Electrocardiographic and Clinical Predictors of Torsades de Pointes Induced by Almokalant Infusion in Patients with Chronic Atrial Fibrillation or Flutter: A Prospective Study

The aim of this study was to identify predictors of torsades de pointes (TdP) in patients with atrial fibrillation (AF) or flutter exposed to the Class III antiarrhythmic drug almokalant. TdP can be caused by drugs that prolong myocardial repolarization. One hundred patients received almokalant infusion during AF (infusion 1) and 62 of the patients during sinus rhythm (SR) on the following day (infusion 2). Thirty-two patients converted to SR. Six patients developed TdP. During AF, T wave alternans was more common prior to infusion (baseline) in patients developing TdP (50% vs 4%, P < 0.01). After 30 minutes of infusion 1, the TdP patients exhibited a longer QT interval (493 ± 114 vs 443 ± 54 ms [mean ± SD], P < 0.01), a larger precordial QT dispersion (50 ± 74 vs 27 ± 26 ms, P < 0.05), and a lower T wave amplitude (0.12 ± 0.22 vs 0.24 ± 0.16 mV. P < 0.01). After 30 minutes of infusion 2, they exhibited a longer QT interval (672 ± 26 vs 489 ± 74 ms, P < 0.001), a larger QT dispersion in precordial (82 ± 7 vs 54 ± 52 ms, P < 0.01) and extremity leads (163 ± 0 vs 40 ± 34 ms, P < 0.001), and T wave alternans was more common (100% vs 0%, P < 0.001). Risk factors for development of TdP were at baseline: female gender, ventricular extrasystoles, and treatment with diuretics; and, after 30 minutes of infusion: sequential bilateral bundle branch block, ventricular extrasystoles in bigeminy, and a biphasic T wave. Patients developing TdP exhibited early during almokalant infusion a pronounced QT prolongation, increased QT dispersion, and marked morphological T wave changes.     

Acute Efficacy and Chronic Follow-Up of Patients with Non-Thoracotomy Third Generation Implantahle Defibrillators

Non-thoracotomy implantation of implantable cardioverter defibrillators (ICDs) has simplified the process of device inserfion, promising to decrease associated procedural coniplications while providing sudden death protection at least equal to epicardial systems. This study presents the acute and chronic results of 110 patients who underwent attempted non-thoracotomy ICD impiuntation wiih the Medtronic Transvene lead system and PCD model 7217 or 7219. Of the 110 patients attempted, 100 (91%) had the system successfully implanted without the need for an epicar-dial patch. One patient died 1 week postoperatively of septic shock related to the implantation (0.9% perioperative mortality). During folloiv-up of 16 ± 11 months, 45% of the patients had an event detected as ventricular tachycardia; 26% of these detections were felt clinically to be due to supraventricular rhythms. Of the remainder, 87% were successfully treated with the first VT therapy, and 98% were terminated by the final therapy; 66% of the patients had at least one episode of ventricular fibrillation, of which 5% were felt to be inappropriate detections; 65% of the appropriate episodes were successfully treated with the first VF therapy, and all were converted by the final therapy. Total mortality at 6, 12, and 24 months was 3%, 11%, and 19% respectively. Only one patient had sudden cardiac death, occurring at 13 months postimplant. Overall, the non-thoracotomy lead system for this ICD displayed infrequent implant complications and proved to be reliable ai terminating arrhythmias and maintaining a low rate of sudden cardiac death in this high risk popuiation.     

