nils-herrmann/clean_scirepeval huggingface dataset:
Activated platelets in subjects at increased risk of IDDM

Activated platelets respond to activated leukocytes and endothelial cells via adhesion molecules linking inflammation and thrombosis. Platelets of recent-onset insulin-dependent diabetic (IDDM) patients have been shown to be activated independent of metabolic control. This study evaluates the levels of circulating activated platelets exposing adhesion molecules in healthy subjects at increased risk of IDDM (surface markers were: P-selectin (CD62), thrombospondin, lysosomal GP53 (CD63) ). From the DENIS and the ENDIT screening programmes 19 identified islet cell antibody positive (titre ≥ 20 Juvenile Diabetes Foundation units) first degree relatives of IDDM patients (male/female 9/10; age 22 ± 15 years; body mass index (BMI): 20.0 ± 4.3 kg/m2) with clearly normal metabolism (HbA1: 6.1 ± 0.8 %; fasting blood glucose: 4.95 ± 0.67 mmol/l) were available for this investigation. Platelet CD62 as well as thrombospondin and CD63 expression were determined by flow cytometry. We matched 50 normal volunteers for age (29 ± 6 years), anthropometric measures (male/female 26/24; BMI: 22.3 ± 2.8 kg/m2) and metabolic parameters (HbA1: 5.8 % ± 0.3; fasting blood glucose: 4.41 ± 0.53 mmol/l) served as control subjects. The mean number of CD62+ platelets was increased 3.2-times in prediabetic patients: 1.94 × 2.91±1 vs 0.60 × 1.83±1 %, p < 0.0001. Thrombospondin+ and CD63+ platelet levels were concomitantly increased (1.45 × 2.38±1/5.97 × 2.89±1 % vs 0.52 × 2.01±1/1.64 × 2.26±1 %, p < 0.0001 for both comparisons). Thus, intravasal platelet activation is already present in potentially prediabetic subjects representing an antecedent, potentially pathogenic feature of IDDM.
Influence of cervical bone mineral density on cage subsidence in patients following stand-alone anterior cervical discectomy and fusion

Anterior cervical discectomy and fusion (ACDF) is a common procedure for the treatment of cervical degenerative diseases. However, cage subsidence remains a frequent problem. We therefore investigated if cage design and site-specific bone mineral density (BMD) contribute to the rate and direction of subsidence following ACDF. Patients were prospectively included and received two different cages (groups 1 and 2) using minimization randomization. The degree and direction of cage subsidence were determined using plain radiographs. Neck pain intensity on the visual analogue scale (VAS), the neck disability index (NDI), and the patient satisfaction index were recorded up to 12 months after surgery. 88 patients were analysed with a mean age of 53.7 ± 11.8 years. BMD values decreased in craniocaudal direction from 302.0 ± 62.2 to 235.5 ± 38.9 mg/cm3. Both groups showed significant height gain after the operation (both p < 0.001), followed by height loss at 3 months (both p < 0.05) and at 3–12 months after the operation (both p > 0.05). Both groups showed improvement of VAS neck pain intensity (both p < 0.05) and NDI (both p < 0.05). The direction of cage subsidence was similar, no correlations were found between cage subsidence and BMD or various clinical parameters. Implant geometry of both cages and variations of the operative procedure promoted a relatively high degree of cage subsidence. Further studies are necessary to identify a relation of BMD and subsidence using optimized implant geometry and by controlling additional intraoperative variables.
Randomized, double-blind, placebo-controlled study of ascorbate on the preventive effect of nitrate tolerance in patients with congestive heart failure.

Reduced cGMP production caused by increased superoxide has been proposed as a mechanism of nitrate tolerance during continuous nitrate therapy. This study was designed to evaluate the effects of ascorbate, an antioxidant, on the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.



