tbuckley/cabot-search huggingface dataset:
Grape Polyphenols Prevent Fructose-Induced Oxidative Stress and Insulin Resistance in First-Degree Relatives of Type 2 Diabetic Patients
Authors: Marie Hokayem, Emilie Blond, Hubert Vidal, Karen Lambert, Emmanuelle Meugnier, Christine Feillet-Coudray, Charles Coudray, Sandra Pesenti, Cedric Luyton, Stéphanie Lambert-Porcheron, Valerie Sauvinet, Christine Fedou, Jean-Frédéric Brun, Jennifer Rieusset, Catherine Bisbal, Ariane Sultan, Jacques Mercier, Joelle Goudable, Anne-Marie Dupuy, Jean-Paul Cristol, Martine Laville, Antoine Avignon
Journal: Diabetes Care (2012)

To assess the clinical efficacy of nutritional amounts of grape polyphenols (PPs) in counteracting the metabolic alterations of high-fructose diet, including oxidative stress and insulin resistance (IR), in healthy volunteers with high metabolic risk.Thirty-eight healthy overweight/obese first-degree relatives of type 2 diabetic patients (18 men and 20 women) were randomized in a double-blind controlled trial between a grape PP (2 g/day) and a placebo (PCB) group. Subjects were investigated at baseline and after 8 and 9 weeks of supplementation, the last 6 days of which they all received 3 g/kg fat-free mass/day of fructose. The primary end point was the protective effect of grape PPs on fructose-induced IR.In the PCB group, fructose induced 1) a 20% decrease in hepatic insulin sensitivity index (P < 0.05) and an 11% decrease in glucose infusion rate (P < 0.05) as evaluated during a two-step hyperinsulinemic-euglycemic clamp, 2) an increase in systemic (urinary F2-isoprostanes) and muscle (thiobarbituric acid-reactive substances and protein carbonylation) oxidative stress (P < 0.05), and 3) a downregulation of mitochondrial genes and decreased mitochondrial respiration (P < 0.05). All the deleterious effects of fructose were fully blunted by grape PP supplementation. Antioxidative defenses, inflammatory markers, and main adipokines were affected neither by fructose nor by grape PPs.A natural mixture of grape PPs at nutritional doses efficiently prevents fructose-induced oxidative stress and IR. The current interest in grape PP ingredients and products by the global food and nutrition industries could well make them a stepping-stone of preventive nutrition.
Randomized Study of Intravenous versus Subcutaneous Interleukin-2, and IFNα in Patients with Good Prognosis Metastatic Renal Cancer
Authors: Sylvie Négrier, David Perol, Alain Ravaud, Jacques O. Bay, Stéphane Oudard, Sylvie Chabaud, Pierre Fargeot, Remy Delva, Gael Deplanque, Gwenaelle Gravis, Bernard Escudier
Journal: Clinical Cancer Research (2008)

Metastatic renal cancer patients with a single metastatic site are potentially amenable to interleukin 2 (IL-2) + IFN-alpha. A French immunotherapy intergroup multicenter trial assessed the potential benefit of i.v. over s.c. administration of IL-2 in this combination.Untreated patients with one metastatic site were randomized to continuous i.v. infusion (18 x 10(6) IU/m(2)/d; arm A) or twice daily s.c. injections (9 x 10(6) or 18 x 10(6) IU; arm B) of IL-2, associated with s.c. IFN-alpha (6 x 10(6) IU) 3 days per week in both arms. Tumor response was assessed (WHO criteria) at weeks 12 and 24 to 26. The primary end point was overall survival, with an expected 15% improvement at 4 years with i.v. IL-2. The planned sample size was 220 (80% power, 5% significance, one-sided test). Intent-to-treat analysis was done and survivals were compared using log-rank tests.From January 2000 to January 2005, 80 and 75 patients were randomized to arms A and B, respectively. Enrollment was stopped early because of low accrual; analysis was done at 42.5 months median follow-up. Patient characteristics were well balanced between groups. Response rates were 17.9% versus 21.3% in arms A and B. Progression-free survival rates were not significantly different. Overall survival difference was not significant: median 33 months (95% confidence interval, 27.0-40.2; P = 0.202).In combination with IFN-alpha in selected, good prognosis metastatic renal cell carcinoma patients, i.v. IL-2 offers no significant advantage over s.c. IL-2 and induces higher toxicity. Although i.v. IL-2 induced longer responses, it seems unreasonable to continue recommending this regimen after the recent introduction of more effective therapies.
Massive and destructive T cell response to homeostatic cue in CD24-deficient lymphopenic hosts
Authors: Ou Li, Xing Chang, Huiming Zhang, Ergun Kocak, Cheng Ding, Pan Zheng, Yang Liu
Journal: The Journal of Experimental Medicine (2006)

