tbuckley/cabot-search huggingface dataset:
Effects of High-Energy Phosphate Depletion and Repletion on the Dynamics and Electrocardiogram of Isolated Rat Hearts
Authors: JAMES SCHEUER, S. WILLIAM STEZOSKI
Journal: Circulation Research (1968)

To explore the sequence of metabolic, mechanical, and electrocardiographic (ECG) events during myocardial anoxia, isolated rat hearts were paced from the atrium. Anoxic and recovery periods were studied. Adenosine triphosphate (ATP) and creatine phosphate (CP) declined to 50% of control during the first minute and remained at that level for the 5-minute anoxic period. ATP and CP returned to control values after 10 and 20 seconds of recovery. Lactate and potassium efflux from the myocardium closely followed the highenergy phosphate changes. During anoxia, left ventricular systolic pressure increased initially, then fell below the control level after 2 minutes, and recovered within 20 seconds of reoxygenation. In catecholamine-depleted hearts, it fell immediately with anoxia, and recovery was incomplete. The conduction time for the pacing stimulus to reach the ventricle increased with anoxia and decreased with reoxygenation. S-T alterations in the ECG also lagged behind high-energy phosphate reduction and recovery. The study demonstrates that in the isolated heart, ECG evidence of myocardial hypoxia may be absent when high-energy phosphate levels in the myocardium are very low. Mechanical changes are more closely related temporally to high-energy phosphate alterations than are ECG changes. The release of endogenous catecholamines is important to maintain mechanical function in the hypoxic heart.
Achieving the health Millennium Development Goals for South Africa: challenges and priorities
Authors: Mickey Chopra, Joy E Lawn, David Sanders, Peter Barron, Salim S Abdool Karim, Debbie Bradshaw, Rachel Jewkes, Quarraisha Abdool Karim, Alan J Flisher, Bongani M Mayosi, Stephen M Tollman, Gavin J Churchyard, Hoosen Coovadia
Journal: The Lancet (2009)
Quality of Life, Coping Ability, and Metabolic Control in Patients With Type 1 Diabetes Managed By Group Care and a Carbohydrate Counting Program
Authors: Marina Trento, Enrica Borgo, Claudia Kucich, Pietro Passera, Anna Trinetta, Lorena Charrier, Franco Cavallo, Massimo Porta
Journal: Diabetes Care (2009)

Group care is a clinical-pedagogic model in which traditional routine visits are substituted by sessions of group education. This approach improves quality of life and metabolic control in patients with type 2 diabetes (1) but only quality of life in those with type 1 diabetes (2). The latter must match multiple daily insulin administrations with blood glucose monitoring, dietary intake, and energy expenditure (3). We hypothesized that to improve their coping strategies, patients with type 1 diabetes need more specific training in the technical aspects of day-to-day management of insulin therapy. To verify this, we studied the effects of embedding a carbohydrate counting program within group care on quality of life, knowledge …
Generation of antigen receptor-specific suppressor T cell clones in man.
Authors: N Mohagheghpour, N K Damle, S Takada, E G Engleman
Journal: The Journal of Experimental Medicine (1986)

We have shown previously that CD8+ T cells proliferate upon exposure to autologous, antigen primed CD4+ T cells, and suppress the response of fresh T cells to the priming antigen but not irrelevant antigens. The stimulus and target of suppression in this system appears to be the antigen receptor on the surface of CD4+ cells, rather than the nominal antigen. In the current study, alloantigen primed CD4+ inducer cells and IL-2-containing medium were used to generate clones of suppressor cells from several individuals. The clones inhibited the response of fresh autologous T cells only to the original allogeneic stimulator cell and to stimulator cells that shared HLA-DR antigens with the priming cell. The clones were also genetically restricted, since they inhibited the response of HLA-A,B-compatible but not HLA-A,B-incompatible individuals. The availability of a method for reproducibly generating antigen receptor-specific suppressor T cell clones in vitro should make it possible to clarify the mechanism, whereby such cells are activated and exert their suppressive effect.
CFTR: cystic fibrosis and beyond
Authors: Marcus A. Mall, Dominik Hartl
Journal: European Respiratory Journal (2014)

