tbuckley/cabot-search huggingface dataset:
Certain class I HLA alleles and haplotypes implicated in susceptibility play a role in determining specific features of the psoriatic arthritis phenotype
Authors: Muhammad Haroon, Robert Winchester, Jon T Giles, Eric Heffernan, Oliver FitzGerald
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> Psoriatic arthritis (PsA) susceptibility is associated with several different class I alleles, suggesting separate patterns of MHC effect. This exploratory study was based on the hypothesis that heterogeneity of the clinical phenotype of PsA might be explained by differing associations of clinical features with these susceptibility genes. <h3>Methods</h3> The clinical phenotype of 282 PsA patients in a cohort previously studied for associations with <i>human leukocyte antigen</i> (<i>HLA</i>)<i>-B</i> and <i>HLA-C</i> genotypes was first preliminarily assessed by univariate associations of susceptibility genes with specific clinical characteristics. To explore the potential genotypic effects of pairwise combinations of different HLA-B and C alleles/haplotypes, we created a series of allele/haplotype risk scores combining single alleles/haplotypes separately associated with being in the highest PsA severity propensity tertile based on the features studied by univariate analysis. <h3>Results</h3> In exploratory univariate analyses, <i>B*27:05:02</i> was positively associated with enthesitis, dactylitis and symmetric sacroiliitis, whereas <i>B*08:01:01-C*07:01:01</i>and its component alleles were positively associated with joint fusion and deformities, asymmetrical sacroiliitis, and dactylitis. <i>HLA-C*06:02:01</i> was negatively associated with asymmetrical sacroiliitis. The highest propensity score for severe PsA was with <i>B*27:05:02-C*02:02:02</i>, <i>B*08:01:01-C*07:01:01</i> and <i>B*37:01:01-C*06:02:01</i>, but not the <i>B*27:05:02-C*01:01:01</i> or <i>B*57:01:01-C*06:02:01</i> haplotypes<i>.</i> In contrast, <i>B*44</i> haplotypes were associated with presence of milder disease, and in univariate analysis with a decreased frequency of enthesitis, joint fusion, deformities and dactylitis. <h3>Conclusions</h3> Different HLA susceptibility genes were associated with particular features that defined the PsA phenotype of a given patient. Additive interactions between different susceptibility HLA alleles defined the propensity for a more severe or milder musculoskeletal phenotype.
GPR109A Is a G-protein–Coupled Receptor for the Bacterial Fermentation Product Butyrate and Functions as a Tumor Suppressor in Colon
Authors: Muthusamy Thangaraju, Gail A. Cresci, Kebin Liu, Sudha Ananth, Jaya P. Gnanaprakasam, Darren D. Browning, John D. Mellinger, Sylvia B. Smith, Gregory J. Digby, Nevin A. Lambert, Puttur D. Prasad, Vadivel Ganapathy
Journal: Cancer Research (2009)

Abstract Short-chain fatty acids, generated in colon by bacterial fermentation of dietary fiber, protect against colorectal cancer and inflammatory bowel disease. Among these bacterial metabolites, butyrate is biologically most relevant. GPR109A is a G-protein–coupled receptor for nicotinate but recognizes butyrate with low affinity. Millimolar concentrations of butyrate are needed to activate the receptor. Although concentrations of butyrate in colonic lumen are sufficient to activate the receptor maximally, there have been no reports on the expression/function of GPR109A in this tissue. Here we show that GPR109A is expressed in the lumen-facing apical membrane of colonic and intestinal epithelial cells and that the receptor recognizes butyrate as a ligand. The expression of GPR109A is silenced in colon cancer in humans, in a mouse model of intestinal/colon cancer, and in colon cancer cell lines. The tumor-associated silencing of GPR109A involves DNA methylation directly or indirectly. Reexpression of GPR109A in colon cancer cells induces apoptosis, but only in the presence of its ligands butyrate and nicotinate. Butyrate is an inhibitor of histone deacetylases, but apoptosis induced by activation of GPR109A with its ligands in colon cancer cells does not involve inhibition of histone deacetylation. The primary changes in this apoptotic process include down-regulation of Bcl-2, Bcl-xL, and cyclin D1 and up-regulation of death receptor pathway. In addition, GPR109A/butyrate suppresses nuclear factor-κB activation in normal and cancer colon cell lines as well as in normal mouse colon. These studies show that GPR109A mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in colon. [Cancer Res 2009;69(7):2826–32]
Potential significance of genomic imprinting defects for reproduction and assisted reproductive technology
Authors: D. Lucifero
Journal: Human Reproduction Update (2004)

