tbuckley/cabot-search huggingface dataset:
Reactive airways dysfunction and systemic complaints after mass exposure to bromine.
Authors: A Woolf, M Shannon
Journal: Environmental Health Perspectives (1999)

Occasionally children are the victims of mass poisoning from an environmental contaminant that occurs due to an unexpected common point source of exposure. In many cases the contaminant is a widely used chemical generally considered to be safe. In the following case, members of a sports team visiting a community for an athletic event were exposed to chemicals while staying at a local motel. Bromine-based sanitizing agents and other chemicals such as hydrochloric acid, which were used in excess in the motel's swimming pool, may have accounted for symptoms experienced by the boy reported here and at least 16 other adolescents. Samples of pool water contained excess bromine (8.2 microg/mL; ideal pool bromine concentration is 2-4 microg/mL). Symptoms and signs attributable to bromine toxicity included irritative skin rashes; eye, nose, and throat irritation; bronchospasm; reduced exercise tolerance; fatigue; headache; gastrointestinal disturbances; and myalgias. While most of the victims recovered within a few days, the index case and several other adolescents had persistent or recurrent symptoms lasting weeks to months after the exposure.
Regulation of myeloproliferation and M2 macrophage programming in mice by Lyn/Hck, SHIP, and Stat5
Authors: Wenbin Xiao, Hong Hong, Yuko Kawakami, Clifford A. Lowell, Toshiaki Kawakami
Journal: Journal of Clinical Investigation (2008)

The proliferation and differentiation of hematopoietic stem cells (HSCs) is finely regulated by extrinsic and intrinsic factors via various signaling pathways. Here we have shown that, similar to mice deficient in the lipid phosphatase SHIP, loss of 2 Src family kinases, Lyn and Hck, profoundly affects HSC differentiation, producing hematopoietic progenitors with increased proliferation, reduced apoptosis, growth factor-independent survival, and skewed differentiation toward M2 macrophages. This phenotype culminates in a Stat5-dependent myeloproliferative disease that is accompanied by M2 macrophage infiltration of the lung. Expression of a membrane-bound form of SHIP in HSCs lacking both Lyn and Hck restored normal hematopoiesis and prevented myeloproliferation. In vitro and in vivo studies suggested the involvement of autocrine and/or paracrine production of IL-3 and GM-CSF in the increased proliferation and myeloid differentiation of HSCs. Thus, this study has defined a myeloproliferative transformation-sensitive signaling pathway, composed of Lyn/Hck, SHIP, autocrine/paracrine cytokines, and Stat5, that regulates HSC differentiation and M2 macrophage programming.
Case-Mix Adjustment: Making Bad Apples Look Good
Authors: H. G. Welch, W. C. Black, E. S. Fisher
Journal: JAMA (1995)

<h3>To the Editor.</h3> —Dr Salem-Schatz and colleagues have done admirable work investigating the influence of case-mix adjustment on physician profiles.<sup>1</sup>Readers should be aware, however, that case-mix adjustment may make bad apples look good. It is important to step back and consider the rationale for adjusting physician profiles in general. Adjustment is a mechanism to control for factors that confound the relationship between physician and practice style. Ideally, the intent is to remove the effect of exogenous factors (ie, those in which the physician has no influence). Age and sex adjustment serves as the classic example. On the other hand, it is important not to adjust away endogenous factors (ie, those that the physician can influence). For example, it would be silly to adjust physician profiles for physician income. In the private sector, at least, one would be adjusting for a factor that is strongly related to what one
A polymorphic microsatellite in the tumor necrosis factor alpha promoter identifies an allele unique to the NZW mouse strain.
Authors: C V Jongeneel, H Acha-Orbea, T Blankenstein
Journal: The Journal of Experimental Medicine (1990)

We have amplified a (CA)n:(GT)n microsatellite from the TNF promoters of a panel of mouse strains using the polymerase chain reaction. The length of the microsatellites was polymorphic, with eight alleles observed among 15 inbred strains bearing seven distinct H-2 haplotypes, and four outbred strains. In B10 congenic strains, the TNF allele detected by microsatellite polymorphism segregated with the MHC, and in recombinant haplotypes (NOD, NZW), it segregated with H-2D. The TNF allele found in the NZW strain (H-2z) was distinct from those of all other haplotypes, consistent with the hypothesis that this strain may carry a genetic defect in TNF production.
Targeted Ablation of Par-4 Reveals a Cell Type–Specific Susceptibility to Apoptosis-Inducing Agents
Authors: El Bachir Affar, Margaret Po-shan Luke, Frédérique Gay, Dominica Calvo, Guangchao Sui, Robert S. Weiss, En Li, Yang Shi
Journal: Cancer Research (2006)

