Extended follow-up and spatial analysis of the American Cancer Society study linking particulate air pollution and mortality.

We conducted an extended follow-up and spatial analysis of the American Cancer Society (ACS) Cancer Prevention Study II (CPS-II) cohort in order to further examine associations between long-term exposure to particulate air pollution and mortality in large U.S. cities. The current study sought to clarify outstanding scientific issues that arose from our earlier HEI-sponsored Reanalysis of the original ACS study data (the Particle Epidemiology Reanalysis Project). Specifically, we examined (1) how ecologic covariates at the community and neighborhood levels might confound and modify the air pollution-mortality association; (2) how spatial autocorrelation and multiple levels of data (e.g., individual and neighborhood) can be taken into account within the random effects Cox model; (3) how using land-use regression to refine measurements of air pollution exposure to the within-city (or intra-urban) scale might affect the size and significance of health effects in the Los Angeles and New York City regions; and (4) what exposure time windows may be most critical to the air pollution-mortality association. The 18 years of follow-up (extended from 7 years in the original study [Pope et al. 1995]) included vital status data for the CPS-II cohort (approximately 1.2 million participants) with multiple cause-of-death codes through December 31, 2000 and more recent exposure data from air pollution monitoring sites for the metropolitan areas. In the Nationwide Analysis, the influence of ecologic covariate data (such as education attainment, housing characteristics, and level of income; data obtained from the 1980 U.S. Census; see Ecologic Covariates sidebar on page 14) on the air pollution-mortality association were examined at the Zip Code area (ZCA) scale, the metropolitan statistical area (MSA) scale, and by the difference between each ZCA value and the MSA value (DIFF). In contrast to previous analyses that did not directly include ecologic covariates at the ZCA scale, risk estimates increased when ecologic covariates were included at all scales. The ecologic covariates exerted their greatest effect on mortality from ischemic heart disease (IHD), which was also the health outcome most strongly related with exposure to PM2.5 (particles 2.5 microm or smaller in aerodynamic diameter), sulfate (SO4(2-)), and sulfur dioxide (SO2), and the only outcome significantly associated with exposure to nitrogen dioxide (NO2). When ecologic covariates were simultaneously included at both the MSA and DIFF levels, the hazard ratio (HR) for mortality from IHD associated with PM2.5 exposure (average concentration for 1999-2000) increased by 7.5% and that associated with SO4(2-) exposure (average concentration for 1990) increased by 12.8%. The two covariates found to exert the greatest confounding influence on the PM2.5-mortality association were the percentage of the population with a grade 12 education and the median household income. Also in the Nationwide Analysis, complex spatial patterns in the CPS-II data were explored with an extended random effects Cox model (see Glossary of Statistical Terms at end of report) that is capable of clustering up to two geographic levels of data. Using this model tended to increase the HR estimate for exposure to air pollution and also to inflate the uncertainty in the estimates. Including ecologic covariates decreased the variance of the results at both the MSA and ZCA scales; the largest decrease was in residual variation based on models in which the MSA and DIFF levels of data were included together, which suggests that partitioning the ecologic covariates into between-MSA and within-MSA values more completely captures the sources of variation in the relationship between air pollution, ecologic covariates, and mortality. Intra-Urban Analyses were conducted for the New York City and Los Angeles regions. The results of the Los Angeles spatial analysis, where we found high exposure contrasts within the Los Angeles region, showed that air pollution-mortality risks were nearly 3 times greater than those reported from earlier analyses. This suggests that chronic health effects associated with intra-urban gradients in exposure to PM2.5 may be even larger between ZCAs within an MSA than the associations between MSAs that have been previously reported. However, in the New York City spatial analysis, where we found very little exposure contrast between ZCAs within the New York region, mortality from all causes, cardiopulmonary disease (CPD), and lung cancer was not elevated. A positive association was seen for PM2.5 exposure and IHD, which provides evidence of a specific association with a cause of death that has high biologic plausibility. These results were robust when analyses controlled (1) the 44 individual-level covariates (from the ACS enrollment questionnaire in 1982; see 44 Individual-Level Covariates sidebar on page 22) and (2) spatial clustering using the random effects Cox model. Effects were mildly lower when unemployment at the ZCA scale was included. To examine whether there is a critical exposure time window that is primarily responsible for the increased mortality associated with ambient air pollution, we constructed individual time-dependent exposure profiles for particulate and gaseous air pollutants (PM2.5 and SO2) for a subset of the ACS CPS-II participants for whom residence histories were available. The relevance of the three exposure time windows we considered was gauged using the magnitude of the relative risk (HR) of mortality as well as the Akaike information criterion (AIC), which measures the goodness of fit of the model to the data. For PM2.5, no one exposure time window stood out as demonstrating the greatest HR; nor was there any clear pattern of a trend in HR going from recent to more distant windows or vice versa. Differences in AIC values among the three exposure time windows were also small. The HRs for mortality associated with exposure to SO2 were highest in the most recent time window (1 to 5 years), although none of these HRs were significantly elevated. Identifying critical exposure time windows remains a challenge that warrants further work with other relevant data sets. This study provides additional support toward developing cost-effective air quality management policies and strategies. The epidemiologic results reported here are consistent with those from other population-based studies, which collectively have strongly supported the hypothesis that long-term exposure to PM2.5 increases mortality in the general population. Future research using the extended Cox-Poisson random effects methods, advanced geostatistical modeling techniques, and newer exposure assessment techniques will provide additional insight.

