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Cadmium and Metabolism of Albumin
133
of the routine screening procedures brain tumours.41 42 The diagnosis of suspected tumours may be improved by scanning posterior-fossa in special positions. Finally, false positives are rare once the normal vascular markings are familiar and when the choroid-plexus pattern is suppressed by giving 1-2 g. of sodium perchlorate. ssmTCO4 brain scans in the diagnosis of brain abscesses, vascular occlusions, intracerebral, subdural, and epidural hsemotomas, and certain non-neoplastic diseases has succeeded at least as well as with brain tumours. as
the
most accurate
in
Stimulated to deploy the advantages of 99mTc to wider clinical use, investigators have devised ingenious techniques to attach the isotope to substances which would not only remain in the peripheral circulation but also attain significant concentration gradients in various tissues. Most compounds are synthesised by first reducing heptavalent pertechnetate to a lower valence stated With a technetium-albumin complex, placentography of considerable accuracy and low dosage to the mother and foetus has been achieved and has proved useful in diagnosing placenta prxvia in third-trimester bleeding.43 44 Placentography with the simpler 99mTc04 anion has also been successful.2s Cisternography has also been achieved with the 99mTc-albumin complex, but it is simpler to give intrathecal pertechnetate-99m shortly after a dose of perchlorate.29 45 The complex, it is hoped, may be improved to make it effective in rapid serial determinations of blood-volume, thereby overcoming the difficulties of a high blood background when a complex of radioiodine and human serum albumin is used. Moreover, macroaggregated albiiniin-99mTc and other forms are being evaluated for lung scanning.45 even
A second technetium
complex for scanning, 99mTcin the liver, spleen, is concentrated colloid,35 44 sulphur and bone-marrow. Both deep and superficial metastatic tumour deposits in the liver have been displayed.45 Spleen scanning gives information about its size and position.46 That the 99mTc-sulphur colloid complex labels the bone-marrow was lately demonstrated in simultaneous studies 47 of the erythron with safe. One American manufacturer is now offering it ready for routine use. Other new 99mTc radiopharmaceuticals continue to appear and are being evaluated.25 26 Such advances in clinical scanning, not only in the isotopes used but in the hardware for detection, display, and measurement of information, mean that only large will be able to maintain a full range of scanning resources. Many skilled people are needed to run the machinery, process the radioisotopes, and synthesise radiopharmaceuticals. Nevertheless, 99mTc has opened areas of clinical scanning previously closed because of radiation hazards; and manufacturers seem
medical
42. 43. 44. 45.
46. 47.
centres
Quinn, J. L., III, Circ, I., Hauser, W. N. J. Am. med. Ass. 1965, 194, 157. McAfee, J. G., Stern, H. S., Fueger, G. F., Baggish, M. S., Holzman, G. B., Zolle, I. J. nucl. Med. 1964, 5, 936. Larson, S. M., Nelp, W. B. ibid. 1965, 6, 364, abst. A-9-e. Harper, P. V., Lathrop, K. A., Jiminez, F., Fink, R., Gottschalk, A. Radiology, 1965, 85, 101. Petasnick, J. P., Gottschalk, A. J. nucl. Med. 1966, 7, 733. Nelp, W. B., Larson, S. M., Lewis, R. J. ibid. 1967. 8, 430.
anxious to make 99mTc compounds more readily available. Thus, diagnostic measures, providing otherwise unobtainable and useful information, may be brought to more doctors and their patients.