Twenty patients with congestive heart failure were randomized to receive intravenous infusion of nitroglycerin concomitantly with placebo (placebo group, n=10) or intravenous ascorbate (vitamin C group, n=10). After baseline measurements were obtained, dose titration was started by the infusion of nitroglycerin at a rate of 0.5 microg/kg per minute (titration period). Measurements of hemodynamic parameters and blood sampling were performed serially at 0, 6, 12, 18, and 24 hours after the titration period. At baseline, mean pulmonary artery pressure (MPAP, mm Hg), mean pulmonary capillary wedge pressure (PCWP, mm Hg), plasma vitamin E level (micromol/L), and platelet cGMP level (pmol/10[9] platelets) were comparable in the two groups (placebo group: MPAP, 48+/-6; PCWP, 24+/-4; cGMP, 0.76+/-0.12; vitamin E, 18.2+/-1.2; vitamin C: MPAP, 49+/-7; PCWP, 24+/-4; cGMP, 0.71+/-0.16; vitamin E, 18.6+/-1.3). In both groups, at 6 hours after the titration period, MPAP and PCWP were significantly decreased (placebo group: MPAP, 26+/-5; PCWP, 15+/-4; vitamin C: MPAP, 26+/-4; PCWP, 16+/-4), and platelet cGMP was significantly increased (placebo group: 2.42+/-0.24; vitamin C: 2.26+/-0.26). However, at 18 hours after titration, in the placebo group, MPAP (44+/-5) and PCWP (23+/-4) were increased, and platelet cGMP (0.85+/-0.20) and plasma vitamin E levels (12.4+/-1.4) were significantly decreased. In contrast, in the vitamin C group, MPAP (31+/-6), PCWP (17+/-5), platelet cGMP (2.49+/-0.23), and plasma vitamin E levels (17.6+/-1.4) were maintained for 18 hours after the titration period.



These findings indicate that ascorbate, an antioxidant, may prevent the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.
Measuring [18F]FDG uptake in breast cancer during chemotherapy: comparison of analytical methods

Over the years several analytical methods have been proposed for the measurement of glucose metabolism using fluorine-18 fluorodeoxyglucose ([18F]FDG) and positron emission tomography (PET). The purpose of this study was to evaluate which of these (often simplified) methods could potentially be used for clinical response monitoring studies in breast cancer. Prior to chemotherapy, dynamic [18F]FDG scans were performed in 20 women with locally advanced (n=10) or metastasised (n=10) breast cancer. Additional PET scans were acquired after 8 days (n=8), and after one, three and six courses of chemotherapy (n=18, 10 and 6, respectively). Non-linear regression (NLR) with the standard two tissue compartment model was used as the gold standard for measurement of [18F]FDG uptake and was compared with the following methods: Patlak graphical analysis, simplified kinetic method (SKM), SUV-based net influx constant ("Sadato" method), standard uptake value [normalised for weight, lean body mass (LBM) and body surface area (BSA), with and without corrections for glucose (g)], tumour to non-tumour ratio (TNT), 6P model and total lesion evaluation (TLE). Correlation coefficients between each analytical method and NLR were calculated using multilevel analysis. In addition, for the most promising methods (Patlak, SKM, SUVLBMg and SUVBSAg) it was explored whether correlation with NLR changed with different time points after the start of therapy. Three methods showed excellent correlation (r>0.95) with NLR for the baseline scan: Patlak10–60 and Patlak10–45 (r=0.98 and 0.97, respectively), SKM40–60 (r=0.96) and SUVLBMg (r=0.96). Good correlation was found between NLR and SUV-based net influx constant, TLE and SUVBSAg (0.90<r<0.95). The 6P model and TNT had the lowest correlation (r≤0.84). SUV was least accurate in predicting changes in [18F]FDG uptake over time during therapy. For all methods, correlation with NLR was significantly lower for bone metastases than for other (primary or metastatic) tumour lesions (P<0.05). In conclusion, three methods with different degrees of complexity appear to be promising alternatives to NLR for measuring glucose metabolism in breast cancer: Patlak, SKM and SUV (normalised for LBM and with a correction for plasma glucose).
Elimination of high-risk human papillomavirus type HPV16 infection by ‘Praneem’ polyherbal tablet in women with early cervical intraepithelial lesions

‘Praneem’, a polyherbal formulation developed by us, has successfully completed Phase II efficacy study for treatment of abnormal vaginal discharge due to reproductive tract infections that act as co-factors for HPV persistence. In the present study we evaluated potential anti-HPV activity of Praneem in women infected with high risk HPV type 16. Twenty women molecularly diagnosed positive for HPV16 infection without or with low grade squamous intraepithelial lesion (LSIL) or inflammation were assigned to receive intra-vaginal, topical application of either Praneem tablet or placebo for 30 days excluding the days of menstrual period and were evaluated for persistence of HPV infection using HPV L1 consensus and HPV type 16-specific PCR as primary outcome. One course of Praneem treatment resulted in elimination of HPV in 6 out of 10 (60%) cases. A repeat treatment of four patients with persisting HPV infection resulted in clearance of HPV in two additional cases resulting in an overall 80% clearance of HPV 16 as against a spontaneous clearance of 10% (1/10) seen in the placebo arm. The elimination of HPV DNA was found to be accompanied by marked improvement in clinical symptoms and cytological abnormalities of Praneem-treated patients. Our results showed for the first time that a 30-day intra-vaginal application of the Praneem can result in elimination of HPV infection from the uterine cervix.
New technologies and concepts for rehabilitation in the acute phase of stroke: a collaborative matrix.

