Update on implantable cardioverter-defibrillators. New, safer devices have led to changes in indications

The safety and efficacy of ICDs have improved significantly in the past few years. Recent evidence supports the value of these devices not only for secondary prevention of sudden cardiac death, but also for primary prevention in post-myocardial infarction patients with poor left ventricular function, unsustained ventricular tachycardia, and inducible ventricular tachycardia on electrophysiologic study. Transvenous defibrillation using the defibrillator case as the high-voltage electrode and a biphasic shock is currently the procedure of choice. Implantation is simple, and the defibrillation thresholds are acceptably low. However, the possibility of interactions must be considered in patients with cardiac pacemakers.     

Distinct biochemical and topological properties of the 31- and 27-kilodalton plasma membrane intrinsic protein subgroups from red beet

Plasma membrane vesicles from red beet (Beta vulgaris L.) storage tissue contain two prominent major intrinsic protein species of 31 and 27 kD (X. Qi, C.Y Tai, B.P. Wasserman [1995] Plant Physiol 108: 387-392). In this study affinity-purified antibodies were used to investigate their localization and biochemical properties. Both plasma membrane intrinsic protein (PMIP) subgroups partitioned identically in sucrose gradients; however, each exhibited distinct properties when probed for multimer formation, and by limited proteolysis. The tendency of each PMIP species to form disulfide-linked aggregates was studied by inclusion of various sulfhydryl agents during tissue homogenization and vesicle isolation. In the absence of dithiothreitol and sulfhydryl reagents, PMIP27 yielded a mixture of monomeric and aggregated species. In contrast, generation of a monomeric species of PMIP31 required the addition of dithiothreitol, iodoacetic acid, or N-ethylmaleimide. Mixed disulfide-linked heterodimers between the PMIP31 and PMIP27 subgroups were not detected. Based on vectorial proteolysis of right-side-out vesicles with trypsin and hydropathy analysis of the predicted amino acid sequence derived from the gene encoding PMIP27, a topological model for a PMIP27 was established. Two exposed tryptic cleavage sites were identified from proteolysis of PMIP27, and each was distinct from the single exposed site previously identified in surface loop C of a PMIP31. Although the PMIP31 and PMIP27 species both contain integral proteins that appear to occur within a single vesicle population, these results demonstrate that each PMIP subgroup responds differently to perturbations of the membrane.     

The effect of transdermal nicotine on digital perfusion in reformed habitual smokers

The effects of transdermal nicotine-assisted smoking cessation on digital perfusion and health-related quality of life were assessed in 10 chronic smokers. Components of digital blood flow were evaluated by digital temperature and laser Doppler fluxmetry before, during, and after a standardized cold challenge. Nutritional flow was measured by vital capillaroscopy; a quantitative perfusion profile was obtained by laser Doppler perfusion imaging. A battery of validated measures were used to evaluate health-related quality of life. The microvascular response of smokers was evaluated before smoking cessation and at 2 and 7 days after smoking cessation and was compared with the response of nonsmoking controls. Results demonstrated that a (1) cutaneous microvascular perfusion was lower in smokers than nonsmokers, (2) the acute administration of transdermal nicotine did not decrease cutaneous perfusion, (3) smoking cessation and transdermal nicotine normalized digital microvascular perfusion by 7 days, and (4) transdermal nicotine and smoking cessation did not negatively impact health-related quality of life.     

Prediction of anticoagulation during hemodialysis by population kinetics and an artificial neural network

All systems currently used for routine hemodialysis require heparin administration to prevent blood clotting in the extracorporeal circuit. We tested the hypothesis that population-based statistical techniques can be used to predict heparin concentrations during routine hemodialysis. Two predictive models were developed, one based on nonlinear mixed effects modeling (NONMEM) and the other on a multilayer perceptron neural network. Serial clotting time data were obtained from forty-nine patients and used to develop the models. The models were used to predict the clotting times of 70 patients in a prospective test. We determined that the neural network provided greater precision, had fewer outliers in its predictions, and did not have the model misspecification in bolus administration that the NONMEM predictions demonstrated. A final NONMEM model was developed using all data from 119 patients to identify important covariates for predicting the heparin pharmacodynamic parameters, volume of distribution, and clearance. Both the volume of distribution and clearance increased following the initiation of dialysis and as the patient's baseline clotting time increased. The volume of distribution also increased as the patient's weight increased but was decreased by smoking and diabetes. Population-based statistical techniques may provide a useful alternative to existing methods for prescribing heparin.     

