Miracle-dz/UniFAR-FTUs huggingface dataset:
Dabigatran versus warfarin in patients with mechanical heart valves.

BACKGROUND Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves. METHODS In this phase 2 dose-validation study, we studied two populations of patients: those who had undergone aortic- or mitral-valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier. Patients were randomly assigned in a 2:1 ratio to receive either dabigatran or warfarin. The selection of the initial dabigatran dose (150, 220, or 300 mg twice daily) was based on kidney function. Doses were adjusted to obtain a trough plasma level of at least 50 ng per milliliter. The warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk. The primary end point was the trough plasma level of dabigatran. RESULTS The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding. CONCLUSIONS The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.).
Influence of brain catecholamines on the development of fatigue in exercising rats in the heat

The purpose of the present study was to identify the effects of an acute injection of a dual dopamine (DA)/noradrenaline (NA) reuptake inhibitor (bupropion) on exercise performance, thermoregulation and neurotransmitters in the preoptic area and anterior hypothalamus (PO/AH) of the rat during exercise in the heat. Body core temperature (Tcore), brain temperature (Tbrain) and tail skin temperature (Ttail) were measured. A microdialysis probe was inserted in the PO/AH, and samples for measurement of extracellular DA, NA and serotonin (5‐HT) levels were collected. Rats received either bupropion (17 mg kg−1; hot‐BUP) or saline (1 ml kg−1; hot) 20 min before the start of exercise and ran at a speed of 26 m min−1 until exhaustion in a warm environment (30°C). Rats also ran until exhaustion in a cool environment (18°C; cool). Running time to exhaustion was significantly influenced by the ambient temperature, and it was increased by bupropion in the heat (cool, 143.6 ± 21 min; hot, 65.8 ± 13 min; hot‐BUP, 86.3 ± 7.2 min). Tcore and Tbrain at exhaustion were significantly higher in the bupropion group compared to the cool and hot groups, respectively. Ttail measured at exhaustion was not significantly different between the two hot conditions. Extracellular concentrations of DA and NA in the PO/AH increased during exercise, and was significantly higher in the bupropion than in cool and hot groups (P < 0.05). No differences were observed between groups for 5‐HT levels. These results suggest that DA and NA in the PO/AH might be responsible for the increase in exercise performance and Tcore and Tbrain in the bupropion group in hyperthermia. Moreover, these results support previous findings in humans that acute bupropion ingestion increases Tcore during exercise in the heat, indicating the possibility of an important role for DA and NA in thermoregulation.
L’apport de l’échographie dans l’exploration des métrorragies post-ménopausiques

Les métrorragies post-ménopausiques représentant un motif fréquent de consultation en gynécologie. Notre étude avait pour but d’évaluer l’apport de l’échographie pelvienne dans l’exploration des lésions endo-cavitaires devant ce symptôme et de comparer les résultats retrouvés à ceux de l’hystéroscopie et de l’histologie. Il s’agissait d’une étude rétrospective analytique à propos de 33 observations de patientes prises en charge pour des métrorragies post-ménopausiques au service de gynécologie obstétrique «A» du centre de maternité et de néonatologie de Tunis durant l’année 2012. Toutes les patientes avaient bénéficié d’une échographie pelvienne et d’une hystéroscopie diagnostique. Nous avons analysé et confronté les données de l’échographie pelvienne, de l’hystéroscopie et de l’examen histologique. L’âge moyen de nos patientes était de 57,78 ans et l'âge moyen de la ménopause était de 48,36 ans. La confrontation des données échographiques et histologiques, a montré que l’échographie a présenté une sensibilité de 80,6%, une spécificité de 79,38%, une valeur prédictive positive (VPP) de l’ordre de 67,03% et une valeur prédictive négative (VPN) de 91,54%. Quant à l’hystéroscopie, ces valeurs étaient respectivement de 84,44%, 82,72%, 69,93% et 92,65%. Le degré de performance de chaque moyen d’exploration a été variable selon la lésion en cause des métrorragies et d’une façon générale l’hystéroscopie a été plus fiable dans l’exploration des métrorragies que l’échographie: indice de Youden 0,67 contre 0,59. Nos résultats rejoignent les données de la littérature qui attribue à l’hystéroscopie une plus grande fiabilité par rapport à l’échographie pelvienne dans le diagnostic des lésions endo-cavitaires à l’origine des métrorragies post-ménopausiques.
Hazard identification of particulate matter on vasomotor dysfunction and progression of atherosclerosis

