Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel.

BACKGROUND: Elevated Epstein-Barr virus (EBV) antibody titers are risk factors for multiple sclerosis (MS), but the strength and consistency of this association are not well characterized. OBJECTIVES: The objectives of this study were to determine whether this association is confounded by vitamin D or modified by gender or race, and the usefulness of EBV nuclear antigen (EBNA) antibodies as a marker for MS. METHODS: We conducted a prospective study among US military personnel. Antibody titers against EBV antigens were measured in serum samples from 222 individuals who developed MS and 444 age, sex, and race/ethnicity matched controls. Conditional logistic regression was used to estimate relative risks. RESULTS: MS risk increased with increasing titers of anti-EBNA complex (p < 10(-9)) and anti-EBNA-1 (p = 5.8 × 10(-9)) titers. MS risk was 36-fold higher among individuals with anti-EBNA complex IgG titers ≥320 than among those with titers <20 (95% confidence interval [CI] 9.6-136), and 8-fold higher among those with anti-EBNA-1 ≥320 than among those with anti-EBNA-1 <20 (95% CI 2.6-23). These associations were consistent across gender and race/ethnicity groups and independent from 25-hydroxyvitamin D levels. Areas under the receiver operating characteristic (ROC) curves were 0.67 for EBNA complex and 0.65 for EBNA-1. CONCLUSIONS: Serum titers of pre-onset anti-EBNA antibodies are strong, robust markers of MS risk and could be useful in an MS risk score.

Serum titers of IgG antibodies against tetanus and diphtheria toxoids and risk of multiple sclerosis.

We conducted a prospective nested case-control study among military service members to investigate whether antibodies against tetanus or diphtheria predict multiple sclerosis (MS) risk. Paired T-tests were used to compare means of anti-tetanus and diphtheria toxoids among 56 MS cases and 112 matched controls. Conditional logistic regression was used to estimate odds ratios (OR). There were no differences between the mean serum IgG antibodies against tetanus (p-value 0.28) or diphtheria (p-value 0.45) in the baseline samples. The OR of MS associated with 1 standard deviation difference in antibody titers was 0.76 (95% CI: 0.48-1.21) for tetanus (SD=4.71) and 1.03 (0.73-1.45) for diphtheria (SD=0.87). Results of this study suggest serum IgG antibodies against tetanus or diphtheria are not predictors of MS risk.

Myelin oligodendrocyte glycoprotein antibodies and multiple sclerosis in healthy young adults.

BACKGROUND: It remains uncertain whether the presence of serum anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in healthy individuals contributes to predict their risk of developing multiple sclerosis (MS). METHODS: Prospective, nested case-control study of more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum Repository. A total of 126 MS cases and 252 controls matched by age, sex, race/ethnicity, and dates of blood collection were included in the analysis. An ELISA was used to detect IgM and IgG antibodies to MOG. Analyses were conducted with and without adjustment for serum titers of antibodies to the Epstein-Barr nuclear antigen (EBNA), which are an established risk factor for MS. RESULTS: The presence of anti-MOG IgG antibodies in serum was associated with an increase in risk of developing MS (relative risk for anti-MOG IgG+/IgM- vs seronegativity to both anti-MOG IgM and IgG: 2.03; 95% CI: 1.19-3.46; p = 0.01). This association, however, was attenuated and no longer significant after adjustment for titers of antibodies to EBNA, which were higher among individuals positive for anti-MOG antibodies. CONCLUSION: Our findings suggest that although individuals with anti-myelin oligodendrocyte glycoprotein (MOG) antibodies have an increased risk of developing multiple sclerosis, this association may at least in part reflect cross-reactivity between MOG and Epstein-Barr nuclear antigen.

A prospective study of Chlamydia pneumoniae infection and risk of MS in two US cohorts.