In response to a lymphopenic cue, T lymphocytes undergo a slow-paced homeostatic proliferation in an attempt to restore T cell cellularity. The molecular interaction that maintains the pace of homeostatic proliferation is unknown. In this study, we report that in lymphopenic CD24-deficient mice, T cells launch a massive proliferation that results in the rapid death of the recipient mice. The dividing T cells have phenotypes similar to those activated by cognate antigens. The rapid homeostatic proliferation is caused by a lack of CD24 on dendritic cells (DCs). Interestingly, although CD24 expression in T cells is required for optimal homeostatic proliferation in the wild-type (WT) host, mice lacking CD24 on all cell types still mount higher homeostatic proliferation than the WT mice. Thus, a lack of CD24 in the non–T host cells bypassed the requirement for T cell expression of CD24 in homeostatic proliferation in the WT host. Our data demonstrate that CD24 expressed on the DCs limits T cell response to homeostatic cue and prevents fatal damage associated with uncontrolled homeostatic proliferation.
Exercise and the platelet activator calcium chloride both influence the growth factor content of platelet-rich plasma (PRP): overlooked biochemical factors that could influence PRP treatment
Authors: Bruce Hamilton, Johannes L Tol, Wade Knez, Hakim Chalabi
Journal: British Journal of Sports Medicine (2013)

There is strong evidence that exercise affects platelet haemostasis factors, but this potential effect on growth factor concentrations in platelet-rich plasma (PRP) has never been studied. In addition, there is a paucity of studies focusing on the effects of activating agents used in conjunction with PRP. The first aim of this study was to evaluate the effect of exercise on platelet and platelet-derived growth factors (PDGF)-AB, hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) concentrations in PRP. The second aim was to study the effect of the activating agent calcium chloride (CaCl2) on growth factor concentration in relation to different exercise states.Controlled laboratory study. Ten healthy participants performed 1 h of submaximal exercise with blood being withdrawn immediately pre, post and 18 h following. PRP was prepared in each condition in both an activated CaCl2 and non-activated form. Concentrations of PDGF-AB, HGF, IGF-1 and VEGF were evaluated using standard ELISA systems.Exercise had no significant effect on platelet concentration, but significantly suppressed both VEGF and PDGF-AB concentrations. Exercise state had no significant effect on IGF-1 or HGF concentration. Activation with CaCl2 resulted in a significant increase in PDGF-AB and IGF-1 concentrations, unchanged VEGF and significantly reduced HGF concentrations.Exercise significantly impacts on PDGFs in PRP with significantly reduced concentrations of VEGF and PDFG-AB. Furthermore, the activation of PRP with CaCl2 results in a differentiated GF release from platelets. These relevant factors can potentially influence outcome in daily clinical practice and are recommended to be accounted for in future study design.
Two B-cell autoepitopes are recognized on the human BCKADC-E2 by PBC sera
Authors: A. Csepregi, A. Kayser, S. Kneip, P. Obermayer-Straub, C.P. Strassburg, E. Nemesánszky, F. Szalay, M.P. Manns
Journal: Journal of Hepatology (2001)
Threatened miscarriage: evaluation and management
Authors: Alexandros Sotiriadis, Stefania Papatheodorou, George Makrydimas
Journal: BMJ (2004)

