tbuckley/cabot-search huggingface dataset:
Overexpression of GLUT2 gene in renal proximal tubules of diabetic Zucker rats.
Authors: M Kamran, R G Peterson, J H Dominguez
Journal: Journal of the American Society of Nephrology (1997)

Renal tubular reabsorption of glucose is substantially increased in humans and rats with diabetes mellitus. The influx of luminal glucose is mediated by Na+/glucose cotransporter system and glucose efflux from tubules to interstitium by facilitative glucose transporters (GLUT). In Zucker diabetic rats, GLUT2 protein levels of renal proximal tubules were higher than in control litter mates: 9.67 +/- 1.95 versus 4.72 +/- 1.55 (P = 0.0073). In the same proximal tubules, diabetes was associated with minor decreases in GLUT1 protein levels: 1.96 +/- 0.37 for diabetics and 2.37 +/- 0.34 for controls (P = 0.12). Na+/glucose cotransporter system protein levels were similar in both groups, whereas Na+/K+ ATPase levels were slightly decreased in diabetic rats, but the difference was not statistically significant. In this report, it is suggested that in long-term uncontrolled diabetes, GLUT2 transporters are overexpressed in renal tubules. This adaptation promotes low-affinity, high-capacity glucose efflux. The higher number of high K(m) GLUT2 ensures that glucose reabsorption is increased by promoting glucose efflux, which could be rate-limiting in the face of hyperglycemia.
Risk Scores for Type 2 Diabetes Can Be Applied in Some Populations but Not All
Authors: Charlotte Glümer, Dorte Vistisen, Knut Borch-Johnsen, Stephen Colagiuri
Journal: Diabetes Care (2006)

OBJECTIVE—Risk scores based on phenotypic characteristics to identify individuals at high risk of having undiagnosed diabetes have been developed in Caucasian populations. The impact of known risk factors on having undiagnosed type 2 diabetes differs between populations from different ethnic origin, and risk scores developed in Caucasians may not be applicable to other ethnic groups. This study evaluated the performance of one risk score in nine populations of diverse ethnic origin. RESEARCH DESIGN AND METHODS—Data provided by centers from around the world to the DETECT-2 project were used. The database includes population-based surveys with information on at least 500 people without known diabetes having a 75-g oral glucose tolerance test. To date, 52 centers have contributed data on 190,000 individuals from 34 countries. In this analysis, nine cross-sectional studies were selected representing diverse ethnic and regional backgrounds. The risk score assessed uses information on age, sex, blood pressure treatment, and BMI. RESULTS—This analysis included 29,758 individuals; 1,805 individuals had undiagnosed diabetes. The performance of the risk score varied widely, with sensitivity, specificity, and percentage needing further testing ranging between 12 and 57%, 72 and 93%, and 2 and 25%, respectively, with the worse performance in non-Caucasian populations. This variation in performance was related to differences in the association between prevalence of undiagnosed diabetes and components of the risk score. CONCLUSIONS—A typical risk score developed in Caucasian populations cannot be applied to other populations of diverse ethnic origins.
S96 Novel biomarkers in idiopathic pulmonary arterial hypertension
Authors: C. J. Rhodes, J. Wharton, L. S. Howard, J. S. R. Gibbs, M. R. Wilkins
Journal: Thorax (2010)

