tbuckley/cabot-search huggingface dataset:
Ventilation-Perfusion Mismatch in Patients with Pleural Effusion
Authors: ALVAR G. N. AGUSTÍ, JAUME CARDÚS, JOSEP ROCA, JOSEP M. GRAU, ANTONI XAUBET, ROBERT RODRIGUEZ-ROISIN
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Pleural effusion (PE) often causes abnormal pulmonary gas exchange. Thoracentesis is commonly used to relieve dyspnea in patients with PE, but its effect upon arterial oxygenation is varied and poorly understood. This investigation sought to: (1) characterize the distribution of ventilation-perfusion (V˙ a/Q˙) ratios in patients with PE and ( 2) assess the effects of PE drainage by thoracentesis upon pulmonary gas exchange. We studied nine patients (two females) with a mean age of 39 ± 20 (SD) yr. All of them had PE of recent clinical onset ( < 2 wk of symptoms), without other apparent medical conditions. Before thoracentesis, PaO2 was 82.3 ± 10.2 mm Hg and AaPo 2 was 28.7 ± 10.0 mm Hg. Patients had broadened unimodal V˙ a/Q˙ distributions with small amounts of blood flow perfusing lung units with low V˙ a/Q˙ ratios ( < 0.1) (1.4 ± 2.2%) and mild intrapulmonary shunt (6.9 ± 6.7%). PaO2 was significantly related to the amount of shunt (rho = − 0.82; p < 0.01) but not to the percentage of blood flow perfusing low V˙ a/Q˙ units. While thoracentesis drained 693 ± 424 ml of fluid and caused a significant fall in mean pleural pressure (by − 10.7 ± 7.1 mm Hg; p < 0.01), PaO2 , AaPo 2, and shunt remained unchanged; only the amount of blood flow perfusing low V˙ a/Q˙ ratios increased slightly (2.4 ± 2.6%; p < 0.05). This study shows that: (1) intrapulmonary shunt is the main mechanism underlying arterial hypoxemia in patients with PE and (2) effective thoracentesis has minor short-term effects upon pulmonary gas exchange. These findings are in accord with delayed ( > 30 min) pulmonary volume re-expansion after thoracentesis with or without the coexistence of mild ex vacuo pulmonary edema. Agustı́ AGN, Cardús J, Roca J, Grau JM, Xaubet A, Rodriguez-Roisin R. Ventilation-perfusion mismatch in patients with pleural effusion: effects of thoracentesis.
Hematopoietic progenitor cell collection and neoplastic cell contamination in breast cancer patients receiving chemotherapy plus granulocyte-colony stimulating factor (G-CSF) or G-CSF alone for mobilization
Authors: F Bertolini, A Lanza, F Peccatori, C Zibera, N Gibelli, C Perotti, G A Da Prada, L Torretta, E Cocorocchio, G Martinelli, G Robustelli della Cuna
Journal: Annals of Oncology (1998)

