tbuckley/cabot-search huggingface dataset:
PTU-026 Prevalence of liver histological abnormalities in type 1 diabetes and the long term consequences: Abstract PTU-026 Figure 1
Authors: D J Harman, R Harris, A Gazis, P Kaye, G Aithal
Journal: Gut (2012)

<h3>Introduction</h3> Patients with type 1 diabetes have a higher prevalence of raised liver enzymes than the general population. Ultrasound diagnosis of non-alcoholic fatty liver disease has been reported to be common in type 1 diabetes despite associated insulin deficiency rather than insulin resistance. However, the histological spectrum of liver disease in type 1 diabetes and the natural history of chronic liver disease in this cohort is unknown. We describe the histological findings of patients with type 1 diabetes who had liver biopsy in a tertiary referral centre, and their long-term clinical outcome. <h3>Methods</h3> The DIAMOND database, which contains longitudinal data for over 95% of type 1 diabetes patients from an overall catchment population of 750 000 in Nottingham, was crossmatched with the clinical pathology database to identify those who had undergone liver biopsy. Case notes were reviewed to obtain follow-up data, and identify liver and non-liver related outcomes. <h3>Results</h3> Out of 2800 patients with Type 1 Diabetes, 57 patients underwent a total of 82 liver biopsies. Common indications for biopsy were abnormal liver enzymes (28 patients), malignancy (8), Hepatitis C staging (7) and clinical evidence of cirrhosis (3). On index biopsy, 86% had significant histological abnormalities (Abstract PTU-026 figure 1) and 10 patients (17.5%) had cirrhosis. During a total follow-up of 336.4 patient years (median 5.6 years), a further four patients developed cirrhosis, giving a cirrhosis prevalence of at least 500 per 100 000 population—this compares with an estimated UK cirrhosis prevalence of 76.3 per 100 000 population.<sup>1</sup> Portal hypertensive sequelae occurred in 11 patients (78.6%) with cirrhosis and hepatocellular carcinoma in three patients. 22 patients (38.6%) died during follow-up. Crude death rate was 6539 per 100 000 person years, compared with national Type 1 Diabetes data<sup>2</sup> of 1878 per 100 000 person years. <h3>Conclusion</h3> Type 1 Diabetes is associated with significant liver histology abnormalities and a higher than expected occurrence of cirrhosis, portal hypertension and mortality. These findings have implications for long-term management of patients with Type 1 Diabetes. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Fleming KM</b>, Aithal GP, Solaymani-Dodaran M, <i>et al.</i> Incidence and prevalence of cirrhosis in the United Kingdom, 1992-2001: a general population-based study. <i>J Hepatol</i> 2008;<b>49</b>:732–8. 2. <b>NHS IC</b>. <i>National Diabetes Audit Mortality Analysis 2007-2008</i>. NHS IC, 2011.
Homologies between cell interaction molecular controlled by major histocompatibility complex- and Igh-V-linked genes that T cells use for communication. Tandem "adaptive" differentiation of producer and acceptor cells.
Authors: P Flood, K Yamauchi, A Singer, R K Gershon
Journal: The Journal of Experimental Medicine (1982)

We have asked the question: how do partner cells in immunoregulatory interactions between T cell subsets acquire the ability to recognize and react appropriately with one another? In particular, we have asked whether these communication events are completely determined by the cell's genetic constitution, or whether the recognition events can be learned during ontogeny. We have found that the T cells of parent into F1 chimeras and homozygous nude mice with F1 thymus grafts not only learn to react with genetically disparate acceptor cells, but that the receptors on the acceptor cells themselves learn to react with genetically disparate producer cells. This learning process can overcome both major histocompatibility complex- and immunoglobulin heavy chain variable region-linked restricted communication between T cell subsets. We interpret these findings to indicate that thymic elements can start a cascade of differential events. The thymic elements, whether endogenous or passively acquired, select from a pool of producer cells those that will react appropriately with the thymic selecting cells, and these cells become expanded. Then, the private markers (idiotype) on the expanded pool of producer cells act as selecting and expanding elements that choose from a pool of acceptor cells those that recognize the producer cells idiotype as self. This second differentiational event, although apparently thymus evidence that this type of acceptor cell differentiation could also take place during the course of an immune response.
Phase 2 study of idarubicin in pediatric brain tumors: Pediatric Oncology Group study POG 9237
Authors: ZoAnn E. Dreyer, Richard P. Kadota, Clinton F. Stewart, Henry S. Friedman, Donald H. Mahoney, Larry E. Kun, Charles W. McCluggage, Peter C. Burger, James Kepner, Richard L. Heideman
Journal: Neuro-Oncology (2003)

