631
EDITORIALS
Carnitine deficiency Carnitine (3-hydroxy, 4-N-trimethylaminobutyric acid) is an essential intracellular constituent in higher animals and is synthesised from peptide-bound lysine. Only in liver, brain, and kidney are all the synthetic steps present;l other tissues depend on uptake from blood by an active transport process. Carnitine in meat and dairy produce is absorbed and utilised but endogenous biosynthesis can meet normal metabolic needs in healthy vegetarian adults.2Almost all the body stores are in skeletal and cardiac muscle (98%); liver contains 1-6% and extracellular fluid 0-6% .3 No mammalian degradation pathways are known; small amounts of carnitine are excreted in urine in the free form or as acyl-camitine esters. Carnitine has a key role in regulating substrate flux and energy balance across cell membranes. It is an essential cofactor for the transport of long-chain fatty-acids into mitochondria catalysed by carnitine palmitoyl transferase, and hence for the normal beta-oxidation of fatty-acids by liver, heart, and skeletal muscle.4 When this transport is compromised, fatty-acid oxidation is reduced and triacylglycerols accumulate producing microscopic fatty change.5 In the liver, ketogenesis is impaired.6 Camitine palmitoyl transferase can also fulfil a detoxifying role by forming and exporting acylcarnitine esters of any acylcoenzyme A (CoA) molecules that accumulate within the mitochondria? Carnitine acetyl transferase modulates the intracellular concentrations of free CoA and acetyl-CoA via reversible formation of acetylcamitine. Since this compound can be exchanged freely across subcellular membranes it acts as a pool from which to regenerate acetyl-CoA and thereby allows transport of metabolic energy and acetyl groups between intracellular organelles.4 In plasma and
tissues camitine is present in the free form and as acylcamitine esters, of which acetylcamitine predominates. For correct interpretation free, shortchain, and long-chain fractions should be measured. The first camitine deficiency state to be described was isolated to skeletal muscle and associated with a lipid-storage myopathy.8 Systemic deficiency with reduced total camitine in muscle, liver, and plasma was described later. Patients presented with skeletal myopathy9 or cardiomyopathyl° or both;l1 with and episodic vomiting, encephalopathy, and with hypoketotic hepatomegaly;9 hypoglycaemia and said
Reye’s-like syndromes.6However, many patients to have systemic camitine deficiency12,13 were later shown to have a defect of beta-oxidation, most commonly medium-chain acyl-CoA dehydrogenase deficiency14 or multiple acyl-CoA dehydrogenase deficiency,ls which had caused a secondary deficiency of camitine. Secondary deficiency is now well recognised in many inherited metabolic disorders, especially the organic acidaemias and disorders of beta-oxidation.3,7 In methylmalonic acidaemia and propionic acidaemia total plasma levels may be normal but the acyl/free ratio is increased; levels in muscle and liver are usually low.16 True primary systemic carnitine deficiency has only lately been delineatedy,18 This is a disorder of the sodium-linked membrane transport of carnitine in muscle, intestinal mucosa, and renal tubules. It is expressed in skin have fibroblasts. Patients with presented hypoglycaemia and encephalopathy, skeletal myopathy, and cardiomyopathy. Total carnitine concentrations in plasma, muscle, and liver are very low. No primary disorders of camitine biosynthesis have been described in man. Inadequate camitine intake or excessive loss may lead to low plasma and tissue concentrations, but it is
632
