tbuckley/cabot-search huggingface dataset:
Series Introduction: Intrinsic and innate defenses in the lung: intersection of pathways regulating lung morphogenesis, host defense, and repair
Authors: Jeffrey A. Whitsett
Journal: Journal of Clinical Investigation (2002)

This Perspective series seeks to summarize the present concepts regarding the biological processes that mediate intrinsic and innate host defense against microbial invasion of the lung. From an evolutionary standpoint, the requirements for an extensive gas exchange region that comes in direct contact with inhaled particles and pathogens present a formidable challenge that has been countered by the layering and intersection of several intrinsic defense systems.

These systems, detailed in the accompanying articles, maintain pulmonary form and function required for ventilation by means of structural, mechanical, chemical, and cellular strategies, as well as innate and acquired host defenses. The epithelial barrier itself represents a first line of defense against pathogens, and its effectiveness is greatly enhanced by fluid homeostasis and mucociliary clearance. As discussed by Knowles and Boucher in this series, these mechanisms protect the epithelium and physically remove inhaled pathogens from the lung. Additional protection comes from polypeptide mediators of the innate host defense, such as the defensins and other antibiotic peptides reviewed by Ganz in this series, and the collectin family, considered by McCormack and Whitsett. Professional phagocytes also play their part in host defense in this tissue, in part by responding to molecules found on the surface of common pathogenic microbes. Finally, the cytokine and chemokine pathways that cooperate with host defense polypeptides to mediate initial host defenses by phagocytes also orchestrate tissue repair and subsequent acquired immune responses following infection, as discussed by Strieter et al. The interplay of these various mechanisms is depicted in Figure ​Figure11.



Figure 1

The sterility of the respiratory tract is maintained by the concerted actions of the epithelial barrier, innate defense molecules, and responses of both the epithelium and professional phagocytes that remove pathogens and their products from the lung. ...



The concerted effects of mechanical, innate, and acquired host defense systems serve to recognize, localize, kill, and remove pathogens to maintain sterility of pulmonary tissues and the host. In general, pathogens are cleared from the lung without persistent or robust inflammation, thus protecting its inherent structure and maintaining its function following exposure to microbes. It is the failure of various arms of the host defense systems that allows local or systemic infection and destruction of lung tissue that are frequently the basis of morbidity and mortality from common lung diseases, whether related to genetic or environmental disease processes. Deficient or uncontrolled host defenses and inflammation underlie some of the most common pulmonary disorders — chronic obstructive pulmonary disease, cystic fibrosis, acute and chronic pneumonia, asthma, emphysema, and bronchopulmonary dysplasia.
Prevention of Progression in Monoclonal Gammopathy of Undetermined Significance
Authors: S. Vincent Rajkumar
Journal: Clinical Cancer Research (2009)

Monoclonal gammopathy of undetermined significance (MGUS) is a common premalignant plasma cell proliferative disorder with a lifelong risk of progression to multiple myeloma. Because myeloma is an incurable malignancy, strategies to delay or prevent progression in high-risk patients are of considerable importance.
Defect of Hepatocyte Growth Factor Secretion by Fibroblasts in Idiopathic Pulmonary Fibrosis
Authors: Sylvain Marchand-Adam, Joëlle Marchal, Murielle Cohen, Paul Soler, Bénédicte Gerard, Yves Castier, Guy Lesèche, Dominique Valeyre, Hervé Mal, Michel Aubier, Monique Dehoux, Bruno Crestani
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Hepatocyte growth factor (HGF) is a growth factor that protects alveolar epithelial cells from pulmonary fibrosis in various animal models. We compared in vitro HGF production by human lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF, n = 8) and from control subjects (n = 6). Basal HGF secretion by IPF fibroblasts was decreased by 50% when compared with control fibroblasts (p < 0.05). HGF was secreted mainly in the cleaved mature form, both in IPF and control fibroblasts. HGF messenger RNA levels were reduced in IPF fibroblasts. Prostaglandin (PG) E2 secretion by IPF fibroblasts was low when compared with control subjects (p < 0.05). After the addition of PGE2 (10−6 M) or dibutyryl cyclic AMP (10−3 M), HGF secretion by IPF fibroblasts reached the level of control subjects. Inhibition of PGE2 synthesis with indomethacin reduced HGF secretion by control fibroblasts but had no effect on IPF fibroblasts. HGF secretion by control fibroblasts was also slightly inhibited by transforming growth factor (TGF)-β1 and stimulated by anti–TGF-β antibody, whereas both agents had no effect on IPF fibroblasts. Our results demonstrate a defect in HGF production by IPF fibroblasts that seems secondary to a defect in PGE2 secretion.
Comment re: Ran-GTP Control of Tumor Cell Mitosis
Authors: Maria Paola Simula, Maria Dolores Marin, Laura Caggiari, Valli De Re, Renato Cannizzaro, Vincenzo Canzonieri
Journal: Cancer Research (2009)