Characterization of Porcine Zona Pellucida Antigens by Immunoaffinity Chromatography and by High-Pressure Liquid Chromatography

ABSTRACT: In the present work, 500 and 50,000 porcine zonae pellucidae were solubilized using Lithium-3,5-diiodosalicylate. The zona antigens were purified by immunoaffinity chromatography (IAC) on immobilized antizona immunoglobulin G (IgG). The antizona-IgG was raised by immunization of female rabbits with 500 heat-solubilized porcine zonae. Four antigens could be detected following IAC: ZP I/1 (M_r = 42,000), ZP II/1 (M_r = 67,000), ZP II/2 (M_r = 32,000), ZP III/1 (M_r = 17,000). In a parallel experiment, 50,000 zonae were solubilized in a similar manner and the mixture was analyzed by high-pressure liquid chromatography (HPLC) using a protein column. Altogether, 9 protein peaks that contained the antigens ZP I/1, ZP II/1, ZP II/2, and ZP III/1 could be detected following HPLC. The carbohydrate composition is characteristic for O-glycosidic-glycoproteins. ZP II/1 and ZP II/2 are probably in close association within the zona. Based on the reaction of the antigens with antibodies induced by intact and heat-solubilized zonae, it is postulated that only ZP I/1 and ZP II/l are expressed on the surface in intact zonae.     

EFFECTS OF THE EXTRADURAL ADMINISTRATION OF MORPHINE OR BUPIVACAINE, ON THE METABOLIC RESPONSE TO UPPER ABDOMINAL SURGERY

The influence of thoracic extradural local anaesthetics (0.5%bupivacaine) or extradural morphine on the metabolic responseto upper abdominal surgery was compared with the administrationof morphine i.v. in the period after operation. The extradurallocal anaesthetic group had significantly lower blood glucoseand plasma FFA concentrations and consistently, but not significantly,lower blood glycerol and lactate concentrations than both theother groups. At 4 h both extradural groups had significantlylower plasma FFA and blood 3-hydroxybutyrate concentrationsthan the control group. Blood alanine concentration decreasedin all three groups with a minimum at 24 h. There were no differencesin serum insulin concentrations between the groups. It is concludedthat thoracic extradural morphine differs from thoracic extradurallocal anaesthetics in being much less able to suppress the metabolicresponse associated with upper abdominal surgery.     

E-SELECTIN EXPRESSION IN EXPERIMENTAL MODELS OF INFLAMMATION IN MICE

E-selectin (CD62E, formerly termed ELAM-1) is a cytokine-inducible adhesion molecule which mediates the binding of neutrophils, monocytes, and skin homing T-cells. The murine homologue of E-selectin has been cloned. A monoclonal antibody (21KC10) was used here to study immunohistochemically the expression and regulation of murine E-selectin in vitro and in vivo . As described for the human system, there was no staining of normal endothelium in skin and other tissues. LPS and tumour necrosis factor-alpha (TNF-α ), but not interleukin-4 (IL-4) or interferon-gamma (IFN- γ), induced a transient expression of E-selectin, both when injected in vivo and when added to endothelial cell lines in vitro. To analyse temporal expression of E-selectin under pathophysiological conditions in vivo, we chose two murine models of inflammation: allergic (ACD) and irritant contact dermatitis (ICD). Expression of E-selectin was found to be induced on vascular endothelium of post-capillary venules in both ACD and ICD. In ICD, maximal staining of endothelial cells occurred earlier than in ACD. Expression of E-selectin during ICD and ACD was then compared between strains of mice which differ with regard to the intensity of their inflammatory reaction. BALB/c mice, which in contrast to C57BI/6 mice show a denser infiltrate and prolonged influx of granulocytes and monocytes, revealed a more pronounced and more prolonged expression of E-selectin than C57BI/6 mice. This held true for both ACD and ICD, and in each case, peak expression of E-selectin was associated with the highest density of the leukocytic infiltrate. This study thus reveals regulatory mechanisms involved in the expression of murine E-selectin in vivo and in vitro . It also demonstrates a correlation between endothelial expression of E-selectin and the genetically determined intensity of the inflammatory response.     

