tbuckley/cabot-search huggingface dataset:
The yin and the yang of immunosuppression with inhaled corticosteroids
Authors: Ian Sabroe, Dirkje Postma, Irene Heijink, David H Dockrell
Journal: Thorax (2013)

A patient who is immunosuppressed is susceptible to mycobacterial infection: are you surprised? Before you jump to conclusions, you might wish to clarify the nature and extent of immunosuppression, and whether it is through disease, therapy, or both, reserving judgement until you know more.

Patients are often concerned about immunosuppressive effects of inhaled and oral corticosteroids. Asthmatics are used to infections putting them in hospital, and not unreasonably view with suspicion any treatment option that might make this more likely to happen. However, healthcare providers know that for asthmatics, appropriate local immunomodulation in the lung with inhaled corticosteroids (ICS) is associated with decreased exacerbations arising from viral infections, fewer symptoms, improved lung function and better outcomes. In subsets of patients with COPD, high-dose fluticasone with salmeterol reduces exacerbations and improves quality of life.1 Thus, if the only exposure of patients to anything remotely immunosuppressive is ICS, you might conclude the extent of immunosuppression is insufficient to regard the patient as immunocompromised.

But will use of ICS increase susceptibility to some infections? The innate immune networks active in the lung, with their multifaceted humoral and cellular components, show intrinsic competence in keeping the human organism mostly free of serious pulmonary infection. At their heart lie strong surface barriers, an effective mechanism of sensing pathogens through a range of pattern recognition receptors,2 the efficient killing of micro-organisms by resident and recruited phagocytes, and efficient resolution of inflammation.3 Alveolar macrophages are the resident phagocytes, which along with epithelial cells and T cells coordinate an immune response that may require recruitment of other inflammatory cells such as neutrophils to clear invading pathogens. Clearance of bacteria such as pneumococci relies heavily on phagocyte competence which is optimised by T cell responses. When phagocyte capacity is stressed by intracellular pathogens, such as Mycobacterium …
PPARγ regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1
Authors: Patricia C. Chui, Hong-Ping Guan, Michael Lehrke, Mitchell A. Lazar
Journal: Journal of Clinical Investigation (2005)

In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentrations of cholesterol and triglycerides are strongly correlated in the adipocyte, but little is known about mechanisms regulating cholesterol metabolism in fat cells. Here we report that antidiabetic thiazolidinediones (TZDs) and other ligands for the nuclear receptor PPARgamma dramatically upregulate oxidized LDL receptor 1 (OLR1) in adipocytes by facilitating the exchange of coactivators for corepressors on the OLR1 gene in cultured mouse adipocytes. TZDs markedly stimulate the uptake of oxidized LDL (oxLDL) into adipocytes, and this requires OLR1. Increased OLR1 expression, resulting either from TZD treatment or adenoviral gene delivery, significantly augments adipocyte cholesterol content and enhances fatty acid uptake. OLR1 expression in white adipose tissue is increased in obesity and is further induced by PPARgamma ligand treatment in vivo. Serum oxLDL levels are decreased in both lean and obese diabetic animals treated with TZDs. These data identify OLR1 as a novel PPARgamma target gene in adipocytes. While the physiological role of adipose tissue in cholesterol and oxLDL metabolism remains to be established, the induction of OLR1 is a potential means by which PPARgamma ligands regulate lipid metabolism and insulin sensitivity in adipocytes.
Absorptive clearance of DTPA as an aerosol-based biomarker in the cystic fibrosis airway
Authors: T. E. Corcoran, K. M. Thomas, M. M. Myerburg, A. Muthukrishnan, L. Weber, R. Frizzell, J. M. Pilewski
Journal: European Respiratory Journal (2009)