<h3>Background</h3> Circulatingosteopontin levels predict survival in right heart failure and lung tissue expression is increased in hypoxic animal models of pulmonary hypertension. Growth differentiation factor (GDF)-15 and red cell distribution width (RDW) are potential biomarkers in idiopathic pulmonary arterial hypertension (IPAH). <h3>Objectives</h3> We assessed the prognostic value of these novel biomarkers, along with the more established N-terminal pro-brain natriuretic peptide (NT-proBNP) and other clinical indices, in treatment-naïve and treated patients with IPAH. <h3>Methods</h3> Plasmaosteopontin, GDF-15, and NT-proBNP levels and RDW were determined in 126 patients with IPAH, who were followed for 4.0±2.2 years. <h3>Results</h3> All four biomarkers correlated with WHO functional class and 6 min walk distance(6MWD) and cut-offs of osteopontin (53.4 ng/ml, p&lt;0.05), GDF-15 (800 pg/ml)and RDW (15.65%) predicted significant differences in survival in patients with IPAH (Abstract S96 Figure 1). Raised NT-proBNP levels also predicted significantly poorer survival (p&lt;0.01). A temporal increase in serially-measured levels ofGDF-15, osteopontin or RDW indicated poorer survival in IPAH. Patients with relatively low NT-proBNP levels (below median) who might normally be considered low risk, displayed higher mortality rates when GDF-15 levels or RDW were raised. Cox regression survival modelling confirmed RDW as a significant predictor of mortality, independent of established markers including NT-proBNP, 6MWD and WHO class. GDF-15, RDW and NT-proBNP predicted significant (p&lt;0.05) survival differences in patients with reduced exercise capacity (6MWD &lt;380 m); median survival with low 6MWD and raised RDW (&gt;15.65%) was &lt;1.5 year vs 3.6 year for low 6MWD irrespective of the RDW value. <h3>Conclusions</h3> Osteopontin, GDF-15 and RDW all predicted survival in IPAH and were associated with poorer clinical status. Temporal changes in biomarkers appear to hold prognostic information. RDW and NT-proBNP may add the most value to 6MWD and WHO class.
Depletion of Guanine Nucleotides Leads to the Mdm2-Dependent Proteasomal Degradation of Nucleostemin
Authors: Min Huang, Koji Itahana, Yanping Zhang, Beverly S. Mitchell
Journal: Cancer Research (2009)

Nucleostemin is a positive regulator of cell proliferation and is highly expressed in a variety of stem cells, tumors, and tumor cell lines. The protein shuttles between the nucleolus and the nucleus in a GTP-dependent fashion. Selective depletion of intracellular guanine nucleotides by AVN-944, an inhibitor of the de novo purine synthetic enzyme, IMP dehydrogenase, leads to the rapid disappearance of nucleostemin protein in tumor cell lines, an effect that does not occur with two other nucleolar proteins, nucleophosmin or nucleolin. Endogenous nucleostemin protein is completely stabilized by MG132, an inhibitor of the 26S proteasome, as are the levels of expressed enhanced green fluorescent protein-tagged nucleostemin, both wild-type protein and protein containing mutations at the G(1) GTP binding site. Nutlin-3a, a small molecule that disrupts the binding of the E3 ubiquitin ligase, Mdm2, to p53, stabilizes nucleostemin protein in the face of guanine nucleotide depletion, as does siRNA-mediated knockdown of Mdm2 expression and overexpression of a dominant-negative form of Mdm2. Neither Doxorubicin nor Actinomycin D, which cause the release of nucleostemin from the nucleolus, results in nucleostemin degradation. We conclude that nucleostemin is a target for Mdm2-mediated ubiquitination and degradation when not bound to GTP. Because this effect does not occur with other chemotherapeutic agents, the induction of nucleostemin protein degradation in tumor cells by IMP dehydrogenase inhibition or by other small molecules that disrupt GTP binding may offer a new approach to the treatment of certain neoplastic diseases.
70 CYLD: A KEY REGULATOR OF HEPATOCELLULAR APOPTOSIS, PROLIFERATION AND CARCINOGENESIS
Authors: T. Urbanik, S. Heine, M. Wörns, N. Hövelmeyer, R.J. Boger, T. Maass, R. Massoumi, R. Fässler, M. Schuchmann, P.R. Galle, A. Waisman, H. Schulze-Bergkamen
Journal: Journal of Hepatology (2010)
Diuretics and Risk of Arrhythmic Death in Patients With Left Ventricular Dysfunction
Authors: Howard A. Cooper, Daniel L. Dries, C. E. Davis, Yuan Li Shen, Michael J. Domanski
Journal: Circulation (1999)

Background-Treatment with diuretics has been reported to increase the risk of arrhythmic death in patients with hypertension. The effect of diuretic therapy on arrhythmic death in patients with left ventricular dysfunction is unknown. Methods and Results-We conducted a retrospective analysis of 6797 patients with an ejection fraction <0.36 enrolled in the Studies Of Left Ventricular Dysfunction (SOLVD) to assess the relation between diuretic use at baseline and the subsequent risk of arrhythmic death. Participants receiving a diuretic at baseline were more likely to have an arrhythmic death than those not receiving a diuretic (3.1 vs 1.7 arrhythmic deaths per 100 person-years, P=0.001). On univariate analysis, diuretic use was associated with an increased risk of arrhythmic death (relative risk [RR] 1.85, P=0.0001). After controlling for important covariates, diuretic use remained significantly associated with an increased risk of arrhythmic death (RR 1.37, P=0.009). Only non-potassium-sparing diuretic use was independently associated with arrhythmic death (RR 1.33, P=0.02). Use of a potassium-sparing diuretic, alone or in combination with a non-potassium-sparing diuretic, was not independently associated with an increased risk of arrhythmic death (RR 0.90, P=0.6). Conclusions-In SOLVD, baseline use of a non-potassium-sparing diuretic was associated with an increased risk of arrhythmic death, whereas baseline use of a potassium-sparing diuretic was not. These data suggest that diuretic-induced electrolyte disturbances may result in fatal arrhythmias in patients with systolic left ventricular dysfunction.
Mechanisms of endotoxin tolerance in patients with alcoholic liver cirrhosis: role of interleukin 10, interleukin 1 receptor antagonist, and soluble tumour necrosis factor receptors as well as effector cell desensitisation
Authors: V. Von Baehr, W.-D. Döcke, M. Plauth, C. Liebenthal, S. Küpferling, H. Lochs, R. Baumgarten, H.-D. Volk
Journal: Gut (2000)

<h3>BACKGROUND</h3> In patients with alcoholic liver cirrhosis, endotoxaemia is a frequent finding. Unknown mechanisms, however, prevent typical clinical symptoms of endotoxaemia in many patients. <h3>METHODS</h3> We determined plasma levels of pro- and anti-inflammatory mediators, ex vivo cytokine secretion capacity, and expression of tumour necrosis factor (TNF) receptors on phagocytic blood cells in 49 patients with alcoholic cirrhosis and 41 age matched healthy controls. <h3>RESULTS</h3> In addition to increased levels of proinflammatory cytokines in cirrhotic patients, we observed consistent upregulation of the anti-inflammatory mediators interleukin 10 (IL-10) (plasma 15.75 (1.6) <i>v</i>6.6 (1.3) pg/ml (p&lt;0.001); ex-vivo 108.4 (22.0)<i>v</i> 40.1 (7.4) pg/ml (p&lt;0.05)), interleukin 1 receptor antagonist (plasma 527.1 (83) <i>v</i>331.4 (56) pg/ml (p&lt;0.05); ex vivo 19.9 (3.4)<i>v</i> 10.2 (2.7) ng/ml (p&lt;0.01)), and soluble TNF receptors (sTNF-R) in plasma (sTNF-RI 3157.2 (506.2)<i>v</i> 607.9 (300.3) pg/ml; sTNF-RII 3331.0 (506.2) <i>v</i> 1066.4 (225.1) pg/ml (p&lt;0.001 for both)). Desensitisation at the target cell level was indicated by reduced expression of TNF receptor I on granulocytes (64.8 (6.5)<i>v</i> 40.1 (7.3)% positive cells; p&lt;0.05) and unaltered plasma levels of soluble E-selectin. <h3>CONCLUSION</h3> In patients with alcoholic liver cirrhosis, upregulation of the pro- and anti-inflammatory cytokine system and simultaneous desensitisation of effector cells could explain the restricted systemic inflammatory response to chronic endotoxaemia. This alteration in immune status may lead to impairment of host defences against infections which are frequent complications of alcoholic cirrhosis.
Cervical interspinous bursitis in active polymyalgia rheumatica
Authors: C Salvarani, L Barozzi, F Cantini, L Niccoli, L Boiardi, M Valentino, N Pipitone, G Bajocchi, P Macchioni, M G Catanoso, I Olivieri, G G Hunder
Journal: Annals of the Rheumatic Diseases (2008)

