tbuckley/cabot-search huggingface dataset:
Remission of childhood asthma after long-term treatment with an inhaled corticosteroid (budesonide): can it be achieved? Dutch CNSLD Study Group
Authors: EE van Essen-Zandvliet, MD Hughes, HJ Waalkens, EJ Duiverman, KF Kerrebijn
Journal: European Respiratory Journal (1994)

This study was undertaken in order to determine whether long-term treatment with inhaled corticosteroid can induce a remission in childhood asthma, and to decide when stabilization of airway responsiveness occurred. We therefore carried out, an extended follow-up of 28-36 months in one of two groups of children who participated in a long-term intervention study. This former study had shown that long-term (median follow-up 22 months) treatment with inhaled corticosteroid plus beta 2-agonist improves symptoms, airway calibre and airway responsiveness in children with asthma, compared with beta 2-agonist alone. On treatment with inhaled corticosteroid plus beta 2-agonist, airway calibre did not further improve after 4 months, whereas the provocative dose of histamine which causes a 20% fall in forced expiratory volume in one second (PD20) histamine showed gradual improvement without reaching an apparent plateau. Remission was defined as being symptom free during any 8 month period. Of the 58 children originally randomized to receive 0.2 mg salbutamol, plus 0.2 mg budesonide, t.i.d., five children withdrew: three due to lack of motivation, one for psychological reasons, and one due to a deterioration of asthma. One patient was hospitalized because of an asthma exacerbation. Airway calibre showed no improvement after 4 months up to 36 months. Mean PD20 histamine stabilized after 20 months at 2.1 doubling doses above baseline, but at a subnormal level of 80 micrograms. Symptoms improved during the first 18 months, and may have been improving further, but slowly, during the period between 18 and 36 months.(ABSTRACT TRUNCATED AT 250 WORDS)
The methionine connection: Homocysteine and hydrogen sulfide exert opposite effects on hepatic microcirculation in rats
Authors: Eleonora Distrutti, Andrea Mencarelli, Luca Santucci, Barbara Renga, Stefano Orlandi, Annibale Donini, Vijay Shah, Stefano Fiorucci
Journal: Hepatology (2007)

Increased intrahepatic resistance in cirrhotic livers is caused by endothelial dysfunction and impaired formation of two gaseous vasodilators, nitric oxide (NO) and hydrogen sulfide (H(2)S). Homocysteine, a sulfur-containing amino acid and H(2)S precursor, is formed from hepatic methionine metabolism. In the systemic circulation, hyperhomocystenemia impairs vasodilation and NO production from endothelial cells. Increased blood levels of homocysteine are common in patients with liver cirrhosis. In this study, we demonstrate that acute liver perfusion with homocysteine impairs NO formation and intrahepatic vascular relaxation induced by acetylcholine in methoxamine-precontracted normal livers (7.3% +/- 3.0% versus 26% +/- 2.7%; P < 0.0001). In rats with mild, diet-induced hyperhomocystenemia, the vasodilating activity of acetylcholine was markedly attenuated, and incremental increases in flow induced a greater percentage of increases in perfusion pressure than in control livers. Compared with normal rats, animals rendered cirrhotic by 12 weeks' administration of carbon tetrachloride exhibited a greater percentage of increments in perfusion pressure in response to shear stress (P < 0.05), and intrahepatic resistance to incremental increases in flow was further enhanced by homocysteine (P < 0.05). In normal hyperhomocysteinemic and cirrhotic rat livers, endothelial dysfunction caused by homocysteine was reversed by perfusion of the livers with sodium sulfide. Homocysteine reduced NO release from sinusoidal endothelial cells and also caused hepatic stellate cell contraction; this suggests a dual mechanism of action, with the latter effect being counteracted by H(2)S.Impaired vasodilation and hepatic stellate cell contraction caused by homocysteine contribute to the dynamic component of portal hypertension.
Disease-modifying effect of strontium ranelate in a subset of patients from the Phase III knee osteoarthritis study SEKOIA using quantitative MRI: reduction in bone marrow lesions protects against cartilage loss
Authors: Jean-Pierre Pelletier, Camille Roubille, Jean-Pierre Raynauld, François Abram, Marc Dorais, Philippe Delorme, Johanne Martel-Pelletier
Journal: Annals of the Rheumatic Diseases (2013)

To explore, using MRI, the disease-modifying effect of strontium ranelate (SrRan) treatment on cartilage volume loss (CVL) and bone marrow lesions (BMLs) in a subset of patients from a Phase III clinical trial in knee osteoarthritis (OA) (SrRan Efficacy in Knee OsteoarthrItis triAl (SEKOIA)).Patients with primary symptomatic knee OA were randomised to receive either SrRan 1 g/day or 2 g/day or placebo (SEKOIA study). A subset of these patients had MRIs at baseline, 12, 24 and 36 months to assess the knee cartilage volume and BMLs. Missing values were imputed and the analyses were adjusted according to Bonferroni.In this MRI subset, the distribution of patients (modified intention-to-treat; n=330) was 113, 105 and 112 for SrRan 1 g/day, 2 g/day and placebo, respectively. The groups were fairly balanced at baseline regarding demographics, clinical symptoms or imaging characteristics. Treatment with SrRan 2 g/day significantly decreased CVL on the plateaus at 12 (p=0.002) and 36 (p=0.003) months compared with placebo. Of note, in the medial femur and plateau, SrRan 1 g/day, but not SrRan 2 g/day, had more CVL than placebo. In patients with BML in the medial compartment at baseline, the BML score at 36 months was decreased in both treatment groups compared with the placebo group (SrRan 1 g/day, p=0.002 and SrRan 2 g/day p=0.001, respectively), and CVL significantly decreased with SrRan 2 g/day (p=0.023) in the plateau compared with placebo.In knee OA patients, treatment with SrRan 2 g/day was found to have beneficial effects on structural changes by significantly reducing CVL in the plateau and BML progression in the medial compartment.
Phase III Trial of Fludarabine Plus Cyclophosphamide Compared With Fludarabine for Patients With Previously Untreated Chronic Lymphocytic Leukemia: US Intergroup Trial E2997
Authors: Ian W. Flinn, Donna S. Neuberg, Michael R. Grever, Gordon W. Dewald, John M. Bennett, Elisabeth M. Paietta, Mohamad A. Hussein, Frederick R. Appelbaum, Richard A. Larson, Dennis F. Moore, Martin S. Tallman
Journal: Journal of Clinical Oncology (2007)

The combination of fludarabine and cyclophosphamide is an effective regimen for patients with chronic lymphocytic leukemia (CLL). However, it may be accompanied by increased toxicity compared with fludarabine alone. E2997 is a phase III randomized Intergroup trial comparing fludarabine and cyclophosphamide (FC arm) versus fludarabine (F arm) alone in patients receiving their first chemotherapy regimen for CLL.Symptomatic, previously untreated patients with CLL were randomly assigned to receive either fludarabine 25 mg/m2 intravenously (IV) days 1 through 5 or cyclophosphamide 600 mg/m2 IV day 1 and fludarabine 20 mg/m2 IV days 1 through 5. These cycles were repeated every 28 days for a maximum of six cycles.A total of 278 patients were randomly assigned in this Intergroup study. Treatment with fludarabine and cyclophosphamide was associated with a significantly higher complete response (CR) rate (23.4% v 4.6%; P < .001) and a higher overall response (OR) rate (74.3% v 59.5%, P = .013) than treatment with fludarabine as a single agent. Progression-free survival (PFS) was also superior in patients treated with fludarabine and cyclophosphamide than those treated with fludarabine (31.6 v 19.2 months, P < .0001). Fludarabine and cyclophosphamide caused additional hematologic toxicity, including more severe thrombocytopenia (P = .046), but it did not increase the number of severe infections (P = .812).Fludarabine and cyclophosphamide produced an increase in OR and CR, and it improved PFS in patients with previously untreated CLL compared with fludarabine alone and was not associated with an increase in infectious toxicity.
Downregulated CD36 and oxLDL uptake and stimulated ABCA1/G1 and cholesterol efflux as anti-atherosclerotic mechanisms of interleukin-10
Authors: T RUBIC, R LORENZ
Journal: Cardiovascular Research (2005)

Marked anti-atheromatous effects of the anti-inflammatory cytokine interleukin-10 (IL-10) were observed in several lipid-driven animal models of arteriosclerosis. We therefore investigated whether IL-10 affects macrophage cholesterol handling.Human THP-1 cells and peripheral monocytes served as macrophage models. Specific mRNA was quantified by real-time RT-PCR, protein expression by flow cytometry and Western blotting. Cellular cholesterol handling was studied by lipoprotein-facilitated uptake and efflux assays. IL-10 effects were also studied in cells transfected with liver X receptor alpha (LXRalpha)-siRNA or a LXRalpha response element (LXRE) reporter construct.Picomolar IL-10 suppressed basal and peroxisome proliferator-activated receptor gamma (PPARgamma)-stimulated transcription of the scavenger receptor CD36 due to reduced PPARgamma protein expression. In contrast, IL-10 stimulated transcription of the active cellular cholesterol exporters ATP-binding cassette transporters A1 and G1 (ABCA1, ABCG1) and the LDL receptor, whereas scavenger receptor-BI (SR-BI) was unchanged. The reduction of CD36 and stimulation of ABCA1 expression was confirmed in human monocytes. Thereby, IL-10 prevented cellular cholesterol overloading from oxidized LDL (oxLDL) and enhanced efflux to apoA-containing particles initiating reverse cholesterol transport. Experiments with inhibitors, LXRalpha silencing and the LXRE reporter gene construct supported the proximal transmission of the IL-10 effect on ABCA1 by the IL-10 receptor/signal transducer and activator of transcription 3 (STAT3) pathway and distal cross-talk to the LXRalpha and PPARalpha/retinoic acid X receptor (RXR) and cAMP/protein kinase A (PKA) pathways.In addition to immune and anti-inflammatory actions, IL-10 redirects macrophage cholesterol handling towards reverse cholesterol transport, which contributes to its anti-atherosclerotic action.
Monovalent cation transport in irreversibly sickled cells.
Authors: M R Clark, C E Morrison, S B Shohet
Journal: Journal of Clinical Investigation (1978)

Using discontinuous density gradients of Stractan II, we have separated sickle cell blood into discrete subpopulations of reticulocytes, mature discoid cells, and irreversibly sickled cells (ISCs). We have measured active and passive fluxes of monovalent cations in mature discoid cells, ISCs, and normal control cells, also separated upon density gradients. These measurements revealed a decreased active cation transport in ISC-rich populations. However, parallel measurements of Na, K-ATPase activity showed normal ouabain-sensitive ATPase activity in ISCs. Passive permeability to external Rb was also normal in ISCs. The observation of depressed pump activity in intact ISCs, contrasted with normal ATPase activity in ISC membranes, suggests the presence of factors in the intact cell which inhibit the active transport of Na and K in ISCs.
Diagnosis and confirmation of epidermolytic palmoplantar keratoderma by the identification of mutations in keratin 9 using denaturing high-performance liquid chromatography
Authors: E.L. Rugg, J.E.A. Common, A. Wilgoss, H.P. Stevens, J. Buchan, I.M. Leigh, D.P. Kelsell
Journal: British Journal of Dermatology (2002)

Summary Background Epidermolytic palmoplantar keratoderma (EPPK) is one of a number of disorders characterized by diffuse thickening of palm and sole skin. Although EPPK is not a life-threatening condition, palmoplantar keratoderma can be associated with cancer and heart disease and therefore differential diagnosis is important so that adequate surveillance can be provided for the more serious conditions. Most cases of EPPK are caused by mutations in the gene encoding the palm- and sole-specific keratin 9 (K9), and this provides an option for molecular diagnosis of this condition. Objectives To identify the molecular basis of diffuse palmoplantar keratoderma in four British families. Methods Denaturing high-performance liquid chromatography (dHPLC) and DNA sequencing were used to screen exon 1 of the k9 gene for sequence variations. Results The dHPLC profiles obtained from individuals with EPPK differed from control samples, indicating sequence variations within the fragment analysed. The profiles varied between families, suggesting that underlying mutations were different for each family; this was confirmed by DNA sequencing. In three cases previously reported mutations were found that resulted in the change of methionine156 to valine and arginine162 to either tryptophan or glutamine. A novel mutation was identified in a fourth family that changed valine170 to methionine. dHPLC was used to screen control samples for this sequence variation and confirmed that it was not a common polymorphism. Conclusions These results confirm the diagnosis of EPPK in these families and underline the usefulness of dHPLC as a method of screening samples for heterozygous mutations.
Taming endothelial activation with a microRNA
Authors: Jason E. Fish, Myron I. Cybulsky
Journal: Journal of Clinical Investigation (2012)

Inflammation plays an essential role in vascular pathologies, including those associated with sepsis and atherosclerosis. Identifying negative regulators of inflammatory signaling pathways may provide novel therapeutic targets for these diseases. In this issue of the JCI, Sun et al. show that in endothelial cells, microRNA-18 1b (miR-18 1b) plays a vital role in controlling inflammation by targeting importin-α3, a regulator of NF-κB nuclear import. These findings provide compelling evidence that modulation of microRNAs may be a useful therapeutic approach for inflammatory vascular diseases.
The presence of anti-cyclic citrullinated peptide antibody is associated with magnetic resonance imaging detection of bone marrow oedema in early stage rheumatoid arthritis
Authors: M Tamai
Journal: Annals of the Rheumatic Diseases (2005)

