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Background: As the retina is suggested to mirror the brain, we hypothesized that diabetic retinopathy and macular edema are indicative of stroke risk in type 1 diabetes and sought to assess this association in individuals with type 1 diabetes. Methods: We included 1,268 adult FinnDiane Study participants with type 1 diabetes (age 38.7 ± 11.8 years, 51.7% men vs. 48.3% women, and 31.5% had diabetic kidney disease), data on baseline diabetic retinopathy severity, and first stroke during our observational follow-up. Retinopathy was graded by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and macular edema as clinically significant (CSME) or not. Strokes identified from registries were confirmed from medical files. Adjusted hazard ratios (HR) for stroke by retinopathy severity and CSME were calculated by Cox models adjusted for clinical confounders, including diabetic kidney disease. Results: During median 18.0 (14.1–19.3) follow-up years, 130 strokes (96 ischemic, 34 hemorrhagic) occurred. With no–very mild (ETDRS 10–20) retinopathy as reference, the adjusted HR for stroke was 1.79 (95%CI 1.02–3.15) in non-proliferative (ETDRS 35–53), and 1.69 (1.02–2.82) in proliferative (ETDRS 61–85) retinopathy. Corresponding adjusted HR for ischemic stroke was 1.68 (0.91–3.10) in non-proliferative and 1.35 (0.77–2.36) in proliferative retinopathy. The adjusted HR for hemorrhagic stroke was 2.84 (0.66–12.28) in non-proliferative and 4.31 (1.16–16.10) in proliferative retinopathy. CSME did not increase HR for any stroke type after adjustment for clinical confounders (data not shown). Conclusions: Stroke incidence increases with the severity of diabetic retinopathy independently of comorbid conditions, including diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Aim: Cerebral small-vessel disease (SVD) is prevalent in type 1 diabetes and has been associated with the haptoglobin variant allele Hp1. Contrarily, the Hp2-allele has been linked to cardiovascular disease and the role of haptoglobin-genotype in asymptomatic SVD is unknown. We, therefore, aimed to evaluate the alleles' association with SVD. Methods: This cross-sectional study included 179 neurologically asymptomatic adults with type 1 diabetes (women 53%, mean age 39 ± 7 years, diabetes duration 23 ± 10 years, HbA1c 8.1 ± 3.2% [65 ± 12 mmol/mol]). Examinations included genotyping (genotypes Hp1-1, Hp2-1, Hp2-2) by polymerase chain reaction, clinical investigation, and magnetic resonance brain images assessed for SVD manifestations (white matter hyperintensities, cerebral microbleeds, and lacunar infarcts). Results: SVD prevalence was 34.6%. Haptoglobin genotype frequencies were 15.6% (Hp1-1), 43.6% (Hp1-2), and 40.8% (Hp2-2). Only diastolic blood pressure differed between the genotypes Hp1-1, Hp1-2, and Hp2-2 (81 [74–83], 75 [70–80], and 75 [72–81] mmHg, p = 0.019). Haptoglobin genotype frequencies by presence versus absence of SVD were 16.1%; 46.8%; 37.1% versus 15.4%; 41.9%; 42.7% (p = 0.758). Minor allele frequencies were 39.5% versus 36.3% (p = 0.553). Hp1 homozygotes and Hp2 carriers displayed equal proportions of SVD (35.7% vs 34.4%, p > 0.999) and SVD manifestations (white matter hyperintensities 14.3% vs 17.9%, p = 0.790; microbleeds 25.0% vs 21.9%, p = 0.904; lacunar infarcts 0% vs 3.6%, p > 0.999). Hp1-1 was not associated with SVD (OR 1.19, 95% CI 0.46–2.94, p = 0.712) when adjusting for age, blood pressure, and diabetic retinopathy. Conclusions: Although the SVD prevalence was high, we detected no significant association between SVD and haptoglobin-genotype. [ABSTRACT FROM AUTHOR]

Moment analysis of ion spectrograms measured by the Ion Composition Analyser (ICA) in the coma of comet 67P typically produces an ion number density estimate markedly lower than the number density of free electrons as measured by the Mutual Impedance Probe and the dual Langmuir Probe. While there are good reasons to distrust the ion density moment estimate in these circumstances, the issue cannot yet be considered fully understood and it is of interest to see whether any natural non-instrumental cause is possible. An obvious such cause would be whether a significant fraction of the positive charge density resides in positively charged dust grains that are not measured by the ICA. Here, we show that this scenario is highly unlikely, even near perihelion where photoemission is the strongest. In our semi-analytical grain charging model, we balance the current contributions to grains of photoelectron emission and electron attachment so as to find the expected charge state for a grain of a given radius. The charge state is affected by the ambient electron number density, the electron temperature, and the heliocentric distance. While at times the bulk of the dust population around comet 67P could be charged positive, dust charging, including photoelectron emission, should have a negligible influence on the overall ionization balance in the cometary coma simply because the dust particles are not ubiquitous enough. [ABSTRACT FROM AUTHOR]

Context. The electrostatic potential of a spacecraft, VS, is important for the capabilities of in situ plasma measurements. Rosetta has been found to be negatively charged during most of the comet mission and even more so in denser plasmas. Aims. Our goal is to investigate how the negative VS correlates with electron density and temperature and to understand the physics of the observed correlation. Methods. We applied full mission comparative statistics of VS, electron temperature, and electron density to establish VS dependence on cold and warm plasma density and electron temperature. We also used Spacecraft-Plasma Interaction System (SPIS) simulations and an analytical vacuum model to investigate if positively biased elements covering a fraction of the solar array surface can explain the observed correlations. Results. Here, the VS was found to depend more on electron density, particularly with regard to the cold part of the electrons, and less on electron temperature than was expected for the high flux of thermal (cometary) ionospheric electrons. This behaviour was reproduced by an analytical model which is consistent with numerical simulations. Conclusions. Rosetta is negatively driven mainly by positively biased elements on the borders of the front side of the solar panels as these can efficiently collect cold plasma electrons. Biased elements distributed elsewhere on the front side of the panels are less efficient at collecting electrons apart from locally produced electrons (photoelectrons). To avoid significant charging, future spacecraft may minimise the area of exposed bias conductors or use a positive ground power system. [ABSTRACT FROM AUTHOR]

In a cometary coma, the ion-neutral decoupling distance, sometimes referred to as the ion exobase or collisionopause, can be defined as the cometocentric distance, r in, where ions, initially moving with the neutral outgassing speed, have a probability of 1/ e of not colliding with neutrals on their subsequent journey radially outwards. We present an analytical model for calculating this decoupling distance in the presence of a static radial electric field. We show that for a logarithmically decaying potential, the value of r incan even decrease to ∼15 per cent of its field-free case value. Moreover, already at this distance, the effective ion speed can be expected to markedly exceed the neutral expansion velocity. These analytical results are in line with previous numerical calculations, adapting similar but not identical field profiles. The presence of a non-negligible ambipolar electric field and limited importance of ion-neutral collisional coupling are further supported by observations in the diamagnetic cavity of comet 67P/Churyumov–Gerasimenko by plasma instruments onboard Rosetta that reveal ion speeds several times higher than the neutral expansion velocity. [ABSTRACT FROM AUTHOR]

The article focuses on nocturnal blood pressure has associated with cerebral small-vessel disease in type 1 diabetes. Topics inlcude the vascular complications are a hallmark of diabetes, the cerebral small-vessel disease (cSVD) in type 1 diabetes remains scarcely studied, and the cSVD is more common in individuals with type 1 diabetes than healthy control subjects and has associated with systolic office blood pressure.