Biomarkers providing in vivo quantification of the basic elements of cystic fibrosis (CF) lung disease are needed. A study was performed to determine whether the absorption of a small radiolabelled hydrophilic molecule (Indium-111 (In-)DTPA) would be increased in CF airways. DTPA clearance has been used previously to assess epithelial permeability and may also be useful for quantifying liquid absorption. The absorptive clearance rate of DTPA was quantified in 10 CF and 11 control subjects using a novel aerosol technique. Subjects inhaled an aerosol containing nonabsorbable technetium-99m sulfur colloid (Tc-SC) particles and In-DTPA. Tc-SC clearance from the lung is exclusively mucociliary, while In-DTPA is cleared by both absorption and mucociliary clearance. The difference between the In-DTPA and Tc-SC clearance rates estimates In-DTPA absorption. Tc-SC (mucociliary) clearance was similar in central and peripheral zones in CF and non-CF lungs. Total In-DTPA clearance was increased in both zones in CF lungs. The absorptive component of In-DTPA clearance was increased in the airway-dominated central lung zones in CF (42%·h −1 versus 32%·h −1 , p = 0.03). The absorption of In-DTPA is increased in the CF airway. Further study is needed to understand the relative roles of fluid absorption, inflammation and other mechanisms potentially affecting epithelial permeability and DTPA absorption.
The need to consider additional variables when summarizing agrammatism research
Authors: M. Cherilyn Young, Judith A. Hutchinson
Journal: Behavioral and Brain Sciences (2000)

Throughout the history of aphasiology, researchers have identified important premorbid and stroke-related predictors of linguistic performance. Although Grodzinsky discusses some of these variables, exclusion of other variables could lead to unnecessary experimental error and erroneous conclusions. Aspects to consider include sources of experimental bias, premorbid differences, nonlinguistic roles of the frontal regions, and comparison of normal and aphasic performance.
Left ventricular midwall mechanics in systemic arterial hypertension. Myocardial function is depressed in pressure-overload hypertrophy.
Authors: G Shimizu, Y Hirota, Y Kita, K Kawamura, T Saito, W H Gaasch
Journal: Circulation (1991)

Left ventricular (LV) midwall geometry has been described conventionally as the sum of the chamber radius and half of the wall thickness; this convention is based on the assumption of uniform transmural thickening during systole. However, theoretical considerations and experimental data indicate that the inner half (inner shell) of the LV wall thickens more than the outer half (outer shell). Thus, an end-diastolic circumferential midwall fiber exhibits a relative migration toward the epicardium during systole. As a result, the conventional method provides an overestimate of the extent of the midwall fiber shortening.We developed an ellipsoidal model with a concentric two-shell geometry (nonuniform thickening) to assess midwall fiber length transients throughout the cardiac cycle. This modified midwall method was used in the analysis of LV cineangiograms from 15 patients with systemic arterial hypertension and 14 normal subjects. Study groups were classified according to LV mass index (LVMI): 14 normal subjects (group I), eight hypertensive patients with a normal LVMI (group II), and seven hypertensive patients with an increased LVMI (group III). There were no significant differences in LV end-diastolic pressure or volume among the three groups; the ejection fraction was slightly greater in group II (70 +/- 5%) than in groups I (65 +/- 8%) and III (66 +/- 4%), but this trend did not achieve statistical significance. Values for endocardial and conventional midwall fractional shortening (FS) were also similar in the three groups. By contrast, FS by the concentric two-shell geometry (modified midwall method) in group III (16 +/- 2%) was significantly less than that seen in groups I and II (21 +/- 4% and 21 +/- 5%, respectively; both p less than 0.05). This difference achieves greater importance when it is recognized that mean systolic circumferential stress was lower in group III (151 +/- 22 g/cm2) than in groups I and II (244 +/- 37 g/cm2 and 213 +/- 38 g/cm2, respectively; both p less than 0.01). The midwall stress-shortening coordinates in six of the seven group III patients were outside the 95% confidence limits for the normal (group I) subjects. Thus, despite a normal ejection fraction, systolic function is subnormal in hypertensive patients with LV hypertrophy.Chamber dynamics provide an overestimate of myocardial function, especially when LV wall thickness is increased. This is due to a relatively greater contribution of inner shell thickening in pressure-overload hypertrophy.
Association between Meckel's diverticulum and Crohn's disease: a retrospective review.
Authors: H J Andreyev, R A Owen, I Thompson, A Forbes
Journal: Gut (1994)

