tbuckley/cabot-search huggingface dataset:
Type 2 diabetes risk variants and colorectal cancer risk: the Multiethnic Cohort and PAGE studies
Authors: I. Cheng, C. P. Caberto, A. Lum-Jones, A. Seifried, L. R. Wilkens, F. R. Schumacher, K. R. Monroe, U. Lim, M. Tiirikainen, L. N. Kolonel, B. E. Henderson, D. O. Stram, C. A. Haiman, L. Le Marchand
Journal: Gut (2011)

<h3>Background</h3> Diabetes has been positively associated with the risk of colorectal cancer. This study investigated whether recently established risk variants for diabetes also have effects on colorectal cancer. <h3>Methods</h3> 19 single nucleotide repeats (SNPs) associated with type 2 diabetes in genome-wide association studies were tested in a case–control study of 2011 colorectal cancer cases and 6049 controls nested in the Multiethnic Cohort study as part of the Population Architecture using Genomics and Epidemiology (PAGE) initiative. ORs and 95% CIs were estimated by unconditional logistic regression to evaluate the association between SNPs and colorectal cancer risk, adjusting for age, sex and race/ethnicity. Permutation testing was conducted to correct for multiple hypothesis testing. <h3>Results</h3> Four type 2 diabetes SNPs were associated with colorectal cancer risk: rs7578597 (<i>THADA</i>), rs864745 (<i>JAZF1</i>), rs5219 (<i>KCNJ11</i>) and rs7961581 (<i>TSPAN8</i>, <i>LGR5</i>). The strongest association was for the rs7578597 (<i>THADA</i>) Thr1187Ala missense polymorphism (<i>P</i><sub>trend</sub>=0.004 adjusted for multiple testing), with the high risk allele for colorectal cancer being the low risk allele for diabetes. Similar patterns of associations were seen with further adjustment for diabetes status and body mass index. The association of diabetes status with colorectal cancer risk was somewhat weakened after adjustment for these SNPs. <h3>Conclusion</h3> The findings suggest that diabetes risk variants also influence colorectal cancer susceptibility, possibly through mechanisms different from those for diabetes.
Autoantibodies of various specificities encoded by genes from the VH J558 family bind to foreign antigens and share idiotopes of antibodies specific for self and foreign antigens.
Authors: M Monestier, B Bonin, P Migliorini, H Dang, S Datta, R Kuppers, N Rose, P Maurer, N Talal, C Bona
Journal: The Journal of Experimental Medicine (1987)

We examined the binding to foreign antigens and the expression of crossreactive idiotypes by a panel of 20 murine monoclonal autoantibodies encoded by V genes from the VH J558 family. 9 of 20 antibodies bound to foreign antigens such as bacterial polysaccharides, poly(Glu50, Tyr50), poly(Glu54,Lys37,Phe9), arsonate, and lysozyme, known to interact with antibodies encoded by genes from the VH J558 family. A high proportion of our panel of autoantibodies expressed crossreactive idiotypes originally borne by monoclonal rheumatoid factors, anti-Sm, and anti-DNA antibodies, all encoded by V genes from the VH J558 family. Some of these VH J558+ autoantibodies shared crossreactive idiotypes with VH J558+ antibodies directed against foreign antigens such as influenza virus hemagglutinin, poly(Glu60,Ala30,Tyr10), arsonate, and dextran. The implications of these findings are discussed with respect to the process of activation of self-reactive clones.
Fc gamma R(CD16) interaction with ligand induces Ca2+ mobilization and phosphoinositide turnover in human natural killer cells. Role of Ca2+ in Fc gamma R(CD16)-induced transcription and expression of lymphokine genes.
Authors: M A Cassatella, I Anegón, M C Cuturi, P Griskey, G Trinchieri, B Perussia
Journal: The Journal of Experimental Medicine (1989)

