Faculty Bibliography

Epidemiologic studies have shown that exposure to particulate air pollution is associated with short-term increases in cardiovascular morbidity and mortality. These adverse effects of inhaled particulate matter (PM*) may be the indirect result of a PM-induced increase in blood coagulability. This explanation is biologically plausible because prospective studies have shown that increases in blood coagulation parameters are significantly associated with risk of adverse cardiovascular events. We examined the hypothesis that acute exposure to elevated levels of PM causes prothrombotic changes in blood coagulation parameters. Rats with indwelling jugular vein catheters were exposed for 6 hours to filtered air or concentrated ambient PM in New York City air (n = 9 per group per experiment). PM less than 2.5 microm in mass median aerodynamic diameter (PM2.5) was concentrated for animal exposures using a centrifugal concentrator. Blood samples were taken at four time points: before and immediately after exposure and at 12 and 24 hours after the start of exposure. At each time point, six coagulation parameters (platelet count, fibrinogen level, factor VII activity, thrombin-antithrombin complex [TAT] level, tissue plasminogen activator [tPA] activity, and plasminogen activator inhibitor [PAI] activity) were measured as well as all standard blood count parameters. Five concentrated-PM exposure experiments were performed over a period of 8 weeks in the summer of 1999. PM exposure concentrations ranged from 95 to 341 microg/m3. Statistical significance was determined by two-way analysis of variance (ANOVA) on the postexposure data with time and exposure status as main effects. There were no consistent exposure-related effects on any of the end points across the five experiments and no indication of any dose-dependent effects. Most of the statistically significant differences that were observed do not represent adverse effects. Therefore, the results of this study do not indicate that exposure to concentrated ambient PM causes adverse effects on blood coagulation in healthy rats

Few studies have examined the sources of variability in cardiac function measurements in unrestrained animals and the impact of this variability on detection of treatment effects. The heart rate was monitored with implanted ECG transmitters in two groups of male rats, age 7 and 23 mo. Animals were monitored in their cages to determine optimal heart rate sampling frequency and sources of variability in heart rate, including whether there were persistent animal-to-animal differences. Ambient temperature was transiently increased to test whether correction for animal-to-animal differences improved sensitivity for detection of treatment effects. Animal-to-animal differences were statistically significant and accounted for about 18.3% and 11.5% of the total variance for old and young rats, respectively. In both the old and young rats, the heart rate decreased during the heat challenges relative to the control group, but the noncorrected differences were not statistically significant. When pre-exposure baseline values for each rat (average of 72 h prior to the first temperature challenge) were subtracted, the decrease in heart rate was statistically significant during all three challenges for both old and young rats. Subtraction of preexposure heart rate data to correct for baseline differences between animals is important for measuring treatment effects

Human immunodeficiency virus-type I (HIV-1) infection elicits antibodies (Abs) directed against several regions of the gp120 and gp41 envelope glycoproteins. Many of these Abs are able to neutralize T-cell-line-adapted strains (TCLA) of HIV-1, but only a few effectively neutralize primary HIV-1 isolates. The nature of HIV-1 neutralization has been carefully studied using human monoclonal Abs (MAbs), and the ability of such MAbs to act in synergy to neutralize HIV-1 has also been extensively studied. However, most synergy studies have been conducted using TCLA strains. To determine the nature of Ab interaction in HIV-1 primary isolate neutralization, a panel of 12 anti-HIV-1 human immunoglobulin G (IgG) MAbs, specific for epitopes in gp120 and gp41, were used. Initial tests showed that six of these MAbs, as well as sCD4, used individually, were able to neutralize the dualtropic primary isolate HIV-1(89.6); MAbs giving significant neutralization at 2 to 10 microg/ml included 2F5 (anti-gp41), 50-69 (anti-gp41), IgG1b12 (anti-gp120(CD4bd)), 447-52D (anti-gp120(V3)), 2G12 (anti-gp120), and 670-D (anti-gp120(C5)). For studies of reagent interaction, 16 binary combinations of reagents were tested for their ability to neutralize HIV-1(89.6). Reagent combinations tested included one neutralizing MAb with sCD4, six pairs consisting of two neutralizing MAbs, and nine pairs consisting of one neutralizing MAb with another non-neutralizing MAb. To assess the interaction of the latter type of combination, a new mathematical treatment of reagent interaction was developed since previously used methods could be used only when both reagents neutralize. Synergy was noted between sCD4 and a neutralizing anti-gp120(V3) MAb. Antagonism was noted between two pairs of anti-gp41 MAbs (one neutralizing and one non-neutralizing). All of the other 13 pairs of MAbs tested displayed only additive effects. These studies suggest that Abs rarely act in synergy to neutralize primary isolate HIV-1(89.6); many anti-HIV-1 Abs act additively to mediate this biological function

