A prospective study of Chlamydia pneumoniae infection and risk of MS in two US cohorts.

BACKGROUND: Chlamydia pneumoniae (Cpn) has been proposed as a possible etiologic agent in multiple sclerosis (MS). However, previous studies were cross-sectional and could not assess whether Cpn infection preceded the onset of MS. METHODS: The authors conducted a prospective nested case-control study among 3 million US Army personnel and 121,466 members of the Kaiser Permanente Medical Care Program (KPMCP) cohort. Serum samples collected prior to onset of MS symptoms were available for 83 MS cases in the Army and 46 in the KPMCP cohort. Two controls were matched to each case on age, sex, and date of blood collection. Microimmunofluorescence was used to measure serum immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody titers to Cpn; IgG titers > or 1:16 were considered positive for past Cpn infection. RESULTS: Seropositivity for Cpn was not significantly associated with risk of MS in either cohort (Army: OR = 1.0; 95% CI 0.6, 1.8; KPMCP: OR = 1.5; 95% CI 0.7, 3.1) or in the pooled analysis (OR = 1.2; 95% CI 0.8, 1.9). Serum levels of anti-Cpn IgG antibody were also not associated with an increased risk of MS in the Army (OR for a fourfold difference in antibody titers = 0.9; 95% CI 0.7, 1.2) or in the pooled analysis (OR = 1.2; 95% CI 0.9, 1.4), but a significant increase in risk was seen in the KPMCP cohort (OR = 1.7; 95% CI 1.2, 2.5). The difference between these results in the Army and the KPMCP cohort was significant (p = 0.01). CONCLUSIONS: Neither Cpn seropositivity nor serum anti-Cpn IgG antibody titers predicted risk of developing MS. However, due to the heterogeneity of results between cohorts, we cannot exclude the possibility that infection with Cpn may modify the risk of MS.

Effect of supplementation with chromium picolinate on antibody titers to 5-hydroxymethyl uracil.

Recent in vitro studies have shown that chromium (III) compounds such as chromium picolinate, a popular dietary supplement among people trying to lose weight, produce chromosome damage. We monitored levels of DNA damage in a chromium picolinate supplement trial by measuring antibodies titers to an oxidized DNA base, 5-hydroxymethyl-2'-deoxyuridine (HMdU), by enzyme-linked immunosorbent assays. Ten obese volunteer women completed a 8-week course of 400 micrograms chromium picolinate per day. In either absolute titers or percent of the baseline value, there were no changes in antibody titers at 4 or 8 weeks. The titers were very stable within individuals and those of one individual rarely crossed over others, which was reflected in an intraclass correlation coefficient of 0.99 (95% confidence interval: 0.96-1.00). There were no effects on glucose and lipid metabolism in this period. The results of this trial suggest that chromium (III) picolinate in a dose typically used for nutrient supplementation dose not increase oxidative DNA damage, as measured by anti-HMdU antibody levels.

Gastrin and colorectal cancer: a prospective study.

BACKGROUND & AIMS: Gastrin is a putative promoter of colorectal carcinomas. The aim of this study was to evaluate the temporal relationship between gastrinemia and development of colorectal malignancy. METHODS: We conducted a nested case-control study among 128,992 subscribers to a health maintenance program who had participated in a multiphasic health checkup between 1964 and 1969. Serum had been frozen since the checkup and the cohort followed up for cancer. Of 1881 incident colorectal carcinoma cases, 250 were randomly selected; 1 control without cancer was matched to each case by age, sex, education, and date of serum collection. Stored sera were tested for Helicobacter pylori immunoglobulin G and for gastrin and glycine-extended gastrin. RESULTS: Verified cases included 166 colon cancers, 58 rectal cancers, and 9 with cancer in both locations. A mean of 15.3 years had elapsed between serum collection and diagnosis of cancer. Median gastrin levels were similar in cases and controls (41.7 vs. 40.7 pg/mL). However, a gastrin level above normal was associated with increased risk for colorectal malignancy (odds ratio, 3.9; 95% confidence interval, 1.5-9.8). If this association is causal, 8.6% of colorectal cancers could be attributed to high serum gastrin level. CONCLUSIONS: Hypergastrinemia is associated with an increased risk of colorectal carcinoma.

