Optimizing the Geometry of Implantable Leads for Recording the Monophasic Action Potential with Fractally Coated Electrodes

This study investigates the influence of various lead geometry on intracardial signals like the monophasic action potential (MAP) to optimize the geometry of implantable MAP leads. The experimental results were compared with a field theoretical approach to the origin of MAP from the transmembrane potential (TAP). During the experiments several lead geometries (tip surface: 1.3 to 12 mm²; tip-ring distance: 0.8 mm to 25 cm; ring surface: 1.8mm² to 40 mm²) were investigated in endo- and epicardial positions in 12 dogs (17±9 kg). The electrodes were fixed passively (tines) or actively (screws). MAP was recorded during several interventions and correlated with MAP measured using an Ag-AgCl MAP catheter. The experimental results showed that small tips provided high MAP amplitudes with less pressure. No difference was observed using active and passive fixations. A tip-ring distance smaller than 5 mm with a ring surface smaller than the tip (<5 mm²) avoided artifacts in the repolarization course. For the theoretical approach the quasistatic, anisotropic bidomain model was calculated in smalt unity volumes V_i where the TAP φ_m was constant and represented by the current density J. Two solutions for electrode positions at and outside the heart were achieved. By superposition of each solution φ_ei the summed potential at the electrode position was calculated. The theoretical findings show in good correlation with the experimental results that a larger distance than 10 mm leads to distortions in repolarization course by signals proportional to φ_out.     

Prevalence and characteristics of brittle diabetes in Britain

We investigated the prevalence and characteristics of 'brittle diabetes', defined as insulin-dependent diabetes mellitus associated with glycaemic instability of any type, leading to life disruption with recurrent and/or prolonged hospitalizations. A questionnaire was sent to all physicians and paediatricians running diabetic clinics in the UK, from lists held at the British Diabetic Association. A total of 414 brittle patients were reported (72% questionnaire return). Most were young (mean age +/- SD was 26 +/- 15 years), though there was a small peak at ages 60-70 years. There was an excess of females (66%) and overall clinic prevalence was 1.2 per 1000 diabetic patients and 2.9 per 1000 insulin-treated diabetic patients. On average, there was 1.0 brittle patient per diabetic clinic. The most common form of brittleness was recurrent ketoacidosis (59%), with 17% having predominant hypoglycaemia, and 24% mixed instability. Female excess was highest and mean age lowest in the recurrent ketoacidosis group, whilst the reverse was true for those with recurrent hypoglycaemia. Causes of brittleness were offered by 58% of consultants, and most (93%) considered various psychosocial problems as likely underlying factors. We conclude that brittle diabetes is a small but significant problem, currently affecting about 1 per 1000 diabetic patients. Most, but by no means all, are young females--often with recurrent ketoacidosis. Older age groups are more likely to have recurrent hypoglycaemic or mixed types of brittleness. Perceived causes of brittleness are usually psychosocial.      

Hepatitis C virus-related autoimmunity in patients with porphyria cutanea tarda

Abstract. Hepatitis C virus (HCV) infection is frequently found in autoimmune hepatitis and mixed cryoglobulinaemia. In these conditions HCV could be responsible for immuno-mediated organ alterations. The aim of this study was to evaluate the presence of immunological alterations in PCT patients, in which HCV infection has been frequently found. Twenty-three PCT patients were evaluated for clinical and serological alterations, including: chronic hepatitis, other systemic symptoms, serum cryoglobulins and rheumatoid factor (RF), haemolytic complement, serum immunoglobulins, anti-nuclear (ANA), anti-smooth muscle (ASMA), anti-liver-kidney-microso-mal (anti-LKMl), anti-soluble-liver-antigen (SLA), anti-mitochondrial (AMA), anti-GOR antibodies, anti-HCV and HCV RNA. Abnormal serum ALT were present in the majority of cases (20/23, 87%), while liver biopsy revealed a chronic persistent hepatitis or chronic active hepatitis in 15/20 (75%) PCT patients. In a high percentage of subjects (91%) the presence of anti-HCV was detected by ELISA and RIBA II (Chiron, Emeryville CA, USA). In 17/22 (77%) cases the ongoing HCV replication in the serum was demonstrated by the detection of HCV genomes (polymerase chain reaction). The prevalence of both anti-HCV and HCV RNA in PCT was significantly higher if compared to 22 systemic immunological diseases ( P< 0.00l) and 47 healthy subjects ( P<0.001 ). A possible HCV-induced autoimmunity in PCT was suggested by the presence of the following immunological parameter alterations: anti-GOR in 13/23 (57%), ANA in 4/23 (17%), ASMA in 18/23 (78%), anti-LKMI in 1/23 (4%), RFin 23/23 (100%), mixed cryoglobulins in 4/23 (170/0), complement consumption in 10/23 (43%). The high prevalence of HCV infection and various immunological abnormalities suggest that HCV in combination with other factors (genetic, alcohol, etc.) could play a relevant role in the pathogenesis of hepatic and metabolic alterations of PCT.     

