The increasing prevalence of the metabolic syndrome in numerous populations throughout the world is currently of major concern, and presents a huge global health problem. The link between low birth weight and the subsequent development of obesity, disrupted glucose homeostasis and hypertension is now well established, and there is extensive evidence supporting these associations in both epidemiological and experimental studies. Alterations in the secretion of, and responses to, the circulating hormones insulin and leptin are likely candidates in terms of disease development. The aim of current research is to define how the central and peripheral pathways in which these signals exert their effects may be disrupted following poor early growth, and how this disruption contributes to the development of metabolic disease. The present review aims to outline the existing evidence whereby alterations in early growth may programme an individual to be at increased risk of the metabolic syndrome. The development of central appetite and expenditure circuits and of peripheral metabolic tissues, are likely to play a key role in the long-term regulation of energy balance.

2006 marked the centenary of the birth of Dr Elsie Widdowson, a pioneer of nutrition science. One of the hallmarks of Elsie Widdowson's research was an integrative approach that recognised the importance of investigating the mechanisms underpinning a public health or clinical issue at all levels, looking into the physiology, comparative biology, intermediate metabolism and basic science. The theme of the present lecture, given in celebration of the work of Dr Widdowson, is mineral nutrition, with a particular focus on Ca, P and vitamin D. The contributions of Dr Widdowson to the early understanding of mineral nutrition are reviewed and the latest scientific findings in this rapidly-expanding field of research are presented.

The complex interplay between neural and endocrine responses following food intake regulates ingestive behaviour and ultimately determines subsequent energy intake. These processes include cognitive, gastrointestinal-derived and metabolic mechanisms. Such physiological responses to the ingestion of food initiate short- to medium-term inhibition of intake (satiety). However, in clinical states in which systemic inflammation is evident there is a more profound satiety response and a clear absence of motivation to eat that is evident as loss of appetite. These negative influences on energy intake can contribute to poor nutritional status, and consequently poor physical function, and impact on rehabilitation and recovery. Cytokine mediators of the inflammatory response directly influence feeding behaviour at the hypothalamic nuclei and may explain the lack of motivation and desire for food. However, additional detrimental effects on appetite are brought about because of alterations in intermediary metabolism present in inflammation-induced catabolism. This process forms part of the host response to inflammation and may explain symptoms, such as early satiety, frequently reported in many patient groups. In clinical states, and cancer in particular, pharmacological strategies have been employed to ameliorate the inflammatory response in an attempt to improve energy intake. Some success of this approach has been reported following administration of substrates such as EPA. Novel strategies to improve intake through administration of anti-cytokine drugs such as thalidomide may also be of benefit. However, drugs that oppose the actions of neurotransmitter pathways involved in central induction of satiety, such as 5-hydroxytryptamine, have failed to improve intake but appear to enhance enjoyment of food. Such findings indicate that therapeutic nutritional targets can only be achieved where novel pharmacological therapies can be supported by more innovative and integrated dietary management strategies. Many of these strategies remain to be elucidated.

The DNA in all cells of the human body is subject to damage continuously from exogenous agents, internal cellular processes and spontaneous decomposition. Failure to repair such damage is fundamental to the development of many diseases and to ageing. Fortunately, the vast majority of DNA damage is detected and repaired by one of five complementary DNA repair systems. However, recent studies have shown that even in healthy individuals there is a wide inter-individual variation in DNA repair capacity. Part of this variation can be accounted for by polymorphisms in the genes encoding DNA repair proteins. However, it is probable that environmental factors, including dietary exposure as well as diet–gene interactions, are also responsible for much of the difference in repair capacity between individuals. Whilst there is some evidence from human studies that generalised malnutrition or low intakes of specific nutrients may affect DNA repair, as yet there is limited understanding of the molecular mechanisms through which nutrients can modulate this key cellular process.

