tbuckley/cabot-search huggingface dataset:
In vivo action of trefoil factor 2 (TFF2) to speed gastric repair is independent of cyclooxygenase
Authors: L. Xue, E. Aihara, D. K. Podolsky, T. C. Wang, M. H. Montrose
Journal: Gut (2010)

<h3>Objective</h3> Trefoil factor (TFF) peptides are expressed in gastric tissues, where they are part of the epithelial defences. To complement previous in vitro work, the goal of the present study was to examine directly if TFF2 was essential for gastric restitution in vivo during the recovery from microscopic damage. <h3>Design</h3> TFF2 mutant (KO) mice were examined to study the epithelial repair process in vivo after laser-induced photodamage (LPD). Using two-photon laser energy absorption (710 nm), LPD was imposed on an ∼3–5 cell region of surface epithelium in anaesthetised mouse stomach. Responses to damage were evaluated during confocal time-lapse microscopy; including area of damage and the extracellular pH adjacent to the damaged surface (Cl-NERF pH sensor). <h3>Results</h3> In control (TFF2+/+ and TFF2+/–) mice, damaged cells were exfoliated and the damaged epithelium was repaired by indomethacin. The resting surface pH was similar between control and TFF2-KO animals, but the post-LPD alkalisation of surface pH observed in control mice (∆pH 0.3±0.05, n=21) was attenuated in the TFF2-KO stomach (∆pH −0.08±0.09, n=18). Recobinant rat TFF3 partially rescued the attenuated surface pH change in TFF2-KO stomach, in the presence or absence of indomethacin. <h3>Conclusions</h3> In the gastric epithelium in vivo, TFFs promote epithelial restitution via a mechanism that does not require cyclooxygenase activation. A novel role for TFFs to affect gastric surface pH is observed.
Macrophage colony-stimulating factor stimulates survival and chemotactic behavior in isolated osteoclasts.
Authors: K Fuller, J M Owens, C J Jagger, A Wilson, R Moss, T J Chambers
Journal: The Journal of Experimental Medicine (1993)

Macrophage colony-stimulating factor (M-CSF) is known to play an important role in osteoclast formation. However, its actions on mature cells have not been fully characterized. We now report that M-CSF dramatically stimulates osteoclastic motility and spreading; osteoclasts responded to a gradient of M-CSF with orientation, and random cell polarization occurred after isotropic exposure. M-CSF also supported the survival of osteoclasts by preventing apoptosis. Paradoxically, M-CSF inhibits bone resorption by isolated osteoclasts. We found that this was effected predominantly by reduction in the number of excavations. Thus, M-CSF showed a propensity to suppress resorption through a reduction in the proportion of cells that were resorbing bone. Our data suggest that apart from the established role of M-CSF in the provision of precursors for osteoclastic induction, a major role for M-CSF in bone resorption is to enhance osteoclastic survival, migration, and chemotaxis. It seems appropriate that during these processes resorptive functions should be suppressed. We suggest that M-CSF continues to modulate osteoclastic activity once osteoclasts are on resorptive sites, through regulation of the balance between resorption and migration, such that not only the quantity, but the spatial pattern of resorption can be controlled by adjacent M-CSF-secreting cells of osteoblastic lineage.
Increase in Prostaglandin E <sub>2</sub> Production by Interleukin-1β in Arterial Smooth Muscle Cells Derived From Patients With Moyamoya Disease
Authors: Mari Yamamoto, Masaru Aoyagi, Naomi Fukai, Yoshiharu Matsushima, Kiyotaka Yamamoto
Journal: Circulation Research (1999)

