Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating-cancer stem cells: distinct, overlapping or same populations.

Cell populations of solid cancers and their distant models, the cancer cell lines, have been categorized in sub-populations: cancer stem-tumor-propagating cells (CSC-TPC) versus derived cells, epithelial- versus mesenchymal-type cells, dormant versus actively proliferating cells and so on. CSC-TPC are minimally defined by their operational properties: immortality and the ability to regenerate in vivo or in vitro the whole panel of cancer cells. The epithelial-to-mesenchymal transition (EMT), mostly observed in vitro, generates mesenchymal-type from epithelial-type cells. The converse transition is mesenchymal-to-epithelial transition. In vitro work suggests that CSC-TPC and EMT cell phenotypes overlap. An analysis of the properties of these sub-populations, as studied in vitro, shows that indeed these two phenotypes may be linked to some extent. However, the in vivo counterpart of this relation in human tumors has barely been investigated. A model in which among the EMT cells released from the tumor only the most competent CSC-TPC will succeed to metastasize is proposed. It is suggested that in the Darwinian evolution of cancer cells, many phenotypes reflecting the expression of various programs, reversible to irreversible, exclusive, overlapping or linked coexist and compete with each other.

Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations.

Three syndromes affecting the thyroid gland are described in the literature separately: familial nonautoimmune hyperthyroidism, sporadic congenital nonautoimmune hyperthyroidism, and autonomous adenomas. Recent studies have shown that these three syndromes are caused by similar activating mutations of the TSH receptor gene (TSHR), and that the consequences of these mutations on the physiology and gene expression of the thyroid are qualitatively, but not quantitatively, similar. The three syndromes and two suggested unrecognized variants are in fact facets of the same disease, genetic hyperthyroidism due to TSHR mutations, the expression of which depends on the intensity of activation, its timing, and on the number of affected cells.

Nutritional concerns, health and survival in old age.

The ageing process is-apart from chance or good luck-not only influenced by factors intrinsic to the individual, but also by extrinsic factors that include environmental and lifestyle variables. This paper deals with the epidemiological evidence for the role of dietary patterns and key nutritional concerns in relation to survival and ageing related disorders that present themselves in later life. Dietary patterns, such as the Mediterranean diet, characterized by mainly plant foods including protective factors e.g. vegetables, nuts and monounsaturated fatty acids and excluding harmful factors e.g. trans-fatty acids and foods with a high glycemic factor, appear to be relevant even in old age. Specific nutritional concerns focus on general undernutrition, vitamin D and vitamin B(12). Prevalence of nutritional inadequacies, diagnostic criteria, causes and health consequences are described. The paper ends with recommendations for guidance on healthy diets for elderly people. An important challenge should be research to further expand the knowledge base, acknowledging the complexity of the ageing process and integrating different dimensions of research into human healthy ageing in properly designed studies. In the mean time reversing poor adherence to existing guidelines for a healthy diet remains a first challenge in public health nutritional practices.

Cancer stem cells: a reality, a myth, a fuzzy concept or a misnomer? An analysis.

The concept of cancer stem cells (CSC) embodies two aspects: the stem cell as the initial target of the oncogenic process and the existence of two populations of cells in cancers: the CSC and derived cells. The second is discussed in this review. CSC are defined as cells having three properties: a selectively endowed tumorigenic capacity, an ability to recreate the full repertoire of cancer cells of the parent tumor and the expression of a distinctive repertoire of surface biomarkers. In operational terms, the CSC are among all cancer cells those able to initiate a xenotransplant. Other explicit or implicit assumptions exist, including the concept of CSC as a single unique infrequent population of cells. To avoid such assumptions, we propose to use the operational term tumor-propagating cells (TPC); indeed, the cells that initiate transplants did not initiate the cancer. The experimental evidence supporting the explicit definition is analyzed. Cancers indeed contain a fraction of cells mainly responsible for the tumor development. However, there is evidence that these cells do not represent one homogenous population. Moreover, there is no evidence that the derived cells result from an asymmetric, qualitative and irreversible process. A more general model is proposed of which the CSC model could be one extreme case. We propose that the TPC are multiple evolutionary selected cancer cells with the most competitive properties [maintained by (epi-)genetic mechanisms], at least partially reversible, quantitative rather than qualitative and resulting from a stochastic rather than deterministic process.

The effect of a nutrient dense drink on mental and physical function in institutionalized elderly people.