Cadmium and Metabolism of Albumin NORMAL young men excrete daily in urine an average of 133 mg. of protein, which can be separated electrophoretically into a number of fractions. Most of the urinary proteins seem to have smaller molecules than the corresponding electrophoretic fractions of the serum. The albumin in normal urine has been found to be indistinguishable from normal serum-albumin,1 although it has been given2 a molecular weight of 30,000. Industrial workers with chronic cadmium poisoning excrete daily in the urine 1-0-3-2 g. of protein per litre,3a finding which confirmed the original observations of FRIBERG. The quantity of protein did not vary with the urinary cadmium level.3 The nature and origin of this protein has been studied in many laboratories. The urinary proteins of cadmiumpoisoned workmen have interesting characteristics,3 both qualitative and quantitative. When traces of protein first appear in the urine, only ot and 3 globulins are present. Later, albumin appears, and the electrophoretic pattern in severe cases is similar to that of normal serum, except that a-globulins do not separate into distinct (Xl and (X2 fractions. Globulins are more abundant than albumin.5 One view is that the proteinuria is quite non-specific, being that seen in any renal tubular disorder.6CREETH et al. observed, consistently, a recognisable pattern of urinary proteins of sedimentation coefficients 2-2-2-8 in all patients with disease localised in the cells of the renal tubules; and they conclude that the urinary proteins of cadmium poisoning arise from such a renal lesion. The renal tubules are undoubtedly damaged in chronic cadmium poisoning, 7 as is evident from the aminoaciduria and glycosuria, renal function tests,4 and the changes in the kidney itself.89s It is unlikely, however, that the proteinuria can be due solely to this action of cadmium, since histologically the lesions do not look severe enough,10 and catalasuria and alkaline-phosphatasuria are absent." Release of catalase from the cells of the renal tubules is probably the most sensitive index of renal damage.12 Since cadmium is excreted by glomerular filtration,133 proteinuria could also arise from changes induced in 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
11. 12.
13.
Webb, T., Rose, B., Sehon, A. H. Can. J. Biochem. 1958, 36, 1159. Merler, E., Remington, J. S., Finland, M., Gitlin, D. Nature, Lond. 1962, 196, 1207. Smith, J. C., Kench, J. E., Lane, R. E. Biochem. J. 1955, 61, 698. Friberg, L. Acta med. scand. 1950, 138, suppl. no. 240. Smith, J. C., Wells, A. R., Kench, J. E. Br. J. ind. Med. 1961, 18, 70. Creeth, J. M., Kekwick, R. A., Flynn, F. V., Harris, H., Robson, E. B. Clin. chim. Acta, 1963, 8, 406. Clarkson, T. W., Kench, J. E. Biochem. J. 1956, 62, 361. Bonnell, J. A., Ross, J. H., King, E. Br. J. ind. Med. 1960, 17, 69. Piscator, M. Archs envir. Hlth, 1966, 12, 335. Timme, A. Addendum, PH.D. thesis of A. C. Gain. University of Cape Town, 1966. Kench, J. E., Wells, A. R., Smith, J. C. S. Afr. med. J. 1962, 36, 390. Dounce, A. L., Roberts, E., Wills, J. H. in Pharmacology and Toxicology of Uranium Compounds (edited by C. Voegtlin and H. C. Hodge). New York, 1949. Smith, J. C., Kench, J. E. Br. J. ind. Med. 1957, 14, 240.
134
the glomeruli during the metal’s passage. In conditions of abnormal glomerular function, as in nephritis or the nephrotic syndrome, however, albumin in the urine is similar in molecular size to normal serum-albumin5 14 ; and the same is true for the proteinuria of poisoning by metallic mercury.15In contrast, the urinary proteins of cadmium poisoning all sediment together during ultracentrifugation, and they have molecular weights in the 20,000-30,000 range.4 16 KENCH and his co-workers have studied in detail the urinary protein migrating electrophoretically as albumin in cadmium-poisoned men and animals, because its low molecular weight seemed to distinguish it from the albumin in other proteinuric states. Despite the great difference in molecular weight between urinary and serum albumins of cadmium-poisoned workmen, no significant difference was detected in their content of several of the constituent aminoacids.5 Rabbits and dogs, given repeated intravenous injections of cadmium chloride, have a pattern of urinary proteins similar to that seen in human intoxication, except that in those animals the albumin fraction contained both low molecular (S20W 199) and normal molecular (S 4-07) species. The low-molecular-weight component has been separated from albumin of normal size by gel filtration and identified as an albumin by its stability in organic solvents at low pH, its similar electrophoretic mobility, its identical immunological behaviour, and its general similarity in aminoacid composition to normal serum-albumin." Low-molecular-weight albumins (mol. wt. 5000-20,000) have been isolated from peritoneal dialysates of a nephrectomised poisoned monkey 18 and from the sera of poisoned monkeys three to five weeks before the onset of proteinuria. 