tbuckley/cabot-search huggingface dataset:
Dietary supplementation with fish oil rich in omega-3 polyunsaturated fatty acids in children with bronchial asthma
Authors: T Nagakura, S Matsuda, K Shichijyo, H Sugimoto, K Hata
Journal: European Respiratory Journal (2000)

Omega-3 polyunsaturated fatty acids have anti-inflammatory effects in vitro, and high dietary levels are associated with a lower incidence of inflammatory diseases. However, only limited effects have been demonstrated in asthma. The effects of dietary supplementation with fish oil for 10 months in 29 children with bronchial asthma was investigated in a randomized controlled fashion. In order to minimize the effects of environmental inhaled allergens and diet, this study was performed in a long-term treatment hospital. Subjects received fish oil capsules containing 84 mg eicosapentaenoic acid (EPA) and 36 mg docosahexaenoic acid (DHA) or control capsules containing 300 mg olive oil. The daily dosages of EPA and DHA were 17.0-26.8 and 7.3-11.5 mg x kg body weight(-1), respectively. Asthma symptom scores decreased and responsiveness to acetylcholine decreased in the fish oil group but not in the control group. In addition, plasma EPA levels increased significantly only in the fish oil group (p&lt;0.0088). No significant side-effects were observed. The present results suggest that dietary supplementation with fish oil rich in the omega-3 polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid is beneficial for children with bronchial asthma in a strictly controlled environment in terms of inhalant allergens and diet.
Early surgical intervention in ulcerative colitis
Authors: M A Kamm
Journal: Gut (2004)

Medical treatment for both fulminant and chronic active colitis is now usually very effective. Given that surgical therapy is associated with substantial morbidity and mortality, the preferred treatment should be conservative.

Intravenous cyclosporin is of proven value in managing fulminant ulcerative colitis. In the definitive study of patients who failed intravenous steroid therapy, nine of 11 patients responded to cyclosporin compared with none of nine patients on placebo.1 Open clinical use has confirmed that colectomy can be avoided in the majority of patients.2–4 with short term response rates of up to 86%.4

Cyclosporin can be continued even if there is mild colonic dilatation, provided the patient is clinically improving.4 Continued close observation by a gastroenterologist and a surgeon is essential.

Criticism of cyclosporin has centred on drug toxicity, possible compromise of surgical outcome if drug therapy fails, and the possibility that successful drug therapy only delays inevitable surgery.

The original trial dose of cyclosporin was 4 mg/kg/day intravenously,1 a dose associated with considerable morbidity. We5 and others6 have used a dose of 2 mg/kg/day, without …
Damage to the Peritoneal Membrane by Glucose Degradation Products Is Mediated by the Receptor for Advanced Glycation End-Products
Authors: Vedat Schwenger, Christian Morath, Alexander Salava, Kerstin Amann, Yuri Seregin, Reinhold Deppisch, Eberhard Ritz, Angelika Bierhaus, Peter P. Nawroth, Martin Zeier
Journal: Journal of the American Society of Nephrology (2005)

Peritoneal dialysis is limited by morphologic changes of the peritoneal membrane. Use of peritoneal dialysis fluids (PDF) that contain glucose degradation products (GDP) generates advanced glycation end-products (AGE) within the peritoneal cavity. It is unknown whether peritoneal damage is causally related to AGE–receptor for AGE (RAGE) interaction. The effects of PDF were compared with different amounts of GDP on morphologic changes of the peritoneal membrane in 48 wild-type (WT) and 48 RAGE-deficient mice. PDF (1 ml) were instilled twice daily over a period of 12 wk. Groups with eight animals each received no manipulation (sham); sham instillation (sham i.p.); or filter-sterilized, glucose-free, conventional low GDP- or high GDP PDF. In vitro (generation of AGE fluorescence in PDF) and in vivo (immunohistochemistry for carboxymethyllysine), a GDP-dependent increase of AGE formation occurred. Inflammation and neoangiogenesis were augmented in WT mice that were treated with high GDP accompanied by upregulation of CD3+ T cells, increased NF-κB binding activity, increased lectin, and vascular endothelial growth factor expression. Furthermore, pronounced submesothelial fibrosis was found with increased expression of TGF-β1. Exposure to low GDP resulted in only mild inflammation and neoangiogenesis (compared with sham i.p.) and no fibrosis in WT mice. The findings in WT contrasted with those in RAGE-deficient mice, which showed no increased inflammation (CD3+ T cells and NF-κB binding activity), neoangiogenesis (by lectin and vascular endothelial growth factor expression), or fibrosis (expression of TGF-β1) after long-term exposure to GDP-containing PDF. Peritoneal damage by GDP in PDF is dependent at least in part on AGE–RAGE interaction.
Elevated Phospho-S6 Expression Is Associated with Metastasis in Adenocarcinoma of the Lung
Authors: J. Matthew McDonald, Christopher E. Pelloski, Alicia Ledoux, Menghong Sun, Gabriela Raso, Ritsuko Komaki, Ignacio I. Wistuba, B. Nebiyou Bekele, Ken Aldape
Journal: Clinical Cancer Research (2008)