Abstract —Moyamoya disease is a progressive cerebrovascular occlusive disease that primarily affects children. The cause is unknown. We examined the production of prostanoids and the expression of cyclooxygenase-2 (COX-2) in cultured arterial smooth muscle cells (SMCs) derived from patients with moyamoya disease. Twelve moyamoya and 8 control cell strains were examined. The steady-state levels of prostanoids in the culture medium did not differ between moyamoya and control SMCs. When the cells were stimulated with interleukin-1β (IL-1β), prostaglandin E 2 (PGE 2 ) release into the medium was significantly greater from moyamoya SMCs than from control SMCs, whereas the amounts of prostacyclin and thromboxane B 2 did not differ. IL-1β–induced PGE 2 production by moyamoya SMCs was completely blocked by the addition of indomethacin or NS-398. IL-1β significantly stimulated cell migration and DNA synthesis in control SMCs but had an inhibitory effect on moyamoya SMCs. The inhibitory effects on the growth and migration of moyamoya SMCs were caused by excessive secretion of PGE 2 and was reversed with indomethacin treatment. Immunofluorescence studies and Western blot analysis showed greater amounts of COX-2 protein expression in IL-1β–stimulated moyamoya SMCs. These findings suggest that moyamoya SMCs respond to inflammatory stimuli to produce excess amounts of PGE 2 through the activation of COX-2, which increases vascular permeability and decreases vascular tone. This facilitates the exposure of vessels to blood constituents and promotes the development of intimal thickening in moyamoya disease.
Identification of the murine beige gene by YAC complementation and positional cloning
Authors: Charles M. Perou, Karen J. Moore, Deborah L. Nagle, Donald J. Misumi, Elizabeth A. Woolf, Sonja H. McGrail, Lisa Holmgren, Thomas H. Brody, Barry J. Dussault, Cheryl A. Monroe, Geoffrey M. Duyk, Robert J. Pryor, Liangtao Li, Monica J. Justice, Jerry Kaplan
Journal: Nature Genetics (1996)
EpCAM and α-Fetoprotein Expression Defines Novel Prognostic Subtypes of Hepatocellular Carcinoma
Authors: Taro Yamashita, Marshonna Forgues, Wei Wang, Jin Woo Kim, Qinghai Ye, Huliang Jia, Anuradha Budhu, Krista A. Zanetti, Yidong Chen, Lun-Xiu Qin, Zhao-You Tang, Xin Wei Wang
Journal: Cancer Research (2008)

Abstract The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification. Recently, we have identified that a hepatic stem cell marker, epithelial cell adhesion molecule (EpCAM), may serve as an early biomarker of HCC because its expression is highly elevated in premalignant hepatic tissues and in a subset of HCC. In this study, we aimed to identify novel HCC subtypes that resemble certain stages of liver lineages by searching for EpCAM-coexpressed genes. A unique signature of EpCAM-positive HCCs was identified by cDNA microarray analysis of 40 HCC cases and validated by oligonucleotide microarray analysis of 238 independent HCC cases, which was further confirmed by immunohistochemical analysis of an additional 101 HCC cases. EpCAM-positive HCC displayed a distinct molecular signature with features of hepatic progenitor cells including the presence of known stem/progenitor markers such as cytokeratin 19, c-Kit, EpCAM, and activated Wnt-β-catenin signaling, whereas EpCAM-negative HCC displayed genes with features of mature hepatocytes. Moreover, EpCAM-positive and EpCAM-negative HCC could be further subclassified into four groups with prognostic implication by determining the level of α-fetoprotein (AFP). These four subtypes displayed distinct gene expression patterns with features resembling certain stages of hepatic lineages. Taken together, we proposed an easy classification system defined by EpCAM and AFP to reveal HCC subtypes similar to hepatic cell maturation lineages, which may enable prognostic stratification and assessment of HCC patients with adjuvant therapy and provide new insights into the potential cellular origin of HCC and its activated molecular pathways. [Cancer Res 2008;68(5):1451–61]
Polycythemia and the budd-chiari syndrome: Study of serum erythropoietin and bone marrow erythroid progenitors
Authors: Victor Georges Levy, Agnès Ruskone, Claude Baillou, Diana Thierman-Duffaud, Albert Najman, Georges Albert Boffa
Journal: Hepatology (1985)

The mechanism of polycythemia associated with the Budd–Chiari syndrome is unknown. Erythropoiesis in 10 patients with Budd–Chiari syndrome was studied in an attempt to distinguish prior unrecognized polycythemia vera from secondary polycythemia. Serum erythropoietin was assayed using a mouse fetal liver erythroblast assay. High concentrations of serum erythropoietin were observed in 6 of 7 patients with acute primary Budd–Chiari syndrome. Levels were normal in four patients who were investigated during the chronic phase and were increased in one with persisting polycythemia. In one patient, erythropoietin concentration in the hepatic vein was twice the level measured in peripheral, caval and renal venous blood. Bone marrow erythroid progenitors developed in vitro in the absence of exogenous erythropoietin in all polycythemia vera cases studied in acute and chronic phases, whether polycythemia persisted or not. These findings indicate that hepatic erythropoietin production occurs in the acute phase of Budd–Chiari syndrome and suggest that, in some cases of Budd Chiari syndrome, polycythemia which resolves after the acute phase may be secondary to liver disease.
The International Rugby Board (IRB) Pitch Side Concussion Assessment trial: a pilot test accuracy study
Authors: Gordon Ward Fuller, Simon P T Kemp, Philippe Decq
Journal: British Journal of Sports Medicine (2014)

