The protective activity of ICRF-187 against doxorubicin-induced cardiotoxicity in the rat

Summary The protective activity of the bisdioxopiperazine ICRF-187 against the cardiotoxicity of doxorubicin was evaluated in the rat using both functional and histological assays. Animals that had received a single i. v. dose of doxorubicin (4 mg/kg) alone were compared with those that had been pretreated with a single i. v. injection of saline or ICRF-187 (40 or 60 mg/kg). All rats showed a transient reduction in body weight during the first 3 weeks after drug administration. The greatest reduction (16%) was observed in animals that had received a combination of ICRF-187 (40 or 60 mg/kg) and doxorubicin. Deaths related to cardiotoxicity were observed only in rats that had received doxorubicin alone and in those treated with saline; most of the deaths occurred at between 8 and 13 weeks after drug administration. Sequential assessments of heart function showed a persistent depression of cardiac output in animals that had received doxorubicin, with or without pretreatment with ICRF-187. The reduction in cardiac output observed in rats that had been pretreated with ICRF-187 (40 or 60 mg/kg) amounted to 15% and 30% after 12 and 20 weeks, respectively, indicating that cardioprotection was only partial. Nevertheless, this represented a marked improvement as compared with the 35% reduction in cardiac output measured at 12 weeks in animals that had received doxorubicin but without pretreatment with ICRF-187. Histological examination of animals that had died during the course of the study and had received doxorubicin after pretreatment with saline revealed severe myocardial lesions typical of doxorubicin-induced damage. In contrast, animals that had been pretreated with ICRF-187 and survived for up to 20 weeks after treatment showed a marked amelioration of these lesions. The present findings may be interpreted as a true cardioprotection or a delay in the onset of the cardiotoxicity of doxorubicin resulting from pretreatment with the bisdioxopiperazine ICRF-187. Although prior and ongoing clinical trials clearly indicate that ICRF-187 protects patients well against doxorubicin-induced heart damage, further investigations are required beforehigh doses of ICRF-187 can be used as a means of increasing the protective activity of this drug against doxorubicin-induced cardiotoxicity.This work was supported by the Cancer Research Campaign     

Anaesthetic considerations in down’s syndrome: experience with 100 patients and a review of the literature

Down’s Syndrome (Trisomy 21, T21) occurs in approximately 0.15 percent of live births. In addition to the stigmata of the syndrome, other congenital defects are frequently found in these patients. Cardiac lesions are particularly prominent. To determine the complications associated with anaesthesia and surgery we examined the records of 100 consecutive patients (58 males, 42 females) who underwent surgery with general anaesthesia during a two year period, from March 1978-March 1980. In addition to the cardiac lesions, the low birth weight of Trisomy 21 infants, increased suceptibility to infections, atlanto-occipital dislocation, and reduced central nervous system catecholamine levels might be expected to result in an increased incidence of complications. This study of 100 patients with Trisomy 21 (T21) indicates that the incidence of complications is low. However, the anaesthetist must understand the pathophysiology of T21 in order to provide optimal anaesthetic care.     

Timing and nature of reconstructive surgery for disorders of sex development – Introduction

The ideal timing and nature of surgical reconstruction in individuals with Disorders of Sex Development (DSD) is highly controversial. Despite the increasing number of publications on this topic, evidence-based recommendations still cannot be made. However it is generally accepted that optimal care for DSD requires an experienced multidisciplinary team. This means that surgical decisions are now made within the context of a multidisciplinary team and all members of the team – and not just specialist surgeons – may be called upon to discuss choices for surgery with patients and parents. To do this well, every clinician in the team should have an understanding of the range of techniques available for genital surgery, the risks and benefits of procedures and the controversies surrounding timing of surgery.The aim of this paper is to give an overview of the variety of surgical procedures in current use and in what situation a particular technique would be indicated. The short-term risks and benefits are described and where available long-term outcome data is discussed. To date, discussions surrounding genital surgery have been led primarily by surgeons. Some non-surgical clinicians have expressed unease about decision making in genital surgery but have felt ill equipped to comment on an area with which they are unfamiliar. This review gives a detailed explanation of current surgical practice offered in a specialized center for DSD and such information should facilitate a more balanced discussion.     

Fat Taxes

Healthcare facilities law. Edited by Dellinger, Anne M. (Little Brown and Co., Boston, MA, 1991), 1162 pages, $95.00.     

Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning

Germ cells undergo epigenetic modifications as they develop, which suggests that they may be ideal donors for nuclear transfer (cloning). In this study, nuclei from confirmed embryonic germ cells were used as donors to determine whether they are competent for cloning and at which stage they are most competent. Embryos cloned from migrating 10.5-days-postcoitum (dpc) primordial germ cells (PGCs) showed normal morphological development to midgestation but died shortly thereafter. In contrast, embryos cloned from later-stage germ cells were developmentally delayed at midgestation. Thus, donor germ cell age inversely correlated with the developmental stage attained by cloned embryos. The methylation status of the H19- and Snrpn-imprinting control regions in germ cell clones paralleled that of the donors, and revealed that demethylation, or erasure of imprints, was already initiated in PGCs at 10.5 dpc and was complete by 13.5 dpc. Similarly, clones derived from male 15.5-dpc germ cells showed increased methylation correlating with the initiation of de novo methylation that resets imprints at this stage, and clones from neonatal germ cells showed nearly complete methylation in the H19 imprinting control region. These results indicate that the epigenetic state of the donor nucleus is retained in cloned embryos, and that germ cells are therefore inadequate nuclear donors for cloning because they are either erasing or resetting epigenetic patterns.