Threatened miscarriage-vaginal bleeding before 20 gestational weeks-is the commonest complication in pregnancy, occurring in about a fifth of cases.w1 Miscarriage is 2.6 times as likely, 1 and 17% of cases are expected to present complications later in pregnancy. 2lthough general practitioners and gynaecologists often see this condition, management of threatened miscarriage is mostly empirical.Bed rest is routinely recommended, and about a third of women presenting with threatened miscarriage are prescribed drugs.w2 However, two thirds of the general practitioners recommending this do not believe it affects outcome. 3n this review, we present available evidence on the initial evaluation and management of threatened miscarriage, focusing mainly on the first trimester of pregnancy and primary healthcare settings.
Chronic Mineral Dysregulation Promotes Vascular Smooth Muscle Cell Adaptation and Extracellular Matrix Calcification
Authors: Rukshana C. Shroff, Rosamund McNair, Jeremy N. Skepper, Nichola Figg, Leon J. Schurgers, John Deanfield, Lesley Rees, Catherine M. Shanahan
Journal: Journal of the American Society of Nephrology (2009)

In chronic kidney disease (CKD) vascular calcification occurs in response to deranged calcium and phosphate metabolism and is characterized by vascular smooth muscle cell (VSMC) damage and attrition. To gain mechanistic insights into how calcium and phosphate mediate calcification, we used an ex vivo model of human vessel culture. Vessel rings from healthy control subjects did not accumulate calcium with long-term exposure to elevated calcium and/or phosphate. In contrast, vessel rings from patients with CKD accumulated calcium; calcium induced calcification more potently than phosphate (at equivalent calcium-phosphate product). Elevated phosphate increased alkaline phosphatase activity in CKD vessels, but inhibition of alkaline phosphatase with levamisole did not block calcification. Instead, calcification in CKD vessels most strongly associated with VSMC death resulting from calcium- and phosphate-induced apoptosis; treatment with a pan-caspase inhibitor ZVAD ameliorated calcification. Calcification in CKD vessels was also associated with increased deposition of VSMC-derived vesicles. Electron microscopy confirmed increased deposition of vesicles containing crystalline calcium and phosphate in the extracellular matrix of dialysis vessel rings. In contrast, vesicle deposition and calcification did not occur in normal vessel rings, but we observed extensive intracellular mitochondrial damage. Taken together, these data provide evidence that VSMCs undergo adaptive changes, including vesicle release, in response to dysregulated mineral metabolism. These adaptations may initially promote survival but ultimately culminate in VSMC apoptosis and overt calcification, especially with continued exposure to elevated calcium.
Mutations of<i>DNAH11</i>in patients with primary ciliary dyskinesia with normal ciliary ultrastructure
Authors: Michael R Knowles, Margaret W Leigh, Johnny L Carson, Stephanie D Davis, Sharon D Dell, Thomas W Ferkol, Kenneth N Olivier, Scott D Sagel, Margaret Rosenfeld, Kimberlie A Burns, Susan L Minnix, Michael C Armstrong, Adriana Lori, Milan J Hazucha, Niki T Loges, Heike Olbrich, Anita Becker-Heck, Miriam Schmidts, Claudius Werner, Heymut Omran, Maimoona A Zariwala
Journal: Thorax (2011)

<h3>Rationale</h3> Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (<i>DNAH11</i>). <h3>Objectives</h3> To test further for mutant <i>DNAH11</i> as a cause of PCD, <i>DNAH11</i> was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology. <h3>Methods</h3> 82 exons and intron/exon junctions in <i>DNAH11</i> were sequenced in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer and/or inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, <i>DNAH11</i> was sequenced in 13 subjects with isolated situs abnormalities to see if mutant <i>DNAH11</i> could cause situs defects without respiratory disease. <h3>Results</h3> Of the 58 unrelated patients with PCD with normal ultrastructure, 13 (22%) had two (biallelic) mutations in <i>DNAH11</i>; and two patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in <i>DNAH11</i>. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or loss-of-function splice-site mutations. <h3>Conclusions</h3> Mutations in <i>DNAH11</i> are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.
Natural T Cell–mediated Protection against Seasonal and Pandemic Influenza. Results of the Flu Watch Cohort Study
Authors: Andrew C. Hayward, Lili Wang, Nilu Goonetilleke, Ellen B. Fragaszy, Alison Bermingham, Andrew Copas, Oliver Dukes, Elizabeth R. C. Millett, Irwin Nazareth, Jonathan S. Nguyen-Van-Tam, John M. Watson, Maria Zambon, Anne M. Johnson, Andrew J. McMichael
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