Prediction of progression of radiologic damage in newly diagnosed rheumatoid arthritis

Objective. To investigate the extent to which early radiologic damage is predicted by joint inflammation in patients with newly diagnosed rheumatoid arthritis (RA). Methods. Regression analysis was performed on 1-year progression of total radiologic damage for baseline characteristics and cumulative disease activity measures, and the effects of continued joint inflammation on the progression of damage in separate joint groups were investigated. Results. Odds ratios for progression of total damage were 12 for the presence of rheumatoid factor, 5 for the presence of damage at baseline, and 2 for cumulative joint inflammation. A positive association between continued joint inflammation and progression of damage was found to be statistically significant for most joint groups. Conclusion. Progression of radiologic damage in patients with newly diagnosed RA is independently associated with the presence of rheumatoid factor and damage at baseline and with cumulative joint inflammation.     

PUVA-induced diminution of contact allergic and irritant skin reactions

A pilot study on the efficiency of treatment with 8-methoxypsoralen and longwave ultraviolet light (PUVA) on three patients with allergic contact dermatitis to nickel sulphate, potassium dichromate and to thiuram mix has been performed. Both the contact allergic reactions and the irritative skin reactions induced by dimethyl sulfoxide (DMSO) and tetrahydrofurfuryl nicotinate (Trafuril) were evaluated before and after PUVA. The total UV-A doses were respectively 69–45 and 76J/cm². These doses induced complete clearance of the eczematous lesions in two cases; the third case showed considerable improvement. In contrast to the pronounced skin reactions seen prior to PUVA, the allergic and irritative reactions evaluated after PUVA were decreased or negative.     

Synthesis of thymosin α1 by fragment condensation using tert.-butyl side chain protection

A novel synthesis of thymosin α₁ by classical methods using seven tert. -butyl side chain protected fragments is described. Optimum conditions were found for the final DCC/HOBt coupling of the two key intermediates; decapeptide and octadecapeptide. Thymosin α₁ was purified by two stages of preparative HPLC (partial purification with C₈ and final purification with C₁₈ reverse phase silica gel) to give a 30% overall yield for the final four stages of synthesis (including catalytic hydrogenation of octadecapeptide, coupling, deprotection and purification). The product was shown to be homogeneous by thin-layer and paper high voltage electrophoresis, isoelectric focusing analysis, thin-layer chromatography and high performance liquid chromatography. Amino acid analysis, optical rotation, ¹ H-n.m.r. spectroscopy, FAB mass spectroscopy and peptide mapping after tryptic digestion confirmed the structure of thymosin α₁. Three minor stereoisomer contaminants were isolated by HPLC and characterized as [D-Lys¹⁴]-thymosin α₁, [D-Lys¹⁷]-thymosin α₁ and [D-Ala³]-thymosin α₁ resulting from racemization at Lys¹⁴, Lys¹⁷ and Ala³ during the coupling of the fragments. A final contaminant, isolated by HPLC, was characterized as N^α-isobutyloxycarbonyl-thymosin α₁ (15–28), which results from “wrong way opening” of an activated mixed anhydride.     

Evaluation of the Atrial Evoked Response for Capture Detection with High-Polarization Leads

AutoCapture™ based on the evoked response can be confounded by electrode polarization. In this study, polarization was measured in human subjects who had chronic atrial leads. The aim of the study was to determine whether electrode polarization can be measured using a time integral atrial evoked-response integral (AERI) of the negative portion of the atrial paced ER evoked-response signal and to determine whether high-polarization atrial leads unsuitable for AutoCapture™ can be identified a priori. Atrial intracardiac-electrogram (IEGM) signals from 39 patients with implanted pacemakers were recorded and analyzed. The signals were recorded during conventional atrial-threshold searches. A total of 221 atrial-capture thresholds were recorded, ranging from 0.25 to 2.75 V with a mean of 0.79 V. Each evoked response was evaluated using the AERI in a 36 ms window following the 0.4 ms atrial stimulus. The polarization was estimated as a linear function of stimulus voltage using the evoked-response signal integral of captured beats identified on the IEGM. The 221 threshold-search datasets were obtained using leads with eight different electrode materials. Polarization could be measured using AERI as a function of stimulus voltage. Furthermore, this polarization measure can be used to identify high-polarization leads, which are ill suited for the atrial AutoCapture™ algorithm.