tbuckley/cabot-search huggingface dataset:
Effect of Candesartan on Cause-Specific Mortality in Heart Failure Patients
Authors: Scott D. Solomon, Duolao Wang, Peter Finn, Hicham Skali, Leonardo Zornoff, John J.V. McMurray, Karl Swedberg, Salim Yusuf, Christopher B. Granger, Eric L. Michelson, Stuart Pocock, Marc A. Pfeffer
Journal: Circulation (2004)

Patients with heart failure are at increased risk of sudden death and death attributed to progressive pump failure. We assessed the effect of candesartan on cause-specific mortality in patients enrolled in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program.The CHARM program consisted of 3 component trials that enrolled patients with symptomatic heart failure: CHARM-Alternative (n=2028; LVEF<=40% [corrected] and ACE intolerant), CHARM-Added (n=2548; LVEF<=40%, [corrected] already on ACE inhibitors), and CHARM-Preserved (n=3023; LVEF >40%). Patients were randomized to candesartan, titrated to 32 mg QD, or placebo and were followed up for a median of 37.7 months. All deaths were reviewed by a blinded adjudication committee and categorized according to prespecified definitions on the basis of a narrative and source documentation. The number and rate of deaths by cause were calculated for each of the component trials and the overall program. Of all the patients, 8.5% died suddenly, and 6.2% died of progressive heart failure. Candesartan reduced both sudden death (HR 0.85 [0.73 to 0.99], P=0.036) and death from worsening heart failure (HR 0.78 [0.65 to 0.94], P=0.008). These reductions were most apparent in the patients with LVEF<=40% [corrected].Candesartan reduced sudden death and death from worsening heart failure in patients with symptomatic heart failure, although this reduction was most apparent in patients with systolic dysfunction.
NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy
Authors: Raquel Gómez-Sintes, José J. Lucas
Journal: Journal of Clinical Investigation (2010)

Use of lithium, the mainstay for treatment of bipolar disorder, is limited by its frequent neurological side effects and its risk for overdose-induced toxicity. Recently, lithium has also been proposed as a treatment for Alzheimer disease and other neurodegenerative conditions, but clinical trials have been hampered by its prominent side effects in the elderly. The mechanisms underlying both the positive and negative effects of lithium are not fully known. Lithium inhibits glycogen synthase kinase-3 (GSK-3) in vivo, and we recently reported neuronal apoptosis and motor deficits in dominant-negative GSK-3-transgenic mice. We hypothesized that therapeutic levels of lithium could also induce neuronal loss through GSK-3 inhibition. Here we report induction of neuronal apoptosis in various brain regions and the presence of motor deficits in mice treated chronically with lithium. We found that GSK-3 inhibition increased translocation of nuclear factor of activated T cells c3/4 (NFATc3/4) transcription factors to the nucleus, leading to increased Fas ligand (FasL) levels and Fas activation. Lithium-induced apoptosis and motor deficits were absent when NFAT nuclear translocation was prevented by cyclosporin A administration and in Fas-deficient lpr mice. The results of these studies suggest a mechanism for lithium-induced neuronal and motor toxicity. These findings may enable the development of combined therapies that diminish the toxicities of lithium and possibly other GSK-3 inhibitors and extend their potential to the treatment of Alzheimer disease and other neurodegenerative conditions.
Effect of exercise on the relationship between myocardial blood flow and systolic wall thickening in dogs with acute coronary stenosis.
Authors: K P Gallagher, M Matsuzaki, G Osakada, W S Kemper, J Ross
Journal: Circulation Research (1983)