Abstract The prostate apoptosis response-4 (Par-4) protein has been shown to function as an effector of cell death in response to various apoptotic stimuli, and down-regulation of this protein has been suggested to be a key event during tumorigenesis. Several studies suggest an essential function for the COOH-terminal leucine repeats/death domain of Par-4 in mediating apoptosis. We investigated the biological role of this domain in vivo by generating knock-out mice expressing a Par-4 mutant protein lacking the COOH terminus domain. We found that the Par-4 mutant mice are viable and fertile with no overt phenotype, thus excluding an essential role for the COOH terminus domain of Par-4 in embryogenesis and developmental apoptosis. To determine the requirement of Par-4 for apoptosis, we treated primary fibroblasts with various stimuli that trigger mitochondria and membrane receptor cell death pathways. Fibroblasts isolated from Par-4 mutant mice are as sensitive as the wild-type cells to these apoptosis-inducing agents. Similar effects were observed following RNA interference (RNAi)–mediated knockdown of Par-4 in these cells. In contrast, RNAi-mediated depletion of Par-4 in HeLa cells resulted in a significant inhibition of apoptosis induced by various proapoptotic agents. Taken together, our findings provide strong genetic evidence that the proapoptotic function of Par-4 is dependent on the cellular context and raise the possibility that alterations of Par-4 function may occur during carcinogenesis. (Cancer Res 2006; 66(7): 3456-62)
Trends in the prevalence of asthma and allergic rhinitis in Italy between 1991 and 2010
Authors: R. de Marco, V. Cappa, S. Accordini, M. Rava, L. Antonicelli, O. Bortolami, M. Braggion, M. Bugiani, L. Casali, L. Cazzoletti, I. Cerveri, A.G. Fois, P. Girardi, F. Locatelli, A. Marcon, A. Marinoni, M.G. Panico, P. Pirina, S. Villani, M.E. Zanolin, G. Verlato
Journal: European Respiratory Journal (2011)

The prevalence of asthma increased worldwide until the 1990s, but since then there has been no clear temporal pattern. The present study aimed to assess time trends in the prevalence of current asthma, asthma-like symptoms and allergic rhinitis in Italian adults from 1990 to 2010. The same screening questionnaire was administered by mail or phone to random samples of the general population (age 20–44 yrs) in Italy, in the frame of three multicentre studies: the European Community Respiratory Health Survey (ECRHS) (1991–1993; n=6,031); the Italian Study on Asthma in Young Adults (ISAYA) (1998–2000; n=18,873); and the Gene Environment Interactions in Respiratory Diseases (GEIRD) study (2007–2010; n=10,494). Time trends in prevalence were estimated using Poisson regression models in the centres that repeated the survey at different points in time. From 1991 to 2010, the median prevalence of current asthma, wheezing and allergic rhinitis increased from 4.1% to 6.6%, from 10.1% to 13.9% and from 16.8% to 25.8%, respectively. The prevalence of current asthma was stable during the 1990s and increased (relative risk 1.38, 95% CI 1.19–1.59) from 1998–2000 to 2007–2010, mainly in subjects who did not report allergic rhinitis. The prevalence of allergic rhinitis has increased continuously since 1991. The asthma epidemic is not over in Italy. During the past 20 yrs, asthma prevalence has increased by 38%, in parallel with a similar increase in asthma-like symptoms and allergic rhinitis.
Continuous Positive Airway Pressure for Treatment of Postoperative Hypoxemia
Authors: Vincenzo Squadrone, Massimiliano Coha, Elisabetta Cerutti, Maria Maddalena Schellino, Piera Biolino, Paolo Occella, Giuseppe Belloni, Giuseppe Vilianis, Gilberto Fiore, Franco Cavallo, V. Marco Ranieri, for the Piedmont Intensive Care Units Network (PICUN)
Journal: JAMA (2005)

Hypoxemia complicates the recovery of 30% to 50% of patients after abdominal surgery; endotracheal intubation and mechanical ventilation may be required in 8% to 10% of cases, increasing morbidity and mortality and prolonging intensive care unit and hospital stay.To determine the effectiveness of continuous positive airway pressure compared with standard treatment in preventing the need for intubation and mechanical ventilation in patients who develop acute hypoxemia after elective major abdominal surgery.Randomized, controlled, unblinded study with concealed allocation conducted between June 2002 and November 2003 at 15 intensive care units of the Piedmont Intensive Care Units Network in Italy.Consecutive patients who developed severe hypoxemia after major elective abdominal surgery. The trial was stopped for efficacy after 209 patients had been enrolled.Patients were randomly assigned to receive oxygen (n = 104) or oxygen plus continuous positive airway pressure (n = 105).The primary end point was incidence of endotracheal intubation; secondary end points were intensive care unit and hospital lengths of stay, incidence of pneumonia, infection and sepsis, and hospital mortality.Patients who received oxygen plus continuous positive airway pressure had a lower intubation rate (1% vs 10%; P = .005; relative risk [RR], 0.099; 95% confidence interval [CI], 0.01-0.76) and had a lower occurrence rate of pneumonia (2% vs 10%, RR, 0.19; 95% CI, 0.04-0.88; P = .02), infection (3% vs 10%, RR, 0.27; 95% CI, 0.07-0.94; P = .03), and sepsis (2% vs 9%; RR, 0.22; 95% CI, 0.04-0.99; P = .03) than did patients treated with oxygen alone. Patients who received oxygen plus continuous positive airway pressure also spent fewer mean (SD) days in the intensive care unit (1.4 [1.6] vs 2.6 [4.2], P = .09) than patients treated with oxygen alone. The treatments did not affect the mean (SD) days that patients spent in the hospital (15 [13] vs 17 [15], respectively; P = .10). None of those treated with oxygen plus continuous positive airway pressure died in the hospital while 3 deaths occurred among those treated with oxygen alone (P = .12).Continuous positive airway pressure may decrease the incidence of endotracheal intubation and other severe complications in patients who develop hypoxemia after elective major abdominal surgery.
Evolutionary genetic dissection of human interferons
Authors: Jérémy Manry, Guillaume Laval, Etienne Patin, Simona Fornarino, Yuval Itan, Matteo Fumagalli, Manuela Sironi, Magali Tichit, Christiane Bouchier, Jean-Laurent Casanova, Luis B. Barreiro, Lluis Quintana-Murci
Journal: The Journal of Experimental Medicine (2011)

Interferons (IFNs) are cytokines that play a key role in innate and adaptive immune responses. Despite the large number of immunological studies of these molecules, the relative contributions of the numerous IFNs to human survival remain largely unknown. Here, we evaluated the extent to which natural selection has targeted the human IFNs and their receptors, to provide insight into the mechanisms that govern host defense in the natural setting. We found that some IFN-α subtypes, such as IFN-α6, IFN-α8, IFN-α13, and IFN-α14, as well as the type II IFN-γ, have evolved under strong purifying selection, attesting to their essential and nonredundant function in immunity to infection. Conversely, selective constraints have been relaxed for other type I IFNs, particularly for IFN-α10 and IFN-ε, which have accumulated missense or nonsense mutations at high frequencies within the population, suggesting redundancy in host defense. Finally, type III IFNs display geographically restricted signatures of positive selection in European and Asian populations, indicating that genetic variation at these genes has conferred a selective advantage to the host, most likely by increasing resistance to viral infection. Our population genetic analyses show that IFNs differ widely in their biological relevance, and highlight evolutionarily important determinants of host immune responsiveness.
Protein Synthesis and Amino Acid Transport in the Isolated Rabbit Right Ventricular Papillary Muscle: EFFECT OF ISOMETRIC TENSION DEVELOPMENT
Authors: Myron B. Peterson, Michael Lesch, Alan G. Ferguson
Journal: Circulation Research (1972)

To investigate the effects of isometric tension development on myocardial protein metabolism, 14 C-phenylalanine incorporation into protein was studied in the isolated rabbit right ventricular papillary muscle. Amino acid incorporation was linear for 6 hours in resting muscles and was totally inhibited by 10 -3 M cycloheximide and 10 -3 M puromycin. Phenylalanine incorporation into total protein was unaltered by 90 minutes of isometric tension development at peak tension at stimulation rates of 30, 50, or 100/min. Significant increases were noted in muscles stimulated at 50 and 100/min for 180 minutes (P &lt; 0.01). Electrical stimulation, in the absence of isometric tension development, was not responsible for this effect. Passive stretch also appeared to stimulate incorporation, although to a lesser degree than did active tension development. The specific activities of the intracellular phenylalanine pools were identical in control and stimulated muscles. Alpha-aminoisobutyric acid was used to evaluate the effect of tension development on myocardial amino acid transport. Enhanced transport was noted in muscles stimulated isometrically at 30, 50, or 100/min at peak tension. The increased transport ratios could not be solely attributed to active tension development since passive stretch resulted in comparable changes. This study indicates that both passive stretch and tension development are important in regulating myocardial protein synthesis.
First- and Second-Line Bevacizumab in Addition to Chemotherapy for Metastatic Colorectal Cancer: A United States–Based Cost-Effectiveness Analysis
Authors: Daniel A. Goldstein, Qiushi Chen, Turgay Ayer, David H. Howard, Joseph Lipscomb, Bassel F. El-Rayes, Christopher R. Flowers
Journal: Journal of Clinical Oncology (2015)

