tbuckley/cabot-search huggingface dataset:
Stem Cell Quiescence
Authors: Ling Li, Ravi Bhatia
Journal: Clinical Cancer Research (2011)

Abstract Adult stem cells are maintained in a quiescent state but are able to exit quiescence and rapidly expand and differentiate in response to stress. The quiescent state appears to be necessary for preserving the self-renewal of stem cells and is a critical factor in the resistance of cancer stem cells (CSCs) to chemotherapy and targeted therapies. Limited knowledge about quiescence mechanisms has prevented significant advances in targeting of drug-resistant quiescent CSCs populations in the clinic. Thus, an improved understanding of the molecular mechanisms of quiescence in adult stem cells is critical for the development of molecularly targeted therapies against quiescent CSCs in different cancers. Recent studies have provided a better understanding of the intrinsic and extrinsic regulatory mechanisms that control stem cell quiescence. It is now appreciated that the p53 gene plays a critical role in regulating stem cell quiescence. Other intrinsic regulatory mechanisms include the FoxO, HIF-1α, and NFATc1 transcription factors and signaling through ATM and mTOR. Extrinsic microenvironmental regulatory mechanisms include angiopoietin-1, TGF-β, bone morphogenic protein, thrombopoietin, N-cadherin, and integrin adhesion receptors; Wnt/β-catenin signaling; and osteopontin. In this article, we review current advances in understanding normal stem cell quiescence, their significance for CSC quiescence and drug resistance, and the potential clinical applications of these findings. Clin Cancer Res; 17(15); 4936–41. ©2011 AACR.
A unique V-J-C-rearranged gene encodes a gamma protein expressed on the majority of CD3+ T cell receptor-alpha/beta- circulating lymphocytes.
Authors: F Triebel, F Faure, M Graziani, S Jitsukawa, M P Lefranc, T Hercend
Journal: The Journal of Experimental Medicine (1988)

We have recently described an mAb, anti-Ti gamma A, that recognizes an antigenic determinant carried by a TCR gamma chain. This antibody binds to approximately 3% of human PBLs and delineates a CD2+, CD3+, TCR-alpha/beta-, CD4-, CD8+/-, CD5+, NKH1-, and HLA class II- subset. The present study was designed to identify the gene encoding the Ti gamma A epitope. A first analysis was carried out on a previously characterized TCR gamma + fetal-cloned cell line termed F6C7. It was found that F6C7 cells have one gamma rearrangement on each chromosome: one joins V gamma 3 to J gamma 1, and the second joins V gamma 9 to J gamma P. Because only the latter allele appeared to be transcribed in the F6C7 lymphocytes, these data strongly suggested that anti-Ti gamma A mAb is specific for either a V gamma 9 or a V gamma 9-J gamma P-encoded peptide. To confirm this point, we studied an additional series of 13 randomly selected Ti gamma A+ cloned cells derived from peripheral blood of three distinct adult individuals. Each one of these lymphocytes was shown to both possess and transcribe a V gamma 9-J gamma P-C gamma 1-rearranged gene. It is therefore concluded that a predominant subpopulation of CD3+ TCR-alpha/beta- human circulating T lymphocytes (namely, the subset defined by anti-Ti gamma A mAb) surface expresses a gamma protein with a limited potential of variability from one cell to another.
Pneumatosis cystoides coli and chloral hydrate
Authors: J H MARIGOLD
Journal: Gut (1998)

Editor,—In an interesting paper ( Gut 1997; 41 :778–85), Dr Florin has postulated a causal association between alkyl halides and the development of pneumatosis cystoides coli (PCC). Review of the notes of two patients with this rare condition seen over the past seven years has revealed that both were taking chloral hydrate at the time of diagnosis.

A 78 year old woman was admitted in February 1991 because of immobility and constipation secondary to longstanding Parkinson’s disease. She was treated with chloral hydrate 500 mg at night for insomnia. In June 1992, she presented with a three month history of intermittent diarrhoea. Flexible sigmoidoscopy suggested mild ulcerative colitis (not confirmed on biopsy) and simultaneous barium enema showed extensive inflammatory polyps up to the proximal transverse colon, with a malignant stricture in the distal sigmoid colon. At laparotomy, no tumour was detected but gas filled cysts …
Guidelines for the genetic diagnosis of hereditary recurrent fevers
Authors: Y Shinar, L Obici, I Aksentijevich, B Bennetts, F Austrup, I Ceccherini, J M Costa, A De Leener, M Gattorno, U Kania, I Kone-Paut, S Lezer, A Livneh, I Moix, R Nishikomori, S Ozen, L Phylactou, L Risom, D Rowczenio, T Sarkisian, M E van Gijn, M Witsch-Baumgartner, M Morris, H M Hoffman, I Touitou
Journal: Annals of the Rheumatic Diseases (2012)