OBJECTIVES: To determine whether in the current study the supply of a nutrient dense drink has a positive effect on mental and physical function of institutionalized elderly people. DESIGN: A 24-week, randomized, double-blind, placebo-controlled, parallel-group, intervention trial. SETTING: Homes for the elderly and nursing homes in the Netherlands. PARTICIPANTS: Institutionalized elderly people older than 60 years, with a BMI < or = 30 kg/m2, and a Mini-Mental State Examination score of at least 10 points. INTERVENTION: In addition to their usual diet the participants (n=176) received either a nutrient dense drink or a placebo drink twice a day during 24 weeks. MEASUREMENTS: The functionality measures included cognitive function, mood, physical performance and the ability to perform activities of daily living. RESULTS: In the supplement group a favorable effect of the intervention drink on body weight (1.6 kg difference in change; P = .035), calf circumference (0.9 cm difference in change; P = .048), and blood values (e.g. Hcy decreased from 16.8 to 11.2 mumol/L in the supplement group) was found. In the total group no significant effect was found on functionality outcomes. However, a subgroup of participants with BMI at baseline below 24.4 kg/m2 performed better on the cognitive subscale of Alzheimer's Disease Assessment Scale (P = .09), and its language sub score (P = .01) after 24 weeks of intervention. CONCLUSION: The results in the total group of this trial suggest that the nutritional supplement used in this study improves nutritional status. Furthermore, the results of this trial suggest that it is effective as treatment for decreasing function in a subgroup of institutionalized elderly people with low BMI.

Optimal preferred MSG concentration in potatoes, spinach and beef and their effect on intake in institutionalized elderly people.

BACKGROUND: Elderly people may benefit from sensory stimulation to increase food intake since anorexia of ageing is prevalent among them. An optimal MSG concentration may increase the palatability of foods but this depends on the food and chemosensory status of the taster. Currently, the results on taste enhancing to increase intake are inconsistent. OBJECTIVE: To find an optimal preferred MSG concentration in mashed potatoes, spinach and ground beef and to determine whether this concentration increases consumption of these foods among institutionalized elderly people. DESIGN: Single blind within subject cross-over study performed at the laboratory and in the residents' own apartments. PARTICIPANTS: 33 elderly and 29 young people in the sensory study and 53 elderly people in the intake study. MEASUREMENTS: Pleasantness of the foods was rated of the foods each with 0, 0.5, 0.8, 1.3 and 2.0 g of MSG/100g. Intake was measured by weighing back leftovers of 2 meals with MSG (0.5% in mashed potatoes, 2% in spinach and ground meat) and without MSG. RESULTS: 0.5% MSG (p < 0.05) was preferred in mashed potatoes but no optimal preferred concentration was found for spinach and ground beef, possibly because of their complex taste. Intake was not different between the foods with and without MSG or the total meal (all p > 0.68). CONCLUSION: MSG (0.5% and 2%) does not guarantee a higher intake among elderly. The chemosensory heterogeneity of the elderly population requires more individual flavor enhancement to improve the dietary intake and sensory experience.

Effect of a nutrient-enriched drink on dietary intake and nutritional status in institutionalised elderly.

OBJECTIVE: (1) To determine whether nutritional supplementation (energy and micronutrients) in institutionalised elderly has a positive effect on dietary intake and nutritional status. (2) To investigate whether individuals tend to compensate for the energy content of the intervention product by decreasing their habitual food consumption. METHODS: A 24-week, randomised, double-blind, placebo-controlled, intervention trial in homes for the elderly (n=3), in nursing homes (n=3) and 'mixed' homes (n=3) in The Netherlands. Institutionalised elderly people (n=176) older than 60 years of age, with a body mass index < or =30 kg/m(2) and a Mini-Mental State Examination score of 10 points or higher, randomly received a nutrient-enriched drink or a placebo drink twice a day during 24 weeks in addition to their usual diet. Allocation to treatment took into account of sex, the Mini-Mental State Examination score and the plasma homocysteine level. Body weight and several nutrition-related analyses in fasting blood samples were measured in all participants. Data on dietary intake were collected in a subsample (n=66). RESULTS: A significantly favourable effect (P<0.001) of the intervention drink was observed on vitamin intake, mineral intake and vitamin status in blood (for example, homocysteine decreased from 14.7 to 9.5 micromol/l in the intervention group as compared with that in the placebo group (17.2-15.9)). The difference in change in total energy intake between the two treatment groups was 0.8 MJ/day (P=0.166). Energy intake from food decreased in both groups to the same extent (-0.5 MJ/day). Therefore, this decrease cannot be considered as compensation for the energy content of the product. CONCLUSIONS: This group of institutionalised elderly people does not compensate for the energy content of a concentrated nutritional supplement. Therefore, this supplement is effective for counteracting the development of malnutrition in this population.

Dietary assessment in elderly people: experiences gained from studies in the Netherlands.

BACKGROUND/OBJECTIVES: In selecting a dietary assessment method, several aspects such as the aim of the study and the characteristics of the target population should be taken into account. In elderly people, diminished functionality and cognitive decline may hamper dietary assessment and require tailored approaches to assess dietary intake. The objective of this paper is to summarize our experience in dietary assessment in a number of different studies in population groups over 65 years of age in the Netherlands, and to discuss this experience in the perspective of other nutrition surveys in the elderly. METHODS: In longitudinal studies, we applied a modified dietary history; in clinical nursing home studies, trained staff observed and recorded food consumption; and in a controlled trial in healthy elderly men, we used a food frequency questionnaire (FFQ). RESULTS: For all methods applied in the community-dwelling elderly people, validation studies showed a similar underestimation of intake of 10-15% compared with the reference value. In the care-depending elderly, the underestimation was less: 5% according to an observational method. The methods varied widely in the resources required, including burden to the participants, field staff and finances. CONCLUSIONS: For effective dietary assessment in older adults, the major challenge will be to distinguish between those elderly who are able to respond correctly to the less intensive methods, such as 24-h recalls or FFQ, and those who are not able to respond to these methods and require adapted techniques, for example, observational records.

Human cancer cell lines: Experimental models for cancer cells in situ? For cancer stem cells?

Established human cancer cell lines are routinely used as experimental models for human cancers. Their validity for such use is analyzed and discussed, with particular focus on thyroid tumors. Although cell lines retain some properties of the cells of origin, from the points of view of their genetics, epigenetics and gene expression, they show clear differences in these properties compared to in vivo tumors. This can be explained by a prior selection of initiating cells and a Darwinian evolution in vitro. The properties of the cell lines are compared to those of the postulated cancer stem cells and their use as models in this regard are discussed. Furthermore, other proper and possible uses of the cell lines are discussed.

Dietary intake and status of folate and vitamin B12 and their association with homocysteine and cardiovascular disease in European populations.

BACKGROUND/OBJECTIVES: Folate and vitamin B12 have been suggested to play a role in chronic diseases like cardiovascular diseases. The objectives are to give an overview of the actual intake and status of folate and vitamin B12 in general populations in Europe, and to evaluate these in view of the current vitamin recommendations and the homocysteine concentration. METHODS: Searches in Medline with 'folic acid', 'folate' and 'vitamin B12', 'B12' or 'cobalamin' as key words were combined with the names of the European countries. Populations between 18 and 65 years were included. RESULTS: Sixty-three articles reporting on studies from 15 European countries were selected. Low folate intakes were observed in Norway, Sweden, Denmark and the Netherlands. Low intakes of vitamin B12 were not common and only seen in one small Greek study. In the countries with a low intake of folate, the recommended levels were generally not achieved, which was also reflected in the folate status. Vitamin B12 intake was not strongly associated with the vitamin B12 status, which can explain why in the Netherlands and Germany the vitamin B12 status was inadequate, despite sufficient intake levels. In countries with a low folate intake in particular, the Hcy concentration was higher than ideal. CONCLUSIONS: Populations from the Nordic countries, the Netherlands, Germany and Greece may need to improve their intakes of folic acid, B12 or both to either meet the recommendations or to optimize their statuses. This could be achieved via a food-based approach, food fortification or supplements.

Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial.

BACKGROUND: High intake of n-3 polyunsaturated fatty acids may protect against age-related cognitive decline. However, results from epidemiologic studies are inconclusive, and results from randomized trials in elderly subjects without dementia are lacking. OBJECTIVE: To investigate the effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation on cognitive performance. METHODS: Double-blind, placebo-controlled trial involving 302 cognitively healthy (Mini-Mental State Examination score > 21) individuals aged 65 years or older. Participants were randomly assigned to 1,800 mg/d EPA-DHA, 400 mg/d EPA-DHA, or placebo capsules for 26 weeks. Cognitive performance was assessed using an extensive neuropsychological test battery that included the cognitive domains of attention, sensorimotor speed, memory, and executive function. RESULTS: The mean age of the participants was 70 years, and 55% were male. Plasma concentrations of EPA-DHA increased by 238% in the high-dose and 51% in the low-dose fish oil group compared with placebo, reflecting excellent compliance. Baseline scores on the cognitive tests were comparable in the three groups. Overall, there were no significant differential changes in any of the cognitive domains for either low-dose or high-dose fish oil supplementation compared with placebo. CONCLUSIONS: In this randomized, double-blind, placebo-controlled trial, we observed no overall effect of 26 weeks of eicosapentaenoic acid and docosahexaenoic acid supplementation on cognitive performance.

Changes in markers of cobalamin status after cessation of oral B-vitamin supplements in elderly people with mild cobalamin deficiency.

Mildly cobalamin-deficient elderly were supplemented with 1000 microg cobalamin (group C, n=34), 1000 microg cobalamin with 400 microg folic acid (group CF, n=31) or a placebo (n=30) for 6 months. Participants provided one single blood sample 3, 5 or 7 months after cessation of supplementation to monitor early changes in plasma concentrations of cobalamin, holotranscobalamin (holoTC) and methylmalonic acid (MMA). At the end of supplementation (groups C+CF), one participant met our criteria for mild cobalamin deficiency, as did 13, 14 and 43% of the participants assessed at respectively 3, 5 and 7 months post-supplementation. Cobalamin and holoTC declined on average with 47 and 56% relative to concentrations at the end of supplementation for the group assessed at 7 months post-supplementation. Essentially similar declines were observed for those participants assessed at 3 and 5 months post-supplementation. Mean MMA concentrations increased by 15% (P=0.07) in those participants assessed at 3 and 5 months post-supplementation, and increased by 50% (P=0.002) in those participants assessed at 7 months post-supplementation. Considering MMA as a sensitive tissue marker for cobalamin status, oral supplementation may afford adequate cobalamin status for a period of up to 5 months after cessation in the majority of participants.

Comparison of three different dietary scores in relation to 10-year mortality in elderly European subjects: the HALE project.

OBJECTIVE: To investigate and compare the associations between dietary patterns and mortality using different European indexes of overall dietary quality. DESIGN, SETTING AND PARTICIPANTS: The HALE (Healthy Ageing: a Longitudinal study in Europe) population includes 2,068 men and 1,049 women, aged between 70 and 90 years of 10 European countries. Subjects were followed for 10 years. This cohort study was conducted between 1988 and 2000. RESULTS: During the follow-up period, 1,382 people died. The Mediterranean Diet Score (MDS) (HR: 0.82 with 95% CI: 0.75-0.91), the Mediterranean Adequacy Index (MDI) (HR: 0.83 with 95% CI: 0.75-0.92) and the Healthy Diet Indicator (HDI)(HR: 0.89 with 95% CI: 0.81-0.98) were inversely associated with all-causes mortality. Adjustments were made for age, gender, alcohol consumption, physical activity, smoking, number of years of education, body mass index, chronic diseases at baseline and study centre. CONCLUSIONS: The MDS, the MDI and the HDI were significantly inversely related with mortality. SPONSORSHIP: This study is based on data of the HALE project and supported by a grant from the European Union (QLK6-CT-2000-00211) to D Kromhout.

Homocysteine and cognitive function in institutionalised elderly A cross-sectional analysis.

BACKGROUND: Several cross-sectional, case-control and prospective studies revealed a relation between homocysteine and cognitive function or dementia. These studies included either patient populations or healthy, community- dwelling elderly people. AIM OF THE STUDY: In this study we tested the hypothesis that homocysteine was inversely associated with cognitive function in a population of institutionalised elderly (aged >/= 60 y; n = 157). METHODS: For testing this hypothesis baseline data of a recently conducted intervention study in institutionalised elderly (median age 83 years) were used. Cognitive function was evaluated by the cognitive subscale of the Alzheimer's disease Assessment Scale (ADAS-cog). The association between fasting plasma homocysteine level and cognitive function was investigated by multiple linear regression analysis. RESULTS: In the crude model homocysteine concentration was not significantly related to ADAS-cog score (beta = 0.061; p = 0.45). Age was found to be related to ADAS-cog score (beta = 0.161; p < 0.05). Adjusting for age did however not result in a relation between homocysteine and cognitive function. CONCLUSIONS: In our study no association was found between homocysteine and cognitive function in a population of very old institutionalised subjects.