tbuckley/cabot-search huggingface dataset:
Respiratory Response to CO<sub>2</sub> during Pressure-support Ventilation in Conscious Normal Humans
Authors: DIMITRIS GEORGOPOULOS, IOANNA MITROUSKA, ZOHEIR BSHOUTY, KIMBERLY WEBSTER, DIMITRIS PATAKAS, MAGDY YOUNES
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The respiratory response to CO2 during pressure-support ventilation (PSV) was studied in 16 conscious normal humans. The subjects breathed through a mouthpiece connected to a ventilator in PSV mode, with pressure set to the highest comfortable level for each subject (10.1 +/- 0.6 cm H2O, mean +/- SE). Compared with breathing spontaneously through the ventilator (CPAP mode with zero positive end-expiratory pressure), with PSV, tidal volume (VT) increased significantly (1.16 +/- 0.1 versus 0.85 +/- 0.04 L), whereas breathing frequency (f) remained stable (16.0 +/- 0.9 versus 15.6 +/- 1.1 breaths/min). As a result, the subjects hyperventilated, decreasing significantly end-tidal PCO2 (PETCO2, 23.5 +/- 1.2 versus 35.5 +/- 1.1 mm Hg). Fraction of inspired CO2 (FICO2) was then increased in steps, and changes in respiratory motor output were quantitated from changes in f, VT, ventilation (VI), peak inspiratory flow (Vpeak), and muscle pressure (Pmus). Pmus was calculated by the equation of motion, based on respiratory system mechanics, which were measured previously by airway occlusion at end-inspiration, VT, VI, and Pmus increased significantly with increasing PETCO2, and the response was detectable even below eupneic levels; f remained relatively stable over a wide range of PETCO2 (23 to 45 mm Hg) and increase significantly only when PETCO2 approached 50 mm Hg. These results indicate that in conscious normal humans during PSV, CO2 responsiveness extends well into hypocapnia and is expressed principally as an increase in intensity of respiratory motor output with little change in respiratory rate.
Islet cell autoantigens in insulin-dependent diabetes.
Authors: M A Atkinson, N K Maclaren
Journal: Journal of Clinical Investigation (1993)

A burgeoning number of antigenic targets of the islet cell autoimmunity in IDD have been identified, and more can be anticipated through improved methods for their identification. The challenge for those investigating the pathogenesis of IDD will be to assign the relative importance of these antigens to the development of the disease, and to resolve whether there is a dominant primary immunologic event that is followed by a series of secondary immunizations to a variety of normally sequestered islet cell antigens in the sequence of pathogenic events that culminate in IDD. One interesting observation that may have potential pathogenic implications is the observation that of all islet cell autoantigens described, only two (i.e., 64 kD/GAD, 38 kD) are reactive in their native configurations, implying that recognition of conformational epitopes is most important. This property argues for primary immunizing agents rather than secondary ones after release of denatured antigens and antigenic recognition through their epitopes. Given the complex and multiple physiological functions of islet cells and the continuous variation in their activity, it is reasonable to speculate that the speed of the progression to IDD could vary between individuals with respect to their insulin needs and the relative activities of their islets. Activated islets may express autoantigens that have only limited expression in quiescent islets. The often times striking variation in the severity of insulitis seen in different islets of a single pancreas may be explained by the level of activity of individual islets. Furthermore, disparity in HLA-DR/DQ associations with disease may involve differences in the immunological recognition of autoantigens. Whereas there is still much to learn, it is clear that disease predictability and disease intervention studies have been enhanced through the identification of the islet cell autoantigens in IDD.
Association of interleukin 18 (IL18) polymorphisms with specific IgE levels to mite allergens among asthmatic patients
Authors: H. D. Shin, L. H. Kim, B. L. Park, Y. H. Choi, H.‐S. Park, S.‐J. Hong, B. W. Choi, J. H. Lee, C.‐S. Park
Journal: Allergy (2005)