Background ‘On the field and on the run’ assessments of head impact events in professional rugby have resulted in a high proportion of players subsequently diagnosed with confirmed concussion not leaving the field of play at the time of injury. The International Rugby Board (IRB) consequently developed a process to support team doctors in the recognition and management of players at risk of concussion, including development of a multimodal assessment instrument—the Pitch Side Concussion Assessment (PSCA) tool. Methods This was a pilot cohort study designed to determine the feasibility of assessing the accuracy of the IRB PSCA tool in elite male rugby. The study population comprised consecutive players identified with a head impact event with the potential to result in concussion during eight international/national competitions. Players were assessed off field by match-day or team doctors, following a temporary substitution. The accuracy of the PSCA tool was measured against a reference standard of postmatch confirmed concussion, based on clinical judgement aided by an established concussion support instrument. Results A total of 165 head injury events with the potential to cause concussion were included in the study. The PSCA tool demonstrated a sensitivity of 84.6% (95% CI 73.5% to 92.4%) and a specificity of 74% (95% CI 64.3% to 82.3%) to identify players subsequently diagnosed with confirmed concussion. The negative predictive value was 88.1% (95% CI 79.2% to 94.1%); the positive predictive value was 67.9% (95% CI 56.6% to 77.8%). There were no major barriers identified that would prevent the evaluation of the PSCA process or tool in a future large-scale study. Conclusions This pilot study has provided the first preliminary estimates for the performance of the PSCA tool, suggesting a potentially favourable balance between positive and negative predictive values. The study has also offered a strong basis to conduct a further larger trial, providing information for sample size calculations and highlighting areas for methodological development.
Elastase-mediated fibrinogenolysis by chemoattractant-stimulated neutrophils occurs in the presence of physiologic concentrations of antiproteinases.
Authors: J I Weitz, A J Huang, S L Landman, S C Nicholson, S C Silverstein
Journal: The Journal of Experimental Medicine (1987)

Plasma levels of the HNE-derived fibrinopeptide A alpha 1-21 reflect in vivo enzyme activity. To provide a possible explanation for the presence of circulating A alpha 1-21 in individuals with normal plasma antiproteinase concentrations we investigated whether PMN-associated HNE is more resistant to inhibition than the free enzyme. PMN were stimulated to migrate across 125I-fibrinogen-coated nitrocellulose filters in response to 10(-7) M FMLP, and the extent of fibrinogenolysis was determined by measuring release of A alpha 1-21 and 125I-labeled fibrinogen degradation products. The fibrinogenolytic activity of migrating PMN was then compared with that of free HNE present in PMN lysates or secreted by PMN stimulated with FMLP. Whereas the fibrinogenolytic activity of soluble HNE was completely inhibited by low concentrations (1%) of plasma or serum and macromolecular antiproteinase (alpha 1 proteinase-inhibitor and soybean trypsin-inhibitor), even in the presence of undiluted plasma or serum the activity of the migrating PMN was incompletely blocked (81-85%). Further, concentrations of alpha 1 proteinase-inhibitor and soybean trypsin-inhibitor that totally inhibited free HNE activity also incompletely blocked (88-89%) the fibrinogenolytic activity of migrating PMN, indicating that FMLP-stimulated PMN demonstrate significant fibrinogenolytic activity in the presence of antiproteinases as small as 20,000 mol wt. A specific low molecular weight HNE inhibitor (MeO-Suc-Ala2-Pro-ValCH2Cl), however, totally blocked PMN-mediated fibrinogenolysis without affecting intracellular HNE activity, HNE secretion from PMN, or PMN migration in response to FMLP. These findings support the hypothesis that PMN migrating on a fibrinogen-coated surface form zones of close contact with fibrinogen, thus preventing access of plasma antiproteinases to HNE released at the cell-substrate interface. The occurrence of this phenomenon in vivo would explain the presence of circulating A alpha 1-21 in individuals with normal antiproteinase concentrations.
Measuring quality of life: Is quality of life determined by expectations or experience?
Authors: A. J Carr
Journal: BMJ (2001)

This is the first in a series of five articles 

The way we think about health and health care is changing. The two factors driving this change are the recognition of the importance of the social consequences of disease and the acknowledgement that medical interventions aim to increase the length and quality of survival. For these reasons, the quality, effectiveness, and efficiency of health care are often evaluated by their impact on a patient's “quality of life.”

There is no consensus on the definition of quality of life as it is affected by health (health related quality of life). Definitions range from those with a holistic emphasis on the social, emotional, and physical wellbeing of patients after treatment1 to those that describe the impact of a person's health on his or her ability to lead a fulfilling life.2 This article assumes it to be those aspects of an individual's subjective experience that relate both directly and indirectly to health, disease, disability, and impairment. The central concern of this paper is the tendency to regard the quality of life as a constant. We contend that perceptions of health and its meaning vary between individuals and within an individual over time. People assess their health related quality of life by comparing their expectations with their experience. We propose a model of the relation between expectations and experience and use it to illustrate problems in measuring quality of life. The implications of these concepts for the use of quality of life as an indicator of the need for treatment and as an outcome of care are discussed.

#### Summary points

Health related quality of life is the gap between our expectations of health and our experience of it

Perception of quality of life varies between individuals and is dynamic within them

People with different …
Electrode revisions in nonthoracotomy implanted defibrillators; incidence, significance, and implications
Authors: Jay Curwin, Glenn Weiss, Ana Baptista, Alfred Casale, Grant Parr, John Brown, David Johnson, Alejandro Rodriguez, Richard Neibart, Denise Neglio, John Banas, Stephen Winters
Journal: Journal of the American College of Cardiology (1998)
Angiotensin II Activates RhoA in Cardiac Myocytes
Authors: Hiroki Aoki, Seigo Izumo, Junichi Sadoshima
Journal: Circulation Research (1998)

Abstract —The organization of actin into striated fibers (myofibrils) is one of the major features of cardiac hypertrophy. However, its signal transduction mechanism is not well understood. Although Rho-family small G proteins have been implicated in actin organization in many cell types, it is not fully elucidated whether Rho mediates the organization of actin fibers by hypertrophic stimuli in cardiac myocytes. Therefore, we examined (1) whether Rho is activated by the hypertrophic stimulus, angiotensin II (Ang II), and (2) whether Rho mediates the Ang II–induced organization of actin fibers in cultured neonatal rat cardiac myocytes. Treatment of myocytes with Ang II caused a rapid formation of both striated (mature myofibrils) and nonstriated (premyofibrils) actin fibers within 30 minutes, as determined by phalloidin stainings of the polymerized actin and troponin T stainings. Immunoblot analyses and immunostainings have indicated that cardiac myocytes express RhoA, but RhoB is undetectable. In the control state, RhoA was observed predominantly in the cytosolic fraction, but it was translocated in part to the particulate fraction in response to Ang II, consistent with activation of RhoA by Ang II. Incubation of myocytes with exoenzyme C3 for 48 hours completely ADP-ribosylated Rho in vivo. The C3 treatment abolished formation of premyofibrils induced by Ang II, suggesting that Ang II causes premyofibril formation via a Rho-dependent mechanism. The Ang II–induced mature myofibril formation was only partly abolished by C3. Expression of constitutively active RhoA (V14RhoA) caused the formation of premyofibrils but not mature myofibrils. The C3 treatment inhibited Ang II–induced atrial natriuretic factor induction, whereas it had no effect on c- fos induction. These results indicate that RhoA is activated by Ang II and mediates the Ang II–induced formation of premyofibrils and induction of a subset of genes. Distinct signaling mechanisms seem to be responsible for striated mature myofibril formation by Ang II.
An inward rectifier and a voltage-dependent K+ current in single, cultured pericytes from bovine heart
Authors: N von Beckerath
Journal: Cardiovascular Research (2000)