Long-Term Results of Hybrid Therapy in Patients with Atrial Fibrillation Who Develop Atrial Flutter During Flecainide Infusion

The flecainide infusion test has been proposed to screen candidates for hybrid pharmacological and ablation therapy. We report the long-term follow-up of 154 consecutive patients with paroxysmal or persistent atrial fibrillation (AF) who developed atrial flutter (AFL) during flecainide infusion (IC AFL), treated with inferior vena cava-tricuspid annulus isthmus catheter ablation and oral flecainide (hybrid therapy). Over a mean of 54.1 ± 13.1 months 82 patients (53%) remained free of AF and AFL. Flecainide was discontinued because of adverse effects in 6 patients (4%). A history of persistent AF, and the documentation of ≥1 spontaneous AFL episode before the flecainide test were independent predictors of successful hybrid therapy. In patients with paroxysmal AF without documented spontaneous AFL, the long-term efficacy of hybrid therapy was 38.5% (P = 0.03). The flecainide infusion test reliably detects candidates for hybrid therapy. The efficacy of this therapy is maintained over the long-term with a high patient compliance.     

Memory B cells at successive stages of differentiation. Affinity maturation and the role of IgD receptors

The following evidence, mainly presented here, suggests that IgD receptors play a crucial role in determining the potential for affinity maturation in memory B cell populations. IgD receptors are present on the first memory B cells to appear after priming. These memory cells give rise to more-mature memory cells that have lost their IgD receptors. The proportions of early (IgD(+)) and mature (IgD(-)) memory cells found in individual donors vary with time, priming conditions, and the availability of T cell help, and both populations frequently coexist for long periods of time. IgD(+) and IgD(-) memory cells carry IgG receptors and give rise to IgG responses with identical isotype representation in adoptive recipients. IgD(+) memory cells, however, always give rise to predominantly low-affinity antibody responses, whereas IgD(-) memory cells consistently generate responses of substantially higher average affinity. This affinity differential is maintained between early and mature memory populations in the same donor and does not appear to be a result of selective differentiation of higher-affinity IgD(+) memory cells into the IgD(-) memory pool. Thus, the selective forces responsible for affinity maturation appear to operate mainly in mature memory cell populations that have already lost IgD receptors; or, stated conversely, little or no selection towards high-affinity memory appears to occur among memory cells that retain IgD receptors. In discussing these findings, we suggest that the IgD receptors themselves are responsible for maintaining early memory populations at a lower average affinity than IgD(-) populations in the same animal. The IgD receptors, we argue, serve to increase the antigen-binding capacity of lower-affinity memory cells so that these cells can survive, expand, and differentiate (to IgD(-)) at antigen concentrations that select against expansion of low- affinity memory cells no longer carrying IgD receptors. Thus, when antigen is limiting, IgD(-) memory populations will be selectively expanded to higher average affinities, whereas coexisting IgD(+) populations will retain their initial affinity profile. This hypothesis suggests that mechanisms that regulate expression and loss of IgD receptors are central to the adaptability of the immune system in its response to invading pathogens. Two related roles can be envisioned for the IgD receptors in this regard. First, they extend the lower boundary of the affinity range of early memory cell populations induced by a given antigenic stimulus and therefore broaden the diversity of responses obtainable from these populations. Secondly, they support the persistence of low-affinity memory populations under conditions where antigen becomes limiting and eventually disappears. These persisting populations then serve as a diversely reactive reservoir from which mature memory populations can be drawn with higher affinities either for the original antigen or, more importantly, for related antigens that the animal may subsequently encounter. Thus the existence of IgD receptors on early memory cells maintains the full range of response diversity despite ongoing selective expansion of (mature) memory populations to produce antibodies with high combining affinities for individual antigens. The flexibility inherent in such an organizational system, we believe, could be expected to account for the evolutionary development of IgD receptors and the regulatory capabilities that support operation of the system.