tbuckley/cabot-search huggingface dataset:
Regulation of Nitric Oxide-Sensitive Guanylyl Cyclase
Authors: Andreas Friebe, Doris Koesling
Journal: Circulation Research (2003)

In this review, we outline the current knowledge on the regulation of nitric oxide (NO)-sensitive guanylyl cyclase (GC). Besides NO, the physiological activator that binds to the prosthetic heme group of the enzyme, two novel classes of GC activators have been identified that may have broad pharmacological implications. YC-1 and YC-1-like substances act as NO sensitizers, whereas the substance BAY 58-2667 stimulates NO-sensitive GC NO-independently and preferentially activates the heme-free form of the enzyme. Sensitization and desensitization of NO/cGMP signaling have been reported to occur on the level of NO-sensitive GC; in the present study, an alternative mechanism is introduced explaining the adaptation of the NO-induced cGMP response by a long-term activation of the cGMP-degrading phosphodiesterase 5 (PDE5). Finally, regulation of GC expression and a possible modulation of GC activity by other factors are discussed.
Cross-tachyphylactic airway response to inhaled bradykinin, kallidin and [desArg9]-bradykinin in asthmatic subjects
Authors: R Polosa, K Rajakulasingam, G Prosperini, LV Milazzo, G Santonocito, ST Holgate
Journal: European Respiratory Journal (1993)

Kinins are oligopeptides that may act as mediators in the pathogenesis of bronchial asthma by interacting with specific cell surface receptors designated B1 and B2. When administered by inhalation to asthmatic subjects, bradykinin and kallidin, but not [desArg9]-bradykinin, provoke potent bronchoconstriction, thus suggesting a specific effect compatible with the stimulation of B2 receptors. To characterize further the receptor(s) mediating this bronchospastic response we have carried out cross-tachyphylactic studies with inhaled bradykinin, kallidin, and [desArg9]-bradykinin, administered in a randomized double-blind fashion in a group of 10 asthmatic subjects. Inhalation of bradykinin and kallidin, but not [desArg9]-bradykinin, elicited concentration-related falls in forced expiratory volume in one second (FEV1) in all the subjects studied. The geometric mean provocation concentrations of inhaled agonists reducing FEV1 by 20% of baseline (PC20) were 0.12 and 0.28 mg.ml-1 for bradykinin and kallidin, respectively. When inhaled at concentrations up to 10.62 mg.ml-1, [desArg9]-bradykinin failed to provoke any significant fall in FEV1 from baseline in any of the subjects studied. Following recovery from the second bradykinin challenge, provocation with kallidin revealed a reduced response to this agonist, the PC20 value increasing from 0.28 to 1.23 mg.ml-1. Similarly, once the airways had recovered from the second kallidin challenge, provocation with bradykinin also showed a reduced response, the PC20Bk increasing from 0.12 to 0.94 mg.ml-1. Surprisingly, despite failing to cause bronchoconstriction, repeated exposures with inhaled [desArg9]-bradykinin reduced the airway response to bradykinin, the PC20Bk increasing from 0.12 to 0.41 mg.ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)
Enhanced Efficacy of Eptifibatide Administration in Patients With Acute Coronary Syndrome Requiring In-Hospital Coronary Artery Bypass Grafting
Authors: Steven P. Marso, Deepak L. Bhatt, Matthew T. Roe, Penny L. Houghtaling, Marino Labinaz, Neal S. Kleiman, Cornelius Dyke, Maarten L. Simmoons, Robert M. Califf, Robert A. Harrington, Eric J. Topol
Journal: Circulation (2000)

Background —Patients with a recent episode of non–ST-segment elevation acute coronary syndrome before CABG have higher rates of operative morbidity and mortality than patients with stable coronary syndromes. The efficacy of administering eptifibatide to these patients undergoing in-hospital CABG is unknown. Methods and Results —The Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial randomized 10 948 patients to receive either eptifibatide or placebo. There were 1558 study participants who underwent in-hospital CABG: 692 received placebo, and 866 received eptifibatide. The main substudy analysis end point was death or myocardial infarction (MI) rates at the 6-month follow-up. The 30-day death or MI rates were 30.8% and 26.1% for the placebo and eptifibatide groups, respectively ( P =0.041). The benefit of eptifibatide administration persisted through 6-months of follow-up (32.7% versus 27.6% for placebo versus eptifibatide, respectively; P =0.029). There was a greater reduction in the 6-month death or MI rate for patients who received eptifibatide within 72 hours of CABG (33.6% versus 23.8%; P =0.002) compared with the &gt;72-hour group (31.6% versus 32%; P =1.0). The incidence of major bleeding was 56.6% for placebo-treated patients versus 58.2% for eptifibatide-treated patients ( P =0.7). Conclusions —Eptifibatide administration in patients undergoing in-hospital CABG with a recent episode of a non–ST-segment elevation acute coronary syndrome results in a significant reduction in death or MI that is evident at 7 days and persists through the 6-month follow-up without a significant increase in perioperative bleeding rates.
PRECIPITIN TO MITE DETECTED IN ASTHMATIC PATIENTS
Authors: KOJI ITO
Journal: Allergy (1975)