Recent studies suggest a possible link between human assisted reproductive technology and genomic imprinting disorders. Assisted reproductive technology includes the isolation, handling and culture of gametes and early embryos at times when imprinted genes are likely to be particularly vulnerable to external influences. Evidence of sex‐specific differences in imprint acquisition suggests that male and female germ cells may be susceptible to perturbations in imprinted genes at specific prenatal and postnatal stages. Imprints acquired first during gametogenesis must be maintained during preimplantation development when reprogramming of the overall genome occurs. In this review, we will discuss both new developments in our understanding of genomic imprinting including the mechanisms and timing of imprint erasure, acquisition and maintenance during germ cell development and early embryogenesis as well as the implications of this research for future epigenetic studies in reproduction and assisted reproductive technology.
Treatment of enteritis in chronic granulomatous disease with granulocyte colony stimulating factor
Authors: B Myrup, N H Valerius, P B Mortensen
Journal: Gut (1998)

Background —In several diseases there is a relation between deficiency of neutrophil granulocytes and granulomatous lesions. Recently, in glycogen storage disease type Ib, this relation has been supported by the beneficial effect of treatment of enteritis with granulocyte-macrophage colony stimulating factor. Aim —To investigate whether chronic granulomatous disease could be treated according to the same principle. Patients and methods —Inflammatory lesions were monitored in two brothers with chronic granulomatous disease demonstrated by very low superoxide production in neutrophil granulocytes. The two patients were treated with recombinant human granulocyte colony stimulating factor on three occasions when the disease was active. Results —In one patient, remission of an inflamed stenosis of the colon sigmoideum was shown by granulocyte scintigraphy after one month of treatment with granulocyte colony stimulating factor. In the other patient, remission of colon disease and later of a non-malignant tumour in the right lung hilum was shown by colonoscopy and computed tomography scans respectively. Conclusion —Remission of inflammatory lesions in two brothers with chronic granulomatous disease was induced by granulocyte colony stimulating factor on three occasions. The mechanism for this effect is not known. The result is similar to the response found in patients with leucocyte deficiency due to glycogen storage disease type Ib.
C4b-Binding Protein (C4BP) Activates B Cells through the CD40 Receptor
Authors: Scott R. Brodeur, Federica Angelini, Leonard B. Bacharier, Anna M. Blom, Emiko Mizoguchi, Hiroshi Fujiwara, Alessandro Plebani, Luigi D. Notarangelo, Bjorn Dahlback, Erdyni Tsitsikov, Raif S. Geha
Journal: Immunity (2003)
STUDIES BASED ON A MALIGNANT TUMOR OF THE RABBIT
Authors: Louise Pearce, Wade H. Brown, Chester M. Van Allen
Journal: The Journal of Experimental Medicine (1924)

The results of transplantation, as recorded in the first section of the paper, are analyzed from the standpoint of the influence of the factors of serial passage, the material used for inoculation, the age and breed of the animals, and the time or season at which the experiments were carried out. The material used for the inoculation of different groups of animals appeared to have comparatively little effect on the ultimate results. The character of the animals used was found to be a factor of more importance in that the tumor displayed definite peculiarities of growth and malignancy referable to age and to breed or color markings. Still, it seemed unlikely that any of these factors would account for the variations in growth and malignancy that had been observed. After considering the various possibilities presented, it appeared that the principal factors concerned in determining the results of transplantation were adaptation to passage and variations in the conditions of season and weather that prevailed during the time the experiments were being carried out-the one affecting the energy of cell growth and the other affecting animal economy.
Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial
Authors: Renato D Lopes, Sana M Al-Khatib, Lars Wallentin, Hongqiu Yang, Jack Ansell, M Cecilia Bahit, Raffaele De Caterina, Paul Dorian, J Donald Easton, Cetin Erol, Justin A Ezekowitz, Bernard J Gersh, Christopher B Granger, Stefan H Hohnloser, John Horowitz, Elaine M Hylek, John JV McMurray, Puneet Mohan, Dragos Vinereanu, John H Alexander
Journal: The Lancet (2012)
Users' Guides to the Medical Literature
Authors: C. David Naylor
Journal: JAMA (1996)