unclear whether such "deficiency" is responsible for clinical illness. There may be a nutritional requirement for carnitine in infancy since synthesis may not meet the demands of rapid growth. However, there is little evidence that this is responsible for symptoms-in the few cases described a coexistent metabolic disease could not be excluded. Plasma concentrations fall in patients on total parenteral nutrition for greater than a month and excess renal carnitine excretion may occur in bums, sepsis, and starvation or after surgery.19 Any cause of Fanconi syndrome leads to low total and free carnitine concentrations. 20 Plasma free carnitine levels may be reduced and the acyl/free ratio is increased in patients on maintenance haemodialysis.21 Muscle carnitine levels are low but cannot be attributed to losses into dialysate or impaired intestinal absorption, reduced synthesis has been suggested. Long-term administration of drugs that are conjugated to camitine may also produce camitine deficiency. Some patients treated with sodium valproate excrete valproyl-carnitine22 and have low concentrations of free camitine in plasma with an increased acyl/free ratio.23 More profound camitine depletion follows treatment with pivmecillinam and pivampicillin;24 the pivalic acid moiety is excreted as pivaloyl-carnitine with depletion of both plasma and muscle pools. The importance of low plasma or tissue camitine levels is not always clear. In vitro, muscle carnitine deficiency must be severe before there is any impairment of fatty-acid oxidation.25 Patients with total camitine concentrations in muscle as low as 1 ’5 % of normal may have no signs or symptoms of myopathy .17 Moreover, it can be difficult, especially in disorders of intermediary metabolism, to separate the consequences of carnitine deficiency from those of the
underlying cause. There is a rationale for the therapeutic use of carnitine in primary systemic camitine deficiencyalthough tissue concentrations, except in liver, remain low, cardiomyopathy resolves.17,18 In the organic acidaemias, carnitine therapy may restore the esterified CoA/free CoA ratio and also promote excretion of acyl-carnitines in urine.However, the evidence that these effects are beneficial is limited. The rise in hippurate excretion after carnitine therapy indicates increased availability of free CoA.26 In isovaleric acidaemia, CoA homoeostasis can be restored,27 but in the other organic acidaemias (eg, propionic acidaemia and methylmalonic acidaemia) the increased excretion of acylcamitines following carnitine supplementation may make quantitatively only a minor contribution when compared with the overall flux. In the disorders of beta-oxidation there is no firm evidence that camitine supplements are beneficial and they might even make the condition worse by priming a defective pathway. Carnitine does
prevent the metabolic crises characteristic of these disorders and has not been assessed in any controlled studies. Camitine may have other uses. Free carnitine levels are reduced in infarcted or ischaemic myocardium29 and intracellular concentrations of long-chain acylCoA esters rise .30 Administration of carnitine to patients after myocardial infarction may limit infarct size 3and protect against arrhythmias.32 In stable effort-induced angina carnitine increases exercise tolerance and reduces ST segment depression, but these effects are minor and have not been compared with standard therapy.33 Camitine supplementation increases exercise tolerance in patients with intermittent claudication. It may protect against the cardiotoxic effects of the anthracycline group of anticancer chemotherapeutic agents.35 Perhaps the most controversial use of carnitine is as a means of improving exercise performance in athletes.36
not
AG. Tissue distribution of carnitine biosynthetic Biochim Biophys Acta 1980; 630: 22-29. 2. Feller AG, Rudman D. Role of carnitine in human nutrition. J Nutr 1988; 118: 541-47. 3. Engel AG, Rebouche CJ. Carnitine metabolism and inborn errors. J Inherited Metab Dis 1984; 7 (suppl 1): 38-43. 4. Bremer J. Carnitine: metabolism and functions. Physiol Rev 1983; 63: 1. Rebouche
CJ, Engel
enzymes in
man.
1420-80. 5. Gilbert EF. Carnitine deficiency. Pathology 1985; 17: 161-69. 6. Chapoy PR, Angelini C, Brown WJ, Stiff JE, Shug AL, Cederbaum SD. Systemic camitine deficiency—a treatable inherited lipid-storage disorder presenting as Reye’s syndrome. N Engl J Med 1980; 303: 1389-94. 7. Chalmers RA, Roe CR, Stacey TE, Hoppel CL. Urinary excretion of L-carnitine and acylcarnitine by patients with disorders of organic acid
metabolism: evidence for secondary insufficicency of L-carnitine. Pediatr Res 1984; 18: 1325-28. 8. Engel AG, Angelini C. Carnitine deficiency of human skeletal muscle with associated lipid storage myopathy: a new syndrome. Science 1973; 179: 899-901. 9.
10.
11.
12. 13.
