, developed liver cirrhosis or non-responders to previous therapies. Therefore, IFN-free regimens are step for future therapies consisting of combinations of novel investigational DAA and host targeting agents. Expert opinion: The introduction of novel DAA with a good safety profile and high barrier to resistance can lead to SVR rates exceeding 90% in treatment naïve patients and non-responders to previous therapy infected with different genotypes.
Impact of 5-aminolevulinic acid with iron supplementation on exercise efficiency and home-based walking training achievement in older women

A reduction in exercise efficiency with aging limits daily living activities. We examined whether 5-aminolevulinic acid (ALA) with sodium ferrous citrate (SFC) increased exercise efficiency and voluntary achievement of interval walking training (IWT) in older women. Ten women [65 ± 3(SD) yr] who had performed IWT for >12 mo and were currently performing IWT participated in this study. The study was conducted in a placebo-controlled, double-blind crossover design. All subjects underwent two trials for 7 days each in which they performed IWT with ALA+SFC (100 and 115 mg/day, respectively) or placebo supplement intake (CNT), intermittently with a 2-wk washout period. Before and after each trial, subjects underwent a graded cycling test at 27.0°C atmospheric temperature and 50% relative humidity, and oxygen consumption rate, carbon dioxide production rate, and lactate concentration in plasma were measured. Furthermore, for the first 6 days of each trial, exercise intensity for IWT was measured by accelerometry. We found that, in the ALA+SFC trial, oxygen consumption rate and carbon dioxide production rate during graded cycling decreased by 12% (P < 0.001) and 11% (P = 0.001) at every workload, respectively, accompanied by a 16% reduction in lactate concentration in plasma (P < 0.001), although all remained unchanged in the CNT trial (P > 0.2). All of the reductions were significantly greater in the ALA+SFC than the CNT trial (P < 0.05). Furthermore, the training days, impulse, and time at fast walking were 42% (P = 0.028), 102% (P = 0.027), and 69% (P = 0.039) higher during the ALA+SFC than the CNT intake period, respectively. Thus ALA+SFC supplementation augmented exercise efficiency and thereby improved IWT achievement in older women.
Serum Tyrosine-to-Phenylalanine Ratio is Low in Parkinson's Disease.

BACKGROUND Noninvasive biomarkers for Parkinson's disease (PD) are currently unavailable. OBJECTIVE To search for a biomarker unique to PD in sweat and serum. METHODS Sweat samples in 42 PD patients and 16 controls were analyzed using liquid chromatography/mass spectrometry (LC/MS). The principal component analysis (PCA) and the orthogonal projections to latent structures (OPLS) analysis were employed. Serum Phe and Tyr levels were determined using the HPLC-fluorescence detection system in 28 de novo PD patients, 52 L-Dopa-treated PD patients, and 27 controls. RESULTS PCA and OPLS analyses of LC/MS of sweat samples revealed that Tyr, Phe, Leu (Ile), and Asp have high effect sizes to differentiate PD and controls. As Phe and Tyr are precursors of dopamine, we quantified the serum Phe and Tyr levels in de novo and treated PD patients, as well as in controls. Phe was high in de novo patients, but not in treated patients. In contrast, Tyr tended to be low in treated patients, but not in de novo patients. Tyr/Phe ratios were lower in both de novo and treated patients than in controls. The Tyr/Phe ratios were all higher than 0.82 in controls, whereas 49% of the de novo and treated patients had Tyr/Phe ratios less than 0.82. The low Tyr/Phe ratios were associated with male patients and low doses of entacapone. However, Tyr/Phe ratios were not different between male and female patients, and between patients with and without entacapone. CONCLUSIONS The low serum Tyr/Phe ratio differentiates PD from controls with sensitivity = 0.49, specificity = 1.00, positive predictive value = 1.00, and negative predictive value = 0.40.
Cost-Effectiveness Analysis of Extended Conservative Therapy Versus Surgical Intervention in the Management of Herniated Lumbar Intervertebral Disc

The management of herniated lumbar intervertebral disc for patients not responding to an initial trial of conservative therapy is generally surgical. Little is known about the effect of continued conservative therapy on patients who have not improved or have deteriorated within the first 3 months. This study assessed which form of treatment, surgical or continued conservative therapy, is more cost–effective once an adequate trial of conservative therapy has failed. The study is a retrospective chart review of 55 white male truck drivers who presented with acutely herniated nucleus pulposus between 1985 and 1989. Twenty–five patients underwent surgery, and 30 underwent continued conservative therapy after initial rehabilitation. No significant difference was found in outcome (80% good or fair in both the surgical and conservative groups) or costs ($55,000 ± $1,000/case during a 5–year period), hence no difference in the costeffectiveness between the two treatment modalities (each $63,000 ± $2,000/adjusted outcome). Conservatively treated patients, however, missed significantly more work. It was concluded that, for a patient not responding to the initial trial of conservative therapy, the option to undergo continued conservative treatment should be made available.
Prevalence and risk factors of nonalcoholic fatty liver disease in HIV-monoinfection

Objective: To identify the prevalence and risk factors of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and fibrosis in HIV-monoinfected patients. Design: Systematic review and meta-analysis. Methods: We searched Medline and Embase and included studies that enrolled HIV-monoinfected patients with NAFLD defined by imaging and/or liver histology. Data on prevalence and risk factors for NAFLD, NASH and fibrosis were collected for meta-analysis using random effects models. Results: Ten studies were included from the United States of America (n = 4), Canada (n = 1), France (n = 2), Italy (n = 1), Japan (n = 1) and China (n = 1). The prevalence of NAFLD (Imaging studies), NASH and fibrosis (biopsied populations) were 35% [95% confidence interval (CI) 29–42], 42% (95% CI 22–64) and 22% (95% CI 13–34), respectively. Meta-analysis of risk factors showed that high BMI, waist circumference, type 2 diabetes, hypertension, triglycerides and high CD4+ cell count were associated with NAFLD, whereas HIV viral load, duration of HIV infection, duration of antiretroviral therapy and CD4+ cell count nadir were not. Patients with high BMI [mean difference (MD) 1.38, 95% CI 0.04–2.71 P = 0.04], fasting glucose (MD 0.80, 95% CI 0.47–1.13 P < 0.00001) and AST level (MD 13.00, 95% CI 4.34–21.65 P = 0.003) were at increased risk of significant liver fibrosis. Conclusion: NAFLD is frequently observed in HIV-monoinfected patients, and NASH is a common cause of unexplained abnormal liver function in patients selected for liver biopsy. Metabolic disorders are key risk factors independently of HIV parameters. Future trials on pharmacological interventions in NASH with fibrosis should include patients with HIV.
Impact of Proficiency Testing on Results of the Microscopic Agglutination Test for Diagnosis of Leptospirosis

ABSTRACT A proficiency testing scheme for the leptospirosis microscopic agglutination test was provided to 37 laboratories in 23 countries in 2002 (round 1) and to 60 laboratories in 34 countries in 2003 (round 2). Thirty-four laboratories participated in both rounds. Each panel consisted of five rabbit serum samples, four of which were antisera raised against pathogenic serovars of Leptospira. One of these samples was a mixture of two different antisera. The rates of false-negative results, calculated on the basis of the assumption that serovars within a serogroup will cross-react, were 11% for round 1 and 14% for round 2. There were regional differences in the rates of false-negative results. The titers reported by laboratories testing for the same sample with the same serovar varied widely. Laboratories that had previously participated in round 1 reported fewer false-negative results in round 2 than new participants (10 and 21%, respectively [P = 0.002]) and reported 0.56 false-negative results per participant, whereas new participants reported 1.23 false-negative results per participant (P = 0.041). Laboratories that had previously participated also reported fewer false-negative results in round 2 than in round 1 when samples common to both rounds were tested (5 and 15%, respectively [P = 0.028]). The titers reported by the new participants were, on average, lower than those reported by the laboratories that had participated previously (P = 0.019) and were significantly more variable (P = 0.001). Analysis of these results suggests a positive impact of proficiency testing on the testing performance of the participating laboratories.
INCIDENCE, AGE AT ONSET AND SEASONAL VARIATION OF DIABETES MELLITUS IN NORWEGIAN CHILDREN, 1973–1977

ABSTRACT. Joner, G. and Søvik, O. (Department of Paediatrics, University of Bergen, Norway). Incidence, age at onset and seasonal variation of diabetes mellitus in Norwegian children, 1973–1977. Acta Paediatr Scand, 70:329, 1980. –A retrospective study was undertaken to estimate the incidence of diabetes mellitus in Norwegian children. Data were collected from all hospitals in the country and from a central insurance register. Eight hundred and forty‐five new cases in the age group 0–14 years and with onset in the five‐year study period 1973–1977 were detected. The calculated mean annual incidence was 17.6 per 100000 children, with a year‐to‐year variation of IS.4–19.3 per 100 000. The geographic variation in incidence was considerable with the lowest rate in the North (6.8/100 000/year) and the highest rates in the South‐Eastern part of the country (approx. 20/100000/year). There was a significantly higher incidence for boys (18.8/100 000/year) than for girls (16.4/100 000/year). The age variation in the incidence rates showed rising values towards a peak at 12 years for girls and a plateau at 12–14 years for boys, with an abrupt decline after 12 and 14 years, respectively. There were more cases with onset in the winter and autumn, with significant peaks in February and October. From these data the prevalence of diabetes mellitus in the age group 0–14 years can be calculated to 1.2 per 1 000 children. In the whole of Norway, about 170 new cases of diabetes mellitus below the age of 15 years can be expected every year. Compared with previous studies, the present data suggest an increasing incidence of childhood diabetes in Norway.
Cerebrospinal Fluid Concentration of Erlotinib and its Active Metabolite OSI-420 in Patients with Central Nervous System Metastases of Non-small Cell Lung Cancer

Background: Although there have been several reports in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) were improved by erlotinib, cerebrospinal fluid (CSF) penetration of erlotinib in such patients has not been reported. We investigated CSF concentrations of erlotinib and its active metabolite OSI-420. Method: We administered 150 mg erlotinib daily to four patients with NSCLC who had CNS metastases, and we investigated plasma pharmacokinetics of erlotinib and OSI-420 on days 1 and 8. In addition, we measured the concentrations of erlotinib and OSI-420 in CSF just before administration of erlotinib on day 8. Results: In all cases except for one case, plasma pharmacokinetics data on day 8 were similar to those previously reported. The mean ± SD CSF concentrations of erlotinib and OSI-420 were 54 ± 30 ng/ml and 10.8 ± 8.2 ng/ml, respectively. The mean ± SD CSF penetration rates of erlotinib and OSI-420 were 5.1% ± 1.9% and 5.8% ± 3.6%, respectively. CSF concentrations of erlotinib exceeded median inhibitory concentration (IC50) of erlotinib in intact tumor cells with wild-type epidermal growth factor receptor gene. Conclusion: The CSF penetrations of erlotinib and OSI-420 in patients with NSCLC who had CNS metastases were approximately 5.1% and 5.8%, respectively. This indicates that erlotinib can become a treatment option for CNS metastases of NSCLC.