<h3>CASE SCENARIO</h3> Your patient, a 78-year-old retired internist, has been complaining of increasing symptoms of benign prostatic hyperplasia. He has long-standing hypertension and coronary artery disease, with remote anterolateral myocardial infarction and bypass surgery 10 years ago. His left ventricular ejection fraction was recently documented at 20%, and he has been started on an angiotensin-converting enzyme inhibitor. Rectal examination confirms a moderately enlarged prostate, without irregularities, nodularity, or tenderness. As you discuss management options, your patient insists that transurethral prostate surgery is dangerous and that international studies of thousands of patients have proved that, as he puts it, "old-fashioned open prostatectomy is safer than that keyhole surgery." You prescribe a trial of an α-blocker, terazosin, and arrange to see him again. However, the retired internist sounds so convinced that you also resolve to look into the evidence about the two forms of prostatectomy. <h3>THE SEARCH</h3> Later, you sit down in
Intermediate steps in positive selection: differentiation of CD4+8int TCRint thymocytes into CD4-8+TCRhi thymocytes.
Authors: K Lundberg, W Heath, F Köntgen, F R Carbone, K Shortman
Journal: The Journal of Experimental Medicine (1995)

The differentiation potential of putative intermediates between CD4+8+ thymocytes and mature T cells has been examined. Such intermediate populations were sorted, in parallel with CD4+8+ thymocytes, from three types of C57BL/6 mice: major histocompatibility complex (MHC) class II-deficient mice, mice transgenic for an alpha/beta T cell receptor (TCR) restricted by class I MHC and normal mice. The sorted populations were then transferred into the thymus of nonirradiated C57BL/Ka mice differing in Thy 1 allotype, and the progeny of the transferred cells were analyzed 2 d later. Surprisingly, with all three types of donor mice, a major proportion of the CD4+8intTCRint-derived progeny were found to be CD4-8+TCRhi cells, thus delineating a new alternative pathway for development of the CD8 lineage. In contrast, the transfer of CD4int8+TCRint thymocytes produced CD4-8+TCRhi cells but no significant proportion of CD4+8-TCRhi cells, suggesting that there is no equivalent alternative pathway for the CD4 lineage. The results negate some of the evidence for a stochastic/selective model of lineage commitment, and point to an asymmetry in the steps leading to CD4-8+ versus CD4+8- T cells.
Activation of Histone Deacetylase-6 Induces Contractile Dysfunction Through Derailment of α-Tubulin Proteostasis in Experimental and Human Atrial Fibrillation
Authors: Deli Zhang, Chia-Tung Wu, XiaoYan Qi, Roelien A.M. Meijering, Femke Hoogstra-Berends, Artavazd Tadevosyan, Gunseli Cubukcuoglu Deniz, Serkan Durdu, Ahmet Ruchan Akar, Ody C.M. Sibon, Stanley Nattel, Robert H. Henning, Bianca J.J.M. Brundel
Journal: Circulation (2013)

Atrial fibrillation (AF) is characterized by structural remodeling, contractile dysfunction, and AF progression. Histone deacetylases (HDACs) influence acetylation of both histones and cytosolic proteins, thereby mediating epigenetic regulation and influencing cell proteostasis. Because the exact function of HDACs in AF is unknown, we investigated their role in experimental and clinical AF models.Tachypacing of HL-1 atrial cardiomyocytes and Drosophila pupae hearts significantly impaired contractile function (amplitude of Ca(2+) transients and heart wall contractions). This dysfunction was prevented by inhibition of HDAC6 (tubacin) and sirtuins (nicotinamide). Tachypacing induced specific activation of HDAC6, resulting in α-tubulin deacetylation, depolymerization, and degradation by calpain. Tachypacing-induced contractile dysfunction was completely rescued by dominant-negative HDAC6 mutants with loss of deacetylase activity in the second catalytic domain, which bears α-tubulin deacetylase activity. Furthermore, in vivo treatment with the HDAC6 inhibitor tubastatin A protected atrial tachypaced dogs from electric remodeling (action potential duration shortening, L-type Ca(2+) current reduction, AF promotion) and cellular Ca(2+)-handling/contractile dysfunction (loss of Ca(2+) transient amplitude, sarcomere contractility). Finally, atrial tissue from patients with AF also showed a significant increase in HDAC6 activity and reduction in the expression of both acetylated and total α-tubulin.AF induces remodeling and loss of contractile function, at least in part through HDAC6 activation and subsequent derailment of α-tubulin proteostasis and disruption of the cardiomyocyte microtubule structure. In vivo inhibition of HDAC6 protects against AF-related atrial remodeling, disclosing the potential of HDAC6 as a therapeutic target in clinical AF.
Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation
Authors: Malte Kelm, Stefan Schäfer, Rüdiger Dahmann, Bahar Dolu, Stefan Perings, Ulrich K.M Decking, Jürgen Schrader, Bodo E Strauer
Journal: Cardiovascular Research (1997)