A high proportion of influenza infections are asymptomatic. Animal and human challenge studies and observational studies suggest T cells protect against disease among those infected, but the impact of T-cell immunity at the population level is unknown.To investigate whether naturally preexisting T-cell responses targeting highly conserved internal influenza proteins could provide cross-protective immunity against pandemic and seasonal influenza.We quantified influenza A(H3N2) virus-specific T cells in a population cohort during seasonal and pandemic periods between 2006 and 2010. Follow-up included paired serology, symptom reporting, and polymerase chain reaction (PCR) investigation of symptomatic cases.A total of 1,414 unvaccinated individuals had baseline T-cell measurements (1,703 participant observation sets). T-cell responses to A(H3N2) virus nucleoprotein (NP) dominated and strongly cross-reacted with A(H1N1)pdm09 NP (P < 0.001) in participants lacking antibody to A(H1N1)pdm09. Comparison of paired preseason and post-season sera (1,431 sets) showed 205 (14%) had evidence of infection based on fourfold influenza antibody titer rises. The presence of NP-specific T cells before exposure to virus correlated with less symptomatic, PCR-positive influenza A (overall adjusted odds ratio, 0.27; 95% confidence interval, 0.11-0.68; P = 0.005, during pandemic [P = 0.047] and seasonal [P = 0.049] periods). Protection was independent of baseline antibodies. Influenza-specific T-cell responses were detected in 43%, indicating a substantial population impact.Naturally occurring cross-protective T-cell immunity protects against symptomatic PCR-confirmed disease in those with evidence of infection and helps to explain why many infections do not cause symptoms. Vaccines stimulating T cells may provide important cross-protective immunity.
Clinical utility of the pulmonary embolism rule-out criteria (PERC) in investigation of possible pulmonary embolism
Authors: Brendan Arnold, Rodric Jenkin, Owain Harris, Ben Brockway
Journal: European Respiratory Journal (2012)

The PERC score was proposed as a means of identifying patients who are at low risk of pulmonary embolism (PE) by Kline et al in 2004. We retrospectively applied the PERC rule to patients who presented to our institution between May 2007 and November 2008 who had a CT Pulmonary Angiogram (CTPA) for the investigation of possible PE. We postulated that a sequential exclusion process - using PERC, a dichotomous Wells score (cutoff at greater than 4), and then d-dimer if indicated would improve the diagnostic process by reducing unnecessary d-dimer testing and exposure to ionizing radiation.  249 CTPAs were performed for possible  clinical notes being available on 220. 186 patients were PERC positive, 34 negative. 174 had elevated quantitative d-dimer assays, and 52 had positive CTPA investigations. The positive predictive value of the PERC score was 28% and the negative predictive value 100%. D-dimer assay had a positive predictive value of 21.8% but a negative predictive value in our series of only 72.4%. Importantly in our study group no patients with a positive CTPA had a negative PERC score. The result of this small, retrospective, study suggest that the addition of the PERC score prior to standard testing would result in fewer negative CTPA examinations and/or d-dimer assays (reducing inappropriate exposure to ionizing radiation and costs). We suggest the PERC score as an additional risk stratification tool first line prior to the Wells (or Geneva) score and d-dimer assays. The format of the PERC domains may also reduce inter-operator variability in junior staff who may struggle with Alternative diagnosis less likely than PE, a clinical gestalt question.
<i>In silico</i> prediction of drug‐binding strengths to human serum albumin
Authors: Gonzalo Colmenarejo
Journal: Medicinal Research Reviews (2003)

Abstract Drug binding to Human Serum Albumin (HSA) is an area of intense research. The pharmacokinetics and pharmacodynamics of drugs are strongly affected by their binding to this protein. In this article, the field is reviewed, as well as our models to predict drug‐binding affinities to HSA from drug structure. The physiological role of HSA is described, as well as its influence in drug action. The crystal structures of this protein are discussed, emphasizing the two drug‐binding sites and the fatty acids binding sites observed therein. The advantages of using high‐performance affinity chromatography to rapidly screen drugs for HSA binding are explained. The different QSAR models for HSA binding of restricted families of drugs (both from other groups and our group) are enumerated. Finally, a detailed description of our general models to predict drug‐binding strengths to HSA from structure is given. It is expected for these models to be useful in drug design and pharmaceutical research. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 3, 275‐301, 2003
What errors do peer reviewers detect, and does training improve their ability to detect them?
Authors: Sara Schroter, Nick Black, Stephen Evans, Fiona Godlee, Lyda Osorio, Richard Smith
Journal: Journal of the Royal Society of Medicine (2008)