The operation notes and pathology records of 294 consecutive patients who had right hemicolectomy for Crohn's disease were reviewed. A Meckel's diverticulum was found in 17 (5.8%) of these patients, 2-3 times the expected rate in the general population. At least 50% of diverticula in the normal population contain heterotopic mucosa, but none was found in those diverticula that were examined from this group. The increased prevalence of Meckel's diverticulum in patients with Crohn's disease confirms previous anecdotal reports, but the cause for the increased frequency remains unexplained. The significance of this finding is discussed.
Mental disorders and vulnerability to homicidal death: Swedish nationwide cohort study
Authors: C. Crump, K. Sundquist, M. A. Winkleby, J. Sundquist
Journal: BMJ (2013)

To determine the risk of people with mental disorders being victims of homicide.National cohort study.Sweden.Entire adult population (n = 7,253,516).Homicidal death during eight years of follow-up (2001-08); hazard ratios for the association between mental disorders and homicidal death, with adjustment for sociodemographic confounders; potential modifying effect of comorbid substance use.615 homicidal deaths occurred in 54.4 million person years of follow-up. Mortality rates due to homicide (per 100,000 person years) were 2.8 among people with mental disorders compared with 1.1 in the general population. After adjustment for sociodemographic confounders, any mental disorder was associated with a 4.9-fold (95% confidence interval 4.0 to 6.0) risk of homicidal death, relative to people without mental disorders. Strong associations were found irrespective of age, sex, or other sociodemographic characteristics. Although the risk of homicidal death was highest among people with substance use disorders (approximately ninefold), the risk was also increased among those with personality disorders (3.2-fold), depression (2.6-fold), anxiety disorders (2.2-fold), or schizophrenia (1.8-fold) and did not seem to be explained by comorbid substance use. Sociodemographic risk factors included male sex, being unmarried, and low socioeconomic status.In this large cohort study, people with mental disorders, including those with substance use disorders, personality disorders, depression, anxiety disorders, or schizophrenia, had greatly increased risks of homicidal death. Interventions to reduce violent death among people with mental disorders should tackle victimisation and homicidal death in addition to suicide and accidents, which share common risk factors.
Redox Changes of Cultured Endothelial Cells and Actin Dynamics
Authors: Leni Moldovan, Nicanor I. Moldovan, Richard H. Sohn, Sahil A. Parikh, Pascal J. Goldschmidt-Clermont
Journal: Circulation Research (2000)

Abstract —We studied the association between the production of reactive oxygen species, actin organization, and cellular motility. We have used an endothelial cell monolayer–wounding assay to demonstrate that the cells at the margin of the wound thus created produced significantly more free radicals than did cells in distant rows. The rate of incorporation of actin monomers into filaments was fastest at the wound margin, where heightened production of free radicals was detected. We have tested the effect of decreasing reactive oxygen species production on the migration of endothelial cells and on actin polymerization. The NADPH inhibitor diphenylene iodonium and the superoxide dismutase mimetic manganese (III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP) virtually abolished cytochalasin D–inhibitable actin monomer incorporation at the fast-growing barbed ends of filaments. Moreover, endothelial cell migration within the wound was significantly retarded in the presence of both diphenylene iodonium and MnTMPyP. We conclude that migration of endothelial cells in response to loss of confluence includes the intracellular production of reactive oxygen species, which contribute to the actin cytoskeleton reorganization required for the migratory behavior of endothelial cells.
The Mechanism of DAB2IP in Chemoresistance of Prostate Cancer Cells
Authors: Kaijie Wu, Daxing Xie, Yonglong Zou, Tingting Zhang, Rey-Chen Pong, Guanghua Xiao, Ladan Fazli, Martin Gleave, Dalin He, David A. Boothman, Jer-Tsong Hsieh
Journal: Clinical Cancer Research (2013)