In this study, we present evidence that interaction of Fc gamma R(CD16) with ligands (immune complexes or anti-CD16 antibodies) induces a rapid rise in [Ca2+]i and fast production of both inositol 1,4,5 triphosphate (IP3) and IP4 in homogeneous NK cell preparations. Part of the initial [Ca2+]i rise observed upon stimulation of NK cells with either anti-CD16 antibodies alone or after their crosslinking at the cell membrane depends on Ca2+ mobilization from intracellular stores, but sustained [Ca2+]i levels are maintained, after the initial spike, through influx of extracellular Ca2+. The [Ca2+]i rise is mediated, at least in part, by increases in IP3 after receptor-induced hydrolysis of membrane polyphosphoinositides (PPI). The role of extracellular Ca2+ in Fc gamma R(CD16)-dependent induction of lymphokine gene expression has been tested by evaluating production, mRNA accumulation and transcription of IFN-gamma and TNF in NK cells stimulated with Fc gamma R(CD16) ligands and/or rIL-2 in the presence of EGTA. Under these conditions, accumulation and transcription of both IFN-gamma and TNF mRNA induced by CD16 ligands, but not that induced by rIL-2, is completely abolished and neither cytokine can be detected at significant levels in the supernatant fluids of cells so treated. These data confirm that NK cell activation by specific ligands occurs through mechanisms distinct from those induced by IL-2, and indicate that extracellular Ca2+ represents a stringent requirement for cytokine production induced in NK cells through specific (Fc gamma R) stimulation. Our data also indicate that the [Ca2+]i rise induced upon Fc gamma R(CD16) crosslinking, though necessary, is not sufficient per se to induce activation of lymphokine genes, compatible with the hypothesis that Fc gamma R(CD16) crosslinking generates additional transducing signals that synergize with IL-2 to maximally activate NK cells.
Carcinoma of the breast in women under the age of 30.
Authors: C J Logan
Journal: BMJ (1978)

tactics summed up by Stevenson in his book Ethics and Language.'Teachers may resort to emotive techniques in order to change the attitudes of children towards various methods of behaviour.It is my opinion, however, that any attempt at crude emotivism will fail.We should present the children with the medical facts against a background of caring, now about their parents, later about their dependants.
Antibody to Rmp (outer membrane protein 3) increases susceptibility to gonococcal infection.
Authors: F A Plummer, H Chubb, J N Simonsen, M Bosire, L Slaney, I Maclean, J O Ndinya-Achola, P Waiyaki, R C Brunham
Journal: Journal of Clinical Investigation (1993)

The severe adverse effects of gonococcal infection on human fertility suggests that Neisseria gonorrhoeae would exert powerful selection for the development of a protective immune response in humans. N. gonorrhoeae is an obligate human pathogen and must persist in humans to survive. Since it is an ecologically successful organism, it must have evolved strategies to evade any human immune response it elicits. In a longitudinal study among 243 women working as prostitutes and experiencing frequent gonococcal infection, younger women, women with HIV infection, and women with antibody to the gonococcal outer membrane protein 3 (Rmp) were at increased risk of infection (adjusted odds ratio 3.4, CI95% 1.1-10.4, P < 0.05). Rmp is highly conserved in N. gonorrhoeae and the blocking of mucosal defences may be one of its functions. As similar proteins occur in many gram negative mucosal pathogens, the enhancing effect of such proteins may be a general strategy whereby bacteria evade human immune responses.
Effects of Adenosine Compounds on Renal Function and Renin Secretion in Dogs
Authors: HITOSHI TAGAWA, ARTHUR J. VANDER
Journal: Circulation Research (1970)

In anesthetized salt-depleted dogs, infusion of adenosine (20 to 500 µg/min) directly into a renal artery induced an initial decrease of renal blood flow for 1 to 2 minutes but did not change or slightly increased this flow during the steady state. Statistically significant decreases occurred in glomerular filtration rate, filtration fraction, sodium excretion, and renal venous renin activity. Calculated afferent arteriolar resistance increased and efferent resistance decreased. 5'-AMP (50 to 200 µg/min) induced changes which were smaller but qualitatively similar to those of adenosine. ATP (50 to 500 µg/min) induced no initial reduction in blood flow, and, during the steady state, caused a significant increase in blood flow and decreases in glomerular filtration rate, filtration fraction, sodium excretion, and renal venous renin. Efferent resistance decreased but afferent resistance did not change. Cyclic AMP (1 to 5 mg/min) caused a very small initial transient reduction in blood flow but induced changes similar to those of ATP during the steady state. Inosine (200 µg/min) and inosine-5'-monophosphate (50 to 200 µg/min) produced no detectable effects. It is suggested that adenosine or 5'-AMP may be normal mediators of both autoregulation and renin secretion.
Chloride Channel Inhibition Blocks the Protection of Ischemic Preconditioning and Hypo-Osmotic Stress in Rabbit Ventricular Myocardium
Authors: Roberto J. Diaz, Vito A. Losito, Gou D. Mao, Meredith K. Ford, Peter H. Backx, Gregory J. Wilson
Journal: Circulation Research (1999)

