bluuebunny/crossref_metadata_2025_split huggingface dataset:
Medium- and high-intensity rTMS reduces psychomotor agitation with distinct neurobiologic mechanisms
Authors: Heath Alesha , Lindberg Daniel R. , Makowiecki Kalina , Gray Avalon , Asp Anders J. , Rodger Jennifer , Choi Doo-Sup , Croarkin Paul E. 
Published: July 2018

AbstractDefinitive data are lacking on the mechanism of action and biomarkers of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression. Low-intensity rTMS (LI-rTMS) has demonstrated utility in preclinical models of rTMS treatments but the effects of LI-rTMS in murine models of depression are unknown. We examined the behavioral and neurobiologic changes in olfactory bulbectomy (OB) mice with medium-intensity rTMS (MI-rTMS) treatment and fluoxetine hydrochloride. We then compared 10-Hz rTMS sessions for 3 min at intensities (measured at the cortical surface) of 4 mT (LI-rTMS), 50 mT (medium-intensity rTMS [MI-rTMS]), or 1 T (high-intensity rTMS [HI-rTMS]) 5 days per week over 4 weeks in an OB model of agitated depression. Behavioral effects were assessed with forced swim test; neurobiologic effects were assessed with brain levels of 5-hydroxytryptamine, brain-derived neurotrophic factor (BDNF), and neurogenesis. Peripheral metabolomic changes induced by OB and rTMS were monitored through enzyme-linked immunosorbent assay and ultrapressure liquid chromatography-driven targeted metabolomics evaluated with ingenuity pathway analysis (IPA). MI-rTMS and HI-rTMS attenuated psychomotor agitation but only MI-rTMS increased BDNF and neurogenesis levels. HI-rTMS normalized the plasma concentration of α-amino-n-butyric acid and 3-methylhistidine. IPA revealed significant changes in glutamine processing and glutamate signaling in the OB model and following MI-rTMS and HI-rTMS treatment. The present findings suggest that MI-rTMS and HI-rTMS induce differential neurobiologic changes in a mouse model of agitated depression. Further, α-amino-n-butyric acid and 3-methylhistidine may have utility as biomarkers to objectively monitor the response to rTMS treatment of depression.
Proprotein convertase furin inhibits matrix metalloproteinase 13 in a TGFβ-dependent manner and limits osteoarthritis in mice
Authors: Lin Hilène , Hay Eric , Latourte Augustin , Funck-Brentano Thomas , Bouaziz Wafa , Ea Hang-Korng , Khatib Abdel-Majid , Richette Pascal , Cohen-Solal Martine 
Published: July 2018

AbstractCartilage loss in osteoarthritis (OA) results from altered local production of growth factors and metalloproteases (MMPs). Furin, an enzyme involved in the protein maturation of MMPs, might regulate chondrocyte function. Here, we tested the effect of furin on chondrocyte catabolism and the development of OA. In primary chondrocytes, furin reduced the expression of MMP-13, which was reversed by treatment with the furin inhibitor α1-PDX. Furin also promoted the activation of Smad3 signaling, whereas activin receptor-like kinase 5 (ALK5) knockdown mitigated the effects of furin on MMP-13 expression. Mice underwent destabilization of the medial meniscus (DMM) to induce OA, then received furin (1 U/mice), α1-PDX (14 µg/mice) or vehicle. In mice with DMM, the OA score was lower with furin than vehicle treatment (6.42 ± 0.75 vs 9.16 ± 0.6, p < 0.01), and the number of MMP-13(+) chondrocytes was lower (4.96 ± 0.60% vs 20.96 ± 8.49%, p < 0.05). Moreover, furin prevented the increase in ALK1/ALK5 ratio in cartilage induced by OA. Conversely, α1-PDX had no effect on OA cartilage structure. These results support a protective role for furin in OA by maintaining ALK5 receptor levels and reducing MMP-13 expression. Therefore, furin might be a potential target mediating the development of OA.
Dietary non-fermentable fiber prevents autoimmune neurological disease by changing gut metabolic and immune status
Authors: Berer Kerstin , Martínez Inés , Walker Alesia , Kunkel Birgit , Schmitt-Kopplin Philippe , Walter Jens , Krishnamoorthy Gurumoorthy 
Published: July 2018

