Early cathepsin K degradation of type II collagen in vitro and in vivo in articular cartilage.

OBJECTIVE: To characterize the initial events in the cleavage of type II collagen mediated by cathepsin K and demonstrate the presence of the resulting products in human and equine articular osteoarthritic cartilage. DESIGN: Equine type II collagen was digested with cathepsin K and the cleavage products characterized by mass spectrometry. Anti-neoepitope antibodies were raised against the most N-terminal cleavage products and used to investigate the progress of collagen cleavage, in vitro, and the presence of cathepsin K-derived products in equine and human osteoarthritic cartilage. RESULTS: Six cathepsin K cleavage sites distributed throughout the triple helical region were identified in equine type II collagen. Most of the cleavages occurred following a hydroxyproline residue. The most N-terminal site was within three residues of the previously identified site in bovine type II collagen. Western blotting using anti-neoepitope antibodies showed that the initial cleavages occurred at the N-terminal sites and this was followed by more extensive degradation resulting in products too small to be resolved by SDS gel electrophoresis. Immunohistochemical staining of cartilage sections from equine or human osteoarthritic joints showed staining in lesional areas which was not observed in non-arthritic sites. CONCLUSIONS: Cathepsin K cleaves triple helical collagen by erosion from the N-terminus and with subsequent progressive cleavages. The liberated fragments can be detected in osteoarthritic cartilage and may represent useful biomarkers for disease activity.

RADON SURVEY IN SCHOOL AND ESTIMATION OF EFFECTIVE DOSE USING CORRECTED RADON CONCENTRATION.

Radon exposure in schools is different from that in dwellings because the residence pattern is very different each other. So, when effective dose is calculated in schools, different approach should be considered from in dwellings. The aim of this study was to estimate actual effective dose due to inhaled radon considering the residence time in schools. It could help avoid overestimation when effective dose is calculated in schools. The range of radon concentration in 376 schools was 18.1-2810 Bq m-3 and that of annual effective dose was estimated 0.0902-8.92 mSv y-1 considering the residence time in spring and autumn semesters.

The consequence of PRELP overexpression on skin.

PRELP is a member of the small leucine-rich repeat proteoglycan family that is abundantly expressed in many cartilages compared to other connective tissues. To study the consequence of PRELP overexpression in tissues where it is normally expressed at low abundance, transgenic mice were generated in which the human PRELP transgene was placed under control of the CMV promoter. A connective tissue phenotype was observed in the skin, where the organization of collagen fibrils in the dermis was perturbed and the thickness of the hypodermal fat layer was diminished.

Direct temperature measurement.

Hyperthermia has little hope of progressing as a clinical modality without accurate assessment of the temperature distributions obtained. At the present time only direct, invasive temperature-measuring techniques are possible, posing severe limitations. Established techniques for clinical temperature measurement have developed over the past few years, and for both ultrasound and electromagnetic hyperthermia it is possible to get temperature-time profiles at a large number of spatial points. Position uncertainty, thermal conduction smearing, and artifactual heating limit the accuracy to about 0.2 degrees (electromagnetic) or 0.5 degrees (ultrasound), but this is probably less of a hindrance than the inadequate percentage of tumor and normal tissue volume for which achieved temperatures can be documented.

Anatomical site-specific modalities for hyperthermia.

The clinical application of hyperthermia in the treatment of deep-seated tumors remains an empirical science. The pleomorphic nature of the neoplasms and the great diversity in the anatomy and physiology of the individual tumor locations make the treatment of nearly every neoplasm a unique challenge. A wide variety of devices is required, both for the administration of hyperthermia and for the measurement of the temperatures achieved. At Stanford University, these include the BSD Medical Corp. annular phased array system, an isospherical ultrasound device, and interstitial radiofrequency for deep heating. Ultrasound transducers and a variety of microwave applicators are used for superficial hyperthermia. Six illustrative case studies, selected from the 91 patients treated in our program since October 1981, are presented, with discussion and comparison of treatment devices. Difficulties in deep heating were encountered in several instances, believed secondary to the thickness of the s.c. fat, the relatively high heat-induced tumor blood flow, and the presence of adjacent bone. It is suggested that ultimate improvement in clinical results will be possible once a better understanding is achieved of such anatomical and physiological factors.

Plasma tocopherol and prevalence of colorectal adenomas in a multiethnic population.