Abstract —The objective of this study was to examine the role of chloride (Cl – ) channels in the myocardial protection of ischemic preconditioning (IP). Isolated rabbit ventricular myocytes were preconditioned with 10-minute simulated ischemia (SI) and 20-minute simulated reperfusion (SR) or not preconditioned (control). The myocytes then received 180-minute SI or 45-minute SI/120-minute SR. Indanyloxyacetic acid 94 (IAA-94, 10 μmol/L) or 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, 1 μmol/L) was administered before IP or before SI or SI/SR to inhibit Cl – channels. Electrophysiological studies indicate that these drugs, at the concentrations used, selectively abolished Cl – currents activated under hypo-osmotic conditions (215 versus 290 mOsm). IP significantly ( P &lt;0.001) reduced the percentage of dead myocytes after 60-minute (30.8±1.3%, mean±SEM), 90-minute (35.3±1.3%), and 120-minute (39.2±1.7%) SI compared with controls (44.7±1.6%, 54.5±1.3%, and 58.9±1.8%, respectively) and after 45-minute SI/120-minute SR (36.3±0.6%) compared with control (56.6±2.2%). Hypo-osmotic stress also produced protection similar to IP. IAA-94 or NPPB abolished the protection of both IP and hypo-osmotic stress. In buffer-perfused rabbit hearts preconditioned with three 5-minute ischemia/10-minute reperfusion cycles given before the 40-minute long ischemia and 60-minute reperfusion, IP significantly (P &lt;0.0001) reduced infarct size (IP+vehicle, 4.7±0.9%, versus control+vehicle, 26.6±3.3%; mean±SEM). Again, IAA-94 or NPPB abolished the protection of IP. Our results implicate Cl – channels in the IP protection of the myocardium against ischemic/reperfusion injury and demonstrate that hypo-osmotic stress is capable of preconditioning cardiomyocytes.
Acetylcholine Increases the Free Intracellular Calcium Concentration in Podocytes in Intact Rat Glomeruli via Muscarinic M5 Receptors
Authors: ROLAND NITSCHKE, ANNA HENGER, SIGRID RICKEN, VICTORIA MU[Combining Diaeresis]LLER, MICHAEL KO[Combining Diaeresis]TTGEN, MARTIN BEK, HERMANN PAVENSTA[Combining Diaeresis]DT
Journal: Journal of the American Society of Nephrology (2001)

Abstract. The effects of acetylcholine (ACh) on the free intracellular calcium concentration ([Ca 2+ ] i ) of microdissected glomeruli were investigated using fura-2 fluorescence digital imaging and two-photon confocal microscopy. ACh caused a concentration-dependent [Ca 2+ ] i increases with an initial peak followed by a sustained plateau, which was suppressed by reduced extracellular Ca 2+ concentrations. The [Ca 2+ ] i plateau was not affected by the L-type Ca 2+ channel blocker nicardipine, whereas gadolinium and lanthanum (both at 1 μM) blocked the plateau. Diphenylacetoxy- N -methylpiperidine methiodide (100 nM), an M 3 /M 5 receptor antagonist, and pirenzepine (1 μM), an M 1 receptor antagonist, completely inhibited the effect of ACh. [Ca 2+ ] i measurements using two-photon excitation of fluo-3 and staining of the cells with calcein/acetoxymethyl ester, for observation of the capillary network together with the glomerular cells, showed that [Ca 2+ ] i was increased in single podocytes. Immunohistochemical studies did not demonstrate M 3 receptor expression in glomerular cells. M 1 receptors could be detected only in the parietal sheet of Bowman's capsule, whereas M 5 receptors were found only in podocytes. The data show that ACh increases [Ca 2+ ] i in podocytes of intact glomeruli, most likely via muscarinic M 5 receptors.
Value of follow-up procedures in patients with large-cell lymphoma who achieve a complete remission.
Authors: J C Weeks, B Y Yeap, G P Canellos, M A Shipp
Journal: Journal of Clinical Oncology (1991)

