Elevated serum homocysteine levels and increased risk of invasive cervical cancer in US women.

OBJECTIVES: To explore the relationship between serum homocysteine, a sensitive biomarker for folate inadequacy and problems in one-carbon metabolism, and invasive cervical cancer. METHODS: A large case-control study was conducted in five US areas with up to two community controls, obtained by random-digit dialing, individually matched to each case. Cervical cancer risk factors were assessed through at-home interview. Blood was drawn at least 6 months after completion of cancer treatment from 51% and 68% of interviewed cases and controls. Serum homocysteine was measured by high-performance liquid chromatography, and exposure to human papillomavirus (HPV) type 16, the most prevalent oncogenic type, was assessed using an enzyme-linked immunosorbent assay. Cases with advanced cancer and/or receiving chemotherapy were excluded, leaving 183 cases and 540 controls. RESULTS: Invasive cervical cancer risk was substantially elevated for women in the upper three homocysteine quartiles (> 6.31 micromol/L); multivariate-adjusted odds ratios ranged from 2.4 to 3.2 (all 95% CIs excluded 1.0). A trend was apparent and significant (p = 0.01). When cases were compared with HPV-16 seropositive controls only, odds ratios were comparable. CONCLUSIONS: Serum homocysteine was strongly and significantly predictive of invasive cervical cancer risk. This association could reflect folate, B12 and/or B6 inadequacy, or genetic polymorphisms affecting one-carbon metabolism.

Low serum and red blood cell folate are moderately, but nonsignificantly associated with increased risk of invasive cervical cancer in U.S. women.

Previous observational epidemiologic studies of folate and cervical cancer, as well as folate supplementation trials for cervical dysplasia, have produced mixed results. We examined the relationship between serum and RBC folate and incident invasive cervical cancer in a large, multicenter, community-based case-control study. Detailed in-person interviews were conducted, and blood was drawn at least 6 mo after completion of cancer treatment from 51% of cases and 68% of controls who were interviewed. Blood folate was measured with both microbiologic and radiobinding assays. Included in the final analyses were 183 cases and 540 controls. Logistic regression was used to control for all accepted risk factors, including age, sexual behavior, smoking, oral contraceptive use, Papanicolaou smear history and human papillomavirus (HPV)-16 serology. For all four folate measures, the geometric mean in cases was lower than in controls (e.g., 11.6 vs. 13.0 nmol/L, P < 0.01 for the serum radiobinding assay). Folate measures using microbiologic and radiobinding assays were correlated (serum: r = 0.90; RBC: r = 0.77). For serum folate, multivariate-adjusted odds ratios (OR) in the lowest vs. highest quartile were 1.3 [95% confidence interval (CI) = 0.8--2.9] and 1.6 (0.9--2.9), using the microbiologic and radiobinding assays, respectively. For RBC folate, comparable OR were 1.2 (0.6--2.2) and 1.5 (0.8--2.7). Similar risks were obtained when restricting analyses to subjects with a history of HPV infection. Thus, low serum and RBC folate were each moderately, but nonsignificantly, associated with increased invasive cervical cancer risk. These findings support a role for one-carbon metabolism in the etiology of cervical cancer.

Alcohol intake, type of beverage, and the risk of cerebral infarction in young women.

BACKGROUND AND PURPOSE: The relationship between alcohol consumption and cerebral infarction remains uncertain, and few studies have investigated whether the relationship varies by alcohol type or is present in young adults. We examined the relationship between alcohol consumption, beverage type, and ischemic stroke in the Stroke Prevention in Young Women Study. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. Case patients (n=224) were aged 15 to 44 years with a first cerebral infarction, and control subjects (n=392), identified by random-digit dialing, were frequency matched by age and region of residence. The interview assessed lifetime alcohol consumption and consumption and beverage type in the previous year, week, and day. ORs were obtained from logistic regression models controlling for age, race, education, and smoking status, with never drinkers as the referent. RESULTS: Alcohol consumption, up to 24 g/d, in the past year was associated with fewer ischemic strokes (<12 g/d: OR 0.57, 95% CI 0. 38 to 0.86; 12 to 24 g/d: OR 0.38, 95% CI 0.17 to 0.86; >24 g/d: OR 0.95, 95% CI 0.43 to 2.10) in comparison to never drinking. Analyses of beverage type (beer, wine, liquor) indicated a protective effect for wine consumption in the previous year (<12 g/wk: OR 0.58, 95% CI 0.35 to 0.97; 12 g/wk to <12 g/d: OR 0.55, 95% CI 0.28 to 1.10; >/=12 g/d: OR 0.92, 95% CI 0.23 to 3.64). CONCLUSIONS: Light to moderate alcohol consumption appears to be associated with a reduced risk of ischemic stroke in young women.

Risk of ovarian cancer according to use of antidepressants, phenothiazines, and benzodiazepines (United States).

OBJECTIVES: An association of increased risk of ovarian cancer with use of antidepressants or benzodiazepine tranquilizers has been reported from a case-control study. We assessed the association between ovarian cancer risk and the use of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), phenothiazine antipsychotics, and benzodiazepines, in data from the Case-Control Surveillance Study. METHODS: From 1976 through 1998, data were collected from hospital patients in Boston, New York, Philadelphia, and Baltimore based on demographic factors, reproductive and medical history, and medication use. In the present analyses, cases of epithelial ovarian cancer (n = 748) were compared with cancer controls (n = 1496) and noncancer controls admitted for trauma and acute infection (n = 1496). We estimated Mantel-Haenszel odds ratios adjusted for age, study center, and year of interview. RESULTS: Odds ratios for regular use (at least 4 days/week for at least 1 month) were compatible with 1.0 for every drug class. For tricyclics and benzodiazepines the upper 95% confidence limits were less than 1.6. For phenothiazines the upper limit was 2.6 with cancer controls and 1.4 with noncancer controls. Only five cases used SSRIs, yielding unstable results. Odds ratios were not increased among women who had used any drug class for at least 5 years, nor among women who had first used them 10 or more years previously. CONCLUSIONS: These data do not support an association between regular use of any of the drugs under study with ovarian cancer risk.

A case-control study of analgesic use and ovarian cancer.

A recent case-control study raised the hypothesis that acetaminophen use 1 day or more per week for at least 6 months reduces the risk of epithelial ovarian cancer. We assessed analgesic use in relation to epithelial ovarian cancer risk using data from our case-control surveillance study of medication use and cancer. Patients were interviewed in hospitals in Baltimore, Boston, New York, and Philadelphia during 1976-1998. We compared 780 women with epithelial ovarian cancer to 2053 cancer controls and 2570 noncancer controls. For acetaminophen use 1 day or more per week for at least 6 months, the odds ratio estimate was 0.9 (95% confidence interval, 0.6-1.4) derived with cancer controls and 1.0 (0.6-1.5) with noncancer controls. Estimates for more frequent and longer term use were also compatible with 1.0. The odds ratios among patients with metastatic ovarian cancer were reduced but not statistically significant. The odds ratio for use of nonsteroidal anti-inflammatory drugs 4 or more days per week for at least 5 years, 0.5, was statistically significant. The present results provide only weak support for a reduction in the risk of epithelial ovarian cancer among acetaminophen users. They raise the possibility of an inverse association with long-term nonsteroidal anti-inflammatory drug use.

Repeat victims of violence: report of a large concurrent case-control study.

HYPOTHESIS: Repeat victims of violence (violence victim recidivism) is a phenomenon known throughout the nation by those who work in hospital emergency departments. A level I trauma center in Baltimore, Md, conducted this study to investigate the postulated risk factors for repeat victims of violence, ie, unemployment, limited educational attainment, and involvement with illicit drug use or drug dealing. DESIGN: A case-control study identified 200 cases and 224 controls during a 16-month period. Cases were persons admitted with traumatic injury secondary to violent assault who had been previously hospitalized for a similar reason. Controls were a random selection of eligible age- and sex-matched patients admitted for reasons unrelated to violent injury. RESULTS: Prominent risk factors associated with recidivism were African American male, median age 31 years, unemployed, lacking medical insurance, annual income less than $10000, current drug user, past or present drug dealer, and a positive test for psychoactive substances on admission to the hospital. One hundred seventy-two (86%) of the cases felt that disrespect (called "dissing" in the local vernacular) was involved with their injury. CONCLUSIONS: The multiplicity of risk factors and the fact that they are interrelated mandate a comprehensive approach to the difficult problem of violence recidivism. Experiments in hospital-based intervention strategies are needed.

Lipoprotein (a) and the risk of ischemic stroke in young women.

BACKGROUND AND PURPOSE: lipoprotein (a) (lp (a)) is a lipid-containing particle similar to LDL which has been found in atherosclerotic plaque. The role of lp (a) in ischemic stroke remains controversial, but some studies suggest lp (a) is particularly important as a risk factor for stroke in young adults. We investigated the role of lp (a) as a risk factor for stroke in young women enrolled in the Stroke Prevention in Young Women Study. METHODS: subjects were participants in a population-based, case-control study of risk factors for ischemic stroke in young women. Cases were derived from surveillance of 59 regional hospitals in the central Maryland, Washington DC, Pennsylvania and Delaware area. Lp (a) was measured in 110 cases and 216 age-matched controls. Demographics, risk factors, and stroke subtype were determined by interview and review of medical records. RESULTS: lp (a) values were higher in blacks than whites, but within racial groups, the distribution of lp (a) values was similar between cases and controls. After adjustment for age, race, hypertension, diabetes, cigarette smoking, coronary artery disease, total cholesterol and HDL cholesterol, the odds ratio for an association of lp (a) and stroke was 1.36 (95% CI 0.80-2.29). There was no dose-response relationship between lp (a) quintile and stroke risk. Among stroke subtypes, only lacunar stroke patients had significantly elevated lp (a) values compared to controls. CONCLUSIONS: we found no association of lp (a) with stroke in a population of young women with ischemic stroke. Small numbers of patients limit conclusions regarding risk in ischemic stroke subtypes, but we could not confirm previous suggestions of an association of lp (a) with atherosclerotic stroke in young adults.

NSAIDs and risk of colorectal cancer according to presence or absence of family history of the disease.

BACKGROUND: We undertook the present analyses to determine whether family history of colorectal cancer in a parent or sibling modifies the inverse association of nonsteroidal anti-inflammatory drug (NSAID) use with colorectal cancer risk. METHODS: We used data from two case-control studies of colorectal cancer. The hospital-based Case Control Surveillance Study included 1526 patients with primary colorectal cancer, 4192 cancer controls and 6036 noncancer controls. A population-based study conducted in Massachusetts enrolled 1201 incident cases of colorectal cancer and 1201 community controls. Data on NSAID use and risk factors for colorectal cancer were collected by interview. RESULTS: In both studies there was a reduction in the odds ratios among subjects who used NSAIDs regularly continuing into the previous year, regardless of family history. In the Case Control Surveillance data, the odds ratio was 0.4 (95% CI 0.2-0.9) among subjects with a family history and 0.5 (95% CI 0.4-0.7) among subjects without a family history. The comparable odds ratios in the Massachusetts data were 0.5 (95% CI 0.3-0.9) and 0.7 (95% CI 0.6-0.9). CONCLUSIONS: These data indicate that regular continuing NSAID use is associated with a reduced risk of colorectal cancer among persons with a family history of the disease, as well as those without such a history.

Reply to commentaries by Drs. Krieger and LaVeist on "race in epidemiology".

Racial categorizations are a dangerous anachronism with a disastrous history and fatal consequences for the human species. They play into the hands of racists and undermine the solidarity of some impoverished and neglected segments of our societies. Race is no longer a constructive tool of health or social research and should be abandoned as a category in research and programs of economic, social, and health amelioration.

Effectiveness of hysterectomy.

OBJECTIVE: To measure the effectiveness of hysterectomy in relieving adverse symptoms and to identify factors associated with lack of symptom relief. METHODS: In a 2-year prospective study, data were collected before and at 3, 6, 12, 18, and 24 months after hysterectomy in 1,299 women who had hysterectomies for benign conditions at 28 hospitals across Maryland. Effectiveness was measured in terms of relief of symptoms such as problematic vaginal bleeding, pelvic pain, and urinary incontinence. Psychologic function and quality of life before and after surgery also were assessed. RESULTS: Symptom severity, depression, and anxiety levels decreased significantly after hysterectomy and quality of life improved, particularly in the area of social function. However, 8% of women had at least as many symptoms at problematic-severe levels 1 and 2 years after hysterectomy as before. In multiple logistic regression, several presurgical patient characteristics predicted lack of symptom relief, including therapy for emotional or psychologic problems, depression, and household income of $35,000 or less. Bilateral oophorectomy predicted lack of symptom relief at 24 months but not at 12 months after hysterectomy. CONCLUSION: Significant improvements were seen after hysterectomy for all three aspects of health status (symptoms, psychologic function, and quality of life), which persisted or continued to improve throughout the 2 years of follow-up. However, hysterectomy did not relieve symptoms for some women, particularly those who had low incomes or were in therapy at the time of hysterectomy.

Nonsteroidal anti-inflammatory drugs and risk of digestive cancers at sites other than the large bowel.

Regular continuing nonsteroidal anti-inflammatory drug (NSAID) use has been associated with a reduction in risk of large bowel cancer in many studies, including our Case-Control Surveillance Study of medication use and cancer risk. We assessed the relation of NSAID use to the risk of digestive cancers at sites other than the large bowel in this database. Nurse-interviewers administered questionnaires to patients admitted to hospitals in four centers from 1977 to 1998. Cases comprised 1149 patients with cancers of the pancreas (n = 504), stomach (n = 254), esophagus (n = 215), gallbladder (n = 125), or liver (n = 51). Controls were 5952 patients admitted for trauma or acute infection. History of NSAID use was elicited by questions about indications for use. Multiple logistic regression models were used to calculate odds ratios (ORs) for categories of regular NSAID use (at least 4 days/week for at least 3 months) relative to never use. The OR for regular use initiated at least 1 year before admission and continuing into that year was reduced for stomach cancer (OR = 0.3; 95% confidence interval, 0.1-0.6) and was compatible with 1.0 for other sites. The ORs for regular continuing use of at least 5 years duration were < 1.0 for cancers of the stomach, pancreas, esophagus, and gallbladder but were statistically significant only for stomach cancer. These data suggest that regular continuing NSAID use may be associated with reduced risk of stomach cancer. For the other sites, the data are consistent with no effect of NSAID use.

Risk factors for infective endocarditis: oral hygiene and nondental exposures.

BACKGROUND: The risks of infective endocarditis (IE) associated with various conditions and procedures are poorly defined. METHODS AND RESULTS: This was a population-based case-control study conducted in 54 Philadelphia, Pa-area hospitals from 1988 to 1990. Community-acquired IE cases unassociated with intravenous drug use were compared with matched community residents. Subjects were interviewed for risk factors. Diagnoses were confirmed by expert review of medical record abstracts with risk factor data removed. Cases were more likely than controls to suffer from prior severe kidney disease (adjusted OR [95% CI]=16.9 [1.5 to 193], P:=0.02) and diabetes mellitus (adjusted OR [95% CI]=2.7 [1.4 to 5.2], P:=0.004). Cases infected with skin flora had received intravenous fluids more often (adjusted OR [95% CI]=6.7 [1.1 to 41], P:=0.04) and had more often had a previous skin infection (adjusted OR [95% CI]=3.5 [0.7 to 17], P:=0.11). No association was seen with pulmonary, gastrointestinal, cardiac, or genitourinary procedures or with surgery. Edentulous patients had a lower risk of IE from dental flora than patients who had teeth but did not floss. Daily flossing was associated with a borderline decreased IE risk. CONCLUSIONS: Within the limits of the available sample size, the data showed that IE patients differ from people without IE with regard to certain important risk factors but not regarding recent procedures.

Risk of breast cancer according to use of antidepressants, phenothiazines, and antihistamines.

In laboratory studies, some antidepressants caused increased growth of mammary tumors. The relation of use of these drugs to the development of breast cancer was examined in a hospital-based case-control study. Information, including lifetime medication history, was collected by interview from 5,814 women with primary breast cancer diagnosed within the previous year, 5,095 women with primary malignancies of other sites, and 5,814 women with other conditions. Relative risks were estimated by using unconditional multiple logistic regression for regular use (> or =4 days per week for > or =4 weeks beginning > or =1 year before admission) of antidepressants and structurally similar drugs. With reference to never use of each drug, relative risks were statistically compatible with 1.0 for selective serotonin reuptake inhibitors (SSRI), tricyclics, other antidepressants, phenothiazines, and antihistamines; results were very similar using both control groups. There were no significant increases in risk for any category of regular use, stratified according to cumulative duration of use or time interval since the most recent use or for any individual drug within the broader classes. However, the estimate for regular SSRI use in the previous year, 1.8, was of borderline statistical significance (95% confidence interval: 1.0, 3.3). The findings do not support an overall association between the use of antidepressants, phenothiazines, or antihistamines and breast cancer. However, the results for SSRIs are not entirely reassuring.

Homocyst(e)ine and risk of cerebral infarction in a biracial population : the stroke prevention in young women study.

BACKGROUND AND PURPOSE: Genetic enzyme variation and vitamin intake are important determinants of blood homocyst(e)ine levels. The prevalence of common genetic polymorphisms influencing homocyst(e)ine levels varies by race, and vitamin intake varies by socioeconomic status. Therefore, we examined the effect of vitamin intake, race, and socioeconomic status on the association of homocyst(e)ine with stroke risk. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. One hundred sixty-seven cases of first ischemic stroke among women aged 15 to 44 years were compared with 328 controls identified by random-digit dialing from the same region. Risk factor data were collected by standardized interview and nonfasting phlebotomy. Plasma homocyst(e)ine was measured by high-performance liquid chromatography and electrochemical detection. RESULTS: Blacks and whites did not differ in median homocyst(e)ine levels, nor did race modify the association between homocyst(e)ine and stroke. After adjustment for cigarettes per day, poverty status, and regular vitamin use, a plasma homocyst(e)ine level of >/=7.3 micromol/L was associated with an odds ratio for stroke of 1.6 (95% CI, 1.1 to 2.5). CONCLUSIONS: The association between elevated homocyst(e)ine and stroke was independent not only of traditional vascular risk factors but also of vitamin use and poverty status. The degree of homocyst(e)ine elevation associated with an increased stroke risk in young women is lower than that previously reported for middle-aged men and the elderly and was highly prevalent, being present in one third of the control group.

The relationship of nonsteroidal anti-inflammatory drug use to the risk of breast cancer.

BACKGROUND: The effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the risk of breast cancer is unclear. We assessed the association in a hospital-based case-control study. METHODS: The cases (n = 6558) were compared with cancer controls (n = 3296) and noncancer controls admitted for trauma or acute infection (n = 2925). Odds ratios were estimated using multivariate logistic regression models. RESULTS: For women who used NSAIDs regularly beginning at least 1 year before admission, the odds ratios (OR) were 0.8 (95% CI 0.7, 1.0) with cancer controls and 0.7 (95% CI 0.6, 0.9) with noncancer controls. With noncancer controls, there was a statistically significant decreasing trend in the odds ratios as duration of use increased, whereas with cancer controls there was not. The reduction in risk for regular use was accounted for largely by a reduced odds ratio for one study center (Boston), which contributed 9% of the cases. CONCLUSIONS: The data are compatible with a small reduction in risk associated with regular NSAID use. However, inconsistencies in the data detract from a causal interpretation.

Elevated tissue plasminogen activator antigen and stroke risk: The Stroke Prevention In Young Women Study.

BACKGROUND AND PURPOSE: Abnormalities in endogenous fibrinolysis are associated with an increased risk for stroke in men and older adults. We tested the hypothesis that elevated plasma tissue plasminogen activator (tPA) antigen, a marker for impaired endogenous fibrinolysis, is an independent risk factor for stroke in young women. METHODS: Subjects were 59 nondiabetic females ages 15 to 44 years with cerebral infarction from the Baltimore-Washington area and 97 control subjects frequency-matched for age who were recruited by random-digit dialing from the same geographic area. A history of cerebrovascular disease risk factors was obtained by face-to-face interview. Plasma tPA antigen was measured by enzyme-linked immunosorbent assay. RESULTS: Mean plasma tPA antigen levels were significantly higher in stroke patients than control subjects (4. 80+/-4.18 versus 3.23+/-3.67 ng/mL; P=0.015). After adjustment for age, hypertension, cigarette smoking, body mass index, and ischemic heart disease, there was a dose-response association between tPA antigen and stroke with a 3.9-fold odds ratio of stroke (95% CI, 1.2 to 12.4; P=0.03) for the upper quartile (>4.9 ng/mL) of tPA antigen compared with the lowest quartile. The dose-response relationship between tPA antigen and stroke was equally present in white and nonwhite women, and further adjustment for total and HDL cholesterol levels only modestly attenuated this association. CONCLUSIONS: This population-based case-control study shows that elevated plasma tPA antigen level is independently associated with an increased risk for ischemic stroke in nondiabetic females 15 to 44 years of age. These findings support the hypothesis that impaired endogenous fibrinolysis is an important risk factor for stroke in young women.

Distribution and correlates of elevated total homocyst(e)ine: the Stroke Prevention in Young Women Study.

PURPOSE: To determine the distribution and correlates of elevated total homocyst(e)ine (tHcy) concentration in a population of premenopausal black and white women. METHODS: Data from the Stroke Prevention in Young Women Study (N = 304), a population-based study of risk factors for stroke in women aged 15-44 years of age, were used to determine the distribution and correlates of elevated tHcy in black (N = 103) and white women (N = 201). RESULTS: The mean tHcy level for the population was 6.58 micromol/L (range 2.89-26.5 micromol/L). Mean tHcy levels increased with age, cholesterol level, alcohol intake, and number of cigarettes smoked (all: p < 0.05). There were no race differences (mean tHcy 6.72 micromol/L among blacks and 6.51 micromol/L among whites; p = 0.4346). Regular use of multivitamins and increasing education was associated with significant reductions in tHcy concentration. Approximately 13% of the sample had elevated tHcy levels, defined as a tHcy concentration > or = 10.0 micromol/L. Multivariate-adjusted correlates of elevated tHcy included education > 12 vs. < or = 12 (odds ratio [OR] = 0.4, 95% confidence interval [CI] = 0.2-0.8); smoking > or = 20 cigarettes/day vs. nonsmokers (OR = 2.8, 95% CI = 1.1-7.3); and the regular use of multivitamins (OR = 0.4, 95% CI = 0.2-0.9). CONCLUSIONS: These results suggest that a substantial proportion of healthy young premenopausal women have tHcy levels that increase their risk for vascular disease. A number of potentially modifiable behavioral and environmental factors appear to be significantly related to elevated tHcy levels in young women.