Impact of thearubigins on the estimation of total dietary flavonoids in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Thearubigins (TR) are polymeric flavanol-derived compounds formed during the fermentation of tea leaves. Comprising ∼70% of total polyphenols in black tea, TR may contribute majorly to its beneficial effects on health. To date, there is no appropriate food composition data on TR, although several studies have used data from the US Department of Agriculture (USDA) database to estimate TR intakes. We aimed to estimate dietary TR in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and assess the impact of including TR or not in the calculation of the total dietary flavonoid intake. Dietary data were collected using a single standardized 24-h dietary recall interviewer-administered to 36 037 subjects aged 35-74 years. TR intakes were calculated using the USDA database. TR intakes ranged from 0.9 mg/day in men from Navarra and San Sebastian in Spain to 532.5 mg/day in men from UK general population. TR contributed <5% to the total flavonoid intake in Greece, Spain and Italy, whereas in the UK general population, TR comprised 48% of the total flavonoids. High heterogeneity in TR intake across the EPIC countries was observed. This study shows that total flavonoid intake may be greatly influenced by TR, particularly in high black tea-consuming countries. Further research on identification and quantification of TR is needed to get more accurate dietary TR estimations.

Dietary intakes and food sources of phytoestrogens in the European Prospective Investigation into Cancer and Nutrition (EPIC) 24-hour dietary recall cohort.

BACKGROUND/OBJECTIVES: Phytoestrogens are estradiol-like natural compounds found in plants that have been associated with protective effects against chronic diseases, including some cancers, cardiovascular diseases and osteoporosis. The purpose of this study was to estimate the dietary intake of phytoestrogens, identify their food sources and their association with lifestyle factors in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. SUBJECTS/METHODS: Single 24-hour dietary recalls were collected from 36,037 individuals from 10 European countries, aged 35-74 years using a standardized computerized interview programe (EPIC-Soft). An ad hoc food composition database on phytoestrogens (isoflavones, lignans, coumestans, enterolignans and equol) was compiled using data from available databases, in order to obtain and describe phytoestrogen intakes and their food sources across 27 redefined EPIC centres. RESULTS: Mean total phytoestrogen intake was the highest in the UK health-conscious group (24.9 mg/day in men and 21.1 mg/day in women) whereas lowest in Greece (1.3 mg/day) in men and Spain-Granada (1.0 mg/day) in women. Northern European countries had higher intakes than southern countries. The main phytoestrogen contributors were isoflavones in both UK centres and lignans in the other EPIC cohorts. Age, body mass index, educational level, smoking status and physical activity were related to increased intakes of lignans, enterolignans and equol, but not to total phytoestrogen, isoflavone or coumestan intakes. In the UK cohorts, the major food sources of phytoestrogens were soy products. In the other EPIC cohorts the dietary sources were more distributed, among fruits, vegetables, soy products, cereal products, non-alcoholic and alcoholic beverages. CONCLUSIONS: There was a high variability in the dietary intake of total and phytoestrogen subclasses and their food sources across European regions.

Dietary beta-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

So far, studies on dietary antioxidant intake, including beta-carotene, vitamin C and vitamin E, and breast cancer risk are inconclusive. Thus, we addressed this question in the European Prospective Investigation into Cancer and Nutrition. During a median follow-up time of 8.8 years, 7,502 primary invasive breast cancer cases were identified. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). All analyses were run stratified by menopausal status at recruitment and, additionally, by smoking status, alcohol intake, use of exogenous hormones and use of dietary supplements. In the multivariate analyses, dietary intake of beta-carotene, vitamin C and E was not associated with breast cancer risk in premenopausal [highest vs. lowest quintile: HR, 1.04 (95% CI, 0.85-1.27), 1.12 (0.92-1.36) and 1.11 (0.84-1.46), respectively] and postmenopausal women [0.93 (0.82-1.04), 0.98 (0.87-1.11) and 0.92 (0.77-1.11), respectively]. However, in postmenopausal women using exogenous hormones, high intake of beta-carotene [highest vs. lowest quintile; HR 0.79 (95% CI, 0.66-0.96), P (trend) 0.06] and vitamin C [0.88 (0.72-1.07), P (trend) 0.05] was associated with reduced breast cancer risk. In addition, dietary beta-carotene was associated with a decreased risk in postmenopausal women with high alcohol intake. Overall, dietary intake of beta-carotene, vitamin C and E was not related to breast cancer risk in neither pre- nor postmenopausal women. However, in subgroups of postmenopausal women, a weak protective effect between beta-carotene and vitamin E from food and breast cancer risk cannot be excluded.

Variation in intakes of calcium, phosphorus, magnesium, iron and potassium in 10 countries in the European Prospective Investigation into Cancer and Nutrition study.

BACKGROUND/OBJECTIVES: Adequate mineral intake is important for the maintenance of bone health, cellular function and general metabolism, and possibly in the aetiology of cancer and other chronic diseases. This study aimed at investigating variation in intakes of selected minerals across 10 European countries participating in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. METHODS: Nutrient intakes for 36 034 subjects, aged between 35 and 74 years, in 27 centres were obtained using standardized 24-h dietary recall software (EPIC-SOFT). Mean intakes of calcium, phosphorus, magnesium, iron and potassium were calculated by centre and weighted by season and day of the week and were also stratified by age group. The contribution of food groups to total nutrient intake was calculated. RESULTS: There was clear geographical variability in intakes, with differences ranging from 35% for magnesium to 90% for iron in men and 36% for potassium to 75% for calcium in women, and a twofold difference in sources of haem iron (meat and fish). There was a geographical gradient in iron intake, with higher intakes in Southern than in Northern Europe and also around a twofold north-south gradient in the contribution of fruits and vegetables to potassium intake. Compared with reference intakes, the majority of age groups and centres had intakes above the recommended levels. Dairy foods and products contributed the most to calcium and phosphorus intake in almost all centres. Cereals and cereal products contributed the most to magnesium and iron intakes, except in Greece and Germany. CONCLUSIONS: Intakes of minerals vary substantially throughout Europe, with some geographical variability in their food sources.

Use of dietary supplements in the European Prospective Investigation into Cancer and Nutrition calibration study.

BACKGROUND: Dietary supplement use is increasing, but there are few comparable data on supplement intakes and how they affect the nutrition and health of European consumers. The aim of this study was to describe the use of dietary supplements in subsamples of the 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: Specific questions on dietary supplement use were asked as a part of single 24-h recalls performed on 36,034 men and women aged 35-74 years from 1995 to 2000. RESULTS: Between countries, the mean percentage of dietary supplement use varied almost 10-fold among women and even more among men. There was a clear north-south gradient in use, with a higher consumption in northern countries. The lowest crude mean percentage of use was found in Greece (2.0% among men, 6.7% among women), and the highest was in Denmark (51.0% among men, 65.8% among women). Use was higher in women than in men. Vitamins, minerals or combinations of them were the predominant types of supplements reported, but there were striking differences between countries. CONCLUSIONS: This study indicates that there are wide variations in supplement use in Europe, which may affect individual and population nutrient intakes. The results underline the need to monitor consumption of dietary supplements in Europe, as well as to evaluate the risks and benefits.

Introduction of sentinel node biopsy and stage migration of breast cancer.

AIM: The purpose of this study was to examine in a large population based group of breast cancer patients treated in a regular care setting whether the introduction of the Sentinel Node Biopsy (SNB) led to detection of a higher percentage of patients with positive regional lymph nodes. METHODS: The study includes 3665 early breast cancer patients, aged 30-85 years, diagnosed in the period 1997-2002 and registered at the Regional Cancer Registry of the Comprehensive Cancer Centre Middle Netherlands. During this period the SNB was introduced. The outcome of staging was compared for groups staged with or without SNB. A logistic regression model was used to adjust for age, calendar period and tumour size. RESULTS: Overall a quarter of all patients over the period 1997-2002 underwent a SNB as method of lymphatic staging. The use of SNB clearly increased over time: from 2% in 1998 to 65% in 2002. The percentage node positive patients also rose significantly; before introduction of the SNB 30% of all patients were diagnosed with positive lymph nodes, and after SNB introduction this percentage was 40%. The increase is largely explained by the increase of patients diagnosed with only micrometastases. Adjustment did not change the results. CONCLUSION: In conclusion, introduction of the SNB in early breast cancer led to significant upstaging of breast cancer patients treated in a regular care setting, due to the detection of more micrometastases. Since the relevance of micrometastases for long term survival is not yet known, this upstaging potentially led to over treatment of patients. On the other side, for some patients axillary lymph node dissection was prevented by the SNB procedure, preventing comorbidity.

Complex thoracic aortic aneurysm: a combined open and endovascular approach.

The authors wish to describe a combined open and endovascular approach to repair a complex thoracic aortic aneurysm. A 72-year-old man with chronic obstructive pulmonary disease, aortic valvular insufficiency and diffuse thoracic aortic aneurysm underwent aortic valve and ascending aorta replacement by a Bentall-procedure and replacement of arch aneurysm using the elephant trunk technique, performed in a first procedure. During the second procedure, endovascular stenting of the descending thoracic aorta was done. Only a few similar case reports have been presented. Endovascular repair after an elephant trunk procedure for complex thoracic aortic aneurysms is an elegant approach to deal with such mega aortas. Further research is necessary to compare open and endovascular repair and to determine long-term follow-up with regard to endoleaks and mortality.

Phytoestrogens and breast cancer risk. Review of the epidemiological evidence.

Phytoestrogens are natural plant substances. The three main classes are isoflavones, coumestans, and lignans. Phytoestrogens have anticarcinogenic potential, but they have also significant estrogenic properties. For an evaluation of the effect of phytoestrogens on breast cancer risk we reviewed the analytical epidemiological data. A total of 18 studies were included. Up to now, there are 13 studies that have assessed the direct relation between the individual dietary intake of soy products and the risk of breast cancer. Overall, results do not show protective effects, with the exception maybe for women who consume phytoestrogens at adolescence or at very high doses. Only four of these 13 studies are prospective, and none of them found statistically significant breast cancer reductions. Four studies assessed urinary isoflavones excretion in relation to breast cancer. Three of these are case control studies, where excretion was measured after breast cancer occurrence and thus seriously limiting causal interpretation of the results. The only prospective study with urinary measurements before breast cancer occurrence was done in a Dutch postmenopausal population and showed a non-significant breast cancer risk reduction for high excretion. Three studies measured enterolactone (lignan): two case control studies reported a preventive effect on breast cancer risk, but the only prospective study did not . In conclusion, few prospective studies (n = 5) were done to assess the effects of phytoestrogens on breast cancer risk. None of them found protective effects. However, these prospective studies did not focus on 'age at consumption', which seems to be important based on results from dietary case control studies done so far.

Dose-finding and efficacy study for i.m. artemotil (beta-arteether) and comparison with i.m. artemether in acute uncomplicated P. falciparum malaria.

AIMS: The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard dose regimen of artemether. METHODS: In part I of the study three different artemotil dose regimens were explored in three groups of 6-9 patients for dose finding: 3.2 mg kg-1 on day 0 and 1.6 mg kg-1 on days 1-4 (treatment A), 1.6 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment B), 3.2 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment C). In part II of the study, artemotil treatments A and C were compared in three groups of 20-22 patients with standard i.m. artemether treatment: 3.2 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment R). RESULTS: Full parasite clearance was achieved in all patients in Part I, but parasite clearance time (PCT) and fever clearance time (FCT) tended to be longer in treatment B. Also the incidence of recrudescence before day 28 (RI) tended to be higher for treatment B. In part II, the mean PCT for each of the two artemotil treatments (52 and 55 h, respectively) was significantly longer than for artemether (43 h). The 95% CI for the difference A vs R was 0, 16 h (P=0.0408) and for difference C vs R it was 2, 19 h (P=0.0140). FCT was similar for the three treatments. The incidence of RI ranged from 5 out of 19 for treatment C to 3 out of 20 for treatment R. Plasma concentration-time profiles of artemotil indicated an irregular and variable rate of absorption after i.m. injection. A late onset of parasite clearance was associated with delayed absorption and/or very low initial artemotil plasma concentrations. Pharmacokinetic-pharmacodynamic evaluations supported a relationship between the rate of parasite clearance and exposure to artemotil during approximately the first 2 days of treatment, and suggested that artemotil has a slower rate of absorption than artemether. Safety assessment, including neurological and audiometric examinations showed no clinically relevant findings. Adverse events before and during treatment included headache, dizziness, nausea, vomiting and abdominal pain. These are characteristic of acute malaria infections and resolved during treatment. CONCLUSIONS: The optimum dose regimen for artemotil in this study was identical to the standard dose regimen of artemether. The findings that artemotil is more slowly absorbed from the i.m. injection site than artemether, and that early systemic availability may be insufficient for an immediate onset of parasite clearance contributed to the decision to choose a higher loading dose of artemotil (divided over two injection sites) and to omit the fifth dose in later studies. With this optimized dosing schedule, the more pronounced depot characteristics of i.m. artemotil can be an advantage, since it may allow shorter hospitalization.

Urinary phytoestrogens and postmenopausal breast cancer risk.

Phytoestrogens are defined as plant substances that are structurally or functionally similar to estradiol. We report the associations of two major phytoestrogens, genistein and enterolactone, with breast cancer risk, using urinary specimens collected 1-9 years before breast cancer was diagnosed. The subjects were 88 breast cancer cases and 268 controls, selected from a cohort of postmenopausal women (n = 14,697) who participated in a breast cancer screening program. Mean levels of urinary genistein and enterolactone were determined by time resolved fluoroimmunoassay, using an average of two overnight urinary samples obtained from each participant on the first and the second screening rounds with a time interval of approximately 1 year. Odds ratios (ORs) of the highest to the lowest tertile of urinary phytoestrogen/creatinine concentrations and 95% confidence intervals (CIs) were computed. Higher urinary genistein excretion was weakly and nonsignificantly associated with a reduced breast cancer risk. OR for the highest tertile compared with lowest tertile was 0.83; 95% CI, 0.46-1.51. Higher urinary enterolactone excretion was weakly and nonsignificantly associated with an increased breast cancer risk. OR for the highest tertile compared with the lowest tertile was 1.43; 95% CI, 0.79-2.59. Tests for trends for both phytoestrogens were nonsignificant. We were not able to detect the previously reported protective effects of genistein and enterolactone on breast cancer risk in our postmenopausal population of Dutch women. Such an effect may be smaller than expected and/or limited to specific subgroups of the population.

Cost minimization analysis of antiepileptic drugs in newly diagnosed epilepsy in 12 European countries.

A recent United Kingdom cost minimization analysis (CMA) of four antiepileptic drugs (AEDs) used to treat newly diagnosed adult epilepsy demonstrated that a new drug, lamotrigine (LTG), incurred higher costs than carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA), whose costs were similar. This analysis took account of each drug's side-effect and tolerability profile. The present analysis investigated the costs of treatment with LTG, CBZ, PHT, and VPA in 12 European countries. Data were derived from published sources and from a panel of locally based experts. When no published data were available, estimates were obtained using expert opinion by a consensus method. These data were incorporated into a treatment pathway model, which considered the treatment of patients during the first 12 months after diagnosis. The primary outcome considered was seizure freedom. Randomized controlled trials demonstrate that the drugs considered are equally effective in terms of their ability to achieve seizure freedom, and thus the most appropriate form of economic evaluation is a CMA. These trials provided data on the incidence of side effects, dosages, and retention rates. The economic perspective taken was that of society as a whole and the analysis was calculated on an "intent-to-treat" basis. Only direct medical costs were considered. In each country considered, LTG was twofold to threefold more expensive than the other drugs considered. A sensitivity analysis demonstrated that varying each of the assumptions (range defined by expert panels) did not significantly alter the results obtained.

Phyto-oestrogens and cardiovascular disease risk.

AIM: To present the currently available evidence on the cardiovascular benefits and risks associated with phyto-oestrogens. DATA-SYNTHESIS: Medline search from 1966-1999 updated with cross-check of references of papers with keywords such as phyto-oestrogens, isoflavones, lignans, genistein, daidzein, enterolactone, enterodiol, cardiovascular disease, cardiovascular disease risk factors. CONCLUSIONS: Phyto-oestrogens are plant chemicals divided into three main classes: isoflavones, coumestans, and lignans that display oestrogen-like activity due to their ability to bind to the oestrogen receptor. They are found in grains, beans, green vegetables, fruits, nuts, and grasses. Isoflavones are primarily found in soybeans and soy foods. For epidemiological studies of the relation between phyto-oestrogen intake and disease parameters, intake is estimated with several measures, such as biomarkers (concentrations in urine or blood) or dietary questionnaires, though the optimal method is not yet clear. Phyto-oestrogens are considered to act as selective oestrogen receptor modulators (SERM), exerting both oestrogen agonist and antagonist action. Supplementation with isolated soy protein containing the isoflavones genistein and daidzein reduces serum total and LDL-cholesterol and triglycerides in animals and in humans. Vascular reactivity might be improved by supplementation with isolated soy protein or isoflavones isolated from red clover. Studies on atherosclerosis in animals indicate a potential for risk reduction. Evidence in humans is still scanty. The little we know of the effects of regular dietary phyto-oestrogen intake comes from studies in which phyto-oestrogens were added to the usual diet. Most supplementation studies have been conducted with soy isoflavones, whereas the importance of lignans has not been determined, though they could be more important sources than isoflavones in Western populations. Research has been focused on risk factors. Studies of clinically manifest endpoints are urgently needed.

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

The efficacy and safety of intramuscular artemotil (ARTECEF) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days.

Enalapril increases antioxidant enzyme activity in renal cortical tissue of five-sixths-nephrectomized rats.

In rats with five-sixths nephrectomy (remnant kidney), blood pressure, glomerulosclerosis, and proteinuria are significantly reduced by administration of the angiotensin-converting enzyme inhibitor enalapril, during 16 weeks after reduction of the nephron number. The activity of catalase in remnant-kidney cortex homogenate is not influenced by enalapril treatment; the activities of superoxide dismutase and glutathione peroxidase are significantly increased. Elevated lipid peroxidation in cortex homogenates, evaluated by malondialdehyde and 4-hydroxynonenal concentrations, is not changed by treatment. Supplementation of dietary vitamin E to enalapril treatment does not alter antioxidant enzyme activities when compared to enalapril monotherapy. These results show that enalapril improves the balance between reactive oxygen intermediates and antioxidant enzymes in the remnant-kidney cortex of the rat. This finding may in part explain the protective effect of angiotensin-converting enzyme inhibitors on the progression of glomerulosclerosis.

[Early functional treatment of humerus shaft fractures by the Sarmiento method]. / Die frühfunktionelle Behandlung der Humerusschaftfrakturen nach Sarmiento.

The functional treatment of humerus shaft fractures with a brace according to Sarmiento is described. Reported are the results of the functional treatment of 47 humerus shaft fractures. Every humerus shaft fracture normally treated conservatively, including the humerus shaft fractures in polytraumatised patients and those patients with a primary radial nerve injury, can be treated in this way. The functional treatment of humerus shaft fractures results in a quick and uneventful healing of the fracture with a good function and cosmetic aspect.