Assessment of genetic and nongenetic influences on pulmonary function. A twin study

To better understand the extent to which familial similarities in pulmonary function (PF) are attributable to genetic rather than to shared environmental influences, we studied the twinship aggregation of PF in 256 monozygotic (MZ) and 158 dizygotic (DZ) adult twin members of the Greater Boston Twin Registry. Genetic influences on various spirometric measures were estimated with twinship intrapair correlations adjusted using a regression model to control for similarities in the anthropomorphic characteristics of twins, and for the effects of a number of environmental factors that included childhood respiratory illness, occupational dust exposure, and smoking history. A significant influence of smoking on all air-flow measures was observed in this population for whom genetic similarities were adjusted. However, highly significant adjusted intrapair correlations for all spirometric measures, ranging from 0.52 to 0.76, were observed for the MZ twins. The intrapair correlations for the DZ twins were approximately one-half the magnitude of those for the MZ twins. These data suggest that a large proportion of the measured variability in PF may be accounted for by genetic influences other than those associated with body size.     

Longitudinal study of the effects of maternal smoking on pulmonary function in children

We investigated the effects of maternal cigarette smoking on pulmonary function in a cohort of children and adolescents observed prospectively for seven years. A multivariate analysis revealed that after correction for previous forced expiratory volume in one second (FEV1), age, height, change in height, and cigarette smoking in the child, or adolescent, maternal cigarette smoking significantly lowered the expected average annual increase in FEV1 (P = 0.015). On the basis of this analysis, it is estimated that if two children have the same initial FEV1, age, height, increase in height, and personal cigarette-smoking history, but the mother of one has smoked throughout the child's life whereas the mother of the other has not, the difference in the change in FEV1 over time in the exposed child, as compared with that in the unexposed child, will be approximately 28, 51, and 101 ml after one, two, and five years, respectively, or a reduction of 10.7, 9.5, and 7.0 per cent, respectively, in the expected increase. These results suggest that passive exposure to maternal cigarette smoke may have important effects on the development of pulmonary function in children.     

The dentino-enamel junction revisited

The dentino-enamel junction is not an simple inert interface between two mineralized structures. A less simplistic view suggests that the dentino-enamel junctional complex should also include the inner aprismatic enamel and the mantle dentin. At early stages of enamel formation, fibroblast growth factor (FGF)-2 is stored in and released from the inner aprismatic enamel, possibly under the control of matrix metalloproteinase (MMP)-3. The concentration peak for MMP-2 and -9 observed in the mantle dentin coincided with a very low labeling for TIMP-1 and -2, favoring the cross-talk between mineralizing epithelial and connective structures, and as a consequence the translocation of enamel proteins toward odontoblasts and pulp cells, and vice versa, the translocation of dentin proteins toward secretory ameloblasts and cells of the enamel organ. Finally, in X-linked hypophosphatemic rickets, large interglobular spaces in the circumpulpal dentin were the major defect induced by the gene alteration, whereas the mantle dentin was constantly unaffected. Altogether, these data plead for the recognition of the dentino-enamel junctional complex as a specific entity bearing its own biological characteristics.     

Angiogenesis is an early event in the development of chemically induced skin tumors

In this study we have analyzed the vascular response induced in the two- stage carcinogenesis model in SENCAR mice. The role of angiogenesis has not been explored in this model, which is the paradigm of multistage carcinogenesis and a model for neoplastic lesions derived from exophytic premalignant lesions (e.g. colon carcinoma, bladder papilloma). We investigated if angiogenesis is involved in the formation of papillomas and in the progression from papilloma to carcinoma. To this end we analyzed the vasculature of normal and hyperplastic skin, focal epidermal hyperplasias that are precursors of papillomas, papillomas at different stages and squamous cell carcinomas. We also analyzed the vascularization of papillomas induced in two strains of mice that differ in their susceptibility to malignant progression. We show here that angiogenesis is turned on in the earliest stages of papilloma formation. In late stages, regardless of state of progression, the predominant response is an increase in the size of blood vessels. Thus, in the SENCAR mouse model, representative of exophytic tumors, the angiogenesis switch is a very early event, probably mechanistically related to the development of the primarily exophytic lesions. Therefore, the density of blood vessels cannot be used as a predictor of malignant progression in this model.      

Association of tobacco smoke exposure and respiratory syncitial virus infection with airways reactivity in early childhood.

Exposure to infectious agents and environmental tobacco smoke are thought to induce bronchial hyperresponsiveness (BHR). This study was undertaken to determine the effects of passive exposure to tobacco smoke and respiratory syncitial virus (RSV) lower respiratory infection (LRI) during infancy on the occurrence of BHR in the first 2 years of life. Eighty-six cases of documented RSV (mean age, 188 days) and 78 controls (mean age, 162 days) were enrolled from the clinic and in-patient service of a single hospital. None had a history of prior LRI. Subjects were studied at 6-month intervals up to 19 months of age with a standardized respiratory illness and parental smoking questionnaire, partial expiratory flow-volume curves by the "hug" (rapid thoracic compression) technique, and methacholine challenge. Exposure to maternal and paternal cigarette smoking, maternal history of asthma, and mold exposure were associated with decreased levels of length-corrected maximal flow at functional residual capacity (V'(maxFRC)). RSV-LRI was not related to V'(maxFRC). After adjustment of V'(maxFRC) for these factors, V'(maxFRC) was a significantly and positively correlated with a methacholine concentration provoking a 40% fall in V'(maxFRC) (PC40) and negatively correlated with dose-response slope. After adjustment for V'(maxFRC), there were no independent effects of tobacco smoke exposure or RSV-LRI on methacholine responses. These data do not support a role for RSV as a risk factor for airways reactivity in childhood and indicate that exposure to tobacco smoke affects airways reactivity through its effects on airways.     

The effect of ozone on inner-city children with asthma: identification of susceptible subgroups

Within a cohort of 846 inner-city asthmatic children aged 4 to 9 yr, we looked for subgroups that were more susceptible to the effects of summer ozone. Daily diaries were compared with ambient ozone levels to evaluate effect modification by demographic and environmental characteristics. Children born > 3 wk prematurely or weighing < 5.5 lb. had greater declines in morning % peak expiratory flow rate (PEFR) (1.8% versus 0.3% per 15 ppb ozone, p < 0.05) and a higher incidence of morning symptoms (odds ratio = 1.42 versus 1.09 per 15 ppb ozone, p < 0.05) than did children who had been full-term infants of normal birthweight. Among children who had been of low birthweight (LBW) or had been premature infants, greater declines were seen among those whose reported baseline medication category was "no medication" (3.2% decline) or "steroids" (2.7%) as opposed to beta agonists or xanthines (0.8%) or cromolyn without steroids (0. 1%). Among the children who had been normal birthweight and full-term infants, the cromolyn without steroids group had the greatest declines in %PEFR (1.3%, versus < 0.5% in each of the other three groups). Nonatopic children also had greater responses to ozone. We conclude that among an asthmatic cohort, children who had had an LBW or a premature birth showed the greatest responses to ozone.