The immunogenetic basis of severe infections caused by bacille Calmette-Guérin vaccine and environmental mycobacteria in humans remains largely unknown. We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele. There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot. Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFNgamma receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNgamma exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.
Bronchial responsiveness is closely associated with asthma in schoolchildren. We wished to test the hypothesis that bronchial responsiveness in the neonatal period might be a risk factor for lower-respiratory illnesses (LRI), typically cough and wheezing with viral infection, in infants. A cohort of 73 full-term healthy infants of atopic parents were observed during the first year of life. Respiratory illness was recorded and ascertained retrospectively by questionnaires administered to parents at 6-mo intervals, and infants were classified as having: LRI (one or more episode of wheezing in the first year) or no LRI (no wheezing). At approximately 1 mo of age, lung function was measured under sedation, and bronchial responsiveness (BR) to histamine aerosol was determined and expressed as PC30, the provocative concentration of histamine that induced a 30% decrease in maximum flow at FRC (V'maxFRC) by the squeeze technique. For the whole group, no index of lung function predicted subsequent wheezing. Among boys, however, there was a trend toward a lower V'maxFRC in those who subsequently developed LRI than in the group without LRI (median values 62 versus 98 ml/s; 95% CI: -1 to 68; p = 0.06), while among girls the major difference was in PC30, for which those who subsequently had LRI were significantly more responsive as neonates (PC30 was lower) than the group without LRI (1.4 versus 8.3 g/L; 95% CI: 1.0 to 13.1; p < 0.05). These findings suggest that sex differences in airway structure and responsiveness present soon after birth, and representing differences in fetal lung development, are associated with differences in the risk of subsequent LRI with wheezing.(ABSTRACT TRUNCATED AT 250 WORDS)
Early liver transplant (LT) has been advocated for patients with cystic fibrosis liver disease (CFLD) and evidence of deterioration in nutritional state and respiratory function to prevent further decline. However, the impact of single LT on long-term respiratory function and nutritional status has not been adequately addressed. We performed a retrospective analysis of the outcomes of 40 (21
Patterns of tidal respiratory flow have been shown to relate well to airway function in adults, and one epidemiological study in infants has demonstrated the value of the ratio of time to reach peak tidal expiratory flow to the total expiratory time (tpef/te) in predicting subsequent wheezing. The aim of this study was to evaluate tpef/te as a measure of lung function, by sequential observations over the first year, on a group of 22 healthy infants and on 32 infants with a history of mild recurrent lower respiratory illness (LRI), and by single observations on 20 infants with asthma and 20 with severe chronic lung disease of prematurity. We compared tpef/te measured in quiet, supine sleep (under sedation) through a face mask and pneumotachograph, with a measure of airway function, maximal flow at functional residual capacity (VmaxFRC), obtained from partial forced expiratory flow volume loops using the "squeeze" technique. In healty infants tpet/te was significantly longer at 1 month than at 6 months (median values, 0.38 (95% CI, 0.36-0.43) and 0.28 (95% CI, 0.26-0.33), respectively). Between 6 and 12 months tpef/te did not alter significantly and it was independent of VmaxFRC. Both tpef and te as well as their ratio varied with frequency of breathing over the first year of life, but not within each individual age band, due to the narrow spread of frequencies at each age. In assessing airway obstruction, tpef/te was less sensitive than VmaxFRC. There was no difference between healthy infants, those with LRI, and infants with asthma.(ABSTRACT TRUNCATED AT 250 WORDS)
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