A prospective evaluation of plasma phospholipid fatty acids and breast cancer risk in the EPIC study.

BACKGROUND: Intakes of specific fatty acids have been postulated to impact breast cancer risk but epidemiological data based on dietary questionnaires remain conflicting. MATERIALS AND METHODS: We assessed the association between plasma phospholipid fatty acids and breast cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition study. Sixty fatty acids were measured by gas chromatography in pre-diagnostic plasma phospholipids from 2982 incident breast cancer cases matched to 2982 controls. Conditional logistic regression models were used to estimate relative risk of breast cancer by fatty acid level. The false discovery rate (q values) was computed to control for multiple comparisons. Subgroup analyses were carried out by estrogen receptor (ER) and progesterone receptor expression in the tumours. RESULTS: A high level of palmitoleic acid [odds ratio (OR) for the highest quartile compared with the lowest OR (Q4-Q1) 1.37; 95% confidence interval (CI), 1.14-1.64; P for trend = 0.0001, q value = 0.004] as well as a high desaturation index (DI16) (16:1n-7/16:0) [OR (Q4-Q1), 1.28; 95% C, 1.07-1.54; P for trend = 0.002, q value = 0.037], as biomarkers of de novo lipogenesis, were significantly associated with increased risk of breast cancer. Levels of industrial trans-fatty acids were positively associated with ER-negative tumours [OR for the highest tertile compared with the lowest (T3-T1)=2.01; 95% CI, 1.03-3.90; P for trend = 0.047], whereas no association was found for ER-positive tumours (P-heterogeneity =0.01). No significant association was found between n-3 polyunsaturated fatty acids and breast cancer risk, overall or by hormonal receptor. CONCLUSION: These findings suggest that increased de novo lipogenesis, acting through increased synthesis of palmitoleic acid, could be a relevant metabolic pathway for breast tumourigenesis. Dietary trans-fatty acids derived from industrial processes may specifically increase ER-negative breast cancer risk.

Meal patterns across ten European countries - results from the European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study.

OBJECTIVE: To characterize meal patterns across ten European countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study. DESIGN: Cross-sectional study utilizing dietary data collected through a standardized 24 h diet recall during 1995-2000. Eleven predefined intake occasions across a 24 h period were assessed during the interview. In the present descriptive report, meal patterns were analysed in terms of daily number of intake occasions, the proportion reporting each intake occasion and the energy contributions from each intake occasion. SETTING: Twenty-seven centres across ten European countries. SUBJECTS: Women (64 %) and men (36 %) aged 35-74 years (n 36 020). RESULTS: Pronounced differences in meal patterns emerged both across centres within the same country and across different countries, with a trend for fewer intake occasions per day in Mediterranean countries compared with central and northern Europe. Differences were also found for daily energy intake provided by lunch, with 38-43 % for women and 41-45 % for men within Mediterranean countries compared with 16-27 % for women and 20-26 % for men in central and northern European countries. Likewise, a south-north gradient was found for daily energy intake from snacks, with 13-20 % (women) and 10-17 % (men) in Mediterranean countries compared with 24-34 % (women) and 23-35 % (men) in central/northern Europe. CONCLUSIONS: We found distinct differences in meal patterns with marked diversity for intake frequency and lunch and snack consumption between Mediterranean and central/northern European countries. Monitoring of meal patterns across various cultures and populations could provide critical context to the research efforts to characterize relationships between dietary intake and health.

Fruit and vegetable consumption in relation to hepatocellular carcinoma in a multi-centre, European cohort study.

BACKGROUND: Vegetable and/or fruit intakes in association with hepatocellular carcinoma (HCC) risk have been investigated in case-control studies conducted in specific European countries and cohort studies conducted in Asia, with inconclusive results. No multi-centre European cohort has investigated the indicated associations. METHODS: In 486,799 men/women from the European Prospective Investigation into Cancer and nutrition, we identified 201 HCC cases after 11 years median follow-up. We calculated adjusted hazard ratios (HRs) for HCC incidence for sex-specific quintiles and per 100 g d(-1) increments of vegetable/fruit intakes. RESULTS: Higher vegetable intake was associated with a statistically significant, monotonic reduction of HCC risk: HR (100 g d(-1) increment): 0.83; 95% CI: 0.71-0.98. This association was consistent in sensitivity analyses with no apparent heterogeneity across strata of HCC risk factors. Fruit intake was not associated with HCC incidence: HR (100 g d(-1) increment): 1.01; 95% CI: 0.92-1.11. CONCLUSIONS: Vegetable, but not fruit, intake is associated with lower HCC risk with no evidence for heterogeneity of this association in strata of important HCC risk factors. Mechanistic studies should clarify pathways underlying this association. Given that HCC prognosis is poor and that vegetables are practically universally accessible, our results may be important, especially for those at high risk for the disease.

High consumption of pulses is associated with lower risk of abnormal glucose metabolism in women in Mauritius.

AIMS: To investigate if consumption of pulses was associated with a reduced risk of developing abnormal glucose metabolism, increases in body weight and increases in waist circumference in a multi-ethnic cohort in Mauritius. METHODS: Population-based surveys were performed in Mauritius in 1992 and in 1998. Pulse consumption was estimated from a food frequency questionnaire in 1992 and outcomes were measured in 1998. At both time points, anthropometry was undertaken and an oral glucose tolerance test was performed. RESULTS: Mauritian women with the highest consumption of pulses (highest tertile) had a reduced risk of developing abnormal glucose metabolism [odds ratio 0.52; 95% CI 0.27, 0.99) compared with those with the lowest consumption, and also after multivariable adjustments. In women, a high consumption of pulses was associated with a smaller increase in BMI. CONCLUSIONS: High consumption of pulses was associated with a reduced risk of abnormal glucose metabolism and a smaller increase in BMI in Mauritian women. Promotion of pulse consumption could be an important dietary intervention for the prevention of Type 2 diabetes and obesity in Mauritius and should be examined in other populations and in clinical trials.

Consumption of filtered and boiled coffee and the risk of first acute myocardial infarction; a nested case/referent study.

BACKGROUND AND AIM: In northern Sweden, consumption of both filtered and boiled coffee is common. Boiled coffee, especially popular in rural areas, is known to raise blood lipids, a risk factor for acute myocardial infarction (MI). To our knowledge, only one epidemiological study, a case-control study from Sweden, has investigated boiled coffee in MI, noting an increased risk at high consumption levels in men, and no association in women. The aim of the present nested case-referent study was to relate consumption of filtered and boiled coffee to the risk of first MI. METHODS AND RESULTS: The study subjects were 375 cases (303 men, 72 women) and 1293 matched referents from the population-based Northern Sweden Health and Disease Study. Coffee consumption was assessed by food frequency questionnaire. Risk estimates were calculated by conditional logistic regression. A statistically significant positive association was found between consumption of filtered coffee and MI risk in men [odds ratio for consumption > or = 4 times/day versus < or = 1 time/day 1.73 (95% CI 1.05-2.84)]. In women, a similar association was observed, but for boiled coffee [odds ratio 2.51 (95% CI 1.08-5.86)]. After adjustment for current smoking, postsecondary education, hypertension, and sedentary lifestyle, the results for women were no longer statistically significant. CONCLUSION: Consumption of filtered coffee was positively associated with the risk of a first MI in men. A similar tendency was observed for boiled coffee in women, but the result was not statistically significant in multivariate analysis. Further investigation in a larger study is warranted.

The influence of Rx-to-OTC changes on drug sales. Experiences from Sweden 1980-1994.

OBJECTIVE: A descriptive study of national sales data from Sweden to find out the effect of over-the-counter (OTC) switches on total sales of a number of drugs. During the period 1980-94, 16 drugs were changed from prescription only (Rx) status to the Swedish OTC market. Total sales increased for 14 out of these 16 drugs. The increase was seen soon after the change to OTC status. Two years after the change an average increase of 36% was seen. In the following 2 years, the increase was typically very modest (average 1%). Large differences in the changes were seen for the individual drugs. The prescription of OTC packs decreased on average by 26% during the first 2 years after the switch. Converting this decrease in sales in terms of number of packs no longer prescribed led to an estimated yearly saving of SEK 200 million ($US 30 million) for the national drug budget. Taking account of the total increase in defined daily doses (DDDs) 2 years after the change for those 16 drugs led to an estimated yearly saving of SEK 2.5 billion ($US 400 million).

Plasma and urine levels of methotrexate and 7-hydroxymethotrexate in children with ALL during maintenance therapy with weekly oral methotrexate.

A new high-performance liquid chromatographic assay was used to determine methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OH-MTX), in the plasma (n = 17) and urine (n = 14) of children (age 3-12 years) on maintenance therapy for acute lymphocytic leukemia (n = 14) or non-Hodgkin's lymphoma (n = 3). Each child received oral doses of weekly MTX (4.0-29 mg/m2) and daily 6-mercaptopurine (40-111 mg/m2). Plasma samples were collected daily from two children during the 1-week dose interval. A limited sampling strategy was designed, whereby 2 days of blood sampling were used in the other 15 patients. Morning urine samples were collected daily for 1 week following MTX intake from 14 of the children. MTX was detectable in all plasma and urine samples for the entire dose interval. The main metabolite, 7-OH-MTX, could be detected in plasma and urine from all patients on the first day after dose intake but only in a few patients during the whole dose interval. Interpatient variability of MTX and 7-OH-MTX levels was high at all points during the week. Significant correlation were found between the urinary MTX levels on days 2 and 7 and plasma MTX levels on day 2 after intake. No significant correlation was found between drug levels in plasma or urine and liver function tests in the children showing signs of mild liver injury. This assay provides a tool for further studies on the role of pharmacokinetics for the clinical effects of weekly oral low-dose MTX given alone or in combination with 6-mercaptopurine.

The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis.

1. The pharmacokinetics of MTX and its 7-hydroxy metabolite (7-OHMTX) were investigated in nine patients with rheumatoid arthritis (RA). Each patient received 15 mg MTX i.v., i.m. and p.o. after an overnight fast in a randomized cross-over design. The plasma concentrations of MTX and 7-OHMTX were measured over 7 days and their urinary excretion over 24 h. 2. Plasma concentrations of MTX were described by a triexponential function after i.v. administration, a triexponential function with zero or first order absorption after oral administration, and a biexponential function with zero of first order absorption after i.m. injection. Plasma concentrations of 7-OHMTX were described by a biexponential function after all three routes of administration. The median terminal elimination half-lives of MTX and 7-OHMTX were 55 h and 116 h, respectively. The area under the plasma concentration-time curve (AUC (0,170 h)) of MTX did not differ between i.m. and oral administration indicating similar bioavailability after these routes of administration. The AUC (0,170 h) values of 7-OHMTX after i.v., oral and i.m. administration were similar. Over 80% of MTX was excreted in urine as intact drug and about 3% was excreted as 7-OHMTX during 24 h after drug administration. 3. Plasma concentrations of MTX and 7-OHMTX were measurable at the end of the dose interval in most of the patients and may help to identify non-responders or patients with increased risk of side-effects.

Factors associated with high-quantity prescriptions of benzodiazepines in Sweden.

An important aspect, when discussing the prescribing and use of psychotropics, is the amount of drug prescribed at each visit. In this study the Swedish Diagnosis and Therapy Survey was used in order to analyze high-quantity prescriptions of benzodiazepines. The total amount of benzodiazepines prescribed--measured as defined daily doses (DDD)--was calculated for each visit. Prescriptions with quantities equal to or greater than the 90th percentile applied on the distribution of prescribed DDD per visit were defined as high-quantity prescriptions. Using this definition, prescriptions on 200 DDD or more--14.9% of all--were classified as high-quantity prescriptions. In the analysis the proportions of high-quantity prescription in different subgroups were compared. The study showed that there was a strong relationship between age of the patient and high-quantity prescriptions while the sex of the patient was of minor importance. Doctors specializing in internal medicine and psychiatrists prescribed high-quantity prescriptions to a greater extent than other doctors but differences with regard to the doctor's ages were small. Patients with sleeping disturbances obtained high-quantity prescriptions to a greater extent than other patients while patients with nervous problems obtained fewer. Patients with new prescriptions on benzodiazepines obtained high-quantity prescriptions to a lesser extent than patients making repeat visits. In addition the study showed that it was not as common with high-quantity prescriptions in the three major cities and in the most sparsely populated communities as in mid-sized communities.

Trace analysis of methotrexate and 7-hydroxymethotrexate in human plasma and urine by a novel high-performance liquid chromatographic method.

A new high-performance liquid chromatographic method for the quantitative determination of methotrexate (MTX) and its metabolite 7-hydroxymethotrexate (7-OHMTX) in blood plasma and urine was developed. The method utilized a solid-phase extraction procedure (Certify II cartridges) for the simultaneous isolation of MTX and 7-OHMTX. Chromatographic separation was achieved using a C18 reversed-phase column with isocratic elution. The eluent was irradiated with UV light of 254 nm, which converted MTX and 7-OHMTX by photolytic oxidation to fluorescent products. The limits of detection of MTX and 7-OHMTX in plasma were approximately 0.2 and 1 nmol/L, respectively. The intraday variability in the quantitation of MTX and 7-OHMTX was less than 8% down to 1 nmol/L and 4.6 nmol/L, respectively. Both MTX and 7-OHMTX could be detected in plasma from a patient being treated for rheumatoid arthritis 1 week after the last dose (10 mg orally).

Determination of urinary 5-hydroxyindole-3-acetic acid by high-performance liquid chromatography with electrochemical detection and direct sample injection.

A method for the routine quantitative determination of the major serotonin metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in urine is described. 5-HIAA was analyzed without prior sample cleanup, using an automated high-performance liquid chromatography system with isocratic elution and electrochemical detection (+0.60 V versus a Ag/AgCl reference electrode). The urine samples were mixed with a solution of the internal standard (5-hydroxyindole-3-propionic acid) and centrifuged. The supernatant was transferred to sealed glass vials, and a 2-microliters aliquot was injected directly onto a C18 reversed-phase analytical column, using an automatic sample injector. Samples of urine could be stored for several months at -80 or at +7 degrees C for 2 days without loss of 5-HIAA. However, a gradual decline with time occurred in crude samples stored at room temperature or above, as well as in urine samples diluted with the mobile phase. The detector response was linear in the range of 0-65 mumol/l 5-HIAA, and the intra- and interassay coefficients of variation were about 5 and 7%, respectively (n = 10).