Search

The requirement for vitamin E is closely related to the dietary intake of polyunsaturated fatty acids (PUFA). By the protective mechanism to prevent PUFA from being peroxidized, vitamin E is metabolically consumed. In addition, PUFA impair the intestinal absorption of vitamin E. Therefore PUFA generate an additional vitamin E requirement on the order of 0.6, 0.9, 1.2, 1.5, and 1.8 mg vitamin E (RRR-alpha-tocopherol-equivalents), respectively, for 1 g of dienoic, trienoic, tetraenoic, pentaenoic, and hexaenoic acid. For this reason, the gross vitamin E content of food containing PUFA does not allow an evaluation of this food as a source of vitamin E. A suitable measure is the net vitamin E content, i.e., gross vitamin E minus the amount needed for PUFA protection. Therefore, some food-stuffs generally considered as vitamin-E sources, as concluded from their gross vitamin E content, cause in reality a vitamin E deficiency if not sufficiently compensated by other vitamin E supplying food constituents. Examples of the net vitamin E content of some fats and oils, fish and nuts are shown. Consequences for food composition data and food labeling and the problem of meeting the vitamin-E requirements are discussed.

Present knowledge on the possible cause of the tryptophan-induced eosinophilia-myalgia syndrome is discussed on the basis of a literature survey. The initially favored hypothesis of metabolites of a deranged tryptophan metabolism in some persons as cause of the syndrome has no plausibility for several reasons discussed in this paper. In the meantime trace backs of implicated tryptophan lots have led to one manufacturer who has changed his production procedure. The implicated lots contain a variety of impurities detectable by HPLC. Whether these impurities are the immediate cause of the syndrome or just markers remains to be established. An animal model suitable to clarify this question has recently been developed. Taking all these measures to identify and eliminate suspicious lots, there is no reason to withhold live saving artificial nutrition with tryptophan-containing preparations.

The effect of vitamin A-deficiency on jejunal Paneth cells in rats was investigated. Crystalloid particles were observed in secretion granules of Paneth cells from 6 out of 8 rats with vitamin A-deficiency. The particles were similar to those found in Paneth cells under other experimental conditions. Using an immuno-electron-microscopic technique we demonstrated a clear lysozyme immunoreactivity of these particles. In 2 vitamin A-deficient rats tubular structures have been detected in addition to the crystalloid particles. Crystalloid particles or tubular structures were not detectable in a control group of 8 vitamin A-supplemented rats. The morphological alterations of Paneth cells may be correlated to an impaired local immunity of the intestine during vitamin A-deficiency.

Parenteral nutrition is incomplete without vitamins. Marginal vitamin deficiency under parenteral nutrition is certainly more common than generally recognized. Even marginal and undiscernable vitamin deficiency interferes with healing processes and increases the rate of complications since vitamins are involved in a variety of ways in wound healing, regeneration processes and immune function. If total parenteral nutrition is necessary for longer periods of time, exceeding 5 days, vitamins should be substituted in the recommended doses. The assessment of a marginal vitamin deficiency is difficult to perform and extremely expensive. It is therefore easier, safer and cheaper to substitute vitamins in total parenteral nutrition from the beginning, if preceeding malnutrition is likely. Recommendations for dosage and mode of application are reported and explained.

Retinoic acid causes a significant inhibition of cell growth of the tumor cell line BA-HAN-1C. This growth inhibition is the same whether the cells are treated with a pulse dose of retinoic acid (RA) or continuously expand to RA. The determination of RA and its degradation products within the culture medium and in the cells showed that after 24 hours 13-cis-RA was the major retinoid in all cells (96 ng/10(6) cells); all-trans-RA represented 56 ng/10(6) cells. After 48 hours 4-hydroxy-RA and a small amount of 5,6-epoxy-RA was found in the cells and also in the culture medium. 4-hydroxy-RA increased up to 96 hours, whereas 13-cis- and all-trans-RA were not detectable in the cells after 96 hours. We conclude that the BA-HAN-1C cells take up and metabolize RA. Nonlinear fit analysis of the time behavior of the RA concentration in medium demonstrates that the RA uptake unexpectedly follows a mono-exponential time function. Discussion of the experimental results in connection with a proper compartment model shows that uptake and metabolism of RA cannot be described really by a first order kinetics. The mathematical analysis leads to a more complicated kinetic model with certain restrictions for the corresponding rate constants.

