Electroanatomically guided catheter ablation of ventricular tachycardias causing multiple defibrillator shocks

With conventional techniques, RF catheter ablation is difficult in patients with unstable VT or with multiple VTs. The feasibility of RF catheter ablation guided by three-dimensional electroanatomic mapping technique in patients whose implanted ICD continued to deliver multiple shocks due to VT despite use of antiarrhythmic medications was assessed in 19 patients (15 men, 4 women; mean age [+/- SD] 70+/-7 years). All had a prior history of MI and subsequently had received an ICD due to VT. During the 12-week preablation period, these patients received 31+/-15 shocks (range 4-62 shocks) due to refractory monomorphic VTs. An electroanatomic mapping technique using the CARTO system was performed to delineate scar tissue. RF catheter ablation was then performed at appropriate sites identified by pace mapping and by substrate mapping. Seventeen patients were on amiodarone at the time of ablation. Twenty-seven VTs were documented clinically, and 45 were induced during electrophysiological evaluation. Of the 45 tachycardias induced, 38 VTs were targeted for ablation. Catheter ablation was performed during sinus rhythm in 31 episodes and during VT in 7 episodes. During a mean follow-up of 26+/-8 weeks (range 18-48 weeks), 13 (66%) patients had no recurrence of VT (P < 0.0001) and antiarrhythmic drugs were discontinued or the number of medications reduced in 17 patients (P < 0.0001). Electroanatomic mapping is helpful in identifying sites for catheter ablation in highly symptomatic patients with refractory VT associated with myocardial scarring.     

Design of the Del-1 for therapeutic angiogenesis trial (DELTA-1), a phase II multicenter, double-blind, placebo-controlled trial of VLTS-589 in subjects with intermittent claudication secondary to peripheral arterial disease

The objective of this phase II investigation is to assess the safety and efficacy of a plasmid mediated approach to induce angiogenesis/arteriogenesis with the angiomatrix protein Del-1 (developmentally regulated endothelial locus 1), in subjects with intermittent claudication (IC) secondary to peripheral arterial disease (PAD). VLTS-589 is an investigational nonviral therapeutic comprising a plasmid-expressing Del-1 formulated with poloxamer 188 (facilitating agent). One hundred subjects with bilateral PAD and IC will be randomized after careful screening to bilateral intramuscular delivery of VLTS-589 or placebo. A total of 84 mg of plasmid or placebo will be delivered as 42 intramuscular injections (2 ml per injection, 21 injections or 42 ml in each extremity of either plasmid or placebo) in both lower extremities. The subjects in the study will be followed at regular intervals for a year after study drug administration (days 30, 90, 180, and 365) with the primary endpoint being the safety and tolerability of VLTS-589 and change in peak walking time (PWT) at day 90. The secondary endpoints include percent and absolute change in resting ankle brachial Index, claudication onset time, and quality of life measured at various time points. DELTA-1 represents the largest plasmid-based gene transfer trial designed to test the efficacy of a Del-1 as a therapeutic approach in patients with IC caused by PAD. The novel aspects of the protocol include the usage of a Del-1 plasmid-polaxamer formulation to enhance gene transfer at doses that are an order of magnitude different than other comparable trials in a unique bilateral intramuscular dosing pattern to maximize transfection/clinical efficacy and general applicability to patients with PAD.     

Hyperglycemia and hypertriglyceridemia in real world patients on antipsychotic therapy

There have been recent reports in the psychiatric literature of the possible association of glucose dysregulation and diabetes mellitus with the use of atypical antipsychotics. This article describes a retrospective chart review of patients from various clinical settings, including a continuing day treatment program, two inpatient programs, and a large private practice. Information was obtained with regard to weight, fasting blood glucose, lipid profiles, EKG changes, and medical comorbidities. The patients included those treated with conventional antipsychotic agents, clozapine, risperidone, olanzapine, and quetiapine. No one antipsychotic agent was associated with a statistically significantly higher prevalence of diabetes, lipid abnormalities, or EKG problems. It was noted, however, that there were higher rates of diabetes (17%), lipid abnormalities (43%), and hypertension (30%) across the sample. This finding suggests that the high prevalence of diabetes, lipid abnormalities, and hypertension in a young, chronically psychiatrically ill population makes the case for aggressive screening.     