Hereditary recurrent fevers (HRFs) are a group of monogenic autoinflammatory diseases characterised by recurrent bouts of fever and serosal inflammation that are caused by pathogenic variants in genes important for the regulation of innate immunity. Discovery of the molecular defects responsible for these diseases has initiated genetic diagnostics in many countries around the world, including the Middle East, Europe, USA, Japan and Australia. However, diverse testing methods and reporting practices are employed and there is a clear need for consensus guidelines for HRF genetic testing. Draft guidelines were prepared based on current practice deduced from previous HRF external quality assurance schemes and data from the literature. The draft document was disseminated through the European Molecular Genetics Quality Network for broader consultation and amendment. A workshop was held in Bruges (Belgium) on 18 and 19 September 2011 to ratify the draft and obtain a final consensus document. An agreed set of best practice guidelines was proposed for genetic diagnostic testing of HRFs, for reporting the genetic results and for defining their clinical significance.
Randomized controlled trial of high concentration oxygen in suspected community-acquired pneumonia
Authors: Meme Wijesinghe, Kyle Perrin, Bridget Healy, Mark Weatherall, Richard Beasley
Journal: Journal of the Royal Society of Medicine (2012)

Objective To determine whether high concentration oxygen increases the PaCO 2 in the treatment of community-acquired pneumonia. Design Randomized controlled clinical trial in which patients received high concentration oxygen (8 L/min via medium concentration mask) or titrated oxygen (to achieve oxygen saturations between 93 and 95%) for 60 minutes. Transcutaneous CO 2 (PtCO 2 ) was measured at 0, 20, 40 and 60 minutes. Setting The Emergency Departments at Wellington, Hutt and Kenepuru Hospitals. Participants 150 patients with suspected community-acquired pneumonia presenting to the Emergency Department. Patients with chronic obstructive pulmonary disease (COPD) or disorders associated with hypercapnic respiratory failure were excluded. Main outcome variables The primary outcome variable was the proportion of patients with a rise in PtCO 2 ≥4 mmHg at 60 minutes. Secondary outcome variables included the proportion of patients with a rise in PtCO 2 ≥8 mmHg at 60 minutes. Results The proportion of patients with a rise in PtCO 2 ≥4 mmHg at 60 minutes was greater in the high concentration oxygen group, 36/72 (50.0%) vs 11/75 (14.7%), relative risk (RR) 3.4 (95% CI 1.9 to 6.2), P &lt; 0.001. The high concentration group had a greater proportion of patients with a rise in PtCO 2 ≥8 mmHg, 11/72 (15.3%) vs 2/75 (2.7%), RR 5.7 (95% CI 1.3 to 25.0), P = 0.007. Amongst the 74 patients with radiological confirmation of pneumonia, the high concentration group had a greater proportion with a rise in PtCO 2 ≥4 mmHg, 20/35 (57.1%) vs 5/39 (12.8%), RR 4.5 (95% CI 1.9 to 10.6) P &lt; 0.001. Conclusions We conclude that high concentration oxygen therapy increases the PtCO 2 in patients presenting with suspected community-acquired pneumonia. This suggests that the potential increase in PaCO 2 with high concentration oxygen therapy is not limited to COPD, but may also occur in other respiratory disorders with abnormal gas exchange.
Gene therapy in autoimmune diseases
Authors: C H EVANS, J D WHALEN, C H EVANS, S C GHIVIZZANI, P D ROBBINS
Journal: Annals of the Rheumatic Diseases (1998)

Leaders Gene therapy in autoimmune diseasesCollectively, autoimmune diseases constitute a major, unmet, clinical challenge.Although no single autoimmune disorder is highly prevalent, there are over 80 of them, and 20% of the population is aVected; approximately 75% of patients are women.Because these diseases are generally incurable and diYcult to manage, there is a pressing need for novel approaches to their treatment.For reasons detailed below, we have proposed that gene therapy merits investigation in this regard. 1 Why genes?Traditional pharmacological approaches to treatment entail the synthesis of small, diVusable compounds given orally or by injection.These approaches have yet to provide ideal agents for use in autoimmune diseases.Recent research, however, has identified a number of proteins with the potential to improve treatment, but these are diYcult to administer long term.Gene transfer provides the opportunity to deliver protein products, as well as therapeutic species of nucleic acids, such as antisense RNA, much more eYciently than traditional methods of drug therapy.Furthermore sustained, in situ production of the gene products would eliminate the need for frequent readministration.In addition, gene delivery and subsequent expression has the potential to be highly localised, if needed.Indeed, gene therapy's greatest strength may be its ability to produce high, sustained concentrations of therapeutic macromolecules within a defined anatomical location.In the case of RA, for example, anti-arthritic proteins are already being delivered systemically to patients by subcutaneous or intravenous injection.There is, however, no practical method for transferring these molecules selectively to joints in a sustained fashion.
Renal bone disease
Authors: Jeffrey H M Lee, Malcolm Stodell, J C Fowler
Journal: Journal of the Royal Society of Medicine (2005)

