Update on transcobalamin deficiency: clinical presentation, treatment and outcome.

Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.

[Recombinant Human Erythropoietin (r-HuEPO) therapy in a newborn with hereditary spherocytosis]. / Utilisation de l'érythropoïétine chez un nouveau-né atteint de sphérocytose héréditaire.

UNLABELLED: The newborn with hereditary spherocytosis can develop severe anemia, requiring red blood cell transfusions. Therapy with r-HuEPO has been proposed to avoid transfusions. CASE REPORT: Hereditary spherocytosis was diagnosed in a newborn who had severe and early jaundice. He was treated with r-HuEPO, and did not require red blood cells transfusion. CONCLUSION: Recombinant erythropoïetin might be an interesting alternative to red blood cells transfusions during the neonatal period in newborns with hereditary spherocytosis.

Leflunomide versus methotrexate: a comparison of the European and American experience.

This paper compares and contrasts the results of two major Phase III clinical trials that compared the efficacy and safety of leflunomide, a new disease-modifying antirheumatic drug (DMARD), and methotrexate. In both the American trial (US301) and the multinational trial (MN302), patients with active rheumatoid arthritis (RA) were given either leflunomide (20 mg/day after a loading dose of 100 mg/day for 3 days) or methotrexate (7.5-15 mg/week) for 52 weeks. US301 was also placebo-controlled. Folate supplementation was mandatory in US301 but was given to < 10% of the patients in MN302. In US301, American College of Rheumatology (ACR) 20% response rates and improvement in tender and swollen joints were significantly better than placebo in both treatment groups, but were not significantly different from each other. Both treatments significantly retarded radiographically assessed progression of RA compared to placebo, but the degree of retardation was significantly greater with leflunomide. In MN302, the ACR response rate and improvement in tender and swollen joints with leflunomide were similar to those seen in US301. The ACR response rate and improvements in all efficacy variables with methotrexate were significantly greater than with leflunomide, however. Radiographically assessed disease progression was not statistically different with the two treatments. Use of methotrexate without folate in MN302 was associated with a higher incidence of clinically significant elevations of liver enzyme levels. These results indicate that both leflunomide and methotrexate are effective DMARDs. The symptomatic relief provided by both drugs is similar when they are given with folate supplementation.

Pituitary gonadotropin-releasing hormone (GnRH) receptor responses to GnRH in hypothalamus-lesioned rats: inhibition of responses by hyperprolactinemia and evidence that testosterone and estradiol modulate gonadotropin secretion at postreceptor sites.

Increased hypothalamic GnRH secretion appears to influence positively the number of pituitary GnRH receptors (GnRH-R). GnRH-R increase after castration in male rats, and this rise can be prevented by testosterone (T), anti-GnRH sera, or hypothalamic lesions. GnRH also increases serum LH and GnRH-R in hypothalamus-lesioned rats, and these animals injected with exogenous GnRH are, therefore, a good model in which to study the site of steroid feedback at the pituitary level. Adult male and female rats were gonadectomized, and radiofrequency lesions were placed in the hypothalamus. Males received T implants, and females received estradiol implants at the time of surgery. Empty capsules were placed in the control animals. Beginning 3-5 days later, animals in each group were injected every 8 h with vehicle (BSA) or GnRH (0.002-200 micrograms/day) for 2 days. After these GnRH injections, all rats received 6.6 micrograms GnRH, sc, 1 h before decapitation to determine acute LH and FSH responses. GnRH-R were determined by saturation analysis using 125I-D-Ala6-GnRH ethylamide as ligand. In males, GnRH injections increased GnRH-R. T inhibited acute LH and FSH responses to GnRH in all groups, but had little effect on GnRH-R, indicating that T inhibits gonadotropin secretion at a post-GnRH receptor site. In females, the GnRH-R response to GnRH was less marked, and only the 200 micrograms/day dose of GnRH increased GnRH-R, indicating that the positive feedback effects of estradiol at the pituitary level are also exerted at a site distal to the GnRH receptor. There was no positive correlation between the number of GnRH-R and GnRH-stimulated gonadotropin release in males or females. Female rats with hypothalamic lesions had markedly elevated serum PRL levels (greater than 300 ng/ml). Suppression of PRL secretion by bromocryptine resulted in augmented GnRH-R responses to GnRH, and GnRH-R concentrations rose to the same values induced in males. This suggests that hyperprolactinemia inhibits GnRH-R responses to GnRH in females by a direct action on the pituitary gonadotroph.