Changes in plasma lipid and lipoprotein cholesterol and weight prior to the diagnosis of cancer.

Changes in lipoprotein cholesterol, total plasma cholesterol, and weight prior to the diagnosis of cancer were examined in 103 men who developed cancer in a cohort of 3805 type IIa hyperlipidemic men aged 35-59 enrolled in the Lipid Research Clinics Coronary Primary Prevention Trial. Study measurements were made bimonthly. After adjusting for the effects of the trial intervention and other determinants of lipid levels, the cholesterol levels of the cases diagnosed with nonlocalized cancer dropped below the expected level approaching diagnosis when compared to the entire study population. The decrease averaged 9.3 mg/dl and began about 2 years prior to diagnosis. Weight levels dropped an average of 1.2 kg over the same period. Weight and cholesterol were significantly lower than expected within 8 months of diagnosis (P less than 0.05). No decrease was seen for those diagnosed with localized malignancies. Patterns for low-density lipoprotein cholesterol reflected those of total cholesterol. There was no clear relationship between cancer diagnosis and patterns of change for triglycerides and high-density lipoprotein cholesterol. In the future, investigations of any relationship between a host physiological state and cancer occurrence should account for the metabolic effects of preclinical disease demonstrated here. To protect against spurious conclusions, incident cases occurring within 2 years of measurement should be analyzed separately. In studies of cancer mortality, deaths occurring within 3.5 years of the base-line measurement should be analyzed separately.

Treatment patterns and distribution of low-density lipoprotein cholesterol levels in treatment-eligible United States adults.

To estimate the fraction of United States (U.S.) adults who are eligible for treatment to reduce elevated low-density lipoprotein (LDL) cholesterol levels based on Adult Treatment Panel II (ATP II) guidelines and the percent reduction in LDL cholesterol required by those who qualify for treatment, we analyzed data on 7,423 respondents to Phase 2 of the third National Health and Nutrition Examination Survey (NHANES III) administered between 1991 and 1994. Approximately 28% of the U.S. adult population aged > or = 20 years is eligible for treatment based on ATP II guidelines. Eighty-two percent of adults with coronary heart disease are not at their target LDL cholesterol level of 100 mg/dl. Of those eligible for treatment, 65% report that they receive no treatment. Overall, 40% of people who qualify for drug therapy require an LDL cholesterol reduction of > 30% to meet their ATP II treatment goal. Approximately 75% of those with coronary heart disease who qualify for drug therapy require an LDL cholesterol reduction of >30%. Although elevated LDL cholesterol levels can be treated, prevalence rates in the U.S. adult population remain high. Several recent studies indicate that a considerable percentage of people treated with drug therapy do not reach their treatment goals. The findings in this study provide at least a partial explanation for why many patients receiving therapy do not reach their treatment goals: they require a larger reduction in LDL cholesterol than many therapies can provide.

Biological markers of intermediate outcomes in studies of indoor air and other complex mixtures.

Biological markers of intermediate health outcomes sometimes provide a superior alternative to traditional measures of pollutant-related disease. Some opportunities and methodologic issues associated with using markers are discussed in the context of exposures to four complex mixtures: environmental tobacco smoke and nitrogen dioxide, acid aerosols and oxidant outdoor pollution, environmental tobacco smoke and radon, and volatile organic compounds. For markers of intermediate health outcomes, the most important property is the positive predictive value for clinical outcomes of interest. Unless the marker has a known relationship with disease, a marker response conveys no information about disease risk. Most markers are nonspecific in that various exposures cause the same marker response. Although nonspecificity can be an asset in studies of complex mixtures, it leads to problems with confounding and dilution of exposure-response associations in the presence of other exposures. The timing of a marker's measurement in relation to the occurrence of exposure influences the ability to detect a response; measurements made too early or too late may underestimate the response's magnitude. Noninvasive markers, such as those measured in urine, blood, or nasal lavage fluid, are generally more useful for field studies than are invasive markers. However, invasive markers, such as those measured in bronchoalveolar lavage fluid or lung specimens from autopsies, provide the most direct evidence of pulmonary damage from exposure to air pollutants. Unfortunately, the lack of basic information about marker properties (e.g., sensitivity, variability, statistical link with disease) currently precludes the effective use of most markers in studies of complex mixtures.

