tbuckley/cabot-search huggingface dataset:
Effect of hypobaric hypoxia on blood gases in patients with restrictive lung disease
Authors: C.C. Christensen, M.S. Ryg, O. Kåre Refvem, O. Henning Skjønsberg
Journal: European Respiratory Journal (2002)

Several publications have reported effects of hypobaric conditions in patients with chronic obstructive pulmonary disease. To the current authors' knowledge, similar studies concerning patients with restrictive lung disease have not been published. The effect of simulated air travel in a hypobaric chamber on arterial blood gases, blood pressure, and cardiac frequency during rest and 20 W exercise, and the response to supplementary oxygen in 17 patients with chronic restrictive ventilatory impairment has been investigated. Resting oxygen tension in arterial blood (Pa,O2) decreased from 10.4+/-1.6 kPa at sea level to 6.5+/-1.1 kPa at 2,438 m simulated altitude, and decreased further during light exercise in all patients (5.1+/-0.9 kPa). Pa,O2 at this altitude correlated positively with sea-level Pa,O2 and transfer factor of the lung for carbon monoxide (TL,CO), and negatively with carbon dioxide tension in arterial blood (Pa,CO2). Pa,O2 increased to acceptable levels with an O2 supply of 2 L x min(-1) at rest and 4 L x min(-1) during 20 W exercise. In conclusion, most of the patients with restrictive ventilatory impairment developed hypoxaemia below the recommended levels of in-flight oxygen tension in arterial blood during simulated air travel. Light exercise aggravated the hypoxaemia. Acceptable levels of oxygen tension in arterial blood, with only a minor increase in carbon dioxide tension in arterial blood, were obtained by supplementary oxygen.
Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer
Authors: Nikhil Wagle, Brian C. Grabiner, Eliezer M. Van Allen, Ali Amin-Mansour, Amaro Taylor-Weiner, Mara Rosenberg, Nathanael Gray, Justine A. Barletta, Yanan Guo, Scott J. Swanson, Daniel T. Ruan, Glenn J. Hanna, Robert I. Haddad, Gad Getz, David J. Kwiatkowski, Scott L. Carter, David M. Sabatini, Pasi A. Jänne, Levi A. Garraway, Jochen H. Lorch
Journal: New England Journal of Medicine (2014)

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.
Body Mass Index and Risk of Adenocarcinomas of the Esophagus and Gastric Cardia
Authors: W H Chow, W J Blot, T L Vaughan, H A Risch, M D Gammon, J L Stanford, R Dubrow, J B Schoenberg, S T Mayne, D C Farrow, H Ahsan, A B West, H Rotterdam, S Niwa, J F Fraumeni
Journal: JNCI Journal of the National Cancer Institute (1998)

Background. Incidence rates have risen rapidly for esophageal adenocarcinoma and moderately for gastric cardia adenocarcinoma, while rates have remained stable for esophageal squamous cell carcinoma and have declined steadily for noncardia gastric adenocarcinoma. We examined anthropometric risk factors in a population-based casecontrol study of esophageal and gastric cancers in Connecticut, New Jersey, and western Washington. Methods: Healthy control subjects (n = 695) and case patients with esophageal squamous cell carcinoma or noncardia gastric adenocarcinoma (n = 589) were frequency-matched to case patients with adenocarcinomas of esophagus or gastric cardia (n = 554) by 5-year age groups, sex, and race (New Jersey only) Classification of cases by tumor site of origin and histology was determined by review of pathology materials and hospital records Data were collected using in-person structured interviews. Associations with obesity, measured by body mass index (BMI), were estimated by odds ratios (ORs). All ORs were adjusted for geographic location, age, sex, race, cigarette smoking, and proxy response status. Results: The ORs for esophageal adenocarcinoma rose with increasing adult BMI. The magnitude of association with BMI was greater among the younger age groups and among nonsmokers. The ORs for gastric cardia adenocarcinoma rose moderately with increasing BMI. Adult BMI was not associated with risk of esophageal squamous cell carcinoma or noncardia gastric adenocarcinoma. Conclusions: Increasing prevalence of obesity in the United States population may have contributed to the upward trends in esophageal and gastric cardia adenocarcinomas. [J Nall Cancer Inst 1998;90:150-5].
Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial
Authors: Stevo Julius, Sverre E Kjeldsen, Michael Weber, Hans R Brunner, Steffan Ekman, Lennart Hansson, Tsushung Hua, John Laragh, Gordon T McInnes, Lada Mitchell, Francis Plat, Anthony Schork, Beverly Smith, Alberto Zanchetti
Journal: The Lancet (2004)
Expression of interleukin 1β and interleukin 1β converting enzyme by intestinal macrophages in health and inflammatory bowel disease
Authors: M E McAlindon, C J Hawkey, Y R Mahida
Journal: Gut (1998)

