tbuckley/cabot-search huggingface dataset:
Body mass index, height and risk of adenocarcinoma of the oesophagus and gastric cardia: a prospective cohort study
Authors: A. H H Merry, L. J Schouten, R A. Goldbohm, P. A van den Brandt
Journal: Gut (2007)

<h3>Background:</h3> In the last decades, the incidence of oesophageal and gastric cardia adenocarcinoma has increased rapidly in the Western world. We investigated the association between body mass index (BMI), height and risk of oesophageal and gastric cardia adenocarcinoma. <h3>Methods:</h3> The Netherlands Cohort Study was initiated in 1986. All participants (n = 120 852), aged 55–69 years, completed a self administered questionnaire. Cases were identified through annual record linkage with the Netherlands Cancer Registry. After 13.3 years of follow-up, excluding the first follow-up year, complete data from 4552 subcohort members, 133 oesophageal and 163 gastric cardia adenocarcinomas were available for case-cohort analyses. Incidence rate ratios (RRs) and corresponding 95% confidence intervals were estimated using Cox proportional hazard models. <h3>Results:</h3> The RRs (95% CI) of oesophageal adenocarcinoma were 1.40 (0.95 to 2.04) and 3.96 (2.27 to 6.88) for overweight (BMI 25.0–29.9 kg/m<sup>2</sup>) and obese subjects (BMI ⩾30.0 kg/m<sup>2</sup>), respectively, compared to subjects with normal weight (BMI 20.0–24.9 kg/m<sup>2</sup>). For gastric cardia adenocarcinoma, these RRs were 1.32 (0.94 to 1.85) and 2.73 (1.56 to 4.79). Also change in BMI during adulthood was positively associated with the risk of oesophageal and gastric cardia adenocarcinoma (p trend 0.001 and 0.02, respectively), while no association was found with BMI in early adulthood (p trend 0.17 and 0.17, respectively). None of the tumour types investigated was significantly associated with height. <h3>Conclusions:</h3> These results confirm higher risks of oesophageal and gastric cardia adenocarcinoma with increasing BMI. This implies that the increasing prevalence of obesity may be one of the explanations for the rising incidence of oesophageal and gastric cardia adenocarcinoma in the Western world.
Hope and hopelessness: theory and reality
Authors: Thaïs Helène Downman
Journal: Journal of the Royal Society of Medicine (2008)

Hope is a positive outlook on life experienced by us all at times, though it is not a permanent state of mind like optimism or its opposite, pessimism. It has been referred to by many philosophers, including some optimists, like Gottfried Leibnitz, who held that we live in the best of all possible worlds, created by God.1 This theodicy was mocked resoundingly by Voltaire in his play Candide. The anarchist philosopher William Godwin espoused a utilitarian approach, and hoped optimistically that society would eventually reach the state where calm reason would replace all violence and force.2 Such secular views embody concepts of hope in projections for the future.

From a non-secular view, hope comes within faith and it is one of the virtues ‘Faith, Hope and Charity’. Consequently it is linked to thoughts about the future and, for some, after death. In our attitude to life and expression of our thoughts, communication is very important. This communication may be direct with our fellow beings or through a belief in thought transference or prayer.
Observations on the Pharmacology of Glaucoma
Authors: I H Leopold, E Duzman
Journal: The Annual Review of Pharmacology and Toxicology (1986)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More
Obesity and the lung: 5 {middle dot} Obesity and COPD
Authors: F M E Franssen, D E O'Donnell, G H Goossens, E E Blaak, A M W J Schols
Journal: Thorax (2008)

Chronic obstructive pulmonary disease (COPD) and obesity are common and disabling chronic health conditions with increasing prevalence worldwide. A relationship between COPD and obesity is increasingly recognised, although the nature of this association remains unknown. This review focuses on the epidemiology of obesity in COPD and the impact of excessive fat mass on lung function, exercise capacity and prognosis. The evidence for altered adipose tissue functions in obesity—including reduced lipid storage capacity, altered expression and secretion of inflammatory factors, adipose tissue hypoxia and macrophage infiltration in adipose tissue—is also reviewed. The interrelationship between these factors and their contribution to the development of insulin resistance in obesity is considered. It is proposed that, in patients with COPD, reduced oxidative capacity and systemic hypoxia may amplify these disturbances, not only in obese patients but also in subjects with hidden loss of fat-free mass. The potential interaction between abnormal adipose tissue function, systemic inflammation and COPD may provide more insight into the pathogenesis and reversibility of systemic pathology in this disease.
Differences in the electrophysiologic response of four canine ventricular cell types to α1-adrenergic agonists
Authors: A Burashnikov
Journal: Cardiovascular Research (1999)

