Anticarcinogenic effect of common carotenoids.

Of the common carotenoids present in food, beta carotene, alpha carotene, lycopene, lutein, zeaxanthin as well as canthaxanthin can be considered potential prophylactic agents against carcinogenesis. They are absorbed by the human organism in reasonable amounts, and they have antioxidant properties, immunomodulating effects and may possibly influence gene expression enhancing gap junction communication. Recent suggestions that beta carotene may be metabolized directly to retinoic acid in retinoic acid target tissue and the discovery of retinoic acid nuclear receptors open up new perspectives for research. The best established chain of evidence for a protective effect of carotenoids against cancer development is available for beta carotene. Positive effects were observed in cell culture and experimental animal studies as well as in dietary and blood level studies in humans. More conclusive evidence will be provided by double-blind intervention trials in humans that are in progress. Beta carotene appears to be active in the promotion phase of carcinogenesis stabilizing initiated cells. Canthaxanthin, which has often been included in animal experiments for comparative purposes having little or no provitamin A activity, also exhibits strong protective effects. Of the other carotenoids only limited data are available. Depending on the experimental model used, lycopene, lutein or alpha carotene was particularly active. In preliminary human blood level studies, lycopene was inversely associated with cancers of the pancreas and cervix. Much work remains to be done. Of particular interest is the question of organ specificity of individual carotenoids.

The use of n-3 PUFAs (fish oil) in enteral nutrition.

Severely ill patients in need of enteral nutrition support must obtain all essential nutrients in at least the amounts recommended for daily intake (RDA) by healthy populations. Until recently essential fatty acids have been entirely omitted from enteral solutions or included only in the form of n-6 PUFAs which are structurally important for cell membranes and play a significant role as precursors (esp. arachidonic acid, AA) of eicosanoids (prostaglandins, thromboxanes, leukotrienes). However, in the absence of n-3 PUFAs, these eicosanoids may produce exaggerated effects in acute stress responses causing immunosuppression, platelet aggregation and excessive or chronic inflammation. n-3 PUFAs act as precursors of complementary eicosanoids which counteract the exaggerated responses of AA-derived eicosanoids. Therefore, n-3 PUFAs should be part of any optimally balanced diet and must be included also in enteral solutions. Since the transformation of the n-3 parent fatty acid, alpha-linolenic acid, to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is slow and unreliable, it is necessary to provide them as preformed nutrients as they occur in fish oil. The British Nutrition Foundation recommends a daily intake of EPA and DHA in amounts corresponding to the intake of 3 to 4 g standardized fish oil. The requirements can also be covered by the weekly consumption of 2 to 3 portions of fatty fish. Preliminary clinical trials have shown certain beneficial effects of fish oil intakes in diseases associated with inflammatory reactions such as rheumatoid arthritis or inflammatory bowel disease, in conditions with impaired immune competence such as burns, post-operative situations and cyclosporine treatment after renal transplants, and in conditions with enhanced platelet aggregation such as after coronary angioplasty. While these findings must be verified in strictly controlled trials, the intake of fish oil n-3 PUFAs in a balanced ratio to n-6 PUFAs can be recommended for all patients including those in need of enteral nutrition support.

High-dose vitamin C: a risk for persons with high iron stores?

The contribution of vitamin C (ascorbic acid) to the prevention of iron deficiency anemia by promoting the absorption of dietary non-heme iron-especially in persons with low iron stores--is well established. But the question has been raised whether high-dose intakes of vitamin C might unduly enhance the absorption of dietary iron in persons with high iron stores or in patients with iron overload, possibly increasing the potential risk of iron toxicity. Extensive studies have shown that overall the uptake and storage of iron in humans is efficiently controlled by a network of regulatory mechanisms. Even high vitamin C intakes do not cause iron imbalance in healthy persons and probably in persons who are heterozygous for hemochromatosis. The uptake, renal tubular reabsorption and storage of vitamin C itself are also strictly limited after high-dose intake so that no excessive plasma and tissue concentrations of vitamin C are produced. The effect of high-dose vitamin C on iron absorption in patients with iron overload due to homozygous hemochromatosis has not been studied. Of special importance is the early identification of hemochromatosis patients, which is assisted by the newly developed PCR test for hereditary hemochromatosis. Specific treatment consists of regular phlebotomy and possibly iron-chelating therapy. These patients should moreover avoid any possibility of facilitated absorption of iron and need to limit their intake of iron. Patients with beta-thalassemia major and sickle cell anemia who suffer from iron overload due to regular blood transfusions or excessive destruction of red blood cells need specialized medical treatment with iron chelators and should also control their intake of iron. The serum of patients with pathological iron overload can contain non-transferrin-bound iron inducing lipid peroxidation with subsequent consumption of antioxidants such as vitamin E and vitamin C. The role of iron in coronary heart disease and cancer is controversial. Early suggestions that moderately elevated iron stores are associated with an increased risk of CHD have not been confirmed by later studies. In vitro, ascorbic acid can act as a prooxidant in the presence of transition metals such as iron or copper, but in the living organism its major functions are as an antioxidant. High intakes of vitamin C have thus not been found to increase oxidative damage in humans. Accordingly, the risk of CHD or cancer is not elevated. On the contrary, most studies have shown that diets rich in vitamin C are inversely related to the incidence of these diseases.