A land use regression model for predicting ambient fine particulate matter across Los Angeles, CA.

Land use regression (LUR) models have been used successfully for predicting local variation in traffic pollution, but few studies have explored this method for deriving fine particle exposure surfaces. The primary purpose of this method is to develop a LUR model for predicting fine particle or PM(2.5) mass over the five county metropolitan statistical area (MSA) of Los Angeles. PM(2.5) includes all particles with diameter less than or equal to 2.5 microns. In the Los Angeles MSA, 23 monitors of PM(2.5) were available in the year 2000. This study uses GIS to integrate data regarding land use, transportation and physical geography to derive a PM(2.5) dataset covering Los Angeles. Multiple linear regression was used to create the model for predicting the PM(2.5) surface. Our parsimonious model explained 69% of the variance in PM(2.5) with three predictors: (1) traffic density within 300 m, (2) industrial land area within 5000 m, and (3) government land area within 5000 m of the monitoring site. These results suggest the LUR method can refine exposure models for epidemiologic studies in a North American context.

The great imitator: miliary peritoneal tuberculosis mimicking stage III ovarian carcinoma.

PURPOSE: To report a case of peritoneal tuberculosis initially mistaken at the time of surgery for metastatic ovarian carcinoma. CASE REPORT: A 31-year-old Filipino female was found to have increasing abdominal pain, ascites, early satiety, increasing abdominal girth and bilateral complex masses. Diagnostic laparoscopy revealed the presence of > 4 liters of ascites, a frozen pelvis secondary to what appeared to be bilateral ovarian carcinomas, along with miliary seeding of the entire anterior abdominal wall, omentum, small bowel and small bowel mesentery, right and left diaphragmatic surfaces, and hepatic surface. Frozen section, at the time of laparotomy, revealed necrotizing granulomas most consistent with disseminated tuberculosis that was confirmed at the time of final pathologic review and culture. CONCLUSION: Peritoneal tuberculosis can be mistaken for widely metastatic ovarian carcinoma at time of surgery.

Papillary serous carcinoma of the cervix: ultrasonographic findings.

BACKGROUND: Papillary serous carcinoma of the uterine cervix is a rare malignancy only recently described. Optimal treatment is unknown. CASE REPORT: A 65 year old white female, approximately 15 years postmenopausal, presented with a recent history of postmenopausal bleeding. Cervical cytology was negative for any abnormalities. Ultrasonography of the pelvis revealed a thickened anterior endometrium with fluid present along with a papillary mass in the endocervix. Hysteroscopy, dilatation and curettage revealed a low uterine segment mass consistent with a pathologic diagnosis of grade 2 endometrioid adenocarcinoma of the endometrium. A total abdominal hysterectomy, bilateral salpingo-oophorectomy and bilateral pelvic and paraaortic lymphadenectomy revealed a papillary serous carcinoma of the cervix metastatic to pelvic and paraaortic lymph nodes. CONCLUSION: Cervical papillary serous carcinoma can be discovered pre-operatively by ultrasonography. Because of its relatively recent description and relative rarity, optimal treatment is unknown.

Recombinant superoxide dismutase (SOD) administered by aerosol inhibits respiratory syncytial virus infection in cotton rats.