1 The aberrant proteins have been named minialbumins. It seems likely that these proteins arise in extra-renal tissues, and they pass into the urine only later when renal tubular reabsorption has become impaired by cadmium ions in the glomerular filtrate. All minialbumins so far analysed resemble one another in aminoacid composition, and they are deficient in lysine and cystine compared with normal serum-albumin. Both the tryptophan residues of normal monkey albumin are missing in the minialbumins of poisoned animals.19 Minialbumins aggregate readily to form molecules of the usual size (mol. wt. 66,000) 20 and even larger (up to 170,000) in low-salt media, including physiological fluids. Aggregation is partially reversible by inorganic salts, urea, edetic acid, and reagents such as mercaptoethanol which attack disulphide bonds. An equilibrium exists between aggregated and disaggregated molecules. Albumins of conventional size in the serum of cadmium-poisoned monkeys-and presumably man-seem to be a mixture of approximately equal numbers of normal molecules and of molecules 14. Rowe, D. S. Biochem. J. 1957, 67, 435. 15. Smith, J. C., Wells, A. R. Br. J. ind. Med. 1960, 17, 205. 16. Kekwick, R. A. ibid. 1955, 12, 196. 17. Kench, J. E., Gain, A. C., Sutherland, E. M. S. Afr. med. J. 1965, 39, 1191. 18. Gain, A. C., Kench, J. E. S. Afr. J. Lab. clin. Med. 1965, 11, 77. 19. Kench, J. E., Sutherland, E. M. Br. J. ind. Med. 1967, 24, 326. 20. Kench, J. E., Sutherland, E. M. S. Afr. med. J. 1966, 40, 1109.
formed by aggregation of minialbumin. 40-60% of the albumin molecules circulating in the serum of cadmiumpoisoned animals are abnormal in aminoacid composition, molecular weight, or both. Urinary albumin of such animals contains relatively fewer molecules (approximately 13%) which are aggregates. Normal human serum-albumin is a single polypeptide chain containing approximately 575 aminoacid residues,21 of which only 1 is tryptophan.22 23 With a similar structure, normal monkey albumin has 2 tryptophan residues only,19which clearly excludes the possibility of minialbumin (mol. wt. 5000) being a repeating unit of the albumin molecule as a whole. The size and aminoacid composition of minialbumins is consistent with some derangement at an early step in catabolism of serumalbumin, perhaps in the liver, by which a mixture of peptides (mol. wt. 5000) accrues by fission of the albumin molecule along its length.2° One or more fragments containing both tryptophan residues and rich in lysine and cystine are metabolically removed. The remaining peptides are then able to aggregate to form molecules which electrophoretically and antigenically are indistinguishable from normal albumin. Microheterogeneity of serum-albumin has been well established by FOSTER and his colleagues.24 25 If this hypothesis is valid, cadmium ions may play an important physiological role in regulating the biosynthesis of molecular variants of albumin and perhaps of other proteins, including enzymes, the prototype only in each case being dependent on a specific D.N.A. code.
Annotations PLASMA PHOSPHOLIPIDS AND PLATELET STICKINESS IN MULTIPLE SCLEROSIS
MULTIPLE sclerosis is
one
of the conditions in which the
blood-platelets stick more readily than normal to each other or to glass.26 27 One suggestion 26 is that a rise in the unsaturated-fatty-acid concentration of the plasma in multiple sclerosis might be the cause of the increase in platelet stickiness; but the in-vitro studies of Kerr et a1.28 showed that the unsaturated fatty acids, linoleic and linolenic, were the only free fatty acids which did not Linolenic acid and lecithin cause platelet aggregation. inhibited platelet aggregation in the presence of the saturated fatty acids. Other phospholipids, however, promoted platelet aggregation in vitro. The aggregation produced by phosphatidic acid, phosphatidyl serine, and phosphatidyl ethanolamine was reversible in suitable conditions, but sphingomyelin and lysolethicin seemed to cause irreversible platelet aggregation. On p. 99 Dr. Bolton and others report findings which indicate that the lysolethicin of the low-density lipoproteins in the plasma of patients with multiple sclerosis is the factor responsible for the increased platelet stickiness 21. 22. 23. 24.
Potgieter, G. M., Hines, M., Kench, J. E. Clin. chim. Acta, 1967, 18, 107. Ramachandran, L. K., Witkop, B. J. Am. chem. Soc. 1959, 81, 4028. Spahr, P. F., Edsall, J. T. J. biol. Chem. 1964, 239, 850. Foster, J. F., Sogami, M., Petersen, H. A., Leonard, W. J. ibid. 1965, 240, 2495.
