tbuckley/cabot-search huggingface dataset:
Degradation of fibrin and elastin by intact human alveolar macrophages in vitro. Characterization of a plasminogen activator and its role in matrix degradation.
Authors: H A Chapman, O L Stone, Z Vavrin
Journal: Journal of Clinical Investigation (1984)

Fibrin deposition is prominent in the histopathology of a number of inflammatory lung diseases. Plasmin, activated locally in the lung, can degrade not only this fibrin but potentially structural proteins important to normal lung architecture. Because alveolar macrophages are prominent in inflammatory processes of the lung, we examined the plasminogen activator (PA) activity of human alveolar macrophages. Intact alveolar macrophages from each of 10 healthy subjects expressed PA activity. There was no difference in activity between smoking and nonsmoking individuals. The activator activity was largely cell-associated, but under certain culture conditions, macrophages released a soluble activator into the culture medium. The membrane-bound activator had an apparent molecular mass of 52-55 kD in nonreduced sodium dodecyl sulfate (SDS) gels, and monospecific antibody to urokinase neutralized the enzyme activity. Immunoprecipitation of [35S]methionine-labeled cells showed that human alveolar macrophages actually synthesize the PA in vitro. SDS-gel analysis of the immunoprecipitated material revealed the predominant species of PA to be structurally similar to reduced, active urokinase. We also examined the role of PA in the degradation of both insoluble fibrin and elastin matrices by live macrophages. Cells degraded an insoluble fibrin matrix in the presence of plasminogen whether or not the macrophages contacted the fibrin as long as proteinase inhibitors were not in the culture medium. In the presence of serum proteinase inhibitors, macrophages still degraded a fibrin matrix, but only if they were in contact with the fibrin. Live macrophages also degraded insoluble elastin only when in contact with the elastin but could do so even in the presence of serum proteinase inhibitors. In matrices containing a mixture of fibrin and elastin, cells did not degrade elastin unless plasminogen was added to the medium. These results indicate that normal alveolar macrophages synthesize and express, probably at the cell surface, a PA. The PA is physically and immunochemically similar to urokinase but is membrane bound. The PA is critical to the degradation of fibrin matrices by normal alveolar macrophages. Under tissue conditions where elastin is embedded within other structural proteins, the activator may be rate-limiting in elastin degradation as well. The findings also suggest that live macrophage proteolytic activity is relatively insensitive to the presence of serum proteinase inhibitors, suggesting a mechanism for proteolytic lung injury even in the presence of proteinase-proteinase inhibitor balance in the soluble phase.
Genetic susceptibility to COPD
Authors: C RUSE
Journal: Thorax (2000)

We read with interest the report by Yim et al of a failure to observe an association between polymorphisms of the microsomal epoxide hydrolase (mEPHX) gene and chronic obstructive pulmonary disease (COPD).1 This contrasts with the findings of earlier studies.2 There is debate in the literature on the place of association studies in the investigation of late onset complex disorders.3Failure to replicate an initial report of a positive association is common4-6 and it is important that the reasons for this are established. The authors correctly state that their failure to replicate the results of earlier studies may be a reflection of the marked racial differences in the frequency of the mEPHX gene within their population. However, their study also lacks power. Given, for example, their reported frequency of 75% for the wild type homozygous exon 4, a sample size of 80 subjects would only be able to detect a difference of 22% (e.g. 75% versus 53%) between the case and control groups (two tailed p value = 0.05, power = 0.8). Phenotypic heterogeneity is a problem in the genetic dissection of complex traits and hampers comparisons between studies. The authors are rigorous in their spirometric criteria used to define cases. However, their COPD group also includes never smokers and those with minimal pack-year histories. It is not restricted to adult onset disease, potentially containing chronic asthmatics. This phenotypically heterogeneous group could reduce the likelihood of demonstrating an association. The calculation of phenotypic “scores” is one solution to the clinical diversity which the label “COPD” describes.7 Finally, the importance of age and sex matching cannot be understated, not only because controls may develop disease, … Dr C-G Yoo Dr S Ishioka Dr C-G Yoo
Prevalence and Effects of Mood Disorders on Work Performance in a Nationally Representative Sample of U.S. Workers
Authors: Ronald C. Kessler, Hagop S. Akiskal, Minnie Ames, Howard Birnbaum, Paul Greenberg, Robert M .A, Robert Jin, Kathleen R. Merikangas, Gregory E. Simon, Philip S. Wang
Journal: American Journal of Psychiatry (2006)