pneumonia and allergic bronchopulmonary aspergillosis: in particular Churg-Strauss manifests, in up to 75% of patients, with mononeuritis multiplex. 7At twenty-four months our patient remained free from neurological symptoms, and had no evidence of cardiac, skin, joint or renal involvement.Hypereosinophilic syndrome may represent a preleukaemic state, or may herald the onset of Hodgkin's disease or T-cell lymphoblastic lymphoma. 8n underlying lymphoproliferative or myeloproliferative disorder is unlikely in the present case in view of the normal bone marrow, rapid response to hydrocortisone and lack of recurrence of the peripheral eosinophilia.Mild eosinophilia associated with adrenocortical insufficiency is well recognized in critically ill patients.However, the pulmonary infiltrates, mediastinal lymphadenopathy and marked eosinophilia seen in our patient cannot be explained by hypocorticism.Furthermore, the strong IgE response suggests a hypersensitivity phenomenon such as a drug reaction.
Role of Extracellular and Intracellular Acidosis for Hypercapnia-Induced Inhibition of Tension of Isolated Rat Cerebral Arteries
Authors: Rong Tian, Pia Vogel, Niels A. Lassen, Michael J. Mulvany, Frederik Andreasen, Christian Aalkjær
Journal: Circulation Research (1995)

Abstract The importance of smooth muscle cell pH i and pH o for the hypercapnic vasodilation of rat cerebral arteries was evaluated in vitro. Vessel segments were mounted in a myograph for isometric tension recording; pH i was measured by loading the smooth muscle cells with the fluorescent dye BCECF, and pH o was measured with a glass electrode. In all studies, Ca 2+ -dependent basal tension (in the absence of any agonist) and tension in the presence of arginine vasopressin were investigated. Control solution was physiological saline bubbled with 5% CO 2 and containing 25 mmol/L HCO 3 − (pH 7.45 to 7.50). Induction of hypercapnic acidosis (10% CO 2 ) or normocapnic acidosis (15 mmol/L HCO 3 − ) caused significant inhibition of smooth muscle tension, and both conditions reduced pH i as well as pH o . N -Nitro- l -arginine significantly inhibited the relaxation to hypercapnic acidosis but had no significant effect on relaxation to normocapnic acidosis. Predominant extracellular acidosis, induced by reducing [HCO 3 − ] from 25 to 9 mmol/L and CO 2 from 5% to 2.5%, also caused inhibition of tension in steady state. By contrast, predominant intracellular acidosis, induced by increasing [HCO 3 − ] from 25 to 65 mmol/L and CO 2 from 5% to 15%, induced a small increase of basal tension and a small decrease of tension in the presence of arginine vasopressin. The responses to predominant intracellular or extracellular acidosis were qualitatively similar in the presence and absence of endothelium and in the presence and absence of N -nitro- l -arginine. It is concluded that the extracellular acidosis and not smooth muscle intracellular acidosis is responsible for the relaxation to hypercapnic acidosis.
Proteolytic cleavage of elafin by 20S proteasome may contribute to inflammation in acute lung injury
Authors: Aoife Kerrin, Sinéad Weldon, Allen Hung-Kang Chung, Thelma Craig, A John Simpson, Cecilia M O'Kane, Danny Francis McAuley, Clifford C Taggart
Journal: Thorax (2012)