Background— In the lipopolysaccharide (LPS) stimulated peripheral blood monocyte, the precursor form of interleukin 1β (IL-1β, 31 kD) is processed by IL-1β converting enzyme (ICE) to the mature, bioactive form (17 kD). IL-1β is a proinflammatory cytokine which is likely to have a role in the pathogenesis of inflammatory bowel disease (IBD). Aims— To investigate the expression and processing of IL-1β and ICE by tissue macrophages from normal and IBD colonic mucosa. Methods— Mucosal biopsy specimens and lamina propria cells from normal and IBD colons were studied by reverse transcription polymerase chain reaction (RT-PCR), western blot analysis, and ELISA (enzyme linked immunosorbent assay). Results— Normal colonic macrophages synthesised only the precursor form of IL-1β whereas in IBD the mature form was also produced. Similarly, cells from normal colonic mucosa synthesised ICE as the precursor (p45) only, whereas macrophages from IBD colons produced active (p20) ICE. Ac-Tyr-Val-Ala-Asp-CHO, a specific peptide aldehyde inhibitor of ICE, significantly reduced the amount of mature IL-1β released by isolated IBD macrophages (from a median of 1.2 (range 0.78–4.42) ng/ml to 0.43 (0.21–1.6) ng/ml; p&lt;0.01). Conclusions— Exposure of normal colonic macrophages to LPS only induces the production of the precursor form of IL-1β, because the cells fail to activate ICE. In contrast, IBD colonic macrophages are able to activate ICE and hence release mature IL-1β in a manner similar to circulating monocytes. This is consistent with IBD macrophages being recently recruited from the circulating monocyte population. Targeted inhibition of ICE may represent a novel form of therapy in IBD.
Fate Mapping Reveals Separate Origins of T Cells and Myeloid Lineages in the Thymus
Authors: Susan M. Schlenner, Vikas Madan, Katrin Busch, Annette Tietz, Carolin Läufle, Celine Costa, Carmen Blum, Hans Jörg Fehling, Hans-Reimer Rodewald
Journal: Immunity (2010)
Changes in creatine kinase M localization in acute ischemic myocardial cells. Immunoelectron microscopic studies.
Authors: N Otsu, I Yamaguchi, E Komatsu, K Miyazawa
Journal: Circulation Research (1993)

To clarify the changes in creatine kinase M localization along with the progress of myocardial ischemia, immunoelectron microscopic studies were performed using rabbit anti-canine creatine kinase M Fab'-horseradish peroxidase conjugate in 21 dogs. Myocardial ischemia was induced by occlusion of the left anterior descending coronary artery for 15 (n = 5), 30 (n = 5), 60 (n = 5), or 180 (n = 4) minutes. Two dogs were used as normal controls. As we have already demonstrated, most creatine kinase M in normal myocardial cells was localized over the entire A band in association with the thick filament, suggesting that creatine kinase in this region (A-band creatine kinase) was the enzyme coupled with myosin ATPase. After 15 minutes of ischemia, creatine kinase M showed only minimal changes in its location, indicating that A-band creatine kinase still has the ability to couple with myosin ATPase (reversible injury). However, after 30 minutes of ischemia, A-band creatine kinase diffused markedly to the I band (transitional phase), and after 60 minutes of ischemia, it leaked out to extracellular spaces (irreversible injury). After 180 minutes of ischemia, most A-band creatine kinase disappeared from the myocardial cells (coagulation necrosis). These features of creatine kinase M localization seemed to reflect each stage of ischemic cell injury. We conclude that myocardial ischemia results in a dissociation of creatine kinase molecules from the thick filament, which leads the energy transport system to destruction.
Studies of Vitamin B Depletion in Perfused Hearts
Authors: JANE SANDS ROBB, IRENE C. L. CHANG
Journal: Circulation Research (1957)

A progress report stated that perfused hearts could be maintained over a longer period if vitamin B complex were added to the perfusate. The present study comprises analyses of four of the B vitamins in muscle of control hearts, of hearts perfused with oxygenated Locke's solution and of hearts perfused with the same solution plus dihydropaveril. Statistically significant amounts of B vitamins disappear from the muscle during perfusion in comparison to values for control hearts.
PTU-155 Is the glucose hydrogen methane breath test an accurate diagnostic tool for small intestinal bacterial overgrowth?
Authors: R I Rusu, E Grace, K Thomas, K Whelan, C Shaw, H J N Andreyev
Journal: Gut (2012)

<h3>Introduction</h3> Small intestinal bacterial overgrowth (SIBO) is probably the most common cause for chronic gastrointestinal (GI) symptoms following cancer treatments. There is no diagnostic gold standard. We assessed whether the glucose hydrogen methane breath test has greater value than the hydrogen breath test alone and whether a duodenal (D2) aspirate improves the diagnostic yield. <h3>Methods</h3> Patients in a cancer centre referred for potential SIBO. Breath hydrogen (H2) and methane (CH4) were measured in parts/million (ppm) using a QuinTron BreathTracker DP at baseline, then—after 75 g oral glucose—at 20 min time points up to 3 h or until positive. Positive test: fasting H<sub>2</sub> ≥20 or CH<sub>4</sub> ≥10 ppm or a rise in H<sub>2</sub> ≥12 or CH<sub>4</sub> ≥6 ppm. Some patients also had duodenal aspirates collected endoscopically. Positive result: &gt;10<sup>4</sup> colony forming units/ml. Patients with positive tests were treated with antibiotics. Results were assessed retrospectively. <h3>Results</h3> 126 patients, 66 males and 60 females, median group age 61 years (range 35–86), treated for gynaecological (30%), upper GI (25%), lower GI (9%), urological (28%), other cancers (10%—myeloma, ependymoma, bronchial, breast and lymphoma) were referred. Daily troublesome GI symptoms included flatulence (85%), borborygmi (63%), belching (54%), bloating (52%), abdominal pain (50%), steatorrhoea (38%), nausea/vomiting (23%) and diarrhoea (19%). 60 (48%) had a positive breath test—5% H2, 10% CH4 and 33% both gases. 21 (17%) of 86 patients with D2 aspirates tested positive for Streptococcus (n=6), E. Coli (3), Candida (3), Klebsiella (2), Enterococcus (2), Pseudomonas (2), Neisseria (1), Aeromonas (1) and Stenotrophomonas (1). 17 (33%) had negative breath tests. Six of these had positive D2 aspirates with 3 (50%) responsive to antibiotics, 11 had negative aspirates but a 73% antibiotic response rate. 24 (46%) tested positive for both gases. 33% of these had a positive D2 aspirate with a 75% response rate to antibiotics and 67% negative aspirates but 81% response. Six patients (12%) were positive only for H2 (all had negative aspirates), 1 responded to antibiotics. 5 (10%) tested positive for CH4 only, of which 1 had a positive D2 aspirate with a response to antibiotics and 4 (80%) had negative aspirate but 2 responded. <h3>Conclusion</h3> Methane breath testing identifies 10% more patients with SIBO compared to the glucose hydrogen breath test alone. D2 aspirate increases the detection rate by 12%. A trial of antibiotics, with other tests negative, benefits 15% of patients. All current diagnostic methods are flawed. Better diagnostic tests for SIBO are required. <h3>Competing interests</h3> None declared.
Polyphenol E Enhances the Antitumor Immune Response in Neuroblastoma by Inactivating Myeloid Suppressor Cells
Authors: Giorgia Santilli, Izabela Piotrowska, Sandra Cantilena, Olesya Chayka, Marco D'Alicarnasso, Daniel A. Morgenstern, Nourredine Himoudi, Katie Pearson, John Anderson, Adrian J. Thrasher, Arturo Sala
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Neuroblastoma is a rare childhood cancer whose high risk, metastatic form has a dismal outcome in spite of aggressive therapeutic interventions. The toxicity of drug treatments is a major problem in this pediatric setting. In this study, we investigated whether Polyphenon E, a clinical grade mixture of green tea catechins under evaluation in multiple clinical cancer trials run by the National Cancer Institute (Bethesda, MD), has anticancer activity in mouse models of neuroblastoma. Experimental Design: We used three neuroblastoma models: (i) transgenic TH-MYCN mouse developing spontaneous neuroblastomas; (ii) nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenotransplanted with human SHSY5Y cells; and (iii) A/J mice transplanted with syngeneic Neuro 2A cells. Mice were randomized in control and Polyphenon E–drinking