tbuckley/cabot-search huggingface dataset:
Impaired Fasting Glucose Is Associated With Renal Hyperfiltration in the General Population
Authors: Toralf Melsom, Ulla Dorte Mathisen, Ole C. Ingebretsen, Trond G. Jenssen, Inger Njølstad, Marit D. Solbu, Ingrid Toft, Bjørn O. Eriksen
Journal: Diabetes Care (2011)

Increased glomerular filtration rate (GFR), also called hyperfiltration, is a proposed mechanism for renal injury in diabetes. The causes of hyperfiltration in individuals without diabetes are largely unknown, including the possible role of borderline hyperglycemia. We assessed whether impaired fasting glucose (IFG; 5.6-6.9 mmol/L), elevated HbA1c, or hyperinsulinemia are associated with hyperfiltration in the general middle-aged population.A total of 1,560 individuals, aged 50-62 years without diabetes, were included in the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6). GFR was measured as single-sample plasma iohexol clearance. Hyperfiltration was defined as GFR>90th percentile, adjusted for sex, age, weight, height, and use of renin-angiotensin system inhibitors.Participants with IFG had a multivariable-adjusted odds ratio of 1.56 (95% CI 1.07-2.25) for hyperfiltration compared with individuals with normal fasting glucose. Odds ratios (95% CI) of hyperfiltration calculated for a 1-unit increase in fasting plasma glucose (FPG) and HbA1c, after multivariable-adjustment, were 1.97 (1.36-2.85) and 2.23 (1.30-3.86). There was no association between fasting insulin levels and hyperfiltration. A nonlinear association between FPG and GFR was observed (df=3, P<0.0001). GFR increased with higher glucose levels, with a steeper slope beginning at FPG≥5.4 mmol/L.Borderline hyperglycemia was associated with hyperfiltration, whereas hyperinsulinemia was not. Longitudinal studies are needed to investigate whether the hyperfiltration associated with IFG is a risk factor for renal injury in the general population.
Arrhythmogenic Substrate of the Pulmonary Veins Assessed by High-Resolution Optical Mapping
Authors: Rishi Arora, Sander Verheule, Luis Scott, Antonio Navarrete, Vikram Katari, Emily Wilson, Dev Vaz, Jeffrey E. Olgin
Journal: Circulation (2003)

Background— It has recently been recognized that atrial fibrillation can originate from focal sources in the pulmonary veins (PVs). However, the mechanisms of focal atrial fibrillation have not been well characterized. We assessed the electrophysiological characteristics of the PVs using high-resolution optical mapping. Methods and Results— Coronary-perfused, isolated whole-atrial preparations from 33 normal dogs were studied. Programmed electrical stimulation was performed, and a 4-cm 2 area of the PV underwent optical mapping of transmembrane voltage to obtain 256 simultaneous action potentials. Marked conduction slowing was seen at the proximal PV, compared with the rest of the vein, on both the epicardial (31.3±4.47 versus 90.2±20.7 cm/s, P =0.001) and endocardial (45.8±6.90 versus 67.6±10.4 cm/s, P =0.012) aspects. Pronounced repolarization heterogeneity was also noted, with action potential duration at 80% repolarization being longest at the PV endocardium. Nonsustained reentrant beats were induced with single extrastimuli, and the complete reentrant loop was visualized (cycle length, 155±30.3 ms); reentrant activity could be sustained with isoproterenol. Sustained focal discharge (cycle length, 330 to 1100 ms) was seen from the endocardial surface in the presence of isoproterenol; each focus was localized near the venous ostium. Conclusions— The normal PV seems to have the necessary substrate to support reentry as well as focal activity. Although reentry occurred more distally in the vein, focal activity seemed to occur more proximally.
UK children are more likely than others in Europe to rank their health as poor
Authors: Bryan Christie
Journal: BMJ (2008)

The government and the drug industry this week reached an outline agreement on a new contract for drug prices in the United Kingdom over the next five years.It is expected that the deal will cut the annual £9bn (€11bn; $18bn) drug bill in the UK's health services by 5% by 2009.The announcement follows a year of intense and tough negotiations after the Department of Health said it was unilaterally cancelling the current pharmaceutical price regulation scheme (PPRS) halfway through its planned duration (BMJ 2007;335:273).The PPRS, which normally runs for five years, allows companies to set drug prices freely but caps their overall profits.The current scheme began in 2005, with a 7% price cut, and was supposed to end in 2010.Under pressure to cut costs at a time when the growth in the NHS budget is slowing, the government sought a fresh reduction of 10%, arguing that drug prices in Britain were among the highest in Europe.Partly aided by changing exchange rates, the industry claimed instead that British prices were nearer to the European average.It also expressed concerns that the government risked undermining the UK's historical attractiveness for research and development investment by creating instability through reneging on the PPRS deal.The new contract entails a price freeze until the end of this year and then a minimum price cut of 2% in patented drugs at the start of 2009.There will also be bigger reductions in the price of branded drugs no longer on patent, providing an overall reduction of 5%.Further price cuts are possible in future years if the drug bill increases by more than 6.7% annually.In line with recommendations last year from the Office of Fair Trading (BMJ 2007;334:383), the government plans to ensure that prices paid for new drugs more closely reflect the value that they offer.Andrew Jack is the pharmaceuticals correspondent for the Financial Times. Government and industry reach pricing deal to cut drugs bill
ZP Domain Proteins in the Abalone Egg Coat Include a Paralog of VERL under Positive Selection That Binds Lysin and 18-kDa Sperm Proteins
Authors: J. E. Aagaard, V. D. Vacquier, M. J. MacCoss, W. J. Swanson
Journal: Molecular Biology and Evolution (2009)

Identifying fertilization molecules is key to our understanding of reproductive biology, yet only a few examples of interacting sperm and egg proteins are known. One of the best characterized comes from the invertebrate archeogastropod abalone (Haliotis spp.), where sperm lysin mediates passage through the protective egg vitelline envelope (VE) by binding to the VE protein vitelline envelope receptor for lysin (VERL). Rapid adaptive divergence of abalone lysin and VERL are an example of positive selection on interacting fertilization proteins contributing to reproductive isolation. Previously, we characterized a subset of the abalone VE proteins that share a structural feature, the zona pellucida (ZP) domain, which is common to VERL and the egg envelopes of vertebrates. Here, we use additional expressed sequence tag sequencing and shotgun proteomics to characterize this family of proteins in the abalone egg VE. We expand 3-fold the number of known ZP domain proteins present within the VE (now 30 in total) and identify a paralog of VERL (vitelline envelope zona pellucida domain protein [VEZP] 14) that contains a putative lysin-binding motif. We find that, like VERL, the divergence of VEZP14 among abalone species is driven by positive selection on the lysin-binding motif alone and that these paralogous egg VE proteins bind a similar set of sperm proteins including a rapidly evolving 18-kDa paralog of lysin, which may mediate sperm–egg fusion. This work identifies an egg coat paralog of VERL under positive selection and the candidate sperm proteins with which it may interact during abalone fertilization.
Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40).
Authors: J Van Snick, A Goethals, J C Renauld, E Van Roost, C Uyttenhove, M R Rubira, R L Moritz, R J Simpson
Journal: The Journal of Experimental Medicine (1989)

Recently, we described a murine helper T cell-derived molecule with T cell growth factor activity that is functionally and structurally distinct from IL-2, IL-4, and other known growth factors. This molecule, designated P40, was identified as a glycoprotein capable of supporting antigen-independent growth of certain helper T cell clones. Here, we report the cloning and expression of a cDNA for this new growth factor. The predicted mature protein is a cationic cysteine-rich polypeptide of 14 kD without significant homology to previously sequenced proteins.
Phase III placebo-controlled double-blind randomized trial of radiotherapy for stage IIB–IVA cervical cancer with or without immunomodulator Z-100: a JGOG study
Authors: T. Sugiyama, K. Fujiwara, Y. Ohashi, H. Yokota, M. Hatae, T. Ohno, Y. Nagai, N. Mitsuhashi, K. Ochiai, K. Noda
Journal: Annals of Oncology (2014)
Randomized Study of the Crush Technique Versus Provisional Side-Branch Stenting in True Coronary Bifurcations
Authors: Antonio Colombo, Ezio Bramucci, Salvatore Saccà, Roberto Violini, Corrado Lettieri, Roberto Zanini, Imad Sheiban, Leonardo Paloscia, Eberhard Grube, Joachim Schofer, Leonardo Bolognese, Mario Orlandi, Giampaolo Niccoli, Azeem Latib, Flavio Airoldi
Journal: Circulation (2008)