BACKGROUND: Chlamydia pneumoniae (Cpn) has been proposed as a possible etiologic agent in multiple sclerosis (MS). However, previous studies were cross-sectional and could not assess whether Cpn infection preceded the onset of MS. METHODS: The authors conducted a prospective nested case-control study among 3 million US Army personnel and 121,466 members of the Kaiser Permanente Medical Care Program (KPMCP) cohort. Serum samples collected prior to onset of MS symptoms were available for 83 MS cases in the Army and 46 in the KPMCP cohort. Two controls were matched to each case on age, sex, and date of blood collection. Microimmunofluorescence was used to measure serum immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody titers to Cpn; IgG titers > or 1:16 were considered positive for past Cpn infection. RESULTS: Seropositivity for Cpn was not significantly associated with risk of MS in either cohort (Army: OR = 1.0; 95% CI 0.6, 1.8; KPMCP: OR = 1.5; 95% CI 0.7, 3.1) or in the pooled analysis (OR = 1.2; 95% CI 0.8, 1.9). Serum levels of anti-Cpn IgG antibody were also not associated with an increased risk of MS in the Army (OR for a fourfold difference in antibody titers = 0.9; 95% CI 0.7, 1.2) or in the pooled analysis (OR = 1.2; 95% CI 0.9, 1.4), but a significant increase in risk was seen in the KPMCP cohort (OR = 1.7; 95% CI 1.2, 2.5). The difference between these results in the Army and the KPMCP cohort was significant (p = 0.01). CONCLUSIONS: Neither Cpn seropositivity nor serum anti-Cpn IgG antibody titers predicted risk of developing MS. However, due to the heterogeneity of results between cohorts, we cannot exclude the possibility that infection with Cpn may modify the risk of MS.

Prostate-specific antigen levels in young white and black men 20 to 45 years old.

OBJECTIVES: To determine the prostate-specific antigen (PSA) levels and PSA change over time in young white and black men 20 to 45 years old. METHODS: The Department of Defense Serum Repository, a serum bank that stores all residual serum from the military human immunodeficiency virus screening program at -25 degrees C, was sampled to obtain a total of 588 black and 588 white subjects 20 to 45 years old. This was a retrospective study with only demographic data available on the studied subjects. The samples used for this study were collected between June 24, 1988 and June 12, 1996. Individuals with a history of prostate disease were excluded by query of a centralized Department of Defense diagnosis database. Three serum specimens evenly distributed over a mean of 6 years were selected for each individual to determine the free and total PSA levels and PSA velocity. The Hybritech Tandem-E PSA assay was used for the total PSA measurement, and the Hybritech Tandem-R assay was used for the free PSA measurement. RESULTS: The baseline serum PSA levels differed by race (P = 0.04). The median (25th, 75th percentile) baseline serum PSA levels for black men 20 to 29, 30 to 39, and 40 to 45 were 0.38 ng/mL (0.26, 0.61), 0.45 ng/mL (0.32, 0. 67), and 0.52 ng/mL (0.37, 0.73), respectively. The median baseline serum PSA levels for the same decade groups in white men were 0.38 ng/mL (0.27, 0.57), 0.45 ng/mL (0.28, 0.68), and 0.40 ng/mL (0.26, 0. 64), respectively. The PSA velocity was higher in white men than in black men (mean 2.8%/yr and 1.6%/yr, respectively, P = 0.032). CONCLUSIONS: These results suggest that although black men 20 to 45 years old have higher baseline serum PSA levels than white men of the same age, the PSA velocity is greater in young white than in young black men. Additional work is needed to determine the clinical significance of these findings.

HIV-1 seroconversion and risk behaviors among young men in the US army. The Seroconversion Risk Factor Study Group.