AbstractThe autoimmune neurological disease, Multiple Sclerosis (MS), have increased at alarming rates in the Western society over the last few decades. While there are numerous efforts to develop novel treatment approaches, there is an unmet need to identify preventive strategies. We explored whether central nervous system (CNS) autoimmunity can be prevented through dietary manipulation using a spontaneous autoimmune encephalomyelitis mouse model. We report that the nutritional supplementation of non-fermentable fiber, common components of a vegetarian diet, in early adult life, prevents autoimmune disease. Dietary non-fermentable fiber alters the composition of the gut microbiota and metabolic profile with an increase in the abundance of long-chain fatty acids. Immune assays revealed that cecal extracts and a long chain fatty acid but not cecal lysates promoted autoimmune suppressive TH2 immune responses, demonstrating that non-fermentable fiber-induced metabolic changes account for the beneficial effects. Overall, these findings identify a non-invasive dietary strategy to prevent CNS autoimmunity and warrants a focus on nutritional approaches in human MS.
Surgically-Treated Locoregionally Advanced Hypopharyngeal Cancer: Outcomes
Authors: Rodrigues Jorge , Breda Eduardo , Monteiro Eurico 
Published: July 2018

Introduction Hypopharyngeal tumors are head and neck malignancies associated with a great mortality rate, and the treatment of advanced lesions constitutes a challenging problem. Pharyngolaryngectomy continues to be the gold standard treatment modality for locally-advanced diseases, and it is currently used as the primary treatment or in cases of relapse after an organ preservation strategy.
Objective This study aims to compare the survival rates of patients with advanced hypopharyngeal tumors treated with pharyngolaryngectomy as a primary or salvage option, and identify possible prognostic factors.
Methods All patients with advanced hypopharyngeal squamous cell carcinomas who performed pharyngolaryngectomy between 2007 and 2014 were reviewed retrospectively.
Results A total of 87 patients fulfilled the aforementioned criteria, and the sample had a mean age of 57.2 years and a male predominance of 43:1. The tumors were located in the pyriform sinus walls (81 tumors), in the posterior pharyngeal wall (4 tumors) and in the postcricoid region (2 tumors). A total of 60 patients underwent surgery as the primary treatment option, and 27 were submitted to salvage pharyngolaryngectomy after a previous treatment with chemoradiotherapy or radiotherapy. The 5-year overall survival was of 25.9%, the 5-year disease-free survival was of 24.2%, and the disease-specific survival was of 29.5%.
Conclusion The patients treated with pharyngolaryngectomy as the primary option revealed a better 5-year-disease free survival than the patients who underwent the salvage surgery (35.8% versus 11.7% respectively; p < 0.05). The histopathological criteria of capsular rupture of the lymph nodes (30.1% versus 19.8% respectively for the primary and salvage groups; p < 0.05) and vascular invasion (30.5% versus 22.5% respectively; p < 0.05) reduced the 5-year disease-free survival. Pharyngolaryngectomy as the primary intent revealed a lower local recurrence rate than the salvage surgery (40.6% versus 83.3% respectively; p < 0.05).
The Additive Effect of Low Molecular Weight Heparins on Thrombin Inhibition by Dermatan Sulfate
Authors: Cosmi Benilde , Agnelli Giancarlo , Young Edward , Hirsh Jack , Weitz Jeffrey 
Published: July 2018

SummaryThe aim of this study was to investigate the mechanism by which the anticoagulant activity of dermatan sulfate (DS) is increased by low molecular weight heparin (LMWH). In platelet poor plasma, LMWH enhances the effect of DS on thrombin (IIa) inhibition as determined by thrombin clotting times and with a chromogenic substrate assay. Analysis of the results of the chromogenic assays using either the algebraic fractional or the graphic isobole method suggests that LMWH has an additive effect on the anti-IIa activity of DS. This additive effect was lost when the experiments were repeated in plasma immunodepleted of antithrombin III (ATIII), indicating that the anti-IIa activity of LMWH is ATIII-dependent. To further explore the mechanism of the interaction between LMWH and DS, 125I-labeled IIa was added to plasma in the presence or absence of DS and/or LMWH and the formation of IIa-inhibitor complexes was assessed using SDS-PAGE followed by autoradiography. DS addition selectively increases the formation of heparin cofactor II (HCII)-IIa complexes, whereas LMWH enhances ATIII-IIa complex generation. Compared to plasma containing DS alone, the formation of ATIII-IIa complexes also is increased when the combination of DS and LMWH is added. These findings suggest that the additive effect of LMWH on the anti-IIa activity of DS reflects their different modes of IIa inhibition; DS potentiates IIa inhibition by HCII, while LMWH catalyses ATIII-dependent IIa inactivation. The potential clinical significance of these findings requires further investigation.
The Significance of TFPI in Clotting Assays – Gomparison and Combination with other Anticoagulants
Authors: Nordfang Ole , Kristensen Hanne I , Valentin Sanne , Østergaard Per , Wadt Johnny 
Published: July 2018

SummaryThe anticoagulant activities of Tissue Factor Pathway Inhibitor (TFPI), heparin and hirudin were compared in intrinsic (APTT) and extrinsic (PT) activated clotting assays. In contrast to the thrombin inhibitor hirudin, heparin was 10 fold more potent in the APTT assay than in the PT assay, indicating that inhibition of intrinsic activation is important for the anticoagulant activity of heparin as measured in an APTT assay. TFPI was most potent in the PT assay and the effect of TFPI was most pronounced in the presence of other anticoagulants (heparin and hirudin). The activities of the two natural anticoagulants antithrombin III (ATIII) and TFPI were compared in a PT assay with very dilute tissue factor. In this assay system TFPI in normal plasma affected the clotting time more than ATIII in the plasma. However, when heparin was added ATIII was the major anticoagulant, but profound Prolongation of the clotting time was only seen when TFPI was also added. In an ATIII deficient plasma heparin did not augment the effect of TFPI, showing that the increased effect of TFPI in the presence of heparin is dependent on the anticoagulant activity of ATIII/heparin. The effect of TFPI at prolonged clotting times was also illustrated by the significant effect of blocking TFPI in the plasma from warfarin-treated patients. Thus TFPI is a major anticoagulant in normal plasma and the effect of TFPI is especially seen at prolonged clotting times.
Comparison of the In Vitro Fibrinolytic Activities of Low and High Molecular Weight Single-Chain Urokinase-Type Plasminogen Activator
Authors: de Munk Gerard A W , Groeneveld Eleonore , Rijken Dingeman C 
Published: July 2018

SummaryThe fibrinolytic activity of low molecular weight (LMW) single-chain urokinase-type plasminogen activator (scu-PA) lacking the epidermal growth factor domain and the kringle domain was compared with the activity of high molecular weight (HMW) scu-PA. LMW scu-PA was 1-5 times less active than HMW scu-PA in a fibrin plate method, in a purified fibrin clot lysis assay and in a plasma clot lysis assay. Time course experiments in a chromogenic plasminogen activator assay suggested that LMW scu-PA was less sensitive to activation by plasmin than HMW scu-PA. This was confirmed in a scu-PA activation test, which showed that at a concentration of 40 IU/ml LMW scu-PA required a three-fold higher plasmin concentration for 50% activation in 20 min than did HMW scu-PA. Kinetic experiments in the presence of 0.1 M NaCl showed non-standard Michaelis-Menten kinetics for the activation by plasmin of both HMW and LMW scu-PA. In contrast, standard kinetics was observed at 0.15 M NaCl, showing a 2.6-fold lower catalytic efficiency for LMW scu-PA than for HMW scu-PA. It is concluded that the plasmin activation of LMW scu-PA is about three times slower than the activation of HMW scu-PA. This explains, at least partially, the lower fibrinolytic activity of LMW scu-PA in comparison with HMW scu-PA.
The Platelet-Stimulating Effect of Adrenaline Through α2-Adrenergic Receptors Requires Simultaneous Activation by a True Stimulatory Platelet Agonist
Authors: Steen Vidar M , Holmsen Holm , Aarbakke Grethe 
Published: July 2018

SummaryThe stimulating effect of adrenaline on human platelet phospholipase C (PLC) activation and responses in vitro (shape change, aggregation and dense granule secretion) was investigated with respect to its dependence on exogenously added agonists. All experiments were performed with human gel-filtered platelets pretreated with acetylsalicylic acid to prevent endogenous stimulation by the arachidonate pathway. (1) Preliminary experiments demonstrated the presence of trace amounts of extracellular ADP (0.05-0.58 μM) in non-stimulated platelet suspensions; ADP was effectively converted to ATP by the enzyme system creatine phosphate (CP)/creatine phosphokinase (CPK). (2) The adrenaline-induced optical aggregation and single particle (platelet) disappearance in the presence of trace amounts of ADP were almost abolished by the ADP-scavanger system CP/ CPK. (3) The response of CP/CPK-treated thrombin- or platelet-activating factor (PAF)-stimulated platelets was markedly increased by a subsequent addition of adrenaline. When hirudin or BN 50726 was added just prior to adrenaline to terminate the activation by thrombin or PAF, respectively, the stimulating effect of adrenaline was also abolished. (4) CP/CPK-treated, PAF-stimulated platelets rapidly developed decreased responsiveness to a subsequent addition of PAF. When adrenaline was added instead of a second addition of PAF, the stimulating effect of adrenaline was gradually decreased and prevented in parallel with the homologous desensitization of PAF. (5) The weak platelet agonist serotonin by itself induced only shape change in CP/CPK-treated platelets. Adrenaline failed to enhance the extent of this serotonin-induced platelet activation. (6) These results strongly suggest that adrenaline per se is not a platelet agonist in vitro but acts to enhance the stimulation induced by true agonists.
Antiphospholipid Antibodies: Prevalence, Clinical Significance and Correlation to Cytokine Levels in Acute Myeloid Leukemia and Non-Hodgkin’s Lymphoma
Authors: Stasi Roberto , Stipa Elisa , Masi Mario , Oliva Felicia , Sciarra Alessandro , Perrotti Alessio , Zaccari Giuseppe , Papa Giuseppe 
Published: July 2018