Cystic fibrosis (CF) remains the most common fatal hereditary lung disease. The discovery of the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene 25 years ago set the stage for: 1) unravelling the molecular and cellular basis of CF lung disease; 2) the generation of animal models to study in vivo pathogenesis; and 3) the development of mutation-specific therapies that are now becoming available for a subgroup of patients with CF. This article highlights major advances in our understanding of how CFTR dysfunction causes chronic mucus obstruction, neutrophilic inflammation and bacterial infection in CF airways. Furthermore, we focus on recent breakthroughs and remaining challenges of novel therapies targeting the basic CF defect, and discuss the next steps to be taken to make disease-modifying therapies available to a larger group of patients with CF, including those carrying the most common mutation ΔF508-CFTR. Finally, we will summarise emerging evidence indicating that acquired CFTR dysfunction may be implicated in the pathogenesis of chronic obstructive pulmonary disease, suggesting that lessons learned from CF may be applicable to common airway diseases associated with mucus plugging.
Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study.
Authors: B F Cole, R D Gelber, J M Kirkwood, A Goldhirsch, E Barylak, E Borden
Journal: Journal of Clinical Oncology (1996)

PURPOSE To evaluate the quality-of-life effects of adjuvant high-dose interferon alfa-2b (IFN alpha 2b) treatment of high-risk melanoma. PATIENTS AND METHODS A quality-of-life-adjusted survival analysis (Quality-Adjusted Time Without Symptoms, and Toxicity [Q-TWiST]) was applied to the Eastern Cooperative Oncology Group Trial E1684, which compared high-dose IFN alpha 2b treatment for 1 year versus observation in 280 high-risk patients. IFN alpha 2b was administered at a dosage of 20 mU/m2 intravenously daily for 5 days per week for 4 weeks, and then three times weekly at 10 mU/m2 subcutaneously for 48 weeks. RESULTS After 84 months of median follow-up time, the IFN alpha 2b group gained a mean of 8.9 months without disease relapse (P = .03) and 7.0 months of overall survival (P = .07) as compared with the observation group, but had severe treatment-related toxicity for 5.8 months, on average. The IFN alpha 2b group had more quality-of-life-adjusted time than the observation group regardless of the relative valuations placed on time with toxicity (Tox) and time with relapse (Rel). This gain was significant (P &lt; .05) for patients who consider Tox to have a high relative value and Rel to have a low relative value. In contrast, for patients who value Tox about the same as Rel, the quality-adjusted gain for IFN alpha 2b was not statistically significant. An analysis stratified according to tumor burden indicated that the benefit of IFN alpha 2b was greatest in the node-positive strata. CONCLUSION For patients with high-risk melanoma, the clinical benefits of high-dose IFN alpha 2b can offset the toxic effects. The optimal treatment for an individual patient depends on the patient's tumor burden and preferences regarding toxicity and disease relapse.
A NOTE ON MILKER'S NODES
Authors: H. J. WALLACE
Journal: British Journal of Dermatology (1947)

Journal Article A NOTE ON MILKER'S NODES Get access H. J. WALLACE, M.D.Camb., M.R.C.P. H. J. WALLACE, M.D.Camb., M.R.C.P. Hon. Assistant Physician to the Skin Department, St. Thomas's Hospital, London Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 59, Issue 11, 1 November 1947, Pages 379–380, https://doi.org/10.1111/j.1365-2133.1947.tb10881.x Published: 01 November 1947
Kawasaki Disease
Authors: Brian W. McCrindle
Journal: Circulation (2009)

awasaki disease (KD) is an acute systemic inflammatory illness that occurs predominately in children Ͻ5 years of age.The reported incidence varies widely depending on the ethnicity of the population and the method of case ascertainment.Recent reports would suggest the annual incidence is Ϸ20 to 25 per 100 000 children Ͻ5 years of age in North America, with the highest reported incidence of 188 being in Japan, where the disease was first described in 1967. 1 The illness is self-limited and of unknown cause, but is complicated by a systemic vasculitis with a predilection for small-to medium-sized arteries, particularly the coronary arteries.The majority of patients will have either transient coronary artery dilation or no coronary artery luminal changes as noted on echocardiography.Long-term prognosis for these patients is considered to be excellent.Coronary artery aneurysms occur in 25% of patients, but the prevalence is reduced to Ϸ4% for patients treated with intravenous immunoglobulin infusion within 10 days of illness onset.Aneurysms are associated with an intense inflammatory cell infiltrate, destruction of the internal elastic lamina, and smooth muscle cell death.Coronary artery involvement is usually maximal within 6 to 8 weeks after the acute episode.Regression of aneurysms can occur primarily through myointimal proliferation, although the arterial structure and function remains abnormal, 2 and there is an important ongoing risk of stenoses and occlusions. 3Long-term cardiology assessment and management is required, and some of these patients may require revascularization procedures or, rarely, cardiac transplantation.KD has become the most prevalent acquired cardiac disease in children in developed countries.
Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain
Authors: Purna Mukherjee, Tiernan J Mulrooney, Jeremy Marsh, Derek Blair, Thomas C Chiles, Thomas N Seyfried
Journal: Molecular Cancer (2008)