OBJECTIVES: This study sought to examine risk factors associated with human immunodeficiency virus type 1 (HIV-1) seroconversion among active-duty men in the US Army. METHODS: One hundred twenty-eight men with documented HIV-1 seroconversion between 1988 and 1991 were matched to control subjects on demographic variables. Risk factor information was collected for the seroconversion period. RESULTS: Forty-nine case subjects and no control subjects reported same-gender sex; this includes 34 case subjects who also reported sex with women. Seventy case and 118 control subjects reported no risk factors other than heterosexual intercourse. Among heterosexuals, excess risk was noted for men who had sex with women in risk categories defined by the Centers for Disease Control and Prevention (odds ratio = 10.0; 95% confidence interval = 1.3, 78.1). Significant trends of increasing risk for seroconversion were found with increasing numbers of female partners, nonsteady partners, and partners with whom sex occurred on the first day of acquaintance. CONCLUSIONS: In this population, the major risk factor for HIV-1 seroconversion was same-gender sex. Among heterosexuals, sex with anonymous or causal partners increased this risk. Intervention programs should emphasize the risk of indiscriminate partner selection in addition to "safe sex" practices.

Predictors of HIV-1 disease progression in early- and late-stage patients: the U.S. Army Natural History Cohort. Military Medical Consortium for Applied Retrovirology.

HIV-infected individuals in both early and late stages of HIV disease were evaluated over 2 years to assess temporal trends and determinants of disease progression. The Walter Reed (WR) staging system was used to categorize patients into an early-stage cohort (WR Stages 1 and 2, N = 1183) and a late-stage cohort (WR Stage 5, N = 260) based on the initial clinical evaluation. Progression was defined as the occurrence of Stage 5 disease or beyond for the early cohort and Stage 6 disease or beyond for the late cohort. The cumulative incidence of progression was 15.7% (137 events) for the early-stage cohort, and 53.7% (85 events) for the late-stage cohort. Baseline CD4+ T lymphocyte (T4) count was the most significant marker of progression: 26% of WR Stage 1 or 2 patients with T4 lymphocytes below 500/mm3 progressed, compared with 12% with T4 lymphocytes at or above 500/mm3. In late-stage individuals, 83% with T4 lymphocytes under 200/mm3 progressed, compared with 27% with T4 lymphocytes at or above 200/mm3. Older age was associated with progression in both early- and late-stage groups. Differences in the rates of disease progression were not significant between blacks and whites or between men and women. Two-year rates of progression among the late-stage patients dropped from 78 to 47% between 1986 and 1988. This contrasted with progression rates in the early-stage cohort, which remained stable: 18% for those entering follow-up in 1986 and 17% for those entering follow-up in 1988. These data indicate a significant slowing of HIV disease progression rates and mortality rates among individuals with late-stage disease that is temporally associated with the increased availability and use of therapies. With control of T4 lymphocyte count, age, and calendar time, neither gender nor race was significantly associated with progression in either early- or late-stage patients.

Occupational risks of bladder cancer among white women in the United States.

The relation between occupation and bladder cancer in women was examined based on data collected during the National Bladder Cancer Study, a population-based, case-control study conducted in 10 areas of the United States. Occupational hazards among women have received little attention in previous bladder cancer studies, in part because most studies have included too few females to accurately estimate risks. In this large case-control study, 652 white female bladder cancer patients and 1,266 white female controls were interviewed to obtain lifetime occupational histories. Patterns of bladder cancer risk by occupation in women tended to be similar to those previously observed among men. Increased risk was apparent for women ever employed in metal working and fabrication occupations (relative risk (RR) = 1.5; 95% confidence interval (CI) 0.9-2.6). Within this summary occupation category, punch and stamping press operatives had a significant trend in risk with increasing duration of employment (p = 0.012); the RR for women employed 5 years or more was 5.6 (95% CI 1.4-26.4). The authors also observed an increased risk for women employed as chemical processing workers (RR = 2.1; 95% CI 0.9-5.1 = with a significant, contrast, a decreased risk was apparent for female textile workers (RR = 0.6; 95% CI 0.3-1.1) with a significant, negative trend in risk with increasing duration of employment (p = 0.031); the relative risk for textile workers employed 10 years or more was 0.4. The authors estimate that 11% of bladder cancer diagnosed among white women in the United States is attributable to occupational exposures; this percentage is considerably lower than the 21-25% previously reported for white men in this study.