Until recently, a glance at a standard undergraduate textbook would have given the impression that the colon was merely a storage organ for faeces and maybe something about the absorption of electrolytes and water. In reality, the colon is a highly-metabolically-active organ, the function of which has implications not only for the remainder of the digestive tract, but also for peripheral organs such as adipose tissue (AT), liver and skeletal muscle. The present review focuses on two distinct but complementary areas: (1) the metabolic adaptation that occurs following surgical removal of colonic tissue; (2) the effect of modulating the colon in situ in terms of postprandial metabolism, insulin sensitivity and disease risk. Work in these two areas points to the colon being important in modulating normal tissue insulin sensitivity. The role of fatty acids is central to the insulin sensitivity hypothesis. AT acts as a daily ‘buffer’ for fatty acids. However, following colonic resection there is an apparent change in AT function. There is an increase in the AT lipolysis rate, resulting in the release of excess fatty acids into the circulation and consequently the take up of excess fatty acids into skeletal muscle. This resultant increase in either storage of lipid or its oxidation would result in a reduction in insulin sensitivity. The insulin-sensitising effects of high-fibre diets are also related to changes in AT function and fatty acid metabolism, but manipulating colonic tissue in situ allows the mechanisms to be elucidated. This research area is an exciting one, involving the potential role of SCFA (the absorbed by-products of colonic bacterial fermentation) acting directly on peripheral tissues, following the recent identification of G-protein-coupled receptors specific for these ligands.

Malnutrition (undernutrition) is one of the many health inequalities facing governments in the 21st century. Malnutrition is a common condition affecting millions of individuals in the UK, particularly older adults, the sick and those cared for within the healthcare system. It costs the National Health Service >£7·3×109 annually. New data highlight marked geographical differences in the prevalence of malnutrition across England and an inter-relationship between deprivation, malnutrition and poor outcome. As malnutrition is a largely treatable condition, prompt identification and effective prevention and treatment of this costly condition is imperative. Routine screening for malnutrition in high-risk groups (e.g. the elderly and those in areas with high deprivation) and within the healthcare system should be a priority, with screening linked to appropriate plans for the management of malnutrition. Use should be made of specialised interventions, including oral nutritional supplements and artificial nutrition, to aid recovery and improve outcome, with skilled health professionals, including dietitians, involved where possible. Equity of access to nutritional services and treatments for malnutrition needs to occur across the UK and, although complex and multi-factorial, the effects of deprivation and other relevant socio-economic and geographical factors should be addressed. Ultimately, as malnutrition is a public health problem, its identification and treatment must become a priority for governments, healthcare planners and professionals.

The elevation of blood lipid concentrations in response to the consumption of low-fat high-carbohydrate diets is known as carbohydrate-induced hypertriacylglycerolaemia (HPTG). An understanding of the mechanisms involved in the interaction between carbohydrates and plasma lipids may help determine whether carbohydrate-induced HPTG would increase cardiovascular risk. There is growing evidence to suggest that the sugar component of the diet may be largely responsible, rather than the total carbohydrate. In most studies designed to investigate the mechanisms of carbohydrate-induced HPTG, the amounts and types of sugars and starches used in the diets are not specified. Findings have been mixed and inconsistent. It is proposed that the elucidation of mechanisms from current studies could have been confounded by the different ways in which sugars are metabolized in the body. At present, there are few studies that have evaluated the independent effects of dietary sugars. Interest has been focused on de novo lipogenesis (DNL), as it has recently been found to be positively correlated with increases in fasting TAG levels produced on high-carbohydrate diets, indicating that DNL may contribute to carbohydrate-induced HPTG. DNL has been found to be determined by starch:sugar in a high-carbohydrate diet and affected by different types of sugars. The presence of DNL in adipose tissue is supported by emerging gene-expression studies in human subjects. In the wake of rising intakes of sugars, further research is needed to investigate the mechanisms associated with different sugars, so that appropriate therapeutic strategies can be adopted.

Epidemiological studies showing a protective effect of diets rich in fruits and vegetables against cancer have focused attention on the possibility that biologically-active plant secondary metabolites exert anti-carcinogenic activity. This huge group of compounds, now collectively termed ‘phytochemicals’, provides much of the flavour and colour of edible plants and the beverages derived from them. Many of these compounds also exert anti-carcinogenic effects in animal models of cancer, and much progress has been made in defining their many biological activities at the molecular level. Such mechanisms include the detoxification and enhanced excretion of carcinogens, the suppression of inflammatory processes such as cyclooxygenase-2 expression, inhibition of mitosis and the induction of apoptosis at various stages in the progression and promotion of cancer. However, much of the research on phytochemicals has been conducted in vitro, with little regard to the bioavailability and metabolism of the compounds studied. Many phytochemicals present in plant foods are poorly absorbed by human subjects, and this fraction usually undergoes metabolism and rapid excretion. Some compounds that do exert anti-carcinogenic effects at realistic doses may contribute to the putative benefits of plant foods such as berries, brassica vegetables and tea, but further research with human subjects is required to fully confirm and quantify such benefits. Chemoprevention using pharmacological doses of isolated compounds, or the development of ‘customised’ vegetables, may prove valuable but such strategies require a full risk–benefit analysis based on a thorough understanding of the long-term biological effects of what are often surprisingly active compounds.