Cardiovascular responses mediated by protease-activated receptor-2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1

We developed mice deficient in protease-activated receptor-2 (PAR-2) or PAR-1 to explore the pathophysiological functions of these receptors. In this report, we evaluated mean arterial pressure and heart rate (HR) changes in response to PAR-1 or PAR-2 activation in anesthetized wild-type (WT), PAR-1-deficient (PAR-1(-/-)), and PAR-2-deficient (PAR-2(-/-)) mice. In WT mice, TFLLRNPNDK, a PAR-1 selective activating peptide, caused hypotension and HR decreases at 1 micromol/kg. TFLLRNPNDK also caused secondary hypertension following L-NAME pretreatment. These responses were absent in PAR-1(-/-) mice. In WT mice, SLIGRL, a PAR-2 selective activating peptide, caused hypotension without changing HR at 0.3 micromol/kg. SLIGRL did not induce hypertension following Nomega-nitrol-arginine-methyl ester-HCl (L-NAME). The response to SLIGRL was absent in PAR-2(-/-) mice. SFLLRN, a nonselective receptor activating peptide caused hypotension and HR decreases in WT mice at 0.3 micromol/kg, as well as secondary hypertension following L-NAME. SFLLRN still induced hypotension in PAR-1(-/-) mice, but HR decrease and secondary hypertension following L-NAME were absent. The hypotensive and bradycardic responses to SFLLRN and TFLLRNPNDK in PAR-2(-/-) mice were accentuated compared with WT mice. By using mouse strains deficient in either PAR-1 or PAR-2, we confirmed the in vivo specificity of TFLLRNPNDK and SLIGRL as respective activating peptides for PAR-1 and PAR-2, and the distinct hemodynamic responses mediated by activation of PAR-1 or PAR-2. Moreover, the accentuated response to PAR-1 activation in PAR-2-deficient mice suggests a compensatory response and potential receptor cross-talk.     

Influence of sex and age on serum total immunoglobulin E concentration in Beagles

Previous studies have shown that the intestinal peristaltic reflex initiated by mucosal stimulation is mediated by release of 5-hydroxytryptamine (HT) from enterochromaffin cells; 5-HT acts via 5-HT4 receptors in rat and human, and via both 5-HT4 and 5-HT3 receptors in guinea pig to activate intramural sensory neurons that release calcitonin gene-related peptide. In this study, selective agonists and antagonists were used to examine the involvement of 5-HT4 and 5-HT3 receptors in colonic propulsion. The velocity of propulsion was measured with artificial fecal pellets introduced into the orad end of an isolated guinea pig colonic segment. Control velocity ranged from 0.5 to 3.3 mm/s; mean +/- S.E.M., 1.3 +/- 0.1 mm/s. The 5-HT4 antagonist, GR 113808A, and the 5-HT3 antagonist, LY 278584, decreased the velocity of pellet propulsion in a concentration-dependent fashion (39 +/- 2% and 47 +/- 1% decrease at 10 microM, respectively). A combination of both antagonists (10 microM each) was additive, decreasing the velocity by 82 +/- 3% to 84 +/- 4%. The selective 5-HT4 agonists, HTF 919 and R093877, as well as 5-HT in the presence of the 5-HT2a antagonist, ketanserin, increased the velocity of propulsion in a concentration-dependent fashion with EC50s of 6.9 +/- 0.1 nM, 37.4 +/- 1.0 nM, and 3.9 +/- 0. 1 nM, respectively. Compared with HTF 919, R093877 was less potent and appeared to be a partial agonist. All three agonists were effective at submicromolar concentrations; at concentrations above 1 microM, there was no increase in the velocity of propulsion. We conclude that the presence of fecal pellets triggers the release of 5-HT, which acts via both 5-HT3 and 5-HT4 receptors to regulate propulsive activity in guinea pig colon.     

Miller Fisher anti-GQ1b antibodies: alpha-latrotoxin-like effects on motor end plates

In the Miller Fisher syndrome (MFS) variant of the Guillain-Barré syndrome, weakness is restricted to extraocular muscles and occasionally other craniobulbar muscles. Most MFS patients have serum antibodies against ganglioside type GQ1b of which the pathophysiological relevance is unclear. We examined the in vitro effects of MFS sera, MFS IgG, and a human monoclonal anti-GQ1b IgM antibody on mouse neuromuscular junctions (NMJs). It was found that anti-GQ1b antibodies bind at NMJs where they induce massive quantal release of acetylcholine from nerve terminals and eventually block neuromuscular transmission. This effect closely resembled the effect of the paralytic neurotoxin alpha-latrotoxin at the mouse NMJs, implying possible involvement of alpha-latrotoxin receptors or associated downstream pathways. By using complement-deficient sera, the effect of anti-GQ1b antibodies on NMJs was shown to be entirely dependent on activation of complement components. However, neither classical pathway activation nor the formation of membrane attack complex was required, indicating the effects could be due to involvement of the alternative pathway and intermediate complement cascade products. Our findings strongly suggest that anti-GQ1b antibodies in conjunction with activated complement components are the principal pathophysiological mediators of motor symptoms in MFS and that the NMJ is an important site of their action.