Can adults adequately convert alpha-linolenic acid (18:3n-3) to eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3)?

A diet including 2-3 portions of fatty fish per week, which corresponds to the intake of 1.25 g EPA (20:5n-3) + DHA (22:6n-3) per day, has been officially recommended on the basis of epidemiological findings showing a beneficial role of these n-3 long-chain PUFA in the prevention of cardiovascular and inflammatory diseases. The parent fatty acid ALA (18:3n-3), found in vegetable oils such as flaxseed or rapeseed oil, is used by the human organism partly as a source of energy, partly as a precursor of the metabolites, but the degree of conversion appears to be unreliable and restricted. More specifically, most studies in humans have shown that whereas a certain, though restricted, conversion of high doses of ALA to EPA occurs, conversion to DHA is severely restricted. The use of ALA labelled with radioisotopes suggested that with a background diet high in saturated fat conversion to long-chain metabolites is approximately 6% for EPA and 3.8% for DHA. With a diet rich in n-6 PUFA, conversion is reduced by 40 to 50%. It is thus reasonable to observe an n-6/n-3 PUFA ratio not exceeding 4-6. Restricted conversion to DHA may be critical since evidence has been increasing that this long-chain metabolite has an autonomous function, e.g. in the brain, retina and spermatozoa where it is the most prominent fatty acid. In neonates deficiency is associated with visual impairment, abnormalities in the electroretinogram and delayed cognitive development. In adults the potential role of DHA in neurological function still needs to be investigated in depth. Regarding cardiovascular risk factors DHA has been shown to reduce triglyceride concentrations. These findings indicate that future attention will have to focus on the adequate provision of DHA which can reliably be achieved only with the supply of the preformed long-chain metabolite.

Intermediate cancer biomarkers and their use in beta-carotene studies in humans.

The most effective means of avoiding the development of squamous cell carcinomas is the elimination of risk factors such as tobacco smoke and alcohol and of exposure to occupational and dietary carcinogens. In addition, chemoprevention by micronutrients such as beta-carotene may be promising. However, studies verifying such effects using cancer incidence or mortality as study endpoint are extremely costly of financial and manpower resources. Therefore, premalignant intermediate biomarkers such as histological lesions (dysplasias/leukoplakias/ polyps), genetic changes (DNA damage, mutations) or enzymatic changes (protein kinase C or ornithine decarboxylase activation) are increasingly being used as surrogate endpoints. Even though most preneoplastic biomarkers still need to be verified and shown to be linked to malignancy, their use in clusters may enhance their predictability. In human trials beta-carotene has reversed some lesions such as micronuclei, leukoplakias and dysplasias in the oral cavity, whereas other lesions, e.g. colorectal polyps (i.e. their recurrence after resection) have not been found to respond. But proliferation markers in the colon mucosa have been modified by beta-carotene. Preliminary findings are also available of a potential reduction of esophageal dysplasias in a high-risk Chinese population and of cervical dysplasias in a group of American women. The available beta-carotene data are sufficiently encouraging to justify continuation of trials using intermediate cancer markers.

Vitamin A--functions, dietary requirements and safety in humans.

In recent years, new physiological functions of vitamin A have been identified in addition to its role in vision, namely its role in immune defence reducing morbidity of measles, of respiratory and possibly HIV infections, in gene regulation, in cell differentiation and morphogenesis. With the discovery of nuclear receptors for retinoic acid additional functions are likely to be found. The recommended dietary allowances (RDA) for vitamin A, including provitamin A carotenoids, vary greatly between countries. This may be explained by difficulties in establishing needs: Homeostatic mechanisms tightly control absorption, storage, release and transport of vitamin A to target tissue, and plasma concentrations do not reflect status unless there is vitamin A deficiency or excess. In the United States RDAs were established on the basis of vitamin A depletion-repletion studies with radio-labelled retinol. Intake requirements were calculated to amount to 1,000 micrograms retinol equivalents (RE) for men, 800 micrograms RE for non-pregnant as well as pregnant women and 1,300 micrograms RE for lactating women. Dietary intake studies in different countries have shown that it is in principle possible to obtain these values from the diet either as preformed vitamin A or in the form of provitamin A carotenoids or both. Risk groups for inadequate intakes include low-income groups and younger persons following weight-reducing and other unbalanced diets. Since experience with recommended intake values in the United States has been excellent, attempts at reducing these levels are unjustified and should be resisted. At intakes of up to three RDA values (approximately 3,000 micrograms RE) no unwanted side-effects are to be expected. Even higher doses, if not taken chronically, have been well tolerated, e.g. in deprived populations with low liver reserves. The suggestion derived from a case-control study that vitamin A taken at supplemental doses of 2,400 micrograms RE may be teratogenic have not been confirmed by several other studies. But it is judicious to follow the recommendations of the American Pediatric Society that women should not exceed a total daily intake of 3,000 micrograms RE. In developing countries where acute and chronic vitamin A deficiency is endemic causing xerophthalmia and blindness and increasing the prevalence of infectious diseases and death in children, special efforts are being made by WHO/UNICEF to provide programs for the eradication of vitamin A deficiency by immediate treatment and by long-term changes in dietary practices.

Prevention of platelet dysfunction by vitamin E in diabetic atherosclerosis.

Premature atherosclerosis and other vascular disorders are serious complications of diabetes mellitus. Contributing factors include (i) increased peroxidation of LDL leading to foam cell formation, fatty streaks and plaque formation in the arterial wall, and (ii) hyperreactivity of blood platelets leading to increased platelet adhesion and aggregation. Vitamin E may play a protective role as an antioxidant and/or membrane stabilizing agent in either mechanism. In platelets it appears to regulate arachidonic acid metabolism. Decreased vitamin E levels in platelets are associated with increased aggregation. This is reversible by correction of the vitamin E status. In diabetics, platelet vitamin E levels tend to be reduced with concomitant increase in platelet aggregation. Several studies in patients with insulin-dependent diabetes mellitus and, to some extent, in those with non-insulin-dependent diabetes mellitus have shown that supplementation with several hundred IU vitamin E significantly reduced platelet aggregation and lipid peroxidation. In healthy volunteers high-dose supplementation had no notable effect on platelet aggregation. However, doses as low as 200 IU vitamin E significantly reduced platelet adhesion and inhibited the formation of protruding pseudopods typically occurring in activated platelets. In diabetic patients a decrease in the nonenzymatic glycation of proteins by vitamin E supplementation has been observed. Controlled studies are needed to confirm the effect of vitamin E on platelet function in well-defined groups of diabetics, followed by large-scale trials investigating the prevention of diabetic vascular complications as clinical end point.

Function of vitamin E in physical exercise: a review.

Even though vitamin E may not improve physical achievements in sports competitions, as shown in several swimming experiments, it is important for the health of skeletal muscle: in its role as the major lipid-soluble chainbreaking antioxidant in lipid cell membranes, vitamin E protects muscle tissue in aerobic exercise, in which oxygen metabolism and, consequently, free radical production are greatly accelerated. Animal studies in several laboratories have shown that endurance exercise results in the same type of oxidative muscle damage as does vitamin E deficiency: there is an increase in the peroxidation products pentane and malondialdehyde and in enzymes leaked from muscles to plasma. Oxidative tissue damage in vitamin-E deficient animals is exacerbated by endurance training and, conversely, it is reduced by high-dose vitamin E supplementation; also, preliminary studies in humans have demonstrated antioxidant protection by high-dose vitamin E supplementation. After endurance exercise leakage of enzymes into the plasma and output of pentane in the breath were significantly reduced. During a high-altitude expedition in the Himalayas, protection was shown to be significantly better in the supplemented group than in the placebo group, as determined by anaerobic threshold and pentane exhalation.

Human vitamin C requirements.

The importance of vitamin C is reflected in its multifunctional roles which include participation in collagen and carnitine syntheses, promotion of iron absorption and the more recently discovered participation in noradrenaline synthesis, inactivation of free radical chain reactions, prevention of N-nitroso compound formation and more. Given the many extra-antiscorbutic functions of the vitamin, the Recommended Dietary Allowances (RDA) should not just prevent deficiency disease but should aim at providing sufficient amounts for all vitamin C-dependent functions to operate at full capacity. The concept of vitamin C tissue saturation is best able to meet this demand. The use of kinetic models has shown that the body pool is saturated with a daily intake of 100 mg vitamin C in non-smokers and 140 mg in smokers, amounts that may be regarded as optimal RDA values. Certain disease states may be accompanied by still higher vitamin C requirements but the exact amounts are not yet known.

The potential role of lycopene for human health.