Objective: Research on the workplace costs of mood disorders has focused largely on major depressive episodes. Bipolar disorder has been overlooked both because of the failure to distinguish between major depressive disorder and bipolar disorder and by the failure to evaluate the workplace costs of mania/hypomania. Method: The National Comorbidity Survey Replication assessed major depressive disorder and bipolar disorder with the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) and work impairment with the WHO Health and Work Performance Questionnaire. A regression analysis of major depressive disorder and bipolar disorder predicting Health and Work Performance Questionnaire scores among 3,378 workers was used to estimate the workplace costs of mood disorders. Results: A total of 1.1% of the workers met CIDI criteria for 12-month bipolar disorder (I or II), and 6.4% meet criteria for 12-month major depressive disorder. Bipolar disorder was associated with 65.5 and major depressive disorder with 27.2 lost workdays per ill worker per year. Subgroup analysis showed that the higher work loss associated with bipolar disorder than with major depressive disorder was due to more severe and persistent depressive episodes in those with bipolar disorder than in those with major depressive disorder rather than to stronger effects of mania/hypomania than depression. Conclusions: Employer interest in workplace costs of mood disorders should be broadened beyond major depressive disorder to include bipolar disorder. Effectiveness trials are needed to study the return on employer investment of coordinated programs for workplace screening and treatment of bipolar disorder and major depressive disorder.
Quality of life in patients at risk of medullary thyroid carcinoma and followed by a comprehensive medical network: Trends for future evaluations
Authors: G. Freyer, B. Ligneau, M. Schlumberger, C. Blandy, B. Contedevolx, V. Trillet-Lenoir, G.M. Lenoir, N. Chau, A. Dazord
Journal: Annals of Oncology (2001)
Paronychia and excess granulation tissue of the toes and finger in a patient treated with indinavir
Authors: E. DaudÉn, M. Pascual-LÓpez, C. MartÍnez-GarcÍa, A. GarcÍa-DÍez
Journal: British Journal of Dermatology (2000)

Journal Article Paronychia and excess granulation tissue of the toes and finger in a patient treated with indinavir Get access E. DaudÉn, E. DaudÉn Departments of Dermatology and Search for other works by this author on: Oxford Academic Google Scholar M. Pascual‐LÓpez, M. Pascual‐LÓpez Departments of Dermatology and Search for other works by this author on: Oxford Academic Google Scholar C. MartÍnez‐GarcÍa, C. MartÍnez‐GarcÍa Internal Medicine, Hospital Universitario de la Princesa, Diego de León 62, 28006 Madrid, Spain E‐mail: edaudent@medynet.com Search for other works by this author on: Oxford Academic Google Scholar A. GarcÍa‐DÍez A. GarcÍa‐DÍez Departments of Dermatology and Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 5, 1 May 2000, Pages 1063–1064, https://doi.org/10.1046/j.1365-2133.2000.03509.x Published: 01 May 2000
Nonmuscle Myosin Light-Chain Kinase Deficiency Attenuates Atherosclerosis in Apolipoprotein E–Deficient Mice via Reduced Endothelial Barrier Dysfunction and Monocyte Migration
Authors: Chongxiu Sun, Mack H. Wu, Sarah Y. Yuan
Journal: Circulation (2011)

Background— Endothelial dysfunction and monocyte migration are key events in the pathogenesis of atherosclerosis. Nonmuscle myosin light-chain kinase (nmMLCK), the predominant MLCK isoform in endothelial cells, has been shown to contribute to vascular inflammation by altering endothelial barrier function. However, its impact on atherogenesis remains unknown. Methods and Results— We investigated the role of nmMLCK in the development of atherosclerotic lesions in apolipoprotein E–deficient ( apoE −/− ) mice fed an atherogenic diet for 12 weeks. Histopathological examination demonstrated that nmMLCK deficiency ( apoE −/− nmmlck −/− ) reduced the size of aortic lesions by 53%, lipid contents by 44%, and macrophage deposition by 40%. Western blotting and reverse-transcription polymerase chain reaction revealed the expression of nmMLCK in aortic endothelial cells and peripheral blood monocytes. Measurements of transendothelial electric resistance indicated that nmMLCK deficiency attenuated endothelial barrier dysfunction caused by thrombin, oxidized low-density lipoprotein, and tumor necrosis factor α. In monocytes, nmMLCK deficiency reduced their migration in response to the chemokine monocyte chemoattractant protein-1. Further mechanistic studies showed that nmMLCK acted through both myosin light chain phosphorylation-coupled and -uncoupled pathways; the latter involved Rous sacracoma virus homolog genes-encoded tyrosine kinases (Src) signaling. Moreover, depletion of Src via gene silencing, site-specific mutagenesis, or pharmacological inhibition of Src greatly attenuated nmMLCK-dependent endothelial barrier dysfunction and monocyte migration. Conclusions— Nonmuscle myosin light-chain kinase contributes to atherosclerosis by regulating endothelial barrier function and monocyte migration via mechanisms involving not only kinase-mediated MLC phosphorylation but also Src activation.
HER2 Overexpression Increases Sensitivity to Gefitinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, through Inhibition of HER2/HER3 Heterodimer Formation in Lung Cancer Cells
Authors: Akira Hirata, Fumihito Hosoi, Miho Miyagawa, Shu-ichi Ueda, Seiji Naito, Teruhiko Fujii, Michihiko Kuwano, Mayumi Ono
Journal: Cancer Research (2005)