Relationships between regional myocardial perfusion and transmural function, both during treadmill exercise and at rest, were examined in conscious dogs with varying degrees of coronary stenosis produced by a hydraulic occluder. In 13 dogs we measured myocardial blood flow with microspheres (10-12 microns in diameter) and regional systolic wall thickening (%). During exercise with coronary stenosis, myocardial blood flow was characterized by nonuniform distribution, and associated with regional dysfunction. The relationships between normalized myocardial blood flow and normalized %wall thickening during exercise with coronary stenosis were linear, with significantly different slopes (mean myocardial blood flow: y = 1.23x - 0.16, r = 0.93; subendocardial myocardial blood flow: y = 1.50x - 0.02, r = 0.86; subepicardial myocardial blood flow: y = 0.83x - 0.18, r = 0.87). To fill the gap between available subendocardial and subepicardial data during exercise with coronary stenosis and control points, however, would require nonlinear components. In 10 of the dogs, coronary stenosis at rest was also produced to compare regional myocardial blood flow - %wall thickening relations at rest with those during steady state exercise. The absolute mean myocardial blood flow - %wall thickening relation during exercise with coronary stenosis (y = 11.6x - 1.9, r = 0.90) was significantly shifted rightward from the resting relation (y = 25.3x -2.1, r = 0.80). However, when changes in %wall thickening were plotted vs. myocardial blood flow per beat, the relationships at rest and exercise were nearly superimposable. Likewise, relations between normalized myocardial blood flow and changes in %wall thickening at rest and exercise were not significantly different. We conclude: %wall thickening during exercise is directly related to changes in mean myocardial blood flow but is related in nonlinear fashion to changes in subepicardial and subendocardial myocardial blood flow; %wall thickening may provide a reliable index of the relative transmural flow distribution during exercise as well as at rest; during brief bouts (5-8 minutes) of exercise with coronary stenosis, the relationship between stabilized regional contractile dysfunction and level of myocardial blood flow per beat is the same as that during coronary stenosis at rest.
Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of β-Amyloid in Mice with Alzheimer’s Disease Pathology
Authors: Jee Hoon Roh, Yafei Huang, Adam W. Bero, Tom Kasten, Floy R. Stewart, Randall J. Bateman, David M. Holtzman
Journal: Science Translational Medicine (2012)

Decreased sleep and attenuation of circadian fluctuations in Aβ reflect amyloid-associated pathology in Alzheimer’s disease.
SURFACE TENSION OF SERUM
Authors: P. Lecomte du Noüy
Journal: The Journal of Experimental Medicine (1927)

Experiments are reported which indicate that a shift toward higher concentrations is observed in the minimum value of the static surface tension when plasma instead of serum solutions is used. The amount of the shift, expressed as a function of the concentration, shows that the figures are in satisfactory agreement with the determined amount of fibrinogen in the plasma. Some evidence is given that "plasma molecules" capable of organizing themselves on adsorbing surfaces exist in plasma, and that their length would be approximately 4.3 mmicroin round figures,instead of 4.0 mmicro for the serum. The area occupied in the plane of adsorption by one individual molecule is, however, smaller than that occupied by the "serum molecule," thus indicating a marked structural difference between the two, the "plasma molecule" being narrower but longer than the "serum molecule." This difference may be due either to a different orientation accompanied by an increase in one of the dimensions, or else to an actual difference in structure with respect to the main axis, resulting in a decrease in the mean diameter of the "serum molecule" with an increase in the length of its main axis. The mass of the "plasma molecule" is about 6.3 per cent larger than that of the "serum molecule, " in the case of rabbit serum.
A lesson learnt: the rise and fall of Lariam and Halfan
Authors: Ashley M Croft
Journal: Journal of the Royal Society of Medicine (2007)

Lariam (pharmacological name mefloquine) is an antimalaria drug discovered by the US Army shortly after the Vietnam War, and subsequently marketed worldwide by F. Hoffmann-La Roche. The first reported trials of mefloquine were in prisoners, and were performed at the Joliet Correctional Center, Illinois, in 1975, and at the Maryland House of Correction in 1976.1,2

Halfan (pharmacological name halofantrine) is an antimalaria drug chemically related to mefloquine and quinine. Like Lariam, Halfan emerged from the US Army's huge post-Vietnam antimalaria drug discovery programme.3 Halfan was first described in the literature in November 1982.4 During the 1980s and 1990s, Halfan was marketed by Smith Kline Beecham.

There is no question that safe and effective antimalaria drugs were needed in the second half of the twentieth century, once it became apparent that the Plasmodium had developed resistance to the mainstay of antimalaria therapy, namely chloroquine. Chloroquine resistance was observed first in Thailand in 1957, then on the Colombian-Venezuelan border in 1959, and in Kenya and Tanzania in 1978.5 Within a decade of Lariam and Halfan being marketed, however, the safety of both these novel agents was in doubt.