During continuous infusions of 24--48 hours, glycerol utilization and turnover capacity in rats were estimated in a range from physiological to toxic doses. Total clearance, elimination constant, half life, transfer and pool size were calculated for various rates of infusion as well as for the endogenous turnover. With increasing blood level, the turnover rate rises like an enzyme saturation curve, first rapidly and then ever more slowly to a maximum value. Therefore, the steady state blood levels do not increase linearly with the infusion rate. The renal excretion of glycerol is below 1 per cent of the supply up to rates of infusion of 0.4g with kg-1 with h-1. Even beyond the upper limit of the metabolic turnover a steady state is reached due to the high renal excretion. Beginning with 2 mumol/ml the excretion rises linearly with the blood level. At rates higher than 0.5g with kg-1 with h-1 the individual differences of the steady state levels are high. A significant negative correlation between the steady state levels of glycerol in blood and the activity of glycerol kinase in the liver and kidneys was observed. Necroses of the renal tubuli were found at infusion rates exceeding the turnover capacity in animals with low enzyme activity. The conclusions which may be drawn from these data regarding the parenteral supply of energy-yielding substrates are discussed.

Sulfites are added to certain infusion solutions in order to prevent non-enzymic browning and decomposition during sterilization. Sulfites are extremely reactive, pharmacologically active compounds. Some undesired reactions are proven, others are suspected. Of special relevance with regard to the application of sulfite-containing infusion solutions is the destruction of thiamine, a possibly hepatotoxic effect of tryptophan-conversion products, and reports on severe asthmatic reactions. Therefore, declaration of sulfite addition to infusion solutions (calculated as SO2) and a warning notice is recommended.

Michaelis-constants and enzyme activities for dehydrogenation and transamination of the three branched chain alpha-keto acids in liver, kidney, skeletal muscle, and brain of rats are reported. After oral load only 11-22% of the keto acids pass the liver unchanged. Blood levels in pharmacokinetic and absorption studies are related to the Michaelis-constants. At the low keto-acid concentrations after oral application, dehydrogenation in the non-hepatic tissues is supposed to prevail over transamination. Data on feed efficiency of branched chain alpha-keto acids reported in the literature support this view. The chance for transamination is better after intravenous administration. The transferability of our data to humans, and various factors influencing the efficiency of branched chain alpha-keto acids are discussed in connection with data reported in the literature.

The simultaneous determination of alpha-tocopherol and retinol in human serum is reported. The separation is carried out by means of isocratic HPLC on adsorption columns. UV-Detection is possible by using either one wavelength for both compounds (300 nm), or after a lambda change mode with typical wavelengths for alpha-tocopherol (292 nm) and retinol (325 nm). According to short retention times (10 min) and rapid extraction the method is useful for clinical research and allows about 50 analyses per day and operator. Blood from 176 human volunteers was collected and alpha-tocopherol and retinol levels in serum determined with this method. Statistical evaluation of different selected groups shows typical significant differences of alpha-tocopherol and retinol concentrations in smokers and oral contraceptive users.

Young male Sprague-Dawley rats (weighing approximately 170 gs) are entirely maintained by parenteral nutrition over a period of 4 weeks. The nutrient solution - a mixture of amino acids, glucose, fat, electrolytes, vitamins, and trace elements in a composition optimal for rats - is infused by means of a roller pump through a catheter leading to the vena cava and having its outlet in the midscapular region. The animals are provided with a little harness and kept in metabolic cages. They are freely movable during the entire infusion period. The average weight gain with an energy supply of 350 kcal and 1 g N/kg/24 h was recorded to be 3.8g/day. Since the requirement of nitrogen and energy per unit of body weight decreases with growth, nitrogen balance becomes increasingly positive in the course of the experimental period. Cumulative nitrogen retention during 24 days was 4.23 g. Operation techniques, treatment of the animals and composition of the infusion solutions are described in detail.