SummaryThis study was designed to explore the prevalence and clinical significance of elevated antiphospholipid antibodies (APA) titres in patients affected by acute myeloid leukemia (AML) and highgrade non-Hodgkin’s lymphoma (NHL). We also analyzed possible correlations with circulating levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and the soluble form of the receptor for interleukin-2 (sIL-2r). Nineteen patients with de novo AML and 14 patients with newly-diagnosed NHL were investigated. Tests for APA included the measurement of anticardiolipin antibodies (ACA) with a solid-phase immunoassay, and the detection of the lupus-like anticoagulant (LA) activity. Five patients with AML (26.3%) and 5 patients with NHL (35.7%) presented elevated APA at diagnosis, as compared to 3 of 174 persons of the control group (p <0.0001). APA titres became normal in all patients responding to treatment, whereas nonresponders retained elevated levels. In addition, 6 patients (4 with AML and 2 with NHL), who had normal APA at diagnosis and were either refractory to treatment or in relapse, subsequently developed LA and/or ACA positivity. At presentation, the mean levels of IgG- and IgM-ACA in patients were not significantly different from Controls, and concordance between ACA and LA results reached just 30%. With regard to the clinical course, we were not able to detect any statistically significant difference between patients with normal and elevated APA. Pretreatment concentrations of IL-6 and TNF-alpha in AML, and sIL-2r in NHL were found significantly elevated compared to Controls (p = 0.003, p = 0.009 and p = 0.024 respectively). In addition, the levels of these cytokines correlated with IgG-ACA at the different times of laboratory investigations. These results demonstrate that APA may have a role as markers of disease activity and progression in some haematological malignancies.
Inhibition of Endothelial Cell Expression of Plasminogen Activator Inhibitor Type-1 by Gemfibrozil
Authors: Fujii Satoshi , Sawa Hirofumi , Sobel Burton E 
Published: July 2018

SummaryIncreased concentrations of plasminogen activator inhibitor type-1 (PAI-1) in plasma are associated with impaired fibrinolysis and venous and arterial thrombo-embolic disease. In pilot studies designed to identify pharmacologic approaches capable of diminishing such increases, we found that gemfibrozil attenuated the Stimulation of synthesis of PAI-1 in a human, immortal, hepatoma cell line (Hep G2) induced by platelets. The present study was performed to determine whether it exerts analogous effects in non-immortal endothelial cells and whether it may therefore facilitate fibrinolysis locally in vivo. Human umbilical vein endothelial cells were incubated with pharmacologic concentrations of gemfibrozil. Gemfibrozil, 100 μM, suppressed basal PAI-1 production by 15% and attenuated the augmentation of synthesis of PAI-1 induced by lysates from platelets (4 × 107/ml) by 36% over 24 h without inhibiting overall protein synthesis. In addition, the increases in PAI-1 mRNA otherwise induced by platelet lysates over 6 h were suppressed by 49% (Northern blots) without any demonstrable change in the intracellular half-life of PAI-1 mRNA. Pulse-chase experiments demonstrated diminution of PAI-1 protein synthesis in parallel with the changes observed in PAI-1 mRNA. To determine whether these effects of gemfibrozil on endothelial cells in vitro were paralleled by consistent changes in the concentrations of PAI-1 in plasma in vivo, we studied rabbits with induced carotid artery thrombosis and thrombolysis. The increases in plasma PAI-1 induced by thrombosis and thrombolysis were inhibited by gemfibrozil (8.75 mg/kg i.v.), by 14% and 75%, respectively, Increases in endothelial cell PAI-1 gene expression in aorta, liver, and heart (4–6 fold over control) induced by thrombolysis were attenuated by gemfibrozil as well. Thus, gemfibrozil can attenuate shut down of the fibrinolytic system that is known to accompany thrombosis and thrombolysis and may therefore diminish the likelihood of early, thrombotic coronary artery reocclusion following revascularization with fibrinolytic agents.
Antiphospholipid Antibodies Enhance Thrombin-Induced Platelet Activation and Thromboxane Formation
Authors: Martinuzzo M E , Maclouf J , Carreras L O , Lévy-Toledano S 
Published: July 2018