To evaluate the inflammatory involvement of cervical interspinous bursae in patients with polymyalgia rheumatica (PMR) using MRI.In all, 12 consecutive, untreated new patients with PMR were investigated. Five patients with fibromyalgia, two patients with cervical osteoarthritis and six patients with spondyloarthritis with neck pain served as controls. MRI of the cervical spine was performed in all 12 PMR case patients and in 13 control patients. Two of the four patients with PMR with pelvic girdle pain also had MRI of the lumbar spine.MRI evidence of interspinous cervical bursitis was found in all patients with PMR, and in three patients with fibromyalgia, in two with psoriatic spondylitis and one with cervical osteoarthritis. A moderate to marked (grade >or=2 on a semiquantitative 0-3 scale) cervical bursitis occurred significantly more frequently in patients with PMR than in control patients (83.3% compared with 30.7%, p = 0.015). In all patients and controls with cervical bursitis the involvement was found at the C5-C7 cervical interspaces. MRI of the lumbar spine showed lumbar interspinous bursitis at the L3-L5 lumbar interspaces in the two patients with PMR and pelvic girdle pain examined.Cervical interspinous bursitis is a likely basis for discomfort in the neck of patients with PMR. The prominent inflammatory involvement of cervical bursae supports the hypothesis that PMR is a disorder of prominent involvement of extra-articular synovial structures.
IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells
Authors: Yenkel Grinberg-Bleyer, Audrey Baeyens, Sylvaine You, Rima Elhage, Gwladys Fourcade, Sylvie Gregoire, Nicolas Cagnard, Wassila Carpentier, Qizhi Tang, Jeffrey Bluestone, Lucienne Chatenoud, David Klatzmann, Benoît L. Salomon, Eliane Piaggio
Journal: The Journal of Experimental Medicine (2010)

Regulatory T cells (T reg cells) play a major role in controlling the pathogenic autoimmune process in type 1 diabetes (T1D). Interleukin 2 (IL-2), a cytokine which promotes T reg cell survival and function, may thus have therapeutic efficacy in T1D. We show that 5 d of low-dose IL-2 administration starting at the time of T1D onset can reverse established disease in NOD (nonobese diabetic) mice, with long-lasting effects. Low-dose IL-2 increases the number of T reg cells in the pancreas and induces expression of T reg cell–associated proteins including Foxp3, CD25, CTLA-4, ICOS (inducible T cell costimulator), and GITR (glucocorticoid-induced TNF receptor) in these cells. Treatment also suppresses interferon γ production by pancreas-infiltrating T cells. Transcriptome analyses show that low-dose IL-2 exerts much greater influence on gene expression of T reg cells than effector T cells (T eff cells), suggesting that nonspecific activation of pathogenic T eff cells is less likely. We provide the first preclinical data showing that low-dose IL-2 can reverse established T1D, suggesting that this treatment merits evaluation in patients with T1D.
THE PRODUCTION OF RUNT DISEASE IN RATS THYMECTOMIZED AT BIRTH
Authors: Alan C. Aisenberg, Barbara Wilkes, Byron H. Waksman
Journal: The Journal of Experimental Medicine (1962)

Thymectomy of Sprague-Dawley rats on the 3rd day of life failed to influence the time of onset, incidence, clinical, or histologic picture of runt disease produced by the intraperitoneal injection of adult Long-Evans spleen cells. The fact that severe immunologic impairment of the host by thymectomy does not modify runt disease was felt to be consistent with the current view that the if direction of the immunologic event in this syndrome is graft versus host. Following the injection of 800 to 1000 million Long-Evans spleen cells into adult Sprague-Dawley rats, a severe illness comprised of dermatitis, gastrointestinal bleeding, arthritis, weight loss, and death ensued in 37 per cent of adults thymectomized neonatally and 13 per cent of normal controls. Histologic lesions were observed in 69 per cent of adequately thymectomized animals and 17 per cent of normal controls, and involved lymph nodes, spleen, liver, lungs, kidneys, joints, heart, and skin. The time of onset and the histologic and clinical pictures are consistent with the adult disease being a typical graft versus host reaction.
Measure for Measure: The Cost of Improving Quality
Authors: Jason D. Wright, Dawn L. Hershman
Journal: JNCI Journal of the National Cancer Institute (2014)

