tbuckley/cabot-search huggingface dataset:
Rapid resetting of low pressure vagal receptors in the superior vena cava of the rat.
Authors: S W Mifflin, D L Kunze
Journal: Circulation Research (1982)

The discharge characteristics of mechanoreceptors located in the left superior vena cava were determined in an in vitro preparation developed from the rat. Two classes of receptors with afferent fibers in the vagus were identified on the basis of their response to steps of pressure. Slowly adapting receptors (n = 18) discharged as long as pressure was above threshold and exhibited a biphasic decline in discharge frequency in response to a pressure step. There was a rapid, initial decline in discharge frequency, complete within 15 seconds, followed by a slow, gradual decline complete within 5 minutes. Rapidly adapting receptors (n = 15) discharged irregularly or ceased firing after 5-10 seconds of a step increase in pressure. Following a 15-minute increase in perfusion pressure from 0 to 5 mm Hg, the threshold pressure of the slowly adapting receptors was increased and maximal discharge frequency and slope were decreased, whereas, in the rapidly adapting receptors, the threshold pressure was increased but maximal discharge frequency and slope were unchanged. Additional perfusion of the vessel at 5 mm Hg for up to 60 minutes produced no further increase in the degree of resetting. The resetting was reversible with discharge returning to control levels after a 15- to 25-minute return to 0 mm Hg. To determine whether the resetting of discharge following the acute pressure increase reflected a change within the receptor or an alteration of the vessel wall due to sustained distension, we examined the passive mechanical properties of the superior vena cava. Pressure-radius relationships were determined with an ocular micrometer. A 15-minute increase in pressure had no significant effect upon the mechanical properties of the vessel. Rapid resetting in these low pressure mechanoreceptors occurs with no discernible alteration in the vessel wall.
Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome
Authors: Yoshiyuki Minegishi, Masako Saito, Masayuki Nagasawa, Hidetoshi Takada, Toshiro Hara, Shigeru Tsuchiya, Kazunaga Agematsu, Masafumi Yamada, Nobuaki Kawamura, Tadashi Ariga, Ikuya Tsuge, Hajime Karasuyama
Journal: The Journal of Experimental Medicine (2009)

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic manifestations and susceptibility to infections with extracellular pathogens, typically Staphylococcus aureus, which preferentially affect the skin and lung. Previous studies reported the defective differentiation of T helper 17 (Th17) cells in HIES patients caused by hypomorphic STAT3 mutations. However, the apparent contradiction between the systemic Th17 deficiency and the skin/lung-restricted susceptibility to staphylococcal infections remains puzzling. We present a possible molecular explanation for this enigmatic contradiction. HIES T cells showed impaired production of Th17 cytokines but normal production of classical proinflammatory cytokines including interleukin 1beta. Normal human keratinocytes and bronchial epithelial cells were deeply dependent on the synergistic action of Th17 cytokines and classical proinflammatory cytokines for their production of antistaphylococcal factors, including neutrophil-recruiting chemokines and antimicrobial peptides. In contrast, other cell types were efficiently stimulated with the classical proinflammatory cytokines alone to produce such factors. Accordingly, keratinocytes and bronchial epithelial cells, unlike other cell types, failed to produce antistaphylococcal factors in response to HIES T cell-derived cytokines. These results appear to explain, at least in part, why HIES patients suffer from recurrent staphylococcal infections confined to the skin and lung in contrast to more systemic infections in neutrophil-deficient patients.
Survival in Patients with Primary Pulmonary Hypertension
Authors: Gilbert E. D'Alonzo, Robyn J. Barst, Stephen M. Ayres, Edward H. Bergofsky, Bruce H. Brundage, Katherine M. Detre, Alfred P. Fishman, Roberta M. Goldring, Berton M. Groves, Janet T. Kernis, Paul S. Levy, Giuseppe G. Pietra, Lynne M. Reid, John T. Reeves, Stuart Rich, Carol E. Vreim, George W. Williams, Margaret Wu
Journal: Annals of Internal Medicine (1991)