The docetaxel-based chemotherapy is the standard of care for castration-resistant prostate cancer (CRPC), inevitably, patients develop resistance and decease. Until now, the mechanism and predictive marker for chemoresistance are poorly understood.Immortalized normal prostate and cancer cell lines stably manipulated with different DAB2IP expression levels were used and treated with chemotherapeutic drugs commonly used in prostate cancer therapy. Cell proliferation was measured using MTT assay; Western blot, quantitative PCR, and luciferase reporter assays were used to analyze Clusterin gene regulation by DAB2IP. Immunohistochemical analysis was conducted for evaluating DAB2IP, Clusterin and Egr-1 expression in human prostate cancer tissue.DAB2IP Knockdown (KD) cells exhibited resistance to several chemotherapeutic drugs, whereas increased DAB2IP in C4-2 cells restored the drug sensitivity. Parallel, DAB2IP KD cells exhibited higher expression of Clusterin, an antiapoptotic factor, whereas elevated DAB2IP in C4-2 cells decreased Clusterin expression. Functionally, knocking down Clusterin by short-hairpin RNA or antisense oligonucleotide OGX-011 decreased drug resistance, whereas overexpressing Clusterin in C4-2 D2 enhanced drug resistance. Mechanistically, DAB2IP blocked the cross-talk between Wnt/β-catenin and IGF-I signaling, leading to the suppression of Egr-1 that is responsible for Clusterin expression. A similar result was observed in the prostate of DAB2IP knockout animals. In addition, we observed a significantly inverse correlation between DAB2IP and Egr-1 or Clusterin expression from clinical tissue microarray.This study unveils a new regulation of the Egr-1/Clusterin signaling network by DAB2IP. Loss of DAB2IP expression in CRPC cells signifies their chemoresistance. Clusterin is a key target for developing more effective CRPC therapy.
Undetected viral infection in diffuse alveolar damage associated with bone marrow transplantation
Authors: JA Barbera, JM Martin-Campos, T Ribalta, E Carreras, A Liopart, J Sierra, C Rozman, R Rodriguez-Roisin
Journal: European Respiratory Journal (1996)

To investigate the presence of nondiagnosed viral lung infections in patients who developed acute respiratory failure and diffuse pulmonary infiltrates after bone marrow transplantation (BMT), we studied necropsy-obtained lung specimens with features of diffuse alveolar damage (DAD) where no other specific histological diagnosis could be established, by using in situ hybridization and immunohistochemistry. Lung tissue samples obtained at necropsy from 19 patients (12 males and 7 females; 31 +/- 11 yrs mean +/- SD age) who died 56 +/- 36 days after BMT (12 allogeneic and 7 autologous), were studied retrospectively using specific deoxyribonucleic acid (DNA) probes to detect cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), and adenovirus genomes. Tissue samples were additionally processed with antibodies to CMV and HSV antigens. Cells infected by CMV were detected by in situ hybridization in five cases, and by immunohistochemistry in four cases. Combining the results of both procedures, a previously undiagnosed CMV infection was found in six patients. All of them had received an allogeneic BMT and had developed graft-versus-host disease (GVHD). No evidence of cells infected by HSV, EBV, or adenovirus was found in any case. No viral infection was detected either in recipients of autologous marrow or in recipients of allogeneic BMT without GVHD. These results indicate that pulmonary cytomegalovirus infection not detected by conventional histological examinations may be present in patients with diffuse alveolar damage associated with bone marrow transplantation, especially in recipients of allogeneic marrow who develop graft-versus-host disease. Furthermore, the use of in situ hybridization and/or immunohistochemistry on pulmonary histology might improve the diagnosis of viral lung infections in patients receiving bone marrow transplantation.
Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival
Authors: Sandra L. Haberichter, Michael Balistreri, Pamela Christopherson, Patricia Morateck, Stefana Gavazova, Daniel B. Bellissimo, Marilyn J. Manco-Johnson, Joan Cox Gill, Robert R. Montgomery
Journal: Blood (2006)
Conserved responses to oxygen deprivation
Authors: Patrick H. O’Farrell
Journal: Journal of Clinical Investigation (2001)

Genetically tractable model organisms such as the fruit fly offer powerful experimental systems that have illuminated conserved biological phenomena and so guided research in human biology. Still, researchers concerned with the pathologies of stroke and myocardial infarct might consider their fields beyond the reach of even the most fundamental discoveries that could be made in an insect. Recent work, including a paper appearing in this issue of the JCI (1), suggests otherwise.

Given the obvious anatomical differences between the nutrient and oxygen delivery systems of mammals and arthropods, the etiologies of stroke and myocardial infarct are unlikely to be mimicked in the fruit fly Drosophila. Still, the pathologies caused by an interruption in blood supply are fundamentally the result of a shortage of oxygen, and the cellular responses to hypoxia in an insect may well be relevant to normal and pathological responses to oxygen deprivation. Interestingly, many organisms tolerate hypoxia without the devastating damage incurred by human heart and brain tissue (2, 3). Turtles, for example, hibernate buried in mud, with little access to oxygen. We understand little of the differences among species regarding tolerance to hypoxia, but identification of the relevant parameters could aid clinical management of acute interruptions in blood flow.

However great the relevance of cellular adaptations to hypoxia to stroke or heart attack, Drosophila might not appear an obvious choice of system for studying these pathologies. However, those of us who witnessed how the powerful genetic strategies available in Drosophila pried open the profoundly difficult problem of embryonic patterning have become champions of this organism. Its attributes can be used to probe a wide range of problems. Still, a fly is a long way from a human. Or is it?
Omega-3 Fatty Acid Treatment and T<sub>2</sub> Whole Brain Relaxation Times in Bipolar Disorder
Authors: Fuyuki Hirashima, Aimee M. Parow, Andrew L. Stoll, Christina M. Demopulos, Karen E. Damico, Michael L. Rohan, Justin G. Eskesen, Chun S. Zuo, Bruce M. Cohen, Perry F. Renshaw
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: The authors hypothesized that changes in brain membrane composition resulting from omega-3 fatty acid administration in patients with bipolar disorder would result in greater membrane fluidity, as detected by reductions in T2 values. METHOD: Women with bipolar disorder (N=12) received omega-3 fatty acids for 4 weeks. A cohort of bipolar subjects (N=9) and a group without bipolar disorder (N=12) did not receive omega-3 fatty acids. T2 values were acquired at baseline and after 4 weeks. RESULTS: Bipolar subjects who received omega-3 fatty acids had significant decreases in T2. There was a dose-dependent effect when the bipolar omega-3 fatty acid group was subdivided into high- and low-dose cohorts. CONCLUSIONS: Omega-3 fatty acids lowered T2 values, consistent with the hypothesis that the fluidity of cell membranes was altered. Further studies are needed to clarify the significance of alterations in brain physiology induced by omega-3 fatty acids, as reflected in T2 values.
Anorexia Nervosa Mortality in Northeast Scotland, 1965–1999
Authors: Harry R. Millar, Fiona Wardell, Juliet P. Vyvyan, Simon A. Naji, Gordon J. Prescott, John M. Eagles
Journal: American Journal of Psychiatry (2005)

Most previous studies of mortality in anorexia nervosa patients have shown an increased risk of premature death but have been limited by methodological constraints. This study aimed to overcome some of these constraints by having a large original sample size, diagnosis confirmed by case note review, a long duration of follow-up, and a clear base population.The authors identified 524 anorexia nervosa cases seen in specialist services in Northeast Scotland; anorexia nervosa diagnosis was confirmed by scrutinizing case notes. Those who had died were identified from the National Health Service register or register of deaths. The death rates and causes of death were analyzed.Twenty-three patients died, giving a crude death rate of 4.4% and a standardized mortality rate of 3.3 (95% CI=2.2-4.9). In only one-third of the cases was anorexia nervosa on the death certificate, but an eating disorder or other psychiatric pathology probably contributed to several of the other deaths. Older age at the time the patient was seen at the specialist service was the only identifiable risk factor in the group of patients who died. The median length of time between diagnosis and death was 11 years.Anorexia nervosa is associated with increased risk of premature death. It is possible that death rates could be reduced by early diagnosis and by long-term specialist care.