The primary objective of this study was to determine whether markers of differentiation and activation of the Akt pathway are associated with metastasis in adenocarcinoma of the lung.Paired primary and metastatic tumor samples were obtained from 41 patients who had undergone resection of both primary lung adenocarcinoma and brain metastatic lesions. Paired samples were compared for relative expression of thyroid transcription factor 1 (TTF-1) and E-cadherin as potential markers of differentiation. Activation of the Akt pathway was assessed by expression of p-Akt and p-S6. Biomarkers that showed relative discordance in expression between the matched pairs were then assessed in a cohort of 77 primary lung adenocarcinomas. Validation was done in an independent cohort of 82 primary lung adenocarcinomas.Among the 41 matched pairs, E-cadherin (23 discordant pairs) and TTF-1 (18 discordant pairs) were overexpressed in primary tumors (20 of 23 and 15 of 18, respectively). In contrast, p-S6 overexpression was significantly associated with metastatic tumors (20 of 21 discordant pairs). The expression of E-cadherin, p-S6, and TTF-1 was evaluated in 77 primary lung adenocarcinomas, in which high p-S6 expression was associated with shorter time to metastasis. The association of p-S6 with metastasis was then validated in an independent set of 82 tumors. In multivariable analysis, p-S6 expression was a negative independent predictor of metastasis-free survival after adjustment for tumor stage.The biomarker p-S6 is overexpressed in metastatic tumors. In primary tumors, higher p-S6 expression is associated with shorter metastatic-free survival. This biomarker has the potential for risk stratification in future clinical trials.
Effectiveness of Continuous Positive Airway Pressure in Mild Sleep Apnea–Hypopnea Syndrome
Authors: CARMEN MONASTERIO, SILVIA VIDAL, JOAQUIN DURAN, MONTSE FERRER, CARMEN CARMONA, FERRAN BARBÉ, MERCE MAYOS, NICOLAS GONZALEZ-MANGADO, MONTSERRAT JUNCADELLA, ANNA NAVARRO, ROCIO BARREIRA, FRANCISCO CAPOTE, LOLA R. MAYORALAS, GERMAN PECES-BARBA, JORDI ALONSO, JOSEP M. MONTSERRAT
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

The aim of this trial was to evaluate the effectiveness of continuous positive airway pressure (CPAP) in patients with mild sleep apnea- hypopnea syndrome (SAHS). One hundred forty-two consecutive patients with mild SAHS (apnea-hypopnea index 10-30, without severe sleepiness) were randomly assigned to receive conservative treatment (CT)-sleep hygiene and weight loss-(65 patients) or CT plus CPAP (77 patients), and 125 patients (86% males, age: 54 +/- 9 yr, BMI: 29 +/- 4 kg/m(2), AHI: 20 +/- 6, ESS: 12 +/- 4) completed the follow-up. The following outcomes were assessed at inclusion and after 3 and 6 mo of treatment: sleepiness (Epworth scale, multiple sleep latency test [MSLT]), other symptoms related to SAHS, cognitive function, and perceived health status (Functional Outcomes of Sleep Questionnaire [FOSQ], Nottingham Health profile). The relief of SAHS-related clinical symptoms was significantly greater in the CPAP group than in the CT group; the Epworth scale and FOSQ also showed more improvement in the CPAP group but did not reach significance. There were no significant differences in the other tests performed probably because the baseline values were normal. CPAP compliance was 4.8 +/- 2.2 h and treatment continuation was accepted by 62% of the patients at the end of the study. These results suggest that CPAP can be considered in treating patients with mild SAHS on the basis of an improvement in symptoms.
Regulation of macrophage functions by L-arginine.
Authors: J E Albina, M D Caldwell, W L Henry, C D Mills
Journal: The Journal of Experimental Medicine (1989)

