Ventricular Tachycardia/Ventricular Fibrillation Ablation in the Setting of Ischemic Heart Disease

Recurrent ventricular tachycardia (VT) in the setting of coronary artery disease is frequently a life-threatening electrophysiologic emergency. Even in patients with an implantable defibrillator, recurrent VT is frequently accompanied by repeated and disabling shock therapy. Catheter ablative therapy offers the ability to provide immediate control of recurrent VT. Long-term elimination of VT should be anticipated in most patients. This article reviews the strategies, tools, techniques, and expected outcome for catheter ablation of stable and unstable ventricular arrhythmias in the setting ischemic heart disease.     

THE DEVELOPMENT OF CUSHING'S SYNDROME FROM A PREVIOUSLY SILENT PITUITARY TUMOUR

Abstract A 60 year old woman originally presented with headache. Investigations revealed a pituitary tumour and endocrine investigations at that time showed normal plasma Cortisol levels. Seven years after removal of this tumour, the patient developed the clinical and biochemical features of Cushing's disease. Immunoperoxidase staining of the original tumour was positive for adrenocor-ticotrophic hormone. This report suggests that immunocytochemistry may have an important role in the routine evaluation of pituitary tumours.     

OPTIMAL SAMPLE ALLOCATION IN CLINICAL TRIALS DESIGNED TO INVESTIGATE RELATIVE RISKS

Clinical trials with more than two groups are becoming increasingly common, especially trials with both active and placebo control groups. Equal allocation of subjects to each of the groups is the most common sample allocation, but in clinical trials where the purpose is to test hypotheses of relative risk, such as vaccine trials, equal allocation can be substantially sub-optimal. Optimal allocation for clinical trials has been considered previously, but not for trials with more than two groups. In this paper optimal sample allocation for relative risk trials is investigated in a variety of situations. The main results are as follows: (i) there are many situations where reductions of more than 20 per cent in sample size can be obtained by using optimal allocation instead of equal allocation; (ii) the optimal allocation for two group studies is not optimal in general; (iii) in many situations optimal allocation increases a subject's chances of being enrolled to a test treatment, and (iv) in most cases a grid search using the likelihood score asymptotic power function is the easiest method of finding an approximately optimal allocation. Extensions to situations more general than those covered here are sketched.     

JOB STRESS AMONG BRITISH GENERAL PRACTITIONERS: PREDICTORS OF JOB DISSATISFACTION AND MENTAL ILL-HEALTH

Questionnaires assessing levels of job satisfaction, mental well-being and sources of stress were distributed to a random sample of 850 general practitioners (GPs) in England. The final sample size was 414. Compared to a normative sample, male GPs exhibit significantly higher levels of anxiety, whereas female GPs compare favourably to the population norms. Job satisfaction levels among male and female GPs were significantly lower than when they were measured in 1987. Multivariate analysis revealed five major stressors that were predictive of high levels of job dissatisfaction and negative mental well-being; these were practice administration and demands of the job, interference with family and social life, routine medical work, interruptions and working environment. In addition, emotional involvement and type A behaviour were predictive of lack of mental well-being. It is concluded that there may be substantial benefit in providing training in management skills and introducing a stress management programme for GPs.     

Muscle fibre size and type distribution in thoracic and lumbar regions of erector spinae in healthy subjects without low back pain: normal values and sex differences

This study sought to investigate the normal muscle fibre size and type distribution of the human erector spinae, both in thoracic and lumbar regions, in a group of 31 young healthy male (n=17) and female (n=14) volunteers. Two percutaneous muscle biopsy samples were obtained under local anaesthesia, from the belly of the left erector spinae, at the levels of the 10th thoracic and 3rd lumbar vertebrae. Samples were prepared for routine histochemistry for the identification of fibre types. Fibre size (cross-sectional area (CSA) and narrow diameter (ND)) was quantified using computerised image analysis. The mean CSA/ND for each fibre type was greater in the thoracic than the lumbar region, but there was no difference between the 2 regions either for percentage type I (i.e. percentage distribution by number), percentage type I area (i.e. relative area of the muscle occupied by type I fibres) or the ratio describing the size of the type I fibre relative to that of the type II. Men had larger fibres than women, for each fibre type and at both sampling sites. In the men, each fibre type was of a similar mean size, whereas in the women the type I fibres were considerably larger than both the type II A and type II B fibres, with no difference between the latter two. In both regions of the erector spinae there was no difference between men and women for the proportion (%) of a given fibre type, but the percentage type I fibre area was significantly higher in the women. The erector spinae display muscle fibre characteristics which are clearly very different from those of other skeletal muscles, and which, with their predominance of relatively large type I (slow twitch) fibres, befit their function as postural muscles. Differences between thoracic and lumbar fascicles of the muscle, and between the muscles of men and women, may reflect adaptive responses to differences in function. In assessing the degree of any pathological change in the muscle of patients with low back pain, it seems clear that (1) sex cannot be disregarded and (2) ‘atrophied’ (using the criteria from other muscles) type II fibres are not necessarily abnormal for the erector spinae, particularly in women.     

Prophylactic immune tolerance induced by changing the ratio of antigen-specific effector to regulatory T cells

Summary.  Background : Gene and protein replacement therapies for inherited protein deficiencies such as hemophilia or lysosomal storage disorders are limited by deleterious immune responses directed against their respective therapeutic proteins. Therefore, the development of protocols preventing such responses is key to providing successful long-term therapy. Objectives : We sought to develop a protocol, utilizing a drug/peptide cocktail, that would effectively shift the antigen-specific CD4+ T-cell population, tipping the balance from effector T cells (Teffs) towards regulatory T cells (Tregs). Methods : Treg-deficient (DO11.10-tg Rag2^−/−) BALB/c mice were used to screen for an optimal protocol addressing the aforementioned goal and to study the mechanisms underlying in vivo changes in T-cell populations. Muscle-directed gene transfer to hemophilia B mice was also performed in order to test the optimal protocol in a therapeutically relevant setting. Results: Specific antigen administration (4-week repeated dosing) combined with rapamycin and interleukin-10 led to substantial reductions in Teffs, via activation-induced cell death, and induced CD4+CD25+FoxP3+ Tregs to a large extent in multiple organs. The proportion of apoptotic T cells also increased over time, whereas Teffs and Tregs were differentially affected. When applied to a model of protein deficiency (gene therapy for hemophilia B), the protocol successfully prevented inhibitor formation, whereas non-specific immunosuppression was only marginally effective. Conclusions : It is feasible to provide a short-term, prophylactic protocol allowing for the induction of immune tolerance. This protocol may provide a marked advance in efforts seeking to improve clinical outcomes in disorders involving therapeutic protein replacement.