Background: Allergy is regarded as a multifactorial condition. Its onset and severity are influenced by both genetic and environmental factors. Identification of genetic factors involved in asthma development and related phenotypes is a major task in understanding the genetic background of asthma. The possible involvement of IL18 polymorphisms in asthma was examined in a Korean asthma cohort. Methods: Direct sequencing was performed to discover single‐nucleotide polymorphisms (SNPs) in the IL18 gene. Single‐base extension (SBE) method was employed for genotyping. Genotypic influence of IL18 was analysed using logistic and multiple‐regression models. Results: Although no polymorphisms in the IL18 gene showed significant association with the risk of asthma development, analyses of the association with specific serum IgE levels to Dermatophagoides farinae (D.f.) and D. pteronyssinus (D.p.) among asthmatic patients revealed significant associations with two completely linked SNPs, i.e. −148G&gt;C and +13925A&gt;C(Ser35Ser) ( P = 0.01–0.11 for D.f. and P = 0.005–0.11 for D.p.). Both C allele of −148G&gt;C and C allele of +13925A&gt;C showed gene dose‐dependent effects on the levels of specific IgE. The lowest IgE levels in homozygotes of minor alleles (1.13 and 1.22 of D.f.; 1.38 and 1.33 of D.p., respectively), intermediate IgE levels in heterozygotes (1.60 and 1.70 of D.f.; 1.84 and 1.92 of D.p., respectively), and the highest levels in homozygotes for major allele (1.93 and 1.93 of D.f.; 2.24 and 2.24 of D.p., respectively), were found. Conclusion: The genetic relevance of IL18 to specific IgE might offer an important step in understanding the genetic background of allergic diseases.
Attitudes of European physicians, nurses, patients, and families regarding end-of-life decisions: the ETHICATT study
Authors: Charles L. Sprung, Sara Carmel, Peter Sjokvist, Mario Baras, Simon L. Cohen, Paulo Maia, Albertus Beishuizen, Daniel Nalos, Ivan Novak, Mia Svantesson, Julie Benbenishty, Beverly Henderson
Journal: Intensive Care Medicine (2006)
Contrasting effects of hypoglycemia on plasma renin activity and cyclic adenosine 3',5'-monophosphate (cyclic AMP) in low renin and normal renin essential hypertension.
Authors: S C Lowder, P Hamet, G W Liddle
Journal: Circulation Research (1976)

Insulin-induced hypoglycemia previously has been shown to provoke a beta-adrenergic response that normally results in an increase in plasma renin activity (PRA). In our study, hypoglycemia induced definite increases in PRA in a group of five patients with normal renin essential hypertension but failed to do so in a group of six patients with low renin essential hypertension. In both groups, plasma cyclic adenosine 3',5'-monophosphate (cyclic AMP; cAMP) increased more than 2-fold during hypoglycemia, but the response in the low renin group was significantly less than that previously observed in normal subjects under the same conditions. Plasma cortisol increased to an equal extent in both groups of hypertensive patients during hypoglycemia. Infusion of the phosphodiesterase inhibitor, theophylline, resulted in definite increases of PRA in patients with normal renin hypertension but not in patients with low renin hypertension. Because changes in the level of plasma cAMP during hypoglycemia have been thought to reflect adrenal catecholamine release, our finding of a blunted increase in plasma cAMP during hypoglycemia in patients with low renin hypertension may suggest that there is a generalized alteration in adrenergic responsiveness in this condition.
TRANSIENT GRANULOCYTOPENIA ASSOCIATED WITH ADMINISTRATION OF A NEW THIORIDAZINE DERIVATIVE: TPS-23
Authors: D. M. GALLANT, M. P. BISHOP
Journal: American Journal of Psychiatry (1965)

A case of transient granulocytopenia is reported during the seventh week of administration of TPS-23, a thioridazine derivative, in a patient who had received no medication for 59 days prior to the initiation of this new psychopharmacologic compound. However, the one occurrence of this serious toxic effect should not deter further evaluation of this compound which has obvious anti-psychotic and anti-depressant activity(1), unless additional evidence by other investigators reveals that the incidence of agranulocytosis is significantly greater with TPS-23 than it is with other phenothiazines.
Nomenclature for Mononucleosis Syndromes
Authors: M. Colin Jordan
Journal: JAMA (1975)