Risk factors for prevalent human immunodeficiency virus (HIV) infection in active duty Army men who initially report no identified risk: a case-control study.

A large proportion of human immunodeficiency virus antibody (HIV-Ab) positive male soldiers are considered to be at no identified risk (NIR) because they do not disclose histories of sexual activity with other men, intravenous drug use, blood transfusions, or sexual activity with persons at known high risk for HIV infection. A case-control study involving personal interviews with 26 NIR cases and 74 controls was conducted to determine if lifestyle information that might jeopardize a soldier's military career could be obtained from an Army population and to evaluate risk factors for prevalent HIV infection. Subjects consented to a voluntary, anonymous, and confidential interview containing information on demographic characteristics, medical history, drug use, and sexual behavior. Of 26 cases interviewed, 20 (76.9%) reported behaviors defined by the Centers for Disease Control (CDC) as risk factors for HIV infection, while 11 of 74 (14.9%) controls also reported such behaviors. This proportion of reclassified NIR cases was similar to that reported from the NIR case series study conducted by the CDC. Of the six (23.1%) cases who remained at NIR, all reported at least one of the following risks: a history of sexually transmitted diseases, sexual contact with prostitutes, or sexual activity with female partners which caused bleeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Smoking patterns by occupation and duration of employment.

Lifetime patterns of smoking and occupation based on personal interviews were examined among 3,627 white men and 1,200 white women who were randomly selected from ten areas in the United States during the period 1977-1978. These individuals participated in the control series of the National Bladder Cancer Study. We estimated, based on Axelson's method, the extent to which smoking habits for given occupational groups would confound the estimated relative risk for lung cancer for 62 occupations among men and 18 occupations among women. Among men, confounding by smoking resulted in a 30% or greater increased risk of lung cancer in only three occupational groups--namely, stationary engineers and power station operators (relative risk (RR) = 1.6), printers (RR = 1.3), and fishermen and sailors (RR = 1.3). A decrease in lung cancer risk of 0.8 or less due to smoking habits was observed among the clergy (RR = 0.5) and chemical workers (RR = 0.7). Among women, a 30% increase or greater in the risk of lung cancer based on smoking habits alone was found for food service workers (RR = 1.5), building managers and administrators (RR = 1.3), telephone and telegraph operators (RR = 1.3), and operatives (RR = 1.3). A risk ratio of 0.8 or less was observed for those women employed as farmers (RR = 0.5) and teachers (RR = 0.8). Smoking habits by duration of employment were also examined for 38 occupations among men. The largest increase in the risk of lung cancer based on the smoking habits among long-term workers was only 1.3 and was observed for those men employed 20 or more years as painters and as electricians. These findings suggest that the smoking patterns, in only a few occupational groups that we evaluated, confound estimates of the relative risk by more than 30%, and for most occupational groups under investigation in this study, confounding by smoking alone did not produce trends in relative risks by duration of employment.

Occupational risks of bladder cancer in the United States: I. White men.

We examined the relationship between occupation and bladder cancer risk using data obtained from interviews conducted with 2,100 white males with bladder cancer and 3,874 population controls during the National Bladder Cancer Study, a population-based, case-control study conducted in 10 areas of the United States. The strongest evidence of increased risk among white men was observed for painters, truck drivers, and drill press operatives. For painters, the overall relative risk was 1.5 [95% confidence intervals (CI) = 1.2-2.0]. Among painters who started working prior to 1930, a significant trend in risk with increasing duration of employment as a painter was apparent; the relative risk for such painters employed 10 or more years was 3.0. For truck drivers and drill press operatives, overall risks were 1.3 (CI = 1.1-1.4) and 1.4 (CI = 0.9-2.1), respectively. We observed a significant, positive trend in risk with increasing duration of employment in each of these occupations, with relative risks peaking at approximately two for long-term workers. Excess risks were also observed for workers in several other occupations. In all, we estimate that 21%-25% of bladder cancer diagnosed among white men in the United States is attributable to occupational exposures.

