Variance components analysis of forced expiration in families.

Familial aggregation of forced expiration (as measured by forced expiratory volume in 1 sec (FEV1) and the ratio of this to total forced vital capacity (FEV1/FVC) was analyzed in 439 adult members of 108 families ascertained through control patients who had participated in a genetic and epidemiologic study of chronic obstructive pulmonary disease. Residual values for both FEV1 and FEV1/FVC obtained from regression on age, sex, race, and cigarette smoking (and height for FEV1) were used in a variance components analysis to assess the relative importance of genetic and nongenetic factors influencing familial aggregation of pulmonary function among adults. For both residual FEV1 and residual FEV1/FVC, the "best" model among a series of genetic and nongenetic models was a simple additive genetic model. A modified score test, which is robust to the assumption of multivariate normality, was used to test the significance of these estimated components. Under the most parsimonious model, additive genetic variation accounted for 28% of the variation in residual FEV1 in 108 families and 24% of the variation in residual FEV1/FVC. After outlying individuals were identified by examining goodness-of-fit statistics, the simple genetic model still gave the best fit to these data. There was little indication of non-normality in FEV1 in these families; however, FEV1/FVC did show evidence of non-normality when examining goodness-of-fit statistics. This genetic component contributing to the distribution of forced expiration may be a factor in the familial aggregation of certain respiratory diseases.

Familial risks of congenital heart defect assessed in a population-based epidemiologic study.

Congenital heart defects (CHD) represent a heterogeneous group of disorders caused by chromosome abnormalities, mendelian disorders, teratogenic exposures, and unknown etiologic mechanisms. A large group of various isolated defects is presumably multifactorial in origin. Previous studies of familial risks for specific anatomic defects obtained from clinical series may include significant biases and obscured pathogenic relationships. In this population-based study we analyzed all cases of CHD in infants and a control birth cohort in the Baltimore-Washington area. The rates of CHD were defined for first-degree relatives of cases with isolated defects, grouped by a pathogenic classification scheme. Precurrence risks were found to vary among the groups, and risks for flow lesions were higher than previously reported. The sibling precurrence risk for hypoplastic left heart syndrome (13.5%) was not significantly different from that expected for an autosomal recessive mechanism; the risks for different types of ventricular septal defects (VSD) varied among mechanistic groups. The results indicate that the additive multifactorial model does not adequately account for the risks in all forms of isolated CHD of unknown etiology.

The effect of low-level 60-Hz electromagnetic fields on human lymphoid cells. II. Sister-chromatid exchanges in peripheral lymphocytes and lymphoblastoid cell lines.

Dividing human peripheral lymphocytes from 10 normal adults (5 males and 5 females) as well as lymphoid cell lines from patients with the chromosomal instability syndromes were exposed to low-level 60-Hz sinusoidal electromagnetic fields (EMF). The current density of the electrical field was 30 microA/cm2 while the strength of the magnetic field was either 1 or 2 gauss. The cytological endpoints measured included the frequency of sister-chromatid exchanges per chromosome; the distribution of first-, second-, and third-division cells and chromosome breakage (lymphoblastoid cells only). No statistically significant differences, indicative of EMF effects were observed between the treated and control cells regarding SCE frequency, cell cycle progression or chromosome breakage.

Repeated measurement of spontaneous and clastogen-induced sister-chromatid exchange.

Sister-chromatid exchanges (SCE), both spontaneous and chemically-induced [bleomycin (BLM), mitomycin-C (MMC), streptonigrin (SN), and 4-nitroquinoline-1-oxide (4NQO)], were studied in the lymphocytes of 24 normal individuals on 2 or 3 different occasions, separated by periods of up to 2 years. For all BLM-induced SCEs, the variation in SCE frequency among the samples from a single individual was significantly greater than the variation between replicate cultures on a given day. These results raise questions concerning the validity of conclusions based on a single observation of chemically-induced SCEs.

Clinical and laboratory characterization of early onset periodontitis.

Clinical and laboratory data were compared in 72 patients with localized periodontitis (LP) and 103 patients with generalized periodontitis (GP). Significantly more LP than GP cases had decreased neutrophil chemotaxis (CTX), and were seropositive for Actinobacillus actinomycetemcomitans (Aa). Significantly, more GP cases were seropositive for Bacteroides gingivalis (Bg). All clinical indices were similar on affected teeth in LP and GP, but the attachment loss was greater on clinically unaffected teeth in GP when compared with LP. LP cases with CTX defects had a significantly lower mean age, were more often seropositive for Aa antibodies, and were more often female than LP patients with normal CTX. Significantly more GP cases with CTX defects were seropositive for Aa antibody. GP patients with normal CTX had a higher plaque index on both affected and unaffected teeth than did GP patients with a CTX defect. Our data suggest that chemotaxis and/or specific bacteria may be contributory, but not always necessary, factors in these disorders. The overlap in clinical and laboratory profiles of LP and GP continues to cloud the distinction of these early onset forms of periodontitis.