The process of developing a successful stroke rehabilitation methodology requires four key components: a good understanding of the pathophysiological mechanisms underlying this brain disease, clear neuroscientific hypotheses to guide therapy, adequate clinical assessments of its efficacy on multiple timescales, and a systematic approach to the application of modern technologies to assist in the everyday work of therapists. Achieving this goal requires collaboration between neuroscientists, technologists and clinicians to develop well-founded systems and clinical protocols that are able to provide quantitatively validated improvements in patient rehabilitation outcomes. In this article we present three new applications of complementary technologies developed in an interdisciplinary matrix for acute-phase upper limb stroke rehabilitation - functional electrical stimulation, arm robot-assisted therapy and virtual reality-based cognitive therapy. We also outline the neuroscientific basis of our approach, present our detailed clinical assessment protocol and provide preliminary results from patient testing of each of the three systems showing their viability for patient use.
TBL1XR1/TP63: a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma.

Recently, the landscape of single base mutations in diffuse large B-cell lymphoma (DLBCL) was described. Here we report the discovery of a gene fusion between TBL1XR1 and TP63, the only recurrent somatic novel gene fusion identified in our analysis of transcriptome data from 96 DLBCL cases. Based on this cohort and a further 157 DLBCL cases analyzed by FISH, the incidence in de novo germinal center B cell-like (GCB) DLBCL is 5% (6 of 115). The fusion appears exclusive to GCB and was not seen in 138 non-GCB cases examined (P = .008, Fisher exact test) but was present at low incidence in follicular lymphoma (1 of 81). In all 7 cases identified, the 3' end of the fusion consists of exons 4 and onwards of TP63. The recurrence, subtype enrichment, and the remarkably conserved nature of the TP63 portion of the fusion suggest an important functional role in the lymphomas that harbor this event.
A phase I trial of perillyl alcohol in patients with advanced solid tumors

Perillyl alcohol is a plant-derived lipid with preclinical antitumor activity. Its proposed mechanism of action involves inhibition of post-translational isoprenylation of small G proteins, including the proto-oncogene p21-ras, thereby blocking signal transduction. This phase I trial was conducted to determine the optimal dose of perillyl alcohol.  The study group comprised 21 adults with advanced solid tumors who were treated with perillyl alcohol, delivered orally, four times daily, without interruption. Doses ranged from 4,800 to 11,200 mg/m2 per day.  The maximum tolerated dose (MTD) for this schedule was determined to be 8400 mg/m2 per day. The dose-limiting toxicities in this trial were nausea and vomiting, encountered in all patients at the highest dose level. No antitumor activity was observed. Pharmacokinetic data suggest dose-dependent increases in Cmax of perillic acid, a metabolite of perillyl alcohol, but with high inter- and intrapatient variability.  The MTD of perillyl alcohol for this schedule was determined to be 8400 mg/m2 per day. This is higher than the MTDs determined in other similar phase I trials. This may have been due to the fact that the gastrointestinal symptoms caused by perillyl alcohol are highly subjective, with high interpatient variability. Phase II trials of perillyl alcohol in hormone-refractory prostate, breast, ovarian and colorectal cancer using doses in the range 4800–6400 mg/m2 per day are underway.
Specification and Design Considerations for Reliable Embedded Systems

The objective of this paper is to introduce a novel representation as a means to consider both permanent and temporal errors in order to increase the overall reliability of an embedded system. The deployment of embedded systems in safety critical applications, e.g. in the automotive domain, demands that the fundamental set of design criteria consisting of functionality, timeliness, and production costs be extended to consider of reliability as an optimization criterion. Thus reliability engineering becomes part of the overall design flow for embedded systems. The proposed approach is based on the introduction of Permanent/Transient error Decision Diagrams and on dedicated algorithms for the generation of system implementation sets which feature maximum reliability at minimal costs in terms of redundant resources. The proposed approach is demonstrated for a control system taken from the automotive domain.
Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA†

We characterized the incidence of central nervous system (CNS) metastases after treatment with trastuzumab emtansine (T-DM1) versus capecitabine-lapatinib (XL), and treatment efficacy among patients with pre-existing CNS metastases in the phase III EMILIA study.