Objective To analyse data from a trial and report the frequencies with which major and minor errors are detected at a general medical journal, the types of errors missed and the impact of training on error detection. Design 607 peer reviewers at the BMJ were randomized to two intervention groups receiving different types of training (face-to-face training or a self-taught package) and a control group. Each reviewer was sent the same three test papers over the study period, each of which had nine major and five minor methodological errors inserted. Setting BMJ peer reviewers. Main outcome measures The quality of review, assessed using a validated instrument, and the number and type of errors detected before and after training. Results The number of major errors detected varied over the three papers. The interventions had small effects. At baseline (Paper 1) reviewers found an average of 2.58 of the nine major errors, with no notable difference between the groups. The mean number of errors reported was similar for the second and third papers, 2.71 and 3.0, respectively. Biased randomization was the error detected most frequently in all three papers, with over 60% of reviewers rejecting the papers identifying this error. Reviewers who did not reject the papers found fewer errors and the proportion finding biased randomization was less than 40% for each paper. Conclusions Editors should not assume that reviewers will detect most major errors, particularly those concerned with the context of study. Short training packages have only a slight impact on improving error detection.
Trauma and Psychosis: An Analysis of the National Comorbidity Survey
Authors: Mark Shevlin, Martin J. Dorahy, Gary Adamson
Journal: American Journal of Psychiatry (2007)

The authors hypothesized that the likelihood of psychosis classification would increase with traumatic experiences.Data from the National Comorbidity Survey were used to estimate the relationship between interpersonal trauma and the likelihood of a classification of psychosis.Childhood physical abuse predicted psychosis, and there was a significant cumulative relationship between trauma and psychosis, with number of trauma types experienced increasing the probability of psychosis.Overall, physical abuse predicted psychosis. In addition, a significant gender-by-rape interaction was observed, with rape having higher predictive value for psychosis in male subjects.
High Risk of Subsequent Neoplasms Continues With Extended Follow-Up of Childhood Hodgkin’s Disease: Report From the Late Effects Study Group
Authors: Smita Bhatia, Yutaka Yasui, Leslie L. Robison, Jillian M. Birch, Monica K. Bogue, Lisa Diller, Cyndi DeLaat, Franca Fossati-Bellani, Elaine Morgan, Odile Oberlin, Gregory Reaman, Frederick B. Ruymann, Jean Tersak, Anna T. Meadows
Journal: Journal of Clinical Oncology (2003)

We present an update of a previously reported Late Effects Study Group cohort of 1,380 children with Hodgkin's disease (HD) diagnosed between 1955 and 1986 in patients aged 16 years or younger. We describe the pattern and incidence of subsequent neoplasms (SNs) occurring with extended follow-up.Median age at diagnosis of HD was 11.7 years (range, 0.3 to 16.9 years) and at last follow-up was 27.8 years. Median length of follow-up was 17.0 years.An additional 103 SNs were ascertained (total SNs = 212). The cohort was at an 18.5-fold increased risk of developing SNs compared with the general population (standardized incidence ratio [SIR], 18.5, 95% CI, 15.6 to 21.7). The cumulative incidence of any second malignancy was 10.6% at 20 years, increasing to 26.3% at 30 years; and of solid malignancies was 7.3% at 20 years, increasing to 23.5% at 30 years. Breast cancer was the most common solid malignancy (SIR, 56.7). Other commonly occurring solid malignancies included thyroid cancer (SIR, 36.4), bone tumors (SIR, 37.1), and colorectal (SIR, 36.4), lung (SIR, 27.3), and gastric cancers (SIR, 63.9). Risk factors for solid tumors included young age at HD and radiation-based therapy. Thirty-two patients developed third neoplasms, with the cumulative incidence approaching 21% at 10 years from diagnosis of second malignancy.Additional follow-up of this large cohort of HD survivors documents an increasing occurrence of known radiation-associated solid tumors, (breast and thyroid cancers), as well as emergence of epithelial neoplasms common in adults, (colon and lung cancers) at a younger age than expected in the general population, necessitating ongoing surveillance of this high risk population.