that the measures were variable in impact and level of evidence, a weighted global measure may have been a more sensitive tool. With regard to cost, the analysis measured expenditures in the year after diagnosis. For patients with breast cancer and DCIS, there is a short-term investment in toxicity and cost of therapy in the hopes of preventing a local or metastatic recurrence at a future date. The costs associated with treatment of metastatic cancer are substantially higher than the initial costs (8). Another approach would be to model the expected savings at the time of recurrence based on expected recurrence rates in each of the subsets evaluated. Finally, with regard to outcome, the investigators chose to look at five-year overall survival. Not surprisingly, the proportion of patients alive at five years was high overall (approximately 89%), given the inclusion of patients with early-stage breast cancer and DCIS. It would be counterintuitive to think that adherence to evidence-based quality measures based on treatments proven to be beneficial in randomized trials would not lead to improvement in breast cancer outcomes over time, therefore this limitation may have obscured finding a relationship.
Prediction of Myocardial Infarction by N-Terminal-Pro-B-Type Natriuretic Peptide, C-Reactive Protein, and Renin in Subjects With Cerebrovascular Disease
Authors: Duncan J. Campbell, Mark Woodward, John P. Chalmers, Samuel A. Colman, Alicia J. Jenkins, Bruce E. Kemp, Bruce C. Neal, Anushka Patel, Stephen W. MacMahon
Journal: Circulation (2005)

B-type natriuretic peptide (BNP), C-reactive protein (CRP), and renin are elevated in persons at risk for cardiovascular disease. However, data that directly compare these markers in the prediction of myocardial infarction (MI) are limited.N-terminal-proBNP (NT-proBNP), CRP, and renin were measured in baseline blood samples from a nested case-control study of the 6105 participants of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a placebo-controlled study of a perindopril-based blood pressure-lowering regimen among individuals with previous stroke or transient ischemic attack. Each of 206 subjects who experienced MI, either fatal or nonfatal, during a mean follow-up of 3.9 years was matched to 1 to 3 control subjects. Most MI cases (67%) occurred in subjects without a history of coronary heart disease. NT-proBNP, CRP, and renin each predicted MI; the odds ratio for subjects in the highest compared with the lowest quarter was 2.2 (95% CI, 1.3 to 3.6) for NT-proBNP, 2.2 (95% CI, 1.3 to 3.6) for CRP, and 1.7 (95% CI, 1.1 to 2.8) for renin. NT-proBNP and renin, but not CRP, remained predictors of MI after adjustment for all other predictors, including LDL and HDL cholesterol levels. Individuals with both NT-proBNP and renin in their highest quarters had 4.5 times the risk of MI compared with subjects with both biological markers in their lowest quarters.NT-proBNP and renin, but not CRP, are independent predictors of MI risk after stroke or transient ischemic attack, providing information additional to that provided by classic risk factors, and may enable more effective targeting of MI prevention strategies.
CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model
Authors: Chang H. Lee, Bhranti Shah, Eduardo K. Moioli, Jeremy J. Mao
Journal: Journal of Clinical Investigation (2015)