groups. Blood from patients with neuroblastoma and normal controls was used to assess the phenotype and function of myeloid cells. Results: Polyphenon E reduced the number of tumor-infiltrating myeloid cells, and inhibited the development of spontaneous neuroblastomas in TH-MYCN transgenic mice. In therapeutic models of neuroblastoma in A/J, but not in immunodeficient NOD/SCID mice, Polyphenon E inhibited tumor growth by acting on myeloid-derived suppressor cells (MDSC) and CD8 T cells. In vitro, Polyphenon E impaired the development and motility of MDSCs and promoted differentiation to more neutrophilic forms through the 67 kDa laminin receptor signaling and induction of granulocyte colony-stimulating factor. The proliferation of T cells infiltrating a patient metastasis was reactivated by Polyphenon E. Conclusions: These findings suggest that the neuroblastoma-promoting activity of MDSCs can be manipulated pharmacologically in vivo and that green tea catechins operate, at least in part, through this mechanism. Clin Cancer Res; 19(5); 1116–25. ©2012 AACR.
The Effects of a Monoclonal Antibody Directed against Tumor Necrosis Factor-α in Asthma
Authors: Edward M. Erin, Brian R. Leaker, Grant C. Nicholson, Andrew J. Tan, Linda M. Green, Helen Neighbour, Angela S. Zacharasiewicz, Jackie Turner, Elliot S. Barnathan, Onn Min Kon, Peter J. Barnes, Trevor T. Hansel
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: Neutralization of tumor necrosis factor-α (TNF-α) is an effective antiinflammatory therapy for several chronic inflammatory diseases.Methods and Objectives: We undertook a double-blind, placebo-controlled, parallel-group design study in 38 patients with moderate asthma treated with inhaled corticosteroids but symptomatic during a run-in phase. Infliximab (5 mg/kg) or placebo was administered by intravenous infusion at Weeks 0, 2, and 6. We assessed clinical response by monitoring lung function, symptoms, and inhaled β2-agonist usage using hand-held electronic devices.Results: The primary endpoint, change in morning PEF at Days 50–56 compared with the last 7 d of the run-in, was not significantly different on treatment. However, infliximab was associated with a decrease in mean diurnal variation of PEF at Week 8 (p = 0.02; 95% confidence interval [CI], −8.1 to −0.72). Furthermore, there was a decrease in the number of patients with exacerbations of asthma (p = 0.01; 95% CI, 4.4 to 52.7) and an increased probability of freedom from exacerbation with time (p = 0.03) in patients on infliximab (n = 14) compared with placebo (n = 18). In addition, infliximab decreased levels of TNF-α (p = 0.01) and other cytokines in sputum supernatants. There were no serious adverse events related to the study agent.Conclusions: Treatment with infliximab was well tolerated and caused a decrease in the number of patients with exacerbations in symptomatic moderate asthma. The promising preliminary findings underscore the need to evaluate therapy directed against TNF-α in larger trials enrolling patients with more severe asthma.
Quantitative Acid-Base Dynamics in Chronic Pulmonary Disease
Authors: EARLE B. WEISS
Journal: Annals of Internal Medicine (1968)

The defense of the extracellular pH was evaluated in 17 patients with chronic obstructive lung disease and chronic hypercapnia during superimposed acute respiratory acidosis. In group I the chronic stable state PaCO2-pH-HCO3 was not defined; in groups IA and II the stable state was defined. Duration of acute acidosis in groups I and IA was 16 and 23¼ hr, respectively; in group II, 30 min. The defense of pH in groups I and IA was greater than acute hypercapnia in normal man but less than chronic stable hypercapnia (P < 0.05). The pH in group II approached that of normal man during acute respiratory acidosis. Plasma bicarbonate concentrations paralleled the ( H+ ) responses. A wide confidence band based on these observations overlapped the previously established bands for acute and chronic hypercapnia. In the clinical situation, variable PaCO2 exposures create variable in vivo carbon dioxide titration curves. Thus, the defense of the extracellular pH during acute respiratory acidosis superimposed upon chronic hypercapnia is related temporally to renal buffering mechanisms. Under these circumstances, prediction bands for steady state acute or stable chronic hypercapnia are not valid for the interpretation of coexisting metabolic disorders.
Cholesterol dependent downregulation of mouse and human apical sodium dependent bile acid transporter (ASBT) gene expression: molecular mechanism and physiological consequences
Authors: C Thomas
Journal: Gut (2006)

Faecal bile acid elimination greatly contributes to cholesterol homeostasis. Synthesised from cholesterol in the liver, bile acids are actively reclaimed in the ileum by the apical sodium dependent bile acid transporter (ASBT). Although the expression level of ASBT affects body cholesterol balance, the impact of cholesterol on ASBT gene expression remains unclear. In this study, the effect of cholesterol on ASBT expression and ileal bile acid uptake was explored in vivo and in vitro.ASBT gene expression was assessed by real time quantitative polymerase chain reaction and northern or western blotting, or both, in mice subjected to a 2% cholesterol diet for two weeks, in mouse ileal explants, or in human enterocyte-like Caco-2 cells cultured in sterol enriched or depleted media. Bile acid uptake was determined by measuring [3H]-taurocholic acid influx into in situ isolated ileal loops from mice or into differentiated Caco-2 cells. Molecular analysis of mouse and human ASBT promoters was undertaken with reporter assays, site directed mutagenesis, and electrophoretic mobility shift assays.In mice, cholesterol enriched diet triggered a downregulation of ASBT expression (mRNA and protein), a fall in ileal bile acid uptake, and a rise in the faecal excretion of bile acids. This effect was direct as it was reproduced ex vivo using mouse ileal explants and in vitro in differentiated Caco-2 cells.This regulation, which involves an original partnership between SREBP-2 and HNF-1alpha transcription factors, affects ileal bile acid recycling and thus might participate in the maintenance of body cholesterol homeostasis.
Exposure to a Complex Cocktail of Environmental Endocrine-Disrupting Compounds Disturbs the Kisspeptin/GPR54 System in Ovine Hypothalamus and Pituitary Gland
Authors: Michelle Bellingham, Paul A. Fowler, Maria R. Amezaga, Stewart M. Rhind, Corinne Cotinot, Beatrice Mandon-Pepin, Richard M. Sharpe, Neil P. Evans
Journal: Environmental Health Perspectives (2009)

Ubiquitous environmental chemicals, including endocrine-disrupting chemicals (EDCs), are associated with declining human reproductive health, as well as an increasing incidence of cancers of the reproductive system. Verifying such links requires animal models exposed to "real-life," environmentally relevant concentrations/mixtures of EDC, particularly in utero, when sensitivity to EDC exposure is maximal.We evaluated the effects of maternal exposure to a pollutant cocktail (sewage sludge) on the ovine fetal reproductive neuroendocrine axes, particularly the kisspeptin (KiSS-1)/GPR54 (G-protein-coupled receptor 54) system.KiSS-1, GPR54, and ERalpha (estrogen receptor alpha) mRNA expression was quantified in control (C) and treated (T) maternal and fetal (110-day) hypothalami and pituitary glands using semiquantitative reverse transcription polymerase chain reaction, and colocalization of kisspeptin with LHbeta (luteinizing hormone beta) and ERalpha in C and T fetal pituitary glands quantified using dual-labeling immunohistochemistry.Fetuses exposed in utero to the EDC mixture showed reduced KiSS-1 mRNA expression across three hypothalamic regions examined (rostral, mid, and caudal) and had fewer kisspetin immunopositive cells colocalized with both LHbeta and ERalpha in the pituitary gland. In contrast, treatment had no effect on parameters measured in the adult ewe hypothalamus or pituitary.This study demonstrates that the developing fetus is sensitive to real-world mixtures of environmental chemicals, which cause significant neuroendocrine alterations. The important role of kisspeptin/GPR54 in regulating puberty and adult reproduction means that in utero disruption of this system is likely to have long-term consequences in adulthood and represents a novel, additional pathway through which environmental chemicals perturb human reproduction.