tbuckley/cabot-search huggingface dataset:
Adenosine A2 receptor function in rat ventricular myocytes
Authors: J Dobson
Journal: Cardiovascular Research (1997)

Objective: This study was undertaken to investigate the functional significance of adenosine A2 receptor stimulation in a mammalian ventricular myocyte preparation. Methods: Isolated contracting rat ventricular myocytes were employed to assess the contractile, adenylyl cyclase and cyclic AMP responses to adenosine receptor stimulation. Results: In single myocytes the presence of A1 receptors was confirmed, as indicated by the A1 receptor agonist, phenylisopropyladenosine (PIA), reducing by 60 and 74% the inotropic response and activation of adenylyl cyclase, respectively, elicited by the β-adrenergic agonist, isoproterenol. An A1 receptor antagonist, dipropylcyclopentylxanthine (DPCPX), prevented the antiadrenergic action of PIA. The A2 receptor agonist, carboxyethylphenethyl-aminoethylcarboxamido-adenosine (CGS-21680; 0.01–10 μM) increased myocyte inotropy in a concentration-dependent manner, reaching a maximum of 41–45%. Ethylcarboxamidoadenosine (NECA), naphthyl-substituted aralkoxy-adenosine (SHA-082) and adenosine in the presence of DPCPX also increased myocyte inotropy, as evidenced by increases in myocyte shortening, duration of shortening, time-to-peak shortening, time-to-75% relaxation and rate of maximal shortening. The agonists, however, did not effect the maximal rate of relaxation. The A2 receptor antagonists, chlorofuranyldihydrotri-azoloquinazolinimine (CGS-15943) and chlorostyrylcaffeine (CSC), the latter selective for the A2a receptor, prevented the contractile responses elicited by the A2 agonists. Compared to the concentrations of A2 receptor agonists necessary to increase myocyte contractile variables, 3–12 times greater concentrations of the agonist were required to increase myocyte adenylyl cyclase activity and cAMP levels. Conclusion: The results suggest the presence of adenosine A2a receptors in the rat ventricular myocyte that appear to be responsible for an increase in inotropy via cAMP-dependent and -independent mechanisms. © 1997 Elsevier Science B.V.
Dominant optic atrophy, OPA1, and mitochondrial quality control: understanding mitochondrial network dynamics
Authors: Marcel V Alavi, Nico Fuhrmann
Journal: Molecular Neurodegeneration (2013)

Mitochondrial quality control is fundamental to all neurodegenerative diseases, including the most prominent ones, Alzheimer's Disease and Parkinsonism. It is accomplished by mitochondrial network dynamics – continuous fission and fusion of mitochondria. Mitochondrial fission is facilitated by DRP1, while MFN1 and MFN2 on the mitochondrial outer membrane and OPA1 on the mitochondrial inner membrane are essential for mitochondrial fusion. Mitochondrial network dynamics are regulated in highly sophisticated ways by various different posttranslational modifications, such as phosphorylation, ubiquitination, and proteolytic processing of their key-proteins. By this, mitochondria process a wide range of different intracellular and extracellular parameters in order to adapt mitochondrial function to actual energetic and metabolic demands of the host cell, attenuate mitochondrial damage, recycle dysfunctional mitochondria via the mitochondrial autophagy pathway, or arrange for the recycling of the complete host cell by apoptosis. Most of the genes coding for proteins involved in this process have been associated with neurodegenerative diseases. Mutations in one of these genes are associated with a neurodegenerative disease that originally was described to affect retinal ganglion cells only. Since more and more evidence shows that other cell types are affected as well, we would like to discuss the pathology of dominant optic atrophy, which is caused by heterozygous sequence variants in OPA1, in the light of the current view on OPA1 protein function in mitochondrial quality control, in particular on its function in mitochondrial fusion and cytochrome C release. We think OPA1 is a good example to understand the molecular basis for mitochondrial network dynamics.
Muscle Wasting Is Associated With Mortality in Patients With Cirrhosis
Authors: Aldo J. Montano–Loza, Judith Meza–Junco, Carla M.M. Prado, Jessica R. Lieffers, Vickie E. Baracos, Vincent G. Bain, Michael B. Sawyer
Journal: Clinical Gastroenterology and Hepatology (2011)
In vitro insulin resistance of human adipocytes isolated from subjects with noninsulin-dependent diabetes mellitus.
Authors: A Kashiwagi, M A Verso, J Andrews, B Vasquez, G Reaven, J E Foley
Journal: Journal of Clinical Investigation (1983)