Idarubicin (IDA), the 4-demethoxy analog of daunomycin, has had significant cytotoxicity in many malignancies. In previous reports, the alcohol metabolite of IDA, 4-demethoxydaunorubicinol (idarubicinol, or IDOL), had cytotoxic activity and the ability to penetrate the blood-brain barrier. For this reason, the Pediatric Oncology Group conducted a Phase 2 trial of IDA for children with recurrent or progressive brain tumors. Ninety-one eligible children were entered on this study, with ages ranging from 3 months to 19 years. Patients were stratified by tumor types into 6 categories: stratum 1, low-grade astrocytoma; stratum 2, malignant glioma (glioblastoma multiforme and anaplastic astrocytoma); stratum 3, medulloblastoma; stratum 4, brainstem glioma; stratum 5, ependymoma; and stratum 6, miscellaneous malignant tumors not included in the previous diagnoses. IDA(18 mg/m2) was infused over 4 h and followed by granulocyte colony-stimulating factor (G-CSF) beginning day 5 after infusion of IDA. G-CSF was continued until blood cell count recovery. Cycles were repeated at approximately 21-day intervals until patients developed progressive disease or had completed 6 cycles with stable or improved disease. Pharmacokinetic plasma and cerebrospinal fluid (CSF) samples were collected from a subset of these patients. Response was poor in all strata. Most patients developed progressive disease; however, in 21 patients with medulloblastoma there was 1 partial response, and 6 patients had stable disease (SD) that in 4 patients lasted more than 20 weeks. Grades 3/4 hematopoietic toxicities were the most common toxic events, and 14 infection-related events resulted in hospitalization of patients. Only 1 patient developed reduced cardiac function. The systemic clearance data for IDA and IDOL were nearly identical to those published on patients with leukemia, and the plasma elimination of the IDOL metabolite was substantially longer than that of the parent drug IDA. The peak CSF:plasma ratios of IDA and IDOL were very low. The overall response rates to IDA were disappointing despite periods of prolonged SD in nearly a fourth of the patients. We conclude from this data and from that in nonhuman primates that it is unlikely that IDA, daunomycin, or other related anthracyclines will be useful for treating primary CNS tumors.
Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study
Authors: J T Merrill, R F van Vollenhoven, J P Buyon, R A Furie, W Stohl, M Morgan-Cox, C Dickson, P W Anderson, C Lee, P-Y Berclaz, T Dörner
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> To evaluate the efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that neutralises membrane and soluble B-cell activating factor (BAFF). <h3>Methods</h3> This randomised, placebo-controlled study enrolled 1124 patients with moderate-to-severe systemic lupus erythematosus (SLE) (Safety of Estrogens in Lupus Erythematosus National Assessment- SLE Disease Activity Index ≥6 at baseline). Patients received standard of care plus subcutaneous study drug, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every 2 weeks (120 Q2W), 120 mg every 4 weeks (120 Q4W) or placebo. Primary endpoint was proportion achieving SLE Responder Index 5 (SRI-5) improvement at week 52. <h3>Results</h3> Clinical characteristics were balanced across groups. The primary endpoint was met with 120 Q2W (38.4% vs 27.7%, placebo; p=0.002), but not with the less frequent 120 Q4W regimen (34.8%, p=0.051). Although key secondary endpoints (time to severe flare, corticosteroid sparing and fatigue) were not met, patients treated with tabalumab had greater SRI-5 response rates in a serologically active subset and improvements in more stringent SRI cut-offs, SELENA-SLEDAI, Physician9s Global Assessment, anti-double-stranded DNA antibodies, complement, total B cells and immunoglobulins. The incidences of deaths, serious adverse events (AEs), and treatment-emergent AEs were similar in the 120 Q2W, 120 Q4W and placebo groups, but depression and suicidal ideation, albeit rare events, were more commonly reported with tabalumab. <h3>Conclusion</h3> SRI-5 was met with 120 Q2W and although key secondary endpoints were not met, numerous other secondary endpoints significantly improved in addition to pharmacodynamic evidence of BAFF pathway blockade. The safety profile for tabalumab was similar to placebo, except for depression and suicidality, which were uncommon. <h3>Trial registration number</h3> NCT01205438.
Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting
Authors: Deepak L Bhatt, Michel E Bertrand, Peter B Berger, Philippe L L’Allier, Issam Moussa, Jeffrey W Moses, George Dangas, Megumi Taniuchi, John M Lasala, David R Holmes, Stephen G Ellis, Eric J Topol
Journal: Journal of the American College of Cardiology (2002)
Transcriptional Regulation of TMP21 by NFAT
Authors: Shengchun Liu, Si Zhang, Kelley Bromley-Brits, Fang Cai, Weihui Zhou, Kun Xia, Jill Mittelholtz, Weihong Song
Journal: Molecular Neurodegeneration (2011)

