Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis

Background

Lipoprotein(a) [Lp(a)], a major carrier of oxidized phospholipids (OxPL), is associated with an increased incidence of aortic stenosis (AS). However, it remains unclear whether elevated Lp(a) and OxPL drive disease progression and are therefore targets for therapeutic intervention.

Opening of ATP-sensitive potassium channels causes generation of free radicals in vascular smooth muscle cells

Recent evidence suggests that opening of mitochondrial K_ATP channels in cardiac muscle triggers the preconditioning phenomenon through free radical production. The present study tested the effects of K_ATP channel openers in a vascular smooth muscle cell model using the fluorescent probe MitoTracker (MTR) Red™ for detection of reactive oxygen species (ROS). Rat aortic smooth muscle cells (A7r5) were incubated with 1 μM reduced MTR (non-fluorescent) and the MTR oxidation product (fluorescent) was quantified. Thirty-minute pretreatment with either diazoxide (200 μM) or pinacidil (100 μM), both potent mitochondrial K_ATP channel openers, increased fluorescent intensity (FI) to 149 and 162 % of control (p < 0.05 for both), respectively, and the K_ATP channel inhibitor 5-hydroxydecanoate (5HD) blocked it. Valinomycin, a potassium-selective ionophore, raised FI to 156 % of control (p <: 0.05). However, 5HD did not affect the valinomycin-induced increase in FI. Inhibition of mitochondrial electron transport (myxothiazol) or uncoupling of oxidative phosphorylation (dinitrophenol) also blocked either valinomycin- or diazoxide-induced increase in FI, and free radical scavengers prevented any diazoxide-mediated increase in fluorescence. Finally the diazoxide-induced increase in fluorescence was not blocked by the PKC inhibitor chelerythrine, but was by HMR 1883, a putative surface K_ATP channel blocker. Thus opening of K_ATP channels increases generation of ROS via the mitochondrial electron transport chain in vascular smooth muscle cells. Furthermore, a potassium-selective ionophore can mimic the effect of putative mitochondrial KATP channel openers. We conclude that potassium movement through KATP directly leads to ROS production by the mitochondria. Received: 7 January 2002, Returned for revision: 31 January 2002, Revision received: 21 February 2002, Accepted: 14 March 2002     

Stigma,sex work,and substance use: a comparative analysis

Stigma is a widely used concept in social science research and an extensive literature claims that stigmatisation contributes to numerous negative health outcomes. However, few studies compare groups that vary in the extent to which they are stigmatised and even fewer studies examine stigma's independent and mediating effects. This article addresses these gaps in a comparative study of perceived stigma and drug use among three low‐income feminised service occupations: sex work, food and alcoholic beverage serving, and barbering and hairstyling. An analysis of longitudinal data shows positive associations between sex work, perceived stigma, and socially less acceptable drug use (for example, heroin and cocaine), and that stigma mediates part of the link between sex work and the use of these drugs. Our overall findings suggest that perceived stigma is pronounced among those who work in the sex industry and negatively affects health independently of sex work involvement.     

Fluid resuscitation in pre-hospital management of septic shock

Background

Septic shock is associated with hypovolemia resulting in organs failure and poor prognosis. The first step in hemodynamic resuscitation relies on early fluid expansion. In this study, we describe qualitative and quantitative fluid resuscitation of septic shock initially managed in a pre-hospital setting by a mobile intensive care unit.

Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure

Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated whether long-lasting artemisinin pressure selects a novel multidrug-tolerance profile. Although 50% inhibitory concentrations for 10 antimalarial drugs tested were unchanged, drug-tolerant parasites showed higher recrudescence rates for endoperoxides, quinolones, and an antifolate, including partner drugs of recommended combination therapies, but remained susceptible to atovaquone. Moreover, the age range of intraerythrocytic stages able to resist artemisinin was extended to older ring forms and trophozoites. Multidrug tolerance results from drug-induced quiescence, which enables parasites to survive exposure to unrelated antimalarial drugs that inhibit a variety of metabolic pathways. This novel resistance pattern should be urgently monitored in the field because this pattern is not detected by current assays and represents a major threat to antimalarial drug policy.     

Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohumoral effects

OBJECTIVES: We investigated the acute and long-term hemodynamic and neurohumoral effects of the vasopeptidase inhibitor omapatrilat in human heart failure. BACKGROUND: Angiotensin-converting enzyme (ACE) inhibition constitutes a major advance in the treatment of chronic heart failure (CHF). Simultaneous inhibition of both neutral endopeptidase and ACE with omapatrilat may represent a new treatment strategy in CHF. METHODS: Three hundred and sixty-nine patients with symptomatic heart failure were randomized to double-blind treatment with omapatrilat (first 190 patients: 2.5 mg, 5 mg or 10 mg; last 179 patients: 2.5 mg, 20 mg or 40 mg once daily) for 12 weeks. RESULTS: Acutely, the 10 mg, 20 mg and 40 mg doses of omapatrilat produced greater reductions in pulmonary capillary wedge pressure (PCWP), systolic blood pressure (SBP) and systemic vascular resistance compared with 2.5 mg. Higher doses were associated with greater increases in vasodilator and natriuretic peptides, in addition to ACE inhibition. After 12 weeks, omapatrilat 20 mg and 40 mg showed greater falls from baseline in PCWP (40 mg: 0 h to 12 h average change -7.3 +/- 0.8 mm Hg) and SBP (40 mg: -11.7 +/- 1.7 mm Hg) than 2.5 mg (both p < 0.01 vs. 2.5 mg). The incidence of adverse experiences and patient withdrawal were similar in all groups. CONCLUSIONS: In CHF, the acute hemodynamic benefit seen with higher doses of omapatrilat was associated with increases in plasma vasodilator and natriuretic peptide levels in addition to ACE inhibition. After 12 weeks, the hemodynamic benefit was maintained. Omapatrilat may be a promising new agent in CHF.     

Endothelial hyperplasia and endothelial galectin-3 expression are prognostic factors in primary central nervous system lymphomas

Recently, considerable attention has been focused on the identification of clinically relevant prognostic markers for primary central nervous system lymphomas (PCNSL). The present study investigated whether three morphological features, i.e. necrosis, reactive perivascular T-cell infiltrate and endothelial hyperplasia, and galectin-1 and galectin-3 immunohistochemical expression have prognostic roles in a series of 58 PCNSL samples from 44 immunocompetent and 14 immunocompromised patients. The presence of endothelial hyperplasia (identified in 21% of the assessable cases) was identified as a bad prognostic factor for immunocompetent PCNSL patients, whereas the other morphological features were not associated with any prognostic value. Lymphomatous cells of eight PCNSL cases expressed galectin-3 without any prognostic value, and lymphomatous cells did not express galectin-1. In contrast, endothelial expression of galectin-3 was identified (by means of uni- and multi-variate analyses) as a bad prognostic factor for immunocompetent PCNSL patients. In addition, a combination of endothelial hyperplasia and/or endothelial galectin-3 expression was shown to be an independent prognostic factor for immunocompetent PCNSL patients treated with methotrexate-based chemotherapy. In summary, this study suggests that endothelial-related markers can identify risk groups of PCNSL patients and indicates that galectin-3 could be involved in PCNSL angiogenesis.     

Pulmonary vein isolation using transvenous catheter cryoablation for treatment of atrial fibrillation without risk of pulmonary vein stenosis

OBJECTIVES: We sought to evaluate the efficacy and safety of pulmonary vein (PV) isolation using transvenous cryoablation for the treatment of atrial fibrillation (AF). BACKGROUND: Although electrical isolation of PVs with radiofrequency energy for the treatment of AF is feasible, it is associated with a significant risk of PV stenosis. Cryoablation is a new alternative therapy allowing ablation of tissue while preserving its underlying architecture. METHODS: In 52 patients with paroxysmal (n = 45) or persistent (n = 7) AF, PV isolation using the CryoCor cryoablation system (CyroCor Inc., San Diego, California) with a 10F deflectable transvenous catheter was performed as guided by ostial PV potentials. Cryoablation was applied twice at each targeted site (2.5 to 5 min/application). Computed tomography (CT) of the thorax was performed at baseline and at 3 and 12 months to evaluate for PV stenosis. RESULTS: All targeted PVs were completely isolated in 49 (94%) of 52 of patients. Of 152 PVs targeted, 147 (97%) were successfully isolated (mean 3.0 PVs isolated per patient). After a mean period of 12.4 +/- 5.5 months of follow-up, 37 (71%) of 52 patients had no recurrence of AF or were clinically improved, including 29 patients (56%) who had no recurrence of AF with (n = 11) or without the use of anti-arrhythmic drugs. At 3 and 12 months, the CT scan showed no evidence of PV stenosis associated with cryoablation in any patients. CONCLUSIONS: Transvenous catheter cryoablation is an effective method to create PV electrical isolation for the treatment of AF. A clinically satisfactory result can be achieved in 71% of patients with AF, without the risk of PV stenosis.