Karpati G, Carpenter S, Engel AG, et al. The syndrome of systemic carnitine deficiency. Clinical, morphologic, biochemical and pathophysiologic features. Neurology 1975; 25: 16-24. Tripp ME, Katcher ML, Peters HA, et al. Systemic carnitine deficiency presenting as familial endocardial fibroelastosis. A treatable cardiomyopathy. N Engl J Med 1980; 305: 385-90. Waber LJ, Valle D, Neill C, Di Mauro S, Shug A. Camitine deficiency presenting as familial cardiomyopathy: a treatable defect in carnitine transport. J Pediatr 1982; 101: 700-05. Glasgow AM, Eng G, Engel AG. Systemic carnitine deficiency simulating recurrent Reye syndrome. Pediatrics 1980; 96: 889-91. Comelio F, Di Donato S, Peluchetti D, et al. Fatal cases of lipid storage myopathy with carnitine deficiency. J Neurol Neurosurg Psychiatry 1977; 40: 170-76.
14. Coates PM, Hale DE, Stanley CA. Systemic camitine deficiency simulating Reye syndrome. J Pediatr 1984; 105: 679. 15. Di Donato S, Frerman FE, Rimoldi M, Rinaldo P, Taroni F, Weisman UN. Systemic carnitine deficiency due to lack of electron transfer flavoprotein: ubiquinone oxidoreductase. Neurology 1986; 36: 957-63. 16. Kurczynski TW, Hoppel CL, Goldblatt PJ, Gunning WT. Metabolic studies of carnitine in a child with propionic acidemia. Pediatr Res 1989; 26: 63-66. 17. Rodrigues Pereira R, Scholte HR, Luyt-Houwen IEM, VaandragerVerduin MHM. Cardiomyopathy associated with camitine loss in kidneys and small intestine. Eur J Pediatr 1988; 148: 193-97. 18. Stanley CA, Treem WR, Hale DE, Coates PM. A genetic defect in carnitine transport causing primary carnitine deficiency. In: Tanaka K, Coates PM, eds. Fatty acid oxidation: clinical biochemical and molecular aspects. New York: Alan R Liss, 1990: 457-64. 19. Nanni G, Pittiruti M, Castagneto M. Camitine plasma levels during total parenteral nutrition. Am J Clin Nutr 1983; 38: 339-41. 20. Bernardini I, Rizzo WM, Dalakas M, Bernar J, Gahl WA. Plasma and muscle free carnitine deficiency due to renal Fanconi syndrome. J Clin Invest 1985; 75: 1124-30.
633
21. Guarnieri G, Toigo G, Crapesi L, et al. Carnitine metabolism in chronic renal failure. Kidney Int 1987; 32 (suppl 22): S116-27. 22. Millington DS, Bohan TP, Roe CR, Yergey AL, Liberato DJ. a novel drug metabolite identified by fast atom bombardment and thermospray liquid chromatography-mass spectrometry. Clin Chim Acta 1985; 145: 69-76. 23. Laub MC, Paetzke-Brunner I, Jaeger G. Serum carnitine during valproic acid therapy. Epilepsia 1986; 27: 559-62. 24. Holme E, Greter J, Jacobson C-E, et al. Carnitine deficiency induced by pivampicillin and pivmecillinam therapy. Lancet 1989; ii: 469-73. 25. Carroll JE, Carter AL, Perlmann S. Carnitine deficiency revisited. J Nutr 1987; 117: 1501-03. 26. Roe CR, Hoppel CL, Stacey CE, Chalmers RA, Tracey BM, Millington DS. Metabolic response to carnitine in methylmalonic aciduria. An effective strategy for elimination of propionyl groups. Arch Dis Child 1983; 58: 916-20. 27. de Sousa C, Chalmers A, Stacey TE, Tracey BM, Weaver CM, Bradley D. The response to L-carnitine and glycine therapy in isovaleric acidaemia. Eur J Pediatr 1986; 144: 451-56. 28. Thompson GN, Walter JH, Bresson J-L, et al. Substrate disposal in metabolic disease: a comparison between rates of in vivo propionate oxidation and urinary metabolite excretion in children with methylmalonic acidemia. J Pediatr 1989; 115: 735-39. 29. Spagnoli LG, Corsi M, Villaschi S, Palmieri G, Maccari F. Myocardial carnitine deficiency in acute myocardial infarction. Lancet 1982; i: 1419-20. 30. Liedtke AJ, Nellis S, Neely JR. Effects of excess free fatty acids on mechanical and metabolic function in normal and ischemic myocardium in swine. Circ Res 1978; 43: 652-61. 31. Chiariello M, Brevetti G, Policicchio A, Nevola E, Condorelli M. L-carnitine in acute myocardial infarction. A multicenter randomised trial. In: Borum PR, ed. Clinical aspects of human carnitine deficiency. New York: Pergamon, 1986: 242-43. 32. Rizzon P, Biasco G, Boscia F, et al. High doses of L-carnitine in acute myocardial infarction: metabolic and antiarrhythmic effects. Eur Heart J 1989; 10: 502-08. 33. Cherchi J, Lai C, Angelino F, et al. Effects of L-carnitine on exercise tolerance in chronic stable angina: a multicenter, double-blind, randomised, placebo controlled crossover study. Int J Clin Pharmacol Ther Toxicol 1985; 23: 569-72. 34. Brevetti G, Chariello M, Ferulano G, et al. Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study. Circulation 1988; 77: 767-83. 35. Goa KL, Brogden RN. L-carnitine. A preliminary review of its pharmacokinetics, and its therapeutic use in ischaemic heart disease and primary and secondary carnitine deficiencies in relationship to its role in fatty acid metabolism. Drugs 1987; 34: 1-27. 36. Angelini C, Vergani L, Costa L, et al. Use of carnitine in exercise physiology. In: Goldberg A, et al, eds. Carnitine, enzymes and isoenzymes in disease. Basel: Karger, 1986: 103-10.
Valproylcarnitine:
THE THIRD WORLD’S VIP The difficulties of effective sanitation with a limited supply of water seldom trouble people in developed nations as they thoughtlessly flush another 10 litres or so of the precious liquid down the toilet. In the developing world, with limited resources and growing populations, other methods have to be considered, especially in rural areas. To install waterborne santitation, a supply of 45 litres per person per day needs to be guaranteed. Many people are lucky if they can get a bucketful of water a day, and even that often has to be carried on a woman’s head for 2 or 3 km. Pit latrines have been advocated as the best alternative to "going to bush". A pit of roughly 1 m diameter and 3 m depth is dug, and covered with a 7 cm thick concrete slab 15m square with a 10-15 cm hole in it, cast close by then lifted on. A "small house" is built on top of that for privacy. In theory the latrine hole should be kept covered when not in use to keep the flies out and the smell in. With the addition of the little water used for cleaning the latrine, the excreta in the pit slowly digests to a smaller volume. However, the pit eventually fills, and a new one has to be dug. Care of such latrines, especially if shared by more than one family, is not
edges of the latrine hole and thus the wooden become soiled, so the cover tends to be left off. Flies breed freely, the smell is unbearable, and people return to the piece of waste ground outside the village, which becomes infinitely preferable even if it does mean walking some distance. Research sponsored by the World Bank at the Blair Research Laboratory in Zimbabwe in cooperation with the Faculty of Civil Engineering in Leeds has led to the development of the ventilated improved pit (VIP) latrine.1 easy. The cover
By some very simple modifications to the ordinary pit latrine Morgan and Mara have found a way to eliminate flies and odour almost completely, without adding too much to the cost of construction. The main feature is a large ventilation pipe 22 cm in diameter-hence the name. The pit is no different, but the covering slab is cast to provide two holes, the latrine hole a little towards one side and a second hole large enough for the ventilation pipe towards the other side. The slab is laid over the pit, and the little house built over it around the latrine hole, but with the ventilation hole and pipe just outside and rising to 1 m above the house. The ventilation pipe, which should be on the south side of the house in the northern hemisphere (and vice versa in the southern), is painted black to promote heat absorption from the sun, and so induce a rising current of air which carries smells away from the latrine. (Standard 10 cm asbestos cement soil-pipes were first tried but found to be inadequate.) A stainless steel or fibreglass gauze fly screen is fixed over the top of the pipe. The house is built without a window and with a sprung door to ensure self-closure after use. Better still, a simple light-trap entrance, as into an X-ray dark room, may be provided. The door opening should not face east or west to eliminate early morning or late afternoon sun slanting in. It is important to keep the latrine house semi-dark. Air is drawn freely into the pit via the uncovered latrine hole to replace the warm air escaping through the ventilation pipe. Some flies will enter and breed, but since they are phototropic they will be attracted by the brighter light entering the pit from the ventilator and fly up that way only to find their exit blocked by the screen. They
