Decreased macular leukocyte velocity in human immunodeficiency virus-infected individuals.

PURPOSE: To determine whether human immunodeficiency virus (HIV)-infected individuals have decreased macular capillary blood flow in vivo. DESIGN: Case control study. METHODS: Macular leukocyte velocity and perceived leukocyte density were determined in 41 HIV-infected individuals without cytomegalovirus retinitis and 31 HIV-negative control subjects using the blue field simulation technique (BFS-2000, Oculix, Inc., Jenkintown, PA). Velocity and density measurements for HIV-infected individuals were compared to current and lowest previous CD4+ T-lymphocyte counts, HIV RNA blood levels, and blood leukocyte counts. RESULTS: Mean macular leukocyte velocity was lower in HIV-infected individuals than in controls (P = 0.0006). No correlations were identified between velocity measurements and the following factors in HIV-infected individuals: current or lowest previous CD4+ T-lymphocyte count; or HIV RNA blood level. Mean perceived leukocyte density in HIV-infected individuals was lower than in controls (P = 0.003), but was not correlated with blood leukocyte count in HIV-infected individuals. No relationships were identified between macular leukocyte velocity and duration of medication use or duration of elevated CD4+ T-lymphocyte count in patients receiving potent antiretroviral therapy. CONCLUSIONS: Reduced macular leukocyte velocity may have important implications for understanding the retinal microvasculopathy of HIV disease, the pathogenesis of opportunistic retinal infections, and visual dysfunction in HIV-infected individuals who do not have opportunistic retinal infections. We found no evidence that macular leukocyte velocity increased with immune reconstitution.

Sample size determination for equivalence test using rate ratio of sensitivity and specificity in paired sample data.

Before implementing a new diagnostic test, we may wish to study whether this test is noninferior to a reference test with respect to the sensitivity and/or the specificity. This paper discusses sample size determination for one-sided equivalence (or noninferiority) testing of the rate ratio using paired-sample data. Using large sample theory, this paper derives asymptotic sample size formulae for the required number of subjects giving a desired power 100(1 - beta)% at a specified alpha-level. To evaluate the accuracy of these formulae, this paper considers several test statistics and uses Monte Carlo simulation to estimate the corresponding type I error and power with the given resulting sample sizes in a variety of situations. Finally, this paper notes those situations for which the asymptotic sample size formulae developed here are of limited use and suggests a simple empirical adjustment to alleviate this limitation.

Increased polymorphonuclear leucocyte rigidity in HIV infected individuals.

AIM: Individuals with human immunodeficiency virus (HIV) infection were evaluated for evidence of abnormal polymorphonuclear leucocyte (PMN) rigidity, which can alter capillary blood flow. METHODS: The transit time of individual PMN through 8 microm pores in a cell transit analyser was used as a measure of cell rigidity. PMN transit time was compared between HIV infected individuals (n=45) with and without CMV retinitis and HIV negative controls (n=17). RESULTS: Transit times were longer for PMN from HIV infected individuals than for PMN from controls (p<0.001). PMN from HIV infected individuals with CMV retinitis (n=13) had longer transit times than PMN from those without CMV retinitis (n=32, p<0.001). Transit times were longer in HIV infected individuals with lower CD4+ T lymphocyte counts (p<0.001). Regression analysis indicated that the relation between transit times and the presence of CMV retinitis could not be explained solely on the basis of low CD4+ T lymphocytes. In HIV infected individuals, mean transit time was not correlated with age, blood pressure, or serum creatinine, cholesterol, or triglycerides. CONCLUSIONS: HIV infected individuals appear to have increased PMN rigidity, a cellular change that might be involved in the pathogenesis of HIV related retinal microvasculopathy. PMN rigidity appears to be related to severity of immune dysfunction. PMN rigidity may remain high in patients with CMV retinitis after elevations of CD4+ T lymphocyte counts that result from potent antiretroviral therapy.

CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency.

The CD8+ T-cell response is central to control and eventual elimination of persistent viral infections. Although it might be expected that CD8+ T-cell activation would be associated with a better clinical outcome during viral infections, in long-term HIV-1 infection, high levels of CD8+ T-cell activation are instead associated with faster disease progression. In this study, cell surface expression of CD38, a flow cytometric marker of T-cell activation of CD8+ T cells, had predictive value for HIV-1 disease progression that was in part independent of the predictive value of plasma viral burden and CD4+ T-cell number. Measurements of CD38 antigen expression on CD8+ T cells in HIV-1-infected patients may be of value for assessing prognosis and the impact of therapeutic interventions. The pathogenetic reason why CD8+ T-cell activation is associated with poor outcome in HIV-1 disease remains unknown. Possibly CD8+ T-cell activation contributes to immunologic exhaustion, hyporesponsiveness of T cells to their cognate antigens, or perturbations in the T-cell receptor repertoire.

Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression.

The prognostic value of several immunologic markers were compared in Los Angeles Multicenter AIDS Cohort Study (MACS) participants, most of whom had been infected with HIV for >8 years. Markers studied included CD4+ cell number, flow cytometric measurements of CD8+ cell expression of CD38 and HLA-DR antigens, and serum markers of immune activation including neopterin, beta2-microglobulin, soluble interleukin-2 receptor, soluble CD8, and soluble tumor necrosis factor receptor-alpha (TNF-alpha) type II. Cox proportional hazards models indicated that elevated CD38 on CD8, a flow cytometric measurement of CD8+ T-lymphocyte activation, was the most predictive marker of those studied for development of a clinical AIDS diagnosis and death. As compared with the reference group, who had CD38 on CD8 <2470 molecules per CD8+ cell and in whom 4 of 99 developed clinical AIDS within 3 years, participants with CD38 on CD8 between 2470 and 3899, 3900 and 7250, and >7250 had relative risks (and numbers developing AIDS within 3 years) of 5.0 (15 of 81), 12.3 (24 of 60), and 41.4 (36 of 49), respectively. The strong prognostic value of CD38 on CD8 measurements and the fundamental importance of chronic immune activation in the pathogenesis of HIV disease suggests that this marker might have utility in the clinical management of HIV-infected persons.

A stochastic model for the analysis of bivariate longitudinal AIDS data.

We present a model for multivariate repeated measures that incorporates random effects, correlated stochastic processes, and measurement errors. The model is a multivariate generalization of the model for univariate longitudinal data given by Taylor, Cumberland, and Sy (1994, Journal of the American Statistical Association 89, 727-736). The stochastic process used in this paper is the multivariate integrated Ornstein-Uhlenbeck (OU) process, which includes Brownian motion and a random effects model as special limiting cases. This process is an underlying continuous-time autoregressive order [AR(1)] process for the derivatives of the multivariate observations. The model allows unequally spaced observations and missing values for some of the variables. We analyze CD4 T-cell and beta-2-microglobulin measurements of the seroconverters at multiple time points from the Los Angeles section of the Multicenter AIDS Cohort Study. The model allows us to investigate the relationship between CD4 and beta-2-microglobulin through the correlations between their random effects and their serial correlation. The data suggest that CD4 and beta-2-microglobulin follow a bivariate Brownian motion process. The fit of the model implies that an increase in beta-2-microglobulin is associated with a decrease in future CD4 but not vice versa, agreeing with immunologic postulates about the relationship between these two variables.

Elevated relative fluorescence intensity of CD38 antigen expression on CD8+ T cells is a marker of poor prognosis in HIV infection: results of 6 years of follow-up.

Relative fluorescence intensity measurements from a flow cytometer were used to evaluate expression of CD38 and HLA-DR antigens. These molecules are associated with cellular activation and are present at increased levels on the CD8+ lymphocytes of HIV-infected subjects. In the current study, the prognostic value of mean fluorescence intensity measurements of CD38 and HLA-DR on CD8+ cells was compared to results from our previous study in which we reported prognostic value for an elevated percentage of CD8+ cells that were positive for expression of the CD38 antigen (Giorgi et al.: JAIDS 6:904-912, 1993). Using the proportional hazards model, elevated mean fluorescence intensity of CD38 expression on CD8+ cells had prognostic value for development of AIDS that was almost identical to the prognostic value of the percentage of CD8+ cells that were positive for expression of CD38. This prognostic value was in addition to that provided by the patient's CD4+ cell measurement. To our knowledge, this is the first report that a measurement of fluorescence intensity can be used as a prognostic marker in an immunodeficiency disease. Efforts are needed to establish methods that will allow widespread application of this observation in the clinical management of HIV-infected subjects.

Normal range estimation for repeated immunologic measures.

A method for estimating a normal range from a set of immunologic measurements on control subjects when there may be more than one observation per subject is described. The method is nonparametric, makes efficient use of all observations, and is very simple to apply. It is illustrated on a set of 152 CD38 measurements from 58 healthy men.

Elevated serum levels of soluble CD23 (sCD23) precede the appearance ofacquired immunodeficiency syndrome--associated non-Hodgkin's lymphoma.

Human immunodeficiency virus (HIV) infection-associated B-cell hyperstimulation, in particular, the chronic stimulation of B cells to undergo isotype switching, may play an important role in the pathogenesis of acquired immunodeficiency syndrome-associated lymphoma (AIDS lymphoma). Isotype switching can be induced by various immune system factors, including cytokines, cell-surface stimulatory molecule interactions, and CD23. CD23 is a B-cell differentiation and activation marker expressed on mature B cells that is lost after isotype switching; soluble CD23 (sCD23) also is a B-cell-stimulatory factor. Because sCD23 is associated with Ig isotype switching, and because an enhancement of isotype switching may contribute to the genesis of AIDS lymphoma, we examined serum sCD23 levels in a retrospective study of HIV-seropositive subjects who had gone on to develop lymphomas. Subjects were participants in the Multicenter AIDS Cohort Study at UCLA, a study of the natural history of AIDS. Greatly elevated sCD23 serum levels were seen in subjects who developed AIDS lymphoma, when compared with others with AIDS (without lymphoma), or to HIV-seronegative or HIV-seropositive subjects who did not have AIDS. Because the induction of IgE has been tied to the activity of CD23, serum IgE levels were also examined in this study, and found to be significantly elevated in those who developed AIDS lymphoma. These findings suggests that serum sCD23 levels potentially may serve as a clinical tool for early detection of lymphomas in people who have HIV infection. Also, these observations provide clues on possible pathogenetic mechanisms that result in lymphomagenesis in the context of HIV infection and AIDS.

Zidovudine and dideoxycytidine differ in their effects on human immunodeficiency virus-induced pathologic activation of the immune system. AIDS Clinical Trial Research Group 047.

When zidovudine and dideoxycytidine (ddC) were given on schedules of 1 week on drug and 1 week off, results differed substantially in effects on HIV (human immunodeficiency virus type 1)-induced immune activation. Zidovudine (200 mg every 4 h) caused marked lowering toward normal of serum neopterin and beta 2-microglobulin within 1 week. This effect was lost within 1 week off zidovudine. Intermittent ddC (0.03 mg/kg every 4 h) had a smaller 1-week effect but had a delayed cumulative suppressive effect on HIV-associated immune activation that was not seen with intermittent zidovudine therapy. Zidovudine and ddC given in alternating weeks had synergistic effects in the first 10 weeks (e.g., early and rapid reduction followed by cumulatively greater effects on immune cell activation). The identical sawtooth effect of intermittent zidovudine was also evident in serum HIV p24 antigen levels. This is consistent with the hypothesis that the increased serum levels of the immune activation markers seen in HIV infection reflect stimulatory effects of HIV viral components on immune system cells.

Immunization status of children of employees in a large corporation.

OBJECTIVE: To assess immunization levels for children of employees of a large corporation. DESIGN: A mail survey of a random sample of employees on the immunization history of one child per family. SETTING: US employees of Johnson & Johnson. PARTICIPANTS: 1500 employees with children born between 1984 and 1991. MAIN OUTCOME MEASURES: Coverage rates for recommended vaccines at different ages up to 6 years. MAIN RESULTS: Only 45.2% and 55.3% of the study children at ages 2 and 6 years were current for all recommended immunizations (65.1% and 70.3%, respectively, excluding the Haemophilus influenzae type b vaccine). Using the minimum standard required by many states for school entry, the coverage level at age 6 years was 90.4%. Factors associated with higher immunization rates at age 2 years were the corporate health plan (choices), higher pay level, greater parental formal education, white race, and knowing when to initiate immunization. Lower immunization rates at age 2 years were associated with delayed receipt of the first dose of diphtheria, tetanus, and pertussis vaccine, use of city or county clinics, employee-reported barriers of difficulty leaving work, and provider access problems, but not cost of services. After adjusting for the effects of other variables through logistic regression, race, pay level, and plan choice were no longer significant. Modeling with the remaining variables predicted rates of adequate immunization at age 2 years from 15% to 81%. CONCLUSION: Even in this relatively affluent group with good insurance (including immunizations), preschool immunization rates did not reach public health goals. Changing modifiable factors, such as knowing when to initiate immunization, enabling parents to leave work more easily, and improving provider access, might improve preschool immunization rates.

Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study.

A cohort of 98 HIV-infected initially AIDS-free homosexual men from the Multicenter AIDS Cohort Study (MACS) was followed for 6 years to investigate whether CD8+ cell subsets have prognostic value for progression to AIDS. In the present study, four subsets of CD8+ T cells that previously have been shown to be selectively elevated in HIV-infected asymptomatic persons, specifically the CD8+ T cell subsets that were CD38+, HLA-DR+, CD57+ and L-selectin negative (Leu8-), were measured. Forty-nine of the 98 developed AIDS. Prognostic value of these CD8+ cell subsets was evaluated using the proportional hazards model. Levels of both CD38+ CD8+ and Leu8- CD8+ cells individually had prognostic value for progression to AIDS. In contrast, CD57+ CD8+ and HLA-DR+ CD8+ cell subsets levels did not have prognostic value. After adjustment for level of CD4+ T cells, however, only the elevation in the CD38+ CD8+ cell subset had additional prognostic value. These results suggest that the level of CD38+ CD8+ cells could be used together with the CD4+ T cell level to more accurately predict progression to AIDS among HIV-infected men. These results provide further support for the observation that dramatic and progressive activation of CD8+ T cells in HIV infection occurs. The power of elevated levels of the CD38+ CD8+ subset to predict poor prognosis in this cohort suggests these CD8+ T cells reflect an immune stimulation that is ultimately unable to control disease progression.

Sample size requirement for repeated measurements in continuous data.

In this paper we extend Bloch's discussion on the usefulness and the limitations in the application of repeated measurements per subject in study designs. We derive general sample size formulae for any finite number of comparison groups to calculate the required number of subjects with repeated measurements, that do not have to be conditionally independent. For fixed total cost, we discuss the optimal sample allocation for repeated measurements needed to maximize the power and the underestimation when using Bloch's sample size formula if in the hypothesis testing procedure the variance parameters are unknown. We have also included a quantitative investigation of the effectiveness of taking repeated measurements per subjects to reduced the required number of subjects for a given power at a given alpha-level.

13-cis retinoic acid enhances in vivo B-lymphocyte differentiation in patients with common variable immunodeficiency.

Retinoic acid (RA) has been demonstrated to drive both phenotypic and functional in vitro differentiation of B cell hybridomas from patients with common variable immunodeficiency (CVI) who manifest an "intrinsic" defect in terminal B cell differentiation (J Exp Med 1988;168: 55-71). Therefore, we conducted an open trial to determine the effects of oral 13-cis RA (0.5 mg/kg/day; 12 weeks receiving and 12 weeks without drug) on in vivo B cell differentiation in subjects with CVI. At various times before, during, and after drug administration, patients' B cells were tested for changes in cell-surface phenotype and in vitro immunoglobulin production in response to recombinant cytokines. Before 13-cis RA, all patients had decreased Leu-8 coexpression on CD20+ cells. Seven of eight subjects demonstrated "normalization" of this phenotype after 8 to 16 weeks of 13-cis RA administration. Patients whose B cells demonstrated more than normal CD20 display also had a fall toward normal in this parameter. These effects persisted for 6 to 12 weeks after drug was stopped. It appears that 13-cis RA drives B cells of patients with CVI to express a more differentiated cell-surface phenotype and may promote functional differentiation in some patients.

Serum beta 2-microglobulin level increases in HIV infection: relation to seroconversion, CD4 T-cell fall and prognosis.

Beta 2-microglobulin (beta 2-M), a marker that is increased in serum during immune activation, was investigated during the course of HIV infection. beta 2-M rose promptly in the first phase of HIV infection in people who were participating in a longitudinal study where serum samples and lymphocyte subset data were obtained at 6-monthly intervals. A rise in beta 2-M level in the first seropositive sample was seen in 93% of 50 HIV seroconverters, and those with high (or low) levels of beta 2-M at the end of year 1 tend to remain high (or low) in the ensuing years. Eighty-three per cent of seroconverters experienced a fall in CD4 T cells in the first year. The magnitude of the CD4 T-cell decline, however, did not correlate with the rise in beta 2-M in specific individuals in the first year. Nevertheless, 2-3 years after seroconversion, the initially increased beta 2-M levels did correlate inversely with the (reduced) level of CD4 T cells (P less than 0.001). Thus, the pattern of disease reflected by beta 2-M level is established in the first year of infection and persists through the following 2 years. beta 2-M levels were found to correlate with rate of CD4 T-cell fall in individuals with established HIV infection. Three groups of HIV-seropositive people with similar CD4 T-cell numbers at the first measurements (about 600-800 x 10(6)/l) but different rates of CD4 T-cell fall over the following 2 years were evaluated by beta 2-M levels. The group with stable CD4 T-cell numbers showed a significantly lower level of beta 2-M than the groups with moderately or rapidly declining CD4 T-cell numbers. Increases in beta 2-M levels during the 2 years of observation were found in people exhibiting a rapid decline in CD4 T cells (about 200 cells/year). The level of beta 2-M appears to be an indicator of HIV activity and of the rate of CD4 T-cell fall.(ABSTRACT TRUNCATED AT 250 WORDS)

Variability in biological monitoring of organic solvent exposure. II. Application of a population physiological model.

A physiological population model is used to study the variability associated with the biological monitoring of solvent exposure. The model consists of a combination of a physiological compartmental model and statistical simulation technique. Variable components considered are: exposure concentration, physical workload, body build, liver function, and renal function. The model is applied to six solvents: trichloroethylene, tetrachloroethylene, methylchloroform, benzene, toluene, and styrene. Biological indicators and air monitoring are compared as predictors of exposure, both external and internal (uptake, brain concentration, reactive metabolite formation). It appears that the choice of the best indicator depends on the type of exposure which is to be predicted. The effects of the various factors, environmental, physiological, or metabolic, are quantified and discussed. It is shown that fluctuation in exposure plays a large part in the final variability of biological indicator results. Further improvements and applications of this population model are considered.

Variability in biological monitoring of solvent exposure. I. Development of a population physiological model.

Biological indicators of exposure to solvents are often characterised by a high variability that may be due either to fluctuations in exposure or individual differences in the workers. To describe and understand this variability better a physiological model for differing workers under variable industrial environments has been developed. Standard statistical distributions are used to simulate variability in exposure concentration, physical workload, body build, liver function, and renal clearance. For groups of workers exposed daily, the model calculates air monitoring indicators and biological monitoring results (expired air, blood, and urine). The results obtained are discussed and compared with measured data, both physiological (body build, cardiac output, alveolar ventilation) and toxicokinetic for six solvents: 1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene, benzene, toluene, styrene, and their main metabolites. Possible applications of this population physiological model are presented.

Progress and objectives in cancer control.

This article reviews progress in cancer control and objectives for achieving further control. In particular, rather than relying on a single composite statistic such as the age-adjusted mortality rate, this review stresses trends in cancer mortality in the United States using a cohort analysis. That method reveals a decline in cancer mortality beginning with young children in the 1950s and proceeding up the age scale in subsequent decades to those persons who were approximately 50 years of age in the mid-1980s. From age 55 years upward, the continuing increase in cancer mortality is due to epidemic lung cancer. The principal cause of that disease and what must be done to control it are well understood. The objectives for cancer control by the year 2000 set by the National Cancer Institute and the feasibility of reducing cancer mortality by as much as 25% to 50% are also considered. Increased cancer prevention research is needed.

Comparison of ultrasonic and direct biparietal diameter measurements and placental localization.

The accuracy of fetal biparietal diameter (BPD) measurements and placental localizations performed by physicians in a university hospital obstetrical service using real-time ultrasound equipment was determined. The sonographic estimations were compared to caliper measurements on the neonate and to the implantation site of the placenta found at surgery in 40 patients undergoing repeat cesarean section. The correlation coefficient 0.93 and p less than 0.00001 indicate high agreement between the BPD measurements. The regression of caliper on sonar measurements gave 95% prediction intervals of +/- 3.50 mm compared to +/- 2.4 mm calculated from data reported by ultrasonic laboratories. Placental localization was in error in 5.9% of the cases. Thus, physicians should be aware that their errors are likely to be larger than those which have been published by experts in ultrasound diagnosis.