Fibroblasts are ubiquitous cells that demonstrate remarkable diversity. However, their origin and pathways of differentiation remain poorly defined. Here, we show that connective tissue growth factor (CTGF; also known as CCN2) is sufficient to induce human bone marrow mesenchymal stem/stromal cells (MSCs) to differentiate into fibroblasts. CTGF-stimulated MSCs lost their surface mesenchymal epitopes, expressed broad fibroblastic hallmarks, and increasingly synthesized collagen type I and tenacin-C. After fibroblastic commitment, the ability of MSCs to differentiate into nonfibroblastic lineages - including osteoblasts, chondrocytes, and adipocytes - was diminished. To address inherent heterogeneity in MSC culture, we established 18 single MSC-derived clones by limiting dilution. CTGF-treated MSCs were alpha-SMA-, differentiating into alpha-SMA+ myofibroblasts only when stimulated subsequently with TGF-beta1, suggestive of stepwise processes of fibroblast commitment, fibrogenesis, and pathological fibrosis. In rats, in vivo microencapsulated delivery of CTGF prompted postnatal connective tissue to undergo fibrogenesis rather than ectopic mineralization. The knowledge that fibroblasts have a mesenchymal origin may enrich our understanding of organ fibrosis, cancer stroma, ectopic mineralization, scarring, and regeneration.
Geometry and Degree of Apposition of the CoreValve ReValving System With Multislice Computed Tomography After Implantation in Patients With Aortic Stenosis
Authors: Carl J. Schultz, Annick Weustink, Nicolo Piazza, Amber Otten, Nico Mollet, Gabriel Krestin, Robert J. van Geuns, Pim de Feyter, Patrick W.J. Serruys, Peter de Jaegere
Journal: Journal of the American College of Cardiology (2009)
Common variation at 12q24.13 (OAS3) influences chronic lymphocytic leukemia risk
Authors: G P Sava, H E Speedy, M C Di Bernardo, M J S Dyer, A Holroyd, N J Sunter, H Marr, L Mansouri, S Deaglio, L Karabon, I Frydecka, K Jamroziak, D Woszczyk, G Juliusson, K E Smedby, S Jayne, A Majid, Y Wang, C Dearden, A G Hall, T Mainou-Fowler, G H Jackson, G Summerfield, R J Harris, A R Pettitt, D J Allsup, J R Bailey, G Pratt, C Pepper, C Fegan, R Rosenquist, D Catovsky, J M Allan, R S Houlston
Journal: Leukemia (2014)

Chronic lymphocytic leukemia (CLL) is the most common form of lymphoid malignancy in Western countries 1 .][4][5][6] Current projections for the number of independent regions harbouring common variants that are associated with CLL suggest that additional risk loci conferring modest effects should be identified by the expansion of discovery GWAS data sets. 2 In this study, we have made use of a meta-analysis of GWAS data, followed by validation in multiple independent case-control series, to identify a novel susceptibility locus for CLL at 12q24.13.
Identification of a restriction fragment length polymorphism by a CR1 cDNA that correlates with the number of CR1 on erythrocytes.
Authors: J G Wilson, E E Murphy, W W Wong, L B Klickstein, J H Weis, D T Fearon
Journal: The Journal of Experimental Medicine (1986)

A genetic basis for the regulation of the number of CR1 on E of different normal individuals was investigated by probing Southern blots of their genomic DNA with a 0.75-kb fragment of CR1 cDNA. Using Hind III, we observed a RFLP involving fragments of 7.4 kb and 6.9 kb that correlated with the number of CR1 on E. 32 individuals having only the 7.4-kb restriction fragment had a mean of 661 +/- 33 (SEM) CR1/E, 11 donors having both restriction fragments had a mean of 455 +/- 52 CR1/E, and 7 individuals having only the 6.9-kb fragment had a mean of 156 +/- 13 CR1/E, all means being significantly different (p less than 0.005). Cosegregation in a normal family of the Hind III restriction fragments with the S, F, and F' structural allotypes of CR1 confirmed that the regulatory element identified by these fragments is linked to the CR1 gene. Moreover, an analysis of the relative expression on E of these structural allotypes in association with either the 7.4-kb Hind III fragment or the 6.9-kb fragment showed that this regulatory element is cis-acting. In contrast, quantitation of CR1 of B lymphocytes and neutrophils revealed no differences in total CR1 expression between individuals homozygous for the 7.4-kb and 6.9-kb Hind III fragments. Thus, we have identified a genomic polymorphism that is linked to the CR1 gene and is associated with a cis-acting regulatory element for the expression of CR1 on E.