Salvage therapy for relapsed large-cell lymphoma (LCL) is more effective in patients with minimal disease, suggesting that early detection of relapse might increase the chance of long-term survival. To determine whether current follow-up procedures are effective in identifying preclinical disease, we analyzed patterns of relapse in 139 LCL patients who achieved a complete remission (CR) with high/moderate-dose methotrexate with leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (M/m-BACOD). The timing and results of all posttreatment follow-up tests were examined in the 36 patients who relapsed from complete remission (CR) and 46 controls who remain in CR. Despite conscientious posttreatment follow-up, only two of the 36 relapses (6%) were detected before the development of symptoms. Sixty-seven percent of patients relapsed in new disease sites (42% in new and old sites, and 25% in new sites only). Consistent with this observation, the tests most sensitive to clinical relapse were those not targeted to specific sites of disease: gallium scan (sensitivity, 90%), physical examination (80%), and lactate dehydrogenase (LDH) (65%). Of screening tests performed, only LDH was successful in detecting preclinical relapse, with a sensitivity of 42% and specificity of 85% for impending symptomatic relapse. These results indicate that conventional screening was ineffective in detecting preclinical relapse in LCL patients. We recommend prospective evaluation of a strategy that (1) screens with a frequency appropriate to a patient's risk of relapse, (2) uses sensitive test(s) not targeted to specific sites, and (3) limits aggressive screening to those high-risk patients eligible for potentially curative salvage therapy.
Immune complex disease.
Authors: P M Carter
Journal: Annals of the Rheumatic Diseases (1973)

Over the last decade it has become increasingly apparent that the deposition of immune complexes is a major feature of a wide range of human disease.Before discussing such disease processes it is necessary first to consider the immune complexes themselves and the factors which govern their composition, formation, and deposition in the tissues. Complex compositionThe complexes which result in disease usually have a molecular weight in excess of 500,000 and comprise both immunoglobulins and the antigens which stimulated their formation.The antigens responsible range from altered immunoglobulins, as in rheuma- toid arthritis (Whaley and Carson Dick, 1969), to viruses (Gyorkey, Min, Sincovics, and Gyorkey, 1969; Dixon, Oldstone, and Tonietti, 1970; Onion, Crumpacker, and Gilliland, 1971), and complexes of virus and antibody have been detected both circu- lating and at the sites of tissue injury (Oldstone and Dixon, 1971).Complexes which contain only immunoglobulins are 'mixed' (Cream, 1972) and may be IgM --> IgG (the common rheumatoid factor), IgG1 --> IgG3, copyright.
Saliva is one likely source of leukotriene B4 in exhaled breath condensate
Authors: F. Gaber, F. Acevedo, I. Delin, B-M. Sundblad, L. Palmberg, K. Larsson, M. Kumlin, S-E. Dahlen
Journal: European Respiratory Journal (2006)

Leukotriene (LT)B4 in exhaled breath condensate (EBC) has been reported to be elevated in airway inflammation. The origin of leukotrienes in EBC is, however, not established. The aims of this study are to measure LTB4 levels in EBC collected in two challenges characterised by a strong neutrophilic airway inflammation and to compare LTB4 levels in EBC with levels in sputum and saliva. LTB4 and α-amylase were measured in EBC from 34 healthy subjects exposed in a pig confinement building or to a lipopolysaccharide provocation. These markers were also measured in induced sputum in 11 of the subjects. For comparison, LTB4 and α-amylase were measured in saliva from healthy subjects. Only four out of 102 EBC samples had detectable LTB4 (28–100 pg·mL-1). α-amylase activity was detected in the LTB4-positive samples. In contrast, LTB4 was detected in all examined sputum supernatants in the same study (median 1,190 pg·mL-1). The median LTB4 level in saliva was 469 pg·mL-1. High levels of leukotriene B4 in saliva and the presence of leukotriene B4 in exhaled breath condensate only when α-amylase was detected, indicate that leukotriene B4 found in exhaled breath condensate is the result of saliva contamination. As leukotriene B4 was consistently present in sputum supernatants, exhaled breath condensate may be inappropriate for monitoring airway leukotriene B4.
COX-2 inhibitors and the gastrointestinal tract
Authors: I Bjarnason
Journal: Gut (2001)

The discovery of cyclooxygenase 2 (COX-2) a decade ago heralded one of the most rapid and expensive development and marketing of a new class of drug that we have witnessed. This has resulted in publication of an interesting mixture of exceptionally high quality basic and clinical research. Based on the COX dogma, that COX-1 is good and COX-2 is bad , we were promised equal therapeutic efficacy to conventional non-steroidal inflammatory drugs (NSAIDs) with the COX-2 selective inhibitors and absence of gastrointestinal side effects that otherwise represent a significant public health problem. Have these promises come to fruition?

The semantic problem about the term COX-2 selective agents is acknowledged,1-3 but for our purpose (accepting that nimesulide and etodolac, at least, have …
Bone Mass and Vitamin D Deficiency in Adults with Advanced Cystic Fibrosis Lung Disease
Authors: DANIEL S. DONOVAN, ANASTASIO PAPADOPOULOS, RONALD B. STARON, VICKI ADDESSO, LARRY SCHULMAN, CARLTON McGREGOR, FELICIA COSMAN, ROBERT L. LINDSAY, ELIZABETH SHANE
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Osteoporosis and fractures are increasingly recognized in children and adults with cystic fibrosis. To investigate the prevalence and pathogenesis of osteoporosis and low bone mass in adults with advanced pulmonary disease due to cystic fibrosis, we examined the relationships between bone mineral density (BMD), anthropomorphic variables, pulmonary status, glucocorticoid therapy, and vitamin D concentrations. BMD of the lumbar spine, hip, and proximal radius was measured by dual energy X-ray absorptiometry in 30 white adults (16 women), age 30 ± 2 yr (mean ± SEM). Compared with a normal control population, the patients had significantly reduced BMD at the lumbar spine (17 ± 3%), total hip and femoral neck (24 ± 3% and 20 ± 4%, respectively). The radius was significantly less demineralized (4 ± 2%; p ⩽ 0.003) than the other sites. Moreover, only 21% of patients with cystic fibrosis had normal BMD (T score > − 1.0) at the lumbar spine, 23% at the hip sites, and 39% at the radius. Age, weight, and body mass index (BMI) were most strongly correlated with bone mass, whereas glucocorticoid therapy and pulmonary function were not predictive. Despite oral vitamin D (400 to 800 IU daily), the mean serum 25-hydroxyvitamin D (25-OHD) concentration was at the low end of the normal range (16 ± 2 ng/ml; normal 10 to 52 ng/ml); 8 of 20 patients (40%) had frankly low ( ⩽ 10 ng/ml) levels. BMD was significantly lower in patients with low 25-OHD concentrations at the lumbar spine (0.774 ± 0.02 versus 0.913 ± 0.04 g/cm2; p = 0.01) and total hip (0.648 ± 0.04 versus 0.811 ± 0.04 g/cm2; p = 0.01). Vertebral fractures were present in 19% of subjects and 41% had a confirmed history of previous fracture. In summary, osteoporosis, low bone mass, and fractures are common in adults with advanced cystic fibrosis lung disease. Despite oral supplements, vitamin D deficiency is also common and is associated with more severe demineralization at the lumbar spine and hip. We conclude that the widespread practice of oral supplementation with 400 to 800 units of vitamin D is ineffective in maintaining normal vitamin D stores in many patients with cystic fibrosis. To ensure adequacy of vitamin D stores, measurement of serum 25-OHD should be included in the routine management of patients with cystic fibrosis.
Iron Therapy, Advanced Oxidation Protein Products, and Carotid Artery Intima-Media Thickness in End-Stage Renal Disease
Authors: Tilman Drüeke, Véronique Witko-Sarsat, Ziad Massy, Béatrice Descamps-Latscha, Alain P. Guerin, Sylvain J. Marchais, Valérie Gausson, Gérard M. London
Journal: Circulation (2002)

Background— Increased common carotid artery intima-media thickness (CCA-IMT) is a marker of early atherosclerosis. Low-grade inflammation is associated with the pathogenesis of atherosclerosis. Low-grade inflammation and increased CCA-IMT are observed in end-stage renal disease (ESRD). Oxidative stress is involved in uremia-related inflammation. Advanced oxidation protein products (AOPP) are markers of oxidant-mediated protein damage in ESRD. Intravenous iron given to patients on hemodialysis (HD) might induce oxidative stress. We investigated the relationships between AOPP, iron therapy, and CCA-IMT in stable HD patients. Methods and Results— Plasma AOPP and blood chemistry, including iron status, were analyzed in a cohort of 79 ESRD patients on HD. Measurements of CCA-IMT and CCA diameter, as assessed by B-mode ultrasonography, were obtained in 60 patients. AOPP levels were elevated in ESRD patients, and in univariate ( r =0.42, P &lt;0.0001) and multivariate analyses ( r =0.38, P &lt;0.001), they correlated with serum ferritin and with the intravenous iron dose received during the 12 months preceding the study (ferritin, P &lt;0001; AOPP, P &lt;0.01). Univariate and multivariate analyses identified the AOPP concentration as being significantly associated with CCA-IMT ( P =0.0197) and CCA wall-to-lumen ratio ( r =0.560, P &lt;0.0001). Independently of AOPP concentration, cumulative iron dose was positively related to CCA-IMT ( P =0.015) in patients &lt;60 years. Conclusion— In ESRD patients, CCA-IMT and CCA wall-to-lumen ratio were associated with plasma AOPP, serum ferritin, and the annual intravenous iron dose administered. These findings support the concept of a role of oxidative stress in the early atherosclerosis of ESRD patients, which may be increased by the usually recommended doses of intravenous iron.