Leucodysplasia, microcephaly, cerebral malformation (LMC): a novel recessive disorder linked to 2p16.

We report three related and one unrelated child with an apparently novel neurodevelopmental disorder. The clinical course was very similar in all the four patients: congenital microcephaly with severe failure of post-natal brain growth, neonatal onset of intractable seizures associated with lack of developmental progression and death within the first 3 years of life. The appearance on cerebral neuroimaging was almost identical, with simplified gyration associated with a non-thickened cortex, severe hypoplasia of the corpus callosum, a small flattened brain stem, and specific cystic lesions in the white matter around the temporal and occipital horns. To our knowledge these patients represent a previously unreported, autosomal recessive syndrome. Homozygosity mapping in the consanguineous family has identified a candidate region on the chromosome 2p16.

Trials of the bronchodilator activity of the isoenzyme-selective phosphodiesterase inhibitor AH 21-132 in healthy volunteers during a methacholine challenge test.

1. An approximately steady-state reduction of specific airway conductance was induced in normal human subjects by means of a methacholine individualized loading+maintenance dose regime. Tested against this background bronchoconstriction, the mixed type III/IV phosphodiesterase inhibitor AH 21-132, ingested in doses up to 90 mg, had no detectable bronchodilator activity. 2. AH 21-132, infused intravenously over 15 min, evoked short-lived bronchodilatation at doses of 20 and 40 mg, without affecting blood pressure or heart rate. 3. AH 21-132, mixed 1:18.5 by weight with sucrose, dissolved in saline, nebulized and inhaled in doses between 2 and 24 mg of AH 21-132, produced dose-dependent bronchodilation. The ED50 was estimated as 9.2 mg AH 21-132. The peak relief of imposed bronchoconstriction was 80% and the apparent half-time of removal of AH 21-132 from its site of action was 25 min. 4. Inhaled, nebulized, hypertonic sucrose had a minor bronchodilator action. 5. AH 21-132, by intravenous and inhaled routes of administration, provides relief of methacholine-induced bronchoconstriction.

A method for bioassay of potency and effectiveness of inhaled bronchodilators in normal subjects.

1. Bioassay of inhaled bronchodilator drugs for potency and effectiveness in normal human subjects is rendered difficult and imprecise because bronchomotor tone is low. When attempting to determine log dose-effect relationships for inhaled, nebulised bronchodilator drugs and measuring increased specific airways conductance (sGaw), the coefficient of variation of each mean response is likely to be so large that an intermediate response is not significantly different from either the maximum or no response. 2. A method is described by which inhaled, nebulised bronchodilator drugs can be bioassayed for potency and effectiveness with high precision. The method involves the use of inhaled, nebulised bronchoconstrictor agents (methacholine or histamine) to provide a highly reproducible, near-constant, background reduction in airway conductance in normal human subjects. The activity of bronchodilators is assessed against this background reduction in airway conductance. 3. Log specific airway conductance (log sGaw) was chosen as the response metameter on grounds of normality of distribution and relative homoscedasticity. A central straight line segment of the bronchoconstrictor drug dose-effect curve extending over a 10-fold dose multiple could be found easily; the upper end of this segment occurred near 67-75% reduction in sGaw and was reproducible. 4. The effect of a dose bronchoconstrictor drug causing 67-75% reduction in sGaw waned linearly with time at first, over the effect segment corresponding to the linear segment of the drug's log dose-effect curve. The rate constant of local elimination of bronchoconstrictor drug from its site of action, in inhaled dose equivalents, was deduced from the ratio of the slopes of the linear segments of the log dose-effect and time-effect curves. 5. The maintenance dose rate to maintain the peak effect (67-75% reduction in sGaw) of the loading dose was calculated. The repeated administration of maintenance doses at regular short intervals, at this calculated dose rate, created a steady state of bronchoconstriction equal in extent to the effect of the loading dose. This steady state bronchoconstriction occurred without undue discomfort for the subject and was reproducible. 6. Against this background bronchoconstriction, inhaled, nebulised salbutamol produced a rapidly developing and slowly waning increase in sGaw. Reproducible log dose-effect curves for the bronchodilator drugs salbutamol and reproterol allowed measurement of their potency and effectiveness; the potency of reproterol relative to salbutamol was 0.082 with 95% confidence limits of 0.0504 and 0.131. 7. Estimation of the subject's pharmacodynamic and pharmacokinetic parameters for inhaled methacholine from just three dosage individualising sessions provides estimates accurate enough to be of practical value.