Objective: The present study was designed to examine regional differences in the response of α1 adrenoceptor stimulation in the canine ventricle. Methods: Standard microelectrode techniques were used to record transmembrane action potentials from epicardial, M cell, and endocardial as well as Purkinje fiber preparations isolated from the canine left ventricle. Results: Phenylephrine (0.1–10 μM+propranolol 0.2 μM) and methoxamine (1–10 μM) produced dose- and rate-dependent prolongation of action potential duration (APD90) in Purkinje fibers (P<0.05, at 0.1–10 μM, BCL=0.5–2 s), but an abbreviation of APD90 in tissues from the M region (P<0.05, at 10 μM, BCL=0.5–2 s). At slow pacing rates (≥2 s), phenylephrine (1 μM) exerted a small, significant (P<0.05) prolongation of APD90 in epicardium and endocardium which returned to control values when the concentration was increased to 10 μM. The amplitude of phase 1 of the action potential in M and epicardial cells was significantly increased by phenylephrine at concentrations of 10 μM (P<0.05). Prazosin (1 μM), a nonspecific α1 antagonist, reversed these effects of phenylephrine (10 μM) and methoxamine (10 μM) on APD90 and the action potential notch. The α1b-antagonist, chloroethylclonidine (0.1–1.0 μM), but not the α1a-antagonist, WB-4101 (0.1–1.0 μM), reversed the APD-abbreviating effect of methoxamine in the M cell. Conclusion: Our results demonstrate striking regional differences in the electrophysiological response of the four canine ventricular cell types to α1 adrenergic agonists. Our data provide support for the hypothesis that different adrenoceptor subtypes underlie the opposite response of M cells (α1b-APD abbreviation) and Purkinje fibers (α1a-APD prolongation) to α1-adrenoceptor activation.
Unphosphorylated STAT1 Promotes Sarcoma Development through Repressing Expression of Fas and Bad and Conferring Apoptotic Resistance
Authors: Mary A. Zimmerman, Nur-Taz Rahman, Dafeng Yang, Guy Lahat, Alexander J. Lazar, Raphael E. Pollock, Dina Lev, Kebin Liu
Journal: Cancer Research (2012)

STAT1 exists in phosphorylated (pSTAT1) and unphosphorylated (uSTAT1) forms each regulated by IFN-γ. Although STAT1 is a key mediator of the IFN-γ signaling pathway, an essential component of the host cancer immunosurveillance system, STAT1 is also overexpressed in certain human cancers where the functions of pSTAT1 and uSTAT1 are ill defined. Using a murine model of soft tissue sarcoma (STS), we show that disruption of the IFN effector molecule IRF8 decreases pSTAT1 and increases uSTAT1 in STS cells, thereby increasing their metastatic potential. We determined that the IRF8 gene promoter was hypermethylated frequently in human STS. An analysis of 123 human STS specimens revealed that high uSTAT1 levels in tumor cells was correlated with a reduction in disease-specific survival (DSS), whereas high pSTAT1 levels in tumor cells were correlated with an increase in DSS. In addition, uSTAT1 levels were negatively correlated with pSTAT1 levels in these STS specimens. Mechanistic investigations revealed that IRF8 suppressed STAT1 transcription by binding the STAT1 promoter. RNAi-mediated silencing of STAT1 in STS cells was sufficient to increase expression of the apoptotic mediators Fas and Bad and to elevate the sensitivity of STS cells to Fas-mediated apoptosis. Together, our findings show how the phosphorylation status of pSTAT1 determines its function as a tumor suppressor, with uSTAT1 acting as a tumor promoter that acts by elevating resistance to Fas-mediated apoptosis to promote immune escape.
Brief Communication: Successful Treatment of Pure Red-Cell Aplasia with an Anti–Interleukin-2 Receptor Antibody (Daclizumab)
Authors: Elaine M. Sloand, Phillip Scheinberg, Jaroslaw Maciejewski, Neal S. Young
Journal: Annals of Internal Medicine (2006)