EDITORIALS
Carnitine deficiency Carnitine (3-hydroxy, 4-N-trimethylaminobutyric acid) is an essential intracellular constituent in higher animals and is synthesised from peptide-bound lysine. Only in liver, brain, and kidney are all the synthetic steps present;l other tissues depend on uptake from blood by an active transport process. Carnitine in meat and dairy produce is absorbed and utilised but endogenous biosynthesis can meet normal metabolic needs in healthy vegetarian adults.2Almost all the body stores are in skeletal and cardiac muscle (98%); liver contains 1-6% and extracellular fluid 0-6% .3 No mammalian degradation pathways are known; small amounts of carnitine are excreted in urine in the free form or as acyl-camitine esters. Carnitine has a key role in regulating substrate flux and energy balance across cell membranes. It is an essential cofactor for the transport of long-chain fatty-acids into mitochondria catalysed by carnitine palmitoyl transferase, and hence for the normal beta-oxidation of fatty-acids by liver, heart, and skeletal muscle.4 When this transport is compromised, fatty-acid oxidation is reduced and triacylglycerols accumulate producing microscopic fatty change.5 In the liver, ketogenesis is impaired.6 Camitine palmitoyl transferase can also fulfil a detoxifying role by forming and exporting acylcarnitine esters of any acylcoenzyme A (CoA) molecules that accumulate within the mitochondria? Carnitine acetyl transferase modulates the intracellular concentrations of free CoA and acetyl-CoA via reversible formation of acetylcamitine. Since this compound can be exchanged freely across subcellular membranes it acts as a pool from which to regenerate acetyl-CoA and thereby allows transport of metabolic energy and acetyl groups between intracellular organelles.4 In plasma and
tissues camitine is present in the free form and as acylcamitine esters, of which acetylcamitine predominates. For correct interpretation free, shortchain, and long-chain fractions should be measured. The first camitine deficiency state to be described was isolated to skeletal muscle and associated with a lipid-storage myopathy.8 Systemic deficiency with reduced total camitine in muscle, liver, and plasma was described later. Patients presented with skeletal myopathy9 or cardiomyopathyl° or both;l1 with and episodic vomiting, encephalopathy, and with hypoketotic hepatomegaly;9 hypoglycaemia and said
Reye’s-like syndromes.6However, many patients to have systemic camitine deficiency12,13 were later shown to have a defect of beta-oxidation, most commonly medium-chain acyl-CoA dehydrogenase deficiency14 or multiple acyl-CoA dehydrogenase deficiency,ls which had caused a secondary deficiency of camitine. Secondary deficiency is now well recognised in many inherited metabolic disorders, especially the organic acidaemias and disorders of beta-oxidation.3,7 In methylmalonic acidaemia and propionic acidaemia total plasma levels may be normal but the acyl/free ratio is increased; levels in muscle and liver are usually low.16 True primary systemic carnitine deficiency has only lately been delineatedy,18 This is a disorder of the sodium-linked membrane transport of carnitine in muscle, intestinal mucosa, and renal tubules. It is expressed in skin have fibroblasts. Patients with presented hypoglycaemia and encephalopathy, skeletal myopathy, and cardiomyopathy. Total carnitine concentrations in plasma, muscle, and liver are very low. No primary disorders of camitine biosynthesis have been described in man. Inadequate camitine intake or excessive loss may lead to low plasma and tissue concentrations, but it is
632