Recombinant (r) human (hu) manganese (Mn) and copper-zinc (CuZn) superoxide dismutase (SOD) were evaluated for their cytotoxicity and antiviral activity against respiratory syncytial virus (RSV) in tissue culture and in cotton rats. No apparent cytotoxicity or inhibition of RSV was observed in the tissue culture studies (both compounds had IC50 and EC50 values > or = 1000 micrograms/ml and a selective index = 1). However, significant reductions in mean pulmonary RSV titers (ranging between 0.5 and 1.9 log10/g of lung compared with the mean pulmonary viral titers detected in similarly inoculated, placebo-treated control animals) were seen in most of the experiments, in which experimentally infected cotton rats were exposed to continuous small-particle aerosols (reservoir concentrations > or = 20 mg/ml) containing either rhuMnSOD or rhuCuZnSOD. This protective effect was dose dependent and not observed when either rSOD compound was administered parenterally (intraperitoneally) or intranasally. No toxic effects were noted in any of the cotton rats exposed to aerosols of either rhuMn or CuZnSOD; nor was any evidence of drug-induced histopathology observed in sections of lung prepared from these animals.

Evaluation of the protective efficacy of reshaped human monoclonal antibody RSHZ19 against respiratory syncytial virus in cotton rats.

Reshaped human MAb RSHZ19, which is specific for the surface fusion protein of respiratory syncytial virus (RSV) is in clinical development for the prevention and treatment of RSV-induced disease in human infants. The current studies profile lung virus clearance and evaluate lung histopathology in MAb-treated, RSV-infected cotton rats, a well characterized model of RSV infection. The highest dose of this MAb (10 mg/kg) administered parenterally 24 h before infection decreased subgroup A or B RSV lung titers to below detectable levels (> or = 2.3 log10 reduction), and significantly reduced lung virus titers (> or = 2.0 log10 reduction) when administered 96 h postinfection. Prophylactic administration of 10 mg/kg RSHZ19 was significantly more protective than 1000 mg/kg conventional human immune serum globulin (HSIg), and protective serum-neutralizing titers in MAb-treated animals (1:32, which correlated with approximately 40 micrograms/ml determined by anti-idiotype ELISA) were significantly lower than those reported previously for HSIg or for convalescent human serum (1:200-1:400). MAb concentration in lung lavages was determined by ELISA to be approximately 1% of the serum MAb concentration, but was not detectable by neutralization assay. The degree of lung histopathology in MAb-treated cotton rats was proportional to lung virus titer, and inversely proportional to the RSHZ19 dose administered. There was no evidence of exacerbated disease in the lungs of MAb-treated animals. These studies thus support the potential clinical utility of RSHZ19 MAb in the prevention and treatment of RSV-induced disease in humans.

Evaluation of the antiviral activity of N-(phosphonoacetyl)-L-aspartate against paramyxoviruses in tissue culture and against respiratory syncytial virus in cotton rats.

N-(phosphonoacetyl)-L-aspartate (PALA), a potent inhibitor of L-aspartic acid transcarbamoylase, was evaluated for cytotoxicity and antiviral activity against three different paramyxoviruses in tissue culture, and for antiviral efficacy and toxicity in vivo using a cotton rat-respiratory syncytial virus (RSV) model. Significant in vitro cytotoxicity was observed in proliferating cultures of HEp-2 (IC50 = 250 micrograms/ml) and Vero cells (IC50 = 32 micrograms/ml), but was less evident in cultures containing confluent monolayers (i.e., stationary cells) of these cells, or in cultures of Madin Darby canine kidney (MDCK) cells (these IC50 values were all > or = 750 micrograms/ml, with 1000 micrograms/ml being the maximum concentration tested). Mean selective indices (ratio of the median cytotoxic dose: median efficacious dose) of 1, 72 and 146 were obtained against parainfluenza virus type 3, RSV and measles virus, respectively, when PALA was tested against these viruses using confluent HEp-2 and Vero cell monolayers. In cotton rats, significant reductions in pulmonary titers (0.8-1.4 log10/g lung) compared to pulmonary viral titers in placebo-treated control animals, were consistently seen in cotton rats given > or = 10 mg of PALA/kg/day (b.i.d.) intraperitoneally on days 1-3 postinfection with either subtype A or B RSV. No toxic effects were noted even in animals given 100 mg of PALA/kg/day for 7 consecutive days.

Genetic association and linkage analysis of the apolipoprotein CII locus and familial Alzheimer's disease.