Although vitamin E can block mutagenesis and cell transformation in vitro and can reduce the number of chemically induced colonic adenomas in mice, previous clinical trials have found no protective effect of vitamin E supplements against colorectal adenomas, and epidemiological studies have found only weak protective effects of dietary or plasma alpha-tocopherol against colorectal cancer. We previously examined first diagnosis of colorectal adenomas in a sigmoidoscopy screening population and failed to find a protective effect of dietary vitamin E. Because measurements of dietary intake may not be a good proxy of vitamin E status, we assayed plasma alpha- and gamma-tocopherol concentration for 332 subjects with colorectal adenomas and 363 control subjects from this previous sigmoidoscopy-based study. Increasing alpha-tocopherol and decreasing gamma-tocopherol levels were associated with decreased occurrence of large (> or = 1 cm) but not of small (<1 cm) adenomas; however, after adjustment for potential confounding variables, these trends were not statistically significant. A strong trend (P = 0.02) was observed by using the alpha-tocopherol:gamma-tocopherol ratio, which may be a more sensitive indicator of alpha-tocopherol intake. Subjects in the highest versus lowest quintile of alpha-tocopherol: gamma-tocopherol ratio had an odds ratio of 0.36 (95% confidence interval, 0.14-0.95) for large adenomas. The finding that a high alpha-tocopherol:gamma-tocopherol ratio is associated with decreased occurrence of large, but not of small, colorectal adenomas is consistent with previous findings that alpha-tocopherol may be protective against colon cancer. A high plasma alpha-tocopherol:gamma-tocopherol ratio may be a better predictor of decreased cancer risk than high plasma alpha-tocopherol alone.

Acetylation polymorphism and prevalence of colorectal adenomas.

Polymorphic N-acetyltransferase (NAT2), an enzyme present in the colon, may effect incidence of colon cancer. Individuals with NAT2 fast acetylator genotypes may have higher colon cancer risks due to faster conversion of certain carcinogens to mutagens. We determined NAT2 genotypes in 447 subjects with distal colon adenomas and in 487 controls. No significant increase in adenoma prevalence among fast acetylators was observed. However, there was a suggestion of ethnic differences in NAT2 effects. For example, white fast acetylators potentially had slightly increased risks for adenomas (odds ratio, 1.29; 95% confidence interval, 0.90-1.84), whereas fast acetylation was potentially protective among blacks (odds ratio, 0.64; 95% confidence interval, 0.32-1.28). The apparent difference between blacks and whites may simply reflect random variation around an overall null effect, or it could represent a real difference. There was preliminary evidence for a possible interaction between NAT2 and the glutathione transferase M1 null genotype. Smokers' adenoma prevalence was 10-fold higher for fast acetylators with the null genotype compared to slow acetylators without the null genotype. Large, multiethnic populations and analysis of combinations of genes for carcinogen metabolism may be needed to further assess the role of NAT2 in colorectal tumorigenesis.

Glutathione transferase (GSTM1) null genotype, smoking, and prevalence of colorectal adenomas.

Colorectal cancer is caused by environmental exposures and genetic predisposition. However, little is known of hereditary factors that influence development of common, non-Mendelian forms of this cancer. Interactions among carcinogen exposure, hereditary variants of enzymes involved in carcinogen metabolism, and other host factors may play a role. Genetic polymorphisms of carcinogen metabolism, such as the glutathione transferase M1 (GSTM1) null genotype, are thus possibly related to cancer risk. The GSTM1 enzyme detoxifies mutagens formed from polycyclic aromatic hydrocarbons which are found in tobacco smoke. We analyzed GSTM1 genotypes and smoking among 488 controls and 446 individuals with a first time diagnosis of colorectal adenomas which are precursors to cancer. Subjects were from two Kaiser Permanente sigmoidoscopy clinics in southern California. We observed no overall effect of the GSTM1 null genotype on the risk for colorectal adenomas (odds ratio, 0.85; 95% confidence interval = 0.65-1.10). The odds ratio for smokers with the null genotype was 2.07 (95% confidence interval = 1.14-3.77) when compared to "never smokers" without the null genotype. Using this same reference group, the odds ratio for smokers without the null genotype was 1.73 (95% confidence interval = 1.03-2.90). These two odds ratios were not significantly different (P = 0.30).

Clinical and microbiological effects of a subantimicrobial dose of oral doxycycline on periodontitis in dogs.

Doxycycline is regarded as an effective treatment for periodontal inflammation. In humans, it has been shown that the long-term administration of a subantimicrobial dose of doxycycline (SDD) does not induce antimicrobial effects on the subgingival microflora and furthermore does not affect antimicrobial susceptibility. The present study was designed to evaluate the influence of oral administration of SDD on normal periodontal microflora and antimicrobial susceptibility in dogs. Experimental periodontitis was induced in 12 experimental dogs using a silk and wire-twisted ligature for 60 days. After the periodontitis induction period, the ligature was removed, and dental cleaning (subgingival and supragingival ultrasonic scaling) was performed. The dogs were randomly assigned to one of two groups: an SDD group with six dogs receiving 2 mg/kg PO once daily and a control group with six dogs receiving a placebo. At weeks 0, 4 and 8, clinical periodontal parameters were evaluated. After the clinical assessments, subgingival plaque was sampled and then cultured in an anaerobic system for one week, and the total anaerobes, Porphyromonas spp., Bacteroides spp. and Pasteurella spp. counts were investigated. Using the agar dilution method, the minimum bactericidal concentration of doxycycline was evaluated and the resistance for doxycycline was monitored during this experimental phase. The clinical periodontal status of the SDD group was significantly improved compared to the control group (P <0.05). Bacterial counts were not significantly different between the two experimental groups (P > 0.05), and antibacterial resistance was not established in the SDD group during the experimental periods (P <0.05). These results suggest that the once daily oral regimen of 2 mg/kg of doxycycline could serve as a SDD in dogs.

Geographical distribution of indoor radon and related geological characteristics in Bonghwa County, a provisional radon-prone area in Korea.

The detailed indoor radon survey was conducted during a year (from September 2012 to August 2013) quarterly in Bonghwa county, one of the provisional radon-prone areas in Korea. The surveyed area was selected on the basis of previously conducted nationwide radon survey results. In order to minimise statistical and environmental uncertainties, ∼3 % of the entire dwellings were carefully selected based on the statistical annual report of Bonghwa county. The measurement is carried out by using solid-state nuclear track detector. The range of indoor radon concentration in each dwelling was 4.36-858 Bq m(-3) and that of annual effective dose due to inhaled radon of the resident in each dwelling was 0.19-23.5 mSv y(-1). Each dwelling was determined for geology criterion using one-way Analysis of Variance for the purpose of comparing indoor radon distribution with geology. Geographical distribution of indoor radon is closely related to the geological characteristics of basement rocks. In addition, the comparison between geographical distribution of indoor radon and terrestrial gamma radiation was done.

Basis of pulmonary toxicity associated with cationic lipid-mediated gene transfer to the mammalian lung.

Studies have indicated that although abundant levels of transgene expression could be achieved in the lungs of mice instilled with cationic lipid:pDNA complexes, the efficiency of gene transfer is low. As a consequence, a relatively large amount of the complex will need to be administered to the human lungs to achieve therapeutic efficacy for indications such as cystic fibrosis. Because all cationic lipids exhibit some level of cytotoxicity in vitro, we assessed the safety profile of one such cationic lipid, GL-67, following administration into the lungs of BALB/c mice. Dose-dependent pulmonary inflammation was observed that was characterized by infiltrates of neutrophils, and, to a lesser extent, macrophages and lymphocytes. The lesions in the lung were multifocal in nature and were manifested primarily at the junction of the terminal bronchioles and alveolar ducts. The degree of inflammation abated with time and there were no apparent permanent fibrotic lesions, even in animals that were treated at the highest doses. Analysis of the individual components of the complex revealed that the pulmonary inflammation was primarily cationic lipid-mediated with a minor contribution from the neutral co-lipid DOPE. Associated with the lesions in the lungs were elevated levels of the pro-inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) that peaked at days 1-2 post-instillation but resolved to normal limits by day 14. Total cell counts, primarily of neutrophils, were also significantly elevated in the bronchoalveolar lavage fluids of GL-67:pDNA-treated mice between days 1 and 3 but returned to normal limits by day 14. No specific immune responses were detected against the cationic lipid or plasmid DNA in mice that had been either instilled or immunized with the individual components or complex, nor was there any evidence of complement activation. These studies indicate that a significant improvement in the potency of cationic lipid:pDNA formulations is desirable to minimize the toxicity associated with cationic lipids.

Detailed analysis of structures and formulations of cationic lipids for efficient gene transfer to the lung.

Cationic lipid-mediated gene transfer of cystic fibrosis transmembrane conductance regulator (CFTR) cDNA represents a promising approach for treatment of cystic fibrosis (CF). Here, we report on the structures of several novel cationic lipids that are effective for gene delivery to the lungs of mice. An amphiphile (#67) consisting of a cholesterol anchor linked to a spermine headgroup in a "T-shape" configuration was shown to be particularly efficacious. An optimized formulation of #67 and plasmid vector encoding chloramphenicol acetyl-transferase (CAT) was capable of generating up to 1 microgram of CAT enzyme/lung following intranasal instillation into BALB/c mice. This represents a 1,000-fold increase in expression above that obtained in animals instilled with naked pDNA alone and is greater than 100-fold more active than cationic lipids used previously for CFTR gene expression. When directly compared with adenovirus-based vectors containing similar transcription units, the number of molecules of gene product expressed using lipid-mediated transfer was equivalent to vector administration at multiplicities of infection ranging from 1 to 20. The level of transgene expression in the lungs of BALB/c mice peaked between days 1 and 4 post-instillation, followed by a rapid decline to approximately 20% of the maximal value by day 7. Undiminished levels of transgene expression in the lung could be obtained following repeated intranasal administration of #67:DOPE:pCF1-CAT in nude mice. Transfection of cells with formulations of #67:DOPE:pCF1-CFTR generated cAMP-stimulated CFTR chloride channel and fluid transport activities, two well-characterized defects associated with CF cells. Taken together, the data demonstrate that cationic lipid-mediated gene delivery and expression of CFTR in CF lungs is a viable and promising approach for treatment of the disease.

Variants of N-acetyltransferase NAT1 and a case-control study of colorectal adenomas.

N-acetyltransferase NAT1, together with enzymes CYP1A2 and NAT2, helps convert heterocyclic amines to mutagens. Epidemiologic studies of the association of variants of these enzymes with colorectal cancer may provide indirect support for a heterocyclic amine mechanism. We used single strand conformation polymorphism and heteroduplex analysis to screen fro mutations in the NAT1 coding region in a case-control study (n = 932) of colorectal adenomas, which are precursors to cancer. Thirteen different single-base mutations were found: C97T, C190T, T402C, G445A-G459A-T640G ( a combination of three mutations), C559T, G560A, A613G, A752T, T777C, G781A, and A787G. Function of novel mutations was tested by bacterial production of enzymes and measurements of Km, Vmax, and stability. However, on 24-control individuals and 18 cases carried an inactivating NAT1 mutation. When combined with our data on the NAT2 acetylation polymorphism, we saw no evidence for an association between N-acetyltransferases and prevalence of adenomas. Larger sample sizes are required for further evaluation.

Serum lipids and adenomas of the left colon and rectum.

Levels of serum lipids are partially determined by several established risk factors for colorectal cancer and are themselves potential risk factors for the disease. However, evaluating serum lipids as risk factors has proved problematic because metabolic events associated with malignant transformation or progression appear to alter serum lipid concentrations. Serum lipid concentrations are less likely to have altered in individuals with precancerous lesions, such as colorectal adenomas. During 1991-1993, we collected fasting blood samples from and provided questionnaires to men and women 50-75 years old, who visited sigmoidoscopy clinics at a health maintenance organization. Serum lipid concentrations from 486 cases with adenomas and 520 controls were analyzed. Compared to subjects in the lowest quintile of serum triglyceride concentrations, subjects in the highest quintile had an adjusted odds ratio of 1.5 (95% confidence interval, 1.0-2.2). The corresponding odds ratio for total cholesterol was 1.3 (0.9-1.9); for high-density lipoprotein cholesterol, it was 1.1 (0.7-1.6); and for low-density lipoprotein cholesterol, it was 1.1 (0.7-1.6). Further adjustment for potential confounding did not alter these results substantively, although determinants of serum triglycerides and high-density lipoprotein cholesterol (e.g., obesity, physical activity, and refined carbohydrate and alcohol intake) in this and other studies may not be sufficiently well measured to avoid residual confounding. Higher levels of serum triglycerides are associated with an increased risk of adenomatous polyps. Consistent with previous studies, serum cholesterol was not inversely related to the risk of colorectal polyps.

Recent use of hormone replacement therapy and the prevalence of colorectal adenomas.

The etiological role of hormone replacement therapy (HRT) (including estrogen only, combined estrogen-progesterone, and progesterone only) in colorectal neoplasia remains unclear. Several large studies have reported a reduced risk of colorectal cancer among HRT users; however, other studies have given inconsistent results. We examined the association between HRT and colorectal adenomatous polyps, precursors of colorectal cancer, among female participants in a case-control study. Subjects were members of a prepaid health plan in Los Angeles who underwent sigmoidoscopy in 1991-1993. Participants received an in-person interview and completed a food frequency questionnaire. A total of 187 histologically confirmed cases and 188 controls, ages 50-75 years, were included in the analysis. Compared with women who did not use HRT during the year before sigmoidoscopy, recent users had an adjusted odds ratio of 0.57 (95% confidence interval, 0.35-0.94). Duration of use was inversely related to the prevalence of colorectal adenomas, with a multivariate-adjusted odds ratio of 0.49 (95% confidence interval, 0.25-0.97) for use of 5 years or more. These results support a protective effect of HRT on colorectal adenomatous polyps.

The methylenetetrahydrofolate reductase 677C-->T polymorphism and distal colorectal adenoma risk.

A common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, where a cytosine at nucleotide 677 is replaced by a thymine (677C-->T), is associated with enzyme thermolability and a reduction in the conversion of 5,10-methyltetrahydrofolate (5,10-MTHF) into 5-methyltetrahydrofolate. We assessed the association between homozygosity for the MTHFR 677CT genotype (TT) and colorectal adenoma risk in a large sigmoidoscopy-based case-control study of members of a prepaid health plan in Los Angeles. MTHFR genotype was determined for 471 cases and 510 age-, sex-, clinic-, and sigmoidoscopy-date-matched controls. Information on RBC and plasma folate levels were analyzed for 331 cases and 350 controls. When compared with the presence of at least one wild-type allele (CT/CC), the odds ratio (OR) for the TT genotype was 1.19 [95% confidence interval (CI), 0.77-1.76] after adjusting for race and the matching factors. Compared with those in the lowest quartiles of RBC and plasma folate and a wild-type allele, adenoma risk was increased for TT homozygotes in the lowest folate quartiles (genotype: OR, 2.04 and 95% CI, 0.6-7.0; OR, 1.84 and 95% CI, 0.6-7.0 for RBCs and plasma folate, respectively) and decreased in TT homozygotes in the highest quartiles (genotype: OR, 0.82 and 95% CI, 0.32-2.10; OR, 0.65 and 95% CI, 0.22-1.95, respectively). There was also a significant interaction between TT genotype and the increased adenoma risk associated with alcohol. These data are consistent with an interaction between MTHFR genotype and folate availability.

Dietary intake of specific carotenoids and vitamins A, C, and E, and prevalence of colorectal adenomas.

We determined whether intakes of the main dietary carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein plus zeaxanthin, and lycopene) and of vitamins A, C, and E were associated with the prevalence of colorectal adenomas among male and female members of a prepaid health plan in Los Angeles who underwent sigmoidoscopy (n = 488 matched pairs). Participants, ages 50-74 years, completed a 126-item semiquantitative food-frequency questionnaire and a non-dietary questionnaire from 1991 to 1993. In the univariate-matched analysis, alpha-carotene, beta-carotene (with and without supplements), beta-cryptoxanthin, lutein plus zeaxanthin, vitamin A (with and without supplements), and vitamin C (with and without supplements) were associated with a decreased prevalence of colorectal adenomas. After adjustment for intake of calories, saturated fat, folate, fiber, and alcohol, and for current smoking status, body mass index, race, physical activity, and use of nonsteroidal anti-inflammatory drugs, only beta-carotene including supplements was inversely associated with adenomas (odds ratio (OR), 0.6; 95% confidence interval (CI), 0.41.1; trend, P= 0.04; ORs compare highest to lowest quartiles0; vitamin C showed a weaker inverse association (OR, 0.8; 95% CI, 0.5-1.5; trend, P = 0.08); and the remaining compounds were no longer clearly associated with risk. After including beta-carotene with supplements and vitamin C simultaneously in the mutivariate model, the association of beta-carotene with supplements with adenomas was weakened (OR, 0.8; 95% CI, 0.5-1.3; trend P = 0.15), and vitamin C was no longer associated with risk. These data provide only modest support for a protective association of beta-carotene with colorectal adenomatous polyps.

A case-control study of colorectal adenomatous polyps and consumption of foods containing partially hydrogenated oils.

The trans fatty acids produced by partially hydrogenating vegetable oils may cause colorectal neoplasia by interfering with cell membrane function or eicosanoid synthesis. This possibility provides a rationale for looking at the relation between colorectal adenomatous polyps and consumption of foods containing partially hydrogenated vegetable oils (PHVOs). A total of 516 cases and 551 controls who underwent screening sigmoidoscopy from 1991-1993 were recruited from a prepaid Los Angeles health plan. Subjects were interviewed and given a self-administered food frequency questionnaire. Food items containing PHVOs were divided into four groups characterized by principal ingredients and preparation methods: sweetened baked goods, candy bars, oils and condiments, and french fries and chips. After adjusting for age, sex, physical activity, body mass index, smoking, total energy, and red meat and vegetable intake, there was a positive association between polyps and sweetened baked goods [350+ versus <50 kcal/day (odds ratio, 2.1; 95% confidence interval, 1.3-3.5)]. No association was found with the other food groups after adjustment for dietary and nondietary covariates. Neither was total dietary trans fatty acid associated with adenomas after adjustment for sweetened baked goods and other covariates. These results do not support the hypothesis that eating foods containing PHVOs increases the risk of colorectal adenomas, but they are consistent with the hypothesis that foods high in fat and sugar and low in fiber and correlated micronutrients increase the risk of adenomas.

Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps.

Epidemiological and experimental evidence suggests that dietary folate may protect against colorectal carcinogenesis. The epidemiological relationship between a biochemical measure of folate status and colorectal neoplasia in a sizeable and generally healthy population does not yet appear to have been reported. We conducted a case-control study of the relationships among red cell folate, plasma folate, folate intake, and adenomatous polyps, intermediate markers for colorectal cancer. During 1991-1993, fasting blood samples were assayed and dietary and nondietary risk factor questionnaires were administered to men and women ages 50-75 years who had a free sigmoidoscopy at a health maintenance organization. We analyzed data from 682 subjects (332 cases and 350 controls), controlling for potential confounding by sex, age, sigmoidoscopy date, and clinic. For red cell folate levels 160 ng/ml (363 nmol/liter) or more, compared to lower levels, the odds ratio was 0.76 [95% confidence interval (CI) = 0.53-1.08]. For men, the corresponding odds ratio was 0.53 (CI = 0.32-0.87); for women, it was 1.16 (CI = 0.67-2.00). Results were essentially unchanged when adjusted for levels of blood nutrients and other potential confounding variables. Plasma folate and folate intake results were similar to red cell folate results, but the associations with polyps were weaker. Results are consistent with a protective effect of red cell folate concentration against the development of colorectal polyps, at least in men. A folate effect may depend on sex-specific interactions with other nutritional or physiological factors.

Glutathione transferase null genotype, broccoli, and lower prevalence of colorectal adenomas.

Cruciferous vegetables, especially broccoli, may prevent cancer through anticarcinogenic compounds. For example, broccoli contains isothiocyanates that induce carcinogen-detoxifying enzymes. Glutathione transferase enzymes conjugate isothiocyanates, leading to excretion. We hypothesized that broccoli consumption in combination with the glutathione transferase M1 (GSTM1) null genotype would be associated with a lower prevalence of colorectal adenomas because of higher isothiocyanate levels. We used a case-control study of mainly asymptomatic subjects aged 50-74 years who underwent a screening sigmoidoscopy at either of two Southern California Kaiser Permanente Medical Centers during 1991-1993. Cases (n = 459) had a first-time diagnosis of histologically confirmed adenomas detected by flexible sigmoidoscopy. Controls (n = 507) had no polyp detected. Subjects had a 45-min in-person interview for information on various risk factors and basic demographic data and completed a 126-item, semiquantitative food frequency questionnaire. Blood samples were used for GSTM1 genotyping. Subjects with the highest quartile of broccoli intake (an average of 3.7 servings per week) had an odds ratio of 0.47 (95% confidence interval, 0.30-0.73) for colorectal adenomas, compared with subjects who reportedly never ate broccoli. When stratified by GSTM1 genotype, a protective effect of broccoli was observed only among subjects with the GSTM1 null genotype (P for trend, 0.001; P for interaction, 0.01). The observed broccoli-GSTM1 interaction is compatible with an isothiocyanate mechanism.