Concepts of vitamin B6 megatherapy are classified in three categories: 1. megatherapy with well-known mechanism of action; 2. megatherapy with hypothetical or unknown, but nevertheless plausible mechanism of action; 3. megatherapy on the basis of pure speculation. Examples of all three categories are shown. The dosages applied extend from 100 mg up to several grams; the duration of treatment varies from weeks to several years. After long-term intake of high doses toxic effects can occur in the form of peripheral sensory neuropathy, in two reported cases combined with a subepidermal vesicular dermatosis. The threshold above which toxic effects can occur appears to be somewhat between 300 and 500 mg/day; however, systematic investigations in this dose range have never been performed. Furthermore, there appears to be an inverse relationship between the dose and the time up to the occurrence of toxic symptoms. The danger consists less in controlled application by a physician as far as he is aware of the clinical picture of sensory neuropathy. Doses in excess of 500 mg are rarely necessary in specific indications. Unlike this situation, self-medication by laymen on the basis of promises in obscure health magazines is much more risky because the dose is frequently raised more and more up to several grams per day when the expected effect does not occur.

L-thiazolidine-(4)-carboxylic acid (TAC) has proven to be a good substrate for long-term parenteral nutrition. In this study the metabolism of TAC in the rat is examined at subcellular level. TAC is oxidized by mitochondrial proline oxidase of liver and kidney to L-thiazoline-(4)-carboxylic acid, which then is hydrolyzed to N-formyl-cysteine (FCYS). FCYS is hydrolyzed to cysteine and formic acid by a cytosolic enzyme.

Postoperative parenteral nutrition can only be optimally effective if the characteristics of post-traumatic metabolism are taken into account. Two main possibilities are discussed for the carbohydrate component of parenteral nutrition during this phase: glucose with high doses of insulin or non-glucose carbohydrates (sugar substitutes) possibly in a suitable combination with glucose. The risks as well as the technical and organisational problems involved in the use of them are discussed and the authors prefer the second of the two alternatives. Possible side effects of non-glucose carbohydrates are pointed out and it is shown how these can be avoided by observing dose guidelines. So far a combination of frucose : glucose : xylitol in a ratio of 2 : 1 :1 with a total dose of 0.50 g/kg/hour has been studied most thoroughly. This combination normalises the fat metabolism and improves glucose tolerance without requiring exogenous insulin. Experiences with this combination as well as individual non-glucose carbohydrates on operated patients have been given continuously for up to 7 days and in some cases even for several weeks. No side effects, no deviations from a steady state and no abnormal changes of the laboratory values occurred. The authors are of the opinion that non glucose carbohydrates are necessary if the facilities for frequent blood sugar controls are not available.

Morphological investigation of tongue, olfactory epithelia, trachea and inner ear in vitamin A deficiency are reported. The results support assumptions concerning the loss of sensory function as been at least a secondary effect of alterations of the neighbourhood of the sensory cells caused by vitamin A deficiency. Taste buds are hindered in function by a dense layer of squamous cells and olfaction is decreased by atrophy of the surrounding respiratory epithelium. Inner ear functionality seems to be affected by vitamin A status via a stabilizing effect on the endolymph-perilymph barrier.

The cardiovascular, blood gas, acid-base and metabolic changes occurring during operative stress were studied in 10 elderly, metabolically healthy patients, suffering from idiopathic trigeminal neuralgia, who underwent electrocoagulation of the gasserian ganglion under neuroleptanalgesia. In a group of 12 patients undergoing the same operative procedure and anesthesthetic management, we investigated the effects of administration of a beta blocking agent on these parameters. Intraoperative rises of blood pressure and tachycardia were prevented by intravenous administration of 0.4 mg Pindolol (Visken), whereas increases in the blood glucose levels at the end of the operation were the same. The increase of glycerol, free fatty acids and ketone bodies was markedly reduced after pretreatment with the beta blocker compared with the controlgroup. In the patients without beta blocker treatment pH and standard bicarbonate at the end of the operation were lower as the result of the stimulation of ketogenesis.

