Duration of general anaesthetic exposure in early childhood and long-term language and cognitive ability.

BACKGROUND: The anaesthetic dose causing neurotoxicity in animals has been evaluated, but the relationship between duration of volatile anaesthetic (VA) exposure and neurodevelopment in children remains unclear. METHODS: Data were obtained from the Western Australian Pregnancy Cohort (Raine) Study, with language (Clinical Evaluation of Language Fundamentals: Receptive [CELF-R] and Expressive [CELF-E] and Total [CELF-T]) and cognition (Coloured Progressive Matrices [CPM]) assessed at age 10 yr. Medical records were reviewed, and children divided into quartiles based on total VA exposure duration before age three yr. The association between test score and exposure duration quartile was evaluated using linear regression, adjusting for patient characteristics and comorbidity. RESULTS: Of 1622 children with available test scores, 148 had documented VA exposure and were split into the following quartiles: ≤25, >25 to ≤35, >35 to ≤60 and >60 min. Compared with unexposed children, CELF-T scores for children in the first and second quartiles did not differ, but those in the third and fourth quartiles had significantly lower scores ([3 rd quartile - Unexposed] -5.3; 95% confidence interval [CI], (-10.2 - -0.4), [4 th quartile - Unexposed] -6.2; 95% CI, (-11.6 - -0.9). CELF-E showed similar findings, but significant differences were not found in CELF-R or CPM for any quartile. CONCLUSIONS: Children with VA exposures ≤35 min did not differ from unexposed children, but those with exposures >35 min had lower total and expressive language scores. It remains unclear if this is a dose-response relationship, or if children requiring longer exposures for longer surgeries have other clinical reasons for lower scores.

A novel C-terminal domain in the thyroid hormone receptor selectively mediates thyroid hormone inhibition.

Resistance to thyroid hormone (RTH) action is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate central secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyrotropin (TSH) from the anterior pituitary in association with abnormal peripheral tissue responses to thyroid hormone. Whether TR-beta mutations cause a selective form of RTH, which only leads to abnormal pituitary TSH secretion (PRTH), is unclear. In a patient with PRTH, a novel mutation of a conserved arginine residue adjacent to the ninth heptad of TR-beta selectively disrupts TR homodimer formation. The mutant TR displays normal or enhanced function on stimulatory thyroid hormone response elements found in peripheral tissues, but has defective function on inhibitory thyroid hormone response elements found in the TRH and TSH subunit genes and explains the PRTH phenotype. This is the first report of a mutation in a member of the nuclear receptor superfamily that selectively abolishes hormone-dependent inhibition and localizes a novel C-terminal domain necessary for this property.