Background— Sirolimus-eluting stents have been reported to be effective in the treatment of coronary bifurcations. Still, it has not been fully clarified which strategy would provide the best results with true bifurcation lesions. Methods and Results— The CACTUS trial (Coronary bifurcations: Application of the Crushing Technique Using Sirolimus-eluting stents) is a prospective, randomized, multicenter study comparing 2 different techniques of stenting, with mandatory final kissing-balloon inflation, in true bifurcations: (1) elective “crush” stenting and (2) stenting of only the main branch, with provisional side-branch T-stenting. From August 2004 to June 2007, 350 patients were enrolled in 12 European centers. The primary angiographic end point was the in-segment restenosis rate, and the primary clinical end point was the occurrence of major adverse cardiac events (cardiac death, myocardial infarction, or target-vessel revascularization) at 6 months. At 6 months, angiographic restenosis rates were not different between the crush group (4.6% and 13.2% in the main branch and side branch, respectively) and the provisional stenting group (6.7% and 14.7% in the main branch and side branch, respectively; P =NS). Additional stenting on the side branch in the provisional stenting group was required in 31% of lesions. Rates of major adverse cardiac events were also similar in the 2 groups (15.8% in the crush group versus 15% in the provisional stenting group, P =NS). Conclusions— In most bifurcations with a significant stenosis in both branches, a provisional strategy of stenting the main branch only is effective, with the need to implant a second stent on the side branch occurring in approximately one third of cases. The implantation of 2 stents does not appear to be associated with a higher incidence of adverse events at 6 months.
Effect of vasoactive intestinal peptide on cyclic adenosine monophosphate production in enterocytes isolated from human duodenal biopsy specimens.
Authors: J A Smith, M Griffin, S E Mireylees, R G Long
Journal: Gut (1990)

A modification of a cell isolation technique used in animal studies was developed to remove enterocytes from duodenal biopsy specimens. Citrate-ethylenediaminetetra-acetic acid treatment removed enterocytes from any underlying lamina propria and produced single cells and strips of cells. A mean (SEM) of 4.39 (2.06) x 10(6) cells was obtained from nine duodenal biopsy specimens. Enterocyte recovery was estimated enzymatically using alkaline phosphatase activity and was found to be 61%. Cytological assessment of the cells with CAM 5.2 showed that 98% of the cells isolated were enterocytes with an intact brush border. The cells responded well to vasoactive intestinal peptide stimulation in the absence of an exogenously added adenosine triphosphate regenerating system. The addition of vasoactive intestinal peptide to duodenal enterocytes produced a biphasic dose dependent increase in cyclic adenosine monophosphate production. Stimulation of these cells with 10(-13)M vasoactive intestinal peptide resulted in a 50% stimulation over basal value while 10(-6)M vasoactive intestinal peptide led to a fivefold increase in cyclic adenosine monophosphate production. We conclude that duodenal biopsy specimens are a good source of human intestinal cells for the study of enterocyte physiology. The cells were viable and highly responsive to vasoactive intestinal peptide.
CD103 or LFA-1 Engagement at the Immune Synapse between Cytotoxic T Cells and Tumor Cells Promotes Maturation and Regulates T-cell Effector Functions
Authors: Katarzyna Franciszkiewicz, Audrey Le Floc'h, Marie Boutet, Isabelle Vergnon, Alain Schmitt, Fathia Mami-Chouaib
Journal: Cancer Research (2012)

Abstract T-cell adhesion/costimulatory molecules and their cognate receptors on target cells play a major role in T-cell receptor (TCR)–mediated activities. Here, we compared the involvement of CD103 and LFA-1, and their respective ligands, in the maturation of the cytotoxic immune synapse (cIS) and in the activation of CTL effector functions. Our results indicate that cytotoxicity toward cancer cells and, to a lesser extent, cytokine production by specific CTL require, together with TCR engagement, the interaction of either CD103 with E-cadherin or LFA-1 with ICAM-1. Flow-based adhesion assay showed that engagement of CD103 or LFA-1, together with TCR, enhances the strength of the T-cell/target cell interaction. Moreover, electron microscopic analyses showed that integrin-dependent mature cIS (mcIS) displays a cohesive ultrastructure, with tight membrane contacts separated by extensive clefts. In contrast, immature cIS (icIS), which is unable to trigger target cell lysis, is loose, with multiple protrusions in the effector cell membrane. Experiments using confocal microscopy revealed polarized cytokine release and degranulation at the mcIS associated with target cell killing, whereas icIS is characterized by failure of IFN-γ and granzyme B relocalization. Thus, interactive forces between CTL and epithelial tumor cells, mainly regulated by integrin engagement, correlate with maturity and the ultrastructure of the cIS and influence CTL effector functions. These results provide new insights into molecular mechanisms regulating antitumor CTL responses and may lead to the development of more efficient cancer immunotherapy strategies. Cancer Res; 73(2); 617–28. ©2012 AACR.
Origins of chromosomal rearrangement hotspots in the human genome: evidence from the AZFadeletion hotspots
Authors: Matthew E Hurles, David Willey, Lucy Matthews, Syed Sufyan Hussain
Journal: Genome biology (2004)

The origins of the recombination hotspots that are a common feature of both allelic and non-allelic homologous recombination in the human genome are poorly understood. We have investigated, by comparative sequencing, the evolution of two hotspots of non-allelic homologous recombination on the Y chromosome that lie within paralogous sequences known to sponsor deletions resulting in male infertility. These recombination hotspots are characterized by signatures of concerted evolution, which indicate that gene conversion between paralogs has been predominant in shaping their recent evolution. By contrast, the paralogous sequences that surround the hotspots exhibit little evidence of gene conversion. A second feature of these rearrangement hotspots is the extreme interspecific sequence divergence (around 2.5%) that places them among the most divergent orthologous sequences between humans and chimpanzees. Several hominid-specific gene conversion events have rendered these hotspots better substrates for chromosomal rearrangements in humans than in chimpanzees or gorillas. Monte Carlo simulations of sequence evolution suggest that extreme sequence divergence is a direct consequence of gene conversion between paralogs. We propose that the coincidence of signatures of concerted evolution and recurrent breakpoints of chromosomal rearrangement (mapped at the sequence level) may enable the identification of putative rearrangement hotspots from analysis of comparative sequences from great apes.
Cyclophosphamide versus Placebo in Scleroderma Lung Disease
Authors: Donald P. Tashkin, Robert Elashoff, Philip J. Clements, Jonathan Goldin, Michael D. Roth, Daniel E. Furst, Edgar Arriola, Richard Silver, Charlie Strange, Marcy Bolster, James R. Seibold, David J. Riley, Vivien M. Hsu, John Varga, Dean E. Schraufnagel, Arthur Theodore, Robert Simms, Robert Wise, Fredrick Wigley, Barbara White, Virginia Steen, Charles Read, Maureen Mayes, Ed Parsley, Kamal Mubarak, M. Kari Connolly, Jeffrey Golden, Mitchell Olman, Barri Fessler, Naomi Rothfield, Mark Metersky
Journal: New England Journal of Medicine (2006)

We conducted a double-blind, randomized, placebo-controlled trial to determine the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with evidence of active alveolitis and scleroderma-related interstitial lung disease.At 13 clinical centers throughout the United States, we enrolled 158 patients with scleroderma, restrictive lung physiology, dyspnea, and evidence of inflammatory interstitial lung disease on examination of bronchoalveolar-lavage fluid, thoracic high-resolution computed tomography, or both. Patients received oral cyclophosphamide (< or =2 mg per kilogram of body weight per day) or matching placebo for one year and were followed for an additional year. Pulmonary function was assessed every three months during the first year, and the primary end point was the forced vital capacity (FVC, expressed as a percentage of the predicted value) at 12 months, after adjustment for the baseline FVC.Of 158 patients, 145 completed at least six months of treatment and were included in the analysis. The mean absolute difference in adjusted 12-month FVC percent predicted between the cyclophosphamide and placebo groups was 2.53 percent (95 percent confidence interval, 0.28 to 4.79 percent), favoring cyclophosphamide (P<0.03). There were also treatment-related differences in physiological and symptom outcomes, and the difference in FVC was maintained at 24 months. There was a greater frequency of adverse events in the cyclophosphamide group, but the difference between the two groups in the number of serious adverse events was not significant.One year of oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and the health-related quality of life. The effects on lung function were maintained through the 24 months of the study.
Creation of tolerogenic human dendritic cells via intracellular CTLA4: a novel strategy with potential in clinical immunosuppression
Authors: Peng H. Tan, John B. Yates, Shao-An Xue, Cliburn Chan, William J. Jordan, Jennifer E. Harper, Martin P. Watson, Rong Dong, Mary A. Ritter, Robert I. Lechler, Giovanna Lombardi, Andrew J. T. George
Journal: Blood (2005)
Putting meat on the bones: The necessity of empirical tests of hypotheses about cognitive evolution.
Authors: P. Thomas Schoenemann
Journal: Behavioral and Brain Sciences (2002)