Mite antigen from dermatophagoides farinae was labelled with 125I, and used for detection of precipitin to mite antigen in sera from asthmatic patients allergic to mite and house dust. By double gel diffusion using this labelled antigen, it was found that 16 out of 37 sera formed precipitin bands which were detected by radioautography. Only one serum formed a precipitin band when non-labelled mite antigen was used in double gel diffusion. The main immunogenic component in mite extract migrated to the beta region in immunoelectrophoresis. The intensity of the precipitin line did not correlate with the relative concentration of IgE antibodies as determined by RAST. IgG antibodies to mite were detected by radioimmunoelectrophoresis in three out of 37 sera.
Biallelic <i>DICER1</i> Mutations in Sporadic Pleuropulmonary Blastoma
Authors: Masafumi Seki, Kenichi Yoshida, Yuichi Shiraishi, Teppei Shimamura, Yusuke Sato, Riki Nishimura, Yusuke Okuno, Kenichi Chiba, Hiroko Tanaka, Keisuke Kato, Motohiro Kato, Ryoji Hanada, Yuko Nomura, Myoung-Ja Park, Toshiaki Ishida, Akira Oka, Takashi Igarashi, Satoru Miyano, Yasuhide Hayashi, Seishi Ogawa, Junko Takita
Journal: Cancer Research (2014)

Pleuropulmonary blastoma (PPB) is a rare pediatric malignancy whose pathogens are poorly understood. Recent reports suggest that germline mutations in the microRNA-processing enzyme DICER1 may contribute to PPB development. To investigate the genetic basis of this cancer, we performed whole-exome sequencing or targeted deep sequencing of multiple cases of PPB. We found biallelic DICER1 mutations to be very common, more common than TP53 mutations also found in many tumors. Somatic ribonuclease III (RNase IIIb) domain mutations were identified in all evaluable cases, either in the presence or absence of nonsense/frameshift mutations. Most cases had mutated DICER1 alleles in the germline with or without an additional somatic mutation in the remaining allele, whereas other cases displayed somatic mutations exclusively where the RNase IIIb domain was invariably affected. Our results highlight the role of RNase IIIb domain mutations in DICER1 along with TP53 inactivation in PPB pathogenesis.
Selenium deficiency augments the pulmonary toxic effects of oxygen exposure in the rat
Authors: FH Hawker, HE Ward, PM Stewart, LA Wynne, PJ Snitch
Journal: European Respiratory Journal (1993)

Selenium (Se) is a component of the antioxidant enzyme glutathione peroxidase (GSHPx). We wanted to determined whether Se deficiency predisposes to pulmonary O2 toxicity. Sixteen weanling rats were fed a Se-free diet (Se-). Sixteen rats fed the same diet had drinking water supplemented with 400 micrograms.l-1 sodium selenite (Se+). After 5 weeks, rats were killed after exposure to either 95% O2 or air for 36 h. Se concentration in blood, lung, liver, heart, muscle and spleen, and blood GSHPx activity were higher in Se+ than in Se- groups. Pulmonary oedema developed in both O2-exposed groups, but was more severe in Se-O2 group than in the Se+O2 group, as judged by the presence of pleural effusions (7 out of 8 versus 0 out of 8), elevated lavage protein concentration (173 +/- 17 versus 120 +/- 14 micrograms.ml-1), and higher wet/dry weight ratio (W:D) (5.8 +/- 0.07 versus 5.4 +/- 0.07). W:D correlated inversely with lung Se content in O2-exposed rats. Both O2-exposed groups had a reduction in the amount of less aggregated lavage phospholipid (PL) compared with the Se+air group. However, the Se-O2 group had increased total PL, because of an increase in more aggregated PL. We conclude that Se deficiency exacerbates pulmonary injury in O2-exposed rats, and that O2 toxicity is associated with an altered physical form of alveolar surfactant.
Antagonism of Guanethidine by Chlorpromazine
Authors: DAVID S. JANOWSKY, M. KHALED EL-YOUSEF, JOHN M. DAVIS, WILLIAM E. FANN
Journal: American Journal of Psychiatry (1973)

