Publications

Acute coronary syndrome (ACS) is common in women, yet we have less sex-specific data in women than in men as a result of lower enrollment in clinical trials and low rates of sex-specific reporting. Women are generally older with more comorbidities when diagnosed with ACS. Women with ACS are less likely than men to be referred for invasive evaluation and procedures and are more likely to have normal coronary arteries when they are referred for coronary angiography. For reasons that are not well understood, women have higher rates of bleeding complications compared with men. This higher bleeding rate is consistently seen in many trials. There are 3 major randomized, controlled trials that compared early invasive therapy with conservative strategy for ACS. Two of these trials found higher rates of myocardial infarction (MI) and death at 1 year in women treated with early invasive strategy, whereas the third trial found a reduction in the composite end point of rehospitalization, MI, and death at 180 days in women treated with early invasive strategy. Sex differences have also been seen in glycoprotein (GP) IIb/IIIa use in women with an increase in death and MI noted for GP use in women with ACS. Continued and increased numbers of women in clinical studies of ACS as well as increased rates of sex-specific reporting will allow us to offer optimal quality care for women and men with ACS.

INTRODUCTION

A substantial number of patients require a second left atrial procedure after ablation for atrial fibrillation (AF), either for left atrial flutter or recurrent AF. The success and complication rates of repeat transseptal catheterization in these patients are unknown. The aim of this study was to determine the difficulty and/or success rates of repeat transseptal catheterization after left atrial ablation for AF.

METHODS AND RESULTS

Consecutive patients undergoing repeat left atrial procedures after ablation for AF over a 1-year period were enrolled. Difficulties with, success rates, and complications of the first and second transseptal catheterizations were recorded. Sixteen patients underwent a repeat transseptal catheterization. Of the 4 in whom the first procedure was performed with an ablation catheter across a patent foramen ovale (PFO), 3 required a transseptal puncture for their repeat procedure. The remaining 12 underwent transseptal puncture without difficulty for their first procedure, and, despite the same operators for each patient, the repeat transseptal was noted to be difficult in 5. Of those 5, the transseptal puncture was unsuccessful due to increased interatrial septal thickness in 2 patients. One repeat transseptal attempt was aborted after posterior right atrial puncture with the transseptal needle occurred, attributed to distorted interatrial septal anatomy not observed prior to the first case.

CONCLUSIONS

Compared with the first procedure, repeat transseptal catheterization after ablation for AF, whether initially performed across a PFO or via a transseptal puncture, is more difficult, less often successful, and potentially associated with more complications.

Botswana, with its estimated HIV prevalence of 37%, instituted a policy of universal access to antiretroviral therapy (ART) in 2002. Initial enrolment lagged behind expectations, with a shortfall in voluntary testing that observers have attributed to HIV-related stigma - although there are no published data on stigma among HIV-positive individuals in Botswana. We interviewed 112 patients receiving ART in 2000, finding evidence of pervasive stigma in patterns of disclosure, social sequelae, and delays in HIV testing. Ninety-four percent of patients reported keeping their HIV status secret from their community, while 69% withheld this information even from their family. Twenty-seven percent of patients said that they feared loss of employment as a result of their HIV status. Forty percent of patients reported that they delayed getting tested for HIV; of these, 51% cited fear of a positive test result as the primary reason for delay in seeking treatment, which was often due to HIV-related stigma. These findings suggest that success of large-scale national ART programmes will require initiatives targeting stigma and its social, economic and political correlates.

Genotyping methods for Plasmodium falciparum drug efficacy trials have not been standardized and may fail to accurately distinguish recrudescence from new infection, especially in high transmission areas where polyclonal infections are common. We developed a simple method for genotyping using previously identified microsatellites and capillary electrophoresis, validated this method using mixtures of laboratory clones, and applied the method to field samples. Two microsatellite markers produced accurate results for single-clone but not polyclonal samples. Four other microsatellite markers were as sensitive as, and more specific than, commonly used genotyping techniques based on merozoite surface proteins 1 and 2. When applied to samples from 15 patients in Burkina Faso with recurrent parasitemia after treatment with sulphadoxine-pyrimethamine, the addition of these four microsatellite markers to msp1 and msp2 genotyping resulted in a reclassification of outcomes that strengthened the association between dhfr 59R, an anti-folate resistance mutation, and recrudescence (P = 0.31 versus P = 0.03). Four microsatellite markers performed well on polyclonal samples and may provide a valuable addition to genotyping for clinical drug efficacy studies in high transmission areas.

OBJECTIVE

Alpha and gamma-melanocyte stimulating hormones (MSH) are peptides that possess potent hypertensinogenic actions when injected intravenously or intracerebroventricularly. We sought to define the central receptor(s) mediating these cardiovascular actions.

METHODS

We gave bolus injections of synthetic alpha or gamma-MSH intravenously or intracerebroventricularly to anesthetized wild-type (Mc3r+/+, Mc4r+/+) mice and mice with targeted disruption of the gamma-MSH receptor (Mc3r-/-) or the melanocortin 4 receptor (Mc4r-/-).

RESULTS

Gamma-MSH injected intravenously increased mean arterial pressure (MAP) and heart rate (HR) dose-dependently, with the effect being evident at 10 mol/kg; the maximum increase, at 10 mol/kg, was 38 mmHg in both strains from similar control MAP. Parallel increases in HR also occurred. Injection of the sodium channel blocker, benzamil, 4 microg/kg intracerebroventricularly, before intravenous gamma-MSH completely prevented the increases in MAP and HR in both strains. Injection of 2 x 10 mol/g body weight alpha-MSH intravenously had no effect on MAP or HR in Mc4r wild-type or -/- mice. However, the same dose given intracerebroventricularly to wild-type mice increased MAP from 76 +/- 4 to 95 +/- 5 mmHg at 10 min (P < 0.01) and HR from 416 +/- 15 to 480 +/- 15 beats/min (P < 0.01). In Mc4r-/- mice, the intracerebroventricular administration of the peptide did not alter these variables, in contrast to the results in wild-type mice.

CONCLUSION

Both MSH peptides exert their hypertensinogenic effects through central sites of action, which probably reflect the activation of sympathetic outflow. The actions of intracerebroventricular alpha-MSH appear to be mediated via Mc4r, whereas those of gamma-MSH are independent of its receptor Mc3r, but reflect the activation of a sodium channel in the central nervous system. These results help to reconcile the hypertensive action of gamma-MSH injections with the hypertension observed in states of gamma-MSH deficiency.

Increased lung vascular permeability is an important contributor to respiratory failure in acute lung injury (ALI). We found that a function-blocking antibody against the integrin alphavbeta5 prevented development of lung vascular permeability in two different models of ALI: ischemia-reperfusion in rats (mediated by vascular endothelial growth factor [VEGF]) and ventilation-induced lung injury (VILI) in mice (mediated, at least in part, by transforming growth factor-beta [TGF-beta]). Knockout mice homozygous for a null mutation of the integrin beta5 subunit were also protected from lung vascular permeability in VILI. In pulmonary endothelial cells, both the genetic absence and blocking of alphavbeta5 prevented increases in monolayer permeability induced by VEGF, TGF-beta, and thrombin. Furthermore, actin stress fiber formation induced by each of these agonists was attenuated by blocking alphavbeta5, suggesting that alphavbeta5 regulates induced pulmonary endothelial permeability by facilitating interactions with the actin cytoskeleton. These results identify integrin alphavbeta5 as a central regulator of increased pulmonary vascular permeability and a potentially attractive therapeutic target in ALI.