Electronic and steric effects in thermal denitrosation of N-nitrosoamides.

N-Alkyl-N-nitrosoamides undergo competitive reactions whose rates are dependent upon the interplay of a number of factors. There already exists a significant body of work delineating the effects of pH on the partitioning of the nitrosoamides along their deaminative (-N(2)) and denitrosative (-"NO(+)") pathways. In this paper, the issue of pH dependence is discussed with particular attention to nitrosoamide decompositions in nonaqueous media. The role of the acidity of the medium in the partitioning of the nitrosoamide between deamination and denitrosation and in the choice of deaminative pathways is revisited. In nonaqueous media under near-neutral conditions, the partitioning's pH dependence is evidently accompanied by a sensitivity to structural features in the nitrosoamide. Thus, diminution of steric crowding around the N-nitroso moiety as well as the presence of strongly electron-withdrawing acyl units (i.e., those derived from strong acids, e.g., tosyl and trifyl) increase the relative yield of amides by encouraging the denitrosative pathway. A mechanism for thermal denitrosation of nitrosoamides under near-neutral conditions is proposed in which rapid protonation at the acyl O rather than slow protonation at the amidic N is the first step in the reaction profile. A rate-limiting, bimolecular reaction between the O-conjugate acid and adventitious nucleophiles at the nitrosyl group then occurs followed by rapid tautomerization to amide.

Management and outcome of children with congenital hypothyroidism detected on neonatal screening in South Australia.

Thirty-eight congenitally hypothyroid children who were detected in a neonatal screening programme have been treated for a mean period of 3.8 years (range, 0.5-8.5 years) by the maintenance of the free thyroxine index in the upper normal range as the main determinant of the dose of thyroxine. Only excessive elevation of, or serial rises in, thyroid stimulating hormone (TSH) level influenced the dose of thyroxine. This treatment strategy, which aims to avoid the potentially adverse effects of thyroxine overdosage, has often resulted in delayed return of TSH levels to normal, especially in athyrotic children (mean TSH +/- SD at one year of age in athyrotic children, 72 +/- 90 mU/L; in children with ectopic thyroid glands, 24 +/- 16 mU/L; normal range, 0-7 mU/L). The mean thyroxine dose of about 100 micrograms/m2 did not change significantly with age, and is lower than the doses that are sometimes quoted in the literature; athyrotic children require significantly more thyroxine (P less than 0.05) than those with ectopic thyroid glands. Symptoms and signs of congenital hypothyroidism, although subtle, were significantly more common (P less than 0.05 for symptoms and P less than 0.001 for signs) in athyrotic children compared with those with ectopic glands. No physical or developmental abnormality related to congenital hypothyroidism has been demonstrated on follow-up; mean height and weight percentiles approximate the 50th percentile at ages one to six years and mean developmental scores +/- SD at about two years of age by the Griffiths Mental Development Scale and at 4.5-6.5 years by the Wechsler Preschool and Primary Scale are 102.4 +/- 10.4 and 111.2 +/- 12.2, respectively. Long-term follow-up studies are necessary to exclude more subtle developmental and neurological abnormalities.