nils-herrmann/clean_scirepeval huggingface dataset:
Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild Alzheimer’s disease following chronic donepezil treatment

To evaluate long-term changes in acetylcholinesterase (AChE) activity in CSF and blood following donepezil treatment in relation to the concentration of donepezil and cognition in AD patients.  CSF or blood (or both) samples of a total of 104 patients with mild AD were used [MMSE score 23 ± 0.4; age 75 ± 1 years (mean ± SEM); n = 53 for CSF and n = 51 for plasma/red blood cell (RBC) samples]. The patients were treated with 5 or 10 mg/day donepezil and clinically followed for 2 years. The CSF and RBC AChE activities were measured by the Ellman’s direct colorimetric assay. Protein levels of two variants of AChE (“read-through” AChE-R and synaptic AChE-S) were determined by an ELISA-like method.  The plasma donepezil concentration was dose-dependent (between 30 and 60 ng/mL in the 5-mg and 10-mg group, respectively). The CSF donepezil concentration was 10 times lower than the plasma level and showed dose- and time-dependent kinetics. The RBC AChE inhibition was moderate (19–29%). CSF AChE-S inhibition was estimated to 30–40% in the 5-mg and 45–55% in the 10-mg group. Positive correlations were observed between the CSF AChE inhibition, an increased protein level of the AChE-R variant and MMSE examination. Patients with high AChE inhibition (≥45%) showed a stabilized MMSE test result after up to two years, while a significant decline was observed in AD patients with lower AChE inhibition (≤30%).  An increase in the protein level of the AChE-R variant corresponded to a high AChE inhibition in CSF and favored less cognitive deterioration.
Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]-fed human apolipoprotein E2 [hApoE2] transgenic mice, methionine- and choline-deficient diet-fed db/db mice, and CCl4 -induced fibrosis in rats). GFT505 demonstrated liver-protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR-α-independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock-in/PPAR-α knockout mice. In these mice, GFT505 also prevented WD-induced liver steatosis and inflammation, indicating a contribution of PPAR-α-independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase.



The dual PPAR-α/δ agonist, GFT505, is a promising liver-targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR-α-dependent and -independent mechanisms.
Working memory training in young children with ADHD: a randomized placebo-controlled trial.

Until now, working memory training has not reached sufficient evidence as effective treatment for ADHD core symptoms in children with ADHD; for young children with ADHD, no studies are available. To this end, a triple-blind, randomized, placebo-controlled study was designed to assess the efficacy of Cogmed Working Memory Training (CWMT) in young children with ADHD.



Fifty-one children (5-7 years) with a DSM-IV-TR diagnosis of ADHD (without current psychotropic medication) were randomly assigned to the active (adaptive) or placebo (nonadaptive) training condition for 25 sessions during 5 weeks. The compliance criterion (>20 sessions) was met for 47 children. The primary outcome measure concerned the core behavioural symptoms of ADHD, measured with the ADHD Rating Scale IV (ADHD-RS). Secondary outcome measures were neurocognitive functioning, daily executive functioning, and global clinical functioning. The influence of the increase in difficulty level (Index-Improvement) for the treatment group was also analysed. 
A significant improvement in favour of the active condition was found on a verbal working memory task (p = .041; adapted Digit Span WISC-III, backward condition). However, it did not survive correction for multiple testing. No significant treatment effect on any of the primary or other secondary outcome measurements was found. The Index-Improvement significantly contributed to ADHD-RS and the Behavior Rating Inventory of Executive Function, both rated by the teacher, but revealed no significant group difference.



This study failed to find robust evidence for benefits of CMWT over the placebo training on behavioural symptoms, neurocognitive, daily executive, and global clinical functioning in young children with ADHD.
Effect of sodium bicarbonate on [HCO3-], pH, and gastrointestinal symptoms.

Sodium bicarbonate (NaHCO₃) is often ingested at a dose of 0.3 g/kg body mass (BM), but ingestion protocols are inconsistent in terms of using solution or capsules, ingestion period, combining NaHCO₃ with sodium citrate (Na₃C₆H₅O₇), and coingested food and fluid.



To quantify the effect of ingesting 0.3 g/kg NaHCO₃ on blood pH, [HCO₃-], and gastrointestinal (GI) symptoms over the subsequent 3 hr using a range of ingestion protocols and, thus, to determine an optimal protocol.



In a crossover design, 13 physically active subjects undertook 8 NaHCO₃ experimental ingestion protocols and 1 placebo protocol. Capillary blood was taken every 30 min and analyzed for pH and [HCO₃-]. GI symptoms were quantified every 30 min via questionnaire. Statistics used were pairwise comparisons between protocols; differences were interpreted in relation to smallest worthwhile changes for each variable. A likelihood of >75% was a substantial change.