Chlorpromazine was found to reverse the antihypertensive effects of guanethidine six times in use with four moderately or severely hypertensive psychiatric patients. Haloperidol and thiothixene caused similar effects. It is postulated that this drug-drug interaction occurs because chlorpromazine blocks the neuronal amine-guanethidine uptake pump, thereby denying guanethidine access to its site of action.
Assessment of a simple scoring system applied to a screening questionnaire of asthma in children aged 5-15 yrs
Authors: TL Frank, PI Frank, R McNamee, T Wright, P Hannaford, J Morrison, S Hirsch, CA Pickering
Journal: European Respiratory Journal (1999)

The aim of the present study was to validate a simple scoring system using a parent-completed screening questionnaire to identify children aged 5-15 yrs who may have asthma. A stratified random sample of 157 children of 1,808 whose parents had answered a postal respiratory questionnaire underwent detailed clinical evaluation. The results were reviewed by three independent paediatricians whose opinions were combined to reach, for each child, decisions regarding three standards: 1) "possible asthma" defined as &gt;50% likelihood of having asthma; 2) "possible asthma" defined as meriting a clinical trial of asthma medication; and 3) "probable asthma" defined as &gt;90% likelihood of having asthma. The combined decisions were compared to three sets of questionnaire scores, in order to determine the positive predictive value, sensitivity and specificity of each set in identifying children with probable/possible asthma. The three sets of chosen questionnaire scores all had positive predictive values of 79-96% for predicting possible asthma, using either the combined expert opinion "&gt;50% likelihood of asthma" or that of "warrants a trial of treatment" as the definition. This suggests that a low proportion of false positives would be obtained were this scoring system to be used for a screening programme. The combined decision &gt;90% chance of asthma could be used as a means of estimating prevalence of asthma in the survey. When used for this, the prevalence of asthma in the surveyed population was 18.8% (95% confidence interval 13.1-26.3). In conclusion, the present scoring system, based on a simple respiratory questionnaire, provides a valid method of identifying children likely to have asthma, and who, if unknown to the medical services, would benefit from clinical review.
Lipid Profiling Reveals Different Therapeutic Effects of Metformin and Glipizide in Patients With Type 2 Diabetes and Coronary Artery Disease
Authors: Yifei Zhang, Chunxiu Hu, Jie Hong, Jun Zeng, Shenghan Lai, Ankang Lv, Qing Su, Yan Dong, Zhiguang Zhou, Weili Tang, Jiajun Zhao, Lianqun Cui, Dajin Zou, Dawang Wang, Hong Li, Chao Liu, Guoting Wu, Jie Shen, Dalong Zhu, Weiqing Wang, Weifeng Shen, Guang Ning, Guowang Xu
Journal: Diabetes Care (2014)

OBJECTIVE We recently demonstrated a beneficial effect of metformin compared with glipizide in type 2 diabetic patients regarding cardiovascular outcomes for 3-year treatment in the SPREAD-DIMCAD study. However, the potential mechanism for the clinical effects remains unclear. Here, we performed a comprehensive lipidomics study to evaluate the different lipid metabolites in serum samples obtained from participants in this study. RESEARCH DESIGN AND METHODS Liquid chromatography–quadrupole time of flight–mass spectrometry was used to evaluate the different lipid metabolites in serum samples obtained from the participants (21 patients in glipizide group and 23 patients in metformin group) before and after each year of treatment (at 0 [baseline], 1, 2, and 3 years of study drug administration). RESULTS A total of 118 serum lipid molecular species was identified and quantified. During treatment, metformin induced a substantially greater change in serum lipid species compared with glipizide, especially at the 2- and 3-year time points (with 2, 11, and 12 lipid species being significantly different between the groups after each year of treatment [1, 2, or 3 years], P &amp;lt; 0.05). Among the significantly changed lipid species, three lipid metabolites were linked to long-term composite cardiovascular events (adjusted P &amp;lt; 0.05). After treatment, triacylglycerols (TAGs) of a relatively higher carbon number showed a clearly increased trend in metformin group compared with the glipizide group, whereas the changes in TAGs with different double bonds were minimal. CONCLUSIONS Our findings revealed the differential therapeutic effects of metformin and glipizide on comprehensive lipidomics, which were comparable with their different long-term effects on cardiovascular outcomes.
Gender Disparities in Metastatic Colorectal Cancer Survival
Authors: Andrew Hendifar, Dongyun Yang, Felicitas Lenz, Georg Lurje, Alexandra Pohl, Cosima Lenz, Yan Ning, Wu Zhang, Heinz-Josef Lenz
Journal: Clinical Cancer Research (2009)

Previous studies have shown that estrogen prevents colon cancer in postmenopausal women, indicating a role in colorectal cancer carcinogenesis and tumor progression. We investigated the interactions between sex, age, ethnicity, and year of diagnosis on overall survival (OS) in patients with metastatic colorectal cancer (MCRC).We screened 52,882 patients with MCRC from 1988 to 2004, using the Surveillance Epidemiology and End Results registry. Age at diagnosis, sex, ethnicity, tumor location, year of diagnosis, OS, and cancer-specific survival were evaluated using Cox proportional hazards model. The models were adjusted for marital status, tumor site, tumor differentiation, and treatment with radiation and/or surgery.We observed that younger women (18-44 years old) with MCRC lived longer than younger men (17 months versus 14; P < 0.0001, log-rank test). In contrast, older women (55 years and older) had significantly worse OS than older men (7 months versus 9; P < 0.0001, log-rank test). In multivariate analysis, we found that gender discrepancies have widened in recent years; young women diagnosed after 2000 have improved cancer-specific survival, compared to men (hazard ratio, 0.778; 95% confidence interval, 0.669-0.904), but those diagnosed before 2000 benefit less (hazard ratio, 0.931; 95% confidence interval, 0.821-1.056).As one of the largest data sets analyzed to establish that younger women with MCRC survive longer than younger men, hormonal status not only seems to play an important role in the development and pathogenesis of colorectal cancer but also may be of prognostic significance. These data warrant further studies to determine the role of estrogen in colorectal cancer.
Interlaboratory Comparison of <b> <i>HER-2</i> </b> Oncogene Amplification as Detected by Chromogenic and Fluorescence <b> <i>in situ</i> </b> Hybridization
Authors: Jorma Isola, Minna Tanner, Amanda Forsyth, Timothy G. Cooke, Amanda D. Watters, John M. S. Bartlett
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Chromogenic in situ hybridization (CISH) is a new modification of the fluorescence in situ hybridization (FISH) technique for detection of oncogene amplification in archival tumor samples. In CISH, the oncogene probe is detected using a peroxidase reaction, allowing use of transmitted light microscopy. We compared detection of HER-2/neu amplification by CISH with a Food and Drug Administration-approved two-color FISH test in an interlaboratory setting. Experimental Design: Formalin-fixed paraffin-embedded tumor samples from 197 breast cancers were analyzed for HER-2 amplification by CISH. Two-color FISH (PathVysion) CISH of 17 centromere was done if the observer considered it necessary to ascertain amplification status in tumors with borderline HER-2 CISH copy numbers. Results: Paired CISH/FISH results were available from 192 (97%) of 197 cases, no clear difference in success rates of either method was observed. Centromere 17 CISH was considered necessary in seven tumors. CISH and two-color FISH results were concordant in 180 cases (93.8%). There were 92 and 88 tumors found HER-2 amplified and nonamplified, respectively, by both methods. Eight tumors were amplified by CISH but not by FISH, and four tumors exhibited the opposite condition (kappa coefficient 0.875). In 7 of 12 cases differences between the two methods could have related to a lack of CISH chromosome 17 information. The remaining cases were explained by difficult histology (ductal carcinoma in situ, poor representativity, dense lymphocytic infiltration, or intratumoral heterogeneity). Conclusions: These results indicate that CISH could provide an accurate and practical alternative to FISH for clinical diagnosis of HER-2/neu oncogene amplification in archival formalin-fixed breast cancer samples.
Effects of psychotherapy in moderately severe COPD: a pilot study
Authors: N Eiser, C West, S Evans, A Jeffers, F Quirk
Journal: European Respiratory Journal (1997)