The addition of bevacizumab to fluorouracil-based chemotherapy is a standard of care for previously untreated metastatic colorectal cancer. Continuation of bevacizumab beyond progression is an accepted standard of care based on a 1.4-month increase in median overall survival observed in a randomized trial. No United States-based cost-effectiveness modeling analyses are currently available addressing the use of bevacizumab in metastatic colorectal cancer. Our objective was to determine the cost effectiveness of bevacizumab in the first-line setting and when continued beyond progression from the perspective of US payers.
Cost-Effectiveness of Intensified Versus Conventional Multifactorial Intervention in Type 2 Diabetes
Authors: Peter Gæde, William J. Valentine, Andrew J. Palmer, Daniel M.D. Tucker, Morten Lammert, Hans-Henrik Parving, Oluf Pedersen
Journal: Diabetes Care (2008)

To assess the cost-effectiveness of intensive versus conventional therapy for 8 years as applied in the Steno-2 study in patients with type 2 diabetes and microalbuminuria.
Aortic incompetence in HLA B27-positive juvenile arthritis.
Authors: W F Kean, T P Anastassiades, P M Ford
Journal: Annals of the Rheumatic Diseases (1980)

The early onset of isolated aortic incompetence in a male child with HLA B27 and peripheral arthritis is reported. Acute anterior uveitis and lone aortic incompetence occurred at 1 and 9 months respectively after the development of the acute inflammatory arthritis. The uveitis resolved with local therapy and the arthritis remitted 10 months after the onset. There has been no recurrence of the arthritis after 10 years of close follow-up but the aortic incompetence has persisted, though it remains haemodynamically insignificant.
Long-Term Adherence to Evidence-Based Secondary Prevention Therapies in Coronary Artery Disease
Authors: L. Kristin Newby, Nancy M. Allen LaPointe, Anita Y. Chen, Judith M. Kramer, Bradley G. Hammill, Elizabeth R. DeLong, Lawrence H. Muhlbaier, Robert M. Califf
Journal: Circulation (2006)

Studies have examined the use of evidence-based therapies for coronary artery disease (CAD) in the short term and at hospital discharge, but few have evaluated long-term use.Using the Duke Databank for Cardiovascular Disease for the years 1995 to 2002, we determined the annual prevalence and consistency of self-reported use of aspirin, beta-blockers, lipid-lowering agents, and their combinations in all CAD patients and of angiotensin-converting enzyme inhibitors (ACEIs) in those with and without heart failure. Logistic-regression models identified characteristics associated with consistent use (reported on > or =2 consecutive follow-up surveys and then through death, withdrawal, or study end), and Cox proportional-hazards models explored the association of consistent use with mortality. Use of all agents and combinations thereof increased yearly. In 2002, 83% reported aspirin use; 61%, beta-blocker use; 63%, lipid-lowering therapy use; 54%, aspirin and beta-blocker use; and 39%, use of all 3. Consistent use was as follows: For aspirin, 71%; beta-blockers, 46%; lipid-lowering therapy, 44%; aspirin and beta-blockers, 36%; and all 3, 21%. Among patients without heart failure, 39% reported ACEI use in 2002; consistent use was 20%. Among heart failure patients, ACEI use was 51% in 2002 and consistent use, 39%. Except for ACEIs among patients without heart failure, consistent use was associated with lower adjusted mortality: Aspirin hazard ratio (HR), 0.58 and 95% confidence interval (CI), 0.54 to 0.62; beta-blockers, HR, 0.63 and 95% CI, 0.59 to 0.67; lipid-lowering therapy, HR, 0.52 and 95% CI, 0.42 to 0.65; all 3, HR, 0.67 and 95% CI, 0.59 to 0.77; aspirin and beta-blockers, HR, 0.61 and 95% CI, 0.57 to 0.65; and ACEIs among heart failure patients, HR, 0.75 and 95% CI, 0.67 to 0.84.Use of evidence-based therapies for CAD has improved but remains suboptimal. Although improved discharge prescription of these agents is needed, considerable attention must also be focused on understanding and improving long-term adherence.
Modulation of eicosanoid and histamine release from human dispersed lung cells by terfenadine
Authors: A. M. Campbell, P. Chanez, C. Marty‐Ané, B. Albat, M. Bloom, F. B. Michel, P. Godard, J. Bousquet
Journal: Allergy (1993)