We previously reported a genetic association between the 3.5 kb (F) Taq I restriction fragment length polymorphism allele of the apolipoprotein CII gene on chromosome 19 and familial Alzheimer's disease. Here, we report an additional analysis of this association performed on an expanded and better defined data set of 23 families with familial Alzheimer's disease. The F allele frequency in affected family members in the expanded set was 0.62 +/- 0.06 (mean +/- standard error, n = 51 subjects), which differed significantly from a frequency of 0.39 +/- 0.02 (n = 226) for unrelated control subjects (Z = 3.75, p less than 0.0002). These results are consistent with our previous findings and suggest an association between the F allele of apolipoprotein CII and familial Alzheimer's disease. When the apolipoprotein CII locus was tested for linkage to familial Alzheimer's disease, LOD scores summed for the complete group of families were negative and close linkage was excluded. Close linkage was also excluded for early-onset families (mean onset age less than or equal to 60 years), but small positive LOD scores were obtained for late-onset kindreds.

Linkage analysis of familial Alzheimer disease, using chromosome 21 markers.

Chromosome 21 markers were tested for linkage to familial Alzheimer disease (FAD) in 48 kindreds. These families had multiple cases of Alzheimer disease (AD) in 2 or more generations with family age-at-onset means (M) ranging from 41 to 83 years. Included in this group are seven Volga German families which are thought to be genetically homogeneous with respect to FAD. Autopsy documentation of AD was available for 32 families. Linkage to the 21 q11-q21 region was tested using D21S16, D21S13, D21S110, D21S1/S11, and the APP gene as genetic markers. When linkage results for all the families were summed, the LOD scores for these markers were consistently negative and the entire region was formally excluded. Linkage results were also summed for the following family groups; late-onset (M greater than 60), early-onset (M less than or equal to 60), Volga Germans (M = 56), and early-onset non-Volga Germans (M less than or equal to 60). For the first three groups, LOD scores were negative for this region. For the early-onset non-Volga German group (six families), small positive LOD scores of Zmax = 0.78 (recombination fraction theta = .15), Zmax = 0.27 (theta = .15), and Zmax = 0.64 (theta = .0), were observed for D21S13, D21S16, and D21S110, respectively. The remainder of the long arm of chromosome 21 was tested for linkage to FAD using seven markers spanning the q22 region. Results for these markers were also predominantly negative. Thus it is highly unlikely that a chromosome 21 gene is responsible for late-onset FAD and at least some forms of early-onset FAD represented by the Volga German kindreds.

The genetics of Alzheimer's disease.

Genetic factors play a major role in some if not all cases of Alzheimer's disease (AD). In certain rare families, the disease is most likely inherited as an autosomal dominant trait. Identification of the genes involved in AD is in progress. One AD-related gene, which codes for the amyloid precursor protein (APP), has been cloned and characterized. This gene, though certainly involved in the pathogenesis of AD, is not defective in AD subjects. Genetic linkage analysis of familial Alzheimer's disease (FAD) should help to identify defective genes directly involved in initiating the pathogenesis of AD. In addition, the study of the genes responsible for the Down syndrome (DS) phenotype may yield information on the sequence of events leading to the dementia of AD.

Absence of linkage of chromosome 21q21 markers to familial Alzheimer's disease.

Alzheimer's disease is the most common form of dementia among the elderly population. Although the etiology is unknown, inheritance plays a role in the pathogenesis of the disease. Recent work indicates that an autosomal dominant gene for Alzheimer's disease is located on chromosome 21 at band q21. In the present study of a group of autopsy-documented kindreds, no evidence for linkage was found between familial Alzheimer's disease (FAD) and chromosome 21q21 markers (D21S1/D21S72 and the amyloid beta gene). Linkage to the D21S1/D21S72 locus was excluded at recombination fractions (theta) up to 0.17. Linkage to the amyloid gene was excluded at theta = 0.10. Apparent recombinants were noted in two families for the amyloid gene and in five families for the D21S1/D21S72 locus. These data indicate that FAD is genetically heterogeneous.

A survey of serious congenital morphological abnormalities in Abu Dhabi.

The overall incidence of severe congenital abnormalities diagnosed within the first week of life was 12.9/1000, which is similar to other surveys (1,2), although the distribution and type of abnormalities encountered varied considerably. The incidence of spina bifida and encephaloceles was lower than elsewhere (0.54/1000).