Phenotypic assessment of early onset periodontitis in sibships.

Early onset periodontitis is a group of familial diseases that are not yet clearly defined by etiologic mechanisms, although some risk factors have been recognized. The disorders include a localized form of juvenile periodontitis (JP), and a more generalized form (GP). In a family study, 39 sibships (116 individuals, aged 13-48) were evaluated for clinical indices, neutrophil chemotaxis, and serum antibodies to A. actinomycetemcomitans (Aa). Of 77 siblings, 41 were healthy at examination. In 14 sibships, all affected persons had JP; 14 other sibships had all affected individuals with GP; and 11 had at least one sib with each form. For probands with decreased chemotaxis, 71% of affected sibs and 36% of clinically healthy sibs had decreased chemotaxis. For Aa seropositive probands, 83% of affected siblings and 65% of currently healthy sibs were also seropositive. The associations of disease with these risk factors were stronger in JP-only sibships. Some affected sibs had neither risk factor, while many currently healthy sibs had 1 or both. While these 2 factors demonstrate population association with disease, neither fits the pattern expected within families to clearly suggest a causal mechanism. The assessment of within and among family variability remains the best approach for recognition of possible causal mechanisms and sources of heterogeneity.

Cytogenetic effects of phenytoin and/or carbamazepine on human peripheral leukocytes.

The cytogenetic effects of phenytoin (PHT) and/or carbamazepine (CBZ) were studied to determine clastogenic potential. Comparative analysis of chromosome breakage and sister chromatid exchange (SCE) was performed between 18 patients with epilepsy receiving PHT and/or CBZ and 10 healthy nontreated controls. These studies failed to detect a significant increase in chromosome aberrations or SCEs in groups of treated individuals as compared with controls. No correlation was observed between the rate of either chromosome damage or SCEs and age, sex, drug blood level, or daily dose. The results indicate no detectable chromosome damaging effects of PHT alone, CBZ alone, or a combination of these two antiepileptic drugs (AEDs).

Genetic analysis of juvenile periodontitis in families ascertained through an affected proband.

Data from 28 families ascertained through a proband with juvenile periodontitis were used to test a series of Mendelian models of inheritance that included both autosomal and X-linked transmission. There was strong evidence of familial aggregation of this progressive dental disease, and the best-fitting model was an autosomal recessive model. Because of the rather limited age range for expression of the disease in this situation, simulations were done, in a model-choice analysis using samples of this size, to assess the chance of mistaking an autosomal dominant disease (with masking of the affected phenotype outside a specified age range) for an autosomal recessive disease. While the rate of Type II error was fairly high (40%) when competing models in these simulations were compared, these data suggest that it is reasonable to infer that juvenile periodontitis is an autosomal recessive disorder.

Effect of low-level, 60-Hz electromagnetic fields on human lymphoid cells: I. Mitotic rate and chromosome breakage in human peripheral lymphocytes.

Dividing human peripheral lymphocytes from 10 normal adults (5 males and 5 females) were exposed in vitro to low level 60-Hz electromagnetic fields for 69 hours. The current density of the electrical field was 30 microA/cm2, while the magnetic field was either 1 or 2 gauss. The cytological endpoints measured were mitotic rate and chromosome breakage. No statistically significant differences, indicative of a field effect, were observed between treated and control cells whether exposed to an electric field, a magnetic field, or to various combinations of the two.

Prenatal detection of cardiovascular malformations by echocardiography: an indication for cytogenetic evaluation.

Prenatal diagnosis of congenital cardiovascular malformations by echocardiography may signal associated chromosome abnormalities. The exact proportion of these associations is not known but is expected to be higher than that with live-birth. To estimate the risk that a fetus with an echocardiographically detected heart defect has an autosomal trisomy or Turner syndrome, we adjusted the known frequency of aneuploidy in live-born infants with congenital cardiovascular malformations by the reported rate of spontaneous abortion, with data from a population-based case-control study of congenital cardiovascular malformations in which 268 cases (12.7%) had both congenital cardiovascular malformations and a chromosome abnormality. Included in the present analysis were 188 aneuploid infants with congenital cardiovascular malformations that would have been detectable by fetal echo. When data are adjusted for the high spontaneous abortion rate of aneuploid fetuses, we estimate that there would have been more than a threefold increase in aneuploidy over the 13% seen at live-birth. Thus cytogenetic analysis is appropriate in a fetus with echo-diagnosed congenital cardiovascular malformations.

Congenital cardiovascular malformations in twins and triplets from a population-based study.

Data from the Baltimore-Washington Infant Study of congenital cardiovascular malformations permitted detailed analysis of congenital cardiovascular malformations in 62 twins and 3 triplets and 2303 singleton cases. A probability sample of controls (n = 2793) included 43 twins. The case prevalence of multiple births was 28 of 1000, compared with a 15 of 1000 prevalence among controls (chi 2 = 5.7). There were more girls among case twins than among case singletons and controls (chi 2 = 9.0). Monozygosity was no more frequent in case twins than in controls. Looping defects occurred in 4 monozygotic twin pairs compared with only 1 dizygotic twin pair. The twinning process itself may be implicated in the development of congenital cardiovascular malformations in some of these infants, especially those with looping defects, but concordance of types of defects in 4 of 65 pairs implicates genetic factors in the determination of some forms of congenital cardiovascular malformations.

Multicenter evaluation of hepatitis C RNA levels among female injection drug users.

The purpose of this investigation was to identify factors that determine the blood level of hepatitis C virus (HCV) RNA. By use of a quantitative polymerase chain reaction assay, the level of HCV RNA was ascertained in stored serum samples from 676 women enrolled in a multicenter prospective investigation who were seropositive for anti-HCV antibodies. HCV RNA levels ranged from undetectable to 22.4x106 copies/mL in these women. Among the 520 women with detectable HCV RNA, levels were higher among those who were >41 years old and those who had human immunodeficiency virus (HIV) infection. After adjusting for age in a multivariate linear regression model, HCV RNA levels were more strongly associated with HIV RNA levels than with CD4(+) lymphocyte counts. However, <6% of person-to-person variance was explained by the factors evaluated. Additional research is needed to ascertain what determines the level of HCV RNA in blood.

The effect of latent Mycobacterium tuberculosis infection on human immunodeficiency virus (HIV) disease progression and HIV RNA load among injecting drug users.

To examine the relationship between latent Mycobacterium tuberculosis infection and human immunodeficiency virus (HIV) disease progression, two studies were done among a cohort of HIV-infected injecting drug users. First, the decline in CD4 cell count after baseline tuberculin skin testing was prospectively compared for 37 tuberculin-positive (induration > or = 5 mm) and 284 tuberculin-negative (induration < or = 2 mm) persons. After adjustment for baseline immune function, the mean 6-month CD4 cell decline was not significantly different (34.5 vs. 45.6 cells, respectively, P = .14). Second, the plasma HIV burden at baseline skin testing was compared for 33 tuberculin-positive cases and 33 matched tuberculin-negative controls. HIV RNA was detected in 8 cases and 10 controls (odds ratio = 0.67, 95% confidence interval = 0.19-2.36). Among the 14 pairs with HIV detected in > or = 1 member, the HIV concentration was higher for the case in 4 and for the control in 10 (P = .18). These findings suggest that unlike active tuberculosis, latent M. tuberculosis infection does not hasten HIV progression.

Persistence and clinical significance of hepatitis G virus infections in injecting drug users.

To assess the persistence of hepatitis G virus (HGV) infection and its association with liver disease, HGV RNA was assessed in the most recent serum sample for 246 long-term injecting drug users (IDUs) and in prior specimens for those found HGV RNA-positive. HGV RNA was detected at the most recent visit in 38 (15.4%). For 31 (82%), HGV RNA was also found at all prior visits occurring a median of 6.1 years earlier. HGV-positive IDUs were younger and had fewer years of drug use, suggesting that HGV RNA had previously been cleared. Serial samples from 29 short-term IDUs were then assessed. HGV RNA was detected in 9 (31%) of 29 short-term IDUs, and 5 (56%) of the 9 HGV infections cleared. No differences were detected in serum levels of liver-related enzymes among HGV RNA-positive and -negative participants (P > .20). HGV infection is not associated with hepatic inflammation. HGV clearance occurs after many acute infections but uncommonly in persons who remain RNA-positive years after exposure.