Abstract Gefitinib (Iressa), an epidermal growth factor receptor targeting drug, has been clinically useful for the treatment of patients with non–small cell lung cancer (NSCLC). Gefitinib is currently being applied in clinical studies as either a monotherapy, or as part of a combination therapy against prostate, head and neck, gastric, breast, and colorectal tumors. However, success rates vary between different tumor types, and thus it is important to understand which molecular target(s) are responsible for limiting the therapeutic efficacy of the drug. In this study, we ask whether expression of HER2 affects sensitivity to gefitinib in human lung cancer cells. We established two clones, LK2/HER2-32 and LK2/HER2-57, by transfecting HER2 cDNA into LK2, a NSCLC line with a low expression level of HER2. We observed no mutations in exons 18, 19, and 21 of EGFR gene in LK2, LK2/mock- and two HER2-trasfectants when we observed in-frame deletion mutations (E746-A750) adjacent to K745 in a gefitinib-sensitive NSCLC cell line, PC9. These LK2/HER2-32 and LK2/HER2-57 were much more sensitive to the cytotoxic effects of gefitinib than the parental LK2 lines. Treatment with 0.5 to 1 μmol/L gefitinib specifically blocked Akt activation in both HER2-transfectant lines, but not in the parental LK2 cells. Extracellular signal-regulated kinase-1/2 activation, however, was not blocked by gefitinib up to 10 μmol/L in either the parent or transfectant lines. Gefitinib was also shown to induce cell cycle arrest in the G1-S phase, and an accompanying increase of p27Kip1 was observed. LK2/HER2 transfectants showed constitutive formation of HER2/HER3 heterodimer, which were seen to associate with a regulatory subunit of phosphoinositide-3-kinase, p85α, when active. Treatment of LK2/HER2 cells with gefitinib markedly decreased the formation of HER2/HER3 heterodimers, HER3 basal phosphorylation, and the association of p85α with HER3. This study is the first to show that under basal growth conditions, HER2 sensitizes low-EGFR NSCLC cell lines to growth inhibition by gefitinib.
S79 Comparing the quality of life and cost-effectiveness of indwelling pleural catheter vs. talc pleurodesis for malignant pleural effusions
Authors: E Penz, E Mishra, H Davies, B Manns, RF Miller, N Rahman
Journal: Thorax (2013)

<h3>Background</h3> The TIME2 Trial[1], a randomised clinical trial comparing indwelling pleural catheter (IPC) with talc pleurodesis for malignant pleural effusion, included a prospective economic analysis. <h3>Methods</h3> 106 patients at 7 UK medical centres were randomly assigned to IPC or talc pleurodesis following chest drain insertion and followed at biweekly, monthly and q3month intervals for one year or until death. Costs associated with the drain insertion, follow up drainage, and adverse events were captured during the trial. Costs for outpatient and inpatient visits, diagnostic imaging, nursing and doctor time were derived from the NHS reference costs and University of Kent’s Unit Costs of Health and Social Care 2011. Procedure supply costs were obtained from the manufacturer. The number of quality adjusted life years (QALYs) was determined by adjusting patient survival by the utility weight obtained from the EQ5D questionnaire at each follow up period. Cost effectiveness was calculated over the duration of the trial given that most patients died during the 1 year follow up (14% alive at 1 year). Confidence intervals were calculated using bootstrap analysis. <h3>Results</h3> Average cost in the IPC group over the trial period was £3087(3504) versus £2892(2706) in the talc pleurodesis group with a mean cost difference of £195(95% CI -1072 to 1463). Average QALY in the IPC group was 0.354(0.29) and 0.328(0.3) in the talc group with a mean QALY difference between groups of 0.026 (95%CI -.08 to. 138). The cost per QALY gained for IPC as compared with talc pleurodesis was £7390 at 1 year. Bootstrap analysis revealed substantial uncertainty around this estimate. <h3>Conclusions</h3> There is no significant difference in cost or QALYs between IPCs and talc pleurodesis. Although the predictions are subject to substantial uncertainty, the probability that IPCs may be cost effective compared with talc pleurodesis is moderately high (60%) using a threshold of willingness to pay of £20,000/QALY. <h3>References</h3> Davies H, Mishra E, Kahan B, <i>et al</i>. Effect of an Indwelling Pleural Catheter vs. Chest Tube and Talc Pleurodesis for Relieving Dyspnea in Patients with Malignant Pleural Effusion. The TIME2 Randomised Controlled Trial. <i>JAMA</i>. 2012;307(22): 2383–2389.
Contemporary Data About Hospital Strategies to Reduce Unplanned Readmissions
Authors: Elizabeth H. Bradley, Heather Sipsma, Leora I. Horwitz, Leslie Curry, Harlan M. Krumholz
Journal: JAMA Internal Medicine (2013)