To assess possible cellular mechanisms of in vitro resistance in noninsulin-dependent diabetes mellitus (NIDDM), maximum insulin-stimulated glucose transport and utilization and insulin binding were measured in adipocytes isolated from weight-matched normal glycemic subjects and patients with NIDDM. Glucose transport rate was determined by measuring the amount of [U-14C]-D-glucose taken up by incubating adipocytes at trace concentrations of glucose (300 nM), and glucose metabolism by estimating the amount of lactate, CO2, triglyceride, and total glucose carbons retained in the cells following incubating at 5.5 mM glucose. Insulin binding was measured at 50, 100, and 200 pM [mono125I-tyrosinyl A14]insulin. Both maximum insulin-stimulated glucose transport and utilization in adipocytes from diabetic subjects were 40% (P less than 0.01) and 32% (P less than 0.05) lower, respectively, than values obtained for subjects with normal glucose tolerance. In addition, the maximum capacity of glucose transport was correlated with the maximum capacity of glucose utilization (r = 0.81, P less than 0.001). Furthermore, fasting plasma glucose concentrations of diabetic subjects were negatively correlated with both maximum insulin-stimulated glucose transport (r = -0.56, P less than 0.05) and glucose utilization (r = -0.67, P less than 0.05). Since basal glucose transport in adipocytes from diabetic subjects was also 33% lower than in adipocytes from normal subjects, there was no change in the relative ability of insulin to stimulate glucose transport. However, there was a 64% decrease in the sensitivity of the glucose transport system to insulin (P less than 0.05), unrelated to concomitant changes in insulin binding. These results demonstrate that both maximal insulin-stimulated glucose transport and utilization, and the sensitivity of the glucose transport system to insulin, was decreased in adipocytes isolated from subjects with NIDDM. These in vitro defects were associated with impaired glucose metabolism in vivo, consistent with the view that the metabolic alterations observed at the cellular level may contribute to the in vivo insulin resistance of NIDDM.
The Hallucinations of Widowhood
Authors: W. D. Rees
Journal: BMJ (1971)

227 widows and 66 widowers were interviewed to determine the extent to which they had hallucinatory experiences of their dead spouse. The people interviewed formed 80.7% of all widowed people resident within a defined area, in mid-Wales, and 94.2% of those suitable, through the absence of incapacitating illness, for interview.Almost half the people interviewed had hallucinations or illusions of the dead spouse. The proportion of men and women who had these experiences was similar. The hallucinations often lasted many years but were most common during the first 10 years of widowhood. Social isolation did not affect the incidence of hallucination, nor was it related to the incidence of known depressive illness. There was no variation within cultural groups and there was no variation with place of residence, whether this was within town, country, or village, or within England and Wales.Young people were less likely to be hallucinated than those widowed after the age of 40. The incidence of hallucination increased with length of marriage and was particularly associated with a happy marriage and parenthood. Members of the "professional and managerial" group were particularly likely to be hallucinated, while widows of "non-manual and sales workers" were the ones least likely to be hallucinated. The incidence was greater with hysteroid than obsessoid people. It was unusual for the hallucinations to have been disclosed, even to close friends or relatives.These hallucinations are considered to be normal and helpful accompaniments of widowhood.
Renal expression of monocyte chemoattractant protein-1 in lupus autoimmune mice.
Authors: C Zoja, X H Liu, R Donadelli, M Abbate, D Testa, D Corna, G Taraboletti, A Vecchi, Q G Dong, B J Rollins, T Bertani, G Remuzzi
Journal: Journal of the American Society of Nephrology (1997)

Mononuclear cell infiltration in glomeruli and renal interstitium is a prominent feature of some types of glomerulonephritis, including lupus nephritis. The mechanism(s) underlying monocyte influx into the kidney is not fully understood. Recently, monocyte chemoattractant protein-1 (MCP-1) has been identified as a chemotactic factor involved in the recruitment of monocytes/macrophages in the glomeruli of rats with mesangioproliferative as well as anti-glomerular basement membrane glomerulonephritis. In the study presented here, renal MCP-1 mRNA expression in New Zealand Black x New Zealand White (NZB/W) F1 mice, a model of genetically determined immune complex disease that mimics systemic lupus in humans, was investigated. Northern blot analysis revealed a single 0.7 kb MCP-1 transcript of very low intensity in kidneys from 2-month-old NZB/W mice that had not yet developed proteinuria nor renal damage. Message levels, which increased markedly with the progression of nephritis and in association with mononuclear cell infiltration, were 10- and 15- fold higher in 8-10-month-old mice than in 2-month-old mice. By in situ hybridization, increased expression of MCP-1 mRNA was demonstrated in glomeruli and, even more striking, in tubular epithelial cells. Western blot analysis demonstrated increased expression of MCP-1 protein in kidneys of 10-month-old NZB/W mice, consistent with MCP-1 mRNA data. When NZB/W mice were treated with cyclophosphamide up to 12 months of age, expression of MCP-1 in the renal tissue remained low, the influx of inflammatory cells did not appear, and glomerular and tubular structures remained well preserved. These data suggest that elevated MCP-1 might act as a signal for inflammatory cells to infiltrate the kidney in lupus nephritis.
Association between intravenous chloride load during resuscitation and in-hospital mortality among patients with SIRS
Authors: Andrew D. Shaw, Karthik Raghunathan, Fred W. Peyerl, Sibyl H. Munson, Scott M. Paluszkiewicz, Carol R. Schermer
Journal: Intensive Care Medicine (2014)

Recent data suggest that both elevated serum chloride levels and volume overload may be harmful during fluid resuscitation. The purpose of this study was to examine the relationship between the intravenous chloride load and in-hospital mortality among patients with systemic inflammatory response syndrome (SIRS), with and without adjustment for the crystalloid volume administered.We conducted a retrospective analysis of 109,836 patients ≥ 18 years old that met criteria for SIRS and received fluid resuscitation with crystalloids. We examined the association between changes in serum chloride concentration, the administered chloride load and fluid volume, and the 'volume-adjusted chloride load' and in-hospital mortality.In general, increases in the serum chloride concentration were associated with increased mortality. Mortality was lowest (3.7%) among patients with minimal increases in serum chloride concentration (0-10 mmol/L) and when the total administered chloride load was low (3.5% among patients receiving 100-200 mmol; P < 0.05 versus patients receiving ≥ 500 mmol). After controlling for crystalloid fluid volume, mortality was lowest (2.6%) when the volume-adjusted chloride load was 105-115 mmol/L. With adjustment for severity of illness, the odds of mortality increased (1.094, 95% CI 1.062, 1.127) with increasing volume-adjusted chloride load (≥ 105 mmol/L).Among patients with SIRS, a fluid resuscitation strategy employing lower chloride loads was associated with lower in-hospital mortality. This association was independent of the total fluid volume administered and remained significant after adjustment for severity of illness, supporting the hypothesis that crystalloids with lower chloride content may be preferable for managing patients with SIRS.
Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings
Authors: Graeme Meintjes, Stephen D Lawn, Fabio Scano, Gary Maartens, Martyn A French, William Worodria, Julian H Elliott, David Murdoch, Robert J Wilkinson, Catherine Seyler, Laurence John, Maarten Schim van der Loeff, Peter Reiss, Lut Lynen, Edward N Janoff, Charles Gilks, Robert Colebunders
Journal: The Lancet Infectious Diseases (2008)
Cultured human endothelial cells stimulated with cytokines or endotoxin produce an inhibitor of leukocyte adhesion.
Authors: M E Wheeler, F W Luscinskas, M P Bevilacqua, M A Gimbrone
Journal: Journal of Clinical Investigation (1988)

