tbuckley/cabot-search huggingface dataset:
Novel Effects of Nitric Oxide
Authors: Karen L Davis, Emil Martin, Illarion V Turko, Ferid Murad
Journal: The Annual Review of Pharmacology and Toxicology (2001)

Nitric oxide (NO), a simple free radical gas, elicits a surprisingly wide range of physiological and pathophysiological effects. NO interacts with soluble guanylate cyclase to evoke many of these effects. However, NO can also interact with molecular oxygen and superoxide radicals to produce reactive nitrogen species that can modify a number of macromolecules including proteins, lipids, and nucleic acids. NO can also interact directly with transition metals. Here, we have reviewed the non–3′,5′-cyclic-guanosine-monophosphate–mediated effects of NO including modifications of proteins, lipids, and nucleic acids.
Hematopoietic Stem-Cell Transplantation for Advanced Systemic Mastocytosis
Authors: Celalettin Ustun, Andreas Reiter, Bart L. Scott, Ryotaro Nakamura, Gandhi Damaj, Sebastian Kreil, Ryan Shanley, William J. Hogan, Miguel-Angel Perales, Tsiporah Shore, Herrad Baurmann, Robert Stuart, Bernd Gruhn, Michael Doubek, Jack W. Hsu, Eleni Tholouli, Tanja Gromke, Lucy A. Godley, Livio Pagano, Andrew Gilman, Eva Maria Wagner, Tor Shwayder, Martin Bornhäuser, Esperanza B. Papadopoulos, Alexandra Böhm, Gregory Vercellotti, Maria Teresa Van Lint, Christoph Schmid, Werner Rabitsch, Vinod Pullarkat, Faezeh Legrand, Ibrahim Yakoub-agha, Wael Saber, John Barrett, Olivier Hermine, Hans Hagglund, Wolfgang R. Sperr, Uday Popat, Edwin P. Alyea, Steven Devine, H. Joachim Deeg, Daniel Weisdorf, Cem Akin, Peter Valent
Journal: Journal of Clinical Oncology (2014)

Advanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown.In a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non-mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1), or unknown (n = 3). Thirty-six patients received myeloablative conditioning (MAC), and 21 patients received reduced-intensity conditioning (RIC).Responses in SM were observed in 40 patients (70%), with complete remission in 16 patients (28%). Twelve patients (21%) had stable disease, and five patients (9%) had primary refractory disease. Overall survival (OS) at 3 years was 57% for all patients, 74% for patients with SM-AHNMD, 43% for those with ASM, and 17% for those with MCL. The strongest risk factor for poor OS was MCL. Survival was also lower in patients receiving RIC compared with MAC and in patients having progression compared with patients having stable disease or response.AlloHCT was associated with long-term survival in patients with advanced SM. Although alloHCT may be considered as a viable and potentially curative therapeutic option for advanced SM in the meantime, given that this is a retrospective analysis with no control group, the definitive role of alloHCT will need to be determined by a prospective trial.
Diffusion permeability of an isolated rete mirabile.
Authors: E A Rasio, M Bendayan, C A Goresky
Journal: Circulation Research (1977)