Objective: It has been suggested that nitric oxide (NO) is involved in the regulation of myocardial function in a variety of diseases such as dilated cardiomyopathy, myocarditis, heart transplant rejection, and septic shock. However, the underlying mechanism of NO mediated reduction of cardiac contractility has not been clearly established so far. Therefore, we studied the effects of authentic NO on left ventricular function and myocardial energy status in the isolated heart. Methods: In 43 isolated perfused guinea pig hearts quantitative and kinetic changes in coronary flow (CF), left ventricular developed pressure (LVDP), the cardiac release of adenosine, lactate, cyclic GMP, and norepinephrine were measured during infusion of authentic NO. In parallel, myocardial phosphocreatine (PCr), ATP and the free energy change of ATP-hydrolysis (ΔGATP) were measured using 31P nuclear magnetic resonance spectroscopy. Results: At low concentrations (0.01 to 1.0 μmol/L) NO increased CF only; at higher concentrations (1 to 100 μmol/L) CF remained elevated and LVDP was significantly reduced. Onset and offset of changes in LVDP occurred always within 2 to 5 s after start and cessation of NO infusion. Contractile dysfunction was significantly correlated to a pronounced increase in adenosine formation (>70-fold), a significant decrease in myocardial PCr (−78%), ATP (−25%) and a decrease in ΔGATP from −61.76 kJ/mol to −50.75 kJ/mol. This was paralleled by a significant decrease in myocardial oxygen consumption (−65%) and a tenfold increase in lactate production. Coronary vasodilation (NO: 0.001 to 1.0 μmol/L) significantly correlated with the increase in cGMP release, whereas at negative inotropic concentrations (NO: 10 to 100 μmol/L) a clear quantitative and kinetic dissociation between NO-induced changes in cGMP and LVDP was observed. Contractile dysfunction was not related to cardiac release of norepinephrine. Conclusions: In the isolated heart NO can potently depress myocardial energy generation thus being an effective modulator of cardiac contractility. This effect of NO may be of pathophysiological significance in cardiac muscle disorders in vivo.
Invasive group A streptococcal infection with pancarditis caused by a new emm-type 12 allele of Streptococcus pyogenes
Authors: Gülşen Özkaya, Ali Shorbagi, Zekeriya Ülger, Arzu Saglam, Melda Aybar, Yeşim Çetinkaya Şardan, Ömrüm Uzun
Journal: Journal of Infection (2005)
A RECEPTOR FOR ANTIBODY ON B LYMPHOCYTES
Authors: A. Basten, J. F. A. P. Miller, J. Sprent, J. Pye
Journal: The Journal of Experimental Medicine (1972)

Evidence is presented for the existence on all B lymphocytes, but not on T lymphocytes, of a membrane-associated receptor for antibody. The receptor was detected by a radioautographic technique in which lymphoid cells were incubated with antibody followed by the corresponding radioiodinated antigen. The ease with which antibody eluted during washing indicated that the bond between antibody and cell was weak. The formation of an antibody-antigen complex on the cell surface, however, stabilized the bond and permitted accurate quantitation of cells with adherent antibody. The ability of several combinations of antibody and antigen to adhere to the cells demonstrated the nonspecificity of the phenomenon and emphasized the need for care in interpretation of antigen-binding studies particularly when immune cells are being used. The identity of antibody-binding lymphocytes was established by two different approaches. In the first, mouse lymphocyte populations greatly enriched for either T cells or B cells were examined. Their T cell content was assessed by means of well-established markers such as the theta C3H isoantigen. When this was compared with the number of antibody-binding cells, an inverse relationship was obtained in each instance; thus almost all thoracic duct cells from athymic mice labeled with an immune complex although none were theta positive. The striking reduction in antibody-binding cells observed in bursectomized chickens provided a second and independent line of evidence suggesting that B cells, not T cells, bind antibody. The ability of B cells from primed animals to bind antibody in vivo made it important to test whether this phenomenon was related to the carriage of immunological memory. No correlation was, however, found between membrane-bound antibody and memory. It was proposed that the existence of a receptor of this kind may provide a rational explanation for antibody-dependent killing of target cells and may prove of importance in antigen concentration particularly during the secondary response.
Extranodal NK / T-cell lymphoma with cutaneous involvement: ‘nasal’ vs. ‘nasal-type’ subgroups- a retrospective study of 18 patients
Authors: Y-L. Choi, J-H. Park, J-H. Namkung, J-H. Lee, J-M. Yang, E-S. Lee, D-Y. Lee, K-T. Jang, Y-H. Ko
Journal: British Journal of Dermatology (2008)