unclear whether such "deficiency" is responsible for clinical illness. There may be a nutritional requirement for carnitine in infancy since synthesis may not meet the demands of rapid growth. However, there is little evidence that this is responsible for symptoms-in the few cases described a coexistent metabolic disease could not be excluded. Plasma concentrations fall in patients on total parenteral nutrition for greater than a month and excess renal carnitine excretion may occur in bums, sepsis, and starvation or after surgery.19 Any cause of Fanconi syndrome leads to low total and free carnitine concentrations. 20 Plasma free carnitine levels may be reduced and the acyl/free ratio is increased in patients on maintenance haemodialysis.21 Muscle carnitine levels are low but cannot be attributed to losses into dialysate or impaired intestinal absorption, reduced synthesis has been suggested. Long-term administration of drugs that are conjugated to camitine may also produce camitine deficiency. Some patients treated with sodium valproate excrete valproyl-carnitine22 and have low concentrations of free camitine in plasma with an increased acyl/free ratio.23 More profound camitine depletion follows treatment with pivmecillinam and pivampicillin;24 the pivalic acid moiety is excreted as pivaloyl-carnitine with depletion of both plasma and muscle pools. The importance of low plasma or tissue camitine levels is not always clear. In vitro, muscle carnitine deficiency must be severe before there is any impairment of fatty-acid oxidation.25 Patients with total camitine concentrations in muscle as low as 1 ’5 % of normal may have no signs or symptoms of myopathy .17 Moreover, it can be difficult, especially in disorders of intermediary metabolism, to separate the consequences of carnitine deficiency from those of the
underlying cause. There is a rationale for the therapeutic use of carnitine in primary systemic camitine deficiencyalthough tissue concentrations, except in liver, remain low, cardiomyopathy resolves.17,18 In the organic acidaemias, carnitine therapy may restore the esterified CoA/free CoA ratio and also promote excretion of acyl-carnitines in urine.However, the evidence that these effects are beneficial is limited. The rise in hippurate excretion after carnitine therapy indicates increased availability of free CoA.26 In isovaleric acidaemia, CoA homoeostasis can be restored,27 but in the other organic acidaemias (eg, propionic acidaemia and methylmalonic acidaemia) the increased excretion of acylcamitines following carnitine supplementation may make quantitatively only a minor contribution when compared with the overall flux. In the disorders of beta-oxidation there is no firm evidence that camitine supplements are beneficial and they might even make the condition worse by priming a defective pathway. Carnitine does
prevent the metabolic crises characteristic of these disorders and has not been assessed in any controlled studies. Camitine may have other uses. Free carnitine levels are reduced in infarcted or ischaemic myocardium29 and intracellular concentrations of long-chain acylCoA esters rise .30 Administration of carnitine to patients after myocardial infarction may limit infarct size 3and protect against arrhythmias.32 In stable effort-induced angina carnitine increases exercise tolerance and reduces ST segment depression, but these effects are minor and have not been compared with standard therapy.33 Camitine supplementation increases exercise tolerance in patients with intermittent claudication. It may protect against the cardiotoxic effects of the anthracycline group of anticancer chemotherapeutic agents.35 Perhaps the most controversial use of carnitine is as a means of improving exercise performance in athletes.36
not
AG. Tissue distribution of carnitine biosynthetic Biochim Biophys Acta 1980; 630: 22-29. 2. Feller AG, Rudman D. Role of carnitine in human nutrition. J Nutr 1988; 118: 541-47. 3. Engel AG, Rebouche CJ. Carnitine metabolism and inborn errors. J Inherited Metab Dis 1984; 7 (suppl 1): 38-43. 4. Bremer J. Carnitine: metabolism and functions. Physiol Rev 1983; 63: 1. Rebouche
CJ, Engel
enzymes in
man.
1420-80. 5. Gilbert EF. Carnitine deficiency. Pathology 1985; 17: 161-69. 6. Chapoy PR, Angelini C, Brown WJ, Stiff JE, Shug AL, Cederbaum SD. Systemic camitine deficiency—a treatable inherited lipid-storage disorder presenting as Reye’s syndrome. N Engl J Med 1980; 303: 1389-94. 7. Chalmers RA, Roe CR, Stacey TE, Hoppel CL. Urinary excretion of L-carnitine and acylcarnitine by patients with disorders of organic acid
metabolism: evidence for secondary insufficicency of L-carnitine. Pediatr Res 1984; 18: 1325-28. 8. Engel AG, Angelini C. Carnitine deficiency of human skeletal muscle with associated lipid storage myopathy: a new syndrome. Science 1973; 179: 899-901. 9.
10.
11.
12. 13.