Sites of inflammation with prominent macrophage infiltration, such as wounds and certain tumors, are uniquely deficient in free arginine. The effects of arginine availability on macrophage physiology were investigated. When cultured in media containing less than 0.1 mM L-arginine, rat resident peritoneal macrophages exhibited enhanced spreading, tumor cytotoxicity, superoxide production, phagocytosis, and protein synthesis. Thus, arginine concentrations similar to those found in sites of inflammation can augment macrophage functions, while those found in plasma (approximately 0.1 mM) and in commonly used culture media (0.4 to 1.2 mM) are inhibitory. Culture in homoarginine, but not D-arginine, ornithine, citrulline, urea, histidine, or lysine also inhibited macrophage tumor cytotoxicity, indicating the specificity of the effect. In contrast to resident macrophages, the tumor cytotoxicity of peritoneal macrophages obtained after C. parvum injection was suppressed by culture in arginine-deficient media. However, L-arginine-deficient media enhanced all other activation-associated functions in C. parvum-elicited macrophages as in resident cells. Arginine-free wound fluid promoted resident macrophage tumoricidal activity when compared with rat serum, and again, the addition of L-arginine was inhibitory. The marked effects of L-arginine availability on macrophage functions, together with the knowledge that these cells modify the extracellular arginine concentration in sites of inflammation through arginase, provide evidence for an autoregulatory mechanism of macrophage activation.
Granulocyte Macrophage Colony-Stimulating Factor Inhibits Breast Cancer Growth and Metastasis by Invoking an Anti-Angiogenic Program in Tumor-Educated Macrophages
Authors: Tim D. Eubank, Ryan D. Roberts, Mahmood Khan, Jennifer M. Curry, Gerard J. Nuovo, Periannan Kuppusamy, Clay B. Marsh
Journal: Cancer Research (2009)

Abstract Tumor-educated macrophages facilitate tumor metastasis and angiogenesis. We discovered that granulocyte macrophage colony-stimulating factor (GM-CSF) blocked macrophages vascular endothelial growth factor (VEGF) activity by producing soluble VEGF receptor-1 (sVEGFR-1) and determined the effect on tumor-associated macrophage behavior and tumor growth. We show GM-CSF treatment of murine mammary tumors slowed tumor growth and slowed metastasis. These tumors had more macrophages, fewer blood vessels, and lower oxygen concentrations. This effect was sVEGFR-1 dependent. In situ hybridization and flow cytometry identified macrophages as the primary source of sVEGFR-1. These data suggest that GM-CSF can re-educate macrophages to reduce angiogenesis and metastases in murine breast cancer. [Cancer Res 2009;69(5):2133–40]
Sputum Proteomics in Inflammatory and Suppurative Respiratory Diseases
Authors: Robert D. Gray, Gordon MacGregor, Donald Noble, Margaret Imrie, Maria Dewar, A. Christopher Boyd, J. Alastair Innes, David J. Porteous, Andrew P. Greening
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: Markers of inflammatory activity are important for assessment and management of many respiratory diseases. Markers that are currently unrecognized may be more valuable than those presently believed to be useful.Objectives: To identify potential biomarkers of suppurative and inflammatory lung disease in induced sputum samples.Methods: Induced sputum was collected from 20 healthy control subjects, 24 patients with asthma, 24 with chronic obstructive pulmonary disease, 28 with cystic fibrosis (CF), and 19 with bronchiectasis. Twelve patients with CF had sputum sampled before and after antibiotic therapy for an infective exacerbation. The fluid phase of induced sputum was analyzed by surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectroscopy on three protein array surfaces. Some protein markers were selected for identification, and relevant ELISA assays sought. For 12 patients with CF, both SELDI-TOF and ELISA monitored changes in inflammatory responses during infective exacerbations.Measurements and Main Results: SELDI-TOF identified potential biomarkers that differentiated each of the disease groups from healthy control subjects: at a significance of P < 0.01, there were 105 for asthma, 113 for chronic obstructive pulmonary disease, 381 for CF, and 377 for bronchiectasis. Peaks selected for protein identification yielded calgranulin A, calgranulin B, calgranulin C, Clara cell secretory protein, lysosyme c, proline rich salivary peptide, cystatin s, and hemoglobin α. On treatment of an infective CF exacerbation, SELDI-TOF determined falls in levels of calgranulin A and calgranulin B that were mirrored by ELISA-measured falls in calprotectin (heterodimer of calgranulins A and B).Conclusions: Proteomic screening of sputum yields potential biomarkers of inflammation. The early development of a clinically relevant assay from such data is demonstrated.
Hedgehog Signaling Requires Motile Cilia in the Sea Urchin
Authors: Jacob F. Warner, Ali M. McCarthy, Robert L. Morris, David R. McClay
Journal: Molecular Biology and Evolution (2013)

