Medical Hypotheses I Medical ffypotheses (1991) 34, 1860 Lonnman Grow UK Ltd 1991
189
Sudden Infant Death Syndrome Factor
(SIDS): A Time Lag
G.M. REID 25 Gilchrist Street,
Te Aroha,
New
Zealand
Abstract - A time lag factor of about five days has been identified in an increased incidence of SIDS in relation to a cold day (I 1. Sudden exposure to chilling appeared to trigger skeletal muscle weakness and renal failure about five days later in a man found to have only 25% of normal camitine palmitoyl transferase (CPT) activity in biopsied skeletal muscle (2). White Muscle Disease is a muscular dystrophy in young ruminants which appears about five days after turnout to pasture in the weaned ruminant raised on a diet deficient in vitamin E and selenium (VESD) (3, 4). Pasture has high levels of linoleic and linolenic acid (high PUFA diet) which are modified by developing rumen bacteria. Corbucci (5) investigated the effects of circulatory shock (cardiogenic) on skeletal muscle mitochondrial activity in humans. Cytochrome oxidase activity fell markedly and, in particular, the capacity to oxidase palmitoyl carnitine was greatly reduced. He considered a consequence of this disorder was sequestration of carnitine as acyl carnitine which could not be recycled. Unusual acyl carnitines have been identified in six out of 13 SIDS victims in a USA group (6). In Finland, researchers (7) identified a rise in SIDS incidence (mostly found in the prone position) after great and rapid temperature changes. Foster (8) found a relationship between 1984 SIDS incidence and the incidence of goitre in World War I troops.
Introduction
Warshaw (9) described cellular energy metabolism and the development of mitochondrial activity as a function of age, of cytochrome oxidase activity in relation to increased aerobic metabolism and energy needs in the post-natal period. The development of CPT and cytochrome oxidase activity were indices of mitochondrial function in the chick and the rat. He states that in view of the Date received 26 June 1990 Date accepted 22 August 1990
increasing cytochrome oxidase activity in the postnatal period, the changes in fatty acid oxidation probably reflect absolute increases in mitochondrial number during development as well as increases in enzyme specific activity. The thyroid hormone also leads to development and an increase in oxygen consumption, and an increase in size, number and metabolic activity of mitochondria in mammalian skeletal muscle and a sustained increase in thermogenesis (10).
187
SlJDDEN INFANT DEATH SYNDROME: A TIME LAG FACTOR
Chilling (2) increased the demand for heat and energy from fatty acid oxidation in skeletal muscle. Owing to a defect in CPT enzyme with only 25% of normal activity the carnitine pathway to fatty acid oxidation of long chain fatty acids (LCFA) failed to meet the increased metabolic demand after sudden chilling. Similarly, following circulatory shock (oligemic shock), cytochrome oxidase activity in skeletal muscle mitchondria fell and oxidation of palmitoyl carnitine fell but responded to carnitine medication (5). Likewise, oxidation of palmitoyl carnitine was higher in selenium supplemented lambs fed a VESD diet compared to Se deficient lambs developing White Muscle Disease (WMD). Fatty acid oxidation was measured in skeletal muscle mitochondria and Se was protective (11). The biosynthesis of palmitoyl-carnitine had an absolute requirement for CoA and ATP, whereas magnesium had a stimulating effect (20). ATP is catabolised in ischemia (17). Magnesium tetany is a disease of livestock exposed to environmental stresses, particularly storms and lack of food. There is a time lag of about three days between a storm and the onset of magnesium tetany in ruminant animals. It is suggested that the extra energy needs in chilling via the carnitine pathway in muscle are stimulated by magnesium.
3.
4.
5.
Discussion
Several metabolic disorders reduce the oxidation of palmitoyl carnitine, in particular in skeletal muscle mitochonria. The LCFA’s permeate mitochondrial membranes as carnitine esters. The LCFA’s ultimately undergo beta oxidation inside the mitochondrial membrane to produce adenosine tri-phosphate (ATP). There are two CPT enzymes involved in LCFA transport. Type 2 CPT is located on the inside of the membrane and catalyses the formation of LCF acyl co-enzyme A. Failure of energy generation in muscle leads to muscle necrosis (2). 1.