Almost one in five hospitalized Medicare beneficiaries will experience an unplanned readmission within 30-days,with an estimated cost to Medicare of more than $17 billion annually.1 In response, many hospitals have enrolled in quality collaboratives or campaigns to implement evidence-based strategies to reduce readmission rates. However, we have little information on the changes in practice that have occurred among the nation’s hospitals. Such information is important to understand hospital responses to the policy changes.
Post-genome respiratory epidemiology: a multidisciplinary challenge
Authors: F. Kauffmann
Journal: European Respiratory Journal (2004)

The introduction of genetic approaches in respiratory epidemiology is novel for most epidemiologists, and the post-genome phase poses new challenges. After describing specific questions pertinent to the field of asthma and chronic obstructive pulmonary disease, two main methodological aspects regarding technological and scientific advances are presented in this review. The first one concerns biological aspects in the genome and post-genome phases, i.e. how to study the genome, the transcriptome and the proteome. The second area concerns genetic epidemiology, considering design (case control and family based) and statistical analytical issues. Key aspects are large sample size, good phenotyping and the consideration of environment-by-gene interaction according to windows of opportunity. Needs that have been identified include the following. 1) Networking for setting standards in the field and access to sufficiently large samples. 2) Multidisciplinarity; the collaboration of epidemiologists, clinicians, geneticists and specialists in bioinformatics, in addition to specialists in disciplines less familiar to epidemiologists, to be prepared for new phenotypic characterisations based on transcriptome and proteome. 3) Training in genetic analytical techniques for some respiratory epidemiologists, as well as in respiratory epidemiology for some genetic epidemiologists. Implications for research, considering ethical aspects, public health aspects and organisational aspects in the field of genetic and environmental respiratory epidemiology also need to be addressed.
Schizosaccharomyces pombe Possesses Two Paralogous Valyl-tRNA Synthetase Genes of Mitochondrial Origin
Authors: W. C. Chiu, C. P. Chang, W. L. Wen, S. W. Wang, C. C. Wang
Journal: Molecular Biology and Evolution (2010)

Previous studies showed that VAS1 of Saccharomyces cerevisiae encodes both cytosolic and mitochondrial forms of valyl-tRNA synthetase (ValRS) through alternative initiation of translation. We show herein that except for Schizosaccharomyces pombe, all yeast species studied contained a single ValRS gene encoding both forms, and all of the mature protein forms deduced from those genes possessed an N-terminal appended domain (Ad) that was absent from their bacterial relatives. In contrast, S. pombe contained two distinct nuclear ValRS genes, one encoding the mitochondrial form and the other its cytosolic counterpart. Although the cytosolic form closely resembles other yeast ValRS sequences (∼60% identity), the mitochondrial form exhibits significant divergence from others (∼35% identity). Both genes are active and essential for the survival of the yeast. Most conspicuously, the mitochondrial form lacks the characteristic Ad. A phylogenetic analysis further suggested that both forms of S. pombe ValRS are of mitochondrial origin, and the mitochondrial form is ancestral to the cytoplasmic form.
RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-α and NF-κB
Authors: Guellue Cataldegirmen, Shan Zeng, Nikki Feirt, Nikalesh Ippagunta, Hao Dun, Wu Qu, Yan Lu, Ling Ling Rong, Marion A. Hofmann, Thomas Kislinger, Sophia I. Pachydaki, Daniel G. Jenkins, Alan Weinberg, Jay Lefkowitch, Xavier Rogiers, Shi Fang Yan, Ann Marie Schmidt, Jean C. Emond
Journal: The Journal of Experimental Medicine (2005)