The rete mirabile of the swimbladder of the eeel is a countercurrent exchange organ composed of alternately disposed and venous capillaries. A countercurrent perfusion of these was set up by isolating arterial input and outflow, and venous input and outflow, and perfusing each set of capillaries with oxygenated albumin-containing Krebs-Ringer bicarbonate buffer. Constant arterial infusions containing tracer albumin, inulin, 3-O-methylglucose, urea, and water were begun and tracer concentrations at the outlets of arterial and venous beds were determined. Capillary permeabilities were determined from the resulting steady state values. The method of calculation of permeability values from the data acquired in the rete involves no approximations and appears to yield unequivocal values. For the solutes, the values appear compatible with transcapillary passage by free diffusion. No evidence of increasing restriction (in comparison to the diffuse coefficients) was found over the range of molecular sizes explored. The permeability for labeled water, in relation to the solutes, was too high, and this augmentation was attributed to the larger surface available for its exchange. Despite this larger value, labeled water did not undergo flow-limited exchange. A significant barrier to its distribution is present in this capillary system.
Effect of Center- Versus Patient-Specific Factors on Variations in Dialysis Adequacy
Authors: JEFFREY C. FINK, STEVEN A. BLAHUT, ANDREW E. BRIGLIA, JAMES F. GARDNER, PAUL D. LIGHT
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Efforts to improve the delivery of hemodialysis have focused mostly on identifying patient-related factors that lead to inadequate dialysis. Less consideration has been given to the impact of the dialysis center on adequacy. This study evaluated whether the dialysis facility or individual-level factors were the primary influence on variations in dialysis adequacy. This was a retrospective analysis of 4971 hemodialysis patients in 189 centers with urea reduction ratio (URR) values obtained in the final quarter of 1997. The between-center variation and the within-center correlation in URR values were quantified to determine the contribution of a center effect on variations in adequacy; furthermore, the proportion of variance attributable to the centers' effect and individual-level dialysis covariates were compared. There was a wider between-center variation in mean URR values (SD, 4.8%) than expected if there were no center effect (SD, 2.5%). There was a strong within-center correlation in URR values, measured by the parameter ρ, which was only minimally diminished after adjusting for individual-level covariates (adjusted ρ, 0.14; P &lt; 0.0001). The variation in URR attributable to the center effect, quantified by R 2 , was greater than that related to individual-level dialysis factors (facility- and individual-level dialysis covariates R 2 , 23.6 and 11.3%, respectively). Initiatives to improve the delivery of dialysis in patients with end-stage renal disease should be directed at facility policies governing dialysis care, along with patient-specific problems, because center effects have a major influence on dialysis adequacy.
Effect of Heart Rate and Intracoronary Isoproterenol, Levarterenol, and Epinephrine on Coronary Flow and Resistance
Authors: F. BRUCE LEWIS, JAY D. COFFMAN, DONALD E. GREGG
Journal: Circulation Research (1961)

The effect was determined of changes in heart rate and of intracoronary isoproterenol, levarterenol, and epinephrine on coronary flow in the stopped and beating heart. It was possible by this means to estimate the relative action of these variables on the extravascular and intravascular resistance of the coronary bed in a heart perfused at constant pressure. As heart rate was increased extravascular resistance rose, but intravascular resistance fell to a greater extent indicating a fall in net coronary resistance. Isoproterenol had the greatest and epinephrine the least effect in decreasing the total coronary resistance. The three drugs tested caused only a small fall in extravascular resistance. Since the effect was small, it was concluded that extravascular resistance can be ignored in determining the direct effect of these drugs upon the coronary vasculature.
Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors.
Authors: R De Maria, M G Cifone, R Trotta, M R Rippo, C Festuccia, A Santoni, R Testi
Journal: The Journal of Experimental Medicine (1994)

The expression and function of CD69, a member of the natural killer cell gene complex family of signal transducing receptors, was investigated on human monocytes. CD69 was found expressed on all peripheral blood monocytes, as a 28- and 32-kD disulfide-linked dimer. Molecular cross-linking of CD69 receptors induced extracellular Ca2+ influx, as revealed by flow cytometry. CD69 cross-linking resulted also in phospholipase A2 activation, as detected by in vivo arachidonic acid release measurement from intact cells and by direct in vitro measurement of enzymatic activity using radiolabeled phosphatidylcholine vesicles. Prostaglandin E 2 alpha, 6-keto-prostaglandin F 1 alpha, and leukotriene B4 were detected by radioimmunoassay in supernatants from CD69-stimulated monocytes, suggesting the activation of both cyclooxygenase and lipoxygenase pathways after CD69 stimulation. CD69 cross-linking, moreover, was able to induce strong nitric oxide (NO) production from monocytes, as detected by accumulation of NO oxydixed derivatives, and cyclic GMP. It is important to note that NO generation was responsible for CD69-mediated increase in spontaneous cytotoxicity against L929 murine transformed fibroblast cell line and induction of redirected cytotoxicity towards P815 FcRII+ murine mastocytoma cell line. These data indicate that CD69 can act as a potent stimulatory molecule on the surface of human peripheral blood monocytes.
Number of Target Lesions for EASL and Modified RECIST to Predict Survivals in Hepatocellular Carcinoma Treated with Chemoembolization
Authors: Beom Kyung Kim, Seung Up Kim, Myeong-Jin Kim, Kyung Ah Kim, Do Young Kim, Jun Yong Park, Sang Hoon Ahn, Kwang-Hyub Han, Chae Yoon Chon
Journal: Clinical Cancer Research (2012)