Terfenadine is an H1-blocker that may have antiallergic properties. A study was carried out to examine the ability of terfenadine to inhibit the release of histamine and arachidonic-acid-derived mediators from human lung cells. Cells were dispersed from fresh human lung tissue obtained from four accident victims whose hearts were donated for transplantation and four lung cancer resections. Cells were dispersed by enzymatic digestion with type XIV protease and chymopapain, and this resulted in a cell population containing approximately 5% mast cells. The remaining cells were mainly macrophages. The cells were challenged with anti-IgE at a 1/1000 dilution. Cells were challenged without terfenadine and after a preincubation of 0.1, 1, and 10 mumol terfenadine. The release of PGD2 and LTC4/D4 was assessed with an EIA. Histamine was assayed by RIA with a monoclonal antibody against acylated histamine. A release of both eicosanoids and histamine was observed in all experiments. An inhibition of eicosanoids was observed at both 1 and 10 mumol terfenadine (median percentage of inhibition of PGD2: 38.00 +/- 15.65 and 56.00 +/- 13.12; median percentage of inhibition of LTC4/D4: 37.5 +/- 19.80 and 52.5 +/- 26.8). On the other hand, histamine release was not blocked by terfenadine. Terfenadine inhibits, in a dose-dependent manner, the release of eicosanoids after challenge of dispersed lung cells by anti-IgE, and this effect may have some clinical relevance.
PHARMACOLOGIC ENHANCEMENT OF WOUND HEALING
Authors: Glenn F. Pierce, Ph.D., M.D, Thomas A. Mustoe, M.D
Journal: Annual Review of Medicine (1995)

▪ Abstract The field of pharmacologic modulation of soft tissue repair is in its infancy. Although the soluble, cellular, and insoluble mediators that govern repair have not been elucidated, the application of pharmacologic concentrations of purified polypeptide growth factors, cytokines, and matrix molecules has nonetheless resulted in the acceleration of normal repair and the reversal of deficient repair in a wide variety of dermal wound models in animals. However, early clinical results using these factors have been less than encouraging, and their potential roles in the armamentarium of chronic wound therapies remain to be established.
PEGylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu-sTNF-RI): novel high affinity TNF receptor designed for chronic inflammatory diseases
Authors: C. K Edwards
Journal: Annals of the Rheumatic Diseases (1999)

The proinflammatory cytokine, tumour necrosis factor alpha (TNFalpha) has been shown to play a pivotal part in mediating acute and chronic inflammation. The activities of TNFalpha are modulated by the proteolytic shedding of the soluble extracellular domains of the two TNF receptors, p55 sTNF-RI and p75 sTNF-RII. Amgen Inc has cloned and expressed a recombinant form of a natural inhibitor of TNFalpha, referred to as recombinant human soluble TNF receptor type I (r-Hu-sTNF-RI, sTNF-RI). sTNF-RI is an E coli recombinant, monomeric form of the soluble TNF-type I receptor. A high molecular weight polyethylene glycol (PEG) molecule is attached at the N-terminus position to form the molecule intended for clinical evaluations (PEG sTNF-RI). Preclinical studies to date demonstrate that PEG sTNF-RI is efficacious in rodent models of chronic inflammatory disease including rheumatoid arthritis and Crohn's disease at doses as low as 0.3 mg/kg given every other day. This dose results in plasma concentrations of 0.3 to 0.5 microg/ml. Higher doses with correspondingly higher plasma concentrations yield higher efficacy. It has also demonstrated efficacy in E coli lipopolysaccharide, and Staphylococcus enterotoxin B mediated models of acute inflammation in rodents and primates. Pharmacokinetic studies in mice, rats, cynomolgus monkeys, baboons, and chimpanzees have been conducted with PEG sTNF-RI. Absorption from a subcutaneous dose was slow, with the time to reach maximal plasma concentrations of 24-48 hours in rats, and in monkeys, and 3-29 hours in chimpanzees. The initial volume of distribution of PEG sTNF-RI was essentially equivalent to that of plasma (40 ml/kg). This suggests the protein does not appear to extensively distribute from the systemic circulation with a volume of distribution at steady state (Vss) less than 200 ml/kg in all species studied. These results are consistent with previous experience with PEGylated proteins in which PEGylation decreases both the rate of absorption and the plasma clearance of human recombinant proteins in animals and humans. The use of a PEG molecule will probably provide a more advantageous dosing schedule (that is, less frequent dosing) for the patient compared with a non-PEG sTNF-RI.