Background: Pure red-cell aplasia (PRCA) is a rare hematologic disease characterized by anemia, reticulocytopenia, and absence of bone marrow erythroid precursors. Most patients respond to some form of immunosuppressive treatment, but few prospective clinical trials have been performed. Objective: To examine the efficacy of a humanized monoclonal antibody to the interleukin-2 receptor (daclizumab) for treating PRCA. Design: Pilot study. Setting: Federal government research hospital. Patients: 15 patients with idiopathic PRCA. Intervention: Daclizumab, 1 mg/kg of body weight, every 2 weeks for a total of 5 infusions. Pure red-cell aplasia was defined as transfusion-dependent anemia with a reticulocyte count of 60 × 109 cells/L or less and bone marrow showing absent or diminished erythroid precursors. Measurements: Response to therapy was assessed by transfusion independence, increments in reticulocyte count, and nontransfused hemoglobin. Results: Daclizumab had little toxicity. Of the 15 patients, 6 patients (40%) responded to treatment. All responders became transfusion-independent and achieved normal or near-normal hemoglobin values and normal reticulocyte counts. Limitations: The study was unblinded, and the number of patients was too small to assess drug safety reliably. Conclusions: Daclizumab seems safe. Its efficacy in this pilot protocol suggests that expanded study in PRCA and other bone marrow failure syndromes is warranted.
Erythrocytosis associated with hemoglobin Rainier: oxygen equilibria and marrow regulation
Authors: John W. Adamson, Julian T. Parer, George Stamatoyannopoulos, S. Heinenberg
Journal: Journal of Clinical Investigation (1969)

Hemoglobin Rainier (beta(145) tyrosine-->histidine) is an abnormal hemoglobin associated with increased oxygen affinity, decreased heme-heme interaction, presence of a Bohr effect, and erythrocytosis, but without obvious clinical sequelae. Regulation of erythropoiesis was studied in affected members of families having either hemoglobin Rainier or Yakima, abnormal hemoglobins associated with erythrocytosis. Apart from the elevated but stable hemoglobin concentration and red cell mass, parameters of red cell production in the subjects were normal. Initially normal values of erythropoietin excretion were increased by phlebotomy indicating a significant hypoxic stress at an otherwise normal hematocrit. This stress led to increased reticulocyte production and an eventual return to the prephlebotomy hematocrit. The erythrocytosis in carriers of hemoglobins Rainer and Yakima appears to be secondary to the increased oxygen affinity and this, with the response to phlebotomy, is consistent with the postulate that the renal sensor tissue regulating erythropoietin production is primarily influenced by the oxygen tensions of venous rather than arterial blood.
Efficacy of area under the curve cyclosporine monitoring in renal transplantation.
Authors: M M Meyer, M Munar, J Udeaja, W Bennett
Journal: Journal of the American Society of Nephrology (1993)

Previous studies suggest that area-under-the-curve (AUC) pharmacokinetic monitoring is superior to trough level monitoring for proper cyclosporin A (CSA) dosing, but AUC monitoring is expensive and unwieldy. The utility of a simplified AUC monitoring method was evaluated for predicting AUC on the basis of three timed levels. CSA pharmacokinetic profiles were studied in 27 renal transplant patients at steady state early (days), late (months), and in some patients, serially posttransplantation. Whole-blood RIA levels were obtained at 2, 4, 6, 10, 12, 14, and 24 h after a once-daily CSA dose. The 6- and 24-h levels were the best single-level predictors of AUC (r = 0.77 and 0.76, respectively). The best model predictive of AUC curves used three time points at 2, 6, and 24 h postdose: AUC predicted = 8.6 x (24 h) + 1.4 x (2 h) + 6.2 x (6 h) + 1.57 mg x h/L; r2 = 0.986, P = 0.00001. The greatest pharmacokinetic variability occurred between 0 and 10 h postdose (absorption and distribution) between patients and even within individual patients monitored serially over time. The 12- to 24-h postdose portion (elimination) of the curve was consistently flat and uniform among patients. AUC were not consistent in individual patients over time. An AUC of more than 13 mg x h/L correlated with nephrotoxicity, whereas a value of 8 mg x h/L correlated with protection from rejection in first-transplant recipients. This AUC, however, was not able to prevent rejection in reengrafted or highly sensitized patients.
Reduction of Tumor Blood Flow by Flavone Acetic Acid: A Possible Component of Therapy
Authors: M. C. Bibby, J. A. Double, P. M. Loadman, C. V. Duke
Journal: JNCI Journal of the National Cancer Institute (1989)