3-Methylhistidine in a defined amount of meat, consumed by 7 healthy persons is excreted quantitatively in the urine within 2 days. Simultaneously recorded creatinine excretion remained constant in 4 of the participants while in 3 cases a considerable increase was observed during the day of meat consumption. An increase in nitrogen excretion as a result of meat consumption was observed in 5 out of 7 persons.

23 patients received controlled infusions of 10% glycerol solution using an "Infusomat". During various rates of infusion biokinetic parameters and renal excretion were measured. The concentration of glycerol in the serum rises over-proportional with increasing rates of infusion. The extrapolated maximal metabolic turnover capacity is 54 micronmol.kg-1.min-1. Halb-maximal turnover rate is reached at a serum level of 0,56 micronmol.ml-1. After an infusion of 0,3 g.kg-1.min-1 glycerol disappears from the blood with an elimination constant of 0,024 min-1 and a half life of 28,9 minutes. Renal excretion increases with the dose but remains below 10% of the dose in the investigated range. From the data it can be concluded that glycerol cannot be applicated in higher doses than other polyols. No adverse reactions have been observed in the range up to 0,3 g.kg-1.min-1.

Utilization of N-acetyl-L-tryptophan as a source of L-tryptophan is tested in growing rats receiving total parenteral nutrition for twelve days. The three solutions tested are isonitrogenous and isocaloric. Solution 1 contains an adequate amount of L-tryptophan, while in solution 2 two thirds of the L-tryptophan are substituted by a corresponding amount of glycine. In solution 3, the entire L-tryptophan is replaced by N-acetyl-L-tryptophan. Weight gain and nitrogen balance are similar under the infusion with either the adequate amount of L-tryptophan or the N-acetyl-L-tryptophan. The solution 2 in which two thirds of the L-tryptophan are replaced by glycine yields significantly lower results for weight gain and nitrogen retention. The results indicate that tryptophan from N-acetyl-L-tryptophan, when given intravenously, is utilized by the rat for protein synthesis and growth as well as free tryptophan.

The uptake and chemical identification of 14C-retinyl acetate in the inner ear of the guinea-pig after oral administration is reported. For methodological reasons the experiment was carried out in vitamin A-deficient guinea-pigs. In the sensory tissues a time-dependent distribution was found similar to that in other organs. The chemical identification shows that the orally administered labeled retinyl acetate can be detected as retinyl palmitate in the membranous structures of the inner ear. This may be an indication for the ability of the inner ear tissues to esterize and probably store the transport form of vitamin A, retinol.

The estimation of vitamin A in serum of patients suffering from different diseases (M. Crohn, Hypothyroidism, Hyperthyroidism, Liver cirrhosis, Renal insufficiency, Carcinoma of Prostate, ENT-Carcinomas) and healthy controls by means of a recent developed method (HPLC) is reported. Decreased and increased vitamin A serum levels had been reported in literature during different diseases but we could not reveal identical results in all cases. Significantly lowered values were only estimated in patients suffering from liver cirrhosis whereas increased vitamin A serum levels were determined during renal insufficiency. In hypo- or hyperthyroidism there was no difference from healthy persons. In patients with Crohn's disease the distribution of vitamin A concentrations in serum was bimodal, probably depending on extension and localization of the process. Patients with carcinoma of the prostate had only minor deviations from the normal value, whereas patients with tumors of the larynx had in part very low vitamin A concentrations with a bimodal distribution. Causes for the deviations and consequences for the assessment of the vitamin A status of patients under intravenous alimentation are discussed.