The exquisite ability of the liver to regenerate is finite. Identification of mechanisms that limit regeneration after massive injury holds the key to expanding the limits of liver transplantation and salvaging livers and hosts overwhelmed by carcinoma and toxic insults. Receptor for advanced glycation endproducts (RAGE) is up-regulated in liver remnants selectively after massive (85%) versus partial (70%) hepatectomy, principally in mononuclear phagocyte-derived dendritic cells (MPDDCs). Blockade of RAGE, using pharmacological antagonists or transgenic mice in which a signaling-deficient RAGE mutant is expressed in cells of mononuclear phagocyte lineage, significantly increases survival after massive liver resection. In the first hours after massive resection, remnants retrieved from RAGE-blocked mice displayed increased activated NF-κB, principally in hepatocytes, and enhanced expression of regeneration-promoting cytokines, TNF-α and IL-6, and the antiinflammatory cytokine, IL-10. Hepatocyte proliferation was increased by RAGE blockade, in parallel with significantly reduced apoptosis. These data highlight central roles for RAGE and MPDDCs in modulation of cell death–promoting mechanisms in massive hepatectomy and suggest that RAGE blockade is a novel strategy to promote regeneration in the massively injured liver.
Dynamic Changes in Splanchnic Blood Flow and Blood Volume in Dogs during Activation of Sympathetic Nerves
Authors: Gerald A. Brooksby, David E. Donald
Journal: Circulation Research (1971)

Arterial inflow to and venous outflow from the vascularly isolated splanchnic region were measured simultaneously by using cannulating electromagnetic square-wave flow transducers in 25 anesthetized dogs with intact abdomens. Change in splanchnic blood volume (SBV) was calculated as the instantaneous difference between inflow and outflow. Addition of the respective increases and decreases in SBV induced by changing carotid sinus pressure from the control value (mean, 136 mm Hg) to 200 or to 40 mm Hg gave an average total volume of 93 ml of blood ( SD , ±21.7) that could be mobilized reflexly from the splanchnic circulation, Electrical stimulation (15 v, 2 cps, 3 msec duration) of the left thoracic splanchnic nerve for 2 to 10 minutes decreased SBV by 159 ml of blood ( SD , ±84). These mean values represent 32 and 48%, respectively, of the calculated total SBV. In both situations the translocation of blood was rapid, 50% of the total change in splanchnic blood flow and SBV occurring within 30 seconds. During a 2-minute hemorrhage (7.2 ml/kg), a mean volume of 56 ml of blood ( SD , ±16) was mobilized from the splanchnic region. This represented 54% of the total volume bled. Under these circumstances, blood moved out of the splanchnic circulation at a fairly constant rate.
The Death Domain of Kidney Ankyrin Interacts with Fas and Promotes Fas-Mediated Cell Death in Renal Epithelia
Authors: Marcela Del Rio, Abubakr Imam, Maryely DeLeon, Gary Gomez, Jaya Mishra, Qing Ma, Samir Parikh, Prasad Devarajan
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Ankyrins are a ubiquitously expressed family of conserved proteins that mediate the linkage of integral membrane proteins such as transporters and channels with the underlying cytoskeleton. Ankyrins possess a conserved death domain, the functional significance of which has remained puzzling. In this study, the death domain of AnkG190, the isoform of ankyrin expressed in kidney tubules, was used as bait in a yeast two-hybrid screen to identify interacting partners. One of these interactions was with the proapoptotic molecule Fas. This was confirmed by coimmunoprecipitation, colocalization, and glutathione S-transferase pull-down assays in cultured renal epithelial (MDCK) cells. Site-directed mutagenesis of a conserved arginine (R1496 in AnkG190), previously shown to be critical for the binding of Fas (R234 in Fas) to FADD, abolished the interaction of ankyrin's death domain with Fas. Overexpression of constructs containing ankyrin's death domain promoted Fas-mediated apoptosis in MDCK cells. The linkage between ankyrin and Fas was confirmed in vivo in mouse kidney tubule cells by coimmunoprecipitation and colocalization. In an established mouse model of renal ischemia-reperfusion injury characterized by apoptotic tubule cell death, the expression of both ankyrin and Fas was markedly induced, and the interaction between these molecules remained intact. The results identify a novel tethering interaction between ankyrin and Fas in kidney epithelia and suggest that AnkG190 may play a role as an adapter molecule in renal tubule cell death. E-mail: [email protected]