The purpose of this study was to describe passive electrical properties and major membrane currents in coronary pericytes.78 single, cultured bovine pericytes were studied with the patch-clamp technique in the whole-cell mode.The membrane potential of the cells was -48.9+/-9.6 mV (mean+/-S.D.) with 5 mM and -23.2+/-2.2 mV with 60 mM extracellular K+. The membrane capacitance was 150.2+/-123.2 pF. The current-voltage relation of the pericytes was dominated by an inward current at hyperpolarized potentials and an outward current at depolarized potentials. Increasing extracellular K+ from 5 to 60 mM led to an increase of the inward current and to a shift of this current to more depolarized potentials. The inward current was very sensitive to extracellular barium (50 microM). The maximum slope conductance of the cells at hyperpolarized potentials was 2.9+/-2.8 nS. Inward rectification of whole-cell currents was steep (slope factor = 6.8 mV). With elevated external K+ the outward current reversed near the potassium equilibrium potential. Onset of the outward current was sigmoid and inactivation of this current was monoexponential, slow (time constant = 12.8 s) and incomplete. Voltage-dependence of outward current steady-state activation was steep (slope factor = 4.6 mV). The outward current was very sensitive to 4-aminopyridine (dissociation constant = 0.1 mM). The maximum slope conductance at depolarized potentials was 16.6+/-15.6 nS.We report for the first time, patch-clamp recordings from coronary pericytes. An inward rectifier and a voltage-dependent K+ current were identified and characterized. Regulation of these currents may influence coronary blood flow.
K <sub>ATP</sub> Channel Gene Expression Is Induced by Urocortin and Mediates Its Cardioprotective Effect
Authors: K.M. Lawrence, A. Chanalaris, T. Scarabelli, M. Hubank, E. Pasini, P.A. Townsend, L. Comini, R. Ferrari, A. Tinker, A. Stephanou, R.A. Knight, D.S. Latchman
Journal: Circulation (2002)

Urocortin is a novel cardioprotective agent that can protect cardiac myocytes from the damaging effects of ischemia/reperfusion both in culture and in the intact heart and is effective when given at reperfusion.We have analyzed global changes in gene expression in cardiac myocytes after urocortin treatment using gene chip technology. We report that urocortin specifically induces enhanced expression of the Kir 6.1 cardiac potassium channel subunit. On the basis of this finding, we showed that the cardioprotective effect of urocortin both in isolated cardiac cells and in the intact heart is specifically blocked by both generalized and mitochondrial-specific K(ATP) channel blockers, whereas the cardioprotective effect of cardiotrophin-1 is unaffected. Conversely, inhibiting the Kir 6.1 channel subunit greatly enhances cardiac cell death after ischemia.This is, to our knowledge, the first report of the altered expression of a K(ATP) channel subunit induced by a cardioprotective agent and demonstrates that K(ATP) channel opening is essential for the effect of this novel cardioprotective agent.
Bacterial exploitation of phosphorylcholine mimicry suppresses inflammation to promote airway infection
Authors: Christopher B. Hergott, Aoife M. Roche, Nikhil A. Naidu, Clementina Mesaros, Ian A. Blair, Jeffrey N. Weiser
Journal: Journal of Clinical Investigation (2015)

Regulation of neutrophil activity is critical for immune evasion among extracellular pathogens, yet the mechanisms by which many bacteria disrupt phagocyte function remain unclear. Here, we have shown that the respiratory pathogen Streptococcus pneumoniae disables neutrophils by exploiting molecular mimicry to degrade platelet-activating factor (PAF), a host-derived inflammatory phospholipid. Using mass spectrometry and murine upper airway infection models, we demonstrated that phosphorylcholine (ChoP) moieties that are shared by PAF and the bacterial cell wall allow S. pneumoniae to leverage a ChoP-remodeling enzyme (Pce) to remove PAF from the airway. S. pneumoniae-mediated PAF deprivation impaired viability, activation, and bactericidal capacity among responding neutrophils. In the absence of Pce, neutrophils rapidly cleared S. pneumoniae from the airway and impeded invasive disease and transmission between mice. Abrogation of PAF signaling rendered Pce dispensable for S. pneumoniae persistence, reinforcing that this enzyme deprives neutrophils of essential PAF-mediated stimulation. Accordingly, exogenous activation of neutrophils overwhelmed Pce-mediated phagocyte disruption. Haemophilus influenzae also uses an enzyme, GlpQ, to hydrolyze ChoP and subvert PAF function, suggesting that mimicry-driven immune evasion is a common paradigm among respiratory pathogens. These results identify a mechanism by which shared molecular structures enable microbial enzymes to subvert host lipid signaling, suppress inflammation, and ensure bacterial persistence at the mucosa.