TMP21 is a member of the p24 cargo protein family, which is involved in protein transport between the Golgi apparatus and ER. Alzheimer's Disease (AD) is the most common neurodegenerative disorder leading to dementia and deposition of amyloid β protein (Aβ) is the pathological feature of AD pathogenesis. Knockdown of TMP21 expression by siRNA causes a sharp increase in Aβ production; however the underlying mechanism by which TMP21 regulates Aβ generation is unknown, and human TMP21 gene expression regulation has not yet been studied. In this report we have cloned a 3.3-kb fragment upstream of the human TMP21 gene. The transcription start site (TSS) of the human TMP21 gene was identified. A series of nested deletions of the 5' flanking region of the human TMP21 gene were subcloned into the pGL3-basic luciferase reporter plasmid. We identified the -120 to +2 region as containing the minimal sequence necessary for TMP21 gene promoter activity. Gel shift assays revealed that the human TMP21 gene promoter contains NFAT response elements. Expression of NFAT increased TMP21 gene expression and inhibition of NFAT by siRNA reduced TMP21 gene expression. NFAT plays a very important role in the regulation of human TMP21 gene expression. This study demonstrates that the human TMP21 gene expression is transcriptionally regulated by NFAT signaling.
Trends in the Work Hours of Physicians in the United States
Authors: Douglas O. Staiger
Journal: JAMA (2010)

Recent trends in hours worked by physicians may affect workforce needs but have not been thoroughly analyzed.To estimate trends in hours worked by US physicians and assess for association with physician fees.A retrospective analysis of trends in hours worked among US physicians using nationally representative workforce information from the US Census Bureau Current Population Survey between 1976 and 2008 (N = 116,733). Trends were estimated among all US physicians and by residency status, sex, age, and work setting. Trends in hours were compared with national trends in physician fees, and estimated separately for physicians located in metropolitan areas with high and low fees in 2001.Self-reported hours worked in the week before the survey.After remaining stable through the early 1990s, mean hours worked per week decreased by 7.2% between 1996 and 2008 among all physicians (from 54.9 hours per week in 1996-1998 to 51.0 hours per week in 2006-2008; 95% confidence interval [CI], 5.3%-9.0%; P < .001). Excluding resident physicians, whose hours decreased by 9.8% (95% CI, 5.8%-13.7%; P < .001) in the last decade due to duty hour limits imposed in 2003, nonresident physician hours decreased by 5.7% (95% CI, 3.8%-7.7%; P < .001). The decrease in hours was largest for nonresident physicians younger than 45 years (7.4%; 95% CI, 4.7%-10.2%; P < .001) and working outside of the hospital (6.4%; 95% CI, 4.1%-8.7%; P < .001), and the decrease was smallest for those aged 45 years or older (3.7%; 95% CI, 1.0%-6.5%; P = .008) and working in the hospital (4.0%; 95% CI, 0.4%-7.6%; P = .03). After adjusting for inflation, mean physician fees decreased nationwide by 25% between 1995 and 2006, coincident with the decrease in physician hours. In 2001, mean physician hours were less than 49 hours per week in metropolitan areas with the lowest physician fees, whereas physician hours remained more than 52 hours per week elsewhere (P < .001 for difference).A steady decrease in hours worked per week during the last decade was observed for all physicians, which was temporally and geographically associated with lower physician fees.
NF- B activation and iNOS upregulation in skeletal muscle of patients with COPD and low body weight
Authors: A Agusti
Journal: Thorax (2004)

