Erythrocytic uridine diphosphate galactose in galactosaemia

Summary An earlier claim of a deficiency of uridine diphosphate galactose in erythrocytes of galactosaemia patients was not confirmed. Enzymic techniques similar to those of the earlier investigators were used to determine not only the concentration of uridine diphosphate galactose but also the ratio of this concentration to the sum of the uridine sugar diphosphates (uridine diphosphate galactose and uridine diphosphate glucose). The values in erythrocytes of galactosaemic subjects were similar to those of non-galactosaemic children on a galactose-restricted diet and to those of normal adults. These results cast doubt on the claim of a major deficiency of uridine diphosphate galactose in galactosaemia and on the need for treating galactosaemic children with uridine.     

Flash pulmonary edema: association with hypertension and reoccurrence despite coronary revascularization

BACKGROUND: The sudden development of acute (flash) pulmonary edema may be an indication for coronary angiography and revascularization. However, the prevalence of coronary artery disease in these patients and the outcome after revascularization are not known. METHODS AND RESULTS: We evaluated 46 patients with an initial presentation of flash pulmonary edema requiring hospitalization and obtained up to 3 years of follow-up in 45 patients. There were 22 men and 24 women, 44 to 84 years of age (67 +/- 10 years, mean +/- SD). Systolic blood pressure on admission was 194 +/- 38 mm Hg. Twenty-four patients required intubation and mechanical ventilation. Left ventricular ejection fraction was >40% in 27 of 46 patients. Thirty-eight patients underwent coronary angiography; 33 had obstructive coronary artery disease. One other patient had regional wall motion abnormalities. Nineteen patients underwent coronary revascularization surgically and 8 percutaneously. Overall, flash pulmonary edema reoccurred in one half of the patients. Of the 19 patients who underwent coronary revascularization, by 6 months there was 1 death and 9 patients had been hospitalized with recurrent pulmonary edema. CONCLUSIONS: Many patients with flash pulmonary edema have preserved systolic left ventricular function and coronary artery disease. Flash pulmonary edema frequently reoccurs in association with marked systolic hypertension, even after coronary revascularization. This suggests that control of hypertension is important and that coronary revascularization may not be adequate to prevent reoccurrence of flash pulmonary edema.     

Endocrinology: Inhibition of ovarian-derived prorenin to angiotensin cascade in the treatment of ovarian hyperstimulation syndrome

The purpose of this experiment was to determine whether useof the angiotensin-converting enzyme (ACE) inhibitor, enalapril,would prevent the occurrence of ovarian hyperstimulation syndrome(OHSS) in the rabbit model. A total of 20 adult female New Zealandwhite rabbits were studied. All rabbits received 75 IU of humanmenopausal gonadotrophin s.c. each day for 7 days. On day 8,all rabbits received 2500 IU of human chorionic gonadotrophin(HCG). Ten rabbits were randomly chosen to receive enalaprilorally. Five received 1 mg/kg of enalapril and five received2 mg/kg of enalapril twice daily. The remainder received placeboorally twice daily. On day 10, all rabbits underwent surgicalexploration. Total body weight was found to increase significantlyin the placebo group (by 293 g, P < 0.001) but not in eithergroup receiving enalapril. Haematocrit also increased significantlyin the placebo group (by 3%, P < 0.013) but not in the enalaprilgroups. Ovarian weights were highest for the 2 mg/kg enalaprilgroup (5.80 ± 0.52 g), followed by the 1 mg/kg enalaprilgroup (3.64 ± 0.45), and least for the placebo group(2.69 ± 0.17). All 10 placebo rabbits met criteria forsevere OHSS whereas only six in the enalapril groups did. Weconcluded that angiotensin II may play a significant role inthe development of weight gain, third space fluid accumulationand intravascular fluid depletion in OHSS. ACE inhibition resultedin a 40% decrease in the incidence of OHSS in the rabbit model.     

Approaches for incorporating ovulation detection devices and home kits into learning NFP - implications for service delivery

This paper presents demographic data about use of NFP in Europe and the factors which have been identified as influencing that very low use level. Experience with a new ovulation detection device in clinical trials and observations of its over-the-counter promotions is discussed in the context of what is already known about how to maximize uptake of contraception in main-stream service provision.Some suggestions are offered as to appropriate means of encouraging women who are using artificial methods or no method to understand enough about their natural fertile cycle to consider NFP as an acceptable option.     