The hydroquinone-containing cytostatic compound avarol inhibits predominantly growth of those cell lines which have a low level of superoxide dismutase. The substrate of this enzyme, the superoxide anion, was found to be formed during the in vitro oxidation reaction of avarol to its semiquinone radical in the presence of oxygen. Under the same incubation conditions plasmid DNA (pBR322) was converted from the fully supercoiled circular form mainly to the nicked circular form, indicating that the compound causes primarily single-strand breaks. Using Friend erythroleukemia cells (FLC) it was found that avarol induces a dose-dependent DNA damage; the maximum number of DNA strand breaks was observed at 5 h after addition of the compound to the cells. Removal of avarol resulted in a rapid DNA rejoining with biphasic repair kinetics [first half-time, 8 min (90% of the breaks) and a second half-time, 40 min (10% of the breaks)]. When the degree of avarol-induced DNA damage in FLC was compared with the drug-caused inhibition of cell growth a close correlation was established. Avarol displayed no effect on dimethyl sulfoxide-induced erythrodifferentiation of FLC as determined by the benzidine reaction and by dot blot hybridization experiments. From incubation studies of FLC with [3H]avarol no hint was obtained for the formation of an adduct between DNA and the compound. The subcellular distribution of [3H]avarol was studied in liver cells after i.v. application of the compound. The predominant amount of the compound was present in the cytosolic fraction; little avarol was associated with plasma membranes, nuclei, and mitochondria. Using (a) oxidative phosphorylation and (b) oxygen uptake as parameters for mitochondria function, no effect of the compound on the activity of this organelle was determined. These results suggest that avarol forms superoxide anions (and in consequence possibly also hydroxyl radicals) especially in those cells which have low levels of superoxide dismutase. Moreover, evidence is provided that the active oxygen species cause DNA damage resulting in the observed cytotoxic effect.

Utilization of intravenously administered glutathione disulfide was investigated during long-term parenteral nutrition in growing rats. In a series of cross-over studies, three solutions were tested against one another by recording weight gain, nitrogen balance, and plasma amino acid patterns. Solution 1 contained the required amount of methionine for rats, solution 2 had only one third of the required methionine, but was made isonitrogenous with glycine, whereas in solution 3, two thirds of the methionine was replaced by glutathione disulfide. Weight gain was about twice as high during infusion with either the required amount of methionine or the glutathione disulfide when compared with solution 2. Nitrogen retention was significantly higher during infusion with sufficient methionine or a corresponding amount of glutathione disulfide, when compared with the solution low in methionine. Plasma levels of cystine decreased significantly under the low methionine supply, but no difference was observed for the groups receiving sufficient methionine or the corresponding amount of glutathione disulfide. It is concluded that glutathione disulfide permits adequate cysteine supply in parenteral nutrition and may replace part of the methionine in the presence of an impaired conversion of methionine to cysteine.

In this study the question of whether N-N-diacetylcystine (DAC), which is more stable than N-acetylcysteine (AcCYS), may provide a useful cysteine source for parenteral nutrition was investigated. In in vitro studies the release of cysteine from DAC was measured. The Michaelis, constant and maximum velocity were compared with the corresponding results for AcCYS. In in vivo studies 3 groups of growing rats were maintained entirely by parenteral nutrition low in methionine for 15 days. Group I (n = 4) received a solution containing AcCYS, and group II (n = 6) was supplied with a corresponding amount of DAC. In the solution given to group III (n = 6) the CYS derivative was replaced by an isonitrogeneous amount of glycine. Utilization of the respective CYS derivatives was judged from weight gain, nitrogen balance, plasma amino acid pattern, and urinary excretion of free amino acids. The results from both the in vitro and in vivo studies indicate that DAC is not a suitable substitute for AcCYS in parenteral nutrition.

Utilization of methionine and N-acetyl-L-cysteine as a source of cysteine was tested in growing rats receiving total parenteral nutrition for four weeks. The three solutions tested were isonitrogenous and isocaloric. One of the solutions contained an adequate amount of L-methionine, in the other two, two thirds of the L-methionine was substituted by a corresponding amount of either glycine or N-acetyl-L-cysteine. Weight gain and N-balance were similar under the infusion with either the adequate amount of L-methionine or the N-acetyl-L-cysteine substituted. The solution in which two thirds of the L-methionine was replaced by glycine yielded only half of the weight gain and correspondingly reduced values for N-balance. The daily urinary excretion rate for N-acetyl-L-cysteine was 4.6% of the infused amount. Urinary excretion rates of the other amino acids and the plasma amino acid pattern was affected differently by the three solutions. The results indicate that cysteine is more rapidly available from N-acetyl-L-cysteine than from L-methionine when administered intravenously.