INFECTIOUS mononucleosis has fascinated clinicians, epidemiologists, and laboratory investigators for many years. Although the typical case is easily recognized, unusual manifestations or serious complications occur frequently enough to pose problems in diagnosis and management. For this reason, students of the disease have insisted that certain criteria be fulfilled before the term "infectious mononucleosis" is used in a given case. General agreement on the characteristic clinical and hematologic findings has prevailed, but controversy concerning the importance of the serum heterophil agglutination test continues.<sup>1-3</sup>On one side, many authors have referred to cases of apparent mononucleosis that lack the heterophil agglutinin as examples of "heterophil antibody-negative mononucleosis." Others have criticized this practice, reserving the term "infectious mononucleosis" for patients whose illness fulfills the "diagnostic triad" of clinical, hematologic, and serologic (positive heterophil-antibody) findings.<sup>1-3</sup>In light of recent information on the etiology of mononucleosis syndromes, these arguments are no longer necessary.
Cholestatic Interleukin-6–Deficient Mice Succumb to Endotoxin-induced Liver Injury and Pulmonary Inflammation
Authors: Miguel E. Sewnath, Tom van der Poll, Cornelis J. F. van Noorden, Fiebo J. W. ten Kate, Dirk J. Gouma
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Circulating and hepatic interleukin (IL)-6 levels are strongly increased during clinical and experimental cholestasis. Cholestatic liver injury is associated with increased susceptibility to endotoxin-induced toxicity. To determine the role of IL-6 herein, extrahepatic cholestasis was induced by bile duct ligation (BDL) in IL-6-gene deficient (IL-6−/−) and normal (IL-6+/+) mice. BDL elicited increased levels of hepatic IL-6 mRNA and protein in normal mice. Hepatocellular injury 2 weeks after BDL was similar in IL-6−/− and IL-6+/+ mice as demonstrated by clinical chemistry and histopathology. Administration of endotoxin to cholestatic mice 2 weeks after BDL was associated with enhanced cytokine release, severe liver damage, and death when compared with sham-operated mice. Effects of endotoxin were largely similar in sham-operated IL-6−/− and IL-6+/+ mice, but cholestatic IL-6−/− mice were more susceptible to the toxic effects of endotoxin, as reflected by increased cytokine release, more profound liver injury and lung inflammation, and higher mortality. Although endogenous IL-6 is not important in the development of liver injury after experimentally induced obstructive jaundice, this cytokine plays an important role in decreasing hypersensitivity to endotoxin in cholestatic mice.
Daytime Pulmonary Hemodynamics in Patients with Obstructive Sleep Apnea without Lung Disease
Authors: DIMITAR SAJKOV, TINGTING WANG, NICHOLAS A. SAUNDERS, ALEXANDRA J. BUNE, ALISTER M. NEILL, R. DOUGLAS McEVOY
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

It is controversial whether obstructive sleep apnea (OSA) causes pulmonary hypertension (PH) in the absence of hypoxemic lung disease. To investigate this further we measured awake pulmonary hemodynamics, pulmonary gas exchange, and small airways function in 32 patients with OSA (apnea- hypopnea index, mean ± SE, 46.2 ± 3.9/h) who had normal screening lung function. Pulmonary artery pressure (Ppa) and cardiac output were measured by Doppler echocardiography at three levels of inspired oxygen (Fi O2 0.50, 0.21, and 0.11) and during incremental increases in pulmonary blood flow (10, 20, and 30 μ g/kg/min dobutamine infusions) while breathing 50% oxygen. Eleven patients had PH (mean Ppa ⩾ 20 mm Hg, Group I). They did not differ from patients without PH (Group II) in lung function, severity of sleep-disordered breathing, age, or body mass. Compared with Group II, Group I patients had increased small airways closure during tidal breathing (FRC-closing capacity: Group I, − 0.16 ± 0.11; Group II, 0.27 ± 0.09 L; p < 0.05), more ventilation-perfusion inequality (aaPo 2: 23.8 ± 2.8; 19.8 ± 1.4 mm Hg; p = 0.08), a greater pulmonary artery pressor response to hypoxia ( Δ Ppa Fi O2 , 0.50 to 0.11: 16.4 ± 1.93; 6.4 ± 0.77 mm Hg; p < 0.05) and a marked rise in Ppa during increased pulmonary blood flow. We conclude that PH may develop in some patients with OSA without lung disease and that it is associated with small airways closure during tidal breathing and heightened pulmonary pressor responses to hypoxia and during increased pulmonary blood flow. Such changes are consistent with remodeling of the pulmonary vascular bed in affected patients with OSA, seemingly unrelated to severity of sleep-disordered breathing.
The Nature of Genetic Influences on Behavior: Lessons From “Simpler” Organisms
Authors: Kenneth S. Kendler, Ralph J. Greenspan
Journal: American Journal of Psychiatry (2006)