Karpati G, Carpenter S, Engel AG, et al. The syndrome of systemic carnitine deficiency. Clinical, morphologic, biochemical and pathophysiologic features. Neurology 1975; 25: 16-24. Tripp ME, Katcher ML, Peters HA, et al. Systemic carnitine deficiency presenting as familial endocardial fibroelastosis. A treatable cardiomyopathy. N Engl J Med 1980; 305: 385-90. Waber LJ, Valle D, Neill C, Di Mauro S, Shug A. Camitine deficiency presenting as familial cardiomyopathy: a treatable defect in carnitine transport. J Pediatr 1982; 101: 700-05. Glasgow AM, Eng G, Engel AG. Systemic carnitine deficiency simulating recurrent Reye syndrome. Pediatrics 1980; 96: 889-91. Comelio F, Di Donato S, Peluchetti D, et al. Fatal cases of lipid storage myopathy with carnitine deficiency. J Neurol Neurosurg Psychiatry 1977; 40: 170-76.
14. Coates PM, Hale DE, Stanley CA. Systemic camitine deficiency simulating Reye syndrome. J Pediatr 1984; 105: 679. 15. Di Donato S, Frerman FE, Rimoldi M, Rinaldo P, Taroni F, Weisman UN. Systemic carnitine deficiency due to lack of electron transfer flavoprotein: ubiquinone oxidoreductase. Neurology 1986; 36: 957-63. 16. Kurczynski TW, Hoppel CL, Goldblatt PJ, Gunning WT. Metabolic studies of carnitine in a child with propionic acidemia. Pediatr Res 1989; 26: 63-66. 17. Rodrigues Pereira R, Scholte HR, Luyt-Houwen IEM, VaandragerVerduin MHM. Cardiomyopathy associated with camitine loss in kidneys and small intestine. Eur J Pediatr 1988; 148: 193-97. 18. Stanley CA, Treem WR, Hale DE, Coates PM. A genetic defect in carnitine transport causing primary carnitine deficiency. In: Tanaka K, Coates PM, eds. Fatty acid oxidation: clinical biochemical and molecular aspects. New York: Alan R Liss, 1990: 457-64. 19. Nanni G, Pittiruti M, Castagneto M. Camitine plasma levels during total parenteral nutrition. Am J Clin Nutr 1983; 38: 339-41. 20. Bernardini I, Rizzo WM, Dalakas M, Bernar J, Gahl WA. Plasma and muscle free carnitine deficiency due to renal Fanconi syndrome. J Clin Invest 1985; 75: 1124-30.
633
21. Guarnieri G, Toigo G, Crapesi L, et al. Carnitine metabolism in chronic renal failure. Kidney Int 1987; 32 (suppl 22): S116-27. 22. Millington DS, Bohan TP, Roe CR, Yergey AL, Liberato DJ. a novel drug metabolite identified by fast atom bombardment and thermospray liquid chromatography-mass spectrometry. Clin Chim Acta 1985; 145: 69-76. 23. Laub MC, Paetzke-Brunner I, Jaeger G. Serum carnitine during valproic acid therapy. Epilepsia 1986; 27: 559-62. 24. Holme E, Greter J, Jacobson C-E, et al. Carnitine deficiency induced by pivampicillin and pivmecillinam therapy. Lancet 1989; ii: 469-73. 25. Carroll JE, Carter AL, Perlmann S. Carnitine deficiency revisited. J Nutr 1987; 117: 1501-03. 26. Roe CR, Hoppel CL, Stacey CE, Chalmers RA, Tracey BM, Millington DS. Metabolic response to carnitine in methylmalonic aciduria. An effective strategy for elimination of propionyl groups. Arch Dis Child 1983; 58: 916-20. 27. de Sousa C, Chalmers A, Stacey TE, Tracey BM, Weaver CM, Bradley D. The response to L-carnitine and glycine therapy in isovaleric acidaemia. Eur J Pediatr 1986; 144: 451-56. 28. Thompson GN, Walter JH, Bresson J-L, et al. Substrate disposal in metabolic disease: a comparison between rates of in vivo propionate oxidation and urinary metabolite excretion in children with methylmalonic acidemia. J Pediatr 1989; 115: 735-39. 29. Spagnoli LG, Corsi M, Villaschi S, Palmieri G, Maccari F. Myocardial carnitine deficiency in acute myocardial infarction. Lancet 1982; i: 1419-20. 30. Liedtke AJ, Nellis S, Neely JR. Effects of excess free fatty acids on mechanical and metabolic function in normal and ischemic myocardium in swine. Circ Res 1978; 43: 652-61. 31. Chiariello M, Brevetti G, Policicchio A, Nevola E, Condorelli M. L-carnitine in acute myocardial infarction. A multicenter randomised trial. In: Borum PR, ed. Clinical aspects of human carnitine deficiency. New York: Pergamon, 1986: 242-43. 32. Rizzon P, Biasco G, Boscia F, et al. High doses of L-carnitine in acute myocardial infarction: metabolic and antiarrhythmic effects. Eur Heart J 1989; 10: 502-08. 33. Cherchi J, Lai C, Angelino F, et al. Effects of L-carnitine on exercise tolerance in chronic stable angina: a multicenter, double-blind, randomised, placebo controlled crossover study. Int J Clin Pharmacol Ther Toxicol 1985; 23: 569-72. 