Biomedical subjects
Publications and source records attributed to R Fallat.
This report describes a proposed solution to the problem of high-flow bronchopleural fistulae in the adult respiratory distress syndrome. Animal studies and clinical application demonstrate the efficacy of this treatment.
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A pedigree of complex structure, comprising 195 individuals, is shown to be segregating for an autosomal dominant gene for hypercholesterolemia. The same pedigree shows two groups of individuals with respect to plasma triglyceride levels; the cause of this appears to be independent of the locus demonstrated, which accounts for over 50% of the variability in cholesterol levels in the kindred studied. The power of bivariate analyses of multigenerational data, as used in this study, is discussed. The lipid disorders in this family, however, differ from the usual familial hypercholesterolemia described by Harlan et al. (1966) in that there is a group of individuals who have elevated triglycerides, there is a substantial amount of premature cardiovascular disease, and not very many individuals have tendonous xanthomas. It is of course possible that in this family the genetic entity is a variant of the usual hypercholesterolemia mutant; or it may be the usual mutant, acting in concert with some other unknown factor. The cause of the two groups with respect to triglycerides is not clear; but, whether it is genetic or environmental, it is independent of the segregation for hypercholesterolemia.
We examined elderly heterozygotes for alpha-antitrypsin deficiency (phenotype MZ) to determine which of several factors might be associated with the development of chronic obstructive pulmonary disease (COPD). Elderly heterozygotes who smoked had a very high incidence of COPD (70 per cent), whereas homozygotes (phenotype MM) who smoked had a significantly lower incidence of COPD (35 per cent). There was no difference in the incidence of COPD between subjects with MM and MZ phenotypes who did not smoke. To determine if leukocyte enzymes were related to the development of COPD in elderly heterozygotes, we measured the activities of monocytic acid cathepsin, neutrophil acid cathepsin, neutral cathepsin, and elastase. The activities of these enzymes were not associated with the development of COPD or with smoking history in the heterozygotes. In conclusion, cigarette smoking seemed to be a significant determinant of the development of COPD in heterozygotes for alpha-antitrypsin deficiency, but the leukocyte enzyme actitivty that we studied was unrelated.
Univariate and bivariate analyses of cholesterol and triglycerides are performed after appropriate age adjustment on 247 individuals in 33 families where the probands have elevations of cholesterol, low density lipoprotein and triglycerides, and type IIb lipoprotein phenotype. Mixture of lognormal distributions are fitted by maximum likelihood to the data. Best fitting single and mixtures of lognormal distributions are compared with empirical cumulative plots, and the likelihood-ratio criterion is used to test for significance. A mixture of two lognormal distributions fits significantly better than one lognormal distribution for cholesterol but not for triglycerides. When a mixture of bivariate lognormals is fitted to the data, only one local maximum is found, suggesting action of a single genetic determinant in this sample. The best cutoff line is almost parallel to the triglyceride axis, indicating the relatively high involvement of cholesterol compared to triglycerides in separating the normal and abnormal groups. Using the best linear function, the difference in the two bivariate means is found to account for 61% of the total variation in log cholesterol and log triglycerides. To determine if the results are due to enrichment of the sample with familial hypercholesterolemia syndrome, seven families where the proband and/or any relative has tendon xanthomas are removed and the analyses repeated on the remaining 26 kindreds. The results of these analyses are virtually the same as those of the total sample. Also, a subsample of 21 families in which the proband and at least one additional kindred member are affected is analyzed in the same manner with similar results. For comparison, data from a study of families with combined hyperlipidemia [1] are analyzed in an analogous manner, bearing in mind that the populations sampled are probably different. Fitting a mixture of two bivariate distributions and finding the best cutoff to these data indicate that triglycerides are more involved in separating the two groups. Probably because of major differences in ascertainment, the distribution of lipid levels in oour patient group is practically indistinguishable from that of hypercholesterolemia, and the Seattle data [1] are more nearly similar to hypertriglyceridemia. It may be premature to consider familial combined hyperlipidemia as an entity distinct from both hypercholesterolemia and hypertriglyceridemia. We hope it will eventually be possible to analyze these data using a refined genetic model that includes both major gene and polygenic effects and to combine this form of analysis with quantitative tissue culture methods.
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The phenotypes of serum alpha(1)-antitrypsin were determined by antigenantibody crossed electrophoresis. There were five homozygotes and 25 heterozygotes for the deficiency gene found in a group of 103 patients with obstructive lung disease. The frequency of heterozygotes was 14 and 9 percent in two control groups with different mean ages of 36 and 80. There was only one heterozygote among 39 healthy males over 70 years of age. Heterozygosity may be a predisposing factor in chronic obstructive lung disease, especially in the male population.
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