To date, most studies about the optimal number of target lesions for enhancement criteria for hepatocellular carcinoma (HCC) have focused on cross-sectional analyses of concordance. We investigated the optimal number of target lesions for European Association for the Study of the Liver (EASL) and modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines in predicting overall survival (OS).We analyzed 254 consecutive treatment-naïve patients with HCC having at least 2 measurable target lesions undergoing transarterial chemoembolization. Kappa values for intermethod agreement of treatment responses were calculated for comparisons between use of maximum of 1, 2, 3, 4, or 5 targets versus use of all target lesions. Prognostic values of radiologic assessments according to number of target lesions for predicting OS were expressed as C-index.By EASL and mRECIST guidelines, κ values between responses assessing the longest 2, 3, 4, or 5 targets and assessing all targets were 0.924, 0.977, 1.000, or 1.000 and 0.907, 0.959, 1.000, or 1.000, respectively, whereas those between responses assessing only one target and assessing all target lesions were 0.723 and 0.666, respectively. C-index when measuring the longest 1, 2, 3, 4, 5, and all targets was similar, ranging from 0.739 to 0.749 for EASL criteria and from 0.750 to 0.759 for mRECIST. From Cox regression analyses, radiologic response from each calculation method showed independently significant effects on OS for both guidelines, regardless of number of target lesions.Prognostic values for predicting OS were similar regardless of number of target lesions. Assessing the 2 largest targets rather than only 1 index lesion could be recommended considering high concordances from cross-sectional analyses.
Activation of Neutrophils in Cutaneous T-Cell Lymphoma
Authors: Deborah S. Goddard, Kei-ichi Yamanaka, Thomas S. Kupper, David A. Jones
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Cutaneous T-cell lymphoma (CTCL) is a spectrum of disease of unknown etiology defined by infiltrates of activated and malignant T cells in the skin. In working with blood from CTCL patients, we noticed frequent activation of neutrophils; therefore, we tested the hypothesis that neutrophils are activated in CTCL subjects compared with normal healthy controls. Experimental Design: Using peripheral blood of 44 subjects with CTCL and 15 normal controls, we examined three measures of neutrophil activation. These are the presence of neutrophils of reduced buoyant density, the presence of primed neutrophils in a stimulated chemiluminescence assay, and changes in surface markers by flow cytometry. In addition, we tested plasma interleukin-8 (IL-8) and leukotriene B4 (LTB4) levels using ELISA. Results: A significantly larger fraction of hypodense neutrophils was observed in CTCL subjects compared with normals (10.6 ± 1.7% versus 1.5 ± 0.4%). Stimulated chemiluminescence was also significantly increased in CTCL, and analysis of neutrophil surface markers using flow cytometry showed significantly increased CD11b and CD66b and decreased CD62L, consistent with neutrophil activation. These changes were present even in early stages of CTCL. We further found that plasma IL-8 and LTB4 levels are elevated in CTCL, which could form a feedback loop contributing to disease pathophysiology. Conclusions: CTCL is associated with systemic neutrophil activation, even in early disease, and a feedback loop between neutrophils and T cells mediated by IL-8 and LTB4 is a potential contribution to the pathophysiology of CTCL.
Reduction From Seven to Five Cycles of Intensive Induction Chemotherapy in Children With High-Risk Neuroblastoma
Authors: Brian H. Kushner, Kim Kramer, Michael P. LaQuaglia, Shakeel Modak, Karima Yataghene, Nai-Kong V. Cheung
Journal: Journal of Clinical Oncology (2004)