AMP-activated protein kinase (AMPK) is a known physiological cellular energy sensor and becomes phosphorylated at Thr-172 in response to changes in cellular ATP levels. Activated AMPK acts as either an inducer or suppressor of apoptosis depending on the severity of energy stress and the presence or absence of certain functional tumor suppressor genes. Here we show that energy stress differentially affects AMPK phosphorylation and cell-death in brain tumor tissue and in tissue from contra-lateral normal brain. We compared TSC2 deficient CT-2A mouse astrocytoma cells with syngeneic normal astrocytes that were grown under identical condition in vitro. Energy stress induced by glucose withdrawal or addition of 2-deoxyglucose caused more ATP depletion, AMPK phosphorylation and apoptosis in CT-2A cells than in the normal astrocytes. Under normal energy conditions pharmacological stimulation of AMPK caused apoptosis in CT-2A cells but not in astrocytes. TSC2 siRNA treated astrocytes are hypersensitive to apoptosis induced by energy stress compared to control cells. AMPK phosphorylation and apoptosis were also greater in the CT-2A tumor tissue than in the normal brain tissue following implementation of dietary energy restriction. Inefficient mTOR and TSC2 signaling, downstream of AMPK, is responsible for CT-2A cell-death, while functional LKB1 may protect normal brain cells under energy stress. Together these data demonstrates that AMPK phosphorylation induces apoptosis in mouse astrocytoma but may protect normal brain cells from apoptosis under similar energy stress condition. Therefore, using activator of AMPK along with glycolysis inhibitor could be a potential therapeutic approach for TSC2 deficient human malignant astrocytoma.
Nedocromil sodium in obstructive airways disease: effect on symptoms and plasma protein leakage in sputum
Authors: DF Schoonbrood, TA Out, AA Hart, FJ Habets, CM Roos, HM Jansen
Journal: European Respiratory Journal (1997)

In patients with asthma or chronic obstructive pulmonary disease, there is chronic airway inflammation with increased leakage of plasma proteins into the airway lumen, which can be reduced by inhaled glucocorticosteroids. Nedocromil sodium is an anti-inflammatory drug, and we questioned whether it also affects the leakage of plasma proteins. In a double-blind placebo-controlled study we investigated the effect of 12 weeks of treatment with nedocromil on forced expiratory volume in one second (FEV1), provocative concentration of histamine causing a 20% fall in FEV1 (PC20), peak flow, symptom scores, and plasma protein leakage in sputum, in 31 patients with obstructive airways disease and sputum production (mean (range) FEV1 61% of predicted (42-87%); geometric mean (range) PC20 0.39 (0.04-2.9) mg x mL(-1)). As a measure for plasma protein leakage we calculated the relative coefficients of excretion (RCE) of proteins from serum to the soluble phase of sputum. There was a small increase in morning and evening peak flow (p&lt;0.05) and a decrease in night-time bronchodilator use (p&lt;0.02) in favour of nedocromil. The RCE of alpha2-macroglobulin to albumin significantly decreased after treatment with nedocromil (p=0.03). The results show limited clinical efficacy of nedocromil in our study group. They further suggest that the anti-inflammatory properties of nedocromil extend to inhibition of plasma protein leakage into the airways.
Methylation Silencing of Transforming Growth Factor-β Receptor Type II in Rat Prostate Cancers
Authors: Satoshi Yamashita, Satoru Takahashi, Nathalie McDonell, Naoko Watanabe, Tohru Niwa, Kosuke Hosoya, Yoshimi Tsujino, Tomoyuki Shirai, Toshikazu Ushijima
Journal: Cancer Research (2008)

Abstract To identify methylation-silenced genes in prostate cancers, a microarray analysis for genes up-regulated by treatment with a demethylating agent, 5-aza-2′-deoxycytidine, was performed using three rat prostate cancer cell lines. Eight genes (Aebp1, Dysf, Gas6, LOC361288, Nnat, Ocm, RGD1308119, and Tgfbr2) were re-expressed at 16-fold or more, and their promoter CpG islands were shown to be densely methylated in the cancer cell lines. From the eight genes, Tgfbr2, a key mediator of transforming growth factor-β (TGF-β) signaling that has been strongly implicated in human and rat prostate carcinogenesis, was selected, and its silencing in primary samples was analyzed further. Tgfbr2 was methylated and markedly down-regulated in three of seven 3,2′-dimethyl-4-aminobiphenyl–induced invasive adenocarcinomas in the dorsolateral lobe of the rat prostate. In humans, marked down-regulation of TGFBR2 protein was observed in 12 of 20 high-grade prostatic intraepithelial neoplasia and 36 of 60 prostate cancers. DNA methylation of the human TGFBR2 promoter CpG islands repressed transcription, if present, but neither methylation nor mutation were detected in 27 human prostate cancers analyzed. Methylation silencing of rat Tgfbr2 was associated with histone H3 lysine 9 trimethylation, whereas decreased expression of human TGFBR2 was mainly due to decreased transcription activity, sometimes in concert with histone deacetylation and H3 lysine 27 trimethylation. The identification of methylation silencing of Tgfbr2 in rat prostate cancers, in accordance with TGFBR2 down-regulation in human prostate cancers, will enable us to analyze how aberrant methylation is induced in vivo and identify factors that promote and suppress the induction of aberrant methylation. [Cancer Res 2008;68(7):2112–21]
TNF-α mediates SDF-1α–induced NF-κB activation and cytotoxic effects in primary astrocytes
Authors: Yulong Han, Tao He, DeRen Huang, Carlos A. Pardo, Richard M. Ransohoff
Journal: Journal of Clinical Investigation (2001)

Stromal-derived cell factor-1α (SDF-1α; CXCL12) and its receptor, CXCR4, are constitutively expressed on neuroepithelial cells and are believed to be involved in both development and pathological processes, such as AIDS-associated neurologic disorders. Here, we demonstrate that SDF-1α activates NF-κB, stimulates production of chemokines and cytokines, and induces cell death in primary astrocytes, effects that depend on ongoing secretion of TNF-α. SDF-1α upregulated TNF-α mRNA and protein secretion, as well as TNF receptor 2 expression. TNF-α treatment mimicked SDF-1α induction of NF-κB, IL-1α/β, and RANTES, as well as cell death; neutralizing antibodies against TNF-α opposed these responses. We also found that SDF-1α activated Erk1 and Erk2 (Erk1/2) MAPK in a biphasic fashion. Early Erk1/2 activation was stimulated directly by SDF-1α and late activation was mediated by TNF-α. PD98059 suppression of early Erk1/2 activation correlated with reduction of SDF-1α–induced TNF-α expression. Late Erk1/2 activation was involved in TNF-α–stimulated NF-κB activation and cytokine induction. SDF-1α was induced in reactive CXCR4-positive astrocytes near axotomized spinal cord motor neurons, consistent with autocrine SDF-1/CXCR4 signaling in these cells. We propose that these novel effects of SDF-1α are relevant to the pathogenic and developmental roles of SDF-1α in the CNS.
Reduction in bronchodilation following a deep inhalation is poorly related to airway inflammation in asthma
Authors: F Pacini, M Filippelli, R Duranti, E Rosi, I Romagnoli, M Grazzini, L Stendardi, G Misuri, G Scano
Journal: European Respiratory Journal (1999)

In patients with bronchial asthma, forced expiratory flows are differently sensitive to a previous volume history. A reduced ability of a deep inhalation (DI) to dilate obstructed airways has been hypothesized to be a physiological marker for the degree of airway responsiveness and to relate to the presence and magnitude of inflammation in the lung, even in mild stable asthma. However, there are at present doubts as to whether functional changes could be used as a substitute for airway inflammation studies. In order to investigate the interrelations among airway inflammation, bronchial hyperresponsiveness and effects of volume history, 58 consecutive asthmatics with mild to moderate asthma were studied. The effects of DI were assessed as the isovolumic ratio of flows from forced expiratory manoeuvres started from maximal (M) or partial (P) lung inflation. Airway inflammation was assessed by using induced sputum. Sputum was analysed for total and differential cell counts, and levels of eosinophil cationic protein (ECP) which reflects eosinophil activation. Airway responsiveness was assessed as the provocative concentration of histamine which caused a 20% fall in forced expiratory volume in one second (FEV1) from control (PC20). The M/P ratio was significantly related to ECP (r=-0.31, p<0.03) and eosinophils (r=-0.29, p<0.03), FEV1/vital capacity (VC) (r=0.32; p<0.01), clinical score (r=-0.33; p<0.03) and age (r=-0.41; p<0.0001). In a stepwise multiple regression analysis including age, score, baseline lung function, ECP, number of eosinophils and the response to beta2-agonist, age (p<0.037) predicted a small amount of the variance in M/P ratio (r2=0.12). It is concluded that volume history response is substantially independent of both sputum outcomes (inflammatory cell number and eosinophil cationic protein) and bronchial hyperresponsiveness; rather it seems to be associated with anthropometric characteristics. Functional aspects do not provide information on eosinophilic, probably central, airway inflammation.
NORTHAMPTONSHIRE &amp; BEDFORDSHIRE MEDICAL REGISTRATION ASSOCIATIONS.
Authors: D.J.T. Francis, JohnH. Webster, H. Terry, J. Mash, JohnM. Bryan, Benjamin Dulley, Foster Gray, R.S. Stedman, G.F.D. Evans, T. HERBERT BARKER, H.W. Sharpin, C.E. Prior, D.J.T. Francis, JohnH. Webster, H. Terry, J. Mash, JohnM. Bryan, Benjamin Dulley, Foster Gray, R.S. Stedman, G.F.D. Evans, T. HERBERT BARKER, H.W. Sharpin, C.E. Prior
Journal: The Lancet (1859)
Carbon monoxide released by CORM-3 inhibits human platelets by a mechanism independent of soluble guanylate cyclase
Authors: S CHLOPICKI, R OLSZANECKI, E MARCINKIEWICZ, M LOMNICKA, R MOTTERLINI
Journal: Cardiovascular Research (2006)

Objective Carbon monoxide (CO) modulates several physiological functions through activation of a cGMP-dependent pathway similar to that of nitric oxide (NO). Here we investigated the possible involvement of soluble guanylate cyclase in the anti-aggregatory effect of micromolar concentrations of CO released by a novel, water-soluble, CO releasing molecule (CORM) in human platelets. Methods Human platelet aggregation was induced by collagen or thrombin, and the effects of CO releasing molecule (CORM-3) and an NO donor on platelet aggregation were compared. Results CORM-3 liberated CO in a time- and concentration-dependent manner as evidenced by the formation of carbon monoxy myoglobin (MbCO) using a spectrophotometric assay. When added to washed platelets, CORM-3 (10–300 μM) inhibited collagen- and thrombin-induced aggregation in a concentration-dependent manner. The anti-aggregatory effect of CORM-3 was reversed by deoxy-Mb (50 μM). Interestingly, in the presence of an inhibitor of guanylate cyclase (ODQ, 5 μM), inhibition of collagen-induced aggregation by CORM-3 was not blocked but potentiated. Under the same experimental conditions, inhibition of platelet aggregation by an NO donor (SNAP, 1 μM) was prevented by ODQ. In collagen-induced or thrombin-induced platelet aggregation, a stimulator of guanylate cyclase (YC-1, 0.3 μM) did not alter the effect of CORM-3, whereas it markedly potentiated the inhibition of platelet aggregation mediated by SNAP. Notably, CORM-3-induced inhibition of platelet aggregation was of similar degree when platelets were activated by a low (20 mU/ml) or by high concentration of thrombin (100–200 mU/ml), whereas NO donors (SNP and SNAP)- or carbaprostacylin (cPGI2)-induced effects were considerably attenuated when platelets were activated by high concentrations of thrombin. Conclusions Inhibition of platelet aggregation by CO released by a novel, water-soluble CORM is not mediated by activation of soluble guanylate cyclase. In contrast to NO and PGI2, CO effectively inhibits platelets even when cells are activated excessively. We suggest that despite the fact that CO is not a potent inhibitor of platelet activation, it may gain importance when NO and PGI2 alone are insufficient to overcome excessive platelet activation.
MACROPHAGE-LYMPHOCYTE INTERACTION
Authors: Peter E. Lipsky, Alan S. Rosenthal
Journal: The Journal of Experimental Medicine (1973)

The nature of the physical interaction between guinea pig non-glass-adherent lymphoid cells and syngeneic macrophages in vitro was investigated. This cellular interaction was found to require the presence of metabolically intact macrophages but neither serum nor antigen. Peritoneal, splenic, or alveolar macrophages were significantly more capable of interacting with thymocytes than either polymorphonuclear leukocytes or fibroblasts. The role of the non-glass-adherent cell was passive in that heat-killed or metabolically poisoned thymocytes were bound by normal macrophages. Two normal lymphoid cell populations, thymocytes, and lymph node lymphocytes, were bound to macrophages in significantly larger numbers than either L(2)C leukemia cells or erythrocytes. Thus, specificity for each of the participant cell types was demonstrated. These data indicate that macrophages possess a unique ability to recognize and bind lymphocytes and thymocytes by a mechanism which is distinguishable from other known macrophage receptors.