In Response: 

In a recent work, Xia and colleagues ( [1][1]) found that the small GTPase Ran is broadly overexpressed in cancer. In accordance with the emerging evidence that the Ran-GTP signaling pathway may be preferentially exploited in cancer, the authors show that it becomes essential for cell
Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II–induced aortic aneurysms
Authors: Kimio Satoh, Patrizia Nigro, Tetsuya Matoba, Michael R O'Dell, Zhaoqiang Cui, Xi Shi, Amy Mohan, Chen Yan, Jun-ichi Abe, Karl A Illig, Bradford C Berk
Journal: Nature Medicine (2009)
A Prospective Study of Cardiorespiratory Fitness and Risk of Type 2 Diabetes in Women
Authors: Xuemei Sui, Steven P. Hooker, I-Min Lee, Timothy S. Church, Natalie Colabianchi, Chong-Do Lee, Steven N. Blair
Journal: Diabetes Care (2008)

The purpose of this study was to determine the independent and joint associations of cardiorespiratory fitness (CRF) and BMI with the incidence of type 2 diabetes in women.An observational cohort of 6,249 women aged 20-79 years was free of baseline cardiovascular disease, cancer, and diabetes. CRF was measured using a maximal treadmill exercise test. BMI was computed from measured height and weight. The incidence of type 2 diabetes was identified primarily by 1997 American Diabetes Association criteria.During a 17-year follow-up, 143 cases of type 2 diabetes occurred. Compared with the least fit third, the multivariate (including BMI)-adjusted hazard ratio (HR) (95% CI) was 0.86 (0.59-1.25) for the middle third and 0.61 (0.38-0.96) for the upper third of CRF. For BMI, the multivariate (including CRF)-adjusted HR (95% CI) was 2.34 (1.55-3.54) for overweight individuals and 3.70 (2.12-6.44) for obese individuals, compared with normal-weight patients. In the combined analyses, overweight/obese unfit (the lowest one-third of CRF) women had significantly higher risks compared with normal-weight fit (the upper two-thirds of CRF) women.Low CRF and higher BMI were independently associated with incident type 2 diabetes. The protective effect of CRF was observed in individuals who were overweight or obese, but CRF did not eliminate the increased risk in these groups. These findings underscore the critical importance of promoting regular physical activity and maintaining normal weight for diabetes prevention.
Imatinib mesylate therapy may overcome the poor prognostic significance of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia
Authors: Alfonso Quintas-Cardama, Hagop Kantarjian, Moshe Talpaz, Susan O'Brien, Guillermo Garcia-Manero, Srdan Verstovsek, Mary Beth Rios, Kimberly Hayes, Armand Glassman, B. Nebiyou Bekele, Xian Zhou, Jorge Cortes
Journal: Blood (2004)
Expression of the amiloride-sensitive sodium channel beta subunit gene in human B lymphocytes.
Authors: Y Oh, D G Warnock
Journal: Journal of the American Society of Nephrology (1997)

The amiloride-sensitive, epithelial sodium channel (ENaC) is composed of at least three subunits (alpha, beta, and gamma). This study demonstrates that the ENaC beta subunit gene is expressed in human B cell lines, peripheral blood lymphocytes, and lymph node at the mRNA level. Further, this study shows that both wild-type and mutated alleles of the ENaC beta subunit gene are transcribed in human B lymphocytes derived from an individual affected with Liddle's syndrome, an autosomal dominant form of human hypertension.
Intrathymic presentation of circulating non-MHC antigens by medullary dendritic cells. An antigen-dependent microenvironment for T cell differentiation.
Authors: B A Kyewski, C G Fathman, R V Rouse
Journal: The Journal of Experimental Medicine (1986)

We present evidence for intrathymic presentation of soluble circulating antigens in vivo. Our results show that proteins of different molecular weight enter the mouse thymus rapidly after i.v. injection. The intrathymic presence of antigen was assayed by proliferation of cloned antigen-specific T helper cells, which were cocultured with purified thymic stromal cells; stromal cells were isolated and purified as lymphostromal cell complexes, which preexist in vivo. Antigen presentation copurified with non-adherent medullary dendritic cells (DC) (interdigitating cells). I-A- cortical macrophages forming thymocyte rosettes in vivo and I-A+ cortical epithelial cells forming thymic nurse cells (TNC) in vivo did not act as antigen presenting cells (APC) after antigen pulsing in vivo or in vitro. Thymic APC turn over physiologically and are rapidly replaced (within 2-5 wk) after lethal irradiation by donor bone marrow-derived cells. The frequency of thymocyte-DC interactions in vivo strictly correlates with thymic T cell differentiation, and is independent of the immune status of the animal. Fetal thymic APC seem to be secluded from antigen in the maternal circulation. Thymic DC-ROS probably represent the microenvironment where maturing T cells first encounter non-MHC antigens in the context of self-MHC antigens.
Cigarette Smoking in Relation to Depression: Historical Trends From the Stirling County Study
Authors: Jane M. Murphy, Nicholas J. Horton, Richard R. Monson, Nan M. Laird, Arthur M. Sobol, Alexander H. Leighton
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Building on findings about the prevalence and incidence of depression over a 40-year period, the authors provide data on trends in cigarette smoking and associations with depression. METHOD: Data come from interviews with adult population samples (1952, 1970, and 1992) and followed cohorts (1952–1970 and 1970–1992). Logistic regression models and survival regressions were used to analyze the data. RESULTS: The associations between smoking and depression were small and nonsignificant in 1952 and 1970. In 1992, however, the odds that a smoker would be depressed were three times the odds that a nonsmoker would be depressed. The interaction between smoking and study year was significant, indicating that the association was limited to the most recent sample. In the cohort analysis, smoking at baseline did not predict the onset of depression, but subjects who became depressed were more likely to start or continue smoking and less likely to quit than those who never had a depression. CONCLUSIONS: In terms of population trends, the association between depression and cigarette smoking became prominent as the use of tobacco declined because of awareness of the risks involved. The findings about individuals followed over time suggest that those who became depressed were more involved with nicotine than those who never had a depression. The authors discuss hypotheses involving “self-medication,” risk-taking, and changes in the social climate but conclude that the relationships between smoking and depression are probably multiple and complex.
Transmitral pressure-flow velocity relation. Importance of regional pressure gradients in the left ventricle during diastole.
Authors: M Courtois, S J Kovács, P A Ludbrook
Journal: Circulation (1988)

Effects of regional diastolic pressure differences within the left ventricle on the measured transmitral pressure-flow relation were determined by simultaneous micromanometric left atrial (LAP) and left ventricular pressure (LVP) measurements, and Doppler echocardiograms in 11 anesthetized, closed-chest dogs. Intraventricular pressure recordings at sites that were 2, 4, and 6 cm from the apex were obtained. Profound differences between these sites were noted in the transmitral pressure relation during early (preatrial) diastolic filling. In measurements from apex to base, minimum LVP increased (1.6 +/- 0.7 to 3.1 +/- 0.8 mm Hg, mean +/- SD); the time interval between the first crossover of transmitral pressures and minimum LVP increased (31 +/- 3 to 50 +/- 17 msec); the slope of the rapid-filling LVP wave decreased (74 +/- 13 to 26 +/- 5 mm Hg/sec); the maximum forward (i.e., LAP greater than LVP) transmitral pressure gradient decreased (3.6 +/- 1.3 to 2.1 +/- 0.7 mm Hg); the time interval between the first and second points of transmitral pressure crossover increased (71 +/- 9 to 96 +/- 13 msec); and the area of reversed (i.e., LVP greater than LAP) gradient between the second and third points of transmitral pressure crossover decreased (101 +/- 41 to 40 +/- 33 mm Hg.msec). During atrial contraction, significant regional ventricular apex-to-base gradients were also noted. The slope of the LV A wave decreased (26 +/- 10 to 16 +/- 4 mm Hg/sec); LV end-diastolic pressure decreased (8.1 +/- 2.0 to 7.4 +/- 2.0 mm Hg), and the upstroke of the LV A wave near the base was recorded earlier than near the apex. All differences were significant at the 0.05 level. Simultaneous transmitral Doppler velocity profiles and transmitral pressures were measured at the 4-cm intraventricular site. The average interval between the first and second points of pressure crossover and between the onset of early rapid filling and maximum E-wave velocity were statistically similar (81 +/- 13 vs. 85 +/- 12 msec; NS); and the average area of the forward transmitral pressure gradient associated with acceleration of early flow was significantly greater than the area of reversed gradient associated with deceleration of early flow (133 +/- 36 vs. 80 +/- 46 msec.mm Hg; p less than 0.025).(ABSTRACT TRUNCATED AT 400 WORDS)
Bronchodilator Responsiveness to Formoterol (FM)-Containing Treatments Based on Measures of Pulmonary Function and Lung Volume in Patients with Chronic Obstructive Pulmonary Disease (COPD)
Authors: D.P. Tashkin, B. Celli, S.I. Rennard, J. McElhattan, U.J. Martin
Journal: Journal of Allergy and Clinical Immunology (2011)
The pulmonary arterial hypertension quality enhancement research initiative: comparison of patients with idiopathic PAH to patients with systemic sclerosis-associated PAH
Authors: Philip J Clements, Mary Tan, Vallerie V McLaughlin, Ronald J Oudiz, Victor F Tapson, Richard N Channick, Lewis J Rubin, Anatoly Langer
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> The objective of this report is to compare baseline, management and survival characteristics in idiopathic pulmonary arterial hypertension (IPAH) with systemic sclerosis-associated pulmonary arterial hypertension (SSc-APAH) using data from the prospectively enrolled PAH Quality Enhancement Research Initiative. <h3>Methods</h3> Between August 2005 and July 2007, patients with IPAH and SSc-APAH were enrolled across 60 US sites and followed up for 3 years. Data on diagnostic tests, clinical variables, pulmonary arterial hypertension (PAH) medication and outcomes were recorded. <h3>Results</h3> With some exceptions, baseline clinical and laboratory characteristics were similar between the 279 patients with IPAH and the 228 with SSc-APAH. Patients with SSc-APAH were older at the time of PAH diagnosis, were more likely to be female and were antinuclear antibody positive. Patients with SSc-APAH had poorer spirometric results. During the 3-year follow-up, both groups were managed with prostacyclin and prostacyclin analogue treatment, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors (PDE5i) singly or in combination. At 3 years, patients with SSc-APAH were more likely to be treated with PDE5i alone or with an endothelin receptor antagonist. Patients with SSc-APAH had a significantly lower survival rate compared to patients with IPAH (60% vs 77%, p&lt;0.0001). <h3>Conclusions</h3> The cohort with SSc-APAH was older, was more severely ill, was more likely to be female, was managed with PDE5i and had reduced 3-year survival compared with the cohort with IPAH.
Chronic treatment with anesthetic propofol attenuates β-amyloid protein levels in brain tissues of aged mice
Authors: Yiying Zhang, Haijun Shao, Yuanlin Dong, Celeste A Swain, Buwei Yu, Weiming Xia, Zhongcong Xie
Journal: Translational Neurodegeneration (2014)

Alzheimer's disease (AD) is the most common form of dementia. At the present time, however, AD still lacks effective treatments. Our recent studies showed that chronic treatment with anesthetic propofol attenuated brain caspase-3 activation and improved cognitive function in aged mice. Accumulation of β-amyloid protein (Aβ) is a major component of the neuropathogenesis of AD dementia and cognitive impairment. We therefore set out to determine the effects of chronic treatment with propofol on Aβ levels in brain tissues of aged mice. Propofol (50 mg/kg) was administrated to aged (18 month-old) wild-type mice once a week for 8 weeks. The brain tissues of mice were harvested one day after the final propofol treatment. The harvested brain tissues were then subjected to enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Here we report that the propofol treatment reduced Aβ (Aβ40 and Aβ42) levels in the brain tissues of the aged mice. Moreover, the propofol treatment decreased the levels of β-site amyloid precursor protein cleaving enzyme (the enzyme for Aβ generation), and increased the levels of neprilysin (the enzyme for Aβ degradation) in the brain tissues of the aged mice. These results suggested that the chronic treatment with propofol might reduce brain Aβ levels potentially via decreasing brain levels of β-site amyloid precursor protein cleaving enzyme, thus decreasing Aβ generation; and via increasing brain neprilysin levels, thus increasing Aβ degradation. These preliminary findings from our pilot studies have established a system and postulated a new hypothesis for future research.
Rhinosinusitis and nasal polyposis in aspirin sensitive and aspirin tolerant patients: are they different?
Authors: M. L Kowalski
Journal: Thorax (2000)