We present a Rosetta Plasma Consortium (RPC) case study based on four events in 2015 autumn at various radial distances, phase angles and local times, just after the perihelion of comet 67P/Churyumov-Gerasimenko. Pulse-like (high-amplitude, up to minutes in time) signatures are seen with several RPC instruments in the plasma density (with the LAngmuir Probe, LAP and Mutual Impedance Probe, MIP), ion energy and flux (with the Ion Composition Analyzer, ICA) and the magnetic field intensity (with the magnetometer, MAG). Furthermore, the cometocentric distance relative to the electron exobase is seen to be a good organizing parameter for the measured plasma variations. The closer Rosetta is to this boundary, the more pulses are measured. This is consistent with the pulses being filaments of plasma originating from the diamagnetic cavity boundary, as predicted by simulations. [ABSTRACT FROM AUTHOR]

Context. Strong electron cooling on the neutral gas in cometary comae has been predicted for a long time, but actual measurements of low electron temperature are scarce. Aims. Our aim is to demonstrate the existence of cold electrons in the inner coma of comet 67P/Churyumov-Gerasimenko and show filamentation of this plasma. Methods. In situ measurements of plasma density, electron temperature and spacecraft potential were carried out by the Rosetta Langmuir probe instrument, LAP. We also performed analytical modelling of the expanding two-temperature electron gas. Results. LAP data acquired within a few hundred km from the nucleus are dominated by a warm component with electron temperature typically 5-10 eV at all heliocentric distances covered (1.25 to 3.83 AU). A cold component, with temperature no higher than about 0.1 eV, appears in the data as short (few to few tens of seconds) pulses of high probe current, indicating local enhancement of plasma density as well as a decrease in electron temperature. These pulses first appeared around 3 AU and were seen for longer periods close to perihelion. The general pattern of pulse appearance follows that of neutral gas and plasma density. We have not identified any periods with only cold electrons present. The electron flux to Rosetta was always dominated by higher energies, driving the spacecraft potential to order -10 V. Conclusions. The warm (5-10 eV) electron population observed throughout the mission is interpreted as electrons retaining the energy they obtained when released in the ionisation process. The sometimes observed cold populations with electron temperatures below 0.1 eV verify collisional cooling in the coma. The cold electrons were only observed together with the warm population. The general appearance of the cold population appears to be consistent with a Haser-like model, implicitly supporting also the coupling of ions to the neutral gas. The expanding cold plasma is unstable, forming filaments that we observe as pulses. [ABSTRACT FROM AUTHOR]

Background In adults with moderate renal impairment (creatinine clearance [CrCl] 30–50 mL/min) undergoing total hip or knee replacement (THR/TKR), the recommended dose of dabigatran etexilate is 150 mg once daily (qd). We investigated the steady state pharmacokinetics, pharmacodynamics and safety in these patients. Methods Single-arm, open-label phase 4 study ( NCT01184989 ) in Caucasian patients receiving dabigatran etexilate 75 mg 1–4 h after surgery and 150 mg qd on days 2–10 (TKR) or days 2–35 (THR). Plasma total dabigatran concentrations (day 6 ± 1) were determined by high-performance liquid chromatography tandem mass spectrometry and indirectly using the commercially available diluted thrombin time (dTT) assay (Hemoclot® Thrombin Inhibitors). Results Of 112 patients (mean CrCl 42.5 mL/min, age 79.1 years, 69.6% female), 100 completed the study. Geometric mean trough and peak dabigatran concentrations were 47.5 ng/mL (10th–90th percentile 19.7–120) and 166 ng/mL (49.1–364), respectively. There were four major bleeding events and no venous thromboembolic events. Dabigatran concentrations determined from dTT (and falling within the assay range of 50–500 ng/mL) underestimated actual values by 7.6% (90% confidence interval 5.3, 9.9), which is within the acceptance limits of ± 15%. Conclusions These findings in Caucasians with moderate renal impairment undergoing THR or TKR support the use of the 150 mg qd dose of dabigatran etexilate. With adequate set-up, calibration and quality control the dTT assay might be appropriate for situations, such as serious bleeding or a need for urgent surgery, where determination of dabigatran levels would be helpful. [ABSTRACT FROM AUTHOR]

Background: Two phase 3 trials compared 28-35 days of treatment with oral dabigatran 220 mg or 150 mg (RE-NOVATE) or 220 mg (RE-NOVATE II) once daily with subcutaneous enoxaparin 40 mg once daily for prevention of venous thromboembolism (VTE) after elective total hip arthroplasty. Methods: This prespecified pooled analysis compared the outcomes for the dabigatran 220 mg dose with enoxaparin, which included 4,374 patients. Total VTE (venographic and symptomatic) plus all-cause mortality (primary efficacy), major VTE (proximal deep vein thrombosis [DVT] or non-fatal pulmonary embolism) plus VTE-related death, and bleeding events were evaluated. Efficacy analysis was based on the modified intention-to-treat (ITT) population and safety analysis was based on all treated patients. The common risk difference (RD) for dabigatran versus enoxaparin was estimated using a fixed effects model. Results: Total VTE and all-cause mortality occurred in 6.8 % (114/1,672) and 7.7 % (129/1,682) (RD:-0.8 %, 95 % confidence interval [CI] -2.6 to 0.9) for dabigatran and enoxaparin, respectively. Major VTE plus VTE-related mortality occurred in 2.7 % (46/1,714) and 4.0 % (69/1,711) (RD: -1.4 %, 95 % CI -2.6 to -0.2) of patients receiving dabigatran 220 mg and enoxaparin, respectively. Major bleeding occurred in 1.7 % (37/2,156) and 1.3 % (27/2,157) (RD: 0.5 %, 95 % CI -0.2 to 1.2), for dabigatran and enoxaparin respectively. Conclusions: Extended prophylaxis with oral dabigatran 220 mg once daily was as effective as enoxaparin 40 mg once daily in reducing the risk of total VTE and all-cause mortality after total hip arthroplasty, with a similar bleeding profile. The clinically relevant outcome of major VTE and VTE-related death was significantly reduced with dabigatran versus enoxaparin. Trial registration: NCT00657150 and NCT00168818 [ABSTRACT FROM AUTHOR]

The adsorption behavior of phosphopeptides onto TiO2 surfaces was studied using the quartz crystal microbalance with dissipation monitoring (QCM-D) as the main experimental technique. The main focus is the characterization of the emergence of positive cooperativity under conditions where the peptides have a positively charged C-term. It is shown that when carrying no net charge, small water-soluble peptides as a rule develop positive cooperativity. The impact of the adsorption mechanism on the outcome of TiO2 based enrichment methods was investigated with the help of matrix assisted laser desorption-ionization mass spectrometry (MALDI-MS). The data presented illustrate how the phosphopeptide profile in the enriched material may deviate from that in the native sample, as cooperative phosphopeptides are overrepresented in the former. Furthermore, commonly employed washing and elution solutions may facilitate preferential release of certain peptides, leading to further bias in the recovered sample. Taken together, the results of the present study demonstrate that thorough understanding of the mechanisms behind the adsorption of phosphopeptides on the enrichment material is necessary in order to develop reliable qualitative and quantitative methods for phosphoproteomics. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Oral thromboprophylaxis with dabigatran etexilate should be initiated as a half dose 1 to 4h after major orthopaedic surgery. However, a delay in dosing could occur for clinical or logistical reasons. A post hoc analysis was carried out to determine if patients with delayed dosing received adequate anticoagulation. Patients and methods: The RE-MODEL™ and RE-NOVATE® trials compared 220mg and 150mg dabigatran etexilate with 40mg enoxaparin. Pooled data for major venous thromboembolism (VTE) and VTE-related mortality (efficacy outcome) and major bleeding events (MBE), MBE/clinically relevant bleeding events, and all bleeding events (safety outcomes) were analysed. Results in patients with dosing delayed more than 4h postsurgery were compared with those of patients without a delay. Results: Onset of treatment was delayed in 724 (13.3%) of 5425 patients. Efficacy of 220mg dabigatran etexilate was similar in patients without delayed dosing, patients with a delay and patients with a delay until the day after surgery. Rates of efficacy outcome were higher in patients on 150mg dabigatran etexilate, but more than 80% of these patients were undertreated based on age or renal clearance status. Some differences in bleeding events were seen among patient groups by treatment arm. Conclusion: Dabigatran etexilate thromboprophylaxis should be initiated 1 to 4h postsurgery. Results from our post-hoc analysis indicate that no loss of efficacy appears to occur if initiation of dabigatran etexilate 220mg needs to be delayed. [Copyright &y& Elsevier]

Abstract: Introduction: Several anticoagulants have been associated with a ‘rebound effect’ that potentially increases the risk of thrombosis and cardiovascular events following discontinuation. Four Phase 3 trials of dabigatran etexilate in major orthopedic surgery incorporated measures to assess the risk of acute coronary syndrome (ACS) events during and after treatment. Materials and methods: Patients in RE-MOBILIZE®, RE-MODEL™, RE-NOVATE®, and RENOVATE® II were randomized to dabigatran etexilate (150mg or 220mg once daily) or enoxaparin for 6–35days, and followed for up to 90days. ACS data were tabulated from investigator-reported serious adverse events using ACS-specific Medical Dictionary for Regulatory Authorities (MedDRA) lower-level terms. To ensure that all ACS events were identified in the initial three studies, RE-MOBILIZE®, RE-MODEL™, and RE-NOVATE®, a broader list of MedDRA terms was prespecified that would trigger treatment-blinded adjudication. Results: When pooling the four trials, patients receiving dabigatran etexilate 220mg had the fewest treatment-emergent, investigator-reported ACS events (6 [0.16%] vs 14 [0.51%] for dabigatran 150mg and 13 [0.35%] for enoxaparin). Corresponding post-treatment rates were 2 (0.06%), 1 (0.04%), and 4 (0.11%). Similarly, treatment-emergent centrally adjudicated definite or likely ACS events in the first three trials were fewer in patients on dabigatran 220mg (16 [0.60%]) than dabigatran 150mg (26 [0.95%]) and enoxaparin (20 [0.74%]). The corresponding numbers post treatment were 2, 2, and 7. None of these between-group differences were statistically significant. Conclusion: No increased ACS signal was detected with dabigatran etexilate compared with enoxaparin during or after treatment. [Copyright &y& Elsevier]

Abstract: Introduction: The RECORD programme compared oral rivaroxaban with enoxaparin for prevention of venous thromboembolism after elective total hip or knee replacement. This analysis compared the safety of concomitant use of specified medications with rivaroxaban and enoxaparin by evaluating postoperative bleeding rates from the pooled RECORD1–4 data. Materials and methods: The co-medications were non-steroidal anti-inflammatory drugs and platelet function inhibitors, including acetylsalicylic acid (no dose restriction). The endpoints evaluated were the composite of major and non-major clinically relevant bleeding and any bleeding occurring after first oral study drug intake. The time relative to surgery was stratified into three time periods: day 1–3, day 4–7 and after day 7. Relative bleeding rate ratios for co-medication use versus non-use were derived using stratified Mantel–Haenszel methods and compared between rivaroxaban and enoxaparin groups. Results: Co-medication use with rivaroxaban or enoxaparin resulted in non-significant increases in bleeding events. Respective rate ratios were not significantly different between rivaroxaban and enoxaparin for all bleeding endpoints with concomitant use of non-steroidal anti-inflammatory drugs (any bleeding, 1.22 vs 1.22; major and non-major clinically relevant bleeding, 1.28 vs 0.90) and with concomitant use of platelet function inhibitors/acetylsalicylic acid (any bleeding, 1.32 vs 1.40; major and non-major clinically relevant bleeding, 1.11 vs 1.13). Conclusions: This explorative analysis indicates that there is no significant increase in bleeding risk for rivaroxaban compared with enoxaparin when co-administered with non-steroidal anti-inflammatory drugs or acetylsalicylic acid, although, because of low usage, the experience with platelet function inhibitors (except acetylsalicylic acid) was limited. [Copyright &y& Elsevier]

Plasma measurements by electrostatic probes are influenced by the spacecraft-plasma interaction, including the photoelectrons emitted by the spacecraft. Such effects get particularly important in tenuous plasmas with large Debye lengths. We have used the particle-in-cell code package SPIS to study the close environment of the Rosetta spacecraft, and the impact of the spacecraft-plasma interaction on the electrostatic potential at the position of the Langmuir probes onboard. The simulations show that in the solar wind, photoemission has a bigger impact than wake formation. Spacecraft potential estimates based on Langmuir probe data in the solar wind need to be compensated for these effects when the spacecraft attitude varies. The SPIS simulations are validated by comparison to an independent code. [ABSTRACT FROM AUTHOR]

Objective: Cognitive decline accompanies acute illness and surgery, especially in the elderly. Surgery engages the innate immune system that launches a systemic inflammatory response that, if unchecked, can cause multiple organ dysfunction. We sought to understand the mechanisms whereby the brain is targeted by the inflammatory response and how this can be resolved. Methods: C57BL/6J, Ccr2RFP/+Cx3cr1GFP/+, IkkF/F mice and LysM-Cre/IkkF/F mice underwent stabilized tibial fracture operation under analgesia and general anesthesia. Separate cohorts of mice were tested for systemic and hippocampal inflammation, integrity of the blood-brain barrier (BBB), and cognition. The putative resolving effects of the cholinergic pathway on these postoperative responses were also studied. Results: Peripheral surgery disrupts the BBB via release of tumor necrosis factor-alpha (TNFα), which facilitates the migration of macrophages into the hippocampus. Macrophage-specific deletion of Ikappa B kinase (IKK)β, a central coordinator of TNFα signaling through activation of nuclear factor (NF) κB, prevents BBB disruption and macrophage infiltration in the hippocampus following surgery. Activation of the α7 subtype of nicotinic acetylcholine receptors, an endogenous inflammation-resolving pathway, prevents TNFα-induced NF-κB activation, macrophage migration into the hippocampus, and cognitive decline following surgery. Interpretation: These data reveal the mechanisms for bidirectional communication between the brain and immune system following aseptic trauma. Pivotal molecular mechanisms can be targeted to prevent and/or resolve postoperative neuroinflammation and cognitive decline. ANN NEUROL 2011;70:986-995 [ABSTRACT FROM AUTHOR]

Abstract: Anisotropy of magnetic susceptibility (AMS) and rock magnetic studies have been made on three outcrops separated by 12km along strike (NNE–SSW) on the Streitishvarf composite dike in east Iceland. Samples for this study have been collected from the inner quartz-porphyry part of the dike, which show clear field evidence of a lateral flow component from north to south at one of the sites. This flow component is consistent with margin AMS results from all three sites. The quartz-porphyry has a substantial bulk magnetic susceptibility (10−2 SI) mainly carried by magnetically soft titanium-poor titanomagnetite (MDF ~15mT). The ferrimagnetic grains yield a characteristic remanent magnetization in all three sites which gives a virtual geomagnetic pole at latitude 52.6° S and longitude 319.6° E. The degree of anisotropy is low (P J =1.033) and the magnetic fabrics shifts from oblate to prolate shapes depending on dike margin and outcrop. The magnetic fabric has been interpreted according to the imbrication model, using the minor susceptibility axis as shear plane indicator. The absolute directions given by the minor susceptibility are then quantified using vector algebra. The magma flow is indicated as an upward directed flow, flowing from north to south with an inclination between 30° and 64°, with a 95% confidence ellipse of 3°–9°. A model for the intrusion of the Streitishvarf dike has been constructed where a magma pocket with felsic magma is punctured by a mafic dike, enabling the felsic magma to rise and extend to the south within the pathway created. The results of this study confirm the applicability of AMS in studies of magma flow directions in igneous dikes of felsic composition. [Copyright &y& Elsevier]

The last decade has seen the evaluation of several new oral anticoagulants that directly target thrombin or activated factor X (FXa). All demonstrate a rapid onset of action, a low potential for food and drug interactions, and a predictable anticoagulant effect that obviates the need for routine coagulation monitoring. Those agents at the most advanced stages of clinical development are a direct thrombin inhibitor, dabigatran, and direct FXa inhibitors, rivaroxaban and apixaban. Dabigatran and rivaroxaban are approved in more than 70 countries for prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty, and apixaban is being considered for approval by regulatory agencies for this indication. Dabigatran was shown in a large phase III trial to be more effective and safer than warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and has recently been approved for this indication. Edoxaban, an oral FXa inhibitor, is also being evaluated in phase III clinical trials. This review summarizes the pharmacology, clinical trial results, and future role of the new oral anticoagulants in clinical practice. [ABSTRACT FROM AUTHOR]

The article describes the case of a 22-year-old woman who was diagnosed with papillary thyroid cancer. The patient undergone thyroid surgery and was transferred intubated to the general intensive care unit (ICU) and was kept sedated with propofol, midazolam and morphine. The article also discusses the goals of sedation in ICU patients.

Abstract: We have characterized the mouse carotid body (CB) with special attention to nicotinic, purinergic and dopaminergic receptors as well as the TASK-1 K+-channel. Mouse CB sections were stained immunohistochemically and visualized using fluorescent and confocal microscopy. The CB type 1 cells contained the α3 (n =8), α4 (n =7), α7 (n =4) and β2 (n =3) nicotinic acetylcholine receptor (nAChR) subunits, the ATP-receptors P2X2 (n =15) and P2X3 (n =9), the dopamine D2 receptor (n =9) and the TASK-1 K+-channel (n =7). Here we report the presence of α3, α4, α7 and β2 nAChR subunits, the D2 receptor and the TASK-1 K+-channel in the mouse CB. Also, we confirm the presence of the P2X2 and P2X3 receptors in mouse CB. Thus, we have localized nicotinergic, purinergic and dopaminergic receptors and the TASK-1 K+-channel on a protein level in one species. Our data are in line with the theory that the CB chemoreceptor cell hosts an orchestra of receptor systems that ultimately modulate the response to hypoxia. [Copyright &y& Elsevier]

For the past five decades, there has been little progress in the development of oral anticoagulants, with the choices being limited to the vitamin K antagonists (VKAs). The situation is changing with the development of orally active small molecules that directly target thrombin or activated factor X (FXa). The two agents in the most advanced stages of development are dabigatran etexilate and rivaroxaban, which inhibit thrombin and FXa, respectively. Both are approved in the EU and Canada for venous thromboprophylaxis in patients undergoing elective hip- or knee-replacement surgery. Other agents in the early stages of development include several FXa inhibitors (apixaban, DU 176b, LY 517717, YM 150, betrixaban, eribaxaban [PD 0348292] and TAK 442) and one thrombin inhibitor (AZD 0837). With a predictable anticoagulant response and low potential for drug-drug interactions, these new agents can be given in fixed doses without coagulation monitoring. This renders them more convenient than VKAs. While the anticoagulant effect of the new thrombin and FXa inhibitors is similar, differences in the pharmacokinetic and pharmacodynamic parameters may influence their use in clinical practice. Here, we compare the pharmacokinetic and pharmacodynamic features of these new oral agents. [ABSTRACT FROM AUTHOR]

Abstract-Emitters based on the liquid metal ion source principle have been operating on the Cluster spacecraft between 2000 and 2004, in order to control the spacecraft potential. The resulting reduction of positive spacecraft potential reduces perturbations to the plasma measurements on board. Ion currents up to 40 μA have been applied, which reduced the energy band in which photoelectrons disturb the plasma electron measurements to values close to the lower detection limit of the instrument. The experience with this method, meanwhile, covers both the maximum and minimum of the present solar cycle and allows one to study the variations of photoemission and other long-term trends and their effects on the measurements. A long-term trend of the controlled spacecraft potential is indeed observed. In addition, it appears that reconstruction of the uncontrolled spacecraft potential from the controlled one is possible if certain conditions are fulfilled. Spacecraft potential control can thereby improve the plasma measurements while still allowing one to estimate the total plasma density from the residual potential. [ABSTRACT FROM AUTHOR]

