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.     

‘Distensibility’ of the papaverine-relaxed vascular bed in human subcutaneous tissue

The effect of an increase in vascular transmural pressure upon the blood flow in two subcutaneous vascular beds, maximally dilated by papaverine was studied in 6 healthy humans. Blood flow was measured on the dorsum of the hand and at the lateral malleolus by the local ¹³³Xe washout technique. Increase in vascular transmural pressure was induced by lowering the labelled area various distances below heart level. Lowering the area caused an increase in blood flow. The increase was less pronounced in the legs than in the hand. As arterial perfusion pressure head remained constant during lowering, this indicates that the relative decrease in vascular resistance was smaller in the leg than in the hand. Experimental edema did not influence the relative decrease in vascular resistance. The results suggest that ‘distensibility’ of the resistance vessels is smaller in the leg than in the hand. This might be due to a structural adaptation of the vascular wall in vessels often subjected to increased hydrostatic pressure.     

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.     

Interaction between blood type,smoking and factor V Leiden mutation and risk of venous thromboembolism: a Danish case‐cohort study

See also Lowe GDO. Epidemiology of venous thromboembolism: the need for large (including prospective) studies and meta‐analyses. This issue, pp 2186–8 and Rosendaal FR. Etiology of venous thrombosis: the need for small original studies. This issue, pp 2189–90.     

Gender differences in randomised,controlled trials in intensive care units

There is a male dominance among patients in intensive care units (ICUs). Potentially, this will increase the risk of a skewed male/female distribution in randomised, controlled trials (RCTs). We have evaluated if this has in fact happened when randomising and whether the authors have been aware of that. We performed a systematic search on PubMed from 1 January 2011 to 31 May 2012 using the mesh terms ‘randomized controlled trial’ and ‘intensive care unit’. Twenty‐five RCTs with a total of 12,788 patients met the inclusion criteria, with an overall male dominance of 63.6% (P < 0.0001). Eighteen of the 25 papers had an individually statistically significant gender difference in their total trial population. None of the 18 trials with a significant gender difference in their overall trial population had calculated the P‐value for this overall difference. In the randomised groups, there was a significant gender difference in five papers. Seventeen had no significant gender difference in the randomised groups, and three papers did not state gender in the randomised groups. This study show that there is a marked male dominance in RCTs conducted in ICUs. We recommend that when planning future RCTs, the authors contemplate if their results can be used indiscriminately among ICU patients if the distribution of males and females is much skewed. It is relevant to determine if ones endpoint can be influenced by gender differences and if there is a risk of gender influence on data, proportional allocation or stratification should be considered.     

Pharmacokinetics,pharmacodynamics and safety of recombinant canine FVIIa in a study dosing one haemophilia A and one haemostatically normal dog

Summary. Recombinant human FVIIa (rhFVIIa) corrects the coagulopathy in hemophilia A and B as well as FVII deficiency. This is also the case in dogs until canine anti‐human FVIIa antibodies develop (～2 weeks). Recombinant canine factor VIIa (rcFVIIa), successfully over‐expressed by gene transfer in haemophilia dogs, has provided long‐term haemostasis (>2 years). However, pharmacokinetics (PK), pharmacodynamics (PD) and safety of rcFVIIa after pharmacological administration have not been reported. We therefore wanted to explore the safety, PK and PD of rcFVIIa in dogs. A pilot study was set up to evaluate the safety as well as PK and PD of rcFVIIa after a single intravenous dose of 270 μg kg^?1 to one HA and one haemostatically normal dog and to directly compare rcFVIIa with rhFVIIa in these two dogs. Single doses of rcFVIIa and rhFVIIa were well tolerated. No adverse events were observed. Pharmacokinetic characteristics including half‐life (FVIIa activity: 1.2–1.8 h; FVIIa antigen 2.8–3.7 h) and clearance were comparable for rcFVIIa and rhFVIIa. Kaolin‐activated thromboelastography approached normal in the HA dog with the improvement being most pronounced after rcFVIIa. This study provided the first evidence that administering rcFVIIa intravenously is feasible, safe, well tolerated and efficacious in correcting the haemophilic coagulopathy in canine HA and that rcFVIIa exhibits pharmacokinetic characteristics comparable to rhFVIIa in haemophilic and haemostatically competent dogs. This strengthens the hypothesis that rcFVIIa can be administered to dogs to mimic the administration of rhFVIIa to humans.     

INTERLEUKIN-8 SECRETION AND 15-LIPOXYGENASE ACUVTTY IN RHEUMATOID ARTHRITIS: IN VITRO ANTI-INFLAMMATORY EFFECTS BY INTERLEUKIN-4 AND INTERLEUKIN-10, BUT NOT BY INTERLEUKIN-1 RECEPTOR ANTAGONIST PROTEIN

We have examined the ability of interleukin-4 (IL-4), interleukin-10(IL-10) and interleukin-1 receptor antagonist protein (IL-lra)to regulate spontaneous interleukin-8 (IL-8) production in culturedSF mononuclear cells (SFMC) from RA. Furthermore, we examinedwhether IL-4, IL-10, or IL-lra could influence the productionof the arachidonic acid products leukotriene B₄ (LTB₄), 12-hydroxy-eicosatetraenoicacid (12-HETE) and 15-hydroxy-eicosatetraenoic acid (15-HETE).IL-4 induced a maximal suppression of 75% in the IL-8 secretionin SFMC from 10.0 ng/ml down to 2.5 ng/ml after 24 h and from17.2 ng/ml to 4.2 ng/ml after 72 h of culture. IL-10 induceda 55% inhibition of the IL-8 secretion at 24 h and a 40% inhibitionat 72 h. IL-lra did not change the spontaneous IL-8 secretionfrom rheumatoid SFMC. We also examined, whether addition ofIL-4, IL-10 or IL-lra was able to modulate formation of thearachidonic acid products LTB₄,12-HETE and 15-HETE in culturedSF cells, stimulated with the calcium ionophore A23187. 15-HETEwas not detected in untreated cultures, nor in IL-10 or IL-lratreated cultures. IL-4, however, stimulated the formation ofthe anti-inflammatory mediator; 15-HETE (23 ng/10⁶ cells). Theseresults suggest that IL-4 or IL-10, could have beneficial anti-inflammatoryeffects in RA. KEY WORDS: Interleukin-4, Interleukin-10, Interleukin-1 receptor antagonist protein, 15-Hydroxy-eicosatetraenoic acid, Rheumatoid arthritis