Dose-escalation study of rivaroxaban (BAY 59-7939)--an oral, direct Factor Xa inhibitor--for the prevention of venous thromboembolism in patients undergoing total hip replacement

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.     

Large genomic rearrangements in MECP2

In 1999, mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) were first reported in patients with Rett syndrome (RTT). The MECP2 gene is located at Xq28 and consists of 4 exons. About 80-90 % of the classic RTT patients harbor mutations in the coding region of MECP2, while the molecular cause is unknown in the remaining 10-20%. Several groups have searched for large rearrangements within the MECP2 and the results indicate that a fraction of MECP2-negative RTT cases has large deletions of the MECP2. In this study we have used the Multiplex Ligation-dependent Probe Amplification (MLPA) technique to screen 45 RTT patients, who have previously been tested negative for mutations in the coding region of MECP2. The MECP2-MLPA is a semi-quantitative multiplex PCR approach. It determines the relative number of copies of each MECP2 exon. With this approach we detected seven RTT patients with genomic deletions and further characterized the deletions using real time quantitative PCR (qPCR) and long-range PCR. The seven patients were given a severity score and their X chromosome inactivation profiles were determined in order to identify a possible genotype-phenotype correlation. The results from this study indicate that large deletions in MECP2 cause classic RTT.     

Radio frequency electrode system for optical lesion size estimation in functional neurosurgery

Radiofrequency (RF) lesioning in the human brain is one possible surgical therapy for severe pain as well as movement disorders. One obstacle for a safer lesioning procedure is the lack of size monitoring. The aim of this study was to investigate if changes in laser Doppler or intensity signals could be used as markers for size estimation during experimental RF lesioning. A 2 mm in diameter monopolar RF electrode was equipped with optical fibers and connected to a digital laser Doppler system. The optical RF electrode's performance was equal to a standard RF electrode with the same dimensions. An albumin solution with scatterers was used to evaluate the intensity and laser Doppler signal changes during lesioning at 70, 80, and 90 degrees C. Significant signal changes were found for these three different clot sizes, represented by the temperatures (p<0.05, n=10). The volume, width, and length of the created coagulations were correlated to the intensity signal changes (r=0.88, n=30, p<0.0001) and to the perfusion signal changes (r=0.81, n=30, p<0.0001). Both static and Doppler-shifted light can be used to follow the lesioning procedure as well as being used for lesion size estimation during experimental RF lesioning.     

Radionuclide ventriculography detects early anthracycline cardiotoxicity in children with Hodgkin lymphoma

Serial echocardiography to detect doxorubicin dose-related cardiotoxicity correlates poorly with endomyocardial biopsy-proven cardiotoxicity. To compare radionuclide ventriculography (RVG) and echocardiography for the assessment of left ventricular (LV) function in children with Hodgkin disease (HD) receiving doxorubicin, we studied 39 children with HD before radiotherapy, both early (≤ 2 adriamycin, bleomycin, vinblastine, and dacarbazine cycles) (group A; n=10) and late (≥ 6 adriamycin, bleomycin, vinblastine, and dacarbazine cycles) (group B; n=36) during treatment. Seven children were assessed twice. The patients underwent full clinical assessment, echocardiography, and RVG. In group A, LV ejection fraction (LVEF) was significantly lower when measured by RVG compared with echocardiography (P<0.05). Group B had lower LVEF compared with group A by echocardiography (P=0.09), and by RVG (P=0.000). Paired analysis of children studied early and late showed a significant drop in LVEF by echocardiography (58.7 ± 7.3 vs. 52 ± 52.44%; P=0.04) and RVG (51.4 ± 2.6% vs. 47.2 ± 3.1%; P=0.004). The cumulative dose of doxorubicin inversely correlated with RVG-measured LVEF (r=-0.531; P=0.001). No correlation was found between LVEF measured by RVG and echocardiography (r=0.217; P=0.25). Cardiotoxicity occurred early and at low cumulative doses of doxorubicin in children with HD. RVG was more sensitive than echocardiography in detecting early impairment of LV function. We recommend baseline and serial assessment of LV function by RVG in children with HD receiving doxorubicin.     

Human temperature regulation during cycling with moderate leg ischaemia

The effect of graded ischaemia in the legs on the regulation of body temperature during steady-state exercise was investigated in seven healthy males. It was hypothesised that graded ischaemia in the working muscles increases heat storage within the muscles, which in turn potentiates sweat secretion during exercise. Blood perfusion in the working muscles was reduced by applying a supra-atmospheric pressure (+6.6 kPa) around the legs, which reduced maximal working capacity by 29%. Each subject conducted three separate test trials comprising 30 min of steady-state cycling in a supine position. Exercise with unrestricted blood flow (Control trial) was compared to ischaemic exercise conducted at an identical relative work rate (Relative trial), as well as at an identical absolute work rate (Absolute trial); the latter corresponding to a 20% increase in relative workload. The average (SD) increases in both the rectal and oesophageal temperatures during steady-state cycling was 0.3 (0.2)°C and did not significantly differ between the three trials. The increase in muscle temperature was similar in the Control (2.7 (0.3)°C) and Absolute (2.4 (0.7)°C) trials, but was substantially lower (P<0.01) in the Relative trial (1.4 (0.8)°C). Ischaemia potentiated (P<0.01) sweating on the forehead in the Absolute trial (24.2 (7.3) g m^–2 min^–1) compared to the Control trial (13.4 (6.2) g m^–2 min^–1), concomitant with an attenuated (P<0.05) vasodilatation in the skin during exercise. It is concluded that graded ischaemia in working muscles potentiates the exercise sweating response and attenuates vasodilatation in the skin initiated by increased core temperature, effects which may be attributed to an augmented muscle metaboreflex.     

Residual effects of prior exercise and recovery on subsequent exercise-induced metabolic responses

Abstract Data on the metabolic responses to repeated endurance exercise sessions are limited. Thus, the aims of this study were to examine (1) the impact of prior exercise on metabolic responses to a subsequent exercise session and (2) the effect of different recovery periods between two daily exercise sessions on metabolic responses to the second bout of exercise. Nine male elite athletes participated in four 25-h trials: one bout of exercise (ONE), two bouts of exercise separated by 3 h of rest and one meal (SHORT), two bouts of exercise separated by 6 h of rest and two meals (LONG), and a trial with no exercise (REST). All exercise bouts consisted of 10 min cycling at 50% followed by 65 min at 75% of maximal O₂ uptake. Compared to no prior exercise (ONE), a previous bout of exercise (SHORT) was followed by higher mean O₂ uptake, heart rate (HR), rectal temperature (T_R), excess post-exercise oxygen consumption and lower respiratory exchange ratio (R) during and after a similar exercise session 3 h later. A longer rest interval between the two exercise bouts (6 h versus 3 h) and an additional meal resulted in a decrease in O₂ uptake, HR, T_R and an increase in R during the second bout of exercise, but no effects on post-exercise metabolism were found. Thus, augmented metabolic stress was observed when strenuous exercise was repeated after only 3 h of recovery, but this was attenuated when a longer recovery period including an additional meal was provided between the exercise sessions.