25. 26. 27. 28.
Petersen, H. A., Foster, J. F. ibid. p. 2503. Caspary, E. A., Prineas, J., Miller, H., Field, E. J. Lancet, 1965, ii, 1108. Payling Wright, H., Thompson, R. H. S., Zilkha, K. J. ibid. p. 1109. Kerr, J. W., MacAuley, I., Pirrie, R., Bronte-Stewart, B. ibid. 1965, i, 1296.
of the routine screening procedures brain tumours.41 42 The diagnosis of suspected tumours may be improved by scanning posterior-fossa in special positions. Finally, false positives are rare once the normal vascular markings are familiar and when the choroid-plexus pattern is suppressed by giving 1-2 g. of sodium perchlorate. ssmTCO4 brain scans in the diagnosis of brain abscesses, vascular occlusions, intracerebral, subdural, and epidural hsemotomas, and certain non-neoplastic diseases has succeeded at least as well as with brain tumours. as
the
most accurate
in
Stimulated to deploy the advantages of 99mTc to wider clinical use, investigators have devised ingenious techniques to attach the isotope to substances which would not only remain in the peripheral circulation but also attain significant concentration gradients in various tissues. Most compounds are synthesised by first reducing heptavalent pertechnetate to a lower valence stated With a technetium-albumin complex, placentography of considerable accuracy and low dosage to the mother and foetus has been achieved and has proved useful in diagnosing placenta prxvia in third-trimester bleeding.43 44 Placentography with the simpler 99mTc04 anion has also been successful.2s Cisternography has also been achieved with the 99mTc-albumin complex, but it is simpler to give intrathecal pertechnetate-99m shortly after a dose of perchlorate.29 45 The complex, it is hoped, may be improved to make it effective in rapid serial determinations of blood-volume, thereby overcoming the difficulties of a high blood background when a complex of radioiodine and human serum albumin is used. Moreover, macroaggregated albiiniin-99mTc and other forms are being evaluated for lung scanning.45 even
A second technetium
complex for scanning, 99mTcin the liver, spleen, is concentrated colloid,35 44 sulphur and bone-marrow. Both deep and superficial metastatic tumour deposits in the liver have been displayed.45 Spleen scanning gives information about its size and position.46 That the 99mTc-sulphur colloid complex labels the bone-marrow was lately demonstrated in simultaneous studies 47 of the erythron with safe. One American manufacturer is now offering it ready for routine use. Other new 99mTc radiopharmaceuticals continue to appear and are being evaluated.25 26 Such advances in clinical scanning, not only in the isotopes used but in the hardware for detection, display, and measurement of information, mean that only large will be able to maintain a full range of scanning resources. Many skilled people are needed to run the machinery, process the radioisotopes, and synthesise radiopharmaceuticals. Nevertheless, 99mTc has opened areas of clinical scanning previously closed because of radiation hazards; and manufacturers seem
medical
42. 43. 44. 45.
46. 47.
centres
Quinn, J. L., III, Circ, I., Hauser, W. N. J. Am. med. Ass. 1965, 194, 157. McAfee, J. G., Stern, H. S., Fueger, G. F., Baggish, M. S., Holzman, G. B., Zolle, I. J. nucl. Med. 1964, 5, 936. Larson, S. M., Nelp, W. B. ibid. 1965, 6, 364, abst. A-9-e. Harper, P. V., Lathrop, K. A., Jiminez, F., Fink, R., Gottschalk, A. Radiology, 1965, 85, 101. Petasnick, J. P., Gottschalk, A. J. nucl. Med. 1966, 7, 733. Nelp, W. B., Larson, S. M., Lewis, R. J. ibid. 1967. 8, 430.
anxious to make 99mTc compounds more readily available. Thus, diagnostic measures, providing otherwise unobtainable and useful information, may be brought to more doctors and their patients.