Occupational risks of bladder cancer in the United States: II Nonwhite men.

Occupational risks of bladder cancer among nonwhite men were assessed based on interviews with 126 cases and 383 controls conducted during the National Bladder Cancer Study, a population-based, case-control study conducted in 10 areas of the United States. Our findings indicated that nonwhite men who were ever employed as auto workers have an elevated risk of bladder cancer [relative risk (RR) = 2.3; 95% confidence intervals (CI) = 0.8-6.4] with a significant positive trend in RR with increasing duration of employment (P = .017) and with the RR rising to 4.7 for those employed at least 10 years. Dry cleaners, ironers, and pressers also experienced increased bladder cancer risk (RR = 2.8, CI = 1.1-7.4). Nonsignificant excesses of similar magnitude to those seen among white men were found for nonwhite men employed in several other occupations. Overall, our findings suggest that the risk of occupational bladder cancer among white and nonwhite men is similar. When inconsistencies between whites and nonwhites did occur, they appeared either due to chance or possibly racial differences in exposure among men within the same industry and occupation. In all, we estimate that the population attribute risk for occupation among nonwhite U.S. men is 27% (CI = 9% to 56%), which is slightly higher than the estimate of 21% to 25% previously reported for white U.S. men, although this difference was not statistically significant.

Occupation and lung cancer in Shanghai: a case-control study.

Occupation was evaluated as a potential risk factor for lung cancer as part of a large population based case-control study conducted in the ten urban districts of Shanghai. A total of 733 newly diagnosed cases of male lung cancer and 760 controls selected from the general population was interviewed to obtain lifetime occupational histories and information on smoking and other factors. Of the approximately 25 major industrial titles examined, significantly raised risks, adjusted for smoking, were found for employment in agricultural production (odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.0-2.6). A concomitant increase was detected for farmers (OR = 1.6, 95% CI = 1.0-2.5) when 35 major occupational titles were examined. There was a 70% excess among workers in the chemical industry (OR = 1.7, 95% CI = 0.9-3.1) and a significant decrease among textile industry workers (OR = 0.7, 95% CI = 0.5-1.0). Raised risks of 30% to 80% were associated with reported job exposures to wood and coal dusts, smoke from burning fuels, and chemical fumes. Employment categories were also examined for 672 cases and 735 controls among women, but small numbers in many of the industrial and occupational categories precluded detailed analyses. The largest excess risk among women (OR = 5.1, 95% CI 1.3-23.5) was among glass products workers. Although cigarette smoking was the dominant cause of lung cancer among men and a significant risk factor among women in Shanghai, these findings suggest the importance of certain workplace exposures and offer leads to occupational carcinogens.

Decreased risk of lung cancer in the cotton textile industry of Shanghai.

The relationship between lung cancer risk and work in the cotton textile industry was investigated in a large population-based case-control study in urban Shanghai, where the industry is a major employer of men and women. Personal interviews obtained occupational, smoking, and other information from 1405 newly diagnosed lung cancer cases and 1495 controls. A significantly low risk of lung cancer was associated with cotton textile employment [odds ratio (OR) = 0.7,95% confidence interval (CI) = 0.6-0.9]. In men, the decreased risk was observed among both smokers (OR = 0.7, 95% CI = 0.5-1.1) and nonsmokers (OR = 0.3, 95% CI = 0.1-1.0). In women, the risk was also decreased regardless of smoking status (OR = 0.8, 95% CI = 0.4-1.6 among smokers; OR = 0.9, 95% CI = 0.6-1.2 among nonsmokers). In both sexes, the reductions in risk tended to be greater for lung cancer cell types other than adenocarcinoma. Low risks were found regardless of occupations within the cotton textile industry; the OR for workers in textile processing who potentially had greater dust exposure was 0.8 (95% CI = 0.6-1.2), whereas the OR for those in other industry jobs was 0.7 (95% CI = 0.4-1.0). There was little difference in risk according to self-reported exposure to textile dust, and no clear trend with duration of employment or dust exposure. Reasons for the reduced risk of lung cancer in cotton textile workers without a dose response are unclear, although several methodological explanations were considered. The findings, however, appear consistent with prior epidemiological studies and are interesting in light of speculation about tumor-inhibitory factors, such as bacterial endotoxins, that are found in dusts from cotton and other fiber crops.