Role of sensory input and muscle strength in maintenance of balance, gait, and posture in Parkinson's disease: a pilot study

OBJECTIVE: The purpose of this study was to simultaneously evaluate multiple components of disequilibrium in patients with idiopathic Parkinson's disease (PD) in ON and OFF states and healthy age- and sex-matched controls on tests of balance, gait, and dynamometry. DESIGN: Thirty subjects with Parkinson's disease and 30 controls were matched for age and sex. Isokinetic and balance laboratories of a clinical research center were used for assessment. Performance results for static and dynamic balance by dynamic posturography for sensory organization tests (SOT), limits of stability, clinical gait assessment, and dynamometric assessment for the trunk, hip, and ankle at different speeds for concentric muscle strength were obtained. Tests were done both in ON and OFF state in Parkinson's disease patients and results compared. RESULTS: Between OFF state and controls, a significant difference was observed for SOT-2 (proprioception, P < 0.005), SOT-6 (conflicting vision, P < 0.001), and SOT-4 (eyes open with sway support, P < 0.038), and there was less use of ankle strategy in SOT-3 (sway vision, P < 0.04). No significant difference was observed for vestibular function (SOT-5). Significant difference was also observed (P < 0.001) for all variables in limits of stability except for reaction time and for muscle strength of trunk, hip, and ankle (P < 0.001) between OFF state and controls. After antiparkinsonian medications, significant improvement was observed for gait velocity (P < 0.002), muscle strength (P < 0.001), and strategy score in SOT-3 between OFF and ON states. A positive correlation was observed between muscle strength (ankle, hip, and trunk) and gait velocity (ON state r = 0.37, OFF state r = 0.56) and movement velocity (ON state r = 0.39). A positive correlation was also seen between ankle strength and gait velocity in both ON (r = 0.393) and OFF states (r = 0.397) and between ankle strength and ankle strategy in all SOTs except SOT-3 in the OFF state. CONCLUSIONS: The quantitative reduction of muscle strength in the spine, hip, and ankle, along with impaired proprioception, visual sense, and smaller base of support, were the main causes for postural instability in Parkinson's disease patients. A correlation was seen between muscle strength, static and dynamic balance, and gait in both ON and OFF states. In contrast to the previous studies, the present study showed that medications improved the muscle strength, gait speed, and use of ankle strategy but did not worsen proprioceptive sense.     

Novel polymorphisms in mec genes and a new mec complex type in methicillin-resistant Staphylococcus aureus isolates obtained in rural Wisconsin

We determined allelic polymorphisms in the mec complexes of 524 methicillin-resistant Staphylococcus aureus isolates by partial or complete sequencing of three mec genes, mecA, mecI, and mecR1. The isolates had been collected over a 10-year period from patients living in rural Wisconsin, where the use of antibiotics was expected to be lower than in the bigger cities. Of the 18 mutation types identified, 16 had not been described previously. The five most common mutations were a mutation 7 nucleotides (nt) upstream from the start site (G-->T) in the mecA promoter (34.7%), an E246G change encoded by mecA (2.2%), a cytosine insertion at codon 257 in mecA (13.2%), an N121K change encoded by mecI (7.8%), and a major mecI-mecR1 deletion designated as a class B1 mec complex deletion type (25.4%). There was a high degree of conservation of the amino acid sequence of MecR1. Strains with the same mutations had variable resistance to oxacillin, and the median MIC for isolates that harbored the 7-nt-upstream mutation was lower than that for strains harboring other mutations. Our data suggest that the mecA promoter mutation plays a more important role in determining methicillin resistance than mutations in mecI and mecA do. Eighty-five percent of the tested isolates (n = 148) with the mecA promoter mutation and the class B1 mec complex deletion belonged to the same major clonal group, identified as MCG-2, and harbored the type IV staphylococcal cassette chromosome mec DNA. There was also a wide range of oxacillin MICs for strains with wild-type mecA, mecI, and mecR1 sequences, suggesting that the genetic backgrounds of clinical strains are significant in determining susceptibility to methicillin.     

Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities

Increased Rho kinase (ROCK) activity contributes to smooth muscle contraction and regulates blood pressure homeostasis. We hypothesized that potent and selective ROCK inhibitors with novel structural motifs would help elucidate the functional role of ROCK and further explore the therapeutic potential of ROCK inhibition for hypertension. In this article, we characterized two aminofurazan-based inhibitors, GSK269962A [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4, 5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]-oxy}benzamide] and SB-7720770-B [4-(7-{[(3S)-3-amino-1-pyrrolidinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine], as members of a novel class of compounds that potently inhibit ROCK enzymatic activity. GSK269962A and SB-772077-B have IC50 values of 1.6 and 5.6 nM toward recombinant human ROCK1, respectively. GSK269962A also exhibited more than 30-fold selectivity against a panel of serine/threonine kinases. In lipopolysaccharide-stimulated monocytes, these inhibitors blocked the generation of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha. Furthermore, both SB-772077-B and GSK269962A induced vasorelaxation in preconstricted rat aorta with an IC50 of 39 and 35 nM, respectively. Oral administration of either GSK269962A or SB-772077-B produced a profound dose-dependent reduction of systemic blood pressure in spontaneously hypertensive rats. At doses of 1, 3, and 30 mg/kg, both compounds induced a reduction in blood pressure of approximately 10, 20, and 50 mm Hg. In addition, administration of SB-772077-B also dramatically lowered blood pressure in DOCA salt-induced hypertensive rats. SB-772077-B and GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases.