Vitamins for babies and young children.

The Welfare Food Scheme has recently been reviewed, and, although changes are being made, free vitamin supplements for children <4 years old will remain an important part of the new "Healthy Start" scheme. Establishing precise daily requirements for vitamins is not easy, and there is considerable individual variation; however, achieving the reference nutrient intake (RNI) should be possible with a healthy balanced diet for all except vitamins K and D, which require additional physiological or metabolic processes. For vitamin K, there is a well-established neonatal supplementation programme, and clinical deficiency is extremely rare. For vitamin D, however, supplementation is inconsistent, and both clinical and subclinical deficiencies are not uncommon in young children in the UK, particularly infants of Asian and Afro-Caribbean ethnic origin, and those who have prolonged exclusive breast feeding and delayed weaning. Most vitamin supplements contain vitamins A, C and D, with or without some of the B group of vitamins. There is clinical and dietary evidence to support vitamin D supplementation and some evidence from dietary surveys that vitamin A intakes may be low; however, there is no evidence to support supplementation of diets of UK children with water-soluble vitamins. Future strategy should aim at education of the public and health professionals regarding dietary intake and physiological aspects of vitamin sufficiency, as well as increasing awareness and availability of supplements, particularly of vitamin D, for those at increased risk of deficiency.

Membrane effects of the n-3 fish oil fatty acids, which prevent fatal ventricular arrhythmias.

Fish oil fatty acids are known to exert beneficial effects on the heart and vascular systems. We have studied the membrane effects on ion channel conductance by the n-3 fish oil fatty acids that account for these beneficial effects. We have confirmed that these fatty acids prevent fatal cardiac arrhythmias in a reliable dog model of sudden cardiac death. This finding was followed by experiments indicating that the n-3 fatty acids electrically stabilize heart cells and do so largely through modulation of the fast voltage-dependent Na(+) currents and the L-type Ca(2+) channels in a manner, which makes the heart cells resistant to arrhythmias. Others and we have demonstrated that these membrane effects on the heart can prevent fatal cardiac arrhythmias in humans.

The antiarrhythmic effect of n-3 polyunsaturated fatty acids: modulation of cardiac ion channels as a potential mechanism.

Sudden cardiac death remains one of the most serious medical challenges in Western countries. Increasing evidence in recent years has demonstrated that the n-3 polyunsaturated fatty acids (PUFAs) can prevent fatal ventricular arrhythmias in experimental animals and probably in humans. Dietary supplement of fish oils or intravenous infusion of the n-3 PUFAs prevents ventricular fibrillation caused by ischemia/reperfusion. Similar antiarrhythmic effects of these fatty acids are also observed in cultured mammalian cardiomyocytes. Based on clinical observations and experimental studies in vitro and in vivo, several mechanisms have been postulated for the antiarrhythmic effect of the n-3 PUFAs. The data from our laboratory and others have shown that the n-3 PUFAs are able to affect the activities of cardiac ion channels. The modulation of channel activities, especially voltage-gated Na(+) and L-type Ca(2+) channels, by the n-3 fatty acids may explain, at least partially, the antiarrhythmic action. It is not clear, however, whether one or more than one mechanism involves the beneficial effect of the n-3 PUFAs on the heart. This article summarizes our recent studies on the specific effects of the n-3 PUFAs on cardiac ion channels. In addition, the effect of the n-3 PUFAs on the human hyperpolarization-activated cyclic-nucleotide-modulated channel is presented.

Brain uptake and utilization of fatty acids: applications to peroxisomal biogenesis diseases.

The brain is rich in diverse fatty acids saturated, monounsaturated and polyunsaturated fatty acids with chain lengths ranging from less than 16 to more than 24 carbons that make up the complex lipids present in this organ. While some fatty acids are derived from endogenous synthesis, others must come from exogenous sources. The mechanism(s) by which fatty acids enter cells has been the subject of much debate. While some investigators argue for a protein-mediated process, others suggest that simple diffusion is sufficient. In the brain, uptake is further complicated by the presence of the blood-brain barrier. Brain fatty acid homeostasis is disturbed in many human disorders, as typified by the peroxisomal biogenesis diseases. A workshop designed to bring together researchers from varied backgrounds to discuss these issues in an open forum was held in March, 2000. In addition to assessing the current state of knowledge, areas requiring additional investigation were identified and recommendations for future research were made. A brief overview of the invited talks is presented here.

Diet and sudden cardiac death.

The purpose of this paper is to review the evidence that dietary factors, namely the ingestion of the n-3 (or w-3) polyunsaturated fatty acids of fish oils can prevent fatal cardiac arrhythmias (so-called sudden cardiac death) in experimental animals, and probably in humans as well. The mechanism for this striking effect results from the ability of these fatty acids to directly stabilize electrically every contractile myocyte in the heart. This is accomplished by modulation by the free n-3 fatty acids of the ionic currents in heart cells; particularly the voltage-dependent sodium currents which initiate action potentials and the L-type calcium currents, which initiate release of sarcoplasmic reticulum stores of calcium into the cytosol of heart cells. The resultant rise in cytosolic calcium concentration initiates contraction of the heart cells and the beating rate of the heart. The gradually accumulating clinical evidence that these fish oil fatty acids are potent preventors of cardiac sudden death in humans will be reviewed. With some 250,000 deaths occurring within one hour of the onset of acute myocardial infarctions annually in the USA alone and millions more in the whole world, the potential large public health benefit from this understanding is evident.

Emergency treatment of neonatal hyperammonaemic coma with mild systemic hypothermia.

An infant aged 3 days presented with hyperammonaemic coma and seizures, which were found to be a result of a urea-cycle defect. Haemofiltration, alternative pathway metabolites, and glucose and insulin failed to lower the plasma ammonia concentration below 2000 micromol/L. The infant was then cooled to a rectal temperature of 34 degrees C for 48 h and put on haemofiltration for 12 h. Plasma ammonia fell to around 100 micromol/L and remained at this concentration after haemofiltration. He roused from his coma, breathed spontaneously, and resumed bottle feeding. Hypothermia may be therapeutic in such instances of metabolic coma because it lowers the enzymatic rate of production of the toxin while non-enzymatic methods remove the toxin.

Partitioning of polyunsaturated fatty acids, which prevent cardiac arrhythmias, into phospholipid cell membranes.

It has been demonstrated in animal studies that polyunsaturated fatty acids (PUFA) prevent ischemia-induced malignant ventricular arrhythmias, a major cause of sudden cardiac death in humans. To learn how these PUFA, at low micromolar concentrations, exert their antiarrhythmic activity, we studied their effects in vitro on the contractions of isolated cardiac myocytes and the conductances of their sarcolemmal ion channels. These fatty acids directly stabilize electrically every cardiac myocyte by modulating the conductances of specific ion channels in their sarcolemma. In this study, we determined the molar ratio of PUFA to the moles of phospholipid (PL) in cell membranes to learn if the ratio is so low as to preclude the possibility that the primary site of action of PUFA is on the packing of the membrane PL. [(3)H]-arachidonic acid (AA) was used to measure the incorporation of PUFA, and the inorganic phosphorous of the PL was determined as a measure of the moles of PL in the cell membrane. Our results indicate that the mole percent of AA to moles of phospolipid is very low (< or =1.0) at the concentrations that affect myocyte contraction and the conductance of voltage-dependent Na(+) and L-type Ca(2)+ channels in rat cardiomyocytes and in alpha-subunits of human myocardial Na(+) channels. In conclusion, it seems highly unlikely that these fatty acids are affecting the packing of PL within cell membranes as their way of modulating changes in cell membrane ion currents and in preventing arrhythmias in our contractility studies. -- Pound, E. M., J. X. Kang, and A. Leaf. Partitioning of polyunsaturated fatty acids, which prevent cardiac arrhythmias, into phospholipid cell membranes. J. Lipid Res. 2001. 42: 346--351.

The electrophysiologic basis for the antiarrhythmic and anticonvulsant effects of n-3 polyunsaturated fatty acids: heart and brain.

The n-3 polyunsaturated fatty acids (PUFA) have been shown to be antiarrhythmic in animals and probably in humans. PUFA stabilize the electrical activity of isolated cardiac myocytes by modulating sarcolemmal ion channels, so that a stronger electrical stimulus is required to elicit an action potential and the refractory period is markedly prolonged. Inhibition of voltage-dependent sodium currents, which initiate action potentials in excitable tissues, and of the L-type calcium currents, which initiate release of sarcoplasmic calcium stores, thus increasing cytosolic free calcium concentrations and activating the contractile proteins in myocytes, appears at present to be the probable major antiarrhythmic mechanisms of PUFA. Because the ion channels in neurons have channel proteins essentially homologous to those in the heart, the n-3 fatty acids would appear to be likely to affect the electrical activity in the brain in a manner similar to their effects in the heart, and accumulating evidence supports this notion. Evidence of important beneficial neurological effects of dietary n-3 PUFA are emerging with more likely to be discovered.

The antiarrhythmic and anticonvulsant effects of dietary N-3 fatty acids.

It has been shown in animals and probably in humans, that n-3 polyunsaturated fatty acids (PUFAs) are antiarrhythmic. We report recent studies on the antiarrhythmic actions of PUFAs. The PUFAs stabilize the electrical activity of isolated cardiac myocytes by modulating sarcolemmal ion channels, so that a stronger electrical stimulus is required to elicit an action potential and the refractory period is markedly prolonged. Inhibition of voltage-dependent sodium currents, which initiate action potentials in excitable tissues, and of the L-type calcium currents, which initiate release of sarcoplasmic calcium stores that increase cytosolic free calcium concentrations and activate the contractile proteins in myocytes, appear at present to be the probable major antiarrhythmic mechanism of the PUFAs.

n-3 fatty acids in the prevention of cardiac arrhythmias.

In animals and probably in humans n-3 polyunsaturated fatty acids (PUFA) are antiarrhythmic. A report follows on the recent studies of the antiarrhythmic actions of PUFA. The PUFA stabilize the electrical activity of isolated cardiac myocytes by inhibiting sarcolemmal ion channels, so that a stronger electrical stimulus is required to elicit an action potential and the relative refractory period is markedly prolonged. This appears at present to be the probable major antiarrhythmic mechanism of PUFA.

Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs.

BACKGROUND: Rat diets high in fish oil have been shown to be protective against ischemia-induced fatal ventricular arrhythmias. Increasing evidence suggests that this may also apply to humans. To confirm the evidence in animals, we tested a concentrate of the free fish-oil fatty acids and found them to be antiarrhythmic. In this study, we tested the pure free fatty acids of the 2 major dietary omega-3 polyunsaturated fatty acids in fish oil: cis-5,8,11,14, 17-eicosapentaenoic acid (C20:5omega-3) and cis-4,7,10,13,16, 19-docosahexaenoic acid (C22:6omega-3), and the parent omega-3 fatty acid in some vegetable oils, cis-9,12,15-alpha-linolenic acid (C18:3omega-3), administered intravenously on albumin or a phospholipid emulsion. METHODS AND RESULTS: The tests were performed in a dog model of cardiac sudden death. Dogs were prepared with a large anterior wall myocardial infarction produced surgically and an inflatable cuff placed around the left circumflex coronary artery. With the dogs running on a treadmill 1 month after the surgery, occlusion of the left circumflex artery regularly produced ventricular fibrillation in the control tests done 1 week before and after the test, with the omega-3 fatty acids administered intravenously as their pure free fatty acid. With infusion of the eicosapentaenoic acid, 5 of 7 dogs were protected from fatal ventricular arrhythmias (P<0.02). With docosahexaenoic acid, 6 of 8 dogs were protected, and with alpha-linolenic acid, 6 of 8 dogs were also protected (P<0.004 for each). The before and after control studies performed on the same animal all resulted in fatal ventricular arrhythmias, from which they were defibrillated. CONCLUSIONS: These results indicate that purified omega-3 fatty acids can prevent ischemia-induced ventricular fibrillation in this dog model of sudden cardiac death.

Dietary n-3 fatty acids in the prevention of cardiac arrhythmias.

It has been shown that in animals, and probably in humans, n-3 polyunsaturated fatty acids (PUFAs) are antiarrhythmic. We discuss recent studies on the antiarrhythmic actions of polyunsaturated fatty acids. Polyunsaturated fatty acids stabilize the electrical activity of isolated cardiac myocytes by inhibiting sarcolemmal ion channels so that a stronger electrical stimulus is required to elicit an action potential and the relative refractory period is markedly prolonged. This appears at present to be the probable major antiarrhythmic mechanism of polyunsaturated fatty acids.

Prevention of ischemia-induced cardiac sudden death by n-3 polyunsaturated fatty acids in dogs.

The objective of this study was to obtain functional information associated with the prevention by n-3 polyunsaturated fatty acids (PUFA) of ischemia-induced fatal cardiac ventricular arrhythmias in the intact, conscious, exercising dog. Thirteen dogs susceptible to ischemia-induced ventricular fibrillation were prepared surgically by ligation of their anterior descending left coronary artery and placement of an inflatable cuff around their left circumflex artery. After 4 wk of recovery, exercise-plus-ischemia tests were performed without and then with an intravenous infusion of an emulsion of free n-3 PUFA just prior to occluding the left circumflex artery while the animals were running on a treadmill. One week later the exercise-plus-ischemia test was repeated but with a control infusion replacing the emulsion of n-3 PUFA. The infusion of the free n-3 PUFA in quantities of 1.0 to 10 g prevented ventricular fibrillation in 10 of the 13 dogs tested (P < 0.005), apparently without esterification of the PUFA into membrane phospholipids. The antiarrhythmic effect of the n-3 PUFA was associated with slowing of the heart rate, shortening of the QT-interval (electrical action potential duration), reduction of left ventricular systolic pressure, and prolongation of the electrocardiographic atrial-ventricular conduction time (P-R interval). These effects are comparable with those we have reported in studies with cultured neonatal rat cardiac myocytes.

Regulation of sodium channel gene expression by class I antiarrhythmic drugs and n - 3 polyunsaturated fatty acids in cultured neonatal rat cardiac myocytes.

Previous studies have shown that chronic administration of class I antiarrhythmic drugs, which have definite inhibitory action on the fast Na+ channel, result in up-regulation of cardiac Na+ channel expression, and suggest that this effect may contribute to their deleterious effects during chronic administration. Recent studies have shown that the antiarrhythmic effects of free n - 3 polyunsaturated fatty acids (PUFA) are associated with an inhibition of the Na+ channel. Whether the PUFA when used chronically will mimic the effect of the class I drugs on the expression of the Na+ channel is not known. To answer this question, we determined the level of mRNA encoding cardiac Na+ channels and the number of the Na+ channels per cell in cultured neonatal rat cardiac myocytes after supplementation of the cells with the n - 3 PUFA eicosapentaenoic acid (EPA), the class I drug mexiletine, or both EPA and mexiletine for 3-4 days. The number of sodium channels was assessed with a radioligand binding assay using the sodium channel-specific toxin [3H]batrachotoxinin benzoate ([3H]BTXB). The supplementation of myocytes with mexiletine (20 microM) induced a 4-fold increase in [3H]BTXB specific binding to the cells. In contrast, chronic treatment with EPA (20 microM) alone did not significantly affect [3H]BTXB binding. However, the combination of EPA with mexiletine produced a 40-50% reduction in the [3H]BTXB binding, compared with that seen with mexiletine alone. RNA isolated from cardiac myocytes was probed with a 2.5-kb cRNA transcribed with T7 RNA polymerase from the clone Na-8.4, which encodes nucleotides 3361-5868 of the alpha-subunit of the R(IIA) sodium channel subtype. The changes in the level of mRNA encoding sodium channel alpha-subunit were correlated with comparable changes in sodium channel number in the cultured myocytes, indicating that regulation of transcription of mRNA or its processing and stability is primarily responsible for the regulation of sodium channel number. These data demonstrate that chronic EPA treatment not only does not up-regulate the cardiac sodium channel expression but also reduces the mexiletine-induced increase in the cardiac sodium channel expression.

Dietary n-3 fatty acids in the prevention of lethal cardiac arrhythmias.

It has been shown in animals and probably in humans that the n-3 polyunsaturated fatty acids are antiarrhythmic. We report recent studies on the mechanism(s) by which the polyunsaturated fatty acids exert their antiarrhythmic effects. The polyunsaturated fatty acids stabilize the electrical activity of isolated cardiac myocytes by inhibiting sarcolemmal ion channels, so that a stronger electrical stimulus is then required to elicit an action potential and a contraction of the myocyte. This appears at present to be the probable major antiarrhythmic mechanism of the polyunsaturated fatty acids.