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This report describes the clinical characteristics of a group of 59 individuals with the PI*SZ phenotype and alpha 1-antitrypsin (alpha 1-AT) deficiency, identified during recruitment of a registry for subjects with severe alpha 1-antitrypsin deficiency. Currently, 1,129 individuals with levels of alpha 1-AT of 11 microM or below have been enrolled in this registry. Individuals with the SZ phenotype whose alpha 1-AT levels are at or below 11 microM will be followed in the registry; those whose levels exceeded 11 microM had baseline studies and are included in this report. Baseline pulmonary function tests included spirometry before and after an inhaled bronchodilator, diffusing capacity for carbon monoxide (DLCO), and chest roentgenograms. Among nonsmokers, subjects with the SZ phenotype demonstrated airflow obstruction less frequently than those with with the ZZ phenotype. Among ex- and current smokers, the frequency and severity of airflow obstruction was similar between SZ and ZZ subjects. Individuals with the SZ phenotype reported respiratory symptoms less frequently than did ZZ subjects. Overall, airflow obstruction was less common and milder among PI*SZ than PI*ZZ subjects. Cigarette smoking correlated more strongly with airflow obstruction among PI*SZ than PI*ZZ subjects. These observations indicate that in smokers, the PI*SZ phenotype confers a significant risk of the development of chronic obstructive pulmonary disease (COPD). Of itself, except in rare instances in nonsmoking individuals, the PI*SZ phenotype may confer little or no added risk of developing COPD.

We examined the feasibility of a randomized clinical trial of intravenous augmentation therapy for individuals with alpha 1-antitrypsin (alpha1AT) deficiency, basing calculations on newly available data obtained from the NHLBI Registry of Patients with Severe Deficiency of Alpha 1-Antitrypsin. Using rate of FEV(1) decline as the primary outcome and adjusting for noncompliance, a study of subjects with Stage II chronic obstructive pulmonary disease (COPD) (initial FEV(1) 35 to 49% predicted) with biannual spirometry measures obtained over 4 yr of follow-up would require 147 subjects per treatment arm to detect a difference in FEV(1) decline of 23 ml/yr (i.e., a 28% reduction), the difference observed in the NHLBI Registry (1-sided test, alpha = 0.05, 90% power). To detect a 40% reduction in mortality in a 5-year study of subjects with baseline FEV(1) 35 to 49% predicted, recruited over the first 2 yr and then followed an additional 3 yr, 342 subjects per treatment arm would be needed. Though significant impediments to carrying out a clinical trial exist, including the cost of such a trial and the potential difficulties in recruiting patients for a placebo-controlled trial, we recommend a randomized controlled trial as the best method to evaluate the efficacy of intravenous augmentation therapy and of possible future treatments.