34. Brevetti G, Chariello M, Ferulano G, et al. Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study. Circulation 1988; 77: 767-83. 35. Goa KL, Brogden RN. L-carnitine. A preliminary review of its pharmacokinetics, and its therapeutic use in ischaemic heart disease and primary and secondary carnitine deficiencies in relationship to its role in fatty acid metabolism. Drugs 1987; 34: 1-27. 36. Angelini C, Vergani L, Costa L, et al. Use of carnitine in exercise physiology. In: Goldberg A, et al, eds. Carnitine, enzymes and isoenzymes in disease. Basel: Karger, 1986: 103-10.
Valproylcarnitine:
THE THIRD WORLD’S VIP The difficulties of effective sanitation with a limited supply of water seldom trouble people in developed nations as they thoughtlessly flush another 10 litres or so of the precious liquid down the toilet. In the developing world, with limited resources and growing populations, other methods have to be considered, especially in rural areas. To install waterborne santitation, a supply of 45 litres per person per day needs to be guaranteed. Many people are lucky if they can get a bucketful of water a day, and even that often has to be carried on a woman’s head for 2 or 3 km. Pit latrines have been advocated as the best alternative to "going to bush". A pit of roughly 1 m diameter and 3 m depth is dug, and covered with a 7 cm thick concrete slab 15m square with a 10-15 cm hole in it, cast close by then lifted on. A "small house" is built on top of that for privacy. In theory the latrine hole should be kept covered when not in use to keep the flies out and the smell in. With the addition of the little water used for cleaning the latrine, the excreta in the pit slowly digests to a smaller volume. However, the pit eventually fills, and a new one has to be dug. Care of such latrines, especially if shared by more than one family, is not
edges of the latrine hole and thus the wooden become soiled, so the cover tends to be left off. Flies breed freely, the smell is unbearable, and people return to the piece of waste ground outside the village, which becomes infinitely preferable even if it does mean walking some distance. Research sponsored by the World Bank at the Blair Research Laboratory in Zimbabwe in cooperation with the Faculty of Civil Engineering in Leeds has led to the development of the ventilated improved pit (VIP) latrine.1 easy. The cover
By some very simple modifications to the ordinary pit latrine Morgan and Mara have found a way to eliminate flies and odour almost completely, without adding too much to the cost of construction. The main feature is a large ventilation pipe 22 cm in diameter-hence the name. The pit is no different, but the covering slab is cast to provide two holes, the latrine hole a little towards one side and a second hole large enough for the ventilation pipe towards the other side. The slab is laid over the pit, and the little house built over it around the latrine hole, but with the ventilation hole and pipe just outside and rising to 1 m above the house. The ventilation pipe, which should be on the south side of the house in the northern hemisphere (and vice versa in the southern), is painted black to promote heat absorption from the sun, and so induce a rising current of air which carries smells away from the latrine. (Standard 10 cm asbestos cement soil-pipes were first tried but found to be inadequate.) A stainless steel or fibreglass gauze fly screen is fixed over the top of the pipe. The house is built without a window and with a sprung door to ensure self-closure after use. Better still, a simple light-trap entrance, as into an X-ray dark room, may be provided. The door opening should not face east or west to eliminate early morning or late afternoon sun slanting in. It is important to keep the latrine house semi-dark. Air is drawn freely into the pit via the uncovered latrine hole to replace the warm air escaping through the ventilation pipe. Some flies will enter and breed, but since they are phototropic they will be attracted by the brighter light entering the pit from the ventilator and fly up that way only to find their exit blocked by the screen. They