A relatively small number of signaling pathways govern the early patterning processes of metazoan development. The architectural changes over time to these signaling pathways offer unique insights into their evolution. In the case of Hedgehog (Hh) signaling, two very divergent mechanisms of pathway transduction have evolved. In vertebrates, signaling relies on trafficking of Hh pathway components to nonmotile specialized primary cilia. In contrast, protostomes do not use cilia of any kind for Hh signal transduction. How these divergent lineages adapted such dramatically different ways of activating the signaling pathway is an unanswered question. Here, we present evidence that in the sea urchin, a basal deuterostome, motile cilia are required for embryonic Hh signal transduction, and the Hh receptor Smoothened (Smo) localizes to cilia during active Hh signaling. This is the first evidence that Hh signaling requires motile cilia and the first case of an organism requiring cilia outside of the vertebrate lineage.
Alternative pathways for hydrogen disposal during fermentation in the human colon.
Authors: G R Gibson, J H Cummings, G T Macfarlane, C Allison, I Segal, H H Vorster, A R Walker
Journal: Gut (1990)

Hydrogen gas, which is produced during fermentation in the human colon, is either excreted in breath or metabolised by gut bacteria through a variety of pathways. These may include methanogenesis, dissimilatory sulphate reduction, and acetogenesis. To determine which of these routes predominates in the large intestine, stools were taken from 30 healthy subjects and incubated as 5% (w/v) slurries with Lintner's starch. In 23 of 30 subjects, methane production was the main method of hydrogen disposal. In the remaining seven, high rates of sulphate reduction were recorded together with raised production of H2S. All samples showed relatively low rates of hydrogen evolution and of acetate formation from CO2 and H2. Sulphate reduction and methanogenesis seem to be mutually exclusive in the colon and this is probably linked to sulphate availability. Sulphate reduction, methanogenesis, and acetogenesis were strongly influenced by pH. Sulphate reduction was optimal at alkaline pH values whereas methane production was maximal at a neutral pH and acetogenesis favoured acidic conditions. Faecal H2S values were related to carriage of sulphate reducing bacteria. These data show that a number of competing pathways for hydrogen disposal are possible in the large gut and that a variety of factors such as colonic pH and sulphate availability can determine which of these mechanisms predominates.
Cell-mediated immunity: delayed-type hypersensitivity and cytotoxic responses are mediated by different T-cell subclasses.
Authors: B Huber, O Devinsky, R K Gershon, H Cantor
Journal: The Journal of Experimental Medicine (1976)

Cell-mediated immunity includes both the generation of cytotoxic cells and initiation of delayed-type hypersensitivity (DTH). The resting T-cell population, before stimulation by antigen, already contains cells of the Lyl subclass that are programmed to initiate DTH (and helper function) but not cytotoxic responses, as well as Ly23 cells which can generate killer activity (and suppressive function) but not DTH. The central implication of these findings is that the broad division between humoral and cell-mediated immune responses does not precisely correspond to the division of labor among T-cell subclasses. The relative contribution of DTH-competent Lyl cells and cytotoxic Ly23 cells to the classical homograft response remains to be determined.
Intensive Diabetes Therapy and Glomerular Filtration Rate in Type 1 Diabetes
Authors: Ian H. De Boer, Wanjie Sun, Patricia A. Cleary, John M. Lachin, Mark E. Molitch, Michael W. Steffes, Bernard Zinman
Journal: New England Journal of Medicine (2011)

An impaired glomerular filtration rate (GFR) leads to end-stage renal disease and increases the risks of cardiovascular disease and death. Persons with type 1 diabetes are at high risk for kidney disease, but there are no interventions that have been proved to prevent impairment of the GFR in this population.In the Diabetes Control and Complications Trial (DCCT), 1441 persons with type 1 diabetes were randomly assigned to 6.5 years of intensive diabetes therapy aimed at achieving near-normal glucose concentrations or to conventional diabetes therapy aimed at preventing hyperglycemic symptoms. Subsequently, 1375 participants were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. Serum creatinine levels were measured annually throughout the course of the two studies. The GFR was estimated with the use of the Chronic Kidney Disease Epidemiology Collaboration formula. We analyzed data from the two studies to determine the long-term effects of intensive diabetes therapy on the risk of impairment of the GFR, which was defined as an incident estimated GFR of less than 60 ml per minute per 1.73 m(2) of body-surface area at two consecutive study visits.Over a median follow-up period of 22 years in the combined studies, impairment of the GFR developed in 24 participants assigned to intensive therapy and in 46 assigned to conventional therapy (risk reduction with intensive therapy, 50%; 95% confidence interval, 18 to 69; P=0.006). Among these participants, end-stage renal disease developed in 8 participants in the intensive-therapy group and in 16 in the conventional-therapy group. As compared with conventional therapy, intensive therapy was associated with a reduction in the mean estimated GFR of 1.7 ml per minute per 1.73 m(2) during the DCCT study but during the EDIC study was associated with a slower rate of reduction in the GFR and an increase in the mean estimated GFR of 2.5 ml per minute per 1.73 m(2) (P<0.001 for both comparisons). The beneficial effect of intensive therapy on the risk of an impaired GFR was fully attenuated after adjustment for glycated hemoglobin levels or albumin excretion rates.The long-term risk of an impaired GFR was significantly lower among persons treated early in the course of type 1 diabetes with intensive diabetes therapy than among those treated with conventional diabetes therapy. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360815 and NCT00360893.).
The Inflammasomes and Autoinflammatory Syndromes
Authors: Lori Broderick, Dominic De Nardo, Bernardo S. Franklin, Hal M. Hoffman, Eicke Latz
Journal: Annual Review of Pathology Mechanisms of Disease (2014)

Inflammation, a vital response of the immune system to infection and damage to tissues, can be initiated by various germline-encoded innate immune-signaling receptors. Among these, the inflammasomes are critical for activation of the potent proinflammatory interleukin-1 cytokine family. Additionally, inflammasomes can trigger and maintain inflammatory responses aimed toward excess nutrients and the numerous danger signals that appear in a variety of chronic inflammatory diseases. We discuss our understanding of how inflammasomes assemble to trigger caspase-1 activation and subsequent cytokine release, describe how genetic mutations in inflammasome-related genes lead to autoinflammatory syndromes, and review the contribution of inflammasome activation to various pathologies arising from metabolic dysfunction. Insights into the mechanisms that govern inflammasome activation will help in the development of novel therapeutic strategies, not only for managing genetic diseases associated with overactive inflammasomes, but also for treating common metabolic diseases for which effective therapies are currently lacking.
His Bundle Recordings in Patients with Bundle Branch Block and Transient Neurologic Symptoms
Authors: MELVIN SCHEINMAN, ALAN WEISS, FREDERICK KUNKEL
Journal: Circulation (1973)

His bundle electrograms were recorded in 19 patients with bundle branch block (BBB) and transient neurologic symptoms allowing for determination of intra-atrial (P-A), atrioventricular (A-V), nodal (A-H) as well as infranodal conduction (H-Q) times. The patients were initially monitored in a coronary care unit and have been followed for a mean period of 8 ± 4 months. In six patients (Group I) neurologic symptoms were observed in the absence of electrocardiographic evidence of A-V block. In six patients (Group II) the cause of symptoms was uncertain; two of these patients had relief of symptoms after permanent cardiac pacemaker insertion and were presumed to have episodic high grade A-V block. In seven subjects (Group III) complete A-V block was documented as the cause of the symptoms; these patients were studied when 1:1 antegrade A-V conduction returned. There was no significant difference between mean P-A, A-H, and QRS durations among the patients in the three groups. Mean H-Q (89 ± 20 msec) for Group III was significantly longer than that for Group I (56 ± 9 msec) or Group 11 (64 ± 11 msec) ( P &lt; .001). All patients with presumed or documented episodes of high grade A-V block had abnormal H-Q intervals, and six of the nine patients with presumed or documented complete A-V block had H-Q intervals &gt;80 msec. The present data suggest that patients with transient neurologic symptoms, bifascicular or left BBB associated with marked prolongation of H-Q (≧80 msec), should be seriously considered as candidates for insertion of a permanent cardiac pacemaker even in the absence of documented high grade or completeA-V block.