We compared hematopoietic progenitor cell (HPC) collection and neoplastic cell contamination in breast cancer patients given cyclophosphamide (CTX) plus granulocyte-colony stimulating factor (G-CSF) or G-CSF alone for mobilization.In 57 stage II-III breast cancer patients, CD34+ cells, colony-forming units-granulocyte macrophage (CFU-GM), early HPC and breast cancer cells were counted in HPC collections obtained after CTX plus G-CSF (n = 27) or G-CSF-alone mobilization (n = 30).The CD34+ cell collection was about two-fold greater after CTX plus G-CSF mobilization (11.0 +/- 7.9 vs. 5.8 +/- 3.5 x 10(6)/kg, P < 0.001). Similarly, the total number of CFU-GM, CD34+CD38- cells and of week-5 cobblestone area forming cells (CAFC) collected was significantly higher in patients mobilized with CTX plus G-CSF. Breast cancer cells were found in the apheresis products of 22% of patients mobilized with CTX plus G-CSF and in 10% of patients mobilized with G-CSF alone (P = 0.36). Of seven patients who failed G-CSF-alone mobilization and eventually underwent chemotherapy plus G-CSF mobilization, none had cytokeratin-positive cells after G-CSF mobilization, whereas four out of seven had cytokeratin-positive cells after chemotherapy plus G-CSF (P = 0.07 by chi 2 test).The CTX plus G-CSF mobilization protocol was associated with a significantly higher HPC collection. However, this benefit was not accompanied by a reduction in the incidence of tumor-contaminated HPC graft.
Activation of the Ubiquitin–Proteasome Pathway in the Diaphragm in Chronic Obstructive Pulmonary Disease
Authors: Coen A. C. Ottenheijm, Leo M. A. Heunks, Yi-Ping Li, Bingwen Jin, Ronnie Minnaard, Hieronymus W. H. van Hees, P. N. Richard Dekhuijzen
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Studies show that the myosin content of the diaphragm in patients with mild to moderate chronic obstructive pulmonary disease (COPD) is reduced, compromising diaphragm contractile performance. The mechanisms for reduced contractile protein content are unknown. In the present study we hypothesized that the loss of contractile protein content is associated with activation of the ubiquitin-proteasome pathway in the diaphragm of patients with mild to moderate COPD.Proteolytic activity of isolated 20S proteasomes was determined in diaphragm biopsies from patients with and without COPD (predicted mean FEV1, 66 and 93%, respectively). In addition, we determined 20S proteasome subunit C8 protein levels by means of Western blotting, ubiquitin-ligase mRNA levels by means of real-time polymerase chain reaction, and caspase-3 activity by determining the hydrolysis of fluorogenic substrates.The 20S proteasome activity was about threefold increased in the diaphragm of patients with COPD. C8 protein levels were not significantly different between COPD and non-COPD diaphragm, indicating increased specific activity of individual proteasomes, rather than an increased number of proteasomes. mRNA levels of the muscle-specific ubiquitin-ligase MAFbx were significantly higher in diaphragm from patients with COPD compared with patients without COPD. Caspase-3-mediated cleavage of actomyosin complexes is considered an initial step in muscle wasting, yielding fragments that can be degraded by the ubiquitin-proteasome pathway. In line with the increased ubiquitin-proteasome activity, caspase-3 activity was higher in diaphragm homogenates from patients with COPD.The present study is the first to demonstrate increased activity of the ubiquitin-proteasome pathway in COPD diaphragm. Importantly, these changes occur in patients with only mild to moderate COPD (Global Initiative for Chronic Obstructive Lung Disease stage I/II).
Interleukin 12 P40 Production by Barrier Epithelial Cells during Airway Inflammation
Authors: Michael J. Walter, Naohiro Kajiwara, Peter Karanja, Mario Castro, Michael J. Holtzman
Journal: The Journal of Experimental Medicine (2001)

Human airway epithelial cells appear specially programmed for expression of immune response genes implicated in immunity and inflammation. To better determine how this epithelial system operates in vivo, we analyzed its behavior in mouse models that allow for in vitro versus in vivo comparison and genetic modification. Initial comparisons indicated that tumor necrosis factor α induction of epithelial intercellular adhesion molecule 1 required sequential induction of interleukin (IL)-12 (p70) and interferon γ, and unexpectedly localized IL-12 production to airway epithelial cells. Epithelial IL-12 was also inducible during paramyxoviral bronchitis, but in this case, initial IL-12 p70 expression was followed by 75-fold greater expression of IL-12 p40 (as monomer and homodimer). Induction of IL-12 p40 was even further increased in IL-12 p35-deficient mice, and in this case, was associated with increased mortality and epithelial macrophage accumulation. The results placed epithelial cell overgeneration of IL-12 p40 as a key intermediate for virus-inducible inflammation and a candidate for epithelial immune response genes that are abnormally programmed in inflammatory disease. This possibility was further supported when we observed IL-12 p40 overexpression selectively in airway epithelial cells in subjects with asthma and concomitant increases in airway levels of IL-12 p40 (as homodimer) and airway macrophages. Taken together, these results suggest a novel role for epithelial-derived IL-12 p40 in modifying the level of airway inflammation during mucosal defense and disease.
T CELL MEMORY
Authors: R. W. Dutton, L. M. Bradley, S. L. Swain
Journal: Annual Review of Immunology (1998)

▪ Abstract Immunological memory can be defined as the faster and stronger response of an animal that follows reexposure to the same antigen. By this definition, it is an operational property of the whole animal or the immune system. Memory cells express a different pattern of cell surface markers, and they respond in several ways that are functionally different from those of naive cells. Murine memory cells are CD44 high and low in the expression of activation markers such as CD25 (IL-2R), whereas human memory cells are CD45RA − , CD45RO + . In contrast to naive cells, memory cells secrete a full range of T cell cytokines and can be polarized to secrete particular restricted patterns of secretion for both CD4 and CD8 T cells. The requirements for the activation of memory cells for proliferation and cytokine production are not quite as strict as those of naive cells, but costimulation in the broad sense is required for optimum responses and for responses to suboptimum antigen concentrations. It would appear that memory cells can persist in the absence of antigenic stimulation and persist as nondividing cells. Reencounter with the same antigen can expand the population to a new, stable, higher level and generate a separate population of CD44 high effectors that may be required for protection, while competition from other antigens can drive it down to a lower stable level. It is unclear how or where memory cells arise, but once generated they have different pathways of recirculation and homing.
Evolution of the APETALA3 and PISTILLATA Lineages of MADS-Box–Containing Genes in the Basal Angiosperms
Authors: Giulia M Stellari, M Alejandra Jaramillo, Elena M Kramer
Journal: Molecular Biology and Evolution (2004)