Weight loss, mostly due to skeletal muscle atrophy, is a frequent and clinically relevant problem in patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms underlying this phenomenon are unclear. This study sought to investigate whether activation of the nuclear transcription factor NF-kappaB and upregulation of the inducible form of nitric oxide synthase (iNOS) occur in the skeletal muscle of patients with COPD and low body weight as potential molecular mechanisms leading to cachexiaNF-kappaB DNA binding activity was determined by electromobility shift assay and the immunoreactivity of its inhibitory subunit IkappaB-kappa and that of iNOS by Western blot analysis in biopsy specimens of the quadriceps femoris muscle of seven COPD patients with normal body mass index (BMI, 27.5 (1) kg/m(2)) and seven patients with low BMI (18.5 (1) kg/m(2)).Compared with patients with normal body weight, those with low BMI showed a 30% increase in NF-kappaB DNA binding activity, a lower expression of IkappaB-alpha (3.37 (0.47) IOD v 5.96 (0.75) IOD, p<0.05; mean difference 2.59; 95% CI -4.53 to -0.65) and higher iNOS expression (1.51 (0.29) IOD v 0.78 (0.11) IOD, p<0.05; mean difference 0.74; 95% CI 0.04 to 1.42).NF-kappaB activation and iNOS induction occur in skeletal muscle of COPD patients with low body weight. These changes might contribute to the molecular pathogenesis of cachexia in COPD.
Effect of cromolyn on adenosine-induced airway microvascular leakage in sensitized rats
Authors: J Tamaoki, I Yamawaki, M Taira, Y Nagano, J Nakata, A Nagai
Journal: European Respiratory Journal (1999)

Inhalation of adenosine causes bronchoconstriction in asthmatic subjects, but the effect of this purine nucleotide on airway vascular permeability is unknown. In order to determine whether adenosine produces airway microvascular leakage and, if so, to examine the effect of cromolyn (sodium cromoglycate (SCG)) on this extravasation of Evans blue was measured in the airways of ovalbumin-sensitized Brown Norway rats. Inhaled adenosine caused microvascular leakage in sensitized but not in non-sensitized rats, and the response was abolished by capsaicin pretreatment or the tachykinin neurokinin-1 receptor antagonist FK888. Adenosine-induced vascular leakage became apparent in nonsensitized rats when treated with phosphoramidon, and airway neutral endopeptidase activity was lower in sensitized than in non-sensitized animals. The extravasation induced by adenosine in sensitized rats was dose dependently inhibited by SCG aerosols, SCG likewise inhibited microvascular responses to substance P, but had no effect on those to platelet-activating factor. These results suggest that: 1) adenosine induces airway microvascular leakage in sensitized rats through stimulation of neurokinin-1 receptors; 2) this effect is associated with a sensitization-induced decrease in neutral endopeptidase activity; and 3) sodium cromoglycate inhibits adenosine-induced extravasation, presumably via functional antagonism of tachykinins.
Accumulation of extracellular ATP protects against acute reperfusion injury in rat heart endothelial cells☆
Authors: D GUNDUZ, S KASSECKERT, F HARTEL, M ASLAM, Y ABDALLAH, M SCHAFER, H PIPER, T NOLL, C SCHAFER
Journal: Cardiovascular Research (2006)

Objective: Ischemia–reperfusion provokes barrier failure of the coronary microvasculature, leading to myocardial edema development that jeopardizes functional recovery of the heart during reperfusion. Here, we tested whether adenosine 5′-triphosphate (ATP), either exogenously applied or spontaneously released during reperfusion, protects the endothelial barrier against an imminent reperfusion injury and whether interventions preventing ATP breakdown augment this protective ATP effect. Methods Cultured microvascular coronary endothelial monolayers and isolated-perfused hearts of rat were used. Results: After ischemic conditions were induced, reperfusion of endothelial monolayers activated the endothelial contractile machinery and caused intercellular gap formation. It also led to the release of ATP. When its breakdown was inhibited by 6-N,N-diethyl-β,γ-dibromomethylene-d-ATP (ARL 67156; 100 μM), a selective ectonucleotidase inhibitor, contractile activation and gap formation were significantly reduced. Reperfusion in the presence of exogenously added ATP (10 μM) plus ARL caused an additional reduction of both aforementioned effects. In contrast, elevation of ATP degradation by apyrase (1 U/ml), a soluble ectonucleotidase, or addition of adenosine (10 μM) provoked an increase in gap formation during reperfusion that could be completely inhibited by 8-phenyltheophylline (8-PT; 10 μM), an adenosine receptor antagonist. In Langendorff-perfused rat hearts, the reperfusion-induced increase in water content was significantly reduced by ARL plus ATP. Under conditions favouring ATP degradation, an increase in myocardial edema was observed that could be blocked by 8-PT. Conclusion ATP, either released from cells or exogenously applied, protects against reperfusion-induced failure of the coronary endothelial barrier. Inhibition of ATP degradation enhances the stabilizing effect of ATP on barrier function.
The von Hippel-Lindau Tumor Suppressor Protein and Clear Cell Renal Carcinoma
Authors: William G. Kaelin
Journal: Clinical Cancer Research (2007)