Hypersensitivity to aspirin (acetylsalicylic acid; ASA) is present in 5–10% of asthmatic patients and is associated with chronic rhinosinusitis and nasal polyposis, a syndrome referred to as the aspirin triad.1 2 The mechanism of the hypersensitivity reaction to aspirin is not immunological, but may be related to the inhibition of cyclo-oxygenase, an enzyme responsible for prostaglandin synthesis, by aspirin.2 A positive history of aspirin hypersensitivity, which is the hallmark of this syndrome, is a significant and reliable indicator of chronic intractable rhinosinusitis, persistent asthma of greater than average severity, and higher than ordinary medication requirements, including dependence on steroids.1 3 In addition to bronchospasm, most aspirin sensitive asthmatic subjects challenged with aspirin develop nasal symptoms including rhinorrhoea, sneezing and nasal obstruction, but the nasal responses to aspirin are superimposed on the existing pathology of the upper respiratory tract. The incidence of sinusitis identified by radiography in aspirin sensitive asthmatics may be up to 96.2% and the frequency of nasal polyps may be as high as 70.8%2 4compared with 6.7% in the general asthmatic population.5A subgroup of aspirin sensitive patients has a reaction exclusively in the upper respiratory tract. They do not have asthma but the clinical picture of nasal disease (hypertrophic rhinosinusitis) in these patients is similar to that observed in patients with the aspirin triad.6 

This article reviews the similarities and differences in the severity, pathophysiology, and management of upper airway disease in aspirin sensitive and aspirin tolerant patients with asthma and chronic rhinosinusitis.

It is generally assumed that chronic rhinosinusitis in aspirin sensitive asthmatic patients is more severe than in aspirin tolerant patients. A high recurrence of nasal polyps and frequent need for sinal endoscopic surgery is characteristic of this group of patients.4 7 However, no quantitative study has …
Changes in patient characteristics in anti-tumour necrosis factor clinical trials for rheumatoid arthritis: results of an analysis of the literature over the past 16 years
Authors: M. U. Rahman, J. Buchanan, M. K. Doyle, E. C. Hsia, T. Gathany, S. Parasuraman, D. Aletaha, E. L. Matteson, P. G. Conaghan, E. Keystone, D. van der Heijde, J. S. Smolen
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> To evaluate changes in baseline patient characteristics and entry criteria of randomised, controlled studies of tumour necrosis factor alpha (TNFα) inhibitors in rheumatoid arthritis (RA) patients. <h3>Methods</h3> A systematic literature review was performed using predefined inclusion criteria to identify randomised, double-blind, controlled trials that evaluated TNFα inhibitors in adult RA patients. Entry criteria and baseline clinical characteristics were evaluated over time for methotrexate-experienced and methotrexate-naive study populations. Enrolment start date for each trial was the time metric. The anchor time was the study with the earliest identifiable enrolment start date. <h3>Results</h3> 44 primary publications (reporting the primary study endpoint) from 1993 to 2008 met the inclusion criteria. Enrolment start dates of August 1993 and May 1997 were identified as time anchors for the 37 methotrexate-experienced studies and the seven methotrexate-naive studies, respectively. In methotrexate-experienced trials, no significant change was observed over the years included in this study in any inclusion criteria (including swollen joint counts and C-reactive protein (CRP)), but a significant decrease over time was observed in the baseline swollen joint count, CRP and total Sharp or van der Heijde modified Sharp score, but not in baseline tender joint counts. In the methotrexate-naive studies, significant decreases over the years were observed in swollen joint and tender joint inclusion criteria, but not in baseline tender joint count, baseline CRP, CRP inclusion criteria or baseline total Sharp or van der Heijde modified Sharp score. <h3>Conclusion</h3> Inclusion criteria and baseline characteristics of RA patients enrolled in studies of TNFα inhibitors have changed, with more recent trials enrolling cohorts with lower disease activity, especially in methotrexate-experienced trials.