The B class genes, including homologs of the Arabidopsis loci APETALA3 (AP3) and PISTILLATA (PI ), appear to play a conserved role in the determination of petal and stamen identity across core eudicot angiosperms. Understanding how and when these functions evolved is a critical component of elucidating the evolution of flowers, particularly the appearance of petaloid perianth organs. Before comparisons of gene expression patterns or functions can be made, however, it is necessary to establish the orthology of AP3 and PI homologs from basal angiosperms. Here, we report the identification and analysis of 29 new representatives of the B gene lineage from basal ANITA and magnoliid dicot angiosperms. These studies indicate that gene duplications have occurred at every phylogenetic level, both before and after the duplication that produced the separate AP3 and PI lineages. Comparison of genomic structure among PI homologs indicates that a 12-nucleotide deletion that had been considered synapomorphic for the whole PI lineage actually arose within the ANITA grade, after the split of the Nymphaeales but before the separation of the Austrobaileyales. Evidence for alternative splicing of the Nymphaea AP3 homolog is also presented. The implications of these findings for angiosperm systematics, the conservation of AP3 and PI gene function, and the evolution of the ABC program are discussed.
Contribution of Antibodies Against IA-2β and Zinc Transporter 8 to Classification of Diabetes Diagnosed Under 40 Years of Age
Authors: Ilse Vermeulen, Ilse Weets, Milca Asanghanwa, Johannes Ruige, Luc Van Gaal, Chantal Mathieu, Bart Keymeulen, Vito Lampasona, Janet M. Wenzlau, John C. Hutton, Daniel G. Pipeleers, Frans K. Gorus
Journal: Diabetes Care (2011)

We investigated whether measuring autoantibodies against zinc transporter 8 (ZnT8A) and IA-2β (IA-2βA) may improve classification of new-onset type 1 diabetic patients based on detection of autoantibodies against insulin (IAA), GAD (GADA), and IA-2 (IA-2A). In addition, we studied the correlation of IA-2βA and ZnT8A with other biological and demographic variables.Circulating autoantibodies were determined by liquid-phase radiobinding assays from 761 healthy control subjects and 655 new-onset (<1 week insulin) diabetic patients (aged 0-39 years) with clinical type 1 diabetes phenotype consecutively recruited by the Belgian Diabetes Registry.At diagnosis, IA-2βA and ZnT8A prevalences were 41 and 58%, respectively. In IAA-negative, GADA-negative, and IA-2A-negative patients, one IA-2βA-positive and eleven ZnT8A-positive individuals were identified at the expense of eight and seven additional positive control subjects (1%), respectively, for each test. ZnT8A or IA-2βA screening increased (P < 0.001; McNemar) the number of patients with ≥2 antibodies both under (from 78 to 87% for ZnT8A and 82% for IA-2βA) and above age 15 (from 51 to 63% for ZnT8A and 56% for IA-2βA) versus 0% in control subjects. IA-2βA and ZnT8A were preferentially associated with IA-2A, and with younger age at diagnosis. Unlike ZnT8A, IA-2βA levels were positively correlated with HLA-DQ8 and negatively with HLA-DQ2. ZnT8A could replace IAA for classification of patients above age 10 without loss of sensitivity or specificity.ZnT8A, and to a lesser degree IA-2βA, may usefully complement GADA, IA-2A, and IAA for classifying insulin-treated diabetes under age 40 years.
Cd1d-dependent regulation of bacterial colonization in the intestine of mice
Authors: Edward E.S. Nieuwenhuis, Tetsuya Matsumoto, Dicky Lindenbergh, Rob Willemsen, Arthur Kaser, Ytje Simons-Oosterhuis, Sylvia Brugman, Keizo Yamaguchi, Hiroki Ishikawa, Yuji Aiba, Yasuhiro Koga, Janneke N. Samsom, Kenshiro Oshima, Mami Kikuchi, Johanna C. Escher, Masahira Hattori, Andrew B. Onderdonk, Richard S. Blumberg
Journal: Journal of Clinical Investigation (2009)