A high incidence of sudden, unexplained deaths in infants born to HIV-infected mothers has been noted in several epidemiologic studies. During the course of a prospective study of heart and lung disease in children born to HIV-infected mothers, we noted that of 5 unexpected non-HIV-related deaths, 4 were attributed to traumatic events.The Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2) study is a multicenter, prospective investigation of the incidence of heart and lung disease in HIV-infected children. A total of 805 children were enrolled and followed for 5 to 7 years with serial immunologic, pulmonary and cardiac function studies. During the study, a multidisciplinary committee was formed to review the cause of death for those patients who died. The committee used results of pulmonary, cardiac, and laboratory tests, hospital summaries, as well as autopsy and coroners' reports. The committee formed a consensus about the underlying and contributing causes of death for each subject using the definitions from the 1989 US Standard Certificate of Death.A total of 121 deaths occurred during the course of the P2C2 study. Of the 121 deaths, 5 were traumatic or sudden and unexpected and judged by the Mortality Review Committee to be unrelated to HIV infection. The median age at the time of death was 1.3 months and ranged from 1.2 to 37.8 months. Two infants died of trauma: a skull fracture and subdural hematoma in 1 infant and multiple skeletal fractures consistent with battered child syndrome in the other infant. The third infant died of accidental suffocation at home at 1.2 months of age. The fourth infant died suddenly and unexpectedly at home at 1.3 months of age. The autopsy showed no sign of HIV or other infection and was consistent with sudden unexpected death or SIDS. One non-HIV-related death occurred when a 38-month-old child died together with the mother in an unwitnessed drowning. The cumulative mortality rate attributable to trauma and sudden death at 4 months of age was 0.95% (95% CI: 0.02-1. 87%) and the infant mortality rate was 9.5/1000 live births. Three children were born prematurely at 30, 33, and 36 weeks' gestational age, respectively, and 3 mothers admitted using recreational drugs before or during pregnancy.These traumatic and sudden non-HIV-related deaths accounted for 4.1% (5/121) of the deaths during the entire P2C2 study period and for 20% (4/20) of the deaths in the first year of life. Four deaths were attributable to accidental and nonaccidental trauma rather than to other common causes of infant death. One death was a sudden unexpected death, similar to SIDS, a leading cause of infant death in the United States. The majority of previously reported non-HIV-related deaths in infants born to HIV-infected mothers have been attributed to SIDS or to unexplained sudden death. In contrast with other reports, 4 of the 5 children in our series died of accidental or nonaccidental trauma and only 1 was a sudden unexplained death. It is unlikely that HIV exposure is related directly to the deaths described in this report; however, maternal HIV infection may be a marker for factors that place the child at risk for sudden or traumatic death.This report suggests that children born to HIV-infected mothers may be at increased risk for traumatic or sudden, unexplained, non-HIV-related death. These children seem to be at risk regardless of their own HIV infection status. Furthermore, 4 of the deaths in our study occurred within the first few months of life, suggesting that this is a period of increased vulnerability. Studies to identify associated risk factors for non-HIV-related deaths are needed to identify these high-risk infants. Children born to HIV-infected mothers may be more vulnerable than was recognized previously and may be in need of increased social services, especially in early infancy.

The frequency of, course of, and factors associated with cardiovascular abnormalities in pediatric HIV are incompletely understood.A baseline echocardiogram (median age, 2.1 years) and 2 years of follow-up every 4 months were obtained as part of a prospective study on 196 vertically HIV-infected children. Age- or body surface area-adjusted z scores were calculated by use of data from normal control subjects. Although 88% had symptomatic HIV infection, only 2 had CHF at enrollment, with a 2-year cumulative incidence of 4.7% (95% CI, 1.5% to 7.9%). All mean cardiac measurements were abnormal at baseline (decreased left ventricular fractional shortening [LV FS] and contractility and increased heart rate and LV dimension, mass, and wall stresses). Most of the abnormal baseline cardiac measurements correlated with depressed CD4 cell count z scores and the presence of HIV encephalopathy. Heart rate and LV mass showed significantly progressive abnormalities, whereas FS and contractility tended to decline. No association was seen between longitudinal changes in FS and CD4 cell count z score. Children who developed encephalopathy during follow-up had depressed initial FS, and FS continued to decline during follow-up.Subclinical cardiac abnormalities in HIV-infected children are common, persistent, and often progressive. Dilated cardiomyopathy (depressed contractility and dilatation) and inappropriate LV hypertrophy (elevated LV mass in the setting of decreased height and weight) were noted. Depressed LV function correlated with immune dysfunction at baseline but not longitudinally, suggesting that the CD4 cell count may not be a useful surrogate marker of HIV-associated LV dysfunction. However, the development of encephalopathy may signal a decline in FS.