SummaryIn a group of 6 patients with lupus anticoagulant (LA) and antiphospholipid (aPL) antibodies detected by ELISA ovemight urine and blood were simultaneously collected. A significantly increased urinary excretion of the platelet-derived thromboxane (TX) metabolite 11-dehydro-TXB2 was found in this group, as compared to 12 healthy individuals. In contrast, a small but significant reduction of the vascular prostacyclin (PGI2) metabolite 2,3-dinor-6-keto-prostaglandin F1α was observed.To further elucidate the effect of these antibodies on platelet activation we isolated the F(ab’)2 fragments from IgG of the 6 patients and 5 Controls, and we evaluated the effect of these fragments on the responses of isolated normal platelets to thrombin.Patients’ F(ab’)2 increased platelet aggregation and serotonin release of platelets stimulated by low dose thrombin (0.01 U/ml). At threshold thrombin concentration (0.05 U/ml) an enhanced TXB2 production was also observed.In summary, our results show, in addition to the altered TXA2/PGI2 balance observed in vivo, a direct stimulatory effect of aPL antibodies on platelet activation in vitro. This effect is related to recognition of phospholipid epitopes on platelets as shown by its neutralization upon preincubation with phospholipids. This phenomenon may be relevant for the thrombotic tendency of these patients.
Compound Heterozygosity in a Family with Protein C Deficiency Illustrating the Complexity of the Underlying Molecular Mechanism
Authors: Gandrille Sophie , Jude Brigitte , Alhenc-Gelas Martine , Millaire Alain , Aiach Martine 
Published: July 2018

SummaryThe association of two missense mutations, a Leu 223 to Phe and an lie 403 to Met, is described in a family presenting with various protein C deficiency phenotypes. In this family, two subjects were compound heterozygotes with protein C levels of about 25%, the other members being heterozygous for only one of the mutations. The Leu 223 to Phe mutation was also found in 9 members of 3 other families and, in all cases but one, resulted in protein C levels below 60% associated with a high incidence of thrombotic complications. The other mutation, an lie 403 to Met, was identified in those of the family’ members who presented with borderline protein C concentrations. In such a family, the genomic DNA analysis represents the only way to differentiate between the genetic status of each family member. The results highlight the importance of the genotype determination and the poor discriminative power of the plasma assays currently used.
Ro 44-9883, a New Non-Peptidic GPIIb-GPIIIa Antagonist Prevents Platelet Loss in a Guinea Pig Model of Extracorporeal Circulation
Authors: Carteaux Jean-P , Steiner Beat , Roux Sébastien 
Published: July 2018

SummaryExtensive contact between blood and artificial surfaces causes platelet activation and depletion. The aim of the present study was to test the efficacy of Ro 44-9883, a potent and selective peptidomimetic GPIIb-IIIa antagonist, in preventing platelet loss in guinea pigs undergoing extracorporeal circulation (ECC) with bubble oxygenation. In 15 guinea pigs, an arterio-arterial shunt was created and perfused for 1 h from the aortic arch to the descending aorta. The guinea pigs were divided into three groups: A control group receiving only heparin as an i.v. bolus, a low dose-treated group and a high dose-treated group receiving in addition to heparin and before starting ECC, 1 or 7 mg/kg Ro 449883 as an i.v. bolus, respectively. In the control group, the platelet count at 30 and 60 min of ECC was dramatically decreased (35 ± 4% and 25 ± 3% of initial value). In the low dose-treated group, Ro 44-9883 partially prevented the drop in platelet count (69 ± 8% and 54 ± 9%; p <0.05) whereas in the high dose-treated group, the platelet count was normal at 30 min (97 ± 8%) and only slightly decreased at 60 min (80 ± 7%). Mean arterial pressure and hematocrit were not significantly different between groups during the experiment. We conclude that i) ECC in guinea pigs provides an interesting in-vivo model for studying platelet loss by contact activation and ii) Ro 44-9883 prevents platelet loss during ECC in a dose dependent manner.