Hyperglycaemia occurs in the majority of critically-ill patients, partly because patients are hypercatabolic and consequently have increased glucose levels and partly because of insulin resistance. Hyperglycaemia is associated with increased mortality in critical illness. In 2001 it was shown that mortality and other complications of critical illness can be decreased by adopting ‘tight’ glycaemic control (4·1–6·4 mmol/l). The critical care world adopted tight glycaemic control enthusiastically, until it became apparent that profound life-threatening hypoglycaemia could result. Most clinicians, currently, have adopted regimens aiming to control glucose between 4 and 8 mmol/l. Practising this regimen safely requires attention to detail. Patients must be provided with energy as well as insulin; preferably via the enteral route, but parenterally if necessary. Insulin is administered according to a relatively simple scale that is adjustable by nursing staff according to patients' glucose results. Frequent glucose measurement is essential to success, along with using visual charting that makes sudden changes in blood glucose levels obvious. There are several ‘champions’ of safe implementation of glucose control in the intensive care unit at the Royal Liverpool University Hospital who are educators and who feed results back to staff regularly. Further studies will clarify the ultimate role of tight glycaemic control, but it can be done safely with meticulous attention to detail.

A life-course approach to chronic-disease epidemiology uses a multidisciplinary framework to understand the importance of time and timing in associations between exposures and outcomes at the individual and population levels. Such an approach to chronic diseases is enriched by specification of the particular manner in which timing in relation to physical growth, reproduction, infection, social mobility, behavioural transitions etc. can influence various adult chronic diseases in different ways, and more ambitiously by how these temporal processes are interconnected and manifested in health inequalities within a population and in population-level disease trends. The paper will discuss some historical background to life-course epidemiology and theoretical models of life-course processes, and will review some of the empirical evidence linking life-course processes to CHD, haemorrhagic stroke, stomach cancer and other chronic diseases in adulthood. It will also underscore that a life-course approach offers a way to conceptualize how underlying socio-environmental determinants of health, experienced at different life-course stages, can differentially influence the development of chronic diseases, as mediated through proximal specific biological processes.

Fish and fish oil-rich sources of long-chain n-3 fatty acids have been shown to be cardio-protective, through a multitude of different pathways including effects on arrythymias, endothelial function, inflammation and thrombosis, as well as modulation of both the fasting and postprandial blood lipid profile. To date the majority of studies have examined the impact of EPA and DHA fed simultaneously as fish or fish oil supplements. However, a number of recent studies have compared the relative biopotency of EPA v. DHA in relation to their effect on blood lipid levels. Although many beneficial effects of fish oils have been demonstrated, concern exists about the potential deleterious impact of EPA and DHA on LDL-cholesterol, with a highly-heterogenous response of this lipid fraction reported in the literature. Recent evidence suggests that apoE genotype may be in part responsible. In the present review the impact of EPA and DHA on cardiovascular risk and the blood lipoprotein profile will be considered, with a focus on the apoE gene locus as a possible determinant of lipid responsiveness to fish oil intervention.

Parenteral nutrition is life saving in patients with intestinal failure but liver dysfunction is commonly encountered, especially in neonates. Although abnormal liver function tests associated with short-term parenteral nutrition are usually benign and transient, liver dysfunction in both children and adults receiving long-term parenteral nutrition can progress to end-stage liver disease and liver failure. The aetiology of parenteral nutrition-associated liver disease is complex and multifactorial, with a range of patient, disease and nutrition-related factors implicated. Sepsis is of particular importance, as is the lack of enteral nutrition and overfeeding with intravenous glucose and/or lipid. Deficiencies of a number of amino acids including choline and taurine have also been implicated. Management of hepatic dysfunction in parenteral nutrition should initially focus on preventing its occurrence. Sepsis should be managed appropriately, enteral nutrition should be encouraged and maximised where possible and parenteral overfeeding should be avoided. Provision of parenteral lipid should be optimised to prevent the adverse effects of both deficiency and excess, and cyclical rather than continuous parenteral feeding should be administered. There is some evidence of benefit in neonates from oral antibiotics to prevent intestinal bacterial overgrowth and from oral ursodeoxycholic acid, but less to support their use in adults. Similarly, data to support widespread use of parenteral choline or taurine supplementation are lacking at present. Ultimately, severe parenteral nutrition-associated liver disease may necessitate referral for small intestine and/or liver transplantation.

To avoid any negative outcomes associated with under- or overfeeding it is essential to estimate nutrient requirements before commencing nutrition support. The energy requirements of an individual vary with current and past nutritional status, clinical condition, physical activity and the goals and likely duration of treatment. The evidence-base for prediction methods in current use, however, is poor and the equations are thus open to misinterpretation. In addition, most methods require an accurate measurement of current weight, which is problematic in some clinical situations. The estimation of energy requirements is so challenging in some conditions, e.g. critical illness, obesity and liver disease, that it is recommended that expenditure be measured on an individual basis by indirect calorimetry. Not only is this technique relatively expensive, but in the clinical setting there are several obstacles that may complicate, and thus affect the accuracy of, any such measurements. A review of relevant disease-specific literature may assist in the determination of energy requirements for some patient groups, but the energy requirements for a number of clinical conditions have yet to be established. Regardless of the method used, estimated energy requirements should be interpreted with care and only used as a starting point. Practitioners should regularly review the patient and reassess requirements to take account of any major changes in clinical condition, nutritional status, activity level and goals of treatment. There is a need for large randomised controlled trials that compare the effects of different levels of feeding on clinical outcomes in different disease states and care settings.

The protective effects of brassica vegetables against cancer may be partly related to their glucosinolate content. Glucosinolates are hydrolysed by plant myrosinase following damage of plant tissue. Isothiocyanates are one of the main groups of metabolites of glucosinolates and are implicated in the preventive effect against cancer. During cooking of brassica the glucosinolate–myrosinase system may be modified as a result of inactivation of plant myrosinase, loss of enzymic cofactors such as epithiospecifier protein, thermal breakdown and/or leaching of glucosinolates and their metabolites or volatilisation of metabolites. Cooking brassica affects the site of release of breakdown products of glucosinolates, which is the upper gastrointestinal tract following consumption of raw brassica containing active plant myrosinase. After consumption of cooked brassica devoid of plant myrosinase glucosinolates are hydrolysed in the colon under the action of the resident microflora. Feeding trials with human subjects have shown that hydrolysis of glucosinolates and absorption of isothiocyanates are greater following ingestion of raw brassica with active plant myrosinase than after consumption of the cooked plant with denatured myrosinase. The digestive fate of glucosinolates may be further influenced by the extent of cell rupture during ingestion, gastrointestinal transit time, meal composition, individual genotype and differences in colonic microflora. These sources of variation may partly explain the weak epidemiological evidence relating consumption of brassica to prevention against cancer. An understanding of the biochemical changes occurring during cooking and ingestion of brassica may help in the design of more robust epidemiological studies to better evaluate the protective effects of brassica against cancer.

The balance of intake of n-6 and n-3 PUFA, and consequently their relative incorporation into immune cells, is important in determining the development and severity of immune and inflammatory responses. Some disorders characterised by exaggerated inflammation and excessive formation of inflammatory markers have become among the most important causes of death and disability in man in modern societies. The recognition that long-chain n-3 PUFA have the potential to inhibit (excessive) inflammatory responses has led to a large number of clinical investigations with these fatty acids in inflammatory conditions as well as in healthy subjects. The present review explores the presence of dose-related effects of long-chain n-3 PUFA supplementation on immune markers and differences between healthy subjects and those with inflammatory conditions, because of the important implications for the transfer of information gained from studies with healthy subjects to patient populations, e.g. for establishing dose levels for specific applications. The effects of long-chain n-3 PUFA supplementation on ex vivo lymphocyte proliferation and cytokine production by lymphocytes and monocytes in healthy subjects have been studied in twenty-seven, twenty-five and forty-six treatment cohorts respectively, at intake levels ranging from 0·2 g EPA+DHA/d to 7·0 g EPA+DHA/d. Most studies, particularly those with the highest quality study design, have found no effects on these immune markers. Significant effects on lymphocyte proliferation are decreased responses in seven of eight cohorts, particularly in older subjects. The direction of the significant changes in cytokine production by lymphocytes is inconsistent and only found at supplementation levels ≥2·0 g EPA+DHA/d. Significant changes in inflammatory cytokine production by monocytes are decreases in their production in all instances. Overall, these studies fail to reveal strong dose–response effects of EPA+DHA on the outcomes measured and suggest that healthy subjects are relatively insensitive to immunomodulation with long-chain n-3 PUFA, even at intake levels that substantially raise their concentrations in phospholipids of immune cells. In patients with inflammatory conditions cytokine concentrations or production are influenced by EPA+DHA supplementation in a relatively large number of studies. Some of these studies suggest that local effects at the site of inflammation might be more pronounced than systemic effects and disease-related markers are more sensitive to the immunomodulatory effects, indicating that the presence of inflamed tissue or ‘sensitised’ immune cells in inflammatory disorders might increase sensitivity to the immunomodulatory effects of long-chain n-3 PUFA. In a substantial number of these studies clinical benefits related to the inflammatory state of the condition have been observed in the absence of significant effects on immune markers of inflammation. This finding suggests that condition-specific clinical end points might be more sensitive markers of modulation by EPA+DHA than cytokines. In general, the direction of immunomodulation in healthy subjects (if any) and in inflammatory conditions is the same, which indicates that studies in healthy subjects are a useful tool to describe the general principles of immunomodulation by n-3 PUFA. However, the extent of the effect might be very different in inflammatory conditions, indicating that studies in healthy subjects are not particularly suitable for establishing dose levels for specific applications in inflammatory conditions. The reviewed studies provide no indications that the immunomodulatory effects of long-chain n-3 PUFA impair immune function or infectious disease resistance. In contrast, in some conditions the immunomodulatory effects of EPA+DHA might improve immune function.

Despite a great deal of research effort there is still considerable uncertainty surrounding the importance of the B-vitamins in health and disease. This continuing uncertainty is partly a result of the difficulty of measuring intake, confounding in observational studies and the very large numbers required to evaluate primary prevention in randomised controlled trials. Consequently, genetic data are increasingly being used to infer nutritional effects on health and even in the formulation of nutrition policy using the approach of ‘mendelian randomisation’. Genetic information has already contributed greatly to the understanding of B-vitamin metabolism and the heterogeneity of responses to intake. It has the potential to provide further nutritional insights and to assist in the elucidation of causal mechanisms, but it is important that genetic data is not viewed as an alternative to nutritional information, both are necessary when addressing nutritional problems. Similarly, the interpretation of nutrient and biomarker status in some experimental designs may require knowledge of genotype. Formal tests of gene–gene and gene–nutrient interaction are of limited value in nutritional studies and the formulation of policy. Graphical representation of diet–genotype–health data greatly assists in the elucidation of the nature of genetic effects, their interaction with nutrition and the implications for nutrition policy.

The National Institute for Health and Clinical Excellence (NICE) has recommended that nutrition support in seriously-ill or injured patients should start at ⩽50% of the estimated target energy and protein needs. This recommendation has caused some concern, since taking the NICE approach leads to these sick individuals receiving an initial N provision of only ⩽0·12 g N/kg per d, as opposed to levels of approximately 0·25 g N/kg per d that have been widely recommended by other expert groups. The basis of the recommendation for higher levels of N provision is that feeding at levels of ≥0·25 g N/kg per d reduces the inevitable net N loss of catabolism and hence minimises overall lean tissue wasting. However, although it has always been assumed that better N balance must equate with better outcome, there are teleological arguments that question the wisdom of providing more N to sicker patients and studies that imply that best N balance might not equate with best clinical progress. Furthermore, current evidence suggests that in most critical illness low initial intakes of both energy and N lead to improved survival. It therefore seems logical to aim, in the first instance, to feed the seriously ill at only modest levels. Further research is required to determine whether lower-energy higher-N feeding would prove better or worse than this approach in terms of clinical benefit rather than just better N retention. Investigations to explore the use of feeds that are specifically designed to match the amino acid needs of illness are also required.

In the UK vitamin B12 deficiency occurs in approximately 20% of adults aged >65 years. This incidence is significantly higher than that among the general population. The reported incidence invariably depends on the criteria of deficiency used, and in fact estimates rise to 24% and 46% among free-living and institutionalised elderly respectively when methylmalonic acid is used as a marker of vitamin B12 status. The incidence of, and the criteria for diagnosis of, deficiency have drawn much attention recently in the wake of the implementation of folic acid fortification of flour in the USA. This fortification strategy has proved to be extremely successful in increasing folic acid intakes pre-conceptually and thereby reducing the incidence of neural-tube defects among babies born in the USA since 1998. However, in successfully delivering additional folic acid to pregnant women fortification also increases the consumption of folic acid of everyone who consumes products containing flour, including the elderly. It is argued that consuming additional folic acid (as ‘synthetic’ pteroylglutamic acid) from fortified foods increases the risk of ‘masking’ megaloblastic anaemia caused by vitamin B12 deficiency. Thus, a number of issues arise for discussion. Are clinicians forced to rely on megaloblastic anaemia as the only sign of possible vitamin B12 deficiency? Is serum vitamin B12 alone adequate to confirm vitamin B12 deficiency or should other diagnostic markers be used routinely in clinical practice? Is the level of intake of folic acid among the elderly (post-fortification) likely to be so high as to cure or ‘mask’ the anaemia associated with vitamin B12 deficiency?

The metabolic syndrome represents a summation of obesity-driven risk factors for atherosclerotic CVD and type 2 diabetes. Definitions of the syndrome vary but in general agree closely in identifying subjects. The relationships between the metabolic syndrome and atherosclerotic CVD and diabetes also vary, with relative risks of approximately 1·5–3·0 and approximately 3·0–5·0 respectively. Insulin resistance appears to explain much of the pathophysiology of the syndrome. Both increased fatty acid flux and an excess of circulating pro-inflammatory cytokines are likely mediators. With increased waist circumference, increases in fatty acid delivery to the liver result in higher rates of hepatic glucose production and increases in the secretion of apoB-containing lipoproteins. Concomitant changes in HDL ensue, including a replacement of the cholesterol content with TAG, an accelerated clearance from the plasma and thus a reduced number of HDL particles. Typically also present are increases in small dense LDL. Hypertension in part relates to the insulin resistance, but may involve other mechanisms. Impaired fasting glucose often relates to defects in insulin secretion in addition to insulin resistance, and probably more than any other component of the syndrome predicts the increased incidence of type 2 diabetes. Although not included in the diagnostic criteria, increases in pro-inflammatory cytokines and pro-thrombotic factors, in addition to decreases in plasma adiponectin, may also contribute to the increased incidence of atherosclerotic CVD and diabetes. In general, the greater the number of metabolic syndrome components, the greater the risk for these outcomes. The cytokines and pro-thrombotic factors also appear to contribute.

Early weaning of piglets is often accompanied by a severe growth check and diarrhoea. It is well established that this process is multi-factorial and that post-weaning anorexia and undernutrition are major aetiological factors. Gastrointestinal disturbances include alterations in small intestine architecture and enzyme activities. Recent data indicate transiently-increased mucosal permeability, disturbed absorptive–secretory electrolyte balance and altered local inflammatory cytokine patterns after weaning. These responses appear to operate according to two distinct temporal patterns, an acute response followed by a long-lasting adaptation response. Pigs coexist with a diverse and dense commensal microbiota in their gastrointestinal tract. Most of these microbes are beneficial, providing necessary nutrients or protection against harmful pathogens for the host. The microbial colonisation of the porcine intestine begins at birth and follows a rapid succession during the neonatal and weaning period. Following the withdrawal of sow's milk the young piglets are highly susceptible to enteric diseases partly as a result of the altered balance between developing beneficial microbiota and the establishment of intestinal bacterial pathogens. The intestinal immune system of the newborn piglet is poorly developed at birth and undergoes a rapid period of expansion and specialisation that is not achieved before early (commercial) weaning. Here, new insights on the interactions between feed components, the commensal microbiota and the physiology and immunology of the host gastrointestinal tract are highlighted, and some novel dietary strategies are outlined that are focused on improving gut health. Prebiotics and probiotics are clear nutritional options, while convincing evidence is still lacking for other bioactive substances of vegetable origin.