As part of the multicenter National Heart, Lung, and Blood Institute registry of patients with severe deficiency of alpha1-antitrypsin with 1,129 enrollees, this report describes measures undertaken to achieve high-quality FEV1 measurements, the rates of satisfying reproducibility and acceptability criteria, and clinical features of participants unable to achieve reproducible FEV1 values at baseline. Spirograms were performed both before and after an inhaled bronchodilator in enrollees followed up at 37 participating clinical centers. Using a reproducibility criterion of100 mL or 5% (whichever greater), high reproducibility rates for FEV1 measurements at baseline were observed for both prebronchodilator (95.0% of 1,090 sessions) and postbronchodilator measurements (95.7% of 1,077 sessions). Using the more recently published reproducibility criterion ofor = 200 mL, reproducibility rates were even higher. Eighty-four percent of clinical centers submitted FEV1 values that satisfied reproducibility criteria for at least 90% of spirograms. Also, the mean coefficient of variation for prebronchodilator FEV1 values measured over serial visits separated by up to 9 months was 5.6% for participants with baseline FEV1 55 to 90% predicted. This degree of reproducibility is similar to that observed in the Lung Health Study. Rates of satisfying acceptability criteria for prebronchodilator spirograms were lower, almost universally (98% of tests) due to failure to achieve end-of-test criteria (which usually required 15 s of expiration in this population with mean FEV1 = 42.6+/-29.6% [SD] predicted). Multivariate logistic regression models show that clinical correlates of failure to achieve reproducible prebronchodilator FEV1 efforts include symptoms of chronic wheeze, chronic cough, and chronic phlegm, and the degree of airflow obstruction. We conclude that highly reproducible FEV1 measurements are achievable in a population with severe airflow obstruction despite the additional challenges posed by testing in multiple centers on a variety of spirometers. Furthermore, the difficulty of satisfying end-of-test criteria in a large cohort with severe airflow obstruction did not preclude achieving high rates of reproducibility for FEV1 measurements. Finally, our study confirms prior observations that failure to achieve reproducible efforts is associated with the presence of pulmonary symptoms and the degree of airflow obstruction. Thus, excluding patients with nonreproducible FEV1 efforts from epidemiologic studies would bias results by including only healthier participants.

To directly assess the physiological roles of sarcoplasmic reticulum (SR) and mitochondria (MT), we have utilized energy dispersive electron probe microanalysis (EPMA) on ultrathin freeze-dried cryosections from isolated papillary muscles, rapidly frozen at precise time points of the contractile cycle. Using this approach, we can detect redistribution of subcellular Ca2+ during the cardiac contractile cycle. Changes in Ca2+ of less than 1.0 mmol/kg dry wt can be detected. By determining the variability of the Ca2+ measurements in preliminary experiments, we have also demonstrated that it is possible to optimize experimental design, i.e., to predict the number of animals per treatment group and the number of X-ray spectra per animal that are required in order to detect a specified Ca2+ difference. Quantitative EPMA of rapidly frozen contracting papillary muscle has also allowed us to correlate the Ca2+ content of SR and MT with the contractile state of the muscle. Our results show a decrease of 40% in the amount of Ca2+ stored in the junctional SR during a cardiac muscle twitch, thus providing direct evidence for a role of the SR as a primary site of Ca2+ release. In addition, we have demonstrated dissociation between MT Ca2+ uptake and activation of regulatory enzymes, such as pyruvate dehydrogenase, indicating that MT Ca2+ uptake is not required for activation of MT metabolism.

One of the principal targets of HIV infection is the human peripheral blood CD4+ T cell, resulting in progressive CD4+ lymphocyte loss. Hypothesized mechanisms for this loss include apoptosis, cytolytic reactions, V-beta gene deletion of the T-cell receptor (TCR) by superantigens, CD4+ lymphocyte syncytium formation, and autoimmune reactions. In adults with HIV infection, the critical decline in CD4+ lymphocyte number that heralds the onset of AIDS-defining conditions is well characterized, whereas in infants and children the critical level of CD4+ cells predisposing to the development of AIDS-defining conditions or mortality is not fully characterized, due to an incomplete knowledge of CD4+ lymphocyte number and changes with age in normal and HIV-infected children. In a prospective study of 317 infants born to HIV-infected women, early results show that the monthly change in absolute CD4+ lymphocyte number over a 3- to 9-month period in HIV-infected infants was -109 cells/mm3 per month, at least double the rate of decline measured in HIV-noninfected infants in the study or that calculated from normal infants' values reported in the literature. In other clinical studies in HIV-infected infants and children, it was possible to study the effect of low CD4+ cell counts on clinical status and mortality. In HIV-infected pediatric patients younger than 1 year, it was possible to correlate low CD4+ cell number with advanced disease status (CDC pediatric class P-2). It was also possible to correlate extremely low CD4+ cell counts (200 cells/mm3) in HIV-infected children with a significant risk of mortality within the next 3 months of life. Sequential CD4+ cell analysis of HIV-high-risk infants will delineate the rate of HIV-related decline in CD4+ cells, thus facilitating the diagnosis of HIV infection and aiding in identification of HIV-infected children at high risk of disease progression or death.