Lycopene is one of the major carotenoids in Western diets and is found almost exclusively in tomatoes and tomato products. It accounts for about 50% of carotenoids in human serum. Among the common dietary carotenoids lycopene has the highest singlet oxygen quenching capacity in vitro. Other outstanding features are its high concentration in testes, adrenal gland and prostate. In contrast to other carotenoids its serum values are not regularly reduced by smoking or alcohol consumption but by increasing age. Remarkable inverse relationships between lycopene intake or serum values and risk have been observed in particular for cancers of the prostate, pancreas and to a certain extent of the stomach. In some of the studies lycopene was the only carotenoid associated with risk reduction. Its role in cancer risk reduction still needs to be clarified. Patients with HIV infection, inflammatory diseases and hyperlipidemia with and without lipid lowering treatment may have depleted lycopene serum concentrations. Before embarking on large-scale human trials the distribution of lycopene and its biological functions need to be further evaluated.

The role of vitamin C in athletic performance.

There is widespread belief among athletes that special nutritional practices--in particular high-protein diets--will enhance their achievements in competition. Supplementation with vitamins, especially vitamin C, is equally popular. But because genetic predisposition, hard physical training and psychological factors play a most important role in determining performance, and because any potential difference in achievement will be small, it is almost impossible to obtain scientific evidence of a beneficial effect of a particular nutrient. There have been many investigations during the past four decades of the potential effect of high-dose vitamin C supplementation on physical performance. The variables used have included maximum oxygen uptake, blood lactic acid levels, and heart rate after exercise, and in some cases performance was assessed in competitive events. The results have been equivocal: Most studies could not demonstrate an effect. On the other hand, a suboptimal vitamin C status results in an impaired working capacity which can be normalized by restoring vitamin C body pools. Athletes, who follow irrational, unhealthy eating patterns often not including vitamin-C-containing fruit and vegetables, are in need of nutrition education.

Antioxidant vitamins in cataract prevention.

The ocular lens, which is continually exposed to light and ambient oxygen, is at high risk of photooxidative damage resulting in cataract. Oxygen free radicals appear to impair not only lens crystallins which will aggregate and precipitate forming opacities but also proteolytic enzymes whose function it would be to eliminate the damaged proteins. Apart from an enzymatic defense system consisting of superoxide dismutase, catalase and glutathione peroxidase against excited oxygen species the lens contains the antioxidant vitamins C, E and presumably beta-carotene as another line of defense. In vitro and in vivo studies in different animal species have demonstrated a significant protective effect of vitamins C and E against light-induced cataract. Sugar and steroid cataracts were prevented as well. Epidemiological evidence in humans suggests that persons with comparatively higher intakes or blood concentrations of antioxidant vitamins are at a reduced risk of cataract development. These positive findings established by several research groups justify extensive intervention trials with antioxidant vitamins in humans using presenile cataract development as a model.

[The importance of vitamin B 6 for development of the infant. Human medical and animal experiment studies]. / Die Bedeutung von Vitamin B6 für die Entwicklung des Säuglings. Humanmedizinische und tierexperimentelle Studien.

Vitamin B-6 is an important coenzyme in the biosynthesis of the neurotransmitters GABA, dopamine and serotonin and is therefore required for the normal perinatal development of the central nervous system. In rat studies, biochemical and morphological abnormalities (decreased dendritic arborization and reduced numbers of myelinated axons and synapses) in the brains of pups from vitamin B-6 deficient dams were associated with behavioral changes such as epileptiform seizures and movement disorders. In severely vitamin B-6 deficient human infants, similar behavioral abnormalities have been described. Marginally deficient neonates were found to have a lower birthweight and to display less mature reactive and adaptive behavior in the Brazleton Neonatal Assessment Scale than well-fed infants. While it is not yet possible to define the exact amount of vitamin B-6 required to support optimal brain development, pregnant and lactating women should be encouraged to consume a diet that is rich in vitamin B-6.

No contribution of ascorbic acid to renal calcium oxalate stones.

Even though a certain part of oxalate in the urine derives from metabolized ascorbic acid (AA), the intake of high doses of vitamin C does not increase the risk of calcium oxalate kidney stones due to physiological regulatory factor: gastrointestinal absorption as well as renal tubular reabsorption of AA are saturable processes, and the metabolic transformation of AA to oxalate is limited as well. Older assays for urinary oxalate favored in vitro conversion of AA to oxalate during storage and processing of the samples. Recurrent stone formers and patients with renal failure who have a defect in AA or oxalate metabolism should restrict daily vitamin C intakes to approximately 100 mg. But in the large-scale Harvard Prospective Health Professional Follow-Up Study, those groups in the highest quintile of vitamin C intake (> 1,500 mg/day) had a lower risk of kidney stones than the groups in the lowest quintiles.

[Construction of a neoesophagus using lyophilized dura. Animal experiment in dogs]. / Bildung eines Neooesophagus aus lyophilisierter Dura. Tierexperimentelle Untersuchungen an Hunden

The experiments have proven the feasibility of bridging short oesophageal defects as well as longer ones with lyophilized dura. By means of a two-stage-operation respectively a combined homologous-alloplastik oesophageal prosthesis the risk of insufficiency of anastomoses may be minimized. Thus its clinical application seems worthy of consideration.