<h3>Rationale</h3> We hypothesise that elafin levels in acute lung injury (ALI) decrease over time due, in part, to proteolytic degradation as observed in other lung diseases. <h3>Objectives</h3> The aim of this study was to characterise temporal changes in elafin concentration in patients with ALI and to evaluate whether a decrease in elafin levels is due to elevated protease activity. <h3>Methods</h3> Bronchoalveolar lavage fluid (BALF) was obtained from patients with ALI within 48 h of onset of ALI (day 0), at day 3 and at day 7. Elafin levels were quantified by ELISA. Elafin susceptibility to proteolytic cleavage by ALI BALF was assessed by Western blot and by high-performance liquid chromatography–mass spectrometry. <h3>Measurements and main results</h3> Elafin levels were found to be significantly increased at the onset of ALI compared with healthy volunteers and fell significantly by day 7 compared with day 0. In contrast, levels of secretory leukocyte protease inhibitor did not decrease over time. This decrease in elafin was due to cleavage by the 20S proteasome which was significantly increased in ALI BALF. Incubation of ALI BALF with the proteasome inhibitor epoxomicin confirmed that 20S proteasome protease activity was responsible for proteolytic cleavage of elafin, resulting in diminished anti-elastase activity. In addition, free neutrophil elastase activity significantly increased in ALI BALF from day 0 to day 7. <h3>Conclusions</h3> Elafin concentrations fall within the pulmonary compartment over the course of ALI as a result of proteolytic degradation. This loss of elafin may predispose people, in part, to excessive inflammation in ALI.
Bile pigment formation by skin heme oxygenase: studies on the response of the enzyme to heme compounds and tissue injury.
Authors: M D Maines, J Cohn
Journal: The Journal of Experimental Medicine (1977)

Skin heme oxygenase is locally elevated by stimuli such as tissue injury and injections of whole blood, myoglobin, and hematin. The enzyme activity is also increased at the proximity of the injection site of chemicals such as cobalt and cobalt-protoporphyrin-IX (cobalt-heme). Protoporphyrin-IX, the tetrapyrrole nucleus of type-b heme compounds, was ineffective in altering the enzyme activity in vivo. The developmental pattern of heme oxygenase in skin was compared to that of the enzyme in liver. The enzyme activity in both organs was greatest during the 1st postpartum wk and declined to adult levels after 2 wk. The physiological implications of the increased activity of skin heme oxygenase are discussed, and it is concluded that the activity of the hepatic heme oxygenase system and that of the skin are regulated by the same mechanism.
Erythromycin and clarithromycin attenuate cytokine-induced endothelin-1 expression in human bronchial epithelial cells
Authors: H Takizawa, M Desaki, T Ohtoshi, S Kawasaki, T Kohyama, M Sato, J Nakajima, M Yanagisawa, K Ito
Journal: European Respiratory Journal (1998)

Erythromycin and its fourteen-member macrolide analogues have attracted attention for their efficacy in bronchial asthma. However, their mechanisms of action remain unclear. We evaluated the effects of the macrolide antibiotics on endothelin-1 (ET-1) expression in normal and transformed human bronchial epithelial cells, one of the sources of this potent bronchoconstrictor important in the pathogenesis of asthma. Human bronchial epithelial cells were obtained from the resected bronchi, and the effect of several antimicrobial and antiasthmatic drugs on the production and messenger ribonucleic acid (mRNA) levels of ET-1 was evaluated. Bronchoepithelial cells were also isolated from the mucosa of asthmatic patients under fibreoptic bronchoscopy, and the modulating effects of the drugs were studied. Erythromycin and clarithromycin uniquely suppressed mRNA levels as well as the release of ET- at therapeutic and non-cytotoxic concentrations (percentage inhibition of ET-1 protein release: 26.4+/-5.22% and 31.2+/-7.45%, respectively, at 10(-6) M). Furthermore, erythromycin and clarithromycin inhibited ET-1 expression in bronchoepithelial cells from patients with chronic, stable asthma. A glucocorticosteroid, dexamethasone, also inhibited ET-1 expression. In contrast, theophylline, salbutamol and FK506 had no effect on ET-1 production. Our findings demonstrated that these fourteen-member macrolide antibiotics had an inhibitory effect on endothelin-1 expression in human bronchial epithelial cells. Moreover, this new mode of action may have some relevance to their clinical efficacy in bronchial asthma.
Dyspnea on Exertion in Obese Women
Authors: Tony G. Babb, Kamalini G. Ranasinghe, Laurie A. Comeau, Trisha L. Semon, Belinda Schwartz
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: Although exertional dyspnea in obesity is an important and prolific clinical concern, the underlying mechanism remains unclear.Objectives: To investigate whether dyspnea on exertion in otherwise healthy obese women was associated with an increase in the oxygen cost of breathing or cardiovascular deconditioning.Methods: Obese women with and without dyspnea on exertion participated in two independent experiments (n = 16 and n = 14). All participants underwent pulmonary function testing, hydrostatic weighing, ratings of perceived breathlessness during cycling at 60 W, and determination of the oxygen cost of breathing during eucapnic voluntary hyperpnea at 40 and 60 L/min. Cardiovascular exercise capacity, fat distribution, and respiratory mechanics were determined in 14 women in experiment 2. Data were analyzed between groups by independent t test, and the relationship between the variables was determined by regression analysis.Measurements and Main Results: In both experiments, breathlessness during 60 W cycling was markedly increased in over 37% of the obese women (P < 0.01). Age, height, weight, lung function, and %body fat were not different between the groups in either experiment. In contrast, the oxygen cost of breathing was significantly (P < 0.01) and markedly (38–70%) greater in the obese women with dyspnea on exertion. The oxygen cost of breathing was significantly (P < 0.001) correlated with the rating of perceived breathlessness obtained during the 60 W exercise in experiment 1 (r2 = 0.57) and experiment 2 (r2 = 0.72). Peak cardiovascular exercise capacity, fat distribution, and respiratory mechanics were not different between groups in experiment 2.Conclusions: Dyspnea on exertion is prevalent in otherwise healthy obese women, which seems to be strongly associated with an increased oxygen cost of breathing. Exercise capacity is not reduced in obese women with dyspnea on exertion.
Reduced beta-cell compensation to the insulin resistance associated with obesity in members of caucasian familial type 2 diabetic kindreds.
Authors: S C Elbein, K Wegner, S E Kahn
Journal: Diabetes Care (2000)

OBJECTIVE: Both obesity and a family history of diabetes reduce insulin sensitivity, but the impact of obesity on insulin secretion among individuals predisposed to diabetes is uncertain. We used a pedigree-based approach to test the hypothesis that beta-cell compensation to the insulin resistance associated with obesity is defective among individuals predisposed to diabetes by virtue of a strong family history of type 2 diabetes before the development of diabetes or glucose intolerance. RESEARCH DESIGN AND METHODS: A total of 126 members of 26 families ascertained for at least a sib pair with type 2 diabetes with onset before age 65 years underwent a tolbutamide-modified frequently sampled intravenous glucose tolerance test (FSIGT). Family members included 26 individuals with impaired glucose tolerance and 100 individuals with normal glucose tolerance (NGT). The acute insulin response to glucose (AIRglucose) was determined and insulin sensitivity (S(I)) estimated by minimal model analysis of FSIGT data. The beta-cell compensation for insulin sensitivity was estimated from the disposition index (DI), calculated as the product of S(I) and AIRglucose. Obesity was measured by BMI. RESULTS: Among all individuals, BMI was a significant predictor of both S(I) and AIRglucose, as expected. However, BMI also significantly predicted DI (P = 0.002) after correcting for age, sex, family membership, and glucose tolerance status. The relationship of BMI and DI was confirmed in 85 individuals with NGT who were aged &amp;lt;45 (P = 0.002) but not in 91 unrelated control individuals without a family history of diabetes. When normoglycemic individuals aged &amp;lt;45 were separated into three classes by BMI (&amp;lt; or =27, 27-30, &amp;gt;30), S(I) decreased progressively and significantly with obesity whereas AIRglucose rose significantly from lean to most obese classes. In contrast to the expectation of complete beta-cell compensation with obesity D1 fell significantly (P = 0.004) among obese family members. This relationship was not observed in control subjects. CONCLUSIONS: Individuals with a genetic predisposition to diabetes show a reduced beta-cell compensatory response to the reduced insulin sensitivity associated with obesity. We propose that this impaired compensation may be one manifestation of the underlying genetic defect in susceptible individuals. This finding helps explain the multiplicative effects of family history and obesity on risk of type 2 diabetes.
Flu's impact on intensive care
Authors: J. Bion, T. Evans, B. Winter
Journal: BMJ (2011)

O’Dowd’s report on the response to the winter flu surge does not mention the large impact the surge has had on intensive care units (ICUs),1 which responded to the crisis by rapidly increasing capacity through staff working additional hours and by adapting operating theatres and postoperative recovery units. Capacity for extra corporeal membrane oxygenation (ECMO) for the most …
Cost-Effectiveness of Early Versus Standard Antiretroviral Therapy in HIV-Infected Adults in Haiti
Authors: Serena P. Koenig, Heejung Bang, Patrice Severe, Marc Antoine Jean Juste, Alex Ambroise, Alison Edwards, Jessica Hippolyte, Daniel W. Fitzgerald, Jolion McGreevy, Cynthia Riviere, Serge Marcelin, Rode Secours, Warren D. Johnson, Jean W. Pape, Bruce R. Schackman
Journal: PLoS Medicine (2011)

This cost-effectiveness study comparing early versus standard antiretroviral treatment (ART) for HIV, based on randomized clinical trial data from Haiti, reveals that the new WHO guidelines for early ART initiation can be cost-effective in resource-poor settings.