Objective: To characterize mortality in persons diagnosed with primary pulmonary hypertension and to investigate factors associated with survival. Design: Registry with prospective follow-up. Setting: Thirty-two clinical centers in the United States participating in the Patient Registry for the Characterization of Primary Pulmonary Hypertension supported by the National Heart, Lung, and Blood Institute. Patients: Patients (194) diagnosed at clinical centers between 1 July 1981 and 31 December 1985 and followed through 8 August 1988. Measurements: At diagnosis, measurements of hemodynamic variables, pulmonary function, and gas exchange variables were taken in addition to information on demographic variables, medical history, and life-style. Patients were followed for survival at 6-month intervals. Main Results: The estimated median survival of these patients was 2. 8 years (95% Cl, 1.9 to 3.7 years). Estimated single-year survival rates were as follows: at 1 year, 68% (Cl, 61% to 75%); at 3 years, 48% (Cl, 41% to 55%); and at 5 years, 34% (Cl, 24% to 44%). Variables associated with poor survival included a New York Heart Association (NYHA) functional class of III or IV, presence of Raynaud phenomenon, elevated mean right atrial pressure, elevated mean pulmonary artery pressure, decreased cardiac index, and decreased diffusing capacity for carbon monoxide (DLCO). Drug therapy at entry or discharge was not associated with survival duration. Conclusions: Mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables: mean pulmonary artery pressure, mean right atrial pressure, and cardiac index. Such an equation, once validated prospectively, could be used as an adjunct in planning treatment strategies and allocating medical resources.
Infection with chikungunya virus in Italy: an outbreak in a temperate region
Authors: G Rezza, L Nicoletti, R Angelini, R Romi, AC Finarelli, M Panning, P Cordioli, C Fortuna, S Boros, F Magurano, G Silvi, P Angelini, M Dottori, MG Ciufolini, GC Majori, A Cassone
Journal: The Lancet (2007)
Folding and assembly of major histocompatibility complex class I heterodimers in the endoplasmic reticulum of intact cells precedes the binding of peptide.
Authors: J J Neefjes, G J Hämmerling, F Momburg
Journal: The Journal of Experimental Medicine (1993)

Major histocompatibility complex (MHC) class I molecules are heterotrimers consisting of a polymorphic H chain, beta 2-microglobulin (beta 2m) and peptide. Peptides are thought to associate early during biosynthesis but the order of assembly of class I molecules from their component subunits in intact cells is not settled. We have studied the assembly of MHC class I molecules in intact cells with or without peptide transporters. MHC class I H chain/beta 2m heterodimers can be efficiently recovered only 4 min after translation and are preceded by a folding intermediate. Approximately 2 min after their formation, the class I heterodimers are loaded with peptides resulting in stable class I heterotrimers. In these in vivo studies, no evidence was obtained that peptide binding to the H chain preceded the association with beta 2m. In contrast, nonassembled class I H chains could be recovered immediately after translation, but this pool did not participate in the formation of class I molecules.
Collagen degradation and neutrophilic infiltration: a vicious circle in inflammatory bowel disease
Authors: Pim J Koelink, Saskia A Overbeek, Saskia Braber, Mary E Morgan, Paul A J Henricks, Mojtaba Abdul Roda, Hein W Verspaget, Simone C Wolfkamp, Anje A te Velde, Caleb W Jones, Patricia L Jackson, J Edwin Blalock, Rolf W Sparidans, John A W Kruijtzer, Johan Garssen, Gert Folkerts, Aletta D Kraneveld
Journal: Gut (2013)

<h3>Objective</h3> Proline–glycine–proline (PGP) has been shown to have chemotactic effects on neutrophils via CXCR2 in several lung diseases. PGP is derived from collagen by the combined action of matrix metalloproteinase (MMP) 8 and/or MMP9 and prolyl endopeptidase (PE). We investigated the role of PGP in inflammatory bowel disease (IBD). <h3>Design</h3> In intestinal tissue from patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis, MMP8, MMP9 and PE were evaluated by ELISA, immunoblot and immunohistochemistry. Peripheral blood polymorphonuclear cell (PMN) supernatants were also analysed accordingly and incubated with collagen to assess PGP generation ex vivo. PGP levels were measured by mass spectrometry, and PGP neutralisation was achieved with a PGP antagonist and PGP antibodies. <h3>Results</h3> In the intestine of patients with IBD, MMP8 and MMP9 levels were elevated, while PE was expressed at similar levels to control tissue. PGP levels were increased in intestinal tissue of patients with IBD. Similar results were obtained in intestine from DSS-treated mice. PMN supernatants from patients with IBD were far more capable of generating PGP from collagen ex vivo than healthy controls. Furthermore, PGP neutralisation during DSS-induced colitis led to a significant reduction in neutrophil infiltration in the intestine. <h3>Conclusions</h3> The proteolytic cascade that generates PGP from collagen, as well as the tripeptide itself, is present in the intestine of patients with IBD and mice with DSS-induced colitis. PGP neutralisation in DSS-treated mice showed the importance of PGP-guided neutrophilic infiltration in the intestine and indicates a vicious circle in neutrophilic inflammation in IBD.
cGMP-dependent protein kinase (PKG) mediates the anticontractile capacity of perivascular adipose tissue
Authors: Sarah B. Withers, Laura Simpson, Sharif Fattah, Matthias E. Werner, Anthony M. Heagerty
Journal: Cardiovascular Research (2013)

The aim of this study was to investigate the role of cGMP-dependent protein kinase (PKG) in mediating the anticontractile function of perivascular adipose tissue (PVAT) and whether its activation can rescue PVAT activity which is lost in an experimental model of inflammation.Contractile responses to norepinephrine were assessed using wire myography from small arterial segments obtained from PKG(-/-), PKG(+/+), adipo(-/-), and C57Bl6/J mice with and without PVAT during normal oxygenation and hypoxia. An anticontractile effect of PVAT was observed in control blood vessels. This was not present in arteries from PKG(-/-) or PKG(+/+) with inhibition of PKG signalling using DT-2/ODQ. Hypoxia-induced loss of PVAT function was rescued by ANP activation of PKG as there was no effect in blood vessels from PKG(-/-) mice or in the presence of DT-2. Solution transfer studies demonstrated that PKG was necessary for the normal paracrine effects of PVAT on smooth muscle and endothelium. PKG activation by atrial natriuretic peptide (ANP) did not restore the absent PVAT anticontractile capacity in arteries from adiponectin(-/-) mice; however, inhibition of PKG did not further abrogate this effect suggesting dysregulation of PKG signalling pathways in this model. The absence of PKG was associated with reduced adipocyte adiponectin expression.PKG plays a key role in regulating normal PVAT function both in modulating anticontractile factor release from adipocytes as well as being essential for its downstream dilator function in arterial smooth muscle.
Olympics are aimed at boosting sport more than improving public health, says minister
Authors: A. O'Dowd
Journal: BMJ (2012)

One of the main aims of the London 2012 Olympic and Paralympic Games is to encourage more people to participate in sport in the future rather than to boost public health, a minister has told peers.

Hugh Robertson, minister for sports and the Olympics, said he hoped improving public health will be a positive consequence of the games, when he gave evidence to the House of Lords science and technology committee on 26 June.

Boosting participation in sport, particular among younger people, was a “key policy objective,” Robertson told the peers as part of the committee’s inquiry into sports and exercise science medicine, which is looking at how the legacy of the 2012 Games can be used to …
Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412
Authors: Ganesh Suntharalingam, Meghan R. Perry, Stephen Ward, Stephen J. Brett, Andrew Castello-Cortes, Michael D. Brunner, Nicki Panoskaltsis
Journal: New England Journal of Medicine (2006)

Six healthy young male volunteers at a contract research organization were enrolled in the first phase 1 clinical trial of TGN1412, a novel superagonist anti-CD28 monoclonal antibody that directly stimulates T cells. Within 90 minutes after receiving a single intravenous dose of the drug, all six volunteers had a systemic inflammatory response characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythema, vasodilatation, and hypotension. Within 12 to 16 hours after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. Severe and unexpected depletion of lymphocytes and monocytes occurred within 24 hours after infusion. All six patients were transferred to the care of the authors at an intensive care unit at a public hospital, where they received intensive cardiopulmonary support (including dialysis), high-dose methylprednisolone, and an anti-interleukin-2 receptor antagonist antibody. Prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for 8 and 16 days. Despite evidence of the multiple cytokine-release syndrome, all six patients survived. Documentation of the clinical course occurring over the 30 days after infusion offers insight into the systemic inflammatory response syndrome in the absence of contaminating pathogens, endotoxin, or underlying disease.
Annexin II increases osteoclast formation by stimulating the proliferation of osteoclast precursors in human marrow cultures
Authors: Cheikh Menaa, Rowena D. Devlin, Sakamuri V. Reddy, Yair Gazitt, Sun Jin Choi, G. David Roodman
Journal: Journal of Clinical Investigation (1999)

Annexin II (AXII), a calcium-dependent phospholipid-binding protein, has been recently found to be an osteoclast (OCL) stimulatory factor that is also secreted by OCLs. In vitro studies showed that AXII induced OCL formation and bone resorption. However, the mechanism of action by which AXII acts as a soluble extracellular protein to induce OCL formation is unknown. In this paper, we demonstrate that AXII gene expression is upregulated by 1,25-dihydroxyvitamin D3 [1, 25-(OH)2D3] and that addition of AXII significantly increased OCL-like multinucleated cell formation. Time-course studies suggested that AXII acted on the proliferative stage of OCL precursors and that AXII increased thymidine incorporation in OCL precursors. Moreover, AXII enhanced the growth of CFU-GM, the earliest identifiable OCL precursor, when bone marrow cultures were treated with low concentrations of GM-CSF. This capacity of AXII to induce OCL precursor proliferation was due to induction of GM-CSF expression, because the addition of neutralizing antibodies to GM-CSF blocked the stimulatory effect of AXII on OCL formation. RT-PCR analysis using RNA from highly purified subpopulations of marrow cells demonstrated that T cells, especially CD4(+) T cells, produced GM-CSF in response to AXII. Furthermore, FACS(R) analysis of T-cell subpopulations treated with fluorescein-labeled AXII suggested that the CD4(+), but not CD8(+), subpopulation of T cells express an AXII receptor. Taken together, these data suggest that AXII stimulates OCL formation by activating T cells through a putative receptor to secrete GM-CSF. GM-CSF then expands the OCL precursor pool to enhance OCL formation.
Selective stimulation of IL-4 receptor on smooth muscle induces airway hyperresponsiveness in mice
Authors: Charles Perkins, Noriko Yanase, George Smulian, Lucy Gildea, Tatyana Orekov, Crystal Potter, Frank Brombacher, Bruce Aronow, Marsha Wills-Karp, Fred D. Finkelman
Journal: The Journal of Experimental Medicine (2011)

Production of the cytokines IL-4 and IL-13 is increased in both human asthma and mouse asthma models, and Stat6 activation by the common IL-4/IL-13R drives most mouse model pathophysiology, including airway hyperresponsiveness (AHR). However, the precise cellular mechanisms through which IL-4Rα induces AHR remain unclear. Overzealous bronchial smooth muscle constriction is thought to underlie AHR in human asthma, but the smooth muscle contribution to AHR has never been directly assessed. Furthermore, differences in mouse versus human airway anatomy and observations that selective IL-13 stimulation of Stat6 in airway epithelium induces murine AHR raise questions about the importance of direct IL-4R effects on smooth muscle in murine asthma models and the relevance of these models to human asthma. Using transgenic mice in which smooth muscle is the only cell type that expresses or fails to express IL-4Rα, we demonstrate that direct smooth muscle activation by IL-4, IL-13, or allergen is sufficient but not necessary to induce AHR. Five genes known to promote smooth muscle migration, proliferation, and contractility are activated by IL-13 in smooth muscle in vivo. These observations demonstrate that IL-4Rα promotes AHR through multiple mechanisms and provide a model for testing smooth muscle–directed asthma therapeutics.
Bone Sialoprotein Is Predictive of Bone Metastases in Resectable Non–Small-Cell Lung Cancer: A Retrospective Case-Control Study
Authors: Mauro Papotti, Thea Kalebic, Marco Volante, Luigi Chiusa, Elisa Bacillo, Susanna Cappia, Paolo Lausi, Silvia Novello, Piero Borasio, Giorgio V. Scagliotti
Journal: Journal of Clinical Oncology (2006)

