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Fetal liver haematopoietic cells were used to induce neonatal tolerance to cardiac allografts. Newborn mice were injected with fetal or newborn haematopoietic liver cells in two fully allogeneic strain combinations. There was no clinical evidence of graft-versus-host disease. Long-term survival of subsequent cardiac allografts occurred in both strains without immunosuppressants. Unresponsiveness was found not be be donor-specific with prolongation of third-party allografts as well as donor-type grafts. These findings have important implications for inducing tolerance in paediatric organ transplantation.

This study investigated the effect of anti-CD4 MoAb treatment on lymphocyte phenotype and function and correlated these changes with the prolongation of cardiac allograft survival in adult mice. Indefinite survival of heterotopic cardiac allografts was obtained in several fully allogeneic strain combinations when two doses of the anti-CD4 MoAb, YTS 191.1, were given at the time of transplantation. A dose response analysis in the C57BL/10 to C3H/He strain combination showed that very low doses of YTS 191.1 (25 micrograms/dose) were able to induce prolonged allograft survival when administered perioperatively. At the time of transplantation the immunosuppression induced by administration of the anti-CD4 MoAb is not antigen-specific, as heart grafts from different donor strains, mismatched for both major and minor histocompatibility antigens, showed prolonged survival in treated recipients. Immunocompetence was restored by 6 weeks after MoAb treatment, as recipients regained the ability to reject a cardiac allograft transplanted at this time point. However, while recovery of immunocompetence could be demonstrated in vivo, leucocytes isolated from the peripheral lymphoid organs of treated mice continued to be hyporesponsive in mixed leucocyte culture (MLC). Phenotypic analysis of the peripheral lymphoid tissues showed that C3H/He recipients treated with 25 micrograms/dose of YTS 191.1 had a marked, but not complete, elimination of the CD4+ subset at the time of transplantation, which was gradually restored to 50% of normal by 6 weeks after treatment. Thus, complete elimination of the CD4+ subset was not required to achieve indefinite allograft survival, and immunocompetence, as assessed in vivo, returned even when the CD4+ subset was present at half the normal level. Low doses of anti-CD4 MoAb (25 micrograms) had no effect on the expression of the CD4 molecule by thymocytes, and yet thymocytes were hyporesponsive to alloantigen in vitro. At higher doses of YTS 191.1, immature CD4+8+ thymocytes were selectively depleted. These results suggest that anti-CD4 MoAb therapy may modulate the intrathymic T cell selection process. These studies provide further insight into the mechanism of action of low dose, depleting anti-CD4 MoAb therapy in allograft rejection, and form a basis from which rational modifications to therapeutic protocols in transplantation models can be made.

Transplantation tolerance can be induced in the adult mouse by the selective manipulation of the CD4+ T cell subset. C3H/He recipients with prolonged survival (> 120 days) of C57BL/10 cardiac allografts induced by treatment, at the time of transplantation, with the anti-CD4 mAb, YTS 191.1, were skin grafted simultaneously with donor-specific and third-party (BALB/c) skin. The development of donor-specific tolerance was proved by the specific prolongation of C57BL/10 skin graft survival, while third-party grafts were rejected. Further investigation of recipients with long-term surviving primary heart allografts showed that donor-specific tolerance was associated with organ-specific differences. Secondary cardiac allografts were universally accepted, even at 42 days after the primary heart transplant, while prolonged survival of donor-specific skin grafts was not obtained until more than 120 days after primary cardiac transplantation. Analysis of leukocyte reactivity in the mixed leukocyte culture (MLC) showed no correlation between the proliferative response of recipient T cells in vitro to either donor or third-party alloantigen and the survival of either heart of skin allografts. These results illustrate the significant challenge presented when attempting to define and assess accurately the state of transplantation tolerance.

Major depression is a psychiatric disorder in which mood, thought content, and behavioral patterns are impaired for long periods of time. It is a common disorder, with an increasing prevalence among young adults. It may be associated with a disinterest in performing appropriate preventive oral hygiene techniques, a cariogenic diet, diminished salivary flow, rampant dental decay, advanced periodontal disease, and oral dysesthesias. Many medications used to treat the disease magnify the xerostomia and increase the incidence of dental disease. Appropriate dental management necessitates a vigorous preventive dental education program, the use of saliva substitutes and anticaries agents containing fluoride, and special precautions when prescribing or administering analgesics and local anesthetics.

All reports of adverse reactions with pyrimethamine-sulphadoxine (Fansidar), pyrimethamine-dapsone (Maloprim), and amodiaquine spontaneously reported through the UK national post-marketing system were reviewed. Retrospective reporting rates of serious reactions associated with these drugs were analysed using prescription data from the Department of Health, derived from the Prescription Pricing Authority, and relevant pharmaceutical companies. Whilst interpretation of these data requires caution, they allowed comparison with reporting rates from other studies. The reported rate for all serious reactions to pyrimethamine-sulphadoxine was 1:2100 prescriptions, and for cutaneous reactions was 1:4900 prescriptions, with a fatality rate of 1:11,100. The reported rate for serious reactions to pyrimethamine-dapsone was 1:9100 prescriptions, and for blood dyscrasias was 1:20,000 prescriptions, with a fatality rate of 1:75,000. The reported rate of blood dyscrasias associated with amodiaquine was 1:2100 users with a fatality rate of 1:31,000. Serious hepatic disorders occurred in 1:11 1000 pyrimethamine-sulphadoxine prescriptions, 1:75,200 pyrimethamine-dapsone prescriptions, and in 1:15,650 amodiaquine users. 35% of cases received these drugs needlessly as they were not exposed to drug resistant strains of Plasmodium falciparum. Since few serious reactions have been reported to chloroquine plus proguanil, these data support guidelines which restrict the use of reviewed drugs for those at greatest risk of infection. Dosage data indicated that fatalities had taken higher doses and continued prophylaxis after onset of symptoms. Two thirds of serious reactions to the compound antimalarials were reported in females.

Controlled drinking has recently become a controversial alternative to abstinence as an appropriate treatment goal for alcoholics. In this study we reexamine the evidence underlying a widely cited report by Sobell and Sobell of successful controlled drinking by a substantial proportion of gamma (physically dependent) alcoholic subjects in a behavior therapy experiment. A review of the evidence, including official records and new interviews, reveals that most subjects trained to do controlled drinking failed from the outset to drink safely. The majority were rehospitalized for alcoholism treatment within a year after their discharge from the research project. A 10-year follow-up (extended through 1981) of the original 20 experimental subjects shows that only one, who apparently had not experienced physical withdrawal symptoms, maintained a pattern of controlled drinking; eight continued to drink excessively--regularly or intermittently--despite repeated damaging consequences; six abandoned their efforts to engage in controlled drinking and became abstinent; four died from alcohol-related causes; and one, certified about a year after discharge from the research project as gravely disabled because of drinking, was missing.

After heart disease and cancer, alcoholism is America's third largest health problem; it affects 10 million people, costs $ 60 billion, and is implicated in 200 000 deaths annually. Alcohol is involved in 50% of deaths by motor vehicle and fire, 67% of murders, and 33% of suicides. It contributes to morbidity in certain malignancies and to many diseases of the endocrine, cardiovascular, hematopoietic, gastrointestinal, and nervous systems. The fetal alcohol syndrome occurs in a third of the infants born to women who drink more than 150 g of ethanol daily during pregnancy; another third of the infants become mentally retarded. The prevalence of alcoholism is lower in elderly than in middle-aged persons, but detection is difficult and vulnerability to harm is great in the elderly, due to both pharmacokinetic factors and increased tissue sensitivity. Alcohol and aging are additive in their harmful effects. Although modern medical treatment is helpful, alcoholics are frequently misdiagnosed and mismanaged by health professionals. Total abstinence from alcohol should be a primary goal of treatment.

Capital punishment is outdated, immoral, wasteful, cruel, brutalizing, unfair, irrevocable, useless, dangerous, and obstructive to justice. In addition, psychiatric observations reveal that it generates disease through the torture of death row; it perverts the identity of physicians from trials to prison wards to executions; and, paradoxically, it breeds more murder than it deters.