[HCO₃-] and pH were substantially greater than in placebo for all other ingestion protocols at almost all time points. When NaHCO3 was coingested with food, the greatest [HCO₃-] (30.9 mmol/kg) and pH (7.49) and lowest incidence of GI symptoms were observed. The greatest incidence of GI side effects was observed 90 min after ingestion of 0.3 g/kg NaHCO₃ solution.



The changes in pH and [HCO₃-] for the 8 NaHCO₃-ingestion protocols were similar, so an optimal protocol cannot be recommended. However, the results suggest that NaHCO₃ coingested with a high-carbohydrate meal should be taken 120-150 min before exercise to induce substantial blood alkalosis and reduce GI symptoms.
Alcohol consumption is associated with lower self-reported disease activity and better health-related quality of life in female rheumatoid arthritis patients in Sweden: data from BARFOT, a multicenter study on early RA

Earlier studies have found a positive effect of alcohol consumption, with a reduced disease activity in rheumatoid arthritis (RA). The aim of this study was to assess alcohol consumption and its association with disease activity and health related quality of life (HRQL) in Swedish RA patients.



Between 1992 and 2005, 2,800 adult patients were included in the BARFOT study of early RA in Sweden. In 2010 a self-completion postal questionnaire was sent to all 2,102 prevalent patients in the BARFOT study enquiring about disease severity, HRQL, and lifestyle factors. Alcohol consumption was assessed using the validated AUDIT-C questionnaire.



A total of 1,238 out of 1,460 patients answering the questionnaire had data on alcohol consumption: 11% were non-drinkers, 67% had a non-hazardous drinking, and 21% were classified as hazardous drinkers. Women who drank alcohol reported lower disease activity and better HRQL, but there were no association between alcohol consumption and disease activity in men. For current smokers, alcohol use was only associated with fewer patient-reported swollen joints. The outcome was not affected by kind of alcohol consumed.



There was an association between alcohol consumption and both lower self-reported disease activity and higher HRQL in female, but not in male, RA patients.
Association of Physical Activity Measured by Accelerometer, Knee Joint Abnormalities, and Cartilage T2 Measurements Obtained From 3T Magnetic Resonance Imaging: Data From the Osteoarthritis Initiative.

To study the cross-sectional association between physical activity measured with an accelerometer, structural knee abnormalities, and cartilage T2 values assessed with 3T magnetic resonance imaging (MRI).



We included 274 subjects from the Osteoarthritis Initiative cohort without definite radiographic osteoarthritis (Kellgren/Lawrence grades 0 and 1) and with at most mild pain, stiffness, and functional limitation in the study knee (Western Ontario and McMaster Universities Osteoarthritis Index scale 0-1), which had not limited their activity due to knee pain. Physical activity was measured over 7 days with an ActiGraph GT1M accelerometer. Subjects were categorized by quartile of physical activity based on the average daily minutes of moderate to vigorous physical activity (mv-PA). MRI images of the right knee (at 48-month visit) were assessed for structural abnormalities using a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS) and for T2 relaxation times derived from segmented cartilage of 4 femorotibial regions and the patella. WORMS grades and T2 measurements were compared between activity quartiles using a linear regression model. Covariates included age, sex, body mass index, knee injury, family history of knee replacement, knee symptoms, hip and ankle pain, and daily wear time of the accelerometer.



Higher mv-PA was associated with increased severity (P = 0.0087) and number of lesions of the medial meniscus (P = 0.0089) and with severity of bone marrow edema lesions (P = 0.0053). No association between cartilage lesions and mv-PA was found. T2 values of cartilage (loss, damage, and abnormalities) tended to be greater in the higher quartiles of mv-PA, but the differences were nonsignificant.



In knees without radiographic osteoarthritis in subjects with no or mild knee pain, higher physical activity levels were associated with increases in meniscal and bone marrow edema pattern lesions.
Efficacy and safety of immediate angioplasty versus ischemia-guided management after thrombolysis in acute myocardial infarction in areas with very long transfer distances results of the NORDISTEMI (NORwegian study on DIstrict treatment of ST-elevation myocardial infarction).

The goal of this study was to compare a strategy of immediate transfer for percutaneous coronary intervention (PCI) with an ischemia-guided approach after thrombolysis in patients with very long transfer distances to PCI.



Thrombolysis remains the treatment of choice in ST-segment elevation myocardial infarction (STEMI) when primary PCI cannot be performed within 90 to 120 min. The optimal treatment after thrombolysis is still unclear.



A total of 266 patients with acute STEMI living in rural areas with more than 90-min transfer delays to PCI were treated with tenecteplase, aspirin, enoxaparin, and clopidogrel and randomized to immediate transfer for PCI or to standard management in the local hospitals with early transfer, only if indicated for rescue or clinical deterioration. The primary outcome was a composite of death, reinfarction, stroke, or new ischemia at 12 months, and analysis was by intention to treat.



The primary end point was reached in 28 patients (21%) in the early invasive group compared with 36 (27%) in the conservative group (hazard ratio: 0.72, 95% confidence interval: 0.44 to 1.18, p = 0.19). The composite of death, reinfarction, or stroke at 12 months was significantly reduced in the early invasive compared with the conservative group (6% vs. 16%, hazard ratio: 0.36, 95% confidence interval: 0.16 to 0.81, p = 0.01). No significant differences in bleeding or infarct size were observed.



Immediate transfer for PCI did not improve the primary outcome significantly, but reduced the rate of death, reinfarction, or stroke at 12 months in patients with STEMI, treated with thrombolysis and clopidogrel in areas with long transfer distances.
BIM is a prognostic biomarker for early prednisolone response in pediatric acute lymphoblastic leukemia.

Glucocorticoids such as prednisolone (PRED) are widely used in the treatment of pediatric acute lymphoblastic leukemia. In PRED-induced apoptosis, Bcl-2 family members play important regulatory roles. However, the exact members involved remain unknown. In this study, the roles of Bcl-2 family members in PRED-induced apoptosis and their prognostic value to day 8 PRED response are evaluated.



Four clinically important acute lymphoblastic leukemia cell lines, three PRED-sensitive (697, Sup-B15, and RS4;11) and one PRED-resistant (REH) were studied. Thirty paired patient bone marrow samples were obtained at diagnosis (day 0) and after 7 days (day 8) of PRED monotherapy. Twenty-five patients had PRED good response and five PRED poor response. Differential expressions of Bcl-2 members were observed in those samples and BIM was further investigated using gene silencing technology in representative cell line Sup-B15.



The proapoptotic BH3-only Bcl-2 family member BIM was upregulated only in PRED-sensitive cells. Receiver operating characteristic curve analysis showed that BIM expression was highly predictive of PRED response (area under the curve = 0.81; p = 0.032) in paired patient bone marrow samples and is, most excitingly, independent of molecular subtype. Patients whose BIM protein expression levels fail to upregulate at day 8 compared to day 0 (D8/D0 ratio <0.93) have significantly poorer event-free survival (60%) than those patients whose BIM protein expression levels did upregulate (92%). By silencing BIM in PRED-sensitive cells, PRED-induced apoptosis was inhibited.



Upregulation of BIM by PRED in acute lymphoblastic leukemia cells regardless of molecular subtype is significantly prognostic of outcomes, confirming BIM's essential regulatory role in the PRED-induced apoptosis.
Impact of pulmonary vein anatomy assessed by cardiac magnetic resonance imaging on endoscopic pulmonary vein isolation in consecutive patients.

Recently, the novel endoscopic ablation system (EAS) was introduced and proved its potential for successful pulmonary vein isolation (PVI) in patients suffering from paroxysmal atrial fibrillation (PAF). The current study will investigate the impact of pulmonary vein (PV) anatomy assessed by pre-interventional cardiac magnetic resonance imaging (CMRI) on endoscopic PVI.



Fifty-one patients (23 females, age 57 ± 9 years) with a long history (5 ± 5 years) of drug-refractory PAF were included into our analysis. Cardiac magnetic resonance imaging was performed in all patients before ablation. Each CMRI was evaluated for the number of PVs, for separate or common insertion of ipsilateral PVs, for the PV diameter and PV shape (round vs. oval), for the level of first PV branching, and for the level of insertion of the right inferior PV (RIPV) into the left atrium (LA), respectively. Pulmonary vein isolation was performed using exclusively the novel EAS. The CMRI findings were correlated with the ablation results. A total of 195 PVs were identified and targeted. In 192 of 195 (98%) PVs successful isolation was achieved using the novel EAS irrespective of the PV diameter, the PV shape, the level of PV branching, or the type of insertion of the PV into the LA. There was no statistical significance when correlating the CMRI findings with acute isolation success of the respective PVs or the number of laser applications needed until PVI (P> 0.05). A low level of insertion of the RIPV into the LA was not associated with PVI failure or a higher number of laser applications (P> 0.05).



The majority of PVs could have been targeted and successfully isolated using exclusively the novel EAS irrespective of their anatomy assessed by pre-interventional CMRI. Considering the economical impact of CMRI and its minor influence on ablation strategy, success, and safety it is not an essential pre-requisite for subsequent successful EAS-based PVI.
Comparison of Gastrointestinal Blood Loss in Healthy Male Volunteers During Repeated Administration of Standard and Sustained Action Tiaprofenic Acid and Sustained Release Indomethacin

Gastrointestinal blood loss was measured in 30 healthy male volunteers before and during 4 weeks of oral treatment with either tiaprofenic acid tablets 300mg twice daily, tiaprofenic acid sustained action (SA) capsules 600mg once daily, or indomethacin sustained release (SR) capsules 75mg once daily, in an open parallel-group study of 38 days’ duration. Autologous erythrocytes labelled with 51Cr were given intravenously on the first study day. Gastrointestinal blood loss was measured by comparing faecal and red blood cell 5lCr activity during the second and fourth weeks of drug treatment. Blood loss was significantly greater during treatment with all 3 active preparations than during the pretreatment period, but this comparison is of limited value because placebo was not given in parallel and because in 4 subjects, who had to have their erythrocytes relabelled, there was no pretreatment data. The tiaprofenic acid SA group had consistently lower blood loss than the tiaprofenic acid tablet group. Both these groups also had consistently lower blood loss than the indomethacin SR group, although the difference between the treatment groups was not significant. Blood loss during the fourth week of treatment was less than during the second week of treatment for both the tiaprofenic acid SA and indomethacin SR capsule groups. With tiaprofenic acid tablets, blood loss was very similar at weeks 2 and 4 but this result should be viewed with caution because data at week 2 were missing for 3 subjects. Thus, formulation of tiaprofenic acid as a sustained action capsule does not appear to increase gastric irritancy as measured by faecal blood loss.
Does Cognitive Function Increase over Time in the Healthy Elderly?

In dementia screening, most studies have focused on early cognitive impairment by comparing patients suffering from mild dementia or mild cognitive impairment with normal subjects. Few studies have focused on modifications over time of the cognitive function in the healthy elderly. The objective of the present study was to analyze the cognitive function changes of two different samples, born > 15 years apart.



A first sample of 204 cognitively normal participants was recruited in the memory clinic of Broca hospital between 1991 and 1997. A second sample of 177 cognitively normal participants was recruited in 2008-2009 in the same institution. Both samples were from the same districts of Paris and were assessed with the same neuropsychological test battery. Mean cognitive test scores were compared between 1991 and 2008 samples, between < 80 years old and ≥ 80 years old in 1991 and 2008 samples, and finally between subjects < 80 year old of 1991 sample and subjects ≥ 80 years old of the 2008 sample. Means were compared with T-tests stratified on gender, age-groups and educational level.



Cognitive scores were significantly higher in the 2008 sample. Participants < 80 years old outperformed those ≥ 80 in both samples. However, participants < 80 years old in 1991 sample and subjects ≥ 80 in the 2008 sample, born on average in 1923, performed mostly identically.



This study showed a significant increase of cognitive scores over time. Further, contemporary octogenarians in the later sample performed like septuagenarians in the former sample. These findings might be consistent with the increase in life expectancy and life span in good health. The study highlights the necessity to take into account factors which may contaminate and artificially inflate the age-related differences in favor of younger to the older adults.
A Co-Operative Study: Clinical Characteristics of 334 Korean Patients with Moyamoya Disease Treated at Neurosurgical Institutes (1976–1994)

A co-operative study was conducted to determine the clinical characteristics of patients with moyamoya disease who were diagnosed and treated at neurosurgical institutes in Korea before 1995. Twenty-six hospitals contributed 505 cases and among them, the clinical characteristics of 334 patients with definite moyamoya disease were evaluated. The number of patients began to increase from the late 1980s, and after that approximately 20 patients were treated each year. There were two age peaks: from six to 15 and from 31 to 40 years of age. Haemorrhagic manifestations occurred in approximately 43% of the patients. The major clinical manifestations were haemorrhage in adults (62.4%) and ischaemia in children (61.2%). Overall 54.5% of the patients experienced decreased consciousness levels, mainly due to intracranial haemorrhage or cerebral infarction. In the patients with ischemic manifestations, the adult patients were more likely to have cerebral infarction than the pediatric patients (80% vs. 39%) and the pediatric patients were more likely to have TIA (61% vs. 25%). Thirty eight percent of the patients underwent bypass surgery and 53% of these procedures were performed bilaterally. Treatment policies, including indications for bypass surgery and commonly used drugs, were somewhat different according to the institution. Overall favorable outcome was 73%, and the most significant factor affecting poor outcome was haemorrhagic manifestation. This article describes the characteristics of 334 patients with moyamoya disease, who were diagnosed and treated at neurosurgical institutes in Korea before 1995.