Bone metastases (BM) in non-small-cell lung cancer (NSCLC) may be detected at diagnosis or during the course of the disease, and are associated with a worse prognosis. Currently, there are no predictive or diagnostic markers to identify high-risk patients for metastatic bone dissemination.Thirty patients with resected NSCLC who subsequently developed BM were matched for clinicopathologic parameters to 30 control patients with resected NSCLC without any metastases and 26 patients with resected NSCLC and non-BM lesions. Primary tumors were investigated by immunohistochemistry for 10 markers involved in bone resorption or development of metastases. Differences among groups were estimated by chi2 test, whereas the prognostic impact of clinicopathologic parameters and marker expression was evaluated by univariate (Wilcoxon and Mantel-Cox tests) and multivariate (Cox proportional hazards regression model) analyses.The presence of bone sialoprotein (BSP) was strongly associated with bone dissemination (P < .001) and, independently, with worse outcome (P = .02, Mantel-Cox test), as defined by overall survival. To evaluate BSP protein expression in nonselected NSCLC, a series of 120 consecutive resected lung carcinomas was added to the study, and BSP prevalence reached 40%. No other markers showed a statistically significant difference among the three groups or demonstrated a prognostic impact, in terms of both overall survival and time interval to metastases.BSP protein expression in the primary resected NSCLC is strongly associated with BM progression and could be useful in identifying high-risk patients who could benefit from novel modalities of surveillance and preventive treatment.
Relationship between exposure and toxicity in high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin
Authors: A.D.R. Huitema, M. Spaander, R.A.A. Mathôt, M.M. Tibben, M.J. Holtkamp, J.H. Beijnen, S. Rodenhuis
Journal: Annals of Oncology (2002)
The Pathogenic Role of Macrophage Migration Inhibitory Factor in Immunologically Induced Kidney Disease in the Rat
Authors: Hui Y. Lan, Michael Bacher, Niansheng Yang, Wei Mu, David J. Nikolic-Paterson, Christine Metz, Andreas Meinhardt, Richard Bucala, Robert C. Atkins
Journal: The Journal of Experimental Medicine (1997)

Macrophage migration inhibitory factor (MIF) plays a pivotal role in the inflammatory response in endotoxemia and in the delayed-type hypersensitivity response, but its potential as a regulator of immunologically induced disease is unknown. We have addressed this issue by administering a neutralizing anti-MIF antibody in a rat model of immunologically induced crescentic anti-glomerular basement membrane (GBM) glomerulonephritis. Six individual experiments using paired inbred littermates were performed. Rats were primed with rabbit immunoglobulin on day -5 and then injection with rabbit anti-rat GBM serum on day 0. Pairs of animals were treated with anti-MIF or a control monoclonal antibody from the time of anti-GBM serum administration until being killed 14 d later. Control antibody-treated animals developed severe proteinuria and renal function impairment with severe histological damage due to marked leukocytic infiltration and activation within the kidney. In contrast, anti-MIF treatment substantially reduced proteinuria, prevented the loss of renal function, significantly reduced histological damage including glomerular crescent formation, and substantially inhibited renal leukocytic infiltration and activation (all P <0.001 compared with control treatment). Inhibition of renal disease by anti-MIF treatment was attributed to preventing the marked upregulation of interleukin-1beta, leukocyte adhesion molecules including intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and inducible nitric oxide synthase expression seen in the control antibody-treated animals. This inhibition of progressive renal injury was mirrored by the complete suppression of the skin delayed-type hypersensitivity response to the challenge antigen (rabbit IgG). Interestingly, anti-MIF treatment did not effect the secondary antibody response or immune deposition within the kidney, indicating that MIF participates in cellular-based immunity in this primed macrophage-dependent anti-GBM glomerulonephritis. In conclusion, this study has demonstrated a key regulatory role for MIF in the pathogenesis of immunologically induced kidney disease. These results argue that blocking MIF activity may be of benefit in the treatment of human rapidly progressive glomerulonephritis, and suggest that MIF may be important in immune-mediated disease generally.
Visualizing the Landscape of Selection Biomarkers in Current Phase III Oncology Clinical Trials
Authors: Robert Sikorski, Bin Yao
Journal: Science Translational Medicine (2010)

Selection biomarkers are disease-associated analytes whose measurement is either an essential step in patient screening or the primary objective of a clinical trial. The public database ClinicalTrials.gov contains information on most active phase III oncology clinical trials that can be examined for trends in the development of cancer therapies. But for selection biomarkers, such information is not easily accessible and so has not been examined in a comprehensive way. Here we provide a global analysis of selection biomarkers currently in use in the oncology phase III trial arena.