Flavone acetic acid (FAA) is active against normally refractory murine sc tumors. Clinical studies are disappointing despite achievement of plasma profiles associated with the antitumor murine activity in man. To clarify the mechanism of action, we have followed histologic changes, tumor blood volume, and drug concentrations in a well-differentiated, slow-growing cystic adenocarcinoma in mice. FAA causes massive tumor necrosis beginning 2 hours after treatment. Tumor plasma volumes are reduced by 2 hours after treatment and tumor blood vessels are shutdown, which suggests that tumor vasculature plays a role in the dramatic response of sc tumors in pure-strain male NMRI mice. [J Natl Cancer Inst 1989;81:216–220]
Endocardial Fibroelastosis of Large Mammals
Authors: B. BLACK-SCHAFFER, CARL E. GRINSTEAD, JOHN N. BRAUNSTEIN
Journal: Circulation Research (1965)

Normal hearts of a mouse, rat, man, sea lion, hippopotamus, elephant, and blue whale were shown to have different numbers of myocardial fibers, 10 7 to 10 13 , based on calculations involving their myocardial fiber diameters and nuclear density counts. These two parameters did not vary greatly in the different species. However, their heart weights ranged from 10 -1 to 10 5 g. The larger mammals have endocardial fibroelastosis of their hearts and very thick aortas. These anatomic findings were explained by employing principles of hydrostatics and proposing that elastic tissue is required to help withstand the high mural tension resulting from the long radii and the hydrostatic pressures in the heart chambers and aortic lumen.
Quantitative Assessment of Regional Myocardial Function in Mice by Tissue Doppler Imaging
Authors: Igal A. Sebag, Mark D. Handschumacher, Fumito Ichinose, John G. Morgan, Ryuji Hataishi, Ana Clara T. Rodrigues, J. Luis Guerrero, Wolfgang Steudel, Michael J. Raher, Elkan F. Halpern, Geneviève Derumeaux, Kenneth D. Bloch, Michael H. Picard, Marielle Scherrer-Crosbie
Journal: Circulation (2005)

Tissue Doppler imaging (TDI) is a novel echocardiographic method to quantify regional myocardial function. The objective of this study was to assess whether myocardial velocities and strain rate (SR) could be obtained by TDI in mice and whether these indices accurately quantified alterations in left ventricular (LV) systolic function.TDI was performed in 10 healthy mice to measure endocardial (v(endo)) and epicardial systolic velocities and SR. In further experiments, TDI indices were compared with dP/dt(max) and with sonomicrometer-derived regional velocities, at rest and after administration of dobutamine or esmolol. TDI indices were also studied serially in 8 mice before and 4 and 7 hours after endotoxin challenge. Myocardial velocities and SR were obtained in all mice with low measurement variability. TDI indices increased with administration of dobutamine (v(endo) from 2.2+/-0.3 to 3.8+/-0.2 cm/s [P<0.01]; SR from 12+/-2 to 20+/-2 s(-1) [P<0.05]) and decreased with administration of esmolol (v(endo) 1.4+/-0.2 cm/s [P<0.05]; SR 6+/-1 s(-1) [P<0.01]). Both indices correlated strongly with dP/dt(max) (r2=0.79 for SR and r2= 0.69 for v(endo); both P<0.0001). SR and shortening fraction were predictors of dP/dt(max) even after adjustment for the confounding effect of the other variables. V(endo) correlated closely with sonomicrometer-measured velocity (r2=0.71, P<0.0005). After endotoxin challenge, decreases in both v(endo) and SR were detected before decreases in shortening fraction became manifest.Myocardial velocities and SR can be measured noninvasively in mice with the use of TDI. Both indices are sensitive markers for quantifying LV global and regional function in mice.
Dysfunctional very-low-density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis
Authors: Koji Fujita, Yuichi Nozaki, Koichiro Wada, Masato Yoneda, Yoko Fujimoto, Mihoyo Fujitake, Hiroki Endo, Hirokazu Takahashi, Masahiko Inamori, Noritoshi Kobayashi, Hiroyuki Kirikoshi, Kensuke Kubota, Satoru Saito, Atsushi Nakajima
Journal: Hepatology (2009)

