In vitro electrophysiological detection of iatrogenic arrhythmogenicity

Summary— Cardiac arrhythmias and sudden death have been associated with both therapeutic and toxic doses of a number of cardiotropic and non-cardiac drugs. Generally the drug-induced electrocardiographic (ECG) alterations have been well described, whereas corresponding cellular electrophysiological effects are poorly documented or lacking. Taking into account the recent advances in the understanding of the mechanisms underlying arrhythmias and antiarrhythmic effects, suitable relationships can be established between ECG alterations and drug effects on cardiac action potential. Thus, a decrease in maximal upstroke velocity (V_max) and membrane depolarisation leading to cellular inexcitability may slow conduction, prolong QRS interval duration and result in incessant wide QRS ventricular tachycardia. On the other hand, lengthening of the repolarisation phase and early afterdepolarisations (EADs) have been proposed as a mechanism for prolonged QT interval and subsequent Torsades de Pointes. A representative study aimed at detecting the arrhythmogenic potentiality of a drug is given, by examining carefully the concentration- and frequency-dependent effects of four neuroleptics (sultopride, droperidol, thioridazine and clozapine) on Purkinje fibers and comparing them with the reported iatrogenic arrhythmias. The results showed that 10 to 100 μM sultopride and 0.01 to 1 μM droperidol exerted “pure” class III effects. In addition, higher concentrations (3 to 30 μM) of droperidol reversed the prolonging effect on repolarisation concomitantly with a dose- and frequency-dependent decrease in V_max, action potential amplitude and resting membrane potential (class I effects) resulting in cellular inexcitability at 30 μM. Similar class I effects were induced by thioridazine and clozapine concomitantly with a slight prolonging effect on final repolarisation (class la effects). In the presence of sultopride (30 and 100 μM) and droperidol (0.3 to 3 μM), EADs developed at plateau level. Their incidence, amplitude and number were influenced by extracellular K or Mg concentration, stimulation frequency, modification of Ca entry (by nifedipine or isoproterenol). These experimental results fit well with clinical data although they need further development to precise underlying ionic mechanisms. Therefore, in vitro studies should be considered before clinical prospects for future drug development.     

Recent Trends in Dealing with Inguinal Hernial Sac

High ligation of the hernial sac is a hallowed and time-honoured concept in inguinal hernia repair and it is considered essential for preventing recurrence. However, this concept has been contested in recent reports. We conducted a prospective study of 186 cases of inguinal hernia repair. In 92 cases the sac was ligated at the neck and excised, in 94 cases the sac was not ligated at all but either simply inverted or excised without ligation. The type of repair was Bassini''s repair, Shouldice repair or Lichtenstein''s repair. Degree of post-operative pain was significantly less in those cases where sac was not ligated. There were no cases of recurrence in either group at 3 years follow up. Ligation of sac in inguinal hernia surgery is not only unnecessary and time consuming but also leads to increased post-operation pain. Recurrence is unaffected by not ligating the sac.Key Words: Hernial sac, Recurrence     

Acyclovir resistant varicella zoster and HIV infection

A child infected with HIV who developed chronic varicella zoster virus infection resistant to acyclovir is presented. The clinical course of the infection, treatment, virological investigations, and relationship of the infection to the child's immunodeficient state are discussed.     

Effect of gamma irradiation of red blood cell units on T-cell inactivation as assessed by limiting dilution analysis: implications for preventing transfusion-associated graft-versus-host disease

Transfusion-associated graft-versus-host disease can be prevented by treating cellular blood products with gamma irradiation. A wide range of gamma irradiation dose levels has been used in routine practice. We used limiting dilution analysis, which measures clonable T cells, to assess the influence of 500 to 3,000 cGy of gamma irradiation delivered from a 137Cs source on T cells when delivered in situ to ADSOL- preserved red blood cell (RBC) units in blood bags. In a series of experiments using RBC units irradiated within 24 hours after collection, 1,500 cGy inactivated > 4 log10 of T cells; however, viable T cells were detected in all experiments. With 2,000 cGy, a > or = 4.7 log10 decrement in T-cell growth occurred in 7 of 8 experiments. With 2,500 or 3,000 cGy, no T-cell growth (> 5 log10 depletion) was detected. Comparable effects were observed with ADSOL-preserved RBC units in the standard PL 146 plastic container and in the recently developed PL 2209 plastic container. T-cell inactivation, as a function of gamma irradiation dose, was similar when either a 137Cs or a linear accelerator source was used. T cells isolated from ADSOL-preserved RBC units after storage for 7 and 21 days, although reduced in number as compared with a fresh unit stored for 24 hours, were viable, capable of proliferation, and susceptible to inactivation by gamma irradiation. Using a sensitive in vitro assay for T-cell proliferation, we found that a gamma irradiation dose of 2,500 cGy may be required to completely inactivate T cells in RBC units.