2.
A genetic deficiency of CPT in the man who fell into the cold mountain lake led to muscle necrosis and renal failure in about five days (2). Another patient with the same genetic deficiency developed respiratory failure (necrosis in intercostal muscle and myoglobinuria) following an infection (12). These patients responded to carnitine therapy. Corbucci described the effect of circulatory shock on skeletal muscle mitochondria. These
6.
7.
patients responded to carnitine therapy and, like the previous patients, oxidation of palmitoy1 carnitine increased. Lambs with WMD also had a reduced capacity to oxidise palmitoyl carnitine in skeletal muscle mitochondria (11). Se supplementation prevented the disease which was more prevalent in cold, windy weather along with a high LCFA diet. There is always a trigger factor in the VESD diseases. VESD merely renders muscle liable to degeneration when environmental stresses are superimposed (4). Triggers are cold, infection, antibiotics, iron and free radicals such as are generated in ischemia and inflammation. Increasing oxygen consumption leads to increased development, size, number and metabolic activity of mitochondria in muscle (9). Thyroid hormone leads to development and increased oxygen consumption and to increase in size, number and metabolic activity in mammalian skeletal muscle and to a sustained increase in thermogenesis (10). In other words, thyroid hormones promote the development of the carnitine pathway to LCFA oxidation in muscle cell mitochondria in the early post-natal period. As babies do not shiver they need to fall back on the non-shivering thermogenesis of active sodium transport and thyroid thermogenesis which utilises ATP (13). Now Foster (8) produces geographical evidence of SIDS (1984) relationship in USA to goitre incidence in World War I troops. There was a high positive correlation with selenium enriched soils, with iodine (I) deficient soils and soils high in strontium and sodium. (The glacial washed and leached soils and gravels in New Zealand are deficient in both Se and I and the SIDS mortality map 1984 USA points to soils and water of similar origins). It is now said that unless people in low Se areas in New Zealand eat fish, eggs, liver or kidney, then Se intakes can be as low as those reported in the very low Se areas in China (14). Shorrocks (14) states that a new role of Se has been found to be associated with I in the thyroid gland in the production of thyroid hormones. In Zaire Se shortage has been found to exacerbate I deficiency.
The time lag factor in relation to SIDS and a cold day may involve thyroid related mitochondrial development in skeletal muscle.
188 Selenium is now known to promote prostacyclin synthesis when arachidonate levels are elevated in bacterial infections (15) and ischemia, which also activates a phospholipase (5). Corbucci states that phospholipase activity results from free radical peroxidation of mitochondrial phospholipids in circulatory shock (5). Phospholipase enzymes in various bacteria liberate arachidonic acid esters in infected placental membranes (15). These esters lead to prostaglandin synthesis and premature labour in pregnant women. The metabolic activity of arachidonic acid is impaired in Se deficient mice (16). Additional arachidonate induced respiratory distress in mice. The distress was aggravated in the Se deficient group compared to controls. It was considered that the high arachidonate/Se ratio impaired prostacyclin synthesis in the arterial wall, inducing vasoconstriction of the microcirculation. Conclusion
Patients stressed by circulatory shock, sudden chilling or infection, had a reduced capacity to oxidase LCFA’s in mitochondria via the carnitine pathway. Young weaned ruminants on a high PUFA and VESD diet also developed similar mitochondrial lesions in skeletal muscle. The human patients responded to carnitine medication. The circulatory shock patients also responded to allopurinol, an inhibitor of the superoxide-producing enzyme, xanthine oxidase, formed during inflammation and in post-ischemic tissue injury (17). It is significant that B-carotene inhibits lipid peroxidations that have been initiated by xanthine oxidase (18). B-carotene is complementary to vitamin E, being effective at low oxygen concentration while vitamin E is effective at high oxygen concentration (18). B-carotene is a more effective anti-oxidant in tissue more remote from the blood supply (18). Significantly, Se and I compounds are quite volatile and a low Se content of infant formulae may be caused by processing (19). In areas where Se and I in water are also low, the Se and I intake of infants’ milk processed by dry heat may be low (19). The high incidence of six out of 13 SIDS victims with unusual acylcarnitine in urine at time of death suggest that the inherited disorders of carnitine metabolism may be similar to the sequestration of acyl-carnitines in circulatory shock. There seems to be a time lag factor in the development of defective skeletal muscle mitochondria as in WMD in weaned calves (five days, which is
MEDICAL HYPOTHESES
similar to the rise in SIDS incidence after a cold day). Unless cytochrome oxidase activity (copper enzyme) is adequate, this terminal link in the respiratory chain in mitochondria will not provide enough energy to drive biochemical reactions. The cytochromes are no longer oxidised or reduced. Tissue anoxia is the bottom line in cytochrome oxidase deficiency. Thyroid hormone promotes oxygen utilisation in mitochondria and Se protects membranes. B-carotene is an effective anti-oxidant in lipid peroxidations initiated by xanthine oxidase which generates oxygen radicals. It is suggested that the time lag factor in increased incidence of SIDS about five days after a cold day is skeletal muscle degeneration with origins in mitochondria, as in cold and circulatory shock in humans and WMD in weaned ruminants within five days. It is again pointed out that the VESD diseases only render muscle liable to degeneration when environmental stresses are superimposed (4). An example of a superimposed stress is the rise in SIDS victims in Finland (7) following great and rapid temperature falls in November and December, when victims are found in the prone position with no apparent cause of death. Examples of superimposed stress on muscle are the biochemical metabolic disorders of LCFA’s involving the carnitine detoxification of toxic acylCoA compounds (6). It is proposed that carnitine, allopurinol, Bcarotene and selenium all reduce the free radical injury to mitochondrial membranes in the muscle disorders and that thyroid hormones are required for mitochondrial development in the early post-natal period. All these factors are likely to be linked with SIDS and the time lag factor, associated with muscle respiratory decline. The catabolism of ATP during ischemia deprives mitochondria of ATP and impairs the biosynthesis of palmitoyl carnitine and the oxidation of free fatty acids. Magnesium stimulates this process. In livestock farming, magnesium tetany develops about three days after storms and lack of food. All these factors are required to maintain the energy needs of muscle cells. Inadequate oxidation of palmitoyl carnitine is recognised in livestock and in man in the presence of various triggering agents with a time lag factor. Acknowledgement This discussion paper is dedicated to the late Stuart F Reid.
SUDDEN INFANT DEATH SYNDROME:
A TIME LAG FACTOR
References 1. Campbell Michael .I. Sudden Infant Death Syndrome and environmental temperature. Further evidence for a timelagged relationship. Med. J. Aust., 151, pp 365 - 7, October 1989. 2. Brownell A K W, Severson D L, Thompson C D and Fletcher T. Cold Induced Rhabdomyolysis in Carnitine palmutyl Transferase Deficiency. Le Journal des Sciences Neurologiques, 6, 3, pp367 - 70, 1979. 3. McMurray C H and D A Rice. Vitamin E and selenium deficiency diseases. Irish Veterinary Journal 36, pp 57 - 67, 1982. 4. Bradley R. Skeletal Muscle in Health and Disease, In Practice, 5 - 13, march 1981. 5. Corbucci G G, Gasparetto A, Crimi G, Antonelli N, Bufi M, De Blasi R A, Cooper N B and Gohil K. Shock-induced Damage to Mitochondrial Function and Some Cellular Antioxidant Mechanisms in Humans. Circulatory Shock, 15, pp 15-26, 1985. 6. Roe Ch R, Gale R S, Kozakewich H P W, Morton D H and Mandell F. Sudden Infant Death Syndrome: The Role of Inherited Disorders. p.74 (Abstract) in Proc. Sudden Infant Death Syndrome Conference, Graz, Austria, 1988. 7. Tiainen E. Sudden Infant Death in Southern Finland. p64 (Abstract), in Proc. Sudden infant Death Syndrome Conference, Graz, Austria, 1988. 8. Foster H P. Sudden Infant Death Syndrome and Iodine Deficiency: Geographical Evidence. J Orthomolecular Medicine, 3, 4, pp 207 - 11, 1988. 9. Warshaw J B. Cellular Energy Metabolism During Foetal Development. Developmental Biology, 28, pp 537 - 44,
189 1972. 10. Underwood E J. Trace Elements in Human and Animal Nutrition, 4th Edition. ~280. Academic Press N.Y., 1977. 11. Godwin K 0, Kuchel R E and Fuss C. Some Biochemical Features of White Muscle Disease in Lambs and the lnfluence of Selenium. Aust. J. Biol. Sci., 27, pp 633-43, 1974. 12. Bertorini T, Yeh Y Y, Trevisan C, Stradlan E, Sabesin S and DiMauro S. Carnitine Palmityl Transferase Deficiency, Myogiobinuria and Respiratory Failure. Neurol 30, ~263-71, 1980. 13. Edelman I S and lsmail-Beigi F. Thyroid Thermogenesis and Active Sodium Transport. Recent Progress in Hormone Research, 30, pp235 - 7, 1974. 14. Shorrocks V M, In Micronutrient News, 10, 2, ~13, 1990. 15. Bejar R, Curbelo V, Davis C and Gluck L. Premature Labour II: Bacterial Sources of Phospholipase. Obstet Gynecol, 57, pp479 - 82, 1981. 16. Masukawa T, Gotto T and lwata H. Impaired metabolism of arachidonate in selenium deficient animals. Experimentia, 39, pp405 -6, 1983. 17. McCord J M and Roy R S. The Pathophysiology of Superoxide: Roles in Inflammation and ischemia. Can. J Physical Pharmacol, 60, pp 1341-52, 1982. 18. Burton G W and lngold K U. B-Carotene: An unusual type of lipid antioxidant. Science, 224, pp569 -- 73, 1984. 19. Lombeck I, Kasperek G, Harbisch H D, Feinendegen T E and Bremer H J. The Selenium State of Healthy Children. Europ J Pediatrics, 125, pp81- 8, 1977. 20. Bremer J. Carnitine in Intermediary Metabolism. J. Bioi Chem, 238, 8, pp2774-9, 1963.
189
Sudden Infant Death Syndrome Factor
(SIDS): A Time Lag
G.M. REID 25 Gilchrist Street,
Te Aroha,
New
Zealand
Abstract - A time lag factor of about five days has been identified in an increased incidence of SIDS in relation to a cold day (I 1. Sudden exposure to chilling appeared to trigger skeletal muscle weakness and renal failure about five days later in a man found to have only 25% of normal camitine palmitoyl transferase (CPT) activity in biopsied skeletal muscle (2). White Muscle Disease is a muscular dystrophy in young ruminants which appears about five days after turnout to pasture in the weaned ruminant raised on a diet deficient in vitamin E and selenium (VESD) (3, 4). Pasture has high levels of linoleic and linolenic acid (high PUFA diet) which are modified by developing rumen bacteria. Corbucci (5) investigated the effects of circulatory shock (cardiogenic) on skeletal muscle mitochondrial activity in humans. Cytochrome oxidase activity fell markedly and, in particular, the capacity to oxidase palmitoyl carnitine was greatly reduced. He considered a consequence of this disorder was sequestration of carnitine as acyl carnitine which could not be recycled. Unusual acyl carnitines have been identified in six out of 13 SIDS victims in a USA group (6). In Finland, researchers (7) identified a rise in SIDS incidence (mostly found in the prone position) after great and rapid temperature changes. Foster (8) found a relationship between 1984 SIDS incidence and the incidence of goitre in World War I troops.
Introduction
Warshaw (9) described cellular energy metabolism and the development of mitochondrial activity as a function of age, of cytochrome oxidase activity in relation to increased aerobic metabolism and energy needs in the post-natal period. The development of CPT and cytochrome oxidase activity were indices of mitochondrial function in the chick and the rat. He states that in view of the Date received 26 June 1990 Date accepted 22 August 1990
increasing cytochrome oxidase activity in the postnatal period, the changes in fatty acid oxidation probably reflect absolute increases in mitochondrial number during development as well as increases in enzyme specific activity. The thyroid hormone also leads to development and an increase in oxygen consumption, and an increase in size, number and metabolic activity of mitochondria in mammalian skeletal muscle and a sustained increase in thermogenesis (10).
187
SlJDDEN INFANT DEATH SYNDROME: A TIME LAG FACTOR
Chilling (2) increased the demand for heat and energy from fatty acid oxidation in skeletal muscle. Owing to a defect in CPT enzyme with only 25% of normal activity the carnitine pathway to fatty acid oxidation of long chain fatty acids (LCFA) failed to meet the increased metabolic demand after sudden chilling. Similarly, following circulatory shock (oligemic shock), cytochrome oxidase activity in skeletal muscle mitchondria fell and oxidation of palmitoyl carnitine fell but responded to carnitine medication (5). Likewise, oxidation of palmitoyl carnitine was higher in selenium supplemented lambs fed a VESD diet compared to Se deficient lambs developing White Muscle Disease (WMD). Fatty acid oxidation was measured in skeletal muscle mitochondria and Se was protective (11). The biosynthesis of palmitoyl-carnitine had an absolute requirement for CoA and ATP, whereas magnesium had a stimulating effect (20). ATP is catabolised in ischemia (17). Magnesium tetany is a disease of livestock exposed to environmental stresses, particularly storms and lack of food. There is a time lag of about three days between a storm and the onset of magnesium tetany in ruminant animals. It is suggested that the extra energy needs in chilling via the carnitine pathway in muscle are stimulated by magnesium.
3.
4.
5.
Discussion
Several metabolic disorders reduce the oxidation of palmitoyl carnitine, in particular in skeletal muscle mitochonria. The LCFA’s permeate mitochondrial membranes as carnitine esters. The LCFA’s ultimately undergo beta oxidation inside the mitochondrial membrane to produce adenosine tri-phosphate (ATP). There are two CPT enzymes involved in LCFA transport. Type 2 CPT is located on the inside of the membrane and catalyses the formation of LCF acyl co-enzyme A. Failure of energy generation in muscle leads to muscle necrosis (2). 1.
2.
A genetic deficiency of CPT in the man who fell into the cold mountain lake led to muscle necrosis and renal failure in about five days (2). Another patient with the same genetic deficiency developed respiratory failure (necrosis in intercostal muscle and myoglobinuria) following an infection (12). These patients responded to carnitine therapy. Corbucci described the effect of circulatory shock on skeletal muscle mitochondria. These
6.
7.
patients responded to carnitine therapy and, like the previous patients, oxidation of palmitoy1 carnitine increased. Lambs with WMD also had a reduced capacity to oxidise palmitoyl carnitine in skeletal muscle mitochondria (11). Se supplementation prevented the disease which was more prevalent in cold, windy weather along with a high LCFA diet. There is always a trigger factor in the VESD diseases. VESD merely renders muscle liable to degeneration when environmental stresses are superimposed (4). Triggers are cold, infection, antibiotics, iron and free radicals such as are generated in ischemia and inflammation. Increasing oxygen consumption leads to increased development, size, number and metabolic activity of mitochondria in muscle (9). Thyroid hormone leads to development and increased oxygen consumption and to increase in size, number and metabolic activity in mammalian skeletal muscle and to a sustained increase in thermogenesis (10). In other words, thyroid hormones promote the development of the carnitine pathway to LCFA oxidation in muscle cell mitochondria in the early post-natal period. As babies do not shiver they need to fall back on the non-shivering thermogenesis of active sodium transport and thyroid thermogenesis which utilises ATP (13). Now Foster (8) produces geographical evidence of SIDS (1984) relationship in USA to goitre incidence in World War I troops. There was a high positive correlation with selenium enriched soils, with iodine (I) deficient soils and soils high in strontium and sodium. (The glacial washed and leached soils and gravels in New Zealand are deficient in both Se and I and the SIDS mortality map 1984 USA points to soils and water of similar origins). It is now said that unless people in low Se areas in New Zealand eat fish, eggs, liver or kidney, then Se intakes can be as low as those reported in the very low Se areas in China (14). Shorrocks (14) states that a new role of Se has been found to be associated with I in the thyroid gland in the production of thyroid hormones. In Zaire Se shortage has been found to exacerbate I deficiency.
