Fish consumption and breast cancer risk. The European Prospective Investigation into Cancer and Nutrition (EPIC)

There is current interest in fish consumption and marine omega-3 (n-3) fatty acids and breast cancer risk. Some in vitro and animal studies have suggested an inhibitory effect of marine n-3 fatty acids on breast cancer growth, but the results from epidemiological studies that have examined the association between fish consumption and breast cancer risk in humans are inconsistent. We examined fish consumption and breast cancer risk in 310,671 women aged between 25 and 70 yr at recruitment into the European Prospective Investigation Into Cancer and Nutrition (EPIC). The participants completed a dietary questionnaire between 1992-98 and were followed up for incidence of breast cancer for a median of 6.4 yr. Hazard ratio for breast cancer by intake of total and lean and fatty fish were estimated, stratified by study centre and adjusted for established breast cancer risk factors. During follow-up, 4,776 invasive incident breast cancers were reported. No significant associations between intake of total fish and breast cancer risk were observed, hazard ratio (HR) 1.01 (95% confidence interval [CI] 0.99-1.02; p = 0.28 per 10 g fish/day). When examining lean and fatty fish separately, we found a positive significant association only in the highest quintile for fatty fish (HR 1.13, 95% CI 1.01-1.26), but test for trend was not significant (p = 0.10). No associations with breast cancer risk were observed when the study participants were subdivided by menopausal status. Although the period of follow-up is relatively short, the results provide no evidence for an association between fish intake and breast cancer risk.     

Human embryonic stem cells: towards therapies for cardiac disease. Derivation of a Dutch human embryonic stem cell line

Cell transplantation is being discussed as a potential therapy for multiple disorders caused by loss or malfunction of single or at most a few cell types. These include diabetes, Parkinson's disease and myocardial infarction or cardiac failure. However, it is not yet clear whether cells from adult tissues ('adult stem cells') or embryos ('embryonic stem cells') will prove to be the most appropriate replacement cells; most likely, each disease will have its own preferred source. This study presents the background to this discussion and the current state of research in replacement of cardiac tissue, with focus on recent developments using human embryonic stem cells. It also describes a new human embryonic stem cell (HESC) line, NL-HESC1, the first to be derived in the Netherlands, and shows that it forms cardiac cells in a manner comparable with that of hES2 and hES3 cells grown in the same laboratory.     

Evaluating a family-centred intervention for infant sleep problems

AIM: This paper reports a study to describe changes in parents' distress after a family-centred intervention for sleep problems of infants. BACKGROUND: Infant sleep problems are common and are related to depressive symptoms in mothers, but their impact on fathers has rarely been studied. Because childhood sleep problems and parental distress are associated, their interdependence should be recognized in research and in paediatric sleep practice. METHODS: All children hospitalized for sleep problems in a hospital in Iceland in 1997-1998 and their parents were studied using a pre- and post-test quasi-experimental design. The sample consisted of 33 infants (6-23 months of age), 33 mothers and 30 fathers. Parents' distress was assessed before and after treatment with regard to: (1) fatigue and resulting symptom distress; (2) parenting stress; (3) state-anxiety; and (4) depressive symptoms. Infants were treated for a variety of sleep problems by a paediatric nurse. The parents were simultaneously treated for distress by either the paediatric nurse or a specialist, depending on the nature of their problems. RESULTS: Mothers and fathers experienced a high degree of distress before the intervention, with no significant difference between them. Two months after the intervention both parents' distress had significantly improved. Parents' degree of distress was at a psychopathological level before the intervention but was reduced to population norms 2 months after the intervention. The paediatric nurse intervention was sufficient to reduce distress for 83% of parents. CONCLUSIONS: Health care professionals who care for infants with sleep problems should pay attention to the distressed responses of parents and support their recovery. An intervention such as that described here could be used by nurses for this purpose.     

Repeated episodes of hypoglycemia as a potential aggravating factor for preclinical atherosclerosis in subjects with type 1 diabetes

OBJECTIVE

To evaluate through early preclinical atherosclerosis assessment whether repeated episodes of hypoglycemia represent an aggravating factor for macrovascular disease in type 1 diabetes.

RESEARCH DESIGN AND METHODS

After sample-size calculation, a case-control study of 25 patients with type 1 diabetes and repeated severe/nonsevere hypoglycemia (H-group) compared with 20 age- and sex-matched type 1 diabetes control subjects (C-group) was designed. Assessment of preclinical atherosclerosis consisted of flow-mediated brachial dilatation (FMD) and carotid and femoral intima-media thickness (IMT) studies. To consider hypoglycemia awareness, two different questionnaires and symptomatic response to an acute induction to hypoglycemia were used. Evaluation of the glycemic profile was obtained from continuous glucose monitoring. Endothelial function/inflammation markers were measured in euglycemia/hypoglycemia. A multivariate linear regression analysis was performed to test whether repeated hypoglycemia was independently associated with atherosclerosis.

RESULTS

H-group subjects displayed hypoglycemia unawareness and presented a higher percentage of continuous glucose values and area under the curve <70 mg/dl compared with the C-group (14.2 ± 8.9 vs. 6.3 ± 7.1%, P < 0.02 and 2.4 ± 1.8 vs. 0.6 ± 1.0 mg/dl/day, P < 0.01). The percentage of maximal FMD was lower in the H-group than in the C-group (6.52 ± 2.92 vs. 8.62 ± 3.13%, P < 0.05). A significantly higher IMT was observed at both carotid and femoral sites in the H-group (carotid 0.53 ± 0.09 vs. 0.47 ± 0.08 mm, P < 0.05 and femoral 0.51 ± 0.17 vs. 0.39 ± 0.09 mm, P < 0.05). Baseline inflammation and endothelial function markers were higher in the H-group (leukocytes 7.0 ± 1.8 vs. 5.6 ± 1.4 × 10³/ml, von Willebrand factor 119 ± 29 vs. 93 ± 26%, fibrinogen 2.82 ± 0.64 vs. 2.29 ± 0.44g/l, and soluble intercellular adhesion molecule-1 408 ± 224 vs. 296 ± 95 ng/ml; P < 0.05 for all).

CONCLUSIONS

In addition to the induction of hypoglycemia unawareness and an increased risk for severe hypoglycemia, repeated hypoglycemia could be related to and considered an aggravating factor for preclinical atherosclerosis in type 1 diabetes. The precise mechanisms explaining this association remain to be clarified.Even though many of the cardiovascular disease (CVD) risk factors recognized in type 2 diabetes are not present in type 1 diabetic subjects, the age-adjusted relative risk for CVD in type 1 diabetes is even higher than that in type 2 diabetes (1). Since the availability of data from Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) studies, there is no doubt that intensive therapy positively affects the long-term incidence of micro- and macrovascular disease in subjects with type 1 diabetes (2,3). However, because the association between glycemic control and macrovascular disease is mainly obtained from epidemiological data, the role of glycemic control in macrovascular disease is still controversial. In contrast, intensive glucose control invariably increases the risk of hypoglycemia.Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes. Frequent and repeated episodes of hypoglycemia almost unfailingly result in a reduced ability or failure to recognize hypoglycemia symptoms and signs. This syndrome of hypoglycemia unawareness frequently occurs in type 1 diabetes, and patients without warning symptoms are then at a high risk for severe hypoglycemia (4). In addition, hypoglycemia is a major barrier to achieving normoglycemia over a lifetime of using intensive insulin therapy and thus precludes the long-term benefits of euglycemia (4). More recently, Gill et al. (5) reported QT prolongation and cardiac and rhythm disturbances in response to nocturnal hypoglycemia in ambulatory patients with type 1 diabetes, which may support the idea of an arrhythmic basis for “death in bed syndrome.”Carotid intima-media thickness (cIMT) and the assessment of endothelial function have been shown to be markers of preclinical atherosclerosis and correlate with prevalent and incident cardiovascular disease (6). In the DCCT/EDIC, the progression of cIMT in the population of type 1 diabetic subjects was used as a measure of atherosclerosis (7).It has also been reported that patients with type 1 diabetes presented higher cIMT and lower percentages of flow-mediated dilatation (FMD) with respect to healthy control subjects (8). Although hyperglycemia has been proven to increase the stiffness of intermediate-sized arteries and resistance of arteries, the analysis of discontinuous glucose profile datasets from the DCCT failed to find an association between glucose variability and the development of microvascular complications (9). Moreover, various measures for the assessment of glycemic variability have shown that there is no relationship between oxidative stress and glucose fluctuations in type 1 diabetes even though glucose variability was much higher than that in type 2 diabetes (10).Acute hypoglycemia induces a rapid proinflammatory, platelet aggregatory, antifibrinolytic, and prothrombotic response (11,12). Recurrent hypoglycemic episodes may provoke changes in hemostatic factors and viscosity, which may reduce perfusion in diabetic microangiopathy (11,12). Rodrigues et al. (13) have recently reported that higher fibrinogen levels predict progression of coronary artery calcification in adults with type 1 diabetes. The SEARCH study has also described elevated inflammatory markers even in youth with type 1 diabetes and good metabolic control compared with control subjects, suggesting an explanation for accelerated atherosclerosis in type 1 diabetes (14). In addition, Feldman-Billard et al. (15) described hypoglycemia-induced hypertension in a group of diabetic patients. If hypoglycemia acutely provokes intense changes in hemodynamics and several hemorheological parameters, it could play a different role in atherosclerosis when chronically repeated.Therefore, the aim of our study was to evaluate whether repeated episodes of hypoglycemia represent an aggravating factor for macrovascular disease in subjects with type 1 diabetes through early atherosclerosis-vascular assessment.     

Rapid onset of transmission-reducing antibodies in javanese migrants exposed to malaria in papua, indonesia

Transmission of Plasmodium falciparum malaria is initiated by sexual stages in the mosquito. Anti-Pfs48/45 and anti-Pfs230 sexual stage antibodies that are ingested together with parasites can reduce parasite development and subsequently malaria transmission. Acquisition of sexual stage immunity was studied in a cohort of 102 non-immune Javanese individuals migrating to hyperendemic Papua Indonesia. Seroprevalence of antibodies against Pfs48/45 and Pfs230 and functional transmission-reducing activity (TRA) were measured upon arrival and at 6, 12, and 24 months. Asexual parasitemia and gametocytemia were assessed every two weeks. The TRA and seroreactivity increased with the number of P. falciparum infections. The longitudinally sustained association between TRA and antibodies against Pfs48/45 (odds ratio [OR] = 3.74, 95% confidence interval [CI] = 1.51-9.29) and Pfs230 (OR = 3.72, 95% CI = 1.36-10.17) suggests that functional transmission reducing immunity is acquired after limited exposure to infection.     

The p.T191M mutation of the CBS gene is highly prevalent among homocystinuric patients from Spain, Portugal and South America

Classical homocystinuria is due to cystathionine -synthase (CBS) deficiency. More than 130 mutations, which differ in prevalence and severity, have been described at the CBS gene. Mutation p.I278T is very prevalent, has been found in all European countries where it has been looked for with the exception of the Iberian peninsula, and is known to respond to vitamin B₆. On the other hand, mutation p.T191M is prevalent in Spain and Portugal and does not respond to B₆. We analysed 30 pedigrees from Spain, Portugal, Colombia and Argentina, segregating for homocystinuria. The p.T191M mutation was detected in patients from all four countries and was particularly prevalent in Colombia. The number of p.T191M alleles described in this study, together with those previously published, is 71. The prevalence of p.T191M among CBS mutant alleles in the different countries was: 0.75 in Colombia, 0.52 in Spain, 0.33 in Portugal, 0.25 in Venezuela, 0.20 in Argentina and 0.14 in Brazil. Haplotype analyses suggested a double origin for this mutation. No genotype–phenotype correlation other than the B₆-nonresponsiveness could be established for the p.T191M mutation. Additionally, three new mutations, p.M173V, p.I429del and c.69_70+8del10, were found. The p.M173V was associated with a mild, B₆-responsive, phenotype.     

A three-part, mixed-effects model to estimate the habitual total vitamin D intake distribution from food and dietary supplements in Dutch young children

Statistical modeling of habitual micronutrient intake from food and dietary supplements using short-term measurements is hampered by heterogeneous variances and multimodality. Summing short-term intakes from food and dietary supplements prior to simple correction for within-person variation (first add then shrink) may produce estimates of habitual total micronutrient intake so badly biased as to be smaller than estimates of habitual intake from food sources only. A 3-part model using a first shrink then add approach is proposed to estimate the habitual micronutrient intake from food among nonsupplement users, food among supplement users, and supplements. The population distribution of habitual total micronutrient intake is estimated by combining these 3 habitual intake distributions, accounting for possible interdependence between Eq. 2 and 3. The new model is an extension of a model developed by the USA National Cancer Institute. Habitual total vitamin D intake among young children was estimated using the proposed model and data from the Dutch food consumption survey (n = 1279). The model always produced habitual total intakes similar to or higher than habitual intakes from food sources only and also preserved the multimodal shape of the observed total vitamin D intake distribution. This proposed method incorporates several sources of covariate information that should provide more precise estimates of the habitual total intake distribution and the proportion of the population with intakes below/above cutpoint values. The proposed methodology could be useful for other complex situations, e.g. where high concentrations of micronutrients appear in episodically consumed foods.     

Ecological-level associations between highly processed food intakes and plasma phospholipid elaidic acid concentrations: results from a cross-sectional study within the European prospective investigation into cancer and nutrition (EPIC)

Elaidic acid is the main unnatural trans fatty acid isomer occurring during partial hydrogenation of vegetable oils used as ingredients for the formulation of processed foods. The main objective is to assess associations between processed food intakes and plasma phospholipid elaidic acid concentrations within the European Prospective Investigation into Cancer and Nutrition study. A cross-sectional study was used to determine fatty acid profiles in 3,003 subjects from 16 centers. Single 24-h dietary recalls (24-HDR) were collected using a standardized computerized interview program. Food intakes were computed according to their degree of processing (moderately/nonprocessed foods, processed staple foods, highly processed foods). Adjusted ecological and individual correlations were calculated between processed food intakes and plasma elaidic acid levels. At the population level, mean intakes of highly processed foods were strongly correlated with mean levels of plasma elaidic acid in men (P = 0.0016) and in women (P = 0.0012). At the individual level, these associations remained but at a much lower level in men (r = 0.08, P = 0.006) and in women (r = 0.09, P = 0.0001). The use of an averaged 24-HDR measure of highly processed food intakes is adequate for predicting mean levels of plasma elaidic acid among European populations.