Substantial advances have been made in recent years in the understanding of the genetic basis of behavior in "simpler" organisms, especially the mouse and the fruit fly Drosophila . The authors examine the degree of similarity between the genetic underpinnings of psychiatric illness and genetic influences on behavior in such simpler organisms. Six topics are reviewed: 1) the extent of natural genetic variation, 2) the multigenic nature of natural variation, 3) the impact of individual genes on multiple traits, 4) gene-environment interactions, 5) genetic effects on the environment, and 6) gene-by-sex interactions. The results suggest that the pattern of results emerging in psychiatric genetics is generally consistent with the findings of behavioral genetics in simpler organisms. Across the animal kingdom, individual differences in behavior are nearly always influenced by genetic factors which, in turn, result from a substantial number of individual genes, each with a small effect. Nearly all genes that affect behavior influence multiple phenotypes. The impact of individual genes can be substantially modified by other genes and/or by environmental experiences. Many animals alter their environment, and the nature of that alteration is influenced by genes. For some behaviors, the pathway from genes to behavior differs meaningfully in males and females. With respect to the broad patterns of genetic influences on behavior, Homo sapiens appears to be typical of other animal species.
Prognostic Value of Myeloperoxidase in Patients with Chest Pain
Authors: Marie-Luise Brennan, Marc S. Penn, Frederick Van Lente, Vijay Nambi, Mehdi H. Shishehbor, Ronnier J. Aviles, Marlene Goormastic, Michael L. Pepoy, Ellen S. McErlean, Eric J. Topol, Steven E. Nissen, Stanley L. Hazen
Journal: New England Journal of Medicine (2003)

Inflammation is linked to adverse outcomes in acute coronary syndromes. Myeloperoxidase, an abundant leukocyte enzyme, is elevated in culprit lesions that have fissured or ruptured in patients with sudden death from cardiac causes. Numerous lines of evidence suggest mechanistic links between myeloperoxidase and both inflammation and cardiovascular disease.
An Aberrant Leukotriene A<sub>4</sub> Hydrolase–Proline-Glycine-Proline Pathway in the Pathogenesis of Chronic Obstructive Pulmonary Disease
Authors: J. Michael Wells, Philip J. O’Reilly, Tomasz Szul, Daniel I. Sullivan, Guy Handley, Chris Garrett, Carmel M. McNicholas, Mojtaba Abdul Roda, Bruce E. Miller, Ruth Tal-Singer, Amit Gaggar, Stephen I. Rennard, Patricia L. Jackson, J. Edwin Blalock
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Chronic neutrophilic inflammation is a hallmark in the pathogenesis of chronic obstructive pulmonary disease (COPD) and persists after cigarette smoking has stopped. Mechanisms involved in this ongoing inflammatory response have not been delineated.We investigated changes to the leukotriene A4 hydrolase (LTA4H)-proline-glycine-proline (PGP) pathway and chronic inflammation in the development of COPD.A/J mice were exposed to air or cigarette smoke for 22 weeks followed by bronchoalveolar lavage and lung and cardiac tissue analysis. Two human cohorts were used to analyze changes to the LTA4H-PGP pathway in never smokers, control smokers, COPD smokers, and COPD former smokers. PGP/AcPGP and LTA4H aminopeptidase activity were detected by mass spectroscopy, LTA4H amounts were detected by ELISA, and acrolein was detected by Western blot.Mice exposed to cigarette smoke developed emphysema with increased PGP, neutrophilic inflammation, and selective inhibition of LTA4H aminopeptidase, which ordinarily degrades PGP. We recapitulated these findings in smokers with and without COPD. PGP and AcPGP are closely associated with cigarette smoke use. Once chronic inflammation is established, changes to LTA4H aminopeptidase remain, even in the absence of ongoing cigarette use. Acrolein modifies LTA4H and inhibits aminopeptidase activity to the same extent as cigarette smoke.These results demonstrate a novel pathway of aberrant regulation of PGP/AcPGP, suggesting this inflammatory pathway may be intimately involved in disease progression in the absence of ongoing cigarette smoke exposure. We highlight a mechanism by which acrolein potentiates neutrophilic inflammation through selective inhibition of LTA4H aminopeptidase activity. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).
High magnesium improves the postischaemic recovery of cardiac function
Authors: P. Jynge, G. Falck
Journal: Cardiovascular Research (1995)