The time lag factor in relation to SIDS and a cold day may involve thyroid related mitochondrial development in skeletal muscle.
188 Selenium is now known to promote prostacyclin synthesis when arachidonate levels are elevated in bacterial infections (15) and ischemia, which also activates a phospholipase (5). Corbucci states that phospholipase activity results from free radical peroxidation of mitochondrial phospholipids in circulatory shock (5). Phospholipase enzymes in various bacteria liberate arachidonic acid esters in infected placental membranes (15). These esters lead to prostaglandin synthesis and premature labour in pregnant women. The metabolic activity of arachidonic acid is impaired in Se deficient mice (16). Additional arachidonate induced respiratory distress in mice. The distress was aggravated in the Se deficient group compared to controls. It was considered that the high arachidonate/Se ratio impaired prostacyclin synthesis in the arterial wall, inducing vasoconstriction of the microcirculation. Conclusion
Patients stressed by circulatory shock, sudden chilling or infection, had a reduced capacity to oxidase LCFA’s in mitochondria via the carnitine pathway. Young weaned ruminants on a high PUFA and VESD diet also developed similar mitochondrial lesions in skeletal muscle. The human patients responded to carnitine medication. The circulatory shock patients also responded to allopurinol, an inhibitor of the superoxide-producing enzyme, xanthine oxidase, formed during inflammation and in post-ischemic tissue injury (17). It is significant that B-carotene inhibits lipid peroxidations that have been initiated by xanthine oxidase (18). B-carotene is complementary to vitamin E, being effective at low oxygen concentration while vitamin E is effective at high oxygen concentration (18). B-carotene is a more effective anti-oxidant in tissue more remote from the blood supply (18). Significantly, Se and I compounds are quite volatile and a low Se content of infant formulae may be caused by processing (19). In areas where Se and I in water are also low, the Se and I intake of infants’ milk processed by dry heat may be low (19). The high incidence of six out of 13 SIDS victims with unusual acylcarnitine in urine at time of death suggest that the inherited disorders of carnitine metabolism may be similar to the sequestration of acyl-carnitines in circulatory shock. There seems to be a time lag factor in the development of defective skeletal muscle mitochondria as in WMD in weaned calves (five days, which is
MEDICAL HYPOTHESES
similar to the rise in SIDS incidence after a cold day). Unless cytochrome oxidase activity (copper enzyme) is adequate, this terminal link in the respiratory chain in mitochondria will not provide enough energy to drive biochemical reactions. The cytochromes are no longer oxidised or reduced. Tissue anoxia is the bottom line in cytochrome oxidase deficiency. Thyroid hormone promotes oxygen utilisation in mitochondria and Se protects membranes. B-carotene is an effective anti-oxidant in lipid peroxidations initiated by xanthine oxidase which generates oxygen radicals. It is suggested that the time lag factor in increased incidence of SIDS about five days after a cold day is skeletal muscle degeneration with origins in mitochondria, as in cold and circulatory shock in humans and WMD in weaned ruminants within five days. It is again pointed out that the VESD diseases only render muscle liable to degeneration when environmental stresses are superimposed (4). An example of a superimposed stress is the rise in SIDS victims in Finland (7) following great and rapid temperature falls in November and December, when victims are found in the prone position with no apparent cause of death. Examples of superimposed stress on muscle are the biochemical metabolic disorders of LCFA’s involving the carnitine detoxification of toxic acylCoA compounds (6). It is proposed that carnitine, allopurinol, Bcarotene and selenium all reduce the free radical injury to mitochondrial membranes in the muscle disorders and that thyroid hormones are required for mitochondrial development in the early post-natal period. All these factors are likely to be linked with SIDS and the time lag factor, associated with muscle respiratory decline. The catabolism of ATP during ischemia deprives mitochondria of ATP and impairs the biosynthesis of palmitoyl carnitine and the oxidation of free fatty acids. Magnesium stimulates this process. In livestock farming, magnesium tetany develops about three days after storms and lack of food. All these factors are required to maintain the energy needs of muscle cells. Inadequate oxidation of palmitoyl carnitine is recognised in livestock and in man in the presence of various triggering agents with a time lag factor. Acknowledgement This discussion paper is dedicated to the late Stuart F Reid.