Reconstructing the evolution of cognition requires maximal extraction of information from very sparse data. The role that archaeology plays in this process is important, but strong empirical tests of plausible hypotheses are absolutely critical. Quantitative measures of symmetry must be devised, a much deeper understanding of nonhuman primate spatial cognition is needed, and a better understanding of brain/behavior relationships across species is necessary to properly ground these hypotheses.
Molecular Analysis of Colorectal Cancer Tumors from Patients with Mismatch Repair–Proficient Hereditary Nonpolyposis Colorectal Cancer Suggests Novel Carcinogenic Pathways
Authors: Ana Sánchez-de-Abajo, Miguel de la Hoya, Marjo van Puijenbroek, Alicia Tosar, J.A. López-Asenjo, Eduardo Díaz-Rubio, Hans Morreau, Trinidad Caldes
Journal: Clinical Cancer Research (2007)

Abstract Purpose: A subset of colorectal cancers (CRC) arises in families that, despite fulfilling clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC), do not show evidence of a mismatch repair (MMR) deficiency. The main objective of this study was to characterize these tumors at the molecular level. Experimental Design: After comprehensive germ line mutation scanning, microsatellite analysis, and MMR protein expressions, we selected a well-defined cohort of 57 colorectal tumors with no evidence of MMR defects. In this group of tumors, we analyzed KRAS, BRAF, and APC somatic mutations, as well as methylguanine methyltransferase (MGMT) and β-catenin expression. We correlated these alterations with clinicopathologic data and explored the relationship between KRAS G &amp;gt; A transitions and lack of MGMT expression. Results: The mutation profile at the RAS/RAF/MAPK pathway mimics sporadic microsatellite-stable CRCs. We found an average age of diagnosis 10 years older in KRAS-mutated patients (P = 0.001). In addition, we show that KRAS G &amp;gt; A transitions are actively selected by tumors, regardless of MGMT status. Similarities with HNPCC high–microsatellite instability tumors are observed when APC data are analyzed. The APC mutation rate was low and small insertions/deletions accounted for 70% of the alterations. In addition, we found a low frequency of β-catenin nuclear staining. Finally, we did not find evidence of tumors arising in individuals from the same family sharing molecular features. Conclusions: We show evidence that CRC tumors arising in HNPCC families without MMR alterations have distinctive molecular features. Overall, our work shows that systematic analysis of somatic alterations in a well-defined subset of CRCs is a good approach to provide new insights into the mechanisms of colorectal carcinogenesis.
The expression of hepatitis B spliced protein (HBSP) encoded by a spliced hepatitis B virus RNA is associated with viral replication and liver fibrosis
Authors: Patrick Soussan, Rosella Tuveri, Bertrand Nalpas, Florianne Garreau, Flora Zavala, Annie Masson, Stanislas Pol, Christian Brechot, Dina Kremsdorf
Journal: Journal of Hepatology (2003)
A prevalent caveolin-1 gene variant is associated with the metabolic syndrome in Caucasians and Hispanics
Authors: Rene Baudrand, Mark O. Goodarzi, Anand Vaidya, Patricia C. Underwood, Jonathan S. Williams, Xavier Jeunemaitre, Paul N. Hopkins, Nancy Brown, Benjamin A. Raby, Jessica Lasky-Su, Gail K. Adler, Jinrui Cui, Xiuqing Guo, Kent D. Taylor, Yii-Der I. Chen, Anny Xiang, Leslie J. Raffel, Thomas A. Buchanan, Jerome I. Rotter, Gordon H. Williams, Luminita H. Pojoga
Journal: Metabolism (2015)