Activation of cultured human endothelial cells (HEC) by inflammatory stimuli, such as interleukin 1 (IL-1), tumor necrosis factor (TNF), and bacterial endotoxin (lipopolysaccharide, LPS), increases their surface adhesiveness for blood leukocytes and related cell lines. We now report that activated HEC also generate a soluble leukocyte adhesion inhibitor (LAI), which accumulates in conditioned media from IL-1-, TNF-, or LPS-treated, but not sham-treated, HEC cultures. LAI significantly inhibits the adhesion of PMN and monocytes to activated, but not unactivated, HEC. In contrast, LAI has no effect on the adhesion of lymphocytes, the promyelocytic cell line HL-60 or the monocyte-like cell line U937 to HEC monolayers. LAI appears to act directly on the leukocyte, but does not inhibit either agonist-induced responses in PMN (membrane depolarization, changes in cytosolic calcium concentration, superoxide production) or PMN attachment to serum-coated plastic surfaces. Endothelial generation of LAI is blocked by actinomycin D but not by aspirin or indomethacin. Preliminary biochemical characterization indicates that LAI is a soluble, protein-containing molecule that is heat- and acid-stable. Fractionation by HPLC gel filtration yields a single peak of LAI activity (14,000 less than Mr greater than 24,000). Thus, in addition to proadhesive cell surface changes, the endothelium may also actively contribute to the regulation of endothelial-leukocyte interactions at sites of inflammation in vivo through the production of soluble adhesion inhibitors such as LAI.
Radiological and clinical outcomes of using Chartis™ to plan endobronchial valve treatment
Authors: Felix J.F. Herth, Ralf Eberhardt, Daniela Gompelmann, Joachim H. Ficker, Manfred Wagner, Lars Ek, Bernd Schmidt, Dirk-Jan Slebos
Journal: European Respiratory Journal (2012)

One-way endobronchial valves (EBVs) have been shown to relieve symptoms of emphysema, particularly in patients without collateral ventilation (CV) between the target and adjacent lobes. In this study, we investigated the ability of the bronchoscopic Chartis™ Pulmonary Assessment System to predict treatment response by determining the presence of CV. 80 EBV patients underwent a pre-treatment Chartis assessment. Before and 30 days after implantation, high-resolution computed tomography scans were taken to determine target lobe volume reduction (TLVR). A pre- to post-treatment reduction of ≥350 mL was defined as significant. In addition, clinical outcomes (forced expiratory volume in 1 s (FEV 1 ), 6-min walk test and St George’s Respiratory Questionnaire) were compared over the same time period. Of the 51 patients classified as having an absence of CV according to their Chartis reading, 36 showed a TLVR ≥350 mL. 29 patients were classified as having CV, and of these 24 did not meet this TLVR cut-off. Chartis showed an accuracy level of 75% in predicting whether or not the TLVR cut-off would be reached. Those predicted to respond showed significantly greater TLVR (p&lt;0.0001) and FEV 1 improvement (p=0.0013) than those predicted not to respond. Chartis is a safe and effective method of predicting response to EBV treatment.
A Novel Functional Polymorphism C1797G in the <i>MDM2</i> Promoter Is Associated with Risk of Bladder Cancer in a Chinese Population
Authors: Meilin Wang, Zhizhong Zhang, Haixia Zhu, Guangbo Fu, Shouyu Wang, Dongmei Wu, Jianwei Zhou, Qingyi Wei, Zhengdong Zhang
Journal: Clinical Cancer Research (2008)

Abstract Purpose: MDM2 is believed to regulate the p53 level in modulating DNA repair, cell cycle control, cell growth, and apoptosis. We hypothesize that genetic variants in the MDM2 gene are associated with risk of bladder cancer. Experimental Design: We first conducted a case-control study of 234 bladder cancer cases and 253 cancer-free controls, using the haplotype-based tagging single nucleotide polymorphism (SNP) approach involving 13 common SNPs initially identified in 100 control subjects. We then examined the functionality of the important SNP. Results: We found that the C1797G polymorphism in the MDM2 promoter region is an important SNP because its homozygous variant genotype, but none of the haplotypes, was associated with risk of bladder cancer. Electrophoretic mobility shift assay indicated that the 1797C to 1797G transition within the CAAT/enhancer binding protein α (C/EBP α) core sequence greatly enhanced the C/EBPα binding affinity to the promoter region. The in vitro luciferase assays in various cell lines further showed an increased transcriptional activity of the 1797G allele compared with the 1797C allele. Additional experiments with tumor tissues revealed that the transcriptional activator C/EBPα containing the 1797G allele increased levels of the MDM2 mRNA and protein in bladder tumor tissues. Conclusions: These data suggested that the novel MDM2 promoter C1797G polymorphism may affect the MDM2 activity by altering the C/EBPα binding affinity to the promoter and, thus, may be a marker for genetic susceptibility to bladder cancer in Chinese populations. Further validation of the functionality of the MDM2 C1797G polymorphism and its association with risk of bladder and other cancers in other ethnic populations is warranted.
Applications of Functionalized Fullerenes in Tumor Theranostics
Authors: Zhiyun Chen, Lijing Ma, Ying Liu, Chunying Chen
Journal: Theranostics (2012)