The development and use of nanoparticles have alerted toxicologists and regulators to issues of safety testing. By analogy with ambient air particles, it can be expected that small doses are associated with a small increase in risk of cardiovascular diseases, possibly through oxidative stress and inflammatory pathways. We have assessed the effect of exposure to particulate matter on progression of atherosclerosis and vasomotor function in humans, animals, and ex vivo experimental systems. The type of particles that have been tested in these systems encompass TiO2, carbon black, fullerene C60, single-walled carbon nanotubes, ambient air particles, and diesel exhaust particles. Exposure to ambient air particles is associated with accelerated progression of atherosclerosis and vasomotor dysfunction in both healthy and susceptible animal models and humans at risk of developing cardiovascular diseases. The vasomotor dysfunction includes increased vasoconstriction as well as reduced endothelium-dependent vasodilatation; endothelium-independent vasodilatation is often unaffected indicating mainly endothelial dysfunction. Pulmonary exposure to TiO2, carbon black, and engineered nanoparticles generate vasomotor dysfunction; the effect size is similar to that generated by combustion-derived particles, although the effect could depend on the exposure period and the administered dose, route, and mode. The relative risk associated with exposure to nanoparticles may be small compared to some traditional risk factors for cardiovascular diseases, but superimposed on these and possible exposure to large parts of the population it is a significant public health concern. Overall, assessment of vasomotor dysfunction and progression of atherosclerosis are promising tools for understanding the effects of particulate matter.
Thrombin Activation of Factor XI on Activated Platelets Requires the Interaction of Factor XI and Platelet Glycoprotein Ibα with Thrombin Anion-binding Exosites I and II, Respectively*

Activation of factor XI (FXI) by thrombin on stimulated platelets plays a physiological role in hemostasis, providing additional thrombin generation required in cases of severe hemostatic challenge. Using a collection of 53 thrombin mutants, we identified 16 mutants with <50% of the wild-type thrombin FXI-activating activity in the presence of dextran sulfate. These mutants mapped to anion-binding exosite (ABE) I, ABE-II, the Na+-binding site, and the 50-insertion loop. Only the ABE-II mutants showed reduced binding to dextran sulfate-linked agarose. Selected thrombin mutants in ABE-I (R68A, R70A, and R73A), ABE-II (R98A, R245A, and K248A), the 50-insertion loop (W50A), and the Na+-binding site (E229A and R233A) with <10% of the wild-type activity also showed a markedly reduced ability to activate FXI in the presence of stimulated platelets. The ABE-I, 50-insertion loop, and Na+-binding site mutants had impaired binding to FXI, but normal binding to glycocalicin, the soluble form of glycoprotein Ibα (GPIbα). In contrast, the ABE-II mutants were defective in binding to glycocalicin, but displayed normal binding to FXI. Our data support a quaternary complex model of thrombin activation of FXI on stimulated platelets. Thrombin bound to one GPIbα molecule, via ABE-II on its posterior surface, is properly oriented for its activation of FXI bound to a neighboring GPIα molecule, via ABE-I on its anterior surface. GPIbα plays a critical role in the co-localization of thrombin and FXI and the resultant efficient activation of FXI.
Dynamic Knowledge Integration in Socio-Technical Networks: an Interpretive Study of Intranet Use for Knowledge Integration

A major challenge facing firms competing in electronic business markets is the dynamic integration of knowledge within and beyond the firm, enabled by internet-based infrastructure and emergent fluid socio-technical networks. This paper explores how social actors dynamically employ intranets to integrate formal and informal knowledge within evolving socio-technical networks that emerge, permeate and extend beyond the organisational boundary. The paper presents two case studies that illustrate how static intranets can be useful for dynamically integrating knowledge when they are interwoven with other knowledge channels such as e-mail through which flows the informal knowledge needed to make sense of and situate formal organisational knowledge. The findings suggest that businesses should carefully examine how employees integrate intranets with other channels in their work, and the shaping of knowledge outcomes that flows from such use. There are practical implications for the proper skilling of the people who share and integrate knowledge in this way. The paper also provides a framework for dynamic knowledge integration in socio-technical networks, which can help underpin future research in this area.
Pharmacokinetics of Morphine Injected Intravenously into the Anesthetized Dog

This study determined the disposition of morphine in plasma and cerebrospinal fluid (CSF) and its relationship to ventilatory depression. 14C-Morphine sulfate (0.3 mg/kg or 2.0 mg/kg as the base) was injected intravenously into dogs anesthetized with enflurane-N2O-O2. Arterial plasma, cisternal CSF, and urine were analyzed for unchanged morphine and morphine metabolites. By 10 min after injection, 97 per cent of the injected morphine had been cleared from plasma. The terminal elimination half-times for morphine in plasma were not significantly different for the two doses and averaged 75 ± 5 (SEM) min. The volumes of distribution were significantly greater for 0.3 mg/kg than for 2.0 mg/kg morphine; this difference appeared to be related to the lesser hypotension following the smaller dose. Metabolism of morphine was rapid and efficient; metabolites were apparent in plasma by 1.5 min. Morphine conjugates, primarily morphine glucuronide, accounted for more than 90 per cent of the radioactivity in plasma at two hours. By six hours, 66 ± 3 per cent of the administered 14C radioactivity had been recovered in the urine, but only 13 ± 2 per cent had been excreted as unchanged morphine. Morphine concentrations in CSF did not peak until 15–30 min after injection, and the terminal half-time was significantly greater than that of morphine in plasma. Ventilatory depression was prolonged, and its abatement did not correlate with the decline of morphine concentrations in either plasma or CSF. It is concluded that morphine was rapidly cleared from the plasma by its uptake into tissues and by its efficient conjugation with glucuronic acid. Ultimate elimination of the drug was primarily by renal excretion of conjugated morphine. Uptake of morphine into CSF was delayed and its elimination from CSF was prolonged in comparison with its clearance from plasma. The ventilatory depressant effects of morphine were not directly related to its concentration in either CSF or plasma.
Sequential Expression of Bone Matrix Proteins During Rat Calvaria Osteoblast Differentiation and Bone Nodule Formation In Vitro

We investigated the expression of osteocalcin (OC), bone sialoprotein (BSP), osteonectin (ON), and alkaline phosphatase (ALP) during cell differentiation and bone nodule formation by fetal rat calvaria cells, using immunofluorescent and immunogold techniques at light and electron microscopic levels. Six hours after plating all proteins were expressed in calvaria cells. However, expression was not detected during the proliferation phase after plating. Cell morphological modifications were observed in osteoblastic cells expressing ALP, OC, and BSP, but not ON. During the matrix formation phase, all proteins were expressed with various intensities and OC was limited to differentiated osteoblastic cells. EM observations demonstrated that BSP was selectively associated with clusters of needle-like crystals, but not with collagen fibers, in mineralization foci and in the mineralized matrix. OC was localized intracellularly and in all the extracellular compartments, and was concentrated at the mineralization front. ON was distributed uniformly throughout the osteoid and mineralized matrix, which was intensely labeled. The results show that the expression of bone matrix proteins during differentiation of calvaria cells and nodule formation in vitro duplicate what is observed during osteogenesis in vivo.
The Political Economy of Canada's Video and Computer Game Industry

Abstract: Video and computer games are a burgeoning new media industry with global revenues rivaling those of film and music. This article, reporting on a three-year SSHRC-funded research project, analyzes the political economy of Canadian involvement in the interactive game business. After an overview of companies, ownership, markets and regional distribution, it discusses the developmental dynamics and contradictions of the Canadian industry in terms of capital, state, and labour. It concludes by reviewing different ways these interweaving forces may ‘play out’ and their implications for policy decisions affecting the Canadian video and computer game industry. Resume : Les jeux electroniques sont une nouvelle industrie mediatique en plein essor dont les revenus mondiaux rivalisent avec ceux des industries du film et de la musique. Cet article, qui rend compte d’un projet de recherche de trois ans finance par le CRHS, analyse l’economie politique de la participation canadienne a l’industrie du jeu interactif. L’article – suivant une vue d’ensemble des compagnies, de leurs proprietaires, des marches, et de la distribution regionale – traite des dynamiques du developpement ainsi que des contradictions de l’industrie canadienne en fonction de capital, etat et travail. En guise de conclusion, l’article passe en revue les diverses manieres dont ces trois forces interreliees pourront evoluer et l’impact de celles-ci sur les decisions politiques portant sur l’industrie des jeux electroniques au Canada.
Mice Devoid of Tau Have Increased Susceptibility to Neuronal Damage in Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

Abstract The abundant axonal microtubule-associated protein tau regulates microtubule and actin dynamics, thereby contributing to normal neuronal function. We examined whether mice deficient in tau (Tau−/−) or with high levels of human tau differ from wild-type (WT) mice in their susceptibility to neuroaxonal injury in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. After sensitization with MOG35–55, there was no difference in clinical disease course between human tau and WT mice, but Tau−/− mice had more severe clinical disease and significantly more axonal damage in spinal cord white matter than those in WT mice. Axonal damage in gray matter correlated with clinical severity in individual mice. By immunoblot analysis, the early microtubule-associated protein-1b was increased 2-fold in the spinal cords of Tau−/− mice with chronic experimental autoimmune encephalomyelitis versus naive Tau−/− mice. This difference was not detected in comparable WT animals, which suggests that there was compensation for the loss of tau in the deficient mice. In addition, levels of the growth arrest–specific protein 7b, a tau-binding protein that is stabilized when bound to tau, were higher in WT than those in Tau−/−spinal cord samples. These data indicate that loss of tau exacerbates experimental autoimmune encephalomyelitis and suggest that maintaining tau integrity might reduce the axonal damage that occurs in inflammatory neurodegenerative diseases such as multiple sclerosis.
Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS.

BACKGROUND Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P. carinii. METHODS We conducted a double-blind, multicenter study in patients with the acquired immunodeficiency syndrome and mild or moderately severe P. carinii pneumonia. They were randomly assigned to 21 days of orally administered treatment three times daily with either atovaquone (750 mg) or trimethoprim (320 mg) plus sulfamethoxazole (1600 mg). RESULTS Of the 322 patients with histologically confirmed P. carinii pneumonia, 160 received atovaquone and 162 received trimethoprim-sulfamethoxazole. Of those who could be evaluated for therapeutic efficacy, 28 of 138 patients given atovaquone (20 percent) and 10 of 146 patients given trimethoprim-sulfamethoxazole (7 percent) did not respond (P = 0.002). Treatment-limiting adverse effects required a change of therapy in 11 patients in the atovaquone group (7 percent) and 33 patients in the trimethoprim-sulfamethoxazole group (20 percent) (P = 0.001). Therapy involving only the initial drug was successful and free of adverse effects in 62 percent of those assigned to atovaquone and 64 percent of those assigned to trimethoprim-sulfamethoxazole. Within four weeks of the completion of treatment, there were 11 deaths in the atovaquone group (4 due to P. carinii pneumonia) and 1 death in the trimethoprim-sulfamethoxazole group (P = 0.003). Diarrhea at entry was associated with lower plasma drug concentrations (P = 0.009), therapeutic failure (P < 0.001), and death (P < 0.001) in the atovaquone group but not in the trimethoprim-sulfamethoxazole group. CONCLUSIONS For the treatment of P. carinii pneumonia, atovaquone is less effective than trimethoprim-sulfamethoxazole, but it has fewer treatment-limiting adverse effects.
Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in the rat

A method that allows the concurrent localization of an antigen and a retrogradely transported fluorescent dye (true blue) was used to identify, immunohistochemically, cells in the paraventricular nucleus of the hypothalamus (PVH) that project to autonomic centers in the brainstem or in the spinal cord of the adult albino rat. After placing injections of true blue in the dorsal vagal complex or in upper thoracic segments of the spinal cord, series of evenly spaced sections through the PVH were stained with antisera directed against oxytocin, vasopressin, somatostatin, methionine‐enkephalin, or leucine‐encephalin. The results indicate that both oxytocin‐ and vasopressin‐stained cells in the PVH project to the spinal cord and (or) to the dorsal vagal complex, although about three times as many oxytocinstained cells were doubly labeled after injections centered in either terminal field. The oxytocin‐ and vasopressin‐stained cells that give rise to these long descending projections were found primarily in caudal parts of the parvo cellular division of the PVH, where immunoreactive cells were shown to be significantly smaller than oxytocin‐ and vasopressin‐stained cells in parts of the nucleus that project to the posterior pituitary. Small populations of cells in the PVH that cross‐react with antisera against somatostatin, leucine‐enkephalin, or methionine‐enkephalin were also shown to project directly to the region of the dorsal vagal complex and to the spinal cord, and to have a unique distribution within the PVH. Collectively, the total number of doubly labeled cells that were identified in these experiments accounts for only about one‐fourth of the total number of PVH neurons with long descending projections, thus suggesting that additional neuroactive substances are contained within these pathways.
Local establishment of repetitive long‐term potentiation‐induced synaptic enhancement in cultured hippocampal slices with divided input pathways

Long‐term potentiation (LTP) in the rodent hippocampus is a popular model for synaptic plasticity, which is considered the cellular basis for brain memory. Because most LTP analysis involves acutely prepared brain slices, however, the longevity of single LTP has not been well documented. Using stable hippocampal slice cultures for long‐term examination, we previously found that single LTP disappeared within 1 day. In contrast, repeated induction of LTP led to the development of a distinct type of plasticity that lasted for more than 3 weeks and was accompanied by the formation of new synapses. Naming this novel plastic phenomenon repetitive LTP‐induced synaptic enhancement (RISE), we proposed it as a model for the cellular processes involved in long‐term memory formation. However, because in those experiments LTP was induced pharmacologically in the whole slice, it is not known whether RISE has input‐pathway specificity, an essential property for memory. In this study, we divided the input pathway of CA1 pyramidal neurons by a knife cut and induced LTP three times, the third by tetanic stimulation in one of the divided pathways to express RISE specifically. Voltage‐sensitive dye imaging andGolgi‐staining performed 2 weeks after the three LTP inductions revealed both enhanced synaptic strength and increased dendritic spine density confined to the tetanized region. These results demonstrate that RISE is a feasible cellular model for long‐term memory. © 2011 Wiley‐Liss, Inc.