Purpose We previously reported a high response rate with a dose-intensive chemotherapy regimen in 24 children with high-risk neuroblastoma (NB). We now describe similar results with changes that reduce toxicity (fewer cycles, less vincristine, use of granulocyte colony-stimulating factor). Patients and Methods Eighty-seven consecutive newly diagnosed children with high-risk NB underwent induction that initially had seven cycles (57 patients) but was later limited to five (30 patients). Cycles 1, 2, 4, and 6 used cyclophosphamide (140 mg/kg)/doxorubicin (75 mg/m 2 )/vincristine (0.15 mg/kg in the first 27 patients, 0.067 mg/kg subsequently). Cycles 3, 5, and 7 used cisplatin (200 mg/m 2 )/etoposide (600 mg/m 2 ). Tumor resection followed a minimum of three cycles. The induction was eventually modified to include anti-G D2 immunotherapy after each of the last three cycles (38 patients). Results Bone marrow disease resolved in 70 (91%) of 77 patients and was not detected pre- and postinduction in 10 patients. After cycle 3 or 4, 86% of primary tumors were more than 50% smaller. Postinduction metaiodobenzylguanidine scans showed normal radiotracer distribution in metastatic sites in 74 (87%) of 85 patients. Overall results were: 68 (79%) complete/very good partial responses (CR/VGPR); 14 (16%) partial responses (PR); three (3%) less than PR; one (1%) death from infection; and one patient not assessable for response. Five cycles yielded a CR/VGPR rate of 83%, compared with a 77% rate from seven cycles. Side effects were myelosuppression, mucositis, and hearing deficits; neurotoxicity was insignificant with the lower vincristine dosage. Four patients (each received seven cycles) developed myelodysplasia/leukemia. Conclusion Five cycles of this induction regimen, plus surgery, suffice to achieve CR/VGPR in ≈80% of children with high-risk NB.
Cystic Fibrosis and Nutrition: Linking Phospholipids and Essential Fatty Acids with Thiol Metabolism
Authors: Sheila M. Innis, A. George F. Davidson
Journal: Annual Review of Nutrition (2008)

Cystic fibrosis (CF) is the most common lethal inherited disorder among Caucasians and results from mutation in the gene encoding the CF transmembrane conductance regulator. In addition to its multisystem clinical effects, the disease is characterized by increased proinflammatory mediators and oxidant stress, and systemic redox imbalance with reduced glutathione (GSH), together with alterations in circulating and tissue (n-6) and (n-3) fatty acids, particularly a decrease in docosahexaenoic acid. The metabolism of phospholipids and fatty acids is closely related to GSH through the methionine-homocysteine cycle, in which choline via betaine provides methyl groups to regenerate S-adenosylmethionine, important in generating phosphatidylcholine and amino acid precursors for GSH. Current research focuses both on fatty acid supplementations to normalize altered (n-6) to (n-3) fatty acid balance and decrease generation of (n-6) fatty acid-derived inflammatory mediators, and strategies to improve oxidant defenses and redox balance. However, further research is needed before such strategies can be included in clinical care of individuals with CF.
Cardiovascular reflex responses induced by epicardial chemoreceptor stimulation
Authors: J Cinca
Journal: Cardiovascular Research (2000)

The cardiac mechano- and chemoreceptors are broadly distributed in the myocardium and coronary vessels. A portion of these receptors extends over the epicardium and pericardium and therefore can be excited by mechanical or chemical stimuli directly applied to the surface of the heart. Excitation of epicardial receptors by topical application of chemical compounds elicits a variety of reflex cardiovascular responses, without the vascular or systemic effects of the drug administered systemically. A considerable number of studies has used the epicardial sensory field as a tool to delineate the functional characteristics of the cardiac afferent neurones in normal as well as in pathological conditions. In this review we analyze the cardiovascular reflex responses induced by epicardial application of a variety of substances like bradykinin, nicotine, muscarine, isoprenaline, adenosine, potassium chloride, capsaicin, prostaglandins or substance P in physiological models and also in models with acute myocardial ischemia or heart failure. The data highlight the contribution of the epicardial sensory neurites to the overall control of the cardiovascular system and, on the other hand, strengthen the need for further investigations directed to better elucidate the reflex cardiovascular responses that may develop in patients with pericardial abnormalities.
634 BALLOON-OCCLUDED PERCUTANEOUS RADIO-FREQUENCY THERMAL ABLATION (RFA) PLUS TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION (TACE): A NEW COMBINED SINGLE-STEP THERAPY FOR TREATMENT OF MULTINODULAR UNRESECTABLE HEPATOCELLULAR CARCINOMA
Authors: R. Iezzi, V. Cesario, F.R. Ponziani, G. Gigante, G. Caracciolo, E. Rinninella, M.A. Zocco, A.M. de Gaetano, M. Siciliano, A. Milani, L. Miele, G. Gasbarrini, S. Agnes, G. Bombardieri, F. Giuliante, A. Grieco, G. Nuzzo, M. Pompili, M. Basso, G.L. Rapaccini, E. di Stasio, L. Bonomo, A. Gasbarrini
Journal: Journal of Hepatology (2011)
Abnormal erythrocyte fragmentation and membrane deformability in paroxysmal nocturnal hemoglobinuria
Authors: Brian D. Smith
Journal: American Journal of Hematology (1985)

Hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) is considered to be a result of an intrinsic membrane defect. This defect may result in abnormal material properties of PNH erythrocytes. To examine this hypothesis, fragmentation failure, and membrane deformability were assessed in the absence of complement by micropipette techniques. Membrane viscosity was determined by observing relaxation of deformed cells. Results show a bimodal distribution of force for membrane failure, membrane viscoelasticity, and elastic shear modulus. One population requires significantly less force for fragmentation, mean 0.56 X 10(-6) dyne; has increased membrane viscosity, mean 0.205 X 10(-2) dyne sec/cm; and has decreased elastic shear modulus, mean 0.56 X 10(-2) dyne/cm. A second population resembles control with fragmentation force, mean 1.19 X 10(-6) dyne, control 1.05 X 10(-6) dyne; membrane viscosity, mean 0.112 X 10(-2) dyne/cm, control 0.102 X 10(-2) dyne sec/cm; elastic shear modulus, mean 0.70 X 10(-2) dyne/cm, control 0.78 X 10(-2) dyne/cm. The percent of cells with abnormal material properties corresponds to the percent of PNH III cells determined by complement lysis. Thus, the hemolysis attributed to an abnormal clone of erythrocytes in PNH is associated with an intrinsic membrane abnormality which predisposes to lysis.
Treatment strategies in patients with rheumatoid arthritis for whom methotrexate monotherapy has failed: data from the NOR-DMARD register
Authors: E. Lie, D. van der Heijde, T. Uhlig, K. Mikkelsen, S. Kalstad, C. Kaufmann, E. Rodevand, T. K. Kvien
Journal: Annals of the Rheumatic Diseases (2011)

To compare the effectiveness of adding synthetic disease-modifying antirheumatic drugs (sDMARDs) versus tumour necrosis factor α inhibitors (TNFi) to methotrexate (MTX) in patients with rheumatoid arthritis (RA) who were MTX inadequate responders (IR). Second, to examine outcomes in patients receiving MTX+TNFi for whom the MTX+sDMARD combination had also failed.Patients with RA (disease duration ≤ 5 years, MTX IR and naïve to other DMARDs) starting treatment with MTX+TNFi or MTX+sDMARDs were included. From the latter group a subgroup of patients who went on to receive MTX+TNFi was identified.Patients receiving MTX+TNFi (n=98) and MTX+sDMARDs (n=129) had similar baseline disease activity when starting combination therapy (mean Disease Activity Score 28 (DAS28) = 4.90 and 4.96, respectively). Three- and 6-month effectiveness and 2-year drug survival were better for MTX+TNFi than for MTX+sDMARDs: mean DAS28 was -1.61 versus -0.85 after 3 months (p<0.001) and -1.91 versus -1.03 after 6 months (p=0.01); DAS28<2.6 was reached by 29.0% versus 11.6% after 3 and 34.5% versus 12.9% after 6 months. Effectiveness was somewhat better with triple therapy than other MTX+sDMARD combinations but was generally inferior compared with MTX+TNFi. For the patients who received MTX+TNFi as a third step after MTX+sDMARDs had failed (n=38) there was a tendency towards lower remission rates, worse disease activity states and inferior drug survival compared with patients who received MTX+TNFi directly after the failure of MTX.Effectiveness was better for MTX+TNFi than for MTX+sDMARDs. Patients who started MTX+TNFi after two synthetic DMARD regimens had failed had a tendency to less favourable disease states after 3 months than patients who switched directly from MTX to MTX+TNFi.