A sensitive color ELISA for detecting polycyclic aromatic hydrocarbon-DNA adducts in human tissues.

Human exposure to polycyclic aromatic hydrocarbons (PAHs) has been determined by measurement of DNA adducts in human tissues. Competitive enzyme-linked immunosorbent assays (ELISAs) using antisera recognizing benzo[a]pyrenediol-epoxide-modified DNA (BPDE-I-DNA) and color of fluorescence endpoint detection have been used extensively for quantifying PAH-DNA adducts. The fluorescence ELISA (limit of detection 1 adduct/10(8) nucleotides) was previously reported to be more sensitive than the color ELISA (1/10(7)) for measuring PAH adducts (Santella et al. (1988) Carcinogenesis, 9, 1265-1269). However, the fluorescence assay has the disadvantages of greater variation among the replicates and higher background levels than the color assay. Using a newly developed antiserum against BPDE-I-DNA, we have modified the color of ELISA so that it has the same sensitivity as the fluorescence ELISA and requires only 33% of the sample quantity needed for the fluorescence ELISA. The modifications included preincubation of the antiserum with the samples, using microtiter plates with half-size, flat bottom wells, and optimizing the assay conditions. The improved color ELISA was used to analyze DNA samples from human autopsy tissues, including heart, lung, liver, kidney, spleen, pancreas and stomach from smokers and nonsmokers. With the exception of spleen and stomach, all tissues from smokers showed higher PAH-DNA adducts (ranging from 0.3 to 19.0 adducts/10(7) nucleotides) than the tissues from the nonsmokers (0.3 to 3.7 adducts/10(7) nucleotides) in two separate experiments. Among the tissues from smokers, heart showed the highest level of DNA adducts. This study demonstrates that a stable color ELISA with high sensitivity can be useful in assessing human exposure to PAH.

Mortality from heart disease among workers exposed to solvents.

Several rubber industry jobs that are associated with cardiovascular disease (CVD) mortality involve the use of solvents and, since the only known occupational cause of atherosclerosis is a solvent (carbon disulfide), solvent exposures may contribute to the CVD excess observed among rubber industry workers. Detailed exposure estimates for 25 solvents were available for a cohort of 1,282 white male production workers in a large rubber- and tire-manufacturing plant, and a survivorship analysis compared the CVD mortality experience of exposed and nonexposed workers during a 15-year follow-up period. The known association between carbon disulfide exposure and ischemic heart disease (IHD) was apparent among these workers, and two other solvents, ethanol and phenol, were also found to be significant predictors of IHD. These exploratory findings suggest that solvents other than carbon disulfide may cause atherosclerotic disease.

A comparison of direct adjustment and regression adjustment of epidemiologic measures.

Although regression adjustment can provide a useful alternative to direct adjustment, especially when data are sparse, many researchers are unaware that adjusted summary measures can be easily derived from regression coefficients. In a non-technical discussion with examples, the direct adjustment procedure is compared with three methods of regression adjustment based on analysis of covariance models: the conditional prediction method, the stratified prediction method, and the marginal prediction method. Both the stratified prediction and direct adjustment methods yield summary measures that are weighted averages of stratum-specific measures, while adjusted measures from the conditional prediction method are similar to stratum-specific estimates. In contrast to the other adjustment procedures, which can use internal or external weights, the marginal prediction method always gives an internally adjusted measure. Under certain conditions, the three regression adjustment procedures produce identical results. Major advantages of direct adjustment include computational simplicity and relatively few statistical assumptions. Regression adjustment, however, is more convenient for statistical tests for interactions and group differences, and often precludes the need to categorize continuous variables, so that problems with empty strata are avoided.

Solvent exposure and cardiovascular disease.

A review of cardiovascular disease (CVD) resulting from environmental exposures pointed out the lack of studies concerned with the cardiovascular effects of hazardous environmental exposures. A later Working Group report on CVD in the workplace recommended further occupational studies of CVD, and it identified carbon monoxide, nitrates, and organic solvents as exposures especially deserving of study. The literature lacks a detailed, critical epidemiologic overview of work on this last topic. Therefore, the following review focuses on the cardiovascular effects of solvent exposures. Some major difficulties inherent in studies of CVD and environmental exposures are brought out, and some suggested areas for future epidemiologic research are discussed.

Cancer mortality and solvent exposures in the rubber industry.

Some evidence suggests that solvent exposures to rubber industry workers may be associated with excess cancer mortality, but most studies of rubber workers lack information about specific chemical exposures. In one large rubber and tire-manufacturing plant, however, historical documents allowed a classification of jobs based on potential exposures to all solvents that were authorized for use in the plant. A case-control analysis of a 6678 member cohort compared the solvent exposure histories of a 20% age-stratified random sample of the cohort with those of cohort members who died during 1964-1973 from stomach cancer, respiratory system cancer, prostate cancer, lymphosarcoma, or lymphatic leukemia. Of these cancers, only lymphosarcoma and lymphatic leukemia showed significant positive associations with any of the potential solvent exposures. Lymphatic leukemia was especially strongly related to carbon tetrachloride (OR = 15.3, p less than .0001) and carbon disulfide (OR = 8.9, p = .0003). Lymphosarcoma showed similar, but weaker, associations with these two solvents. Benzene, a suspected carcinogen, was not significantly associated with any of the cancers.

Isoniazid-related fatal hepatitis.

To describe the clinical and demographic characteristics of fatal hepatitis due to single-drug isoniazid preventive therapy for tuberculosis, we did a survey of cases from state health departments, published case reports, and reports to the Centers for Disease Control and Prevention from 1970 to 1992. Of 108 reported cases, some clinical information was available for 76. A medical review panel judged 39 of these deaths as probably due to isoniazid hepatitis and 23 deaths as possibly due to isoniazid hepatitis. Of the 62 probable and possible cases combined, 50 (81%) were female, 49 (79%) were non-Hispanic black or Hispanic, and 19 (31%) were younger than 35 years. The median duration of isoniazid preventive therapy before symptom onset was 16 weeks. Of the 60 cases with symptom information, 54 (90%) presented with jaundice. Of the 62 cases, 26 (42%) were monitored monthly in accordance with current recommendations, and 6 of the patients were younger than 35 years. We estimate that the rate of fatal isoniazid hepatitis among patients in the public sector was no greater than 4.2 per 100,000 persons beginning therapy and no greater than 7 per 100,000 persons completing therapy. Adherence to isoniazid preventive therapy guidelines apparently reduces, but does not eliminate, the risk of fatal hepatitis. Careful patient selection, education, and monitoring are critical for minimizing that risk.

Dyslipoproteinemia in black participants. The Lipid Research Clinics Program Prevalence Study.

A comparison of blacks and whites 6 to 49 years old revealed striking differences between races with respect to the prevalence of various dyslipoproteinemias and mean plasma lipid levels. Compared with whites, juvenile and adult blacks of both sexes had higher mean levels of high-density lipoprotein cholesterol (HDL-C), with correspondingly higher prevalences of the hyperHDL and hypoLDL (low-density lipoprotein) phenotypes. In contrast, whites showed a much higher prevalence of type IV hyperlipoproteinemia and higher mean triglyceride levels in most age-sex groups. Although juvenile blacks had higher mean levels of LDL-C than did whites, this race difference was reversed in men, while women showed inconsistent differences between races. Adult black men and juvenile blacks of both sexes had a somewhat higher prevalence of the type IIA phenotype than whites. The distribution of major HDL-C predictors in this population could not account for the difference in prevalence of hyperHDL between races. These findings suggest that health professionals may find differences in plasma lipid and lipoprotein patterns between their black and white patients, but additional research is needed to ascertain the disease risks associated with dyslipoproteinemia among blacks.

Incidence of tuberculosis in the United States among HIV-infected persons. The Pulmonary Complications of HIV Infection Study Group.

BACKGROUND: The resurgence of tuberculosis in the United States is largely linked to the human immunodeficiency virus (HIV) epidemic. Despite this link, the epidemiology of tuberculosis and preventive strategies in patients infected with HIV are not completely understood. OBJECTIVES: To determine the incidence and predictors of tuberculosis in HIV-infected persons. DESIGN: Prospective, multicenter cohort study. SETTING: Community-based cohort of persons with and without HIV infection at centers in the eastern, midwestern, and western United States. PARTICIPANTS: 1130 HIV-seropositive patients without AIDS who were followed for a median of 53 months (814 homosexual men, 261 injection drug users, and 55 women who had acquired HIV through heterosexual contact). MEASUREMENTS: Delayed hypersensitivity response to purified protein derivative (PPD) tuberculin and mumps antigen, CD4 T-lymphocyte counts, and frequency of tuberculosis. RESULTS: 31 HIV-seropositive patients developed tuberculosis (0.7 cases per 100 person-years [95% CI, 0.5 to 1.0]). The most important demographic risk factor was location (adjusted risk ratio for eastern compared with midwestern and western United States, 4.1 [CI, 2.0 to 8.4]). Tuberculosis occurred more frequently in persons with CD4 counts of less than 200 cells/mm3 (1.2 cases per 100 person-years [CI, 0.7 to 1.9]) than in those with higher counts (0.5 cases per 100 person-years [CI, 0.3 to 0.8]). The rate of tuberculosis was highest among tuberculin converters (5.4 cases per 100 person-years [CI, 1.1 to 15.7]), lower among patients who were PPD positive at first testing (4.5 cases per 100 person-years [CI, 1.6 to 9.7]), and lowest among patients who remained PPD negative (0.4 cases per 100 person-years [CI, 0.2 to 0.7]). Tuberculosis was not reported among persons who had PPD reactions of 1 to 4 mm. Compared with that of patients who tested positive for mumps, the risk for tuberculosis of those who tested negative was increased about sevenfold if they were PPD positive (P < 0.03) and fourfold if they were PPD negative (P < 0.02). CONCLUSIONS: Incidence of tuberculosis was higher in the eastern United States, in patients with CD4 counts of less than 200 cells/mm3, and in PPD-positive patients. Analysis of tuberculin reaction size supports the current interpretive criteria of the Centers for Disease Control and Prevention. Nonreactivity to mumps antigen indicated increased risk for tuberculosis independent of PPD response.

Bacterial pneumonia in persons infected with the human immunodeficiency virus. Pulmonary Complications of HIV Infection Study Group.

BACKGROUND: Patients with human immunodeficiency virus (HIV) infection are at increased risk for bacterial pneumonia in addition to opportunistic infection. However, the risk factors for bacterial pneumonia and its incidence in this population are not well defined. METHODS: In a multicenter, prospective, observational study, we monitored 1130 HIV-positive and 167 HIV-negative participating adults for up to 64 months for pulmonary disease. The HIV-positive group comprised 814 homosexual or bisexual men, 261 injection-drug users, and 55 female partners of HIV-infected men. RESULTS: There were 237 episodes of bacterial pneumonia among the HIV-positive participants (rate, 5.5 per 100 person-years), as compared with 6 episodes among the HIV-negative participants (rate, 0.9 per 100 person-years; P < 0.001). The rate of bacterial pneumonia increased with decreasing CD4 lymphocyte counts (2.3, 6.8, and 10.8 episodes per 100 person-years in the strata with more than 500, 200 to 500, and fewer than 200 cells per cubic millimeter, respectively; P < or = 0.022 for each comparison). Injection-drug users had a higher rate of bacterial pneumonia than did homosexual or bisexual men or female partners. In the stratum with the fewest CD4 lymphocytes, cigarette smoking was associated with an increased rate of pneumonia. Mortality was almost four times higher among participants with an episode of pneumonia than among the others. Prophylaxis with trimethoprim-sulfamethoxazole was associated with a 67 percent reduction in confirmed episodes of bacterial pneumonia (P = 0.007). CONCLUSIONS: Bacterial pneumonia is more frequent in HIV-positive persons than in seronegative controls, and the risk is highest among those with CD4 lymphocyte counts below 200 per cubic millimeter and among injection-drug users.

Cellular-telephone use and brain tumors.

BACKGROUND: Concern has arisen that the use of hand-held cellular telephones might cause brain tumors. If such a risk does exist, the matter would be of considerable public health importance, given the rapid increase worldwide in the use of these devices. METHODS: We examined the use of cellular telephones in a case-control study of intracranial tumors of the nervous system conducted between 1994 and 1998. We enrolled 782 patients through hospitals in Phoenix, Arizona; Boston; and Pittsburgh; 489 had histologically confirmed glioma, 197 had meningioma, and 96 had acoustic neuroma. The 799 controls were patients admitted to the same hospitals as the patients with brain tumors for a variety of nonmalignant conditions. RESULTS: As compared with never, or very rarely, having used a cellular telephone, the relative risks associated with a cumulative use of a cellular telephone for more than 100 hours were 0.9 for glioma (95 percent confidence interval, 0.5 to 1.6), 0.7 for meningioma (95 percent confidence interval, 0.3 to 1.7), 1.4 for acoustic neuroma (95 percent confidence interval, 0.6 to 3.5), and 1.0 for all types of tumors combined (95 percent confidence interval, 0.6 to 1.5). There was no evidence that the risks were higher among persons who used cellular telephones for 60 or more minutes per day or regularly for five or more years. Tumors did not occur disproportionately often on the side of head on which the telephone was typically used. CONCLUSIONS: These data do not support the hypothesis that the recent use of hand-held cellular telephones causes brain tumors, but they are not sufficient to evaluate the risks among long-term, heavy users and for potentially long induction periods.

Tuberculin and anergy testing in HIV-seropositive and HIV-seronegative persons. Pulmonary Complications of HIV Infection Study Group.

OBJECTIVE: To determine the prevalence and predictors of reactivity to tuberculin purified protein derivative (PPD) and skin test anergy in patients with human immunodeficiency virus (HIV) infection and in HIV-seronegative controls. DESIGN: Cross-sectional analysis of baseline data from a prospective, multicenter study of pulmonary complications of HIV infection. SETTING: Community-based cohort of persons with and without HIV infection. PATIENTS: A total of 1171 HIV-seropositive patients without AIDS (841 homosexual men, 274 intravenous drug users, and 56 women with heterosexually acquired infection); 182 HIV-seronegative persons (125 homosexual men and 57 intravenous drug users). MEASUREMENTS: Delayed-type hypersensitivity response to tuberculin PPD, trichophytin, mumps, and Candida antigens; T-lymphocyte subsets. RESULTS: The prevalence of tuberculin PPD reactivity was higher among intravenous drug users than among homosexual men, in both HIV-seronegative (19.1% compared with 6.8%, P = 0.03) and HIV-seropositive persons (15.1% compared with 2.5%, P < 0.001). Among HIV-infected patients, the prevalence of tuberculin reactivity varied directly and that of anergy inversely with the absolute CD4 lymphocyte count. Prevalences were 1% and 72%, respectively, in patients with fewer than 200 CD4 cells/mm3, and 8.4% and 25.5%, respectively, in those with 600 CD4 cells/mm3 (P < 0.001 for both comparisons). Patients with HIV infection and fewer than 400 CD4 lymphocytes/mm3 had a lower prevalence of PPD reactivity than HIV-seronegative controls (2.7% compared with 10.0%, P < 0.001). The strongest predictors of tuberculin reactivity were intravenous drug use, black race, a previous positive PPD test result, and a history of Calmette-Guérin bacillus vaccination. The strongest predictor of anergy was HIV seropositivity. CONCLUSIONS: The response to delayed-type hypersensitivity antigens depends on immune status. The value of PPD and anergy testing in HIV-seropositive patients depends on the ability of such testing to predict subsequent tuberculosis, which is imprecisely known. Until more data or better methods are available, these tests should be done as early as possible in the course of HIV infection.