The presence of anti-cyclic citrullinated peptide antibody is associated with magnetic resonance imaging detection of bone marrow oedema in early stage rheumatoid arthritis
Rapamycin-Induced Endothelial Cell Death and Tumor Vessel Thrombosis Potentiate Cytotoxic Therapy against Pancreatic Cancer
Authors: Christiane J. Bruns, Gudrun E. Koehl, Markus Guba, Maksim Yezhelyev, Markus Steinbauer, Hendrik Seeliger, Astrid Schwend, Anna Hoehn, Karl-Walter Jauch, Edward K. Geissler
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Despite current chemotherapies, pancreatic cancer remains an uncontrollable, rapidly progressive disease. Here, we tested an approach combining a recently described antiangiogenic drug, rapamycin, with standard gemcitabine cytotoxic therapy on human pancreatic tumor growth. Experimental Design: Tumor growth was assessed in rapamycin and gemcitabine-treated nude mice orthotopically injected with metastatic L3.6pl human pancreatic cancer cells. H&amp;E staining was performed on tumors, along with Ki67 staining for cell proliferation and immunohistochemical terminal deoxynucleotidyl transferase-mediated nick end labeling and CD31 analysis. Rapamycin-treated tumor vessels were also directly examined in dorsal skin-fold chambers for blood flow after thrombosis induction. Cell death in human umbilical vein endothelial cells was assessed by flow cytometry after annexin-V staining. Results: Rapamycin therapy alone inhibited tumor growth and metastasis more than gemcitabine, with remarkable long-term tumor control when the drugs were combined. Mechanistically, H&amp;E analysis revealed tumor vessel endothelium damage and thrombosis with rapamycin treatment. Indeed, dorsal skin-fold chamber analysis of rapamycin-treated tumors showed an increased susceptibility of tumor-specific vessels to thrombosis. Furthermore, terminal deoxynucleotidyl transferase-mediated nick end labeling/CD31 double staining of orthotopic tumors demonstrated apoptotic endothelial cells with rapamycin treatment, which also occurred with human umbilical vein endothelial cells in vitro. In contrast, gemcitabine was not antiangiogenic and, despite its known cytotoxicity, did not reduce proliferation in orthotopic tumors; nevertheless, rapamycin did reduce tumor proliferation. Conclusions: Our data suggest a novel mechanism whereby rapamycin targets pancreatic tumor endothelium for destruction and thrombosis. We propose that rapamycin-based vascular targeting not only reduces tumor vascularization, it decreases the number of proliferating tumor cells to be destroyed by gemcitabine, thus introducing a new, clinically feasible strategy against pancreatic cancer.
Interferon γ Signaling Alters the Function of T Helper Type 1 Cells
Authors: Gregory Z. Tau, Thierry von der Weid, Binfeng Lu, Simone Cowan, Marina Kvatyuk, Alessandra Pernis, Giorgio Cattoretti, Ned S. Braunstein, Robert L. Coffman, Paul B. Rothman
Journal: The Journal of Experimental Medicine (2000)

One mechanism regulating the ability of different subsets of T helper (Th) cells to respond to cytokines is the differential expression of cytokine receptors. For example, Th2 cells express both chains of the interferon γ receptor (IFN-γR), whereas Th1 cells do not express the second chain of the IFN-γR (IFN-γR2) and are therefore unresponsive to IFN-γ. To determine whether the regulation of IFN-γR2 expression, and therefore IFN-γ responsiveness, is important for the differentiation of naive CD4+ T cells into Th1 cells or for Th1 effector function, we generated mice in which transgenic (TG) expression of IFN-γR2 is controlled by the CD2 promoter and enhancer. CD4+ T cells from IFN-γR2 TG mice exhibit impaired Th1 polarization potential in vitro. TG mice also display several defects in Th1-dependent immunity in vivo, including attenuated delayed-type hypersensitivity responses and decreased antigen-specific IFN-γ production. In addition, TG mice mount impaired Th1 responses against Leishmania major, as manifested by increased parasitemia and more severe lesions than their wild-type littermates. Together, these data suggest that the sustained expression of IFN-γR2 inhibits Th1 differentiation and function. Therefore, the acquisition of an IFN-γ–unresponsive phenotype in Th1 cells plays a crucial role in the development and function of these cells.
Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice.
Authors: R Kitazawa, R B Kimble, J L Vannice, V T Kung, R Pacifici
Journal: Journal of Clinical Investigation (1994)