The Modification of Diet in Renal Disease Trial is a multicenter randomized clinical trial for men and women aged 18-70 years with chronic renal disease who are not on dialysis and who have not had a kidney transplant. Study participants are randomized in a 2 x 2 factorial design to diets containing different amounts of protein and phosphorus and to two levels of blood pressure control. The prescribed modifications differ depending on the level of a patient's kidney function. The primary outcome variable to compare diet or blood pressure groups is each patient's slope (or the change) in glomerular filtration rate with time. This paper describes the study design with particular emphasis on sample size determination. Special statistical analysis issues that arise with slope as the outcome are also discussed.

To evaluate the impact of race on the prevalence of systemic hypertension and its effects on left ventricular function, structure, and allograft survival after cardiac transplantation, 31 heart transplant recipients (7 blacks and 24 whites) were studied at 1 year after surgery. Echocardiographic and hemodynamic evaluation of the allografts was performed in addition to clinical follow-up and estimation of patients' survival. There was no difference in the demographic and clinical data between black and white patients. No differences between black and white cardiac transplant recipients were detected with regard to the prevalence of systemic hypertension, left ventricular hypertrophy, left ventricular function, renal function, or patients' survival. Moreover, racial mismatch did not predispose to allograft rejection. However, black patients had significantly higher resting systolic blood pressure and lower heart rates. We conclude that the race of heart recipients is not a detrimental factor in the early outcome after cardiac transplantation. The long-term cardiovascular consequences of these findings should be explored.

A primary outcome variable in longitudinal studies is often the rate of change of a continuous measurement over time. Examples include the one-second forced expiratory volume (FEV1) in pulmonary studies or glomerular filtration rate (GFR) in renal studies. An individual patient's least-squares estimate of slope obtained from a linear regression is an imprecise measure of the true slope for that patient, and correlations involving the estimated slopes will be biased due to this measurement error. This paper presents methods for estimating the true correlation between these imprecise slope estimates, or between slope estimates and other variables measured with error. In addition to providing a simple consistent estimator of the correlation, we show how the maximum likelihood estimate of the correlation coefficient and a 100(1 - alpha) per cent confidence interval can be obtained. An example estimating the correlation between GFR and inverse serum creatinine slopes in patients with chronic renal disease is given.

This is the final report of a study of single dose pharmacokinetic parameters of nortriptyline in children and adolescents 5 to 16 years old (N = 64). The data were analyzed separately for the 5- to 12-year-olds (N = 41) and for the 13- to 16-year-olds (N = 32). The results confirm the preliminary findings of the similarity of the pharmacology of nortriptyline between the pediatric and adult age groups with respect to a logarithmically linear rate of elimination and a wide interindividual rate of metabolism. The 5- to 12-year-olds had a significantly shorter mean half-life and a significantly greater mean apparent oral clearance than the 13- to 16-year-olds. The mean half-life in the 5- to 12-year-olds was 20.8 +/- 7.2 (range, 11.2 to 42.5) hours and in the 13- to 16-year-olds was 31.1 +/- 19.8 (range, 14.2 to 89.4) hours. A twice a day dosage regimen is recommended for the entire 5- to 16-year-old group based on their range of half-lives.

The resident population of the western portion of a South Carolina county has undergone a public health information and education intervention since October 1982. The purpose of the intervention has been to reduce the occurrence of unintended pregnancies among unmarried adolescents. Intervention messages are targeted at parents, teachers, ministers and representatives of churches, community leaders, and children enrolled in the public school system. The messages emphasize development of decision-making and communication skills, self-esteem enhancement, and understanding human reproductive anatomy, physiology, and contraception. The estimated rate of pregnancy ([live births plus fetal deaths plus induced abortions] per 1000 female population) for females aged 14 to 17 years in the county's western portion has declined remarkably since the intervention began, and the changes are statistically significant when compared with three sociodemographically similar counties and also with the eastern portion of the county.