In EMILIA, patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer previously treated with trastuzumab and a taxane were randomized to T-DM1 or XL until disease progression. Patients with treated, asymptomatic CNS metastases at baseline and patients developing postbaseline CNS metastases were identified retrospectively by independent review; exploratory analyses were carried out.



Among 991 randomized patients (T-DM1 = 495; XL = 496), 95 (T-DM1 = 45; XL = 50) had CNS metastases at baseline. CNS progression occurred in 9 of 450 (2.0%) and 3 of 446 (0.7%) patients without CNS metastases at baseline in the T-DM1 and XL arms, respectively, and in 10 of 45 (22.2%) and 8 of 50 (16.0%) patients with CNS metastases at baseline. Among patients with CNS metastases at baseline, a significant improvement in overall survival (OS) was observed in the T-DM1 arm compared with the XL arm [hazard ratio (HR) = 0.38; P = 0.008; median, 26.8 versus 12.9 months]. Progression-free survival by independent review was similar in the two treatment arms (HR = 1.00; P = 1.000; median, 5.9 versus 5.7 months). Multivariate analyses demonstrated similar results. Grade ≥3 adverse events were reported in 48.8% and 63.3% of patients with CNS metastases at baseline administered T-DM1 and XL, respectively; no new safety signals were observed.



In this retrospective, exploratory analysis, the rate of CNS progression in patients with HER2-positive advanced breast cancer was similar for T-DM1 and for XL, and higher overall in patients with CNS metastases at baseline compared with those without CNS metastases at baseline. In patients with treated, asymptomatic CNS metastases at baseline, T-DM1 was associated with significantly improved OS compared with XL.
Distribution of LGR5+ Cells and Associated Implications during the Early Stage of Gastric Tumorigenesis

Lgr5 was identified as a promising gastrointestinal tract stem cell marker in mice. Lineage tracing indicates that Lgr5(+) cells may not only be the cells responsible for the origin of tumors; they may also be the so-called cancer stem cells. In the present study, we investigated the presence of Lgr5(+) cells and their biological significance in normal human gastric mucosa and gastric tumors. RNAscope, a newly developed RNA in situ hybridization technique, specifically labeled Lgr5(+) cells at the basal glands of the gastric antrum. Notably, the number of Lgr5(+) cells was remarkably increased in intestinal metaplasia. In total, 76% of gastric adenomas and 43% of early gastric carcinomas were positive for LGR5. Lgr5(+) cells were found more frequently in low-grade tumors with active Wnt signaling and an intestinal gland type, suggesting that LGR5 is likely involved in the very early stages of Wnt-driven tumorigenesis in the stomach. Interestingly, similar to stem cells in normal tissues, Lgr5(+) cells were often restricted to the base of the tumor glands, and such Lgr5(+) restriction was associated with high levels of intestinal stem cell markers such as EPHB2, OLFM4, and ASCL2. Thus, our findings show that Lgr5(+) cells are present at the base of the antral glands in the human stomach and that this cell population significantly expands in intestinal metaplasias. Furthermore, Lgr5(+) cells are seen in a large number of gastric tumors ; their frequent basal arrangements and coexpression of ISC markers support the idea that Lgr5(+) cells act as stem cells during the early stage of intestinal-type gastric tumorigenesis.
Effectiveness of laparoscopic total and partial fundoplication on extraesophageal manifestations of gastroesophageal reflux disease: a randomized study.

The aim of the present study was to evaluate the clinical effect of partial and total fundoplication on extraesophageal symptoms in a selected cohort of patients with gastroesophageal reflux disease (GERD). Hundred patients with documented GERD were randomized to either undergo floppy Nissen (n = 50) or Toupet fundoplication (n = 50). Symptom scores of cough, asthma, hoarseness, and distortion of taste were prospectively evaluated using a standardized symptom questionnaire before surgery and at 3- and 12-month follow-up. Statistical significance was set at a P-value of 0.05. All evaluated symptoms exhibited substantial improvement after Nissen fundoplication at 3- and 12-month follow-up. Similar therapeutic results were documented for Toupet fundoplication, although statistical significance could not be reached for asthma at long-term follow-up. In conclusion, the application of laparoscopic fundoplication is justified for patients with documented GERD and atypical symptoms refractory to medical treatment. Toupet fundoplication may have a lesser effect on asthma.
High-dose Chemotherapy in Lung Cancer