Abstract Germ line VHL tumor suppressor gene loss-of-function mutations cause von Hippel-Lindau disease, which is associated with an increased risk of central nervous system hemangioblastomas, clear cell renal carcinomas, and pheochromocytomas. Somatic VHL mutations are also common in sporadic clear cell renal carcinomas. The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the α-subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for polyubiquitylation, and hence, proteasomal degradation, when oxygen is available. pVHL-defective clear cell renal carcinomas overproduce a variety of mRNAs that are under the control of HIF, including the mRNAs that encode vascular endothelial growth factor, platelet-derived growth factor B, and transforming growth factor α. In preclinical models, down-regulation of HIF-α, especially HIF-2α, is both necessary and sufficient for renal tumor suppression by pVHL. These observations are probably relevant to the demonstrated clinical activity of vascular endothelial growth factor antagonists in clear cell renal carcinoma and form a foundation for the testing of additional agents that inhibit HIF, or HIF-responsive gene products, in this disease.
VEGF Exerts an Angiogenesis-Independent Function in Cancer Cells to Promote Their Malignant Progression
Authors: Ying Cao, Guangqi E, Enfeng Wang, Krishnendu Pal, Shamit K. Dutta, Dafna Bar-Sagi, Debabrata Mukhopadhyay
Journal: Cancer Research (2012)

VEGF/vascular permeability factor (VEGF/VPF or VEGF-A) is a pivotal driver of cancer angiogenesis that is a central therapeutic target in the treatment of malignancy. However, little work has been devoted to investigating functions of VEGF that are independent of its proangiogenic activity. Here, we report that VEGF produced by tumor cells acts in an autocrine manner to promote cell growth through interaction with the VEGF receptor neuropilin-1 (NRP-1). Reducing VEGF expression by tumor cells induced a differentiated phenotype in vitro and inhibited tumor forming capacity in vivo, independent of effects on angiogenesis. Autocrine activation of tumor cell growth was dependent on signaling through NRP-1, and Ras was determined to be a critical effector signaling molecule downstream of NRP-1. Our findings define a novel function for VEGF in dedifferentiation of tumor cells expanding its role in cancer beyond its known proangiogenic function.
The Effect of Donor Diabetes History on Graft Failure and Endothelial Cell Density 10 Years after Penetrating Keratoplasty
Authors: Jonathan H. Lass, Tonya D. Riddlesworth, Robin L. Gal, Craig Kollman, Beth A. Benetz, Francis W. Price, Alan Sugar, Mark A. Terry, Mark Soper, Roy W. Beck
Journal: Ophthalmology (2014)
Increasing incidence of <i>Trichophyton tonsurans</i> in Paris, France: a 15‐year retrospective study
Authors: K. Alshawa, C. Lacroix, M. Benderdouche, A. Mingui, F. Derouin, M. Feuilhade de Chauvin
Journal: British Journal of Dermatology (2011)

Funding sources: K.A. is supported by a research fellowship from the Syrian Ministry of Higher Education, Damascus University. Conflicts of interest: none declared. Madam, The anthropophilic Trichophyton tonsurans is known worldwide as a causative agent of tinea capitis and tinea corporis. In the U.S.A. and Canada, T. tonsurans is now responsible for up to 50% of all dermatophytoses and 95% of cases of tinea capitis.1, 2 Since 1990, there has been a marked increase in T. tonsurans infection in Europe as reported in the U.K., Spain, Netherlands and Sweden.3–6 Since 2001, this pathogen has been the cause of nationwide epidemics in wrestlers in some countries such as Japan and Turkey.7, 8 Similarly, in France, T. tonsurans has been the cause of epidemics of tinea capitis and tinea corporis gladiatorum.9 The aim of this retrospective study is to describe the epidemiology of cutaneous T. tonsurans infections diagnosed in our laboratory in Paris, France, from 1996 to 2010, in order to gain more comprehensive insight into the course of this dermatophytosis. The only inclusion criterion was a positive culture for T. tonsurans. Sex, age, geographical origin and sites of involvement were noted. Skin and nail samples were examined directly in black chlorazol E solution and hair samples in a chloral–lactophenol solution. Samples were cultured on Sabouraud agar slants supplemented with antibiotics and with antibiotics and cycloheximide (Bio‐Rad, Marnes la Coquette, France) and incubated at 27 °C for up to 3 weeks. Dermatophyte species were identified according to usual macroscopic and microscopic criteria.