Extranodal natural killer T (NK/T) cell lymphoma is subcategorized into 'nasal' and 'nasal-type' NK/T-cell lymphomas according to the primary sites of anatomical involvement.The aim of this study was to characterize the cutaneous manifestations of the skin involving extranodal NK/T-cell lymphoma and to define the distinctive features of 'nasal' and 'nasal-type'. In addition, the prognostic factors that affect overall survival were investigated.A retrospective case study of 18 patients with extranodal NK/T-cell lymphoma with cutaneous involvement was performed.The NK/T-cell lymphomas usually occurred in middle-aged, male patients. Most of the patients presented with either cellulitis or ulcer. A facial predilection for the location of the lesion was noted. The characteristic features of the 'nasal-type' compared with the 'nasal' were a localized involvement of the skin, less aggressive clinical course and better survival outcome.Extranodal NK/T-cell lymphomas are extremely aggressive regardless of their subgroup. However, the 'nasal-type' NK/T-cell lymphoma was clinically less aggressive, more localized and had a better outcome compared with the other type. Cellulitis and ulcer were the major cutaneous manifestations.
Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis
Authors: Nigel M Williams, Irina Zaharieva, Andrew Martin, Kate Langley, Kiran Mantripragada, Ragnheidur Fossdal, Hreinn Stefansson, Kari Stefansson, Pall Magnusson, Olafur O Gudmundsson, Omar Gustafsson, Peter Holmans, Michael J Owen, Michael O'Donovan, Anita Thapar
Journal: The Lancet (2010)
Diabetic Microangiopathic Hemolytic Anemia: Beneficial Effect of an Antiplatelet Agent?
Authors: Alain G Dupont, Patricia Van Der Niepen, Jacques Sennesael, Guido Somers
Journal: Diabetes Care (1985)

A 66-yr-old man with non-insulin-dependent diabetes mellitus complicated by retinopathy and nephropathy presented with shortened red cell survival associated with prominent fragmentation of erythrocytes and leading to severe hemolytic anemia. Neither abnormal carbohydrate tolerance per se nor renal failure was related to the red cell fragmentation syndrome. Also, a marked platelet hyperaggregability, which disappeared under treatment with ticlopidine, was demonstrated. Furthermore, during treatment with this potent platelet inhibitor, red cell survival normalized and all signs of hemolysis, as well as the schistocytes present in the peripheral blood smears, disappeared. Two weeks after stopping ticlopidine administration, microangiopathic hemolytic anemia relapsed. We suggest that the fragmentation hemolysis in this patient was related to diabetic microangiopathy, and that the beneficial effects of ticlopidine are related to its platelet-inhibiting activities. This case further reaffirms that antiplatelet agents may have a beneficial effect on the vascular disease of diabetes mellitus.
Cyanide in bronchoalveolar lavage is not diagnostic for Pseudomonas aeruginosa in children with cystic fibrosis
Authors: M.D. Stutz, C.L. Gangell, L.J. Berry, L.W. Garratt, B. Sheil, P.D. Sly
Journal: European Respiratory Journal (2010)

Early detection of the cyanobacterium Pseudomonas aeruginosa in the lungs of young children with cystic fibrosis (CF) is considered the key to delaying chronic pulmonary disease. We investigated whether cyanide in bronchoalveolar lavage (BAL) fluid could be used as an early diagnostic biomarker of infection. Cyanide was measured in 226 BAL samples (36 P. aeruginosa infected) obtained from 96 infants and young children with CF participating in an early surveillance programme involving annual BAL. Cyanide was detected in 97.2% of P. aeruginosa infected and 60.5% of uninfected samples. Cyanide concentrations were significantly higher in BALs infected with P. aeruginosa (median (25th–75th percentile) 27.3 (22.1–33.3) μM) than those which were not (17.2 (7.85–23.0) μM, p&lt;0.001). The best sensitivity, specificity, positive and negative predictive values were obtained with a cut-off concentration of 20.6 μM, and were 83%, 66%, 32% and 96%, respectively. Neutrophil number in BAL was a significant predictor of cyanide concentration (p&lt;0.001). Cyanide concentration can distinguish between P. aeruginosa infected and uninfected BALs as a group, but not individually; therefore, cyanide is a poor diagnostic biomarker of P. aeruginosa infection. Cyanide levels in BAL are related to the level of neutrophilic inflammation.