Functionalized fullerenes with specific physicochemical properties have been developed for cancer diagnosis and therapy. Notably, metallofullerene is a new class of magnetic resonance imaging (MRI) contrast-enhancing agent, and may have promising applications for clinical diagnosis. Polyhydroxylated and carboxyl fullerenes have been applied to photoacoustic imaging. Moreover, in recent years, functionalized fullerenes have shown potential in tumor therapies, such as photodynamic therapy, photothermal treatment, radiotherapy and chemotherapeutics. Their antitumor effects may be associated with the modulation of oxidative stress, anti-angiogenesis, and immunostimulatory activity. While various types of novel nanoparticle agents have been exploited in tumor theranostics, their distribution, metabolism and toxicity in organisms have also been a source of concern among researchers. The present review summarizes the potential of fullerenes as tumor theranostics agents and their possible underlying mechanisms are discussed.
Ventilation Strategy Using Low Tidal Volumes, Recruitment Maneuvers, and High Positive End-Expiratory Pressure for Acute Lung Injury and Acute Respiratory Distress Syndrome
Authors: Maureen O. Meade, Deborah J. Cook, Gordon H. Guyatt, Arthur S. Slutsky, Yaseen M. Arabi, D. James Cooper, Andrew R. Davies, Lori E. Hand, Qi Zhou, Lehana Thabane, Peggy Austin, Stephen Lapinsky, Alan Baxter, James Russell, Yoanna Skrobik, Juan J. Ronco, Thomas E. Stewart, for the Lung Open Ventilation Study Investigators
Journal: JAMA (2008)

Low-tidal-volume ventilation reduces mortality in critically ill patients with acute lung injury and acute respiratory distress syndrome. Instituting additional strategies to open collapsed lung tissue may further reduce mortality.To compare an established low-tidal-volume ventilation strategy with an experimental strategy based on the original "open-lung approach," combining low tidal volume, lung recruitment maneuvers, and high positive-end-expiratory pressure.Randomized controlled trial with concealed allocation and blinded data analysis conducted between August 2000 and March 2006 in 30 intensive care units in Canada, Australia, and Saudi Arabia.Nine hundred eighty-three consecutive patients with acute lung injury and a ratio of arterial oxygen tension to inspired oxygen fraction not exceeding 250.The control strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau airway pressures not exceeding 30 cm H2O, and conventional levels of positive end-expiratory pressure (n = 508). The experimental strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau pressures not exceeding 40 cm H2O, recruitment maneuvers, and higher positive end-expiratory pressures (n = 475).All-cause hospital mortality.Eighty-five percent of the 983 study patients met criteria for acute respiratory distress syndrome at enrollment. Tidal volumes remained similar in the 2 groups, and mean positive end-expiratory pressures were 14.6 (SD, 3.4) cm H2O in the experimental group vs 9.8 (SD, 2.7) cm H2O among controls during the first 72 hours (P < .001). All-cause hospital mortality rates were 36.4% and 40.4%, respectively (relative risk [RR], 0.90; 95% confidence interval [CI], 0.77-1.05; P = .19). Barotrauma rates were 11.2% and 9.1% (RR, 1.21; 95% CI, 0.83-1.75; P = .33). The experimental group had lower rates of refractory hypoxemia (4.6% vs 10.2%; RR, 0.54; 95% CI, 0.34-0.86; P = .01), death with refractory hypoxemia (4.2% vs 8.9%; RR, 0.56; 95% CI, 0.34-0.93; P = .03), and previously defined eligible use of rescue therapies (5.1% vs 9.3%; RR, 0.61; 95% CI, 0.38-0.99; P = .045).For patients with acute lung injury and acute respiratory distress syndrome, a multifaceted protocolized ventilation strategy designed to recruit and open the lung resulted in no significant difference in all-cause hospital mortality or barotrauma compared with an established low-tidal-volume protocolized ventilation strategy. This "open-lung" strategy did appear to improve secondary end points related to hypoxemia and use of rescue therapies.clinicaltrials.gov Identifier: NCT00182195.