Cadmium and Metabolism of Albumin NORMAL young men excrete daily in urine an average of 133 mg. of protein, which can be separated electrophoretically into a number of fractions. Most of the urinary proteins seem to have smaller molecules than the corresponding electrophoretic fractions of the serum. The albumin in normal urine has been found to be indistinguishable from normal serum-albumin,1 although it has been given2 a molecular weight of 30,000. Industrial workers with chronic cadmium poisoning excrete daily in the urine 1-0-3-2 g. of protein per litre,3a finding which confirmed the original observations of FRIBERG. The quantity of protein did not vary with the urinary cadmium level.3 The nature and origin of this protein has been studied in many laboratories. The urinary proteins of cadmiumpoisoned workmen have interesting characteristics,3 both qualitative and quantitative. When traces of protein first appear in the urine, only ot and 3 globulins are present. Later, albumin appears, and the electrophoretic pattern in severe cases is similar to that of normal serum, except that a-globulins do not separate into distinct (Xl and (X2 fractions. Globulins are more abundant than albumin.5 One view is that the proteinuria is quite non-specific, being that seen in any renal tubular disorder.6CREETH et al. observed, consistently, a recognisable pattern of urinary proteins of sedimentation coefficients 2-2-2-8 in all patients with disease localised in the cells of the renal tubules; and they conclude that the urinary proteins of cadmium poisoning arise from such a renal lesion. The renal tubules are undoubtedly damaged in chronic cadmium poisoning, 7 as is evident from the aminoaciduria and glycosuria, renal function tests,4 and the changes in the kidney itself.89s It is unlikely, however, that the proteinuria can be due solely to this action of cadmium, since histologically the lesions do not look severe enough,10 and catalasuria and alkaline-phosphatasuria are absent." Release of catalase from the cells of the renal tubules is probably the most sensitive index of renal damage.12 Since cadmium is excreted by glomerular filtration,133 proteinuria could also arise from changes induced in 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
11. 12.
13.
Webb, T., Rose, B., Sehon, A. H. Can. J. Biochem. 1958, 36, 1159. Merler, E., Remington, J. S., Finland, M., Gitlin, D. Nature, Lond. 1962, 196, 1207. Smith, J. C., Kench, J. E., Lane, R. E. Biochem. J. 1955, 61, 698. Friberg, L. Acta med. scand. 1950, 138, suppl. no. 240. Smith, J. C., Wells, A. R., Kench, J. E. Br. J. ind. Med. 1961, 18, 70. Creeth, J. M., Kekwick, R. A., Flynn, F. V., Harris, H., Robson, E. B. Clin. chim. Acta, 1963, 8, 406. Clarkson, T. W., Kench, J. E. Biochem. J. 1956, 62, 361. Bonnell, J. A., Ross, J. H., King, E. Br. J. ind. Med. 1960, 17, 69. Piscator, M. Archs envir. Hlth, 1966, 12, 335. Timme, A. Addendum, PH.D. thesis of A. C. Gain. University of Cape Town, 1966. Kench, J. E., Wells, A. R., Smith, J. C. S. Afr. med. J. 1962, 36, 390. Dounce, A. L., Roberts, E., Wills, J. H. in Pharmacology and Toxicology of Uranium Compounds (edited by C. Voegtlin and H. C. Hodge). New York, 1949. Smith, J. C., Kench, J. E. Br. J. ind. Med. 1957, 14, 240.
134
the glomeruli during the metal’s passage. In conditions of abnormal glomerular function, as in nephritis or the nephrotic syndrome, however, albumin in the urine is similar in molecular size to normal serum-albumin5 14 ; and the same is true for the proteinuria of poisoning by metallic mercury.15In contrast, the urinary proteins of cadmium poisoning all sediment together during ultracentrifugation, and they have molecular weights in the 20,000-30,000 range.4 16 KENCH and his co-workers have studied in detail the urinary protein migrating electrophoretically as albumin in cadmium-poisoned men and animals, because its low molecular weight seemed to distinguish it from the albumin in other proteinuric states. Despite the great difference in molecular weight between urinary and serum albumins of cadmium-poisoned workmen, no significant difference was detected in their content of several of the constituent aminoacids.5 Rabbits and dogs, given repeated intravenous injections of cadmium chloride, have a pattern of urinary proteins similar to that seen in human intoxication, except that in those animals the albumin fraction contained both low molecular (S20W 199) and normal molecular (S 4-07) species. The low-molecular-weight component has been separated from albumin of normal size by gel filtration and identified as an albumin by its stability in organic solvents at low pH, its similar electrophoretic mobility, its identical immunological behaviour, and its general similarity in aminoacid composition to normal serum-albumin." Low-molecular-weight albumins (mol. wt. 5000-20,000) have been isolated from peritoneal dialysates of a nephrectomