Degeneration of oxidative muscle fibers in HTLV-1 tax transgenic mice.

The HTLV-1 tax gene under control of the HTLV-1 long terminal repeat (LTR) was introduced into transgenic mice. Previously tax protein expression in the muscle and peripheral nerves of three independent mouse lines was reported. Here the localization of this transgenic protein at a cellular and subcellular level is described. Tax protein was expressed in oxidative muscle fibers that developed severe progressive atrophy. It localized to the cytoplasma where it was associated with structures resembling degenerating Z bands. This pattern of muscle fiber involvement is similar to that observed in human retroviral associated myopathy. This transgenic mouse model suggests that preferential expression of the HTLV-1 viral promoter in oxidative muscle fibers may explain the productive infection of these fibers in HTLV-1 myopathy.     

Correlation of flunisolide plasma levels to eosinopenic response in humans

Plasma levels of flunisolide were measured in healthy male volunteers after the administration of single doses of the drug by the intravenous, oral, intranasal, and bronchial inhalation routes. The systemic availability of a 1-mg dose orally was only 21%. After a single dose of approximately 0.117 mg intranasally plasma levels ranged up to 1 ng/ml. When 1 mg was administered by bronchial inhalation, peak or near peak plasma levels were recorded at 2 min and remained near this level throughout the first hour before declining at a rate similar to that observed after flunisolide intravenously (plasma ). Gargling with an alcoholic mouthwash immediately after inhalation reduced plasma levels at 30 and 60 min but not earlier, suggesting rate-limiting dissolution of flunisolide in bronchial fluids or rate-limiting diffusion across the mucociliary blanket or pulmonary membrane. The systemic availabilities of the inhaled-mouthwash and inhaled-no mouthwash doses were 32% and 39%, respectively. Systemic potency of flunisolide, measured by eosinopenic response, was oral < inhaled < intravenous and correlated with the systemic availability of flunisolide after drug administration by these three routes. These pharmacokinetic properties of flunisolide are clinically advantageous in that relatively small doses are delivered topically to the target organs, i.e., the nasal mucosa and lungs, whereas a large portion of the dose is swallowed and subsequently extensively metabolized to relatively inactive metabolites.     

Radioimmunoassay of detirelix ([ N-Ac-D-Nal(2)1,D-p-Cl-Phe2,D-Trp3, D-hArg(Et)6(2),D-Ala10]-luteinizing hormone-releasing hormone) in plasma or serum

A procedure for the radioimmunoassay (RIA) of detirelix in plasma or serum at concentrations as low as 0.15 ng/ml is described. Antiserum was produced by deacetylation of the N-terminus amino groups of detirelix and coupling this analog to bovine serum albumin with a carbodiimide and immunizing rabbits with the resultant conjugate. For RIA, 125I-labeled detirelix was used as the tracer and a double antibody procedure was used to separate the free and bound fractions. No purification of samples was required prior to RIA. Accuracy of the method was assessed by adding known quantities of detirelix to detirelix-free plasma and determining the ratio of measured to added analyte. Linear regression analysis for the concentration range 0.15-150.0 ng/ml yielded a regression equation of y = 0.88 X +1.46 and a correlation coefficient of 0.996. Additional validation was obtained from an in vivo study in which [14C]detirelix was administered to monkeys and plasma clearance profiles were determined by RIA and an HPLC-radiochemical method. The RIA results were in good agreement with those obtained by the HPLC method.     

A case series of LMWH use in pregnancy: Should trough anti-Xa levels guide dosing?

Introduction

Pregnancy is a thrombogenic state, increasing the risk for venous thromboembolism (VTE), and the risk of valve thrombosis amongst women with mechanical heart valves (MHV). While low molecular weight heparins (LMWH) are generally dosed based on weight (i.e., enoxaparin 1 mg/kg every 12 hours), data in pregnant women have shown that weight-based dosing does not consistently achieve target anti-Xa levels. In women with MHV, our practice includes titrating LMWH doses to target both trough and peak anti-Xa levels, while for those with VTE peak anti-Xa levels guide dosing.

Materials/Methods

This retrospective case series included pregnant women requiring LMWH treatment doses with at least 3 peak (+/− trough) anti-Xa levels. Our primary objective was to describe the actual LMWH dose required to achieve targeted anti-Xa levels relative to weight-based dosing in patients with MHV. Secondarily, we compared the same for VTE patients; compared actual dosing between those with MHV and VTE; and examined maternal and fetal outcomes.

Results/Conclusion

Women with MHV (N = 4) required greater than weight-based dosing of enoxaparin (1.35 mg/kg Q12H) to achieve targeted anti-Xa levels. Importantly, achieving target peak anti-Xa levels did not always ensure maintenance of minimum trough levels. VTE patients (N = 12) did not require more enoxaparin (0.96 mg/kg Q12H) than weight based dosing. MHV patients received more enoxaparin compared to VTE patients (P < 0.001). No bleeding or clotting complications were associated with LMWH administration. In pregnant women with MHV at high risk of thromboembolism, LMWH dosing guided by trough and peak anti-Xa levels should be considered.     

Gestational Diabetes and Hypertensive Disorders of Pregnancy as Vascular Risk Signals: An Overview and Grading of the Evidence

The occurrence of common pregnancy-related medical disorders identifies women at high risk of developing future vascular disease. Systematic reviews of cohort studies demonstrate that gestational diabetes confers a 7-fold risk increase for type 2 diabetes, and preeclampsia confers a 1.8-fold risk increase for type 2 diabetes and 3.4-fold risk increase for hypertension. Gestational diabetes and hypertensive disorders of pregnancy (HDP) increase the risk of premature vascular disease, but the 2-fold risk increase associated with preeclampsia is only partially explained by the development of traditional vascular risk factors. Despite the compelling evidence for gestational diabetes and HDP as vascular risk indicators, there are no published Canadian vascular prevention guidelines that recognize these postpartum women. In contrast, the 2011 American Heart Association guidelines on cardiovascular disease in women include gestational diabetes and HDP in their vascular risk assessment. Studies indicate that the importance surveillance of vascular risk factors in these women after pregnancy is underappreciated by the women themselves and their physicians. Although a prudent diet and physically active lifestyle were demonstrated to reduce diabetes risk in women with a gestational diabetes history in the American Diabetes Prevention Program trial, adoption of these health behaviours is low; qualitative studies confirm a need for tailored strategies that address barriers and provide social support. Further research is also needed on approaches to reduce vascular risk in women with a history of gestational diabetes and HDP. Otherwise, an early window of opportunity for chronic disease prevention in young, high-risk women will be missed.