The accumulation of certain species of bacteria in the intestine is involved in both tissue homeostasis and immune-mediated pathologies. The host mechanisms involved in controlling intestinal colonization with commensal bacteria are poorly understood. We observed that under specific pathogen-free or germ-free conditions, intragastric administration of Pseudomonas aeruginosa, E. coli, Staphylococcus aureus, or Lactobacillus gasseri resulted in increased colonization of the small intestine and bacterial translocation in mice lacking Cd1d, an MHC class I-like molecule, compared with WT mice. In contrast, activation of Cd1d-restricted T cells (NKT cells) with alpha-galactosylceramide caused diminished intestinal colonization with the same bacterial strains. We also found prominent differences in the composition of intestinal microbiota, including increased adherent bacteria, in Cd1d-/- mice in comparison to WT mice under specific pathogen-free conditions. Germ-free Cd1d-/- mice exhibited a defect in Paneth cell granule ultrastructure and ability to degranulate after bacterial colonization. In vitro, NKT cells were shown to induce the release of lysozyme from intestinal crypts. Together, these data support a role for Cd1d in regulating intestinal colonization through mechanisms that include the control of Paneth cell function.
A proof of concept study by thrombomodulin for acute exacerbations of idiopathic pulmonary fibrosis
Authors: Kenji Tsushima, Toshiki Yokoyama, Yasunori Ichimura, Koichiro Tatsumi
Journal: European Respiratory Journal (2013)

The mortality of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is high. Anticoagulation therapy (recombinant human soluble thrombomodulin (rhTM)) is recognized as treating disseminated intravascular coagulation. The aim was to evaluate whether the coagulation factors were detected in AE-IPF, and whether the rhTM treatment for AE-IPF-patients has beneficial effects. We retrospectively reviewed the data of AE-IPF, IPF with pneumonia and slowly progressive IPF-patients. Next, AE-IPF-patients were prospectively treated with rhTM under mechanical ventilation. The primary outcome was the improvement of oxygenation and intravascular coagulation disturbance in the acute phase. The secondary endopoints were the improvement of high-mobility group box-1 (HMGB-1). Eleven AE-IPF, 21 IPF with pneumonia and 16 slowly progressive IPF-patients were enrolled, and the plasma coagulatory levels of the AE-IPF-patients were found to be significantly higher than in the other patients. In a prospective study of the rhTM administration for 20 AE-IPF-patients, the 28-day mortality and in-hospital mortality were 35% and 45%, respectively. The SpO2/FIO2 rapidly increased on day 1 and continued to improve until day 7 in the survivors. The thrombin-antithrombin complex levels in the survivors on day 7 were significantly different from those observed in the nonsurvivors. The levels of HMGB-1in the nonsurvivors were significantly higher on day 7 compared to those observed in the survivors. Adding the administration of rhTM may improve pulmonary dysfunction in AE-IPF-patients, as demonstrated by significant improvements in oxygenation and microvascular coagulation.
Endogenous expression of FAD-linked PS1 impairs proliferation, neuronal differentiation and survival of adult hippocampal progenitors
Authors: Karthikeyan Veeraraghavalu, Se Hoon Choi, Xiaoqiong Zhang, Sangram S Sisodia
Journal: Molecular Neurodegeneration (2013)

Abstract Background Alzheimer’s disease (AD) is characterized by progressive memory loss and impaired cognitive function. Early-onset familial forms of the disease (FAD) are caused by inheritance of mutant genes encoding presenilin 1 (PS1) variants. We have demonstrated that prion promoter (PrP)-driven expression of human FAD-linked PS1 variants in mice leads to impairments in environmental enrichment (EE)-induced adult hippocampal neural progenitor cell (AHNPC) proliferation and neuronal differentiation, and have provided evidence that accessory cells in the hippocampal niche expressing PS1 variants may modulate AHNPC phenotypes, in vivo . While of significant interest, these latter studies relied on transgenic mice that express human PS1 variant transgenes ubiquitously and at high levels, and the consequences of wild type or mutant PS1 expressed under physiologically relevant levels on EE-mediated AHNPC phenotypes has not yet been tested. Results To assess the impact of mutant PS1 on EE-induced AHNPC phenotypes when expressed under physiological levels, we exposed adult mice that constitutively express the PSEN1 M146V mutation driven by the endogenous PSEN1 promoter (PS1 M146V “knock-in” (KI) mice) to standard or EE-housed conditions. We show that in comparison to wild type PS1 mice, AHNPCs in mice carrying homozygous ( PS1 M146V/M146V ) or heterozygous ( PS1 M146V/+ ) M146V mutant alleles fail to exhibit EE-induced proliferation and commitment towards neurogenic lineages. More importantly, we report that the survival of newborn progenitors are diminished in PS1 M146V KI mice exposed to EE-conditions compared to respective EE wild type controls. Conclusions Our findings reveal that expression at physiological levels achieved by a single PS1 M146V allele is sufficient to impair EE-induced AHNPC proliferation, survival and neuronal differentiation, in vivo . These results and our finding that microglia expressing a single PS1 M146V allele impairs the proliferation of wild type AHNPCs in vitro argue that expression of mutant PS1 in the AHNPC niche impairs AHNPCs phenotypes in a dominant, non-cell autonomous manner.
T cell–independent development and induction of somatic hypermutation in human IgM+IgD+CD27+ B cells
Authors: Ferenc A. Scheeren, Maho Nagasawa, Kees Weijer, Tom Cupedo, Jörg Kirberg, Nicolas Legrand, Hergen Spits
Journal: The Journal of Experimental Medicine (2008)

