Smoking and Parkinson's disease in twins.

OBJECTIVE: To test the hypothesis that cigarette smoking protects against the development of PD. BACKGROUND: Smoking has been inversely associated with PD in many studies, but whether this reflects a biologic effect on the underlying disease process or merely confounding or selection bias remains uncertain. METHODS: The authors compared smoking histories in male twin pairs identified from the National Academy of Sciences--National Research Council World War II Veteran Twins Cohort. The amount of cigarettes smoked (in pack-years) was collected until the time of PD onset in the affected twin or until the time of death for the unaffected twin, whichever came first. Differences in pack-years smoked until PD onset and until 10 and 20 years before onset were compared using paired t-tests. Comparisons were made overall and stratified by zygosity and concordance for PD. To assess the role of shared environment, correlation for smoking behaviors was compared between pairs concordant and discordant for PD. RESULTS: Detailed smoking histories were available for 113 twin pairs in which at least one twin had PD (discordant pairs: 43 monozygotic [MZ], 50 dizygotic [DZ]; concordant pairs: 10 MZ, 10 DZ). Within-pair correlation for ever smoking was high in MZ pairs (phi = 0.47, p = 0.001) but not in DZ pairs (phi = 0.007, p = 0.96). In 33 discordant MZ pairs and 39 discordant DZ pairs in which at least one twin had smoked, the twins without PD smoked more than their brothers smoked (32.5 vs. 22.7 pack-years, p = 0.026). This was more marked in the MZ pairs (37.1 vs. 25.3 pack-years, p = 0.077) than in the DZ pairs (28.6 vs. 20.5 pack-years, p = 0.17). A similar relationship was seen when smoking dose was calculated only until 10 years before PD onset, suggesting that the lower dose of smoking in the twin with PD was not the result of early, undiagnosed disease. CONCLUSION: Within twin pairs, risk of PD is inversely correlated with the dose (in pack-years) of cigarette smoking. This effect is most pronounced in MZ twins, despite the high correlation for smoking. Because MZ twins are genetically identical and are similar behaviorally, this difference is unlikely to result from either genetic factors or environmental confounders. These results are compatible with a true biologic protective effect of cigarette smoking.

Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology.

OBJECTIVE: To determine the relative contribution of genetics and environment to essential tremor using a twin study method. METHODS: Twins with postural or kinetic tremor were identified by movement disorders specialists during the conduct of a study investigating PD in members of the National Academy of Sciences and National Research Council World War II Veteran Twins Registry. The diagnosis of essential tremor was made by consensus using established diagnostic criteria. RESULTS: A total of 196 twins had postural or kinetic tremor on examination. Of these, 137 had PD or had a twin with PD and were excluded from this study. Thirty-three others were excluded because of incomplete data for their twin. Sixteen twin pairs were identified in which at least one twin had essential tremor. Pairwise concordance in monozygotic twins was approximately two times that in dizygotic twins (0.60 monozygotic, 0.27 dizygotic). CONCLUSION: This pattern is consistent with a genetic cause of essential tremor. Because monozygotic concordance is not 100%, environmental factors may also play a role in the cause of the disease.

Epidemiology of Parkinson's disease and akinetic syndromes.

New reports of the incidence, prevalence and mortality of Parkinson's disease and parkinsonism are reviewed. Evidence for occupational and lifestyle risk factors and protective factors is updated. Recent genetic epidemiology studies of parkinsonism in twins and families, and studies that investigated imaging and physiologic markers of dopaminergic function in members without parkinsonism are presented.

Intraocular melanoma linked to occupations and chemical exposures.

We conducted a case-control study in the western United States to determine the relation between occupations or chemical exposures and increased risk of uveal melanoma. Among men (221 patients, 447 controls), we found increased risks for occupational groups who had intense exposure to ultraviolet light [odds ratio (OR) = 3.0; 95% confidence interval (CI) = 1.2-7.8], welding exposure (OR = 2.2; 95% CI = 1.3-3.5), and asbestos exposure (OR = 2.4; 95% CI = 1.5-3.9 for most likely exposed). The highest odds ratio was for the small number of men (nine cases, three controls) who were chemists, chemical engineers, and chemical technicians (OR = 5.9; 95% CI = 1.6-22.7). Odds ratios also were elevated for exposures to antifreeze, formaldehyde, pesticides, and carbon tetrachloride, but these findings, based on recall of specific chemical exposures, are more subject to recall bias than the findings based on occupational groups.

Cutaneous melanoma in women. I. Exposure to sunlight, ability to tan, and other risk factors related to ultraviolet light.

A population-based case-control study of cutaneous malignant melanoma (CMM) was conducted in 452 women with melanoma and 930 control subjects aged 25-59 years in five San Francisco Bay Area counties between 1981 and 1986. Women were interviewed in their homes with regard to history of sunlight exposure and sunburns during different periods in their lives, phenotypic and host characteristics, medical history, occupation, and demographic factors. Data were analyzed by the patients' histologic type of melanoma; 355 women were classified as having superficial spreading melanoma (SSM), 61 had nodular melanoma (NM), 13 had lentigo maligna melanoma, and 23 had other melanomas that could not be further classified upon histologic review by University of California dermatopathologists. Univariate results from analysis of factors related to sun exposure showed that the risk of all histologic types of CMM, SSM, and NM increased with increasing tendency of the subject to sunburn and with history of increased severity and/or frequency of sunburns up to age 12 years. Risk of all types of CMM and SSM also increased with increasing number of sunburns for all age groups and with lack of use of sunscreen. After adjustment for each other and for phenotypic factors, history of sunburn up to age 12 and lack of sunscreen use were the primary sun-related factors associated with an increased risk of all types of CMM and SSM, while tendency to sunburn when exposed to 1/2 hour of noontime sun and lack of use of sunscreen were related to NM. Although having frequent sunburns before age 12 and having severe sunburns before age 12 were both strongly associated with melanoma, having large numbers of sunburns during any time period from elementary school through age 30 years and having sunburns during the 10 years prior to diagnosis or interview were all associated with a doubling of risk for SSM after adjustment for other factors. These results suggest that the increased risk of melanoma related to sunburns is not confined to childhood sunburns. Maintenance of an all-year tan provided no protective effect against melanoma after adjustment for tendency to burn. No association was noted with use of fluorescent lights or exposure to sunlamps for all types of CMM, SSM, or NM.

Cutaneous melanoma in women. II. Phenotypic characteristics and other host-related factors.

A total of 452 women with cutaneous malignant melanoma and 930 control subjects aged 25-59 years participated in a population-based case-control study carried out in the San Francisco Bay Area between 1981 and 1986. Interviews were conducted in the homes of the women. Questions were asked about various phenotypic characteristics, including eye, hair, and complexion color, presence of freckles, and number of nevi, as well as medical history, history of exposure to sunlight, ability to tan, occupation, use of cigarettes and alcohol, and demographic factors. Histologic type of melanoma was considered in the analysis: 355 (79%) women were diagnosed with superficial spreading melanoma, 61 (13%) had nodular melanoma, 13 (3%) had lentigo maligna melanoma, and 23 (5%) had other melanomas that could not be further classified. For all cutaneous melanoma subjects combined, univariate results related to host factors showed that risk increased with the presence of nevi greater than 5 mm in diameter; light eyes, hair, and complexion; freckles; a history of skin cancer other than melanoma; a history of skin cancer in relatives; and maternal and paternal Northern or Central European ancestry. After adjustment for each other and for sun exposure factors, the phenotypic and host factors associated with all types of cutaneous malignant melanoma and superficial spreading melanoma were the presence of large nevi, light hair color, light complexion, and maternal Northern or Central European ancestry. Host factors associated with nodular melanoma after adjustment for other factors were the presence of large nevi, light hair color, ever being overweight by 20 pounds (9 kg) or more, and the presence of freckles.

Contraceptive use among women smokers and nonsmokers in the San Francisco Bay area.

BACKGROUND: Women smokers were previously reported to be more sexually active but less likely to use contraception than nonsmokers. Differences in contraceptive choices between the two groups were investigated. METHODS: Sexually active women, 287 who smoked cigarettes and 263 who did not smoke, were queried about current contraceptive use and demographic, sexual, and reproductive factors. RESULTS: Sexually active smokers were less likely than nonsmokers to use contraceptives, especially oral contraceptives. The deficit of contraceptive use among smokers was most pronounced in women under age 30, black women, single women, women with some college education, nulliparous women, women who reported early age at first intercourse, and women who reported four or more lifetime sexual partners. In contrast, smokers were more than twice as likely as nonsmokers to use sterilization (P = 0.002). Among women over age 30, prevalence of contraceptive use was similar between the two groups. Oral contraceptives were used by fewer smokers than nonsmokers who were under age 24 (P = 0.01), had a high school education or less (P = 0.01), and/or had never been pregnant (P = 0.03). CONCLUSIONS: Young, sexually active women who smoked cigarettes were less likely than nonsmokers to have used contraceptives, especially oral contraceptives, while women smokers over age 30 were more likely than nonsmokers to have used sterilization.

Characteristics of women nonsmokers exposed to passive smoke.

BACKGROUND: Studies that have investigated the association between exposure to passive smoke and increased risk for disease have had inconclusive results and have raised questions about whether women exposed to passive smoke differ from those not exposed. METHODS: The study population included 120 women nonsmokers who reported that they had been exposed to passive smoke in the 24 hr prior to the interview and 213 women who reported no exposure. Women were queried about demographic, lifestyle, sexual, and reproductive factors. RESULTS: Exposed women were younger, less educated, and slightly heavier than nonexposed women. They were more likely to be divorced or separated (OR = 3.3, 95% CI = 1.4-7.6, P = 0.005), to have had first intercourse at or before age 16 (OR = 1.4, 95% CI = 1.0-1.9, P = 0.04), and to have had three or more live births (OR = 2.9, 95% CI = 1.2-6.8, P = 0.02). Women exposed to passive smoke were more likely to have consumed two or more cups of coffee (OR = 2.0, 95% CI = 1.1-3.8, P = 0.03), two or more glasses of beer (OR = 3.7, 95% CI = 1.1-12.5, P = 0.03), or to have smoked marijuana in the past 24 hr (OR = 14.7, 95% CI = 1.8-122.3, P = 0.01) than women who were not exposed. There were no differences noted between exposed and nonexposed women in history of gynecologic diseases or number of cervical microorganisms. CONCLUSION: Women exposed to passive smoke differed from those not exposed on several factors that should be considered in future studies that seek to investigate smoking-related disease risk.

Detection of mutagens in cervical mucus in smokers and nonsmokers.

The Salmonella mutagenicity test was used to analyze cervical mucus specimens from 364 smokers and 333 nonsmokers to determine whether the association between smoking and mutagenic cervical mucus that we reported previously among women diagnosed with dysplasia would apply to a larger group of healthy women (E. A. Holly et al., J. Natl. Cancer Inst., 76: 983-986, 1986). Women smokers and nonsmokers between the ages of 18 and 49 who attended eleven clinics and physicians' offices in the San Francisco Bay area for a routine Pap smear were examined to determine whether smokers were more likely to have mutagenic substances in their cervical mucus. About 4% of smokers and 8% of nonsmokers had positive mutagenicity test results (P = 0.02). Cervical mucus with a large number of microorganisms was more likely to have a positive mutagenicity test result than that with fewer microorganisms (test for trend, P = 0.01). Mutagenicity results varied by race and clinic location but were not associated with smoking behavior, sexual behavior, gynecological diagnosis, or diet. Further work is needed to develop methods to detect mutagens in specific body fluids.

Characteristics of women by smoking status in the San Francisco Bay Area.

To better understand why smokers are more likely to develop cervical cancer than nonsmokers, we investigated laboratory and demographic differences between the two groups. Women between the ages of 18 and 49 who attended eleven community clinics in the San Francisco Bay Area were studied to investigate differences between smokers and nonsmokers. The 332 smokers and 365 nonsmokers were queried about smoking habits, sexual and reproductive history, and recent diet. Cervical mucus specimens were cultured for yeast, lactobacillus, and other microorganisms. Results showed that white Hispanic women were less likely to smoke than white non-Hispanic women. Smokers, when compared to nonsmokers, consumed larger quantities of coffee, soft drinks, liquor, and beer in the 24 h prior to the interview. Women who smoked were more likely than those who did not smoke to have had first sexual intercourse before age 16, had a greater number of lifetime sexual partners, and were more likely than nonsmokers to have been pregnant. After controlling for number of sexual partners, smokers reported a history of chlamydia, gonorrhea, and/or pelvic inflammatory disease more often than did nonsmokers, and cervical mucus of smokers was more likely than that from nonsmokers to contain greater than 8500 microorganisms/ml.

Ewing's bone sarcoma, paternal occupational exposure, and other factors.

To determine risk factors for Ewing's bone sarcoma, the authors interviewed mothers of 43 patients diagnosed between January 1978 and August 1986 and 193 controls in the San Francisco Bay Area, California, regarding medical and occupational history of parents and other factors related to the subjects and their immediate families. Controls were selected by using random digit dial telephone methods. Adjusted relative risk estimates suggest that risks were elevated for children whose fathers were engaged in agricultural occupations during the period from 6 months prior to conception of the subject up to the time of diagnosis for the patients or interview for the controls (relative risk (RR) = 8.8, 95% confidence interval (CI) 1.8-42.7) and for children whose fathers had occupational exposure to herbicides, pesticides, or fertilizers (RR = 6.1, 95% CI 1.7-21.9, p = 0.002). Prior ingestion of poison or an overdose of medication was more common in patients than in controls (RR = 4.4, 95% CI 1.4-13.5). These and other findings should be investigated in larger population-based studies to determine specific factors that may account for the associations.

Temporal trends in the incidence of cutaneous malignant melanoma among Caucasians in the San Francisco-Oakland MSA.

Temporal changes in the incidence of cutaneous malignant melanoma (CMM) were examined in the San Francisco-Oakland (California, United States) Metropolitan Statistical Area (MSA) between 1976 and 1987, using data from the population-based cancer registry. This analysis was conducted after the completion of a project designed to eliminate bias in the reporting of CMM due to changes in medical practice. The incidence of CMM is higher in the San Francisco-Oakland MSA than nationally. From 1976 through 1987, the incidence of invasive CMM increased from 9.8 +/- 0.9 to 16.5 +/- 1.1 per 100,000 (P = 0.0001) among men and from 9.3 +/- 0.8 to 12.7 +/- 0.9 per 100,000 (P = 0.001) among women. Age-specific, histologic-specific, and anatomic site-specific trends were also evaluated. The temporal patterns of CMM suggest that the recent increases are not accounted for solely by ascertainment bias due to reporting practices. The observed trends are consistent with early detection efforts and with changes in the prevalence of risk factors.

No excess prior cancer in patients with uveal melanoma.

To determine whether there were more prior cancers in uveal melanoma patients than in a geographically matched control group, the authors compared the history of prior cancer in 407 uveal melanoma patients who lived in the western United States with that of 870 control subjects. Control subjects were selected by random digit dial and frequency-matched for age at diagnosis of patient, race, and sex. Fifty-one (12.5%) patients and 86 (9.9%) control subjects reported skin cancers whereas 25 (6.1%) patients and 47 (5.4%) control subjects reported other cancers. No statistically significant elevated estimates of relative risk (RR) were found for uveal melanoma with history of skin cancer in either men (RR = 1.4, 95% confidence interval (CI) = 0.87-2.3) or women (RR = 1.1, 95% CI = 0.58-2.0), or with history of other prior cancer in either sex (men, RR = 1.0, 95% CI = 0.42-2.2; women, RR = 1.1, 95% CI = 0.55-2.1). Data from this study do not support an association between prior cancer and increased risk of uveal melanoma.

Uveal melanoma, hormonal and reproductive factors in women.

In a case-control study, we explored a potential association between uveal melanoma and reproductive factors in women. Responses from telephone interviews of 186 women diagnosed with uveal melanoma were compared with responses of 423 women without this disease. All women resided in 11 U.S. western states. We observed a decreased risk of uveal melanoma for women who had ever been pregnant [relative risk (RR) = 0.60, 95% confidence interval (CI) = 0.37 -0.95], with an increase in this protective effect with more live births after adjustment for age, menopausal status, eye color, and skin sensitivity to the sun (1-2 births, RR = 0.47,95% CI 0.29-0.78; 3-4 births, RR = 0.38, 95% CI = 0.22-0.64; 5 or more births, RR = 0.33, 95% CI = 0.15-0.71). The largest effect was observed between nulliparous and parous women. No other reproductive factors, including use of oral contraceptives or postmenopausal estrogens, were shown to be related to risk for uveal melanoma. We conclude that most reproductive factors in this population play little or no role in the etiology of uveal melanoma. The association with number of live births must be confirmed in other studies to assure that it is unrelated to confounding factors not measured in this study.

Uveal melanoma in relation to ultraviolet light exposure and host factors.

We conducted a case-control interview study among 1277 subjects (407 patients, 870 controls selected by using random digit dial) in 11 western United States to determine whether uveal melanoma and cutaneous melanoma shared common risk factors. After adjustment for other factors, the risk of uveal melanoma was increased for those with green, gray, or hazel eyes [relative risk (RR) = 2.5, P less than 0.001] or blue eyes (RR = 2.2, P less than 0.001) when compared to brown. A tendency to sunburn after 0.5 h midday summer sun exposure increased risk for uveal melanoma (burn with tanning RR = 1.5, P = 0.02; burn with little tanning RR = 1.8, P less than 0.001; burn with no tanning RR = 1.7, P = 0.002); as did exposure to UV or black lights (RR = 3.7, P = 0.003); and welding burn, sunburn of the eye, or snow blindness (RR = 7.2, P less than 0.001). An association with uveal melanoma was also noted with an increasing number of large nevi (P = 0.04 for trend), although the individual risk estimates were not remarkable. These data suggest that host factors and exposure to UV light are risk factors for uveal melanoma.

Anal cancer incidence: genital warts, anal fissure or fistula, hemorrhoids, and smoking.

We conducted a study of 126 patients with anal and rectal squamous cell carcinoma and 372 randomly selected control subjects in the San Francisco Bay Area (CA) to test the hypothesis that these tumors are related to a history of anal intercourse, the presence of sexually transmitted diseases and other conditions of the anal area, treatment of these diseases or conditions, and history of use of cigarettes or other substances. The relative risk (RR) of cancer was elevated for men with a history of homosexual activity (RR = 12.4, P less than .001). However, after adjustment for other risk factors, this risk was reduced to 2.7 (P = .28). Risk was elevated for homosexual male patients who reported a history of genital warts (RR = 12.6, P = .03), anal fissure or fistula (RR = 9.1, P = .05), and cigarette smoking (RR = 1.9 for 20 pack-yr, P less than .001; RR = 5.2 for 50 pack-yr, P less than .001). (Pack-year is a unit of cigarette use equal to 365 packs.) There was also elevated risk for heterosexual male and female patients who reported a history of genital warts (RR = 4.4, P = .003), anal fissure or fistula (RR = 2.4, P = .03), and more than 12 episodes of hemorrhoids (RR = 2.6, P less than .001). These findings suggest that anal cancer risk is etiologically related to human papillomaviruses that cause genital warts. In addition, constant irritation, chronic inflammatory changes, and repeated epithelial regeneration that accompany noninfectious conditions may be related to risk of anal cancer. The higher risk among homosexual men is related to the higher prevalence of anal cancer risk factors for this group.

Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy.

Forty-two evaluable endomyocardial biopsies were obtained from 29 patients treated with epirubicin, the 4'-epimer of doxorubicin in cumulative doses ranging from 147 mg/m2 to 888 mg/m2. In this study of the Northern California Oncology Group, myofibrillar loss and sarcoplasmic vacuolization were identified and shown to be identical to those previously described for doxorubicin. However, when these biopsies were compared to 119 biopsies obtained from 98 patients treated with doxorubicin, milligram for milligram, epirubicin caused less endomyocardial injury than doxorubicin (P = 0.0013). Age, sex, type of primary malignancy, prior cardiac disease, and hypertension did not influence the degree of histologically demonstrated anthracycline injury induced by epirubicin.