To investigate the contribution of IL-1, IL-6, and TNF to the increased osteoclastogenesis induced by estrogen deficiency, ovariectomized (ovx) mice were treated with either IL-1 receptor antagonist (IL-1ra), a competitive inhibitor of IL-1, TNF binding protein (TNFbp), an inhibitor of TNF, or the anti-IL-6 antibody (Ab) 20F3 for the first 2 wk after surgery. ovx increased the bone marrow cells secretion of IL-1 and TNF, but not IL-6, and the formation of TRAP-positive osteoclast-like multinucleated cells (MNCs) in bone marrow cultures treated with 1,25(OH)2D3. The increase in MNC formation induced by ovx was prevented by in vivo treatment with either 17 beta estradiol, IL-1ra, TNFbp, or anti-IL-6 Ab. However, the percent change in MNC formation induced by the anti-IL-6 Ab was similar in ovx and sham-operated animals, whereas IL-1ra and TNFbp were effective only in ovx mice. MNC formation was also decreased by in vitro treatment of bone marrow cultures with IL-1ra and TNFbp, but not with anti-IL-6 Ab. Ovx also increased bone resorption in vivo and in vitro, as assessed by the urinary excretion of pyridinoline cross links and the formation of resorption pits, respectively. IL-1ra, TNFbp and estrogen decreased bone resorption in vivo and in vitro whereas the anti-IL-6 Ab inhibited bone resorption in vitro but not in vivo. In conclusion, these data indicate that IL-1 and TNF play a direct role in mediating the effects of ovx on osteoclastogenesis and bone resorption. The data also suggest that IL-6 is not essential for increasing bone resorption in the early postovariectomy period.
High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma
Authors: K. Jahnke, A. Korfel, P. Martus, M. Weller, U. Herrlinger, A. Schmittel, L. Fischer, E. Thiel
Journal: Annals of Oncology (2005)

<h2>Abstract</h2><h3>Background</h3> The dose of high-dose methotrexate (HDMTX) in elderly patients often has to be reduced, resulting in a loss of treatment efficacy. We evaluated HDMTX-related toxicity with special regard to age distribution in patients with primary central nervous system lymphoma (PCNSL) in a phase IV multicenter trial. <h3>Patients and methods</h3> One hundred and fifty-four patients (median age 61 years; 89 patients >60 years old, 21 patients >70 years old) received 619 HDMTX cycles. Toxicity was evaluated prospectively using the WHO classification. Unless a reduced dose was required after calculating a decreased glomerular filtration rate (GFR), the patients received 4g/m<sup>2</sup> HDMTX followed by leucovorin rescue. <h3>Results</h3> Toxicity was generally mild with toxicities of WHO grade ≥3 usually <10%. The differences in the incidence and severity of toxicity were not statistically significant between patients >60 years and ≤60 years old. The same was true for therapy termination owing to MTX toxicity and for delayed serum MTX clearance. Dose reduction significantly differed between patients ≤60 years and those >60 years old (18% versus 44%; <i>P</i>=0.001). <h3>Conclusions</h3> HDMTX is a safe treatment for PCNSL patients regardless of age, with adherence to dose reduction determined by calculating the GFR before each treatment cycle.
Sinus Node Impulses and Atrial Fibrillation
Authors: TOYOMI SANO, FUMIO SUZUKI, SADAYUKI SATO
Journal: Circulation Research (1967)

In atrial muscle strips from rabbits, fibrillation occurred in a solution low in potassium, with or without a high calcium content, and the role of the sinus node in inducing atrial fibrillation was examined by microelectrodes and by direct close bipolar lead electrocardiograms. In right atrial strips that included the sinus node, the sinus node action potential often just preceded spontaneous fibrillation or premature beats. In left atrial strips in a similar condition, the incidence of spontaneous fibrillation or premature beats was very low. However, when electrical stimulation simulating sinus node impulses was applied, fibrillation or the premature beat frequently appeared immediately after the stimulating pulse waves, and its incidence was also remarkably increased, being fairly close to that of the right atrial strip. These findings suggest that the sinus node impulses occasionally caused fibrillation or premature beats during these experiments in a medium low in potassium. In addition, fibrillation was frequently induced even when the impulse fell outside the vulnerable period of the preceding beat.