IgM+IgD+CD27+ B cells from peripheral blood have been described as circulating marginal zone B cells. It is still unknown when and where these cells develop. These IgM+IgD+CD27+ B cells exhibit somatic hypermutations (SHMs) in their B cell receptors, but the exact nature of the signals leading to induction of these SHMs remains elusive. Here, we show that IgM+IgD+CD27+ B cells carrying SHMs are observed during human fetal development. To examine the role of T cells in human IgM+IgD+CD27+ B cell development we used an in vivo model in which Rag2−/−γC−/− mice were repopulated with human hematopoietic stem cells. Using Rag2−/−γC−/− mice on a Nude background, we demonstrated that development and induction of SHMs of human IgM+IgD+CD27+ B cells can occur in a T cell–independent manner.
Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage
Authors: Denise N. Bronner, Basel H. Abuaita, Xiaoyun Chen, Katherine A. Fitzgerald, Gabriel Nuñez, Yongqun He, Xiao-Ming Yin, Mary X.D. O’Riordan
Journal: Immunity (2015)
Nicotinamide phosphoribosyltransferase/visfatin expression by inflammatory monocytes mediates arthritis pathogenesis
Authors: Jessy Présumey, Gabriel Courties, Pascale Louis-Plence, Virginie Escriou, Daniel Scherman, Yves-Marie Pers, Hans Yssel, Jérôme Pène, Diego Kyburz, Steffen Gay, Christian Jorgensen, Florence Apparailly
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Nicotinamide phosphoribosyltransferase (NAMPT)/pre-B-cell colony-enhancing factor/visfatin exerts multiple functions and has been implicated in the pathogenesis of rheumatoid arthritis. To gain insight into its role in arthritis and given that NAMPT is identified as a novel mediator of innate immunity, we addressed the function of monocyte-derived NAMPT in experimental arthritis by selective gene knockdown in inflammatory monocytes. <h3>Methods</h3> siRNA uptake and NAMPT expression were determined in Ly6C<sup>high</sup> and Ly6C<sup>low</sup> monocyte subsets following intravenous injection of siRNA against NAMPT (siNAMPT) or non-targeting siRNA (siCT) formulated with the DMAPAP cationic liposome into mice. Mice with established collagen-induced arthritis (CIA) were treated weekly after disease onset with siNAMPT or siCT and clinical features were assessed. T-helper cell frequencies, cytokine production and percentage of IL-6-producing Ly6C<sup>high</sup> monocytes were analysed. Using a co-culture system consisting of purified CD14 monocytes and autologous CD4 T cells, NAMPT and cytokine production, and the percentage of IL-17-producing CD4 T cells, were determined following transfection of CD14 monocytes with siCT or siNAMPT. <h3>Results</h3> On intravenous injection, siRNA was preferentially engulfed by Ly6C<sup>high</sup> monocytes, and siRNA-mediated silencing of NAMPT expression in Ly6C<sup>high</sup> monocytes inhibited CIA progression. This effect was associated with reduced IL-6 production by Ly6C<sup>high</sup> monocytes, reduced proportion of Th17 cells and autoantibody titers, and decreased activation and infiltration of monocytes/macrophages and neutrophils in arthritic joints. Moreover, NAMPT-RNAi-silenced CD14 monocytes were found to reduce the percentage of IL-17-producing CD4 T cells in vitro. <h3>Conclusions</h3> Our results show that the expression of NAMPT in Ly6C<sup>high</sup> monocytes promotes many downstream effects involved in inflammatory arthritis and demonstrate the utility of targeting disease-causing genes, such as NAMPT, in Ly6C<sup>high</sup> monocytes for therapeutic intervention in arthritis.