Anxiety is common in the "pink puffer" syndrome associated with chronic obstructive pulmonary disease (COPD). The degree of anxiety correlates well with perceived dyspnoea. This pilot study examines the effect of group psychotherapy on anxiety, exercise tolerance, dyspnoea and quality of life. Ten patients with moderately severe, stable COPD (mean forced expiratory volume in one second (FEV1)-1.15 L) had six 90 min sessions of cognitive and behavioural psychotherapy at weekly intervals. Patients completed the Hospital Anxiety and Depression Scale (HADS), Medical Research Council Questionnaire (MRCQ) and St George's Respiratory Questionnaires (SGRQ), 1 week before and after therapy. FEV1, forced vital capacity (FVC), slow vital capacity (SVC), blood gas tensions and 6 min walking distance (6MWD) were measured. Eight control patients attended weekly for lung function and 6MWD for 6 weeks, but had no psychotherapy. Mean baseline HADS score was significantly higher in the psychotherapy group (12) than in controls (7), but otherwise there were no differences in lung function, blood gas tensions, 6MWD, or the other questionnaire scores between groups. After treatment, the physiological and psychological parameters where unchanged in both groups with the exception of the mean 6MWD, which had improved in the psychotherapy group only, from 351 to 423 m (p<0.001), an increase of 24%. Three months after treatment, the 6MWD was still 16% above the baseline value (p=0.02). In conclusion, six sessions of cognitive and behavioural psychotherapy produced a sustained improvement in exercise tolerance in a group of 10 anxious patients with severe chronic obstructive pulmonary disease, without any change in anxiety scores on the Hospital Anxiety and Depression Scale. Further studies of more prolonged, intensive psychotherapy would establish whether better symptom and quality of life scores accompany more dramatic increases in exercise tolerance in "pink puffers".
A Balance Between Nitric Oxide and Oxidants Regulates Mast Cell–Dependent Neutrophil–Endothelial Cell Interactions
Authors: Xiao-Fei Niu, Geoffrey Ibbotson, Paul Kubes
Journal: Circulation Research (1996)

Nitric oxide (NO) synthesis inhibition causes neutrophil adhesion to endothelium via a mast cell– and oxidant-dependent mechanism. The objective of this study was to delineate the cascade of events in the mast cell– and oxidant-induced neutrophil-endothelium interactions after NO synthesis inhibition. Mast cells were isolated and purified from the rat peritoneal cavity and coadministered with neutrophils to wells of endothelium. This system was treated with an NO synthesis inhibitor ( N G -nitro- l -arginine methyl ester; L-NAME) for 60 minutes. L-NAME did not induce neutrophil-endothelium interactions in the absence of mast cells, but the addition of mast cells in a ratio as low as 1:50 mast cells to neutrophils was sufficient to induce a large increase in neutrophil adhesion to endothelium within 20 to 25 minutes. l -arginine, NO donors, and 8-bromo-cGMP reversed the L-NAME effect, whereas N G -nitro- d -arginine methyl ester alone had no proadhesive effect. The adhesion was inhibited by an anti-CD18 or an anti–intracellular adhesion molecule-1 antibody and a platelet-activating factor-receptor antagonist. Inhibition of NO in isolated endothelial monolayers induced oxidant release (reduction of cytochrome C) into extracellular fluid. The endothelium-derived superoxide contributed to the mast cell–induced adhesion, inasmuch as the extracellular antioxidant superoxide dismutase reduced the neutrophil adhesion response as did disruption of endothelial function. There was some direct activation of mast cells with L-NAME (independent of endothelium) inasmuch as intracellular calcium and oxidative stress increased within mast cells after L-NAME treatment, and this translated into increased neutrophil adhesion to nonendothelial substrata. These data demonstrate that depletion of NO increases oxidative stress within mast cells and endothelium and together these events promote neutrophil adhesion within the vasculature.
Treating pulmonary hypertension in COPD: where do we start?
Authors: M. M. Hoeper
Journal: European Respiratory Journal (2008)

Endothelin receptor antagonists, phosphodiesterase (PDE)-5 inhibitors and prostanoids are effective treatments for pulmonary arterial hypertension (PAH), a severe but relatively rare form of pulmonary hypertension 1–3. Other forms of pulmonary hypertension as seen, for instance, in chronic lung disease are much more common than PAH and although usually less severe, they are clinically meaningful as they are associated with aggravated symptoms and shorter survival 4, 5]. Thus, it comes as no surprise that physicians are tempted to use so-called PAH drugs in other forms of pulmonary hypertension, even though there is limited evidence supporting this approach.

In this issue of the European Respiratory Journal ( ERJ ), Stolz et al. 6, from the University Hospital Basel (Basel, Switzerland), report on the results of a small randomised placebo-controlled study they conducted to assess the safety and efficacy of the endothelin receptor antagonist bosentan in patients with chronic obstructive pulmonary disease (COPD). The study included 30 patients with advanced COPD at Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages III and IV. It is noteworthy that the presence of pulmonary hypertension at rest was not an inclusion criterion as the authors reasoned that pulmonary hypertension during exercise was to be expected in the majority of their patients 7. In fact, echocardiography at baseline showed no evidence for pulmonary hypertension at rest in 24 out of the 30 patients. The rationale of the study of Stolz et al. 6 was that by lowering pulmonary artery …