Liver disease in recipients of long-functioning renal allografts

After noting that hepatic failure was the leading cause of death in our transplant recipients whose renal allografts had functioned for more than five years, we reviewed retrospectively the post-transplant course of these patients to assess the long-term effect of liver disease in this population. Sufficient data was available to evaluate 184 of 217 long-term survivors (85%). Twenty-six patients (14%) experienced a doubling of SGOT and/or SGPT of greater than six months' duration and were defined as having chronic liver disease. The etiology of chronic liver disease was identified in 14 patients (54%), of whom 11 were HBsAg positive. Evidence of chronic hepatitis developed in only six of 26 patients (22%) during the first four years post transplant. Once enzyme abnormalities occurred, they were unremitting until death or end of the study in 73% of patients. Actuarial survival of patients with chronic liver disease was markedly decreased compared to long-surviving transplanted controls. Ten of the 12 deaths in patients with hepatocellular abnormalities were due to hepatic failure, of which eight occurred in the setting of extrahepatic sepsis. Chronic liver disease is a late complication of transplantation and is associated with significant mortality due to an increased susceptibility to overwhelming sepsis.     

RO 23-6457 prolongs survival of vascularized allografts in rodents and primates

The ability of RO 23-6457, a retinoid compound with marked in vitro immunosuppressive properties, to prolong vascularized allografts was examined in several in vivo transplantation models. In the murine heterotopic heart model, efficacy was shown in two H-2 incompatible strain combinations, with indefinite graft survival at some doses. In the rat heterotopic heart model, oral administration prolonged Wistar-Furth grafts in Lewis hosts an average of 1 week, with no long-term survivors at a variety of doses. Given subcutaneously, grafts were further prolonged, but the compound proved toxic. In a bilaterally nephrectomized renal transplant model in cynomolgus monkeys treated intravenously at a dose of 2 mg/kg/day, host survival was prolonged to 18, 32, 33, and 74 days, compared with 11, 11, 12, 13, and 26 days in untreated controls (P less than 0.05 by rank-sum testing). The three shorter surviving recipients died from anorexia and weight loss with normal renal function, while the longest survivor rejected its kidney when exhaustion of iv sites precluded further treatment. The toxic effects of the compound resemble the syndrome of hypervitaminosis A. RO 23-6457 will prolong graft survival as a single agent, justifying further preclinical testing and efforts to reduce toxicity.     

Prolongation of cardiac allograft survival in murine recipients treated with a diphtheria toxin-related interleukin-2 fusion protein

A diphtheria toxin-related IL-2 fusion gene has been constructed that encodes a 68KD recombinant toxin in which the diphtheria toxin receptor-binding domain has been replaced with amino acids 2-133 of IL-2. This chimeric IL-2 toxin is cytotoxic for cells expressing the high-affinity IL-2 receptor but not for cells lacking this receptor. The ability of this IL-2 toxin to prolong allograft survival was examined in a murine vascularized, heterotopic heart transplant model in the strain combination B10.BR into C57B1/10. When given at a dose of 1.0 micrograms/day for 10 days, the IL-2 toxin significantly prolonged allograft survival in all recipients. CRM-45, a fragment of diphtheria toxin missing the binding domain, was ineffective, confirming the specificity of the therapy. The results demonstrate that this IL-2 toxin, which targets activated T cells expressing the IL-2 receptor, will prolong allograft survival, offering a new option for immunosuppressive therapy.     

The effect of anti-interleukin-2 receptor monoclonal antibody on allograft rejection

During immune response to an allograft, activated T cells express a number of cell surface activation antigens, among them the membrane receptor for the lymphokine interleukin 2 (IL-2). As the IL-2 receptor is not present on resting T cells, it offers an attractive target for potentially specific immunosuppressive therapy. The rat monoclonal antibody M7/20, which binds to the murine IL-2 receptor, was studied for its effect on allograft survival in two H-2-incompatible strain combinations in inbred mice. Treatment with M7/20 for 10 days markedly prolonged survival of vascularized, heterotopic heart allografts in both strain combinations, with indefinite graft survival in 50% of recipients. The same treatment significantly prolonged skin allograft survival in one of the two combinations. The results support the important role of the IL-2 receptor in the mechanism of graft rejection and confirm its suitability as a target for immunosuppressive therapy in transplantation.