The metabolisms of the sugar substitutes fructose, sorbitol and xylitol and their interdependence with the metabolism of glucose are demonstrated. The metabolic characteristics of these substitutes are discussed with regard to therapeutical utilization. Differences between oral and parenteral administration are shown and finally dosage guidelines for parenteral administration are established on the basis of the different metabolic effects depending on the administered dose.

To estimate the role of vitamin A on ciliated cells we investigated whether ciliated cells undergo any alteration during vitamin A deficiency. The epithelia examined include the ciliated cells of the respiratory tract and the ciliated sensory cells of the inner ear, the tongue, and the olfactory cells. This part of the paper will describe the ciliated epithelium of the tracheobronchial tract and its relation to vitamin A status. During vitamin A deficiency a partial loss of ciliae can be observed before any squamous metaplasia (which usually occurs during longer lasting vitamin A deficiency) develops. The scanning electron microscopic data illustrate the altered surface of the epithelium during vitamin A deficiency better than transmission electron microscopy.

The interactions of fat and carbohydrate metabolism are surveyed. The posttraumatic metabolism is characterized by a stress induced high lipolytic rate and a high concentration of non-esterified fatty acids in the blood. The increased fatty acid oxidation causes by effects of metabolites a catabolic situation with enhanced ketogenesis, gluconeogenesis and protein breakdown. High levels of fatty acids and ketone bodies reduce peripheral glucose utilization. In such a situation, infusions of fat emulsions are disadvantageous, since fatty acids, set free from the triglycerides, would aggravate the catabolic metabolism and change the nitrogen balance for the worse. In normal metabolic situations with high energy need, or in long term parenteral nutrition, fat infusions are necessary to meet the needs of energy and of essential fatty acids. Fat infusions shoudl be combined with carbohydrates and amino acids in an appropriate relation.

The following types of carbohydrate intolerance are discussed as a risk in infusion therapy: Hereditary fructose intolerance, fructose-1,6-biphosphatase deficiency, impairment of glucose utilization during the post-aggression syndrome and/or in latent or overt diabetes mellitus. Asking about symptoms of fructose intolerance has to be part of every routine anamnesis. Application of any kind of carbohydrate requires differential therapeutic considerations. Undiscovered fructose intolerance is more likely the younger the patient is, whereas the frequency of glucose intolerance increases with age. In unconscious patients without anamnesis, fructose or sorbitol should not be applied. Never should an attempt be made to compensate falling blood glucose levels under infusion therapy by application of fructose or sorbitol. As carbohydrate addition to routine fluid and electrolyte substitution xylitol in the specified low dosage is without risk in a diabetes-like metabolic condition as well as in fructose intolerance.

The decrease of ATP-concentration in tissues after rapid intravenous injection is not specific, neither with regard to the organ nor with regard to the substrate. It can be achieved by any substrate which is channeled into metabolism by phosphorylation or activation using ATP, if the organ has the appropriate enzymatic outfit.

Young male rats are randomized into two groups and maintained by total parenteral nutrition with an isocaloric and isonitrogenous regimen for 6 days. Group I receives a 15% amino acid solution containing 17% branched chain amino acids while group II is given a 10% amino acid solution containing 26.6% branched chain amino acids. By this regimen group I receives 1.02 g and group II 1.77 g branched chain amino acids/kg B.W./day. No significant differences are observed in weight gain, nitrogen balance, amino acid excretion and amino acid concentrations in muscle. The higher supply with branched chain amino acids is simply reflected in significant augmented plasma concentrations of these amino acids. Simultaneously there is a significant increase of glycine and threonine in plasma. The infusion of the concentrated amino acid solution is well tolerated by the animals and results in a decreased urinary volume.