Association between high-density lipoprotein cholesterol and breast cancer varies by menopausal status.

A nested case-control study was conducted to investigate the hypothesis that women with high levels of high-density lipoprotein cholesterol (HDL-C) are at an increased risk of breast cancer. The source population was a cohort of 95,000 women enrolled in the Kaiser Permanente Medical Care Program who underwent a routine multiphasic health examination between 1964 and 1971. From the more than 2,000 breast cancer cases diagnosed in this cohort, 200 cases were randomly selected for this study. For each case, one control who matched on age and date of examination was chosen. Lipid and lipoprotein levels were measured in archived serum samples collected at the time of the women's examinations. Breast cancer risk factor information was obtained from questionnaires completed by the women when their blood was drawn and was supplemented with information from medical records. HDL-C levels were not significantly different between the cases and controls overall; however, a statistically significant interaction between the HDL-C level and menopausal status at diagnosis was detected. Premenopausal cases had mean HDL-C levels 3.48 mg/dl lower than matched controls [95% confidence interval (CI), -7.05, 0.09], whereas postmenopausal cases had levels 2.05 mg/dl higher than controls (95% CI, -0.94, 5.03). In multivariate conditional logistic regression analyses, the odds ratio associated with each 1 mg/dl increase in HDL-C was 0.96 (95% Cl, 0.93-1.0) for premenopausal women and 1.02 (95% CI, 0.99-1.05) for postmenopausal women. Although many breast cancer risk factors are associated with high HDL-C, the relationship between breast cancer and HDL-C was independent of other factors evaluated.

Risk for gastric lymphoma in persons with CagA+ and CagA- Helicobacter pylori infection.

Infection with Helicobacter pylori increases the risk for gastric non-Hodgkin's lymphoma (GNHL). Strains that express CagA protein are thought to be particularly virulent. It was determined whether CagA+ H. pylori infection increased the risk for GNHL more than CagA infection. Thirty-two cases and 130 controls previously tested for H. pylori antibodies were tested for CagA antibodies by ELISA. The risk for GNHL was compared among CagA+, CagA-, and uninfected persons by use of conditional logistic regression. CagA+ subjects had 8.2 times the risk for GNHL than uninfected persons (95% confidence interval [CI], 2.5-26.7). CagA- subjects had 4.4 times the risk for GNHL than uninfected persons (95% CI, 1.2-16.5). Among infected subjects only, CagA+ infection was not associated with significantly increased risk for GNHL when compared with CagA- infection (odds ratio, 2.1; 95% CI, 0.8-5.4). This study does not support a major role for CagA in lymphomagenesis.

5 alpha-reductase activity and prostate cancer: a case-control study using stored sera.

We report a nested case-control study of serum biomarkers of 5 alpha-reductase activity and the incidence of prostate cancer. From a cohort of more than 125,000 members of the Kaiser Permanente Medical Care Program who underwent multiphasic health examinations during 1964-1971, we selected 106 incident prostate cancer cases. A control was pair matched to each case on age, date of serum sampling, and clinic location. Serum levels of total testosterone, free testosterone, androsterone glucuronide, and 5 alpha-androstane-3 alpha,17 beta androstanediol glucuronide (3 alpha-diol G) were measured on the stored samples and scored as quartiles. Potential confounders included alcohol, smoking, and body mass index. The adjusted odds ratios and 95% confidence intervals for a one quartile score increase were 1.00 (0.75-1.34) for total testosterone, 1.14 (0.86-1.50) for free testosterone, 1.13 (0.84-1.53) for androsterone glucuronide, and 1.16 (0.86-1.56) for 3 alpha-diol G. A limitation of this study is that there are two different 5 alpha-reductase isoenzymes, only one of which is expressed in high levels within the prostate, yet both of which may affect serum biomarkers. Since the two isoenzymes are encoded on different chromosomes, variation in one would act as an independent source of measurement error in any analysis of serum biomarker effects of the other. Consequently, the odds ratios may be underestimated and the study, although negative, cannot exclude the previously hypothesized possibility that a positive relationship between intraprostatic 5 alpha-reductase activity and prostate cancer may exist. A clinical trial to test this hypothesis is under way.

A simple, differential extraction method for the simultaneous direct radioimmunoassay of androgens and androgen glucuronides in human serum.

A method is described for the differential extraction of unconjugated androgens (testosterone and dihydrotestosterone) and glucuronidated androgens (androstane-3 alpha,17 beta-diol glucuronide and androsterone glucuronide) from human serum using solid-phase, gravity-flow extraction columns. In this method, 100-microL aliquots of serum are loaded onto the normal-phase columns, unconjugated androgens are eluted with ethyl ether, and glucuronides are eluted with ethyl ether containing 2% acetic acid. Glucuronide eluates are washed with 1% aqueous acetic acid to remove cross-reacting steroid sulfates. Assays of sera for the four steroids were performed using standard radioimmunoassay methodology, except for androsterone glucuronide. This steroid was assayed with a novel radioimmunoassay method that employees a tritiated, unconjugated androsterone tracer and an anti-dehydroepiandrosterone sulfate antiserum. The new method is well suited for the assay of conjugated and unconjugated steroids in large numbers of specimens, particularly where the sample volume is limited.

Seasonal variation in vitamin D, vitamin D-binding protein, and dehydroepiandrosterone: risk of prostate cancer in black and white men.

Our previous study provided evidence that higher serum levels of the active form of vitamin D, 1,25-dihydroxyvitamin D (1, 25-D), might possibly slow the progression of subclinical to clinically significant prostate cancer in both black and white men, especially after age 57. This paper extends the prior study by contrasting seasonal variation in 1,25-D and its precursor, 25-hydroxyvitamin D (25-D), in case and control subjects. In addition, the risk of prostate cancer is related to serum levels of vitamin D-binding protein (VDBP) and total dehydroepiandrosterone and to polymorphic variation in VDBP. The expected elevated summer levels of 25-D were seen in case and control subjects and, as expected, 1,25-D did not vary throughout the year in the control subjects. Unexpectedly, lower case levels of 1,25-D were limited largely to the summer months (P = 0.01) in both black and white cases and to cases greater than or equal to the median age of 57 years. Levels of VDBP and dehydroepiandrosterone and the frequencies of VDBP polymorphisms were similar in case and control subjects, although striking differences were seen in allelic frequencies in black and white men. These observations provide additional evidence that vitamin D metabolism may impact the risk of prostate cancer.

Prostate-specific antigen as predictor of prostate cancer in black men and white men.

BACKGROUND: The increasing incidence of prostate cancer creates complex issues in health care management and cost containment. There is a need to evaluate serial measurements of prostate-specific antigen (PSA) as a marker for long-term risk of clinically important prostate cancer (stages B through D). PURPOSE: We used a nested case-control design within a retrospective cohort study to evaluate serial PSA concentrations in relation to subsequent prostate cancer diagnoses. METHODS: Participants included 40 black and 96 white men with subsequent diagnoses of prostate cancer and 84 black and 100 white men without such diagnoses (control subjects) in a multiphasic health screening program conducted by the Kaiser Permanente Medical Care Program of Northern California. Serial serum samples were collected 1.5-23 years before prostate cancer diagnosis. RESULTS: Median serum PSA concentrations, specific for age and subsequent cancer status, were similar in blacks and whites. Concentrations in control subjects increased exponentially with age, with a doubling time of 24.9 years. Concentrations in men with stage A cancer were similar to those in control subjects. Until about 13 years before diagnosis, PSA in men with subsequent cancer stages B through D increased exponentially with age, with a doubling time similar to that of control subjects. Thereafter, the PSA concentrations increased exponentially, with a doubling time of 4.3 years. Rapid increase in PSA concentration started about 1.5 years earlier for men with stage D cancer than for men with stage B or C cancer. The single PSA measurement drawn closest to diagnosis was a more sensitive marker of stages B through D cancer within the next 7 years than was any index of change that also took account of earlier PSA readings. CONCLUSIONS: These data suggest that 1) age-specific PSA concentrations are similar in black men and white men and 2) current PSA concentration, specific for age, outperforms changes in past concentrations in identifying the man who will develop stage B, C, or D cancer within 7 years, albeit at the cost of a slightly higher rate of false-positive results. This interpretation needs confirmation in other data containing many serial PSA measurements within a few years of diagnosis.

Helicobacter pylori infection and gastric lymphoma.

BACKGROUND: Helicobacter pylori infection is a risk factor for gastric adenocarcinoma. We examined whether this infection is also a risk factor for primary gastric non-Hodgkin's lymphoma. METHODS: This nested case-control study involved two large cohorts (230,593 participants). Serum had been collected from cohort members and stored, and all subjects were followed for cancer. Thirty-three patients with gastric non-Hodgkin's lymphoma were identified, and each was matched to four controls according to cohort, age, sex, and date of serum collection. For comparison, 31 patients with nongastric non-Hodgkin's lymphoma from one of the cohorts were evaluated, each of whom had been previously matched to 2 controls. Pathological reports and specimens were reviewed to confirm the histologic type of the tumor. Serum samples from all subjects were tested for H. pylori IgG by an enzyme-linked immunosorbent assay. RESULTS: Thirty-three cases of gastric non-Hodgkin's lymphoma occurred a median of 14 years after serum collection. Patients with gastric lymphoma were significantly more likely than matched controls to have evidence of previous H. pylori infection (matched odds ratio, 6.3; 95 percent confidence interval, 2.0 to 19.9). The results were similar in both cohorts. Among the 31 patients with nongastric lymphoma, a median of six years had elapsed between serum collection and the development of disease. No association was found between nongastric non-Hodgkin's lymphoma and previous H. pylori infection (matched odds ratio, 1.2; 95 percent confidence interval, 0.5 to 3.0). CONCLUSIONS: Non-Hodgkin's lymphoma affecting the stomach, but not other sites, is associated with previous H. pylori infection. A causative role for the organism is plausible, but remains unproved.

Helicobacter pylori, pepsinogen, and risk for gastric adenocarcinoma.

The objective of this project was to determine the association of Helicobacter pylori infection and serum pepsinogen levels on subsequent risk for gastric adenocarcinoma. This nested case-control study was set in a large health maintenance organization. One hundred thirty-six cases of gastric adenocarcinoma and 136 matched controls without adenocarcinoma from a large cohort that had contributed serum in the 1960's were studied. The presence of IgG against H. pylori had previously been determined by enzyme-linked immunosorbent assay. Serum levels of pepsinogens I and II were ascertained by radioimmunoassay. In a sample of subjects, the presence of antiparietal cell antibodies was determined by immunofluorescent antibody assay (Nichols Laboratory). There were 98 cases of adenocarcinoma of the antrum, body, or fundus (distal cancers) and 30 of the cardia or gastroesophageal junction (proximal cancers). By univariate analysis, H. pylori infection [odds ratio (OR), 3.6; P < 0.001] and serum pepsinogen I < 50 ng/ml (OR = 2.9; P = 0.003) were both associated with development of distal cancer. In multivariate analysis, there was interaction between the two variables; H. pylori in the absence of low pepsinogen I was independently associated with cancer (OR, 2.4; P = 0.04) but low pepsinogen I in the absence of H. pylori infection was not associated with cancer (OR, 0.8; P > 0.5). In combination, however, H. pylori infection and a low pepsinogen I were associated with a marked increase in the risk of developing distal malignancy (OR, 10.0; P = 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin D and prostate cancer: a prediagnostic study with stored sera.

This study evaluates the risk of prostate cancer in relation to serum levels of the major vitamin D metabolites, 25-hydroxyvitamin D (25-D3) and 1,25-dihydroxyvitamin D (1,25-D). Between 1964 and 1971, more than 250,000 serum samples were collected from members of the Kaiser Permanente Medical Care Plan in Oakland and San Francisco and stored for future use. Levels of 25-D and 1,25-D were measured in samples from 90 black and 91 white men diagnosed with prostate cancer before December 31, 1987 and controls individually matched on age, race, and day of serum storage. Mean serum 1,25-D was 1.81 pg/ml lower in cases than in matched controls (P = 0.002). Risk of prostate cancer decreased with higher levels of 1,25-D especially in men with low levels of 25-D. However, mean 25-D was not significantly different in cases and controls. The association of lower 1,25-D with prostate cancer was found in men above the median age of 57 years at serum storage but not younger men and was similar in black and white men. In men > or = 57 years of age, 1,25-D was an important predictor of risk for palpable and anaplastic tumors but not for tumors incidentally discovered during surgery to treat the symptoms of benign prostatic hyperplasia or well differentiated tumors.

Senescent decline in serum dehydroepiandrosterone sulfate concentrations in a population of wild baboons.

The physiologic functions of dehydroepiandrosterone sulfate (DS), a precursor of androgens and estrogen and the most abundant steroid in the circulation, are unknown. Nevertheless, numerous studies have shown that low concentrations of DS are correlated with a variety of metabolic and cardiovascular diseases in human beings, and administration of DS to experimental animals is associated with protection from similar diseases. Thus, the marked decline in DS concentrations with age in human beings may be of considerable functional significance. However, because of the difficulties in studying any heterogeneous human population, it has been difficult to assess the extent to which the DS decline with age is confounded by any of a number of factors (e.g., smoking, level of activity, genetics, diet, medication and disease). We studied the effects of age on DS concentrations in a well-characterized population of wild yellow baboons living freely in a national park in East Africa. Study of these animals circumvents many of the confounds just noted. In examining animals ranging in age from juvenile status to old age, we observed a robust decline in DS concentrations with age. The magnitude of the decline is approximately equal in both sexes. In addition, the decline is similar in comparing two baboon groups which have fully natural diets with one group which forages heavily on garbage from people.

Long-term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men.

Dehydroepiandrosterone sulfate (DS) was measured by direct tritium RIA in longitudinal plasma specimens from 97 normal healthy male participants in the Baltimore Longitudinal Study of Aging. Fasting blood was collected at regular visits (approximately 1.5 yr apart) over an average 13 yr of adulthood (cumulative age range: 32-83 yr). DS was measured in 3-4 widely spaced specimens from each subject. A decline in DS was found in 65 (67%) subjects, 13 subjects (13%) showed no change, and increases were found in the 19 remaining subjects during the study period. A plot of individual data points revealed the same pattern we had obtained previously from a cross-sectional study of a different normal male population. A plot of DS values vs. age among subjects whose DS increased during the study also revealed an age-related decline. Thus, the longitudinal decrease in circulating DS, long inferred from cross-sectional data, is confirmed for normal men in the present study. A more detailed study of every specimen collected during the study period from 12 of the Baltimore Longitudinal Study of Aging subjects (4 whose values tended to be low, 4 whose values tended to be high, and 4 whose values were near the mean) failed to reveal any patterns of variation that could be correlated with changes in life circumstances, health status, or any other discernible factors. Hence, the wide variability seen in DS among individuals within normal populations remains unexplained.

Relationship between the concentrations of estriol sulfate and estrone sulfate in human breast cyst fluid.

Estriol-3-sulfate (E3S) is present in human breast cyst fluid (BCF) in median levels of 8.7-10.4 nmol/L, yet is barely detectable in the serum (less than 0.034 nmol/L). The source of this huge concentration of E3S is unknown. It may accumulate from blood by active transport or be synthesized and concentrated within the cyst. Since estrone sulfate (E1S) and its possible precursor, dehydroepiandrosterone sulfate (DHEAS) are elevated in BCF, E3S may originate via 16 alpha-hydroxylation of E1S. The present study examined the correlations between the levels of DHEAS and E1S with those of E3S in BCF. The sodium and potassium ions were also quantified and related to the steroid concentrations. By linear regression analysis of log-normalized data there was a highly significant correlation between the concentrations of E1S and E3S (n = 355, r = 0.690, P less than 0.001) and between DHEAS and E3S (n = 361, r = 0.577, P less than 0.001). The BCF were classified according to their K/Na ion ratios: type 1, greater than 1.0, type II, less than 0.25, and type III, 0.25-1.0. By Student's t test, the concentrations of E3S differed between each BCF Type (P less than 0.002). This was also true for E1S and DHEAS. Type 1 cysts were associated with the highest estrogen sulfate levels and type II with the lowest levels. The possible physiological importance of this observation resides in reports that the BCF type expressing the highest steroid concentrations has been related to an aporcine-like epithelial lining of the cyst wall and a somewhat higher risk for developing breast cancer. The results suggest that E3S in BCF may originate from E1S, but alternate mechanisms are not precluded.

Elevated serum dehydroepiandrosterone sulfate levels in practitioners of the Transcendental Meditation (TM) and TM-Sidhi programs.

Serum dehydroepiandrosterone sulfate (DHEA-S) levels were measured in 270 men and 153 women who were experienced practitioners of the Transcendental Meditation (TM) and TM-Sidhi programs, mental techniques practiced twice daily, sitting quietly with the eyes closed. These were compared according to sex and 5-year age grouping to 799 male and 453 female nonmeditators. The mean DHEA-S levels in the TM group were higher in all 11 of the age groups measured in women and in 6 of 7 5-year age groups over 40 in men. There were no systematic differences in younger men. Simple regression using TM-group data revealed that this effect was independent of diet, body mass index, and exercise. The mean TM-group levels measured in all women and in the older men were generally comparable to those of nonmeditator groups 5 to 10 years younger. These findings suggest that some characteristics of TM practitioners are modifying the age-related deterioration in DHEA-S secretion by the adrenal cortex.

Helicobacter pylori infection and the risk of gastric carcinoma.

BACKGROUND: Infection with Helicobacter pylori has been linked with chronic atrophic gastritis, an inflammatory precursor of gastric adenocarcinoma. In a nested case-control study, we explored whether H. pylori infection increases the risk of gastric carcinoma. METHODS: From a cohort of 128,992 persons followed since the mid-1960s at a health maintenance organization, 186 patients with gastric carcinoma were selected as case patients and were matched according to age, sex, and race with 186 control subjects without gastric carcinoma. Stored serum samples collected during the 1960s were tested for IgG antibodies to H. pylori by enzyme-linked immunosorbent assay. Data on cigarette use, blood group, ulcer disease, and gastric surgery were obtained from questionnaires administered at enrollment. Tissue sections and pathology reports were reviewed to confirm the histologic results. RESULTS: The mean time between serum collection and the diagnosis of gastric carcinoma was 14.2 years. Of the 109 patients with confirmed gastric adenocarcinoma (excluding tumors of the gastroesophageal junction), 84 percent had been infected previously with H. pylori, as compared with 61 percent of the matched control subjects (odds ratio, 3.6; 95 percent confidence interval, 1.8 to 7.3). Tumors of the gastroesophageal junction were not linked to H. pylori infection, nor were tumors in the gastric cardia. H. pylori was a particularly strong risk factor for stomach cancer in women (odds ratio, 18) and blacks (odds ratio, 9). A history of gastric surgery was independently associated with the development of cancer (odds ratio, 17; P = 0.03), but a history of peptic ulcer disease was negatively associated with subsequent gastric carcinoma (odds ratio, 0.2; P = 0.02). Neither blood group nor smoking history affected risk. CONCLUSIONS: Infection with H. pylori is associated with an increased risk of gastric adenocarcinoma and may be a cofactor in the pathogenesis of this malignant condition.

Serum retinol and retinol-binding protein levels do not predict subsequent lung cancer.

Retinol and retinol-binding protein levels were measured in sera previously obtained, and stored in the frozen state, at multiphasic health checkups from 151 persons subsequently found to have lung cancer (cases) and 302 persons who remained free of cancer (controls). Two controls were matched to each case for sex, skin color, age, date of multiphasic health checkup, and aspects of the smoking habit. Mean levels in cases and controls were, respectively, retinol: 82.17 and 82.37 micrograms/dl (p = 0.93), and retinol-binding protein: 6.04 and 6.00 mg/dl (p = 0.81). Mean differences between cases and controls were, retinol: 0.195 micrograms/dl with 95% confidence limits, -3.91 and 4.30 micrograms/dl; retinol-binding protein: -0.033 mg/dl with 95% confidence limits, -0.31 and 0.24 mg/dl. No significant trend in relative risk of lung cancer was observed when the retinol or retinol-binding protein distribution was divided into quintiles. No significant associations were observed in subgroups based on age, sex, histologic type of cancer, cigarette consumption, or interval between blood drawing and cancer diagnosis. In this large study, retinol and retinol-binding protein levels were not useful in predicting the subsequent development of lung cancer.