Background: This phase 3 trial compared the efficacy and safety of rivaroxaban, an oral direct inhibitor of factor Xa, with those of enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. Methods: In this randomized, double-blind study, we assigned 4541 patients to receive either 10 mg of oral rivaroxaban once daily, beginning after surgery, or 40 mg of enoxaparin subcutaneously once daily, beginning the evening before surgery, plus a placebo tablet or injection. The primary efficacy outcome was the composite of deep-vein thrombosis (either symptomatic or detected by bilateral venography if the patient was asymptomatic), nonfatal pulmonary embolism, or death from any cause at 36 days (range, 30 to 42). The main secondary efficacy outcome was major venous thromboembolism (proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death from venous thromboembolism). The primary safety outcome was major bleeding. Results: A total of 3153 patients were included in the superiority analysis (after 1388 exclusions), and 4433 were included in the safety analysis (after 108 exclusions). The primary efficacy outcome occurred in 18 of 1595 patients (1.1%) in the rivaroxaban group and in 58 of 1558 patients (3.7%) in the enoxaparin group (absolute risk reduction, 2.6%; 95% confidence interval [CI], 1.5 to 3.7; P<0.001). Major venous thromboembolism occurred in 4 of 1686 patients (0.2%) in the rivaroxaban group and in 33 of 1678 patients (2.0%) in the enoxaparin group (absolute risk reduction, 1.7%; 95% CI, 1.0 to 2.5; P<0.001). Major bleeding occurred in 6 of 2209 patients (0.3%) in the rivaroxaban group and in 2 of 2224 patients (0.1%) in the enoxaparin group (P=0.18). Conclusions: A once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. The two drugs had similar safety profiles. (ClinicalTrials.gov number, NCT00329628.) N Engl J Med 2008;358:2765-75. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and pharmacodynamics of rivaroxaban in patients participating in two phase II, double-blind, randomized, active-comparator-controlled studies of twice-daily rivaroxaban for the prevention of venous thromboembolism after total hip- or knee-replacement surgery. METHODS: Sparse blood samples were taken from all patients participating in the studies (n = 1009). In addition, a subset of patients in the hip study (n = 36) underwent full profiling. Rivaroxaban plasma concentrations, FXa activity and the prothrombin time were determined. Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of rivaroxaban. RESULTS: An oral one-compartment model described the population pharmacokinetics of rivaroxaban well. On the first postoperative day only, categorization of patients as slow or fast absorbers as a tool to address variability in absorption improved the fit of the model. Clearance of rivaroxaban was lower and more variable on the first postoperative day, and so time was factored into the model. Overall, the only major difference between the models for the hip study and the knee study was that clearance was 26% lower in the knee study, resulting in approximately 30% higher exposure. Residual variability in the models was moderate (37% and 34% in the hip and knee studies, respectively). Plasma concentrations of rivaroxaban increased dose dependently. Pharmacokinetic parameters that were estimated using the models agreed closely with results from full-profile patients in the hip study, demonstrating that rivaroxaban pharmacokinetics are predictable. The pharmacokinetics of rivaroxaban were affected by expected covariates: age affected clearance in the hip study only, haematocrit (on the first postoperative day only) and gender affected clearance in the knee study only, and renal function affected clearance in both studies. Bodyweight affected the volume of distribution in both studies. However, the effects of covariates on the pharmacokinetics of rivaroxaban were generally small, and predictions of ‘extreme’ case scenarios suggested that fixed dosing of rivaroxaban was likely to be possible. FXa activity and the prothrombin time were both affected by surgery, probably because of perioperative bleeding and intravenous administration of fluids; therefore, time was included in the pharmacodynamic models. In both studies, FXa activity correlated with rivaroxaban plasma concentrations following a maximum effect model, whereas prothrombin time prolongation correlated following a linear model with intercept. The slope of the prothrombin time prolongation correlation was 3.2 seconds/(100 µg/L) in the hip study and 4.2 seconds/(100 µg/L) in the knee study. Both pharmacodynamic models in both studies demonstrated low residual variability of approximately 10%. CONCLUSION: This population analysis in patients undergoing major orthopaedic surgery demonstrated that rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of rivaroxaban may be possible in patients undergoing major orthopaedic surgery. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention of thromboembolic disorders. The aim of this study was to demonstrate proof-of-principle for rivaroxaban. Materials and methods: This was an open-label, dose-escalation study to assess the efficacy and safety of rivaroxaban, relative to enoxaparin, for the prevention of venous thromboembolism (VTE) after total hip replacement surgery. Patients were randomized in a 3:1 ratio to rivaroxaban (2.5, 5, 10, 20 and 30 mg twice daily [bid] or 30 mg once daily [od] starting 6–8 h after surgery) or enoxaparin (40 mg od starting the evening before surgery). Therapy continued until mandatory bilateral venography was performed 5–9 days after surgery. Results: A total of 625 patients received therapy, of whom 466 patients were eligible for the per-protocol efficacy analysis. The primary efficacy endpoint – deep vein thrombosis (DVT), pulmonary embolism (PE) or all-cause mortality – occurred in 22.2%, 23.8%, 20.0%, 10.2%, 17.4%, 15.1% and 16.8% of patients receiving rivaroxaban 2.5, 5, 10, 20, 30 mg bid, 30 mg od and enoxaparin, respectively. The dose-response relationship with rivaroxaban for the primary efficacy endpoint was not statistically significant (p =0.0504), although major VTE (proximal DVT, PE and VTE-related death) decreased dose dependently with rivaroxaban (p =0.0108). Major, post-operative bleeding increased dose dependently with rivaroxaban (p =0.0008), occurring in 0–10.8% of patients, compared with 0% in patients receiving enoxaparin. Conclusions: This study demonstrated proof-of-principle for rivaroxaban for the prevention of VTE after total hip replacement surgery. [Copyright &y& Elsevier]

This article reports on a clinical trial assessing the oral, direct thrombin inhibitor dabigatran etexilate against enoxaparin as a prophylactic to reduce the risk of venous thromboembolism following total hip replacement surgery. The study found no significant differences in bleeding rates or in increases in liver enzyme concentrations or of acute coronary events during the study period which was just over one month. The authors conclude that oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of a thromboembolism in the patients who had undergone total hip replacement surgery.

The Rosetta dual Langmuir probe instrument, LAP, utilizes the multiple powers of a pair of spherical Langmuir probes for measurements of basic plasma parameters with the aim of providing detailed knowledge of the outgassing, ionization, and subsequent plasma processes around the Rosetta target comet. The fundamental plasma properties to be studied are the plasma density, the electron temperature, and the plasma flow velocity. However, study of electric fields up to 8 kHz, plasma density fluctuations, spacecraft potential, integrated UV flux, and dust impacts is also possible. LAP is fully integrated in the Rosetta Plasma Consortium (RPC), the instruments of which together provide a comprehensive characterization of the cometary plasma. [ABSTRACT FROM AUTHOR]

Cold flowing tenuous plasmas are common in the terrestrial magnetosphere, particularly in the polar cap and tail lobe regions, which are filled by the supersonic plasma flow known as the polar wind. Electric field measurements with double-probe instruments in these regions suffer mainly from two error sources: 1) an apparent sunward electric field due to photoemission asymmetries in the probe-boom system and 2) an enhanced negatively charged wake forming behind the spacecraft, which will affect the probe measurements. The authors investigate these effects experimentally by Fourier analysis of the spin signature from the double-probe instrument Electric Fields and Waves (EFW) on the Cluster spacecraft. They show that while the signature due to photoemission asymmetry is very close to sinusoidal, the wake effect is characterized by a spectrum of spin harmonics. The Fourier decomposition can therefore be used for identifying wake effects in the data. As a spin-off, the analysis has also given information on the cold flowing ion population. [ABSTRACT FROM AUTHOR]

Event studies and results of a statistical investigation on charging events as detected by the Freja satellite in the auroral zone at an altitude of 1500–1700 km are presented. Charging up to kilovolts is sometimes observed, though lower values are more common. Comparing to Defense Meteorological Satellite Program (DMSP) at 840 km, Freja experiences fewer charging events, but some of them are found in sunlit conditions, which has not been observed on DMSP. No charging event occurred for a density above 2000 cm-3, though correlation between density and charging was weak otherwise. All charging events show enhanced electron fluxes around or above 10 keV, including enhanced tails up to 100 keV, whereas electrons around a few hundreds of electronvolts instead counteract charging, as is expected from high secondary yields in this energy range. Simulations using the POLAR code reproduced moderate charging events, but not the events with kilovolt charging. [ABSTRACT FROM AUTHOR]

Current anticoagulant provision is dominated by parenteral heparin and oral warfarin, which act by inhibiting several steps of the coagulation pathway indirectly. Recent research efforts have focused on the identification of small molecule inhibitors of the coagulation enzymes as novel therapies for thrombotic disorders. There has been particular success in developing nonpeptidic, orally available, small molecules to directly inhibit the key proteases, factor IIa and factor Xa. Of the new oral anticoagulants in development, the two agents in the most advanced stage are dabigatran etexilate (BIBR 1048) and rivaroxaban (BAY 59-7939), which inhibit factor IIa and factor Xa, respectively. Other agents in the early stages of development include several Xa inhibitors (LY-517717, YM150, DU-176b and apixaban [BMS-562247]), a factor IXa inhibitor (TTP889), and an orally active glycosaminoglycan enhancer (odiparcil [SB-424323]), which indirectly enhances thrombin inhibition via heparin cofactor II. Results have been reported from important, phase II dose-finding studies, and a number of registration-track phase III studies have been initiated, reflecting the drive towards potentially more effective, but primarily safer and more convenient therapies for the prevention and treatment of venous and arterial thrombosis. Indeed, two unmet needs for anticoagulation that can be easily identified are safety and ease of use. Safety relates primarily to the incidence of major bleeding and this remains the key concern of orthopaedic surgeons, over and above any efficacy advantage, and convenience of use, which centres on oral administration replacing the need for injections. The clinical development of these new anticoagulants is following the well tested strategy of dose-ranging and registration studies in major orthopaedic surgery, prior to development in arterial indications. There are a number of subtle issues, including the timing of the first perioperative dose, duration of prophylactic treatment and definition/assessment of study endpoints that can influence study outcome and require careful consideration when evaluating study results with new agents and in the comparison with established agents, and which are considered in this review. It is anticipated that over the next 3 years, at least one of these agents will be successfully licensed for the prevention of venous thromboembolism after major orthopaedic surgery, which will act as a springboard for the gradual replacement of current anticoagulants. [ABSTRACT FROM AUTHOR]

Spacecraft in tenuous plasmas become positively charged because of photoelectron emission. If the plasma is supersonically drifting with respect to the spacecraft, a wake forms behind it. When the kinetic energy of the positive ions in the plasma is not sufficient to overcome the electrostatic barrier of the spacecraft potential, they scatter on the potential structure from the spacecraft rather than get absorbed or scattered by the spacecraft body. For tenuous plasmas with Debye lengths much exceeding the spacecraft size, the potential structure extends far from the spacecraft, and consequently in this case the wake is of transverse dimensions much larger than the spacecraft. This enhanced wake formation process is demonstrated by theoretical analysis and computer simulations. Comparison to observations from the Cluster satellites shows good agreement. [ABSTRACT FROM AUTHOR]

Liberal pre-operative fasting routines have been implemented in most countries. In general, clear fluids are allowed up to 2 h before anaesthesia, and light meals up to 6 h. The same recommendations apply for children and pregnant women not in labour. In children <6 months, most recommendations now allow breast- or formula milk feeding up to 4 h before anaesthesia. Recently, the concept of pre-operative oral nutrition using a special carbohydrate-rich beverage has also gained support and been shown not to increase gastric fluid volume or acidity. Based on the available literature, our Task Force has produced new consensus-based Scandinavian guidelines for pre-operative fasting. What is still not clear is to what extent the new liberal fasting routines should apply to patients with functional dyspepsia or systematic diseases such as diabetes mellitus. Other still controversial areas include the need for and effect of fasting in emergency patients, women in labour and in association with procedures done under ‘deep sedation’. We think more research on the effect of various fasting regimes in subpopulations of patients is needed before we can move one step further towards completely evidence-based pre-operative fasting guidelines. [ABSTRACT FROM AUTHOR]

El artículo habla del riesgo de tromboembolismo venoso (TEV) en los pacientes con una implantación de prótesis totales de cadera y de rodilla. Para disminuir este riesgo, se han utilizado varias sustancias de profilaxia, específicamente el uso del fondaparinux. El fondaparinux es el único fármaco aprobado en los Estados Unidos para la profilaxis a corto y largo plazo de las fracturas de cadera.

Objectives: To examine the influence of timing of postoperative initiation of subcutaneous melagatran followed by oral ximelagatran, and of risk factors for venous thromboembolism (VTE; including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and bleeding complications, on the efficacy and safety of this regimen, compared with preoperative enoxaparin sodium, following total hip replacement (THR) or total knee replacement (TKR) surgery. Design: Statistical analyses of efficacy and safety in subgroups of the METHRO III intention-to-treat population. Main outcome measures: Main efficacy outcome measures were major VTE (proximal DVT, PE or VTE-related death) and total VTE (distal or proximal DVT, fatal or non-fatal PE). The main safety outcome measures were blood transfusion, severe bleeding events, blood loss, bleeding-related adverse events and need for reoperation. Results: In the combined THR and TKR population, melagatran initiated 4 – <8 hours postoperatively was non-inferior to enoxaparin sodium with respect to the risks of total VTE (absolute risk reduction [ARR] 0; 95% confidence interval [CI] –4.4, 4.4) and major VTE (ARR –0.63; 95% CI –2.94, 1.67). The rate of major VTE was unaffected by the different risk factors. In the combined THR and TKR population, blood transfusion requirements were lower with melagatran/ximelagatran than enoxaparin sodium (odds ratio 0.83; 95% CI 0.71, 0.96; p = 0.016). Conclusions: Melagatran/ximelagatran initiated 4 – <8 hours postoperatively provided a comparable level of protection against total and major VTE to preoperative enoxaparin sodium. Major VTE rates and safety were consistent across different patient subgroups. Subcutaneous melagatran followed by fixed-dose oral ximelagatran offers an alternative to the standard European low molecular-weight heparin regimen in a wide range of patients. [ABSTRACT FROM AUTHOR]