Lung cancer among Chinese women.

A case-control study involving interviews with 672 female lung cancer patients and 735 population-based controls was conducted to investigate the high rates of lung cancer, notably adenocarcinoma, among women in Shanghai. Cigarette smoking was a strong risk factor, but accounted for only about one-fourth of all newly diagnosed cases of lung cancer. Most patients, particularly with adenocarcinoma, were life-long non-smokers. The risks of lung cancer were higher among women reporting tuberculosis and other pre-existing lung diseases. Hormonal factors were suggested by an increased risk associated with late menopause and by a gradient in the risk of adenocarcinoma with decreasing menstrual cycle length, with a 3-fold excess among women who had shorter cycles. Perhaps most intriguing were associations found between lung cancer and measures of exposure to cooking oil vapors. Risks increased with the numbers of meals cooked by either stir frying, deep frying or boiling; with the frequency of smokiness during cooking; and with the frequency of eye irritation during cooking. Use of rapeseed oil, whose volatiles following high-temperature cooking may be mutagenic, was also reported more often by the cancer patients. The findings thus confirm that factors other than smoking are responsible for the high risk of lung cancer among Chinese women and provide clues for further research, including the assessment of cooking practices.

Lung cancer and prior tuberculosis infection in Shanghai.

In a population-based case-control study of lung cancer in Shanghai involving interviews during 1984-86 with 1,405 cancer patients and 1,495 controls, a significant 50% elevation in the risk of lung cancer, adjusted for cigarette smoking, was observed among persons who had a history of tuberculosis. Among those diagnosed with tuberculosis within the past 20 years, the risk exceeded 2.5-fold. In males the lung cancers tended to occur on the same side as the previous tuberculosis infection. For both sexes, the effect of recent tuberculosis was most apparent for adenocarcinoma and peripheral tumours. No relationship was found between lung cancer risk and the type of tuberculosis therapy, including use of isoniazid. The findings suggest that tuberculosis may predispose to lung cancer, with the association most apparent among recent survivors of the infection.

Selected epidemiologic observations of cell-specific leukemia mortality in the United States, 1969-1977.

Utilizing a newly available data set which includes for the first time cell-specific leukemia mortality rates for the United States during 1969-1977, age and sex distributions, time trends, and geographic patterns were analyzed. Four major cell types of leukemia were considered. Acute lymphatic leukemia had a bimodal distribution with the first peak in the 5-9-year age group and lowest rates in age group 35-44, after which rates rose geometrically. Acute myeloid leukemia had only a very small childhood peak with a low in the age group 5-9, after which the rates also rose geometrically. For both chronic lymphatic and myeloid leukemia the rates rose geometrically after age 15. Rates among females were consistently lower for each age group. The highest sex ratio was found for chronic lymphatic leukemia and is proposed to be the result of a lag period between male and female rates. During the period under study acute lymphatic leukemia mortality in adults declined by almost 10% while acute myeloid leukemia mortality increased by almost 20%. Analysis of the geographic variation of the four major cell types revealed a geographic association between acute lymphatic and acute myeloid leukemia in children, a lack of association between childhood and adult cell types, and an association of acute and chronic cell types in adults.