Numerous time series studies have reported associations between daily ambient concentrations of air pollution and morbidity or mortality. Recent personal exposure studies have also reported relatively high longitudinal correlation between personal exposures to particulate matter (PM) and home outdoor PM concentrations, lending support to the health effects reported in time series studies. However, the question remains as to how well the temporal fluctuations in the air pollution levels observed at an outdoor monitor represent the temporal fluctuations in the population exposures to pollution of outdoor origins in a city, and how such representativeness affects the size and significance of risk estimates. Also, such spatio-temporal correlations would vary from pollutant to pollutant, likely influencing their relative significance of statistical associations with health outcomes. In this study, we characterized the extent of monitor-to-monitor correlation over time among multiple monitoring sites for PM less than 10 microm (PM10), gaseous criteria pollutants, and several weather variables in seven central and eastern contiguous states (IL, IN, MI, OH, PA, WI, and WV) during the study period of 1988-1990. After removing seasonal trends, the monitor-to-monitor temporal correlation among the air pollution/weather variables within 100-mile separation distance in these areas could be generally ranked into three groups: (1 ) temperature, dew point, relative humidity (r>0.9); (2) O3, PM10, NO2 (r: 0.8-0.6); and (3) CO, SO2 (r<0.5). Using the subsets for separation distance less than 100 miles, regression analyses of these monitor-to-monitor correlation coefficients were also conducted with explanatory variables including separation distance, qualitative (land use, location setting, and monitoring objectives) and quantitative (large and small variance) site characteristics, and region indicators for Air Quality Control Region (AQCR). The separation distance was a significant predictor of monitorto-monitor correlation decline especially for PM10 and NO2 (approximately 0.2 drop over 30 miles). Site characteristic variables were, in some cases, significant predictors of monitor-to-monitor correlation, but the magnitude of their impacts was not substantial. Regional differences, as examined by AQCR, were in some cases (e.g., in Metropolitan Philadelphia) substantial. In these areas, the pollutants that had generally poor monitor-to-monitor correlation in the overall seven states data (i.e., for SO2 and CO) showed higher monitor-to-monitor correlations, comparable with PM10 and O3, within the AQCR. These results are useful in interpreting some of the past time series epidemiological results. The differences in monitor-to-monitor correlations found across pollutants in this work (i.e., r approximately 0.8 vs. r approximately 0.4) are sufficiently large that they could be a factor in the different pollutant significance levels reported in the epidemiologic literature. It is recommended that future epidemiological studies collect and incorporate information on spatial variability among air pollutants in the analysis and interpretation of their results

In order to protect against organisms that exhibit significant genetic variation, polyvalent vaccines are needed. Given the extreme variability of human immunodeficiency virus type 1 (HIV-1), it is probable that a polyvalent vaccine will also be needed for protection from this virus. However, to understand how to construct a polyvalent vaccine, serotypes or immunotypes of HIV must be identified. In the present study, we have examined the immunologic relatedness of intact, native HIV-1 primary isolates of group M, clades A to H, with human monoclonal antibodies (MAbs) directed at epitopes in the V3, C5, and gp41 cluster I regions of the envelope glycoproteins, since these regions are well exposed on the virion surface. Multivariate analysis of the binding data revealed three immunotypes of HIV-1 and five MAb groups useful for immunotyping of the viruses. The analysis revealed that there are fewer immunotypes than genotypes of HIV and that clustering of the isolates did not correlate with either genotypes, coreceptor usage (CCR5 and CXCR4), or geographic origin of the isolates. Further analysis revealed distinct MAb groups that bound preferentially to HIV-1 isolates belonging to particular immunotypes or that bound to all three immunotypes; this demonstrates that viral immunotypes identified by mathematical analysis are indeed defined by their immunologic characteristics. In summary, these results indicate (i) that HIV-1 immunotypes can be defined, (ii) that constellations of epitopes that are conserved among isolates belonging to each individual HIV-1 immunotype exist and that these distinguish each of the immunotypes, and (iii) that there are also epitopes that are routinely shared by all immunotypes

Indices of atmospheric particulate matter (PM) have been reported to be associated with daily mortality and morbidity in a large number of recent time-series studies. However, the question remains as to which components of PM are responsible for the reported associations. Multiple PM components rarely are measured simultaneously. To investigate PM effects on mortality and morbidity, we used the multiple PM components measured in Windsor, Ontario, at a site only a few miles from downtown Detroit, Michigan. This study focused primarily on two study periods in which multiple PM components were measured in Windsor: 1985 to 1990, when levels of total suspended particles (TSP), sulfate from TSP (TSP-SO4(2-)), PM less than 10 microns in diameter (PM10), and nonthoracic TSP (TSP-PM10) were measured throughout the year; and 1992 to 1994, when data on PM10, PM2.5 (PM less than 2.5 microns in diameter), PM10-2.5 (PM10 minus PM2.5), particle acidity (H+), and artifact-free sulfates (SO4(2-)) were available for mostly summer months. Mortality data were analyzed for the 1985 to 1990 study period, and data on both mortality and hospital admissions of elderly patients were analyzed for the 1992 through 1994 period. Poisson regressions were used to estimate the effects of these PM components and gaseous criteria pollutants on mortality (nonaccidental, circulatory, respiratory, and nonaccidental without circulatory and respiratory) and on hospital admissions of elderly patients (for pneumonia, chronic obstructive pulmonary disease [COPD], ischemic heart disease, dysrhythmias, heart failure, and stroke), adjusting for temperature and humidity, trends and seasonal cycles, and day of the week. Both PM10 and TSP were associated significantly with respiratory mortality for the 1985 to 1990 period, with similar relative risk (RR) estimates for PM10 (RR = 1.123; 95% confidence interval [CI] 1.0361-1.218) and TSP (RR = 1.109; 95% CI 1.028-1.197), per 5th to 95th percentile increment. The effect-size estimates for TSP-SO4(2-) and TSP-PM10 were smaller and less significant. In two-pollutant models, simultaneous inclusion of gaseous pollutants with PM10 or TSP reduced PM coefficients by 0 to 34%. The effect-size estimates for total mortality, circulatory mortality, and total minus circulatory and respiratory mortality were less than those for respiratory mortality. Ozone (O3) and nitrogen dioxide (NO2) also were associated significantly with total and circulatory mortality, but a simultaneous consideration of these pollutants with PM10 reduced PM10 coefficients only slightly, or even increased them. In these results, pollution coefficients often were positive at multiple lag days (0-day through 3-day lags were examined), but for PM indices, 1-day lag coefficients were most significant. However, when all combinations of multiple-day average exposures were examined, for cases in which multiple lag days were positive, the choice of single-day or multiple-day average exposure did not appreciably change the estimated effect sizes. An examination of temporal correlation showed that the order of spatial uniformity as expressed by the median site-to-site correlation was O3 (0.83), PM10 (0.78), TSP (0.71), NO2 (0.70), carbon monoxide (CO) (0.50), and sulfur dioxide (SO2) (0.49), which suggests less exposure error for O3 and PM10 than for the other measured pollutants. Thus, these results suggest that spatially homogeneous pollution indices show higher associations with measured health outcomes