Patients undergoing total hip or total knee replacement are at high risk of venous thromboembolism (VTE), and are therefore considered to be populations well suited for the evaluation and dose optimisation of new anticoagulants. Deep vein thrombosis may lead to life-threatening pulmonary embolism, disabling morbidity in the form of the post-thrombotic syndrome, and risk of recurrent thrombotic events. There is increasing evidence that anticoagulant treatment for the prevention of VTE should be extended from 1 to at least 4 weeks after surgery. Anticoagulation with vitamin K antagonists (such as warfarin), low molecular weight heparin or unfractionated heparin effectively lowers the risk of VTE, but these anticoagulants have limitations such as the need for coagulation monitoring and subsequent dose adjustment (vitamin K antagonists), difficulty of continuing prophylaxis out of hospital because of the requirement for parenteral administration, and risk of heparin-induced thrombocytopenia. The development of new anticoagulants has been pursued with the aim of finding more effective, safer and/or more convenient therapies.___TAGSTART___BR___TAGEND___Thrombin is a central regulator in the coagulation and inflammation process and several direct thrombin inhibitors (DTIs) with distinct pharmacological profiles, as well as pharmacological differences from the conventional anticoagulants, are currently in clinical use for certain indications or are under development. Clinical experience with parenterally administered DTIs has accumulated since the mid 1990s, although only desirudin (a recombinant hirudin) is currently approved for use in patients undergoing orthopaedic surgery. Two oral DTIs, ximelagatran and dabigatran etexilate, are in clinical development. Dabigatran etexilate has recently been evaluated in phase II clinical trials in patients undergoing total hip replacement. Several large phase III trials have now demonstrated the efficacy and safety of ximelagatran in the prevention of VTE following total hip or knee replacement. Ximelagatran can be used with an oral fixed dose without the need for coagulation monitoring or dose adjustment. Hence, it offers significant potential to facilitate the management of anticoagulation in or out of hospital. [ABSTRACT FROM AUTHOR]

Fondaparinux, a selective inhibitor of factor Xa, is the first of a new class of antithrombotic compounds, the synthetic pentasaccharides. Its benefit-to-risk ratio in preventing venous thromboembolism after major orthopedic surgery was investigated in four randomized, double-blind international phase III trials in patients undergoing surgery for hip fracture, elective hip replacement, and major knee surgery. Compared to enoxaparin, fondaparinux administered at a subcutaneous dose of 2.5 mg qd, starting postoperatively, reduced the overall incidence of venous thromboembolism up to day 11 by 55.2% (p < 0.001). The incidence of clinically relevant bleeding was low and did not differ between the two groups. Overall, fondaparinux achieved optimal efficacy and safety when treatment was initiated ≥ 6 h after the surgical procedure. In a further randomized double-blind trial, 4 weeks of prophylaxis with fondaparinux after hip fracture surgery reduced the risk of venous thromboembolism by 96% as compared to 1 week of prophylaxis, and was well tolerated. Fondaparinux has been recently approved for use in thromboprophylaxis after major orthopedic surgery. The clinical development of fondaparinux in other thromboprophylactic indications is ongoing. [ABSTRACT FROM AUTHOR]

Background: The benefit of thromboprophylaxis for 1 month has never been evaluated in patients undergoing hip fracture surgery, a setting in the highest risk category for postoperative venous thromboembolism (VTE). Methods: In a double-blind multicenter trial, 656 patients undergoing hip fracture surgery were randomly assigned to receive prophylaxis with a once-daily subcutaneous injection of either 2.5 mg of fondaparinux sodium or placebo for 19 to 23 days. Before randomization, all patients had received fondaparinux for 6 to 8 days. The primary efficacy outcome was VTE occurring during the double-blind period (deep vein thrombosis detected by mandatory bilateral venography or documented symptomatic deep vein thrombosis or pulmonary embolism). The main safety outcome was major bleeding. Results: The primary efficacy outcome was assessed in 428 patients. Fondaparinux reduced the incidence of VTE compared with placebo from 35.0% (77/220) to 1.4% (3/208), with a relative reduction in risk of 95.9% (95% confidence interval, 87.2%-99.7%; P < .001). Similarly, the incidence of symptomatic VTE was significantly lower with fondaparinux (1/326; 0.3%) than with placebo (9/330; 2.7%). The relative reduction in risk was 88.8% (P = .02). Although there was a trend toward more major bleeding in the fondaparinux group than in the placebo group (P = .06), there were no differences between the 2 groups in the incidence of clinically relevant bleeding (leading to death, reoperation, or critical organ bleeding). Conclusions: Extended prophylaxis with fondaparinux for 3 weeks after hip fracture surgery reduced the risk of VTE by 96% and was well tolerated. [ABSTRACT FROM AUTHOR]

Summary: Background: Heparins substantially reduce the risk of thromboembolic complications after total hip or knee replacement. However, they can be given only by injection and have several other drawbacks. We did a multicentre, randomised, double-blind study to examine the dose-response relation of subcutaneous melagatran, a direct thrombin inhibitor, followed by oral ximelagatran as thromboprophylaxis after total hip or knee replacement. We aimed to compare the efficacy and safety with that of dalteparin. Methods: Of 1900 patients, 1495 were assigned to four dose categories of subcutaneous melagatran from just before surgery (1.00 mg, 1.50 mg, 2.25 mg, or 3.00 mg twice daily) followed from the day after surgery by oral ximelagatran (8 mg, 12 mg, 18 mg, or 24 mg twice daily). 381 patients were assigned subcutaneous dalteparin 5000 IU once daily, from the evening before surgery. Bilateral venography was done at 7-10 days, and clinically suspected venous thromboembolism (VTE) was confirmed radiologically. The primary endpoint was the rate of deep-vein thrombosis and pulmonary embolism (PE). Analyses were by intention to treat. Findings: 1876 patients underwent total replacement of hip (n=1270) or knee (n=606); evaluable venograms were obtained in 1473 (79%). Four patients without evaluable venograms had PE. Overall, a significant dose-dependent decrease in VTE was seen with melagatran/ximelagatran (lowest to highest group: 111 [37.8%], 70 [24.1%], 71 [23.7%], and 43 [15.1%]; p=0.0001); there were also significant relations for both total hip and total knee replacement individually. The frequency of VTE was significantly lower with the highest dose of melagatran/ ximelagatran than with dalteparin (15.1% vs 28.2%, p<0.0001). There were no reoperations due to bleeding and no critical organ bleeding. Excessive surgical bleeding was uncommon but more frequent in the highest dose group. Interpretation: This sequential therapy was effective and safe in patients... [ABSTRACT FROM AUTHOR]

The first clinical studies evaluating the safety and efficacy of melagatran, a novel, direct thrombin inhibitor, given subcutaneously as prophylaxis for venous thromboembolism (VTE) following total hip (THR) or total knee replacement (TKR) are reported. In Study I, 66 patients received subcutaneous melagatran (1.5–6 mg bid) in a poloxamer depot formulation, and in Study II, 104 patients received subcutaneous melagatran (2–4 mg bid) in saline or as a depot formulation in cyclodextrin. Treatment was given for 8–11 days, with the first dose administered immediately before surgery. Deep vein thrombosis (DVT) was assessed using mandatory bilateral venography on the last day of treatment, and pulmonary scintigraphy was performed if required. Bleeding complications occurred in the only patient who received melagatran 6 mg, and this dose-arm was discontinued. The frequency of VTE was low (12/129=9%, 95% confidence interval [CI]: 5–16%). Eight patients (6%) had distal DVT, three (2%) had proximal DVT, and in one patient (1%) pulmonary embolism (PE) was verified. In conclusion, subcutaneous melagatran 1.5–4.5 mg bid in saline or depot formulation was well tolerated and resulted in a low frequency of VTE. [Copyright &y& Elsevier]

Background: Sedentary behavior, such as excessive sitting, increases risk of cardiovascular disease and premature mortality in the general population, but this has not been assessed in type 1 diabetes. Occupational sitting is increasingly ubiquitous and often constitutes the largest portion of daily sitting time. Our aim was to identify clinical factors associated with excessive occupational sitting in type 1 diabetes and, in a prospective setting, to explore its association with cardiovascular events and all-cause mortality, independent of leisure-time physical activity. Methods: An observational follow-up study of 1,704 individuals (mean age 38.9 ± 10.1 years) from the Finnish Diabetic Nephropathy Study. Excessive occupational sitting, defined as ≥ 6 h of daily workplace sitting, was assessed using a validated self-report questionnaire. Data on cardiovascular events and mortality were retrieved from national registries. Multivariable logistic regression identified independently associated factors, while Kaplan-Meier curves and Cox proportional hazard models were used for prospective analyses. Results: Factors independently and positively associated with excessive occupational sitting included a high occupational category [OR 6.53, 95% CI (4.09‒10.40)] and older age [1.02 (1.00‒1.03)], whereas negatively associated factors included current smoking [0.68 (0.50‒0.92)], moderate albuminuria [0.55 (0.38‒0.80)], and high leisure-time physical activity [0.52 (0.36‒0.74)]. During a median follow-up of 12.5 (6.5–16.4) years, 163 individuals (9.6%) suffered cardiovascular events, and during a median follow-up of 13.7 (9.4–16.6) years, 108 (6.3%) deaths occurred. Excessive occupational sitting increased cardiovascular event risk (hazard ratio [HR] 1.55 [95% CI 1.10‒2.18]) after adjustment for confounders and other covariates. Furthermore, in a stratified multivariable analysis among current smokers, excessive occupational sitting increased the risk of all-cause mortality (2.06 [1.02‒4.20]). Conclusions: Excessive occupational sitting is associated with a higher risk of cardiovascular events and all-cause mortality in individuals with type 1 diabetes. This association persists regardless of leisure-time physical activity, after adjusting for independently associated variables identified in our cross-sectional analyses. These findings underscore the need to update physical activity guidelines to better address sedentary behavior and improve outcomes for individuals with type 1 diabetes. Targeting occupational sitting should be considered a key focus for interventions aimed at reducing overall sedentary time. [ABSTRACT FROM AUTHOR]

Purpose: To determine the cause of inadequate bilateral phlebograms at central assessment. A major antithrombotic trial was evaluated to identify and apply corrective measures for reducing inadequate results in future multicentre trials.Material and Methods: The inadequate results in 253 out of 1,827 patients having undergone bilateral phlebography following total hip replacement were reviewed by two central assessors using strict criteria for evaluability. The reasons for inadequate findings were assessed and ranked.Results and Conclusion: Insufficient contrast filling, especially of the anterior tibial, common femoral and iliac veins, was the most common reason for disqualifying examinations. Unilateral examinations and obscuring metallic devices were the second and third most common reasons, respectively. Efforts should be made to standardize the phlebography technique, to use a large volume of contrast without tourniquets, and to obtain an appropriate number of views to visualize the deep veins. [ABSTRACT FROM AUTHOR]

Compares the two anatomic reconstructions for correction of chronic lateral ankle joint stability. Subjects and methods used in the study; Results of the study and its analysis; Conclusions.

Most subtalar ligamentous injuries occur in combination with ankle ligament injuries, but the exact aetiology and the true incidence remain unknown. The aim of this study was to review the problem, propose a definition and to analyze the results of an anatomic reconstructive surgical technique in the treatment of subtalar instability. Twenty-two patients suffering from chronic subtalar instability of the foot were operated with anatomical reconstruction. The cervical, the lateral talo-calcaneal and the calcaneo-fibular ligaments were imbricated and reinforced with the lateral root of the inferior extensor retinaculum. After a minimum of 2 years follow-up the functional results were excellent or good in 18 of 22 (82%) patients and fair or poor in 4 of 22 (18%). All of the patients with unsatisfactory results suffered from residual ankle pain, two of whom also had residual instability. No reoperations have been performed. Surgical complications were seen in three patients, all minor nerve injuries of the lateral branch of the superficial peroneal nerve. These complications had no bearing on the functional results, however. This procedure was found to be feasible in patients with chronic subtalar instability. [ABSTRACT FROM AUTHOR]

Presents a study on the efficacy of dose levels of CGP 393993, or recombinant hirudin, as compared to unfractionated heparin in the prevention of thromboembolic events following total hip replacement surgery. Patients and methods involved in the study; Findings that CGP 393993 reduced the frequency of deep-vein thrombosis more often than heparin did; Other details of the study.

Abstract: Introduction: Three pivotal phase 3 trials have demonstrated that oral dabigatran etexilate showed similar safety and efficacy to enoxaparin 40mg once daily (qd) for venous thromboembolism (VTE) prevention in patients undergoing total knee or hip replacement. Obesity is an established independent risk factor for VTE. Methods: A post-hoc pooled analysis of the three trials was performed to evaluate the safety and efficacy of dabigatran 220mg qd versus enoxaparin 40mg qd in patients with a normal body mass index (BMI) of >20–25kg/m2, pre-obese patients (BMI >25–30kg/m2) and obese patients (BMI >30kg/m2). The primary efficacy endpoint was major VTE and VTE-related mortality; safety endpoints included major, clinically relevant, or any bleeding events. Results: The mean BMIs for patients in the dabigatran and enoxaparin arms from all three trials, separately, were between 27.5 and 29.9kg/m2. Of the participants, 1417 (24.9%) had a normal BMI, 2373 (41.7%) were pre-obese and 1826 (32.1%) obese. In patients with normal BMI, the rates of the primary efficacy endpoint were significantly lower in the dabigatran than in the enoxaparin group (2.1% versus 4.3%; OR 0.48; 95% CI 0.24–0.97, P =0.037). No significant difference between dabigatran and enoxaparin in the primary efficacy endpoint was observed in the other subgroups. Bleeding rates were also similar between treatments for BMI subgroups. Conclusions: Dabigatran is an effective thromboprophylactic therapy for normal, pre-obese and obese patients, and outcomes in patients with a BMI >25kg/m2 do not differ from the overall population. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "Potent Anticoagulants Are Associated With a Higher All-cause Mortality Rate After Hip and Knee Arthroplasty," by Bengt I. Eriksson and colleagues.

We discuss acceleration of ions by the ambipolar electric field in the diamagnetic cavity of a cometary coma. We challenge the view that ions are collisionally coupled to the neutrals throughout the cavity, arguing that the so-called ion-neutral decoupling distance i) can be severely reduced in the presence of a non-negligible ambipolar electric field and ii) is not to be viewed as a sharp limit where ion velocities start to depart from the neutral velocity. For a given potential profile it is possible to derive analytic expressions for the ion-neutral decoupling distance and to calculate ion speed distributions and mean ion velocities as a function of cometocentric distance. The outstanding issue is that the potential structure is not given and not easily assessed either. Recently developed strategies to infer from MIP- and LAP data the relative abundances of cold versus warm electrons may give some constraints on the potential profile. In the scenario of a very dominant cold electron population the ambipolar electric field would be very low. In such a case there would, within the cavity, be no field to accelerate the ions. The ions would then move outward with the same bulk velocity as the neutrals, and there would in principle be no reason to attribute this to ion-neutral collisional coupling. [ABSTRACT FROM AUTHOR]