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Objective: To describe the clinical, laboratory, radiologic, and histopathologic features of methotrexate (MTX)-induced lung injury in a combined cohort of selected patients with rheumatoid arthritis (RA) and all cases reported in the English-language literature., Methods: Retrospective combined cohort review and abstraction from the medical literature. Case reports were obtained from 6 centers that had 4 or more cases of potential MTX lung injury per site. RA patients who were seen between 1981 and 1993 and who satisfied predetermined criteria for the presence of MTX lung injury were identified., Results: Twenty-seven patients satisfied the criteria for definite MTX lung injury, and 2 for probable MTX lung injury. Predominant clinical features of MTX lung injury included shortness of breath in 27 patients (93.1%), which was present for 23.5 +/- 22.3 days (mean +/- SD), cough in 24 (82.8%), present for 26.9 +/- 28.5 days, and fever in 20 (69.0%), present for 10.4 +/- 12.8 days. Five patients (17.2%) died, compared with 12 of 68 (17.6%) reported in the medical literature. Four of the 6 patients who were re-treated with MTX after an initial pulmonary event developed recurrent lung toxicity, resulting in 2 deaths, compared with a recurrence rate of 3 of 6 in the literature., Conclusion: MTX lung injury is most often a subacute process, in which symptoms are commonly present for several weeks before diagnosis. Approximately 50% of the cases are diagnosed within 32 weeks from initiation of MTX treatment. A patient who recovers from MTX lung injury should not be re-treated. Earlier recognition and drug withdrawal may avoid the serious and sometimes fatal outcome that has been observed in this and other studies.

Background: Toxicity limits the use of methotrexate., Objective: To identify risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis., Design: Case-control study., Setting: One private and five academic rheumatology practices., Participants: Methotrexate recipients with rheumatoid arthritis with and without lung injury., Measurements: Potential risk factors examined were sociodemographic and lifestyle characteristics, medical history, clinical and ancillary features and treatment of rheumatoid arthritis before methotrexate therapy, and characteristics of methotrexate therapy. Cases of lung injury were defined according to the modified criteria of Searles and McKendry., Results: Ninety-four percent of the study participants were white, and 67% were women. Case-patients (n = 29) were older than controls (n = 82) (61.5 compared with 54.5 years of age). The strongest predictors of lung injury, after adjustment for other variables, were older age (odds ratio [OR], 5.1 [95% CI, 1.2 to 21.1]), diabetes (OR, 35.6 [CI, 1.3 to infinity]), rheumatoid pleuropulmonary involvement (OR, 7.1 [CI, 1.1 to 45.4]), previous use of disease-modifying antirheumatic drugs (OR, 5.6 [CI, 1.2 to 27.0]), and hypoalbuminemia (OR, 19.5 [CI, 3.5 to 109.7]). Previous use of disease-modifying antirheumatic drugs and hypoalbuminemia had very large attributable risks., Conclusion: Knowledge of the risk factors that predispose patients with rheumatoid arthritis to the toxic effects of methotrexate on the lung may provide a rationale for monitoring high-risk patients and may facilitate their management.

Sensitivity (S) and specificity (F) of a test can be estimated in a study only if the disease status of all subjects is independently confirmed using a gold standard. A confirmatory procedure, however, rarely is administered to all subjects, and studies comparing two tests often restrict confirmation to subjects classified as positive by either test. In this context, the parameters of interest (S1, S2, F1, and F2) cannot be estimated directly. Two useful comparative measures of accuracy that can be estimated in this design are the relative sensitivity (RSN, S1/S2) and the relative false-positive rate [RFP, (1 - F1)/(1 - F2)]. The comparison of the two tests can be regarded as a self-matched study in which each observation consists of a pair of test results. Common statistical techniques for matched data analysis can be used to make inferences about RSN and REP. A variance estimator developed for the log-risk ratio in a matched cohort study can be applied to estimate confidence intervals for RSN and RFP. In addition, conditional logistic regression is useful to test hypotheses about RSN and RFP and to assess the impact of multiple potential modifiers of RSN and RFP.

Retrospective, quantitative estimates of exposure to 1,3-butadiene, styrene and benzene were developed for a follow-up study of leukemia mortality among 16610 subjects employed at six North American styrene-butadiene rubber manufacturing plants (418846 person-years, 58 leukemia deaths). The estimation procedure entailed identifying work areas within each manufacturing process, historical changes in exposure potential and specific tasks involving exposure, and using mathematical models to calculate job- and time-period-specific average exposures. The resulting estimates were linked with the subjects' work histories to obtain cumulative exposure estimates, which were employed in stratified and Poisson regression analyses of mortality rates. Mantel-Haenszel rate ratios adjusted by race, age, and cumulative styrene exposure increase with cumulative butadiene exposure from 1 in the nonexposed category to 4.5 in the category of 80 ppm-years or more (P = 0.01). The risk pattern is less clear and statistically nonsignificant for styrene exposure. A trend of increasing risk with butadiene exposure is still present after exclusion of the nonexposed category (P = 0.03). A parsimonious interpretation of the findings presented here, in light of previous epidemiologic studies, is that exposure to butadiene in the synthetic rubber industry produces a dose-related increase in the occurrence of leukemia.

Although 1,3-butadiene (BD) has been classified as an animal carcinogen, epidemiologic research has reported inconsistent results on the relationship between BD and lymphopoietic and other cancers in humans. This study evaluated the mortality experience of 15649 men employed for at least 1 year at any of eight North American styrene-butadiene rubber (SBR) plants. About 75% of the subjects were exposed to BD; 83% were exposed to styrene (STY). During 1943-1991, the cohort had a total of 386172 and an average of 25 person-years of follow-up, with 3976 deaths observed compared to 4553 deaths expected based on general population mortality rates (standardized mortality ratio (SMR) = 87, 95% confidence interval (CI) = 85-90). More than expected leukemia deaths occurred in the overall cohort (48 observed/37 expected, SMR = 131, CI = 97-174) and among ever hourly subjects (45/32, SMR = 143, CI = 104-191). The excess was concentrated among ever hourly subjects with 10+ years worked and 20+ years since hire (28/13, SMR = 224, CI = 149-323) and among subjects in polymerization (15/6.0, SMR = 251, CI = 140-414), maintenance labor (13/4.9, SMR = 265, CI = 141-453) and laboratories (10/2.3, SMR = 431, CI = 207-793), three areas with potential for relatively high exposure to BD or STY monomers. Some cohort sub-groups had slight increases in deaths from lymphopoietic cancers other than leukemia, but mortality patterns by race, years worked and process group within the SBR industry did not indicate a causal association with occupational exposures. These results indicate that exposures in the SBR industry cause leukemia.

The study focuses on the assessment of chromosomal damage associated with folate and vitamin B12 deficiency, and with cigarette smoking in a tissue directly exposed to cigarette smoke (buccal mucosa) while controlling for potential confounding factors. A cross-sectional study was carried out among 39 current smokers (CSs) and 60 noncurrent smokers (NCSs). Buccal mucosal cells, saliva, and blood samples were collected from each subject. The Health Habits and History Questionnaire (Block et al., 1986) was modified to obtain dietary and other relevant information. Methods used to measure folate, vitamin B12 levels, and the frequency of micronucleated cells in buccal mucosal cells gave reproducible results. The study results suggest that CSs have buccal mucosal folate and vitamin B12 levels that are lower than those among NCSs. CSs were three times more likely to have micronucleated buccal mucosal cells compared to NCSs. There appeared to be no association between low buccal folate and vitamin B12 levels chromosomal damage. The salivary vitamin B12 concentrations and plasma vitamin C and E concentrations, however, seem to be marginally protective against the occurrence of buccal mucosal micronuclei, whereas plasma beta-carotene seems to increase the occurrence of micronuclei. Overall, the results do not support the concept that localized folate and vitamin B12 deficiencies in the buccal mucosal cells of smokers are associated with chromosomal damage in those cells. The presence of vitamin B12 deficiencies in the buccal mucosal cells of smokers are associated with chromosomal damage in those cells. The presence of vitamin B12 in the immediate environment (saliva) and vitamin C and E in the plasma, however, appear to be marginally protective against chromosomal damage in buccal mucosal cells.

Objectives: To determine the probability of drug continuation in a large cohort of methotrexate treated rheumatoid arthritis (RA) patients, the reasons for discontinuation of methotrexate, the overall survival of the members of this cohort, and the causes of death in these patients., Methods: Yearly follow up was conducted in methotrexate treated RA patients who formed a cohort between 1981 and 1986 at a tertiary care centre. The probability of drug continuation and the patients' survival were calculated using standard statistical procedures; standardised mortality ratios were calculated using death certificate data and USA general population and mortality tables., Results: The probability of methotrexate continuation at 10 years from the time the first members entered the cohort was 30%. Toxicity (and its severity) was the most frequent cause of discontinuing methotrexate. The cumulative probability of survival was 85% for women and 45% for men. A greater than expected number of deaths from infections was observed, but the number of deaths from cancer and cardiovascular diseases were within the range expected., Conclusions: Toxicity remains the most common cause for methotrexate discontinuation. Survival was comparable to that of other RA cohorts. Methotrexate may be implicated as an associated factor in the deaths from infections.

This retrospective follow-up study evaluated the mortality experience of 11,271 women employed in a large motor vehicle manufacturing company in 1973. Company computerized personnel records were used to identify subjects and to obtain their employment histories. Follow-up through December 31, 1985, was conducted using company, state, and national data sources. The mortality rates of the cohort were compared with the rates of the U.S. general population of white or black women, adjusting for age and calendar time and using the standardized mortality ratio (SMR) as the measure of association. The overall mortality rate of the cohort was lower than the U.S. rate by 15% among whites (SMR = 85, 95% confidence interval (CI) = 78-93) and by 40% among blacks (SMR = 59, CI = 49-70). Among whites, the low mortality rate was due primarily to deficits of noncancer deaths, although a 32% deficit also was observed for breast cancer (SMR = 68, CI = 48-92). Black female workers had 40% fewer deaths than expected overall, and their all cancer SMR also was below expectation (SMR = 82, CI = 60-109). Despite evidence of a strong healthy worker effect among women in the motor vehicle manufacturing industry, the study found excesses of lung cancer among white women in assembly jobs (SMR = 158, CI = 107-226) and of pancreatic cancer among white assembly workers in upholstery and trim operations (SMR = 302, CI = 97-704).

We compared the mother's recall of her child's antibiotic use with the information obtained from the child's health records, while studying the association between antibiotic use and prevalence of mutans streptococci among 102 (5-12 years) inner-city black children. Poor recall of the mother (concordance ratio = 62 percent; kappa = 0.18, p = 0.06) and the lower frequency reported by her (p = 0.02) biased the positive association between child's antibiotic use during the second year of life and oral presence of mutans streptococci toward the null value (Odds Ratio [OR] based on health records = 3.1, 95 percent Confidence Interval [CI] = 1.03-9.3; OR based on mother's recall = 1.6, 95 percent CI = 0.44-5.8). Multiple logistic regression analysis failed to identify any significant determinant of the accuracy of the mother's recall. Since mothers considerably underestimate child's use of antibiotics, at least among inner-city low income blacks, this method of data collection should be limited to circumstances where no other options are available, and such results should be interpreted with caution.

This article summarizes published data on employment and cancer patterns in the motor vehicle manufacturing (MVM) industry and presents results from a new study of female MVM workers. Historically, female MVM employees worked primarily in aerospace; electric and electronic equipment manufacturing; and paint, plastic, and trim operations. Women are now moving into vehicle assembly and metal parts production. Investigations of cancer have focused on men and reported excesses of lung cancer in foundry operations, of gastrointestinal cancer in metal processing operations involving exposure to machining fluids, and of colorectal cancer in wood pattern making. Numbers of women were insufficient for a meaningful evaluation of their cancer patterns. A recent study found that white women employed at a MVM company, compared to the female general US population, had small excesses of lung cancer (standardized mortality ratio (SMR) = 1.26; 95% confidence interval (CI) = 0.96-1.63) and of colorectal cancer (SMR = 1.27, 95% CI = 0.87-1.78) and a deficit of breast cancer (SMR = 0.68, 95% CI = 0.48-0.92). The lung cancer increase was concentrated among women in assembly jobs (SMR = 1.58, 95% CI = 1.07-2.26); the colorectal cancer increase, among women in nonproduction jobs (SMR = 1.78, 95% CI = 0.97-2.98); and the breast cancer deficit, among women in production-related jobs (SMR = 0.60, 95% CI = 0.37-0.91). Further investigation is needed to determine if these patterns are due to the occupational environment and to clarify causes of cancer among women in the MVM industry.

A cross-sectional study was carried out among 39 current smokers (CS) and 60 noncurrent smokers (NCS) to evaluate the effects of cigarette smoking on folate and vitamin B-12 concentrations in the circulation and in tissues directly exposed to cigarette smoke. Univariate analysis showed significantly lower plasma, red blood cell (RBC), and buccal mucosa (BM) folate and BM vitamin B-12 concentrations in CS compared with NCS. The association between smoking and folate and vitamin B-12 concentrations in plasma, RBCs, and BM cells was reduced after other variables were controlled for. Total folate intake and plasma vitamin C concentrations were significant predictors of plasma and RBC folate concentrations. The plasma and RBC concentrations of folate were significantly lower in subjects who had last smoked < 1 h before the blood sample was drawn than in subjects who had smoked earlier. At the current recommended dietary allowance (RDA) for folate, CS had 42% lower plasma folate concentrations than NCS, whereas at an intake three times the RDA, the plasma folate concentration was the same for CS and NCS. The results also suggested that CS have BM folate and vitamin B-12 concentrations that are lower than those of NCS.

High plasma homocyst(e)ine (Hcy) concentrations may be a determinant of coronary artery disease (CAD). Folate and vitamin B-12 are required for the primary metabolic pathway to reduce Hcy concentrations. The interrelationships of Hcy and these two vitamin cofactors were investigated in a case-control study of 101 white males aged 30-50 y with angiographically demonstrated CAD, and 108 white male, similarly aged, control subjects living in the same community as the patients. The odds ratio (OR) of CAD per quartile increase of plasma Hcy concentration based on control values was 1.6 (95% CI: 1.3, 2.1). After age, HDL and LDL cholesterol, body mass index, smoking, hypertension, and diabetes were controlled for, Hcy remained an independent risk factor (OR: 1.4; 95% CI: 1.0, 2.0). The OR change per quartile increase of folate concentration was 0.8 (95% CI: 0.6, 1.0). This difference was reduced (OR: 0.9; 95% CI: 0.7, 1.2) after Hcy adjustment. No difference in the geometric mean of vitamin B-12 concentration was found between patients and control subjects, both 5.8 nmol/L. However, after Hcy and the other CAD risk factors were controlled for, the OR per quartile increase in vitamin B-12 concentration was 1.5 (95% CI: 1.0, 1.8). Reduction in plasma Hcy by interventions to increase plasma folate concentration may decrease CAD risk.

In 10 adult patients (5 females and 5 males, aged 13-57 years) with Gitelman's syndrome (GS, or hypocalciuric variant of Bartter's syndrome, characterized by chronic renal hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria), parameters of Ca metabolism and calciotropic hormone levels were evaluated. Hypocalciuria was associated with a marked reduction of fractional excretion of ionized Ca (as compared with 16 sex- and age-matched controls) and normal filtered Ca load, as indicated by serum ionized Ca; hypocalciuria was thus the result of increased tubular reapsorption of filtered Ca. Plasma levels of total Ca were increased in GS (p < 0.02) but ionized Ca was not different from controls; percent fraction of ionized to total Ca was reduced, indicating increased Ca complexation and/or protein binding, possibly related to a metabolic alkalosis-induced increase of plasma albumin affinity for Ca. Levels of plasma total protein and albumin were similar in GS and controls. Despite similar ionized Ca levels, PTH1-84 was lower in GS than in controls, indicating abnormal ionized Ca-PTH relationship, possibly related to hypomagnesemia. Plasma 1,25(OH)2D levels were not different in GS and in controls, and intestinal fractional Ca absorption (evaluated with a simplified method using stable Sr as a tracer) was not reduced in 4 patients. However, in 5 patients bone mineral density in the forearm (3 patients) or lumbar spine (2 patient) was normal. Thus, despite chronic hypocalciuria and normal 1,25(OH)2D levels, Ca 'thesaurosis' does not occur in bones of GS patients; a likely explanation is that, despite normal 'fractional' intestinal Ca absorption, 'net' intestinal absorption is reduced, due to increased intestinal Ca secretion.

Six adult patients (4 females and 2 males, age range 26-57 years) with Gitelman's syndrome (GS) were treated with spironolactone 200-300 mg/day (n = 5) and/or amiloride 10-30 mg/day (n = 3) for 1-18 months. The patients had hypokalemia, hyperreninemia, chloride-resistant metabolic alkalosis, renal hypomagnesemia (n = 5), and hypocalciuria (n = 5). Free water clearance studies during maximal water diuresis and furosemide administration were suggestive of a solute reabsorptive defect beyond the loop of Henle. Antialdosterone therapy induced a significant increase of PK (from 2.6 +/- 0.4 to 3.4 +/- 0.4 mM; p < 0.0001) and a decrease of CK (from 21.4 +/- 13.2 to 10.6 +/- 4.8 ml/min, p < 0.02) and FEK (from 21.0 +/- 13.6 to 13.4 +/- 5.7%; p < 0.03); PMg increased from 1.38 +/- 0.38 to 1.64 +/- 0.21 mg/dl (p < 0.03) with a parallel fall of CMg (from 5.5 +/- 2.3 to 2.9 +/- 1.5 ml/min; p < 0.02) and FEMg (from 5.7 +/- 2.6 to 2.9 +/- 0.6%; p < 0.05); arterial blood pH and HCO3- did not change (P = plasma, C = clearance, FE = fractional excretion). The creatinine clearance fell (from 90.5 +/- 16.8 to 65.8 +/- 20.9 ml/min; p < 0.05), and Prenin rose (from 16.6 +/- 8.9 to 35.3 +/- 25.3 ng/ml/h; p < 0.02, as did Paldo (from 26.1 +/- 12.3 to 109 +/- 82.6 ng/dl; p < 0.01), indicating extracellular fluid volume contraction; however no significant clinical symptoms of hypovolemia ensued.(ABSTRACT TRUNCATED AT 250 WORDS)

The association of nutritional factors with cervical dysplasia was examined through a case-control study. Analysis was conducted in 257 cases and 133 controls confirmed both by cytological examination and colposcopic findings. A 24-h dietary recall questionnaire was used to assess nutritional intake. Various risk factors (including age at first intercourse, number of sexual partners, parity, cigarette smoking, oral contraceptive use, human papillomavirus type 16 infection, and age and race) were adjusted for their potential confounding effects. While analyses were also performed to adjust for total calories, results were not changed significantly. Among the nutrients examined, vitamin A intake showed a significantly increased risk at the lowest quartile compared to the highest quartile, with an odds ratio of 2.2 (95% confidence interval, 1.2-4.2). A significant trend of increasing risk was also observed with lower intake of vitamin A (P = 0.05). Riboflavin showed increased risk at the two lower quartiles of intake with a trend test P value of 0.04. Increased risk was also found for lower intakes of vitamin C compared to the highest intake level. For folate, increased risk was found in the second highest quartile compared with the highest quartile with an odds ratio of 2.0 (95% confidence interval, 1.0-3.8). The calcium:phosphorus ratio showed an increased risk at the lowest level (odds ratio, 2.0; 95% confidence interval, 1.0-4.3). Insufficient intake of vitamin A, riboflavin, ascorbate, and folate is associated with an increased risk of cervical dysplasia.

A retrospective follow-up study of 21,013 workers employed at a foundry and two engine manufacturing plants was conducted to determine if these workers had an unusual mortality experience. A total of 2,235 deaths occurred during the follow-up period of 1970-1987. Mortality from all causes was lower than expected. Men experienced a 6-13% excess of lung cancer deaths, depending on the choice of the comparison group. The data displayed evidence of a positive trend between lung cancer mortality and increasing duration of employment (p = 0.008). White men experienced a statistically significant excess of deaths from stomach cancer (standardized mortality ratio [SMR] = 158; 95% confidence interval [CI] = 101-234). Black men had increased mortality from pancreatic cancer, especially among engine plant workers (SMR = 303; CI = 121-624), and an excess of prostate cancer, concentrated among foundry workers (SMR = 234; CI = 112-430).

This retrospective follow-up study evaluates the mortality experience of 123,232 male hourly workers employed at a motor vehicle manufacturing company in 1973. Company computerized personnel records were used to identify subjects and to obtain their employment history. Follow-up through December 31, 1985 was conducted using company, state, and national data sources. The mortality rates of the cohort were compared with the rates of the United States (U.S.) general population of white or black men, adjusting for age and calendar time, and using the standardized mortality ratio (SMR) as the measure of association. The overall mortality rate of cohort members is lower than the U.S. rate by 11% among whites (11,060 observed/12,427 expected deaths; SMR = 89) and by 24% among blacks (3,744/4,926 deaths; SMR = 76). These low mortality rates reflect deficits of diseases other than cancer. Cancer SMRs are 99 for whites and 90 for blacks. There are slight excesses of stomach cancer (SMR = 113) and of lung cancer (SMR = 108) among whites and of cancer of the large intestine and rectum (SMR = 114) and of the lymphopoietic tissue (SMR = 111) among blacks. Both whites and blacks have a large deficit of buccal cancer and pharynx cancer, and blacks also have a deficit of esophagus cancer. The cohort's overall deficit of deaths is due largely to the favorable mortality experience of active workers. In contrast, white subjects who have left active employment have an 11% mortality excess, and inactive black subjects have a mortality rate that is similar to the general population rate. The increased mortality among inactive whites is not limited to any one particular disease category. This pattern may reflect illness-related employment termination and generalized confounding by socioeconomic status, although the study does not rule out a relationship between workplace exposures and specific diseases.

This study investigated the feasibility and the reproducibility of a retrospective assessment of solvent exposure in the painting operations of a car assembly plant. Five industrial hygienists (the raters) reviewed summary documents on plant operations and solvent exposure levels, developed from plant records and interviews. The raters independently reviewed 695 department-job-year combinations compiled from 29 work histories and used semi-quantitative scores to rate solvent exposure. Inter-rater agreement was evaluated by computing the percent concordance index and the intraclass correlation coefficient (rI). There was discordance among raters, a large proportion of which pertained to low exposure levels (1-5 ppm). The computation of the rI is sensitive to the distribution of exposure levels. A low rI can be observed for a rare exposure even if the percent concordance is high. Inter-rater agreement was good for cumulative exposure scores computed for frequent exposures: coatings (rI = 0.67), aromatic hydrocarbons (rI = 0.66), and petroleum distillates (rI = 0.62).

This survey was designed to assist with planning epidemiologic studies of the effects of solvent exposure among motor vehicle manufacturing workers. The objectives were to identify subgroups of workers with solvent exposure, and to evaluate the availability of data for a job-exposure matrix (JEM). Of 65 plants selected, 31 (48%) participated. Participant plants represent all production activities initially included in the survey, and employ 97,655 hourly workers. About 14% of these workers use organic solvents (direct exposure), and 19% work in the proximity of solvent-using operations (indirect exposure). However, only 3% have direct exposure, and 6% have indirect exposure to large-volume (> or = 100 gallons/month)/high-frequency (hourly)-use solvents. The highest solvent exposure prevalence occurs in plants manufacturing engines and power train components and in metal degreasing/cleaning and painting tasks, and entails exposure to petroleum fractions, aromatic hydrocarbons, alcohols, and ketones. A JEM can be developed using plant records on job titles, work histories, production scheduling, and plant engineering, and using the corporate computerized personnel and industrial hygiene databases. However, information on solvent use and on exposure is adequate only for recent time periods.

This paper describes methods for the exact assignment of person-years of follow-up to strata of time-dependent factors. It reviews methods applicable to variables that directly measure the passing of time and that increase in step with follow-up (monotonic time factors), and it extends their use to nonmonotonic time factors. When the same categorization scheme is used for all time factors (for example, 5-year categories), the follow-up period consists of segments whose length and position in time are predictable. A new exact method presented here uses this property to improve the efficiency of computations. The new method is generally faster than a method previously described. Finally, the paper outlines a method of exact person-year stratification that is applicable to all time-dependent factors.

Objective: Our objective was to examine the relationship between oral contraceptive use and the incidence of cervical intraepithelial neoplasia., Study Design: In a prospective follow-up study of 6622 women participating in the Second Tromsö Study conducted in 1979 and 1980 in Tromsö, Norway, women aged 20 to 49 years answered a questionnaire regarding their smoking history, dietary habits, alcohol consumption, and oral contraceptive use. They were then followed for 10 years with data from the Pathology Registry of the University Hospital., Results: The age-adjusted incidence rate of cervical intraepithelial neoplasia was 897 per 100,000 person years among noncurrent and 1295 per 100,000 person years among current oral contraceptive users as of 1979. After adjusting for age, marital status, smoking, and frequency of alcohol intoxication the relative rate for current users was 1.5 (95% confidence interval 1.1 to 2.1), and the relative rate for past users was 1.4 (95% confidence interval 1.0 to 1.8), as compared with those who had never used oral contraceptives before 1979., Conclusion: These findings support the hypothesis that the occurrence of cervical intraepithelial neoplasia is increased by oral contraceptive use.

The temporal relationship between cervical infection with Trichomonas vaginalis (TV) or human papillomavirus (HPV) and the incidence rate of cervical intraepithelial neoplasia grade three (CIN III) was examined in a cohort of 43,016 Norwegian women. From 1980 to 1989, a cervico-vaginal infection from TV and HPV was diagnosed cytologically in 988 and 678 women, respectively. During the 181,240 person-years of observation, 440 cases of CIN III/cervical cancer developed. The age-adjusted incidence rates (IR) of CIN III were 225 per 100,000 person-years among women with no cytologic evidence of infection, 459 among women with TV infection, and 729 among women with HPV infection. A multiple regression model yielded a relative rate (RR) of CIN III of 2.1 (95 percent confidence interval [CI] = 1.3-3.4) among women with TV infection and 3.5 (CI = 1.9-6.6) among women with HPV infection, compared with women with neither infection. As CIN can be misclassified as HPV infection, the entry Pap-smears of 10 women with HPV infection who later developed CIN III were re-examined. Excluding the four discordant cases with the corresponding person-years decreased the RR of CIN III to 2.1 (CI = 0.9-4.8). Our report demonstrates the limitations of studies that rely only on cytologic detection of HPV infection. Nevertheless, the results support the hypothesis that HPV is a causal factor for CIN III lesions, and also display an association between TV infection and cervical neoplasia.

Objective: We attempted to evaluate the effect of oral folic acid supplementation on the course of cervical dysplasia., Study Design: A total of 235 subjects with grade 1 or 2 cervical intraepithelial neoplasia were randomly assigned to receive either 10 mg of folic acid or a placebo daily for 6 months. Clinical status, human papillomavirus type 16 infection, and blood folate levels were monitored at 2-month intervals. Outcome data were subjected to chi 2 analysis., Results: The prevalence of human papillomavirus type 16 infection initially was 16% among subjects in the upper tertile of red blood cell folate versus 37% in the lower tertile (trend p = 0.035). After 6 months no significant differences were observed between supplemented and unsupplemented subjects regarding dysplasia status, biopsy results, or prevalence of human papillomavirus type 16 infection., Conclusion: Folate deficiency may be involved as a cocarcinogen during the initiation of cervical dysplasia, but folic acid supplements do not alter the course of established disease.

Objective: To test the hypothesis that nutritional deficiency affects the incidence of cervical dysplasia in young women., Design and Setting: Case-control study. Participants were derived from community family-planning clinics and referrals to a colposcopy center., Participants: A total of 726 subjects were screened, yielding 294 cases of dysplasia and 170 controls defined by coexistent cytologic and colposcopic evidence., Main Outcome Measures: Planned prior to data collection. Odds ratios were computed using logistic regression models to evaluate association between cervical dysplasia and sociodemographic, sexual, and reproductive factors; smoking; oral contraceptive use; human papillomavirus (HPV) infection; and 12 nutritional indices determined by blind analysis of nonfasting blood specimens., Results: The number of sexual partners, parity, oral contraceptive use, and HPV-16 infection were significantly associated with cervical dysplasia. Plasma nutrient levels were generally not associated with risk. However, red blood cell folate levels at or below 660 nmol/L interacted with HPV-16 infection. The adjusted odds ratio for HPV-16 was 1.1 among women with folate levels above 660 nmol/L but 5.1 (95% confidence interval, 2.3 to 11) among women with lower levels. Interactions of red blood cell folate levels with cigarette smoking and parity were also present but were not statistically significant., Conclusion: Low red blood cell folate levels enhance the effect of other risk factors for cervical dysplasia and, in particular, that of HPV-16 infection.

We evaluated the Shell Health Surveillance System (HSS) by conducting two mortality studies at an oil refinery. Study A used the HSS to measure the mortality of active and retired workers during 1973 to 1982. Study B used additional information sources and followed up terminated employees. For subjects included in both studies, results were very similar. However, the mortality experience of terminees before 1973 (included only in study B) was different from that of study A subjects, reflecting differences in length of employment and time since hire. HSS-based studies provide valid measures of long-term effects of past exposures among retirees and of short-term effects of recent exposures among active employees. However, they cannot detect short-term effects of past exposures, and they have limited power for evaluating dose-response relationships.

A total of 2642 men employed at a dye and resin manufacturing plant in New Jersey were observed from the opening of the plant in 1952 through 1985, and their mortality rates were compared with the rates of United States white men. The workers' mortality experience was related to former employment at the Cincinnati Chemical Works, which had produced or used benzidine and beta-naphthylamine. The 2553 men who had never worked at the Cincinnati Chemical Works had fewer than expected deaths from all causes combined (317 observed/402 expected) and equal numbers of observed and expected cancer deaths (89/89). The 89 former Cincinnati Chemical Works employees had an excess of cancer (17/8.6, P = .02), which was due to increased mortality from bladder (3/0.25, P = .004), kidney (2/0.21, P = .04), and CNS (2/0.22, P = .04) cancer. There also were several increases in cancers among men employed in certain work areas at the New Jersey plant. These included elevated mortality from lung (18/9.2, P = .01) and liver (3/0.46, P = .02) cancer among maintenance workers, from stomach (3/0.40, P = .02) and CNS (3/0.44, P = .02) cancer among azo dye workers, and from lung cancer (4/0.91, P = .03) among epichlorohydrin workers. The lung cancer excess among maintenance workers increased with length of employment, suggesting an association with an unidentified occupational exposure. Other associations were based on small numbers of deaths, and their interpretation is not clear.

An evaluation is made of the hypothesis of Woods et al. (1) that the number of full-term pregnancies constitutes a factor of growth acceleration in breast cancer. Our results confirm, at least in part, the effect of parity on age at diagnosis of breast cancer. Patients with two or more children were significantly younger at the time of diagnosis than were those with none or one child. Age at first birth and duration of lactation do not seem to be, in this analysis, confounding factors for the observed association.

In the present investigation the diploid numbers 2n = 45, 2n = 46, 2n = 47, and 2n = 48 have been determined for Gobius paganellus. Specimens of different sex were found to have exactly the same karyotype. This species is characterized by two fundamental numbers: NF = 47, and NF = 48. Chromosome polymorphism due to different chromosome rearrangements within the A-type complement is present in this species.

A total of 417 lung cancer cases and 849 controls were interviewed on their life-long tobacco usage and their current intake of four food items rich in retinol or carotene. The study was a hospital-based case control where 'cases' were lung cancer patients diagnosed during the period 1979/80 at seven hospitals in the Lombardy region (90% pathologically confirmed) and controls were patients admitted to the same hospitals for causes unrelated to tobacco smoking (epithelial cancers being excluded from present analysis). Odds ratios (OR) have been computed for increasing frequencies of consumption of liver, cheese, carrots and leafy green vegetables, having controlled for the confounding effects of tobacco usage, residence and birthplace. Current smokers who did not consume carrots showed a three-fold risk of developing lung cancer compared with those who ate them more than once a week (OR = 2.9 less than p less than 0.01); the ORs for consumers in the categories of 1-2 and 3-4 times per month were 1.8 and 2.0 respectively, with a significant test for linear trend (p less than 0.01). Among ex-smokers or non-smokers, no decrease of lung cancer risk is evident associated with carrot consumption. An excess risk was also associated with low intake of green vegetables although it was not significant, while no excess risk was evident for non-consumers of liver and cheese. The effect of carrots is independent of histological type of lung cancer while the effect of green vegetables was confined to epidermoid carcinomas: low versus high intake group OR = 1.3.