68S 5th World Conference on Lung Cancer in oat cell carcinonma of the lung. Cancer 1982; 50:1084-90 18 Minna JI), lhde DC, Buni, PA, et aI. Exteimsive stage small cell carcinon,a of the lung (SSCL): effect of increasing intensity of inductiom, chemotherapy. Proc AACR’ASCO 1980; 21:448 19 VogelSE, Nlehta C. Standard (STD) vs Intensive (INT) ii,duction cheniotherapv of small cell bronchogenic carcinoma (SCBC) with cyclophosphamnide (C), CCNU (Cc) amid methotrexate (M), &illowed by continued CCcM or cyclic miiaintenance therapya randomized trial of the Eastern Cooperative Oi,cologv Group.  22:199 20 Ilide DC, Johnson BE, Nlulshine JL, et al. Randomized trial of high doss’ vs. standard dose etoposide and cisplatin (VP1&’Plat) in extensive stage small cell lung cancer (SCLC).  21 Klastersky J, Nicaise C, Longeval E, etal. Cisplatin, adriarnycimm and etoposide (CA\’) for remission induction of sniall cell bromichogenic carcinoma: Evaluation of efRcacy and toxicity amid
Bilateral subthalamic nucleus stimulation does not improve prolonged P300 latencies in Parkinson's disease

Bilateral deep brain stimulation is an effective treatment for most motor signs of Parkinson's disease (PD), but the effects on cognitive functions are less clear. We therefore examined the effects of bilateral deep brain stimulation on central information processing, using the event-related auditory P300 potential as an electrophysiological index of mental chronometry. Eight PD patients with bilateral stimulators within the subthalamic nuclei (STN) and eight age-matched controls participated. Patients were examined after overnight withdrawal of antiparkinson medication, both “on” and “off” stimulation (in random sequence). The P300 and reaction times were recorded using an auditory oddball paradigm. P300 latencies were prolonged in PD patients off stimulation (440 ± 45 ms) compared to controls (397 ± 16 ms; P < 0.05). STN stimulation significantly reduced clinical disease severity (as indexed by the Unified Parkinson's Disease Rating Scale) and markedly improved reaction times, but did not improve the prolonged P300 latencies in PD patients (429 ± 36 ms). These results confirm that P300 latencies are prolonged in PD. Significantly, bilateral STN stimulation did not improve this electrophysiological measure of cognitive impairment, even though motor disability was markedly reduced. This suggests that some dopa-responsive features are resistant to STN stimulation, possibly due to involvement of dopaminergic deficits outside the nigrostriatal pathway, which are not influenced by outflow from the STN.
Effect of Acetazolamide on Obesity-Induced Glomerular Hyperfiltration: A Randomized Controlled Trial

Obesity is an important risk factor for the development of chronic kidney disease. One of the major factors involved in the pathogenesis of obesity-associated kidney disease is glomerular hyperfiltration. Increasing salt-delivery to the macula densa is expected to decrease glomerular filtration rate (GFR) by activating tubuloglomerular feedback. Acetazolamide, a carbonic anhydrase inhibitor which inhibits salt reabsorption in the proximal tubule, increases distal salt delivery. Its effects on obesity-related glomerular hyperfiltration have not previously been studied. The aim of this investigation was to evaluate whether administration of acetazolamide to obese non diabetic subjects reduces glomerular hyperfiltration.



The study was performed using a randomized double-blind crossover design. Obese non-diabetic men with glomerular hyperfiltration were randomized to receive intravenously either acetazolamide or furosemide at equipotent doses. Twelve subjects received the allocated medications. Two weeks later, the same subjects received the drug which they had not received during the first study. Inulin clearance, p-aminohippuric acid clearance and fractional lithium excretion were measured before and after medications administration. The primary end point was a decrease in GFR, measured as inulin clearance.



GFR decreased by 21% following acetazolamide and did not decrease following furosemide. Renal vascular resistance increased by 12% following acetazolamide, while it remained unchanged following furosemide administration. Natriuresis increased similarly following acetazolamide and furosemide administration. Sodium balance was similar in both groups.



Intravenous acetazolamide decreased GFR in obese non-diabetic men with glomerular hyperfiltration. Furosemide, administered at equipotent dose, did not affect GFR, suggesting that acetazolamide reduced glomerular hyperfiltration by activating tubuloglomerular feedback.