The specific mechanisms of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) pathogenesis remain unknown. In the present study we investigated the differences between NAFL and NASH in terms of liver lipid metabolites and serum lipoprotein. In all, 104 Japanese subjects (50 men and 54 postmenopausal women) with histologically verified NAFL disease (NAFLD) (51 with NAFL, 53 with NASH) were evaluated; all diagnoses were based on liver biopsy findings and the proposed diagnostic criteria. To investigate the differences between NAFL and NASH in humans, we carefully examined (1) lipid inflow in the liver, (2) lipid outflow from the liver, (3) very-low-density lipoprotein (VLDL) synthesis in the liver, (4) triglyceride (TG) metabolites in the liver, and (5) lipid changes and oxidative DNA damage. Most of the hepatic lipid metabolite profiles were similar in the NAFL and NASH groups. However, VLDL synthesis and lipid outflow from the liver were impaired, and surplus TGs might have been produced as a result of lipid oxidation and oxidative DNA damage in the NASH group.A growing body of literature suggests that a deterioration in fatty acid oxidation and VLDL secretion from the liver, caused by the impediment of VLDL synthesis, might induce serious lipid oxidation and DNA oxidative damage, impacting the degree of liver injury and thereby contributing to the progression of NASH. Therefore, dysfunctional VLDL synthesis and release may be a key factor in progression to NASH.
E2F mediates enhanced alternative polyadenylation in proliferation
Authors: Ran Elkon, Jarno Drost, Gijs van Haaften, Mathias Jenal, Mariette Schrier, Joachim AF Oude Vrielink, Reuven Agami
Journal: Genome biology (2012)

Abstract Background The majority of mammalian genes contain multiple poly(A) sites in their 3' UTRs. Alternative cleavage and polyadenylation are emerging as an important layer of gene regulation as they generate transcript isoforms that differ in their 3' UTRs, thereby modulating genes' response to 3' UTR-mediated regulation. Enhanced cleavage at 3' UTR proximal poly(A) sites resulting in global 3' UTR shortening was recently linked to proliferation and cancer. However, mechanisms that regulate this enhanced alternative polyadenylation are unknown. Results Here, we explored, on a transcriptome-wide scale, alternative polyadenylation events associated with cellular proliferation and neoplastic transformation. We applied a deep-sequencing technique for identification and quantification of poly(A) sites to two human cellular models, each examined under proliferative, arrested and transformed states. In both cell systems we observed global 3' UTR shortening associated with proliferation, a link that was markedly stronger than the association with transformation. Furthermore, we found that proliferation is also associated with enhanced cleavage at intronic poly(A) sites. Last, we found that the expression level of the set of genes that encode for 3'-end processing proteins is globally elevated in proliferation, and that E2F transcription factors contribute to this regulation. Conclusions Our results comprehensively identify alternative polyadenylation events associated with cellular proliferation and transformation, and demonstrate that the enhanced alternative polyadenylation in proliferative conditions results not only in global 3' UTR shortening but also in enhanced premature cleavage in introns. Our results also indicate that E2F-mediated co-transcriptional regulation of 3'-end processing genes is one of the mechanisms that links enhanced alternative polyadenylation to proliferation.
Cardiac-Resynchronization Therapy with or without an Implantable Defibrillator in Advanced Chronic Heart Failure
Authors: Michael R. Bristow, Leslie A. Saxon, John Boehmer, Steven Krueger, David A. Kass, Teresa De Marco, Peter Carson, Lorenzo DiCarlo, David DeMets, Bill G. White, Dale W. DeVries, Arthur M. Feldman
Journal: New England Journal of Medicine (2004)

We tested the hypothesis that prophylactic cardiac-resynchronization therapy in the form of biventricular stimulation with a pacemaker with or without a defibrillator would reduce the risk of death and hospitalization among patients with advanced chronic heart failure and intraventricular conduction delays.A total of 1520 patients who had advanced heart failure (New York Heart Association class III or IV) due to ischemic or nonischemic cardiomyopathies and a QRS interval of at least 120 msec were randomly assigned in a 1:2:2 ratio to receive optimal pharmacologic therapy (diuretics, angiotensin-converting-enzyme inhibitors, beta-blockers, and spironolactone) alone or in combination with cardiac-resynchronization therapy with either a pacemaker or a pacemaker-defibrillator. The primary composite end point was the time to death from or hospitalization for any cause.As compared with optimal pharmacologic therapy alone, cardiac-resynchronization therapy with a pacemaker decreased the risk of the primary end point (hazard ratio, 0.81; P=0.014), as did cardiac-resynchronization therapy with a pacemaker-defibrillator (hazard ratio, 0.80; P=0.01). The risk of the combined end point of death from or hospitalization for heart failure was reduced by 34 percent in the pacemaker group (P<0.002) and by 40 percent in the pacemaker-defibrillator group (P<0.001 for the comparison with the pharmacologic-therapy group). A pacemaker reduced the risk of the secondary end point of death from any cause by 24 percent (P=0.059), and a pacemaker-defibrillator reduced the risk by 36 percent (P=0.003).In patients with advanced heart failure and a prolonged QRS interval, cardiac-resynchronization therapy decreases the combined risk of death from any cause or first hospitalization and, when combined with an implantable defibrillator, significantly reduces mortality.