SUDDEN INFANT DEATH SYNDROME:
A TIME LAG FACTOR
References 1. Campbell Michael .I. Sudden Infant Death Syndrome and environmental temperature. Further evidence for a timelagged relationship. Med. J. Aust., 151, pp 365 - 7, October 1989. 2. Brownell A K W, Severson D L, Thompson C D and Fletcher T. Cold Induced Rhabdomyolysis in Carnitine palmutyl Transferase Deficiency. Le Journal des Sciences Neurologiques, 6, 3, pp367 - 70, 1979. 3. McMurray C H and D A Rice. Vitamin E and selenium deficiency diseases. Irish Veterinary Journal 36, pp 57 - 67, 1982. 4. Bradley R. Skeletal Muscle in Health and Disease, In Practice, 5 - 13, march 1981. 5. Corbucci G G, Gasparetto A, Crimi G, Antonelli N, Bufi M, De Blasi R A, Cooper N B and Gohil K. Shock-induced Damage to Mitochondrial Function and Some Cellular Antioxidant Mechanisms in Humans. Circulatory Shock, 15, pp 15-26, 1985. 6. Roe Ch R, Gale R S, Kozakewich H P W, Morton D H and Mandell F. Sudden Infant Death Syndrome: The Role of Inherited Disorders. p.74 (Abstract) in Proc. Sudden Infant Death Syndrome Conference, Graz, Austria, 1988. 7. Tiainen E. Sudden Infant Death in Southern Finland. p64 (Abstract), in Proc. Sudden infant Death Syndrome Conference, Graz, Austria, 1988. 8. Foster H P. Sudden Infant Death Syndrome and Iodine Deficiency: Geographical Evidence. J Orthomolecular Medicine, 3, 4, pp 207 - 11, 1988. 9. Warshaw J B. Cellular Energy Metabolism During Foetal Development. Developmental Biology, 28, pp 537 - 44,
189 1972. 10. Underwood E J. Trace Elements in Human and Animal Nutrition, 4th Edition. ~280. Academic Press N.Y., 1977. 11. Godwin K 0, Kuchel R E and Fuss C. Some Biochemical Features of White Muscle Disease in Lambs and the lnfluence of Selenium. Aust. J. Biol. Sci., 27, pp 633-43, 1974. 12. Bertorini T, Yeh Y Y, Trevisan C, Stradlan E, Sabesin S and DiMauro S. Carnitine Palmityl Transferase Deficiency, Myogiobinuria and Respiratory Failure. Neurol 30, ~263-71, 1980. 13. Edelman I S and lsmail-Beigi F. Thyroid Thermogenesis and Active Sodium Transport. Recent Progress in Hormone Research, 30, pp235 - 7, 1974. 14. Shorrocks V M, In Micronutrient News, 10, 2, ~13, 1990. 15. Bejar R, Curbelo V, Davis C and Gluck L. Premature Labour II: Bacterial Sources of Phospholipase. Obstet Gynecol, 57, pp479 - 82, 1981. 16. Masukawa T, Gotto T and lwata H. Impaired metabolism of arachidonate in selenium deficient animals. Experimentia, 39, pp405 -6, 1983. 17. McCord J M and Roy R S. The Pathophysiology of Superoxide: Roles in Inflammation and ischemia. Can. J Physical Pharmacol, 60, pp 1341-52, 1982. 18. Burton G W and lngold K U. B-Carotene: An unusual type of lipid antioxidant. Science, 224, pp569 -- 73, 1984. 19. Lombeck I, Kasperek G, Harbisch H D, Feinendegen T E and Bremer H J. The Selenium State of Healthy Children. Europ J Pediatrics, 125, pp81- 8, 1977. 20. Bremer J. Carnitine in Intermediary Metabolism. J. Bioi Chem, 238, 8, pp2774-9, 1963.