Journal Article High magnesium improves the postischaemic recovery of cardiac function Get access Per Jynge, Per Jynge * Department of Pharmacology and Toxicology, University of Trondheim, Medisinsk Teknisk Senter, N-7005 Trondheim, Norway *Correspondence to Professor Jynge. Search for other works by this author on: Oxford Academic PubMed Google Scholar Geir Falck Geir Falck Department of Pharmacology and Toxicology, University of Trondheim, Medisinsk Teknisk Senter, N-7005 Trondheim, Norway Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 29, Issue 3, March 1995, Page 439, https://doi.org/10.1016/S0008-6363(96)88604-4 Published: 01 March 1995
Genetically Targeted T Cells Eradicate Systemic Acute Lymphoblastic Leukemia Xenografts
Authors: Renier J. Brentjens, Elmer Santos, Yan Nikhamin, Raymond Yeh, Maiko Matsushita, Krista La Perle, Alfonso Quintás-Cardama, Steven M. Larson, Michel Sadelain
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Human T cells targeted to the B cell–specific CD19 antigen through retroviral-mediated transfer of a chimeric antigen receptor (CAR), termed 19z1, have shown significant but partial in vivo antitumor efficacy in a severe combined immunodeficient (SCID)-Beige systemic human acute lymphoblastic leukemia (NALM-6) tumor model. Here, we investigate the etiologies of treatment failure in this model and design approaches to enhance the efficacy of this adoptive strategy. Experimental Design: A panel of modified CD19-targeted CARs designed to deliver combined activating and costimulatory signals to the T cell was generated and tested in vitro to identify an optimal second-generation CAR. Antitumor efficacy of T cells expressing this optimal costimulatory CAR, 19-28z, was analyzed in mice bearing systemic costimulatory ligand-deficient NALM-6 tumors. Results: Expression of the 19-28z CAR, containing the signaling domain of the CD28 receptor, enhanced systemic T-cell antitumor activity when compared with 19z1 in treated mice. A treatment schedule of 4 weekly T-cell injections, designed to prolong in vivo T-cell function, further improved long-term survival. Bioluminescent imaging of tumor in treated mice failed to identify a conserved site of tumor relapse, consistent with successful homing by tumor-specific T cells to systemic sites of tumor involvement. Conclusions: Both in vivo costimulation and repeated administration enhance eradication of systemic tumor by genetically targeted T cells. The finding that modifications in CAR design as well as T-cell dosing allowed for the complete eradication of systemic disease affects the design of clinical trials using this treatment strategy.
Interleukin 2 high-affinity receptor expression requires two distinct binding proteins.
Authors: K Teshigawara, H M Wang, K Kato, K A Smith
Journal: The Journal of Experimental Medicine (1987)

A cell line established from a patient with acute lymphoblastic leukemia was found to express IL-2 binding sites with a novel, intermediate affinity compared with the characteristic high-affinity IL-2-receptors and low-affinity IL-2 binding sites described previously. Clones were isolated from this cell line that displayed solely this new IL-2-binding protein, and were found to be unreactive with anti-Tac, the mAb that competes with IL-2 for binding. Moreover, these same cloned cells did not express mRNA detectable by hybridization with radiolabeled cDNA encoding the Tac protein. In contrast, the original cell line and similar clones expressed low levels of Tac mRNA and cell surface Tac antigen, both of which could be augmented by exposure to medium conditioned by adult T leukemia cell lines. Particularly noteworthy, induction of Tac antigen expression was paralleled by an increase in the number of high-affinity IL-2-R detectable. Since the expression of the Tac antigen protein by itself makes only for low-affinity IL-2 binding, these data prompted a reevaluation of the structural composition of high-affinity IL-2-R. Analysis of the IL-2-binding proteins expressed by leukemic cell lines lacking high-affinity receptors revealed only a single protein, larger than the Tac antigen protein (Mr = 75,000 vs. 55,000). In contrast, clones induced to express high-affinity receptors had clearly both of these IL-2-binding proteins. Moreover, when IL-2 binding to normal T cells was performed under conditions that favored the proportion of high-affinity receptors occupied, two distinct proteins identical to those already identified on the leukemic cells could be crosslinked covalently to radiolabeled IL-2. The interpretations derived from these varied, assembled data, point to two IL-2-binding proteins, both of which are required for high-affinity IL-2 binding.