This essay looks at the unusual developmental history of Lariam and Halfan, explains the circumstances under which both drugs rose in esteem with policy makers and prescribers and then fell into disfavour with consumers, and summarizes the lessons learnt in the process. These lessons need to be recorded and acted upon, to prevent a repetition of the same mistakes with the next generation of antimalaria compounds.
Acute and Chronic Renal Effects of Recombinant Human TGF-β2 in the Rat
Authors: FRANCIS J. KELLY, SHARON ANDERSON, MICHELE M. THOMPSON, TERRY T. OYAMA, THOMAS M. KENNEFICK, CHRISTOPHER L. CORLESS, RICHARD J. ROMAN, LESLIE KURTZBERG, BRUCE M. PRATT, STEVEN R. LEDBETTER
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The expression of transforming growth factor-β (TGF-β) correlates with the incidence of renal glomerular and interstitial injury, however, nothing is known of the effect of these proteins on renal hemodynamics. This study examines the renal hemodynamic and morphologic effects of recombinant human TGF-β2 in normal male Sprague Dawley rats. Acute infusion of TGF-β2 (1.2 μg/kg per min) induced no hemodynamic changes, except for a modest though significant fall in mean arterial pressure. Administering TGF-β2 at varying doses (20, 100, and 400 μg/kg) for 9 wk caused modest increases in systolic BP and proteinuria and minimal tubular interstitial fibrosis, however, renal hemodynamic end points were not significantly altered. TGF-β2 (800 μg/kg) was also administered to volume-depleted rats for 7 consecutive days. In contrast to the findings in volume-replete animals, administration of TGF-β2 to volume-depleted rats caused a marked reduction in GFR and medullary blood flow. Histologic fibrosis of the medullary vasa recta and cortical interstitium was seen, but glomeruli were unaffected. Thus, acute and short-term chronic TGF-β2 administration did not induce major renal changes in the volume-replete state, however, TGF-β2 combined with volume depletion caused medullary hypoperfusion and reduced GFR.
Association between DNA repair gene polymorphisms and risk of glioma: A systematic review and meta-analysis
Authors: Maral Adel Fahmideh, Judith Schwartzbaum, Paolo Frumento, Maria Feychting
Journal: Neuro-Oncology (2014)

Association studies of germline DNA repair single nucleotide polymorphisms (SNPs) and glioma risk have yielded inconclusive results. We therefore performed a systematic review and meta-analysis of studies investigating this association. We identified 27 eligible studies investigating 105 SNPs in 42 DNA repair genes. Of these, 10 SNPs in 7 genes were analyzed in at least 4 studies and were therefore included in our meta-analysis. The meta-analysis was performed for homozygote comparison, heterozygote comparison, and dominant and recessive models by applying a fixed- or random-effects model. The funnel and forest plots were created using RevMan software. We found that SNPs rs3212986 (odds ratio [OR] = 1.35 (1.08–1.68), P = .008), rs13181 (OR = 1.18 (1.06–1.31), P = .002), and rs25487 (OR = 1.12 (1.03–1.22), P = .007) in DNA repair genes ERCC1, ERCC2 (XPD), and XRCC1 may increase the risk of glioma, while polymorphisms rs1136410 (OR = 0.78 (0.68–0.89), P = .0004) and rs12917 (OR = 0.84 (0.73–0.96), P = .01) in PARP1(ADPRT) and MGMT are associated with decreased susceptibility to glioma. No evidence of significant associations between ERCC2 rs1799793, OGG1 rs1052133, XRCC1 rs25489, XRCC1 rs1799782, or XRCC3 rs861539 and risk of glioma was observed. This study provides evidence that DNA repair genes ERCC1, ERCC2, and XRCC1 might be low-penetrance glioma-risk genes, while MGMT and PARP1 polymorphisms may confer protection against glioma.
Does anti-tumour necrosis factor treatment modify the tuberculin PPD response?
Authors: B E Joven
Journal: Annals of the Rheumatic Diseases (2006)

Tumour necrosis factor α (TNFα) has a key role in chronic arthritis,1 but it also participates in the defence against infection. TNFα, together with interferon γ, contributes to the immune response against mycobacteria.2 This can explain the higher incidence of tuberculosis seen in patients receiving anti-TNFα treatment.3 Therefore, a tuberculin purified protein derivative (PPD) test has been recommended before starting anti-TNFα treatment to better identify patients at risk for tuberculosis reactivation requiring isoniazid treatment.4 However, patients with chronic arthritis can be anergic to delayed-type hypersensitivity (DTH) tests, owing to either active disease or to immunosuppressive treatment.5 Some authors have previously shown that the DTH response in patients given second line treatment improves, but the effect of anti-TNFα treatment is not known.6

We have studied, …
How helpful are serological markers in differentiating crohn's disease from ulcerative colitis in indian asian inflammatory bowel disease patients?
Authors: D. G. Walker, A. S. Bancil, H. R. Williams, C. Bunn, T. R. Orchard
Journal: Gut (2011)

<h3>Introduction</h3> Atypical perinuclear antineutrophil cytoplasmic antibody (pANCA), anti-Saccharomyces cerevisiae antibody (ASCA) and more recently Outer Membrane Porin C (Omp-C) have been extensively studied in European and North American IBD populations. There is emerging evidence that the combination of these autoantibodies may increase the accuracy of diagnosis in IBD, however it is not known how reliable these markers are in IBD patients of different ethnicities. The aims of this study were to first determine the prevalence of ASCA, Omp-C and atypical pANCA in Indian Asian IBD patients and controls. The second aim was to determine the ability of ASCA and atypical pANCA to discriminate between CD and UC in Indian Asians. <h3>Methods</h3> A total of 191 Indian Asian IBD patients (UC 139, CD 52) and 36 healthy ethnically matched controls were included in the study. Sera were analysed for the presence of ASCA IgA and IgG and Omp-C antibodies using a commercially available ELISA (Quanta Lite; INOVA Diagnostics). To test for atypical pANCA, indirect immunofluorescence was performed on sera diluted 1/10 and tested on ethanol fixed neutrophil substrate (INOVA diagnostics) using FITC-conjugated rabbit antihuman IgG. Sensitivity and specificity were estimated for each serological marker and the relationship between disease phenotype and serological positivity was tested using the χ<sup>2</sup> test. <h3>Results</h3> Accuracy of the serological markers ASCA (IgA or IgG isotypes) and Omp-C for differentiation of healthy controls from those with CD showed a sensitivity of 50% and 54% but a higher specificity (75% and 78%). The sensitivity and specificity of pANCA was calculated for differentiating UC from controls as 48% and 97% respectively. The combination of ASCA-/pANCA+ resulted in better diagnostic accuracy for differentiating CD from UC (sensitivity 32% and specificity 92%) than either test alone. There was no significant association with atypical pANCA and UC phenotype (p=0.58). Both ASCA and Omp-C positivity correlated with small bowel involvement in CD patients (p=0.01 and p=0.04 respectively). <h3>Conclusion</h3> The low sensitivity of ASCA, Omp-C and pANCA limits their use for IBD screening in Indian Asian populations but the high specificity of combining ASCA and ANCA can be helpful in differentiating between UC and CD in this ethnic group. The reported sensitivities and specificities of ASCA, Omp-C and pANCA in Indian Asians are similar to those observed in Caucasian populations. In addition, the association of ASCA and Omp-C with CD phenotype has also been reported in Caucasian CD patients suggesting similar pathological mechanisms in both ethnic groups.
Use of recombinant human growth hormone (rhGH) plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) for the mobilization and collection of CD34+ cells in poor mobilizers
Authors: Carmelo Carlo-Stella, Massimo Di Nicola, Raffaella Milani, Anna Guidetti, Michele Magni, Marco Milanesi, Paolo Longoni, Paola Matteucci, Franca Formelli, Fernando Ravagnani, Paolo Corradini, Alessandro M. Gianni
Journal: Blood (2004)
Coffee Consumption and Risk of Type 2 Diabetes Mellitus Among Middle-aged Finnish Men and Women
Authors: Jaakko Tuomilehto
Journal: JAMA (2004)

Only a few studies of coffee consumption and diabetes mellitus (DM) have been reported, even though coffee is the most consumed beverage in the world.To determine the relationship between coffee consumption and the incidence of type 2 DM among Finnish individuals, who have the highest coffee consumption in the world.A prospective study from combined surveys conducted in 1982, 1987, and 1992 of 6974 Finnish men and 7655 women aged 35 to 64 years without history of stroke, coronary heart disease, or DM at baseline, with 175 682 person-years of follow-up. Coffee consumption and other study parameters were determined at baseline using standardized measurements.Hazard ratios (HRs) for the incidence of type 2 DM were estimated for different levels of daily coffee consumption.During a mean follow-up of 12 years, there were 381 incident cases of type 2 DM. After adjustment for confounding factors (age, study year, body mass index, systolic blood pressure, education, occupational, commuting and leisure-time physical activity, alcohol and tea consumption, and smoking), the HRs of DM associated with the amount of coffee consumed daily (0-2, 3-4, 5-6, 7-9, > or =10 cups) were 1.00, 0.71 (95% confidence interval [CI], 0.48-1.05), 0.39 (95% CI, 0.25-0.60), 0.39 (95% CI, 0.20-0.74), and 0.21 (95% CI, 0.06-0.69) (P for trend<.001) in women, and 1.00, 0.73 (95% CI, 0.47-1.13), 0.70 (95% CI, 0.45-1.05), 0.67 (95% CI, 0.40-1.12), and 0.45 (95% CI, 0.25-0.81) (P for trend =.12) in men, respectively. In both sexes combined, the multivariate-adjusted inverse association was significant (P for trend <.001) and persisted when stratified by younger and older than 50 years; smokers and never smokers; healthy weight, overweight, and obese participants; alcohol drinker and nondrinker; and participants drinking filtered and nonfiltered coffee.Coffee drinking has a graded inverse association with the risk of type 2 DM; however, the reasons for this risk reduction associated with coffee remain unclear.
A Step-up Approach or Open Necrosectomy for Necrotizing Pancreatitis
Authors: Hjalmar C. van Santvoort, Marc G. Besselink, Olaf J. Bakker, H. Sijbrand Hofker, Marja A. Boermeester, Cornelis H. Dejong, Harry van Goor, Alexander F. Schaapherder, Casper H. van Eijck, Thomas L. Bollen, Bert van Ramshorst, Vincent B. Nieuwenhuijs, Robin Timmer, Johan S. Laméris, Philip M. Kruyt, Eric R. Manusama, Erwin van der Harst, George P. van der Schelling, Tom Karsten, Eric J. Hesselink, Cornelis J. van Laarhoven, Camiel Rosman, Koop Bosscha, Ralph J. de Wit, Alexander P. Houdijk, Maarten S. van Leeuwen, Erik Buskens, Hein G. Gooszen
Journal: New England Journal of Medicine (2010)

Necrotizing pancreatitis with infected necrotic tissue is associated with a high rate of complications and death. Standard treatment is open necrosectomy. The outcome may be improved by a minimally invasive step-up approach.In this multicenter study, we randomly assigned 88 patients with necrotizing pancreatitis and suspected or confirmed infected necrotic tissue to undergo primary open necrosectomy or a step-up approach to treatment. The step-up approach consisted of percutaneous drainage followed, if necessary, by minimally invasive retroperitoneal necrosectomy. The primary end point was a composite of major complications (new-onset multiple-organ failure or multiple systemic complications, perforation of a visceral organ or enterocutaneous fistula, or bleeding) or death.The primary end point occurred in 31 of 45 patients (69%) assigned to open necrosectomy and in 17 of 43 patients (40%) assigned to the step-up approach (risk ratio with the step-up approach, 0.57; 95% confidence interval, 0.38 to 0.87; P=0.006). Of the patients assigned to the step-up approach, 35% were treated with percutaneous drainage only. New-onset multiple-organ failure occurred less often in patients assigned to the step-up approach than in those assigned to open necrosectomy (12% vs. 40%, P=0.002). The rate of death did not differ significantly between groups (19% vs. 16%, P=0.70). Patients assigned to the step-up approach had a lower rate of incisional hernias (7% vs. 24%, P=0.03) and new-onset diabetes (16% vs. 38%, P=0.02).A minimally invasive step-up approach, as compared with open necrosectomy, reduced the rate of the composite end point of major complications or death among patients with necrotizing pancreatitis and infected necrotic tissue. (Current Controlled Trials number, ISRCTN13975868.)
Oral vinorelbine plus capecitabine (oral vincap) combination in patients with advanced breast cancer (ABC). A phase II study of the GOIM (Gruppo Oncologico dell'Italia Meridionale)
Authors: V. Lorusso, M. Spada, M. Giampaglia, A. Misino, R. Calabrese, A. Latorre, G. Monticelli, M. Guida, D. Sambiasi, G. Colucci
Journal: Annals of Oncology (2006)
OX40 is required for regulatory T cell–mediated control of colitis
Authors: Thibault Griseri, Mark Asquith, Claire Thompson, Fiona Powrie
Journal: The Journal of Experimental Medicine (2010)

The immune response in the gastrointestinal tract is a tightly controlled balance between effector and regulatory cell responses. Here, we have investigated the role of OX40 in influencing the balance between conventional T cells and Foxp3+ regulatory T (T reg) cells. Under steady-state conditions, OX40 was required by T reg cells for their accumulation in the colon, but not peripheral lymphoid organs. Strikingly, under inflammatory conditions OX40 played an essential role in T reg cell-mediated suppression of colitis. OX40(-/-) T reg cells showed reduced accumulation in the colon and peripheral lymphoid organs, resulting in their inability to keep pace with the effector response. In the absence of OX40 signaling, T reg cells underwent enhanced activation-induced cell death, indicating that OX40 delivers an important survival signal to T reg cells after activation. As OX40 also promoted the colitogenic Th1 response, its expression on T reg cells may be required for effective competition with OX40-dependent effector responses. These results newly identify a key role for OX40 in the homeostasis of intestinal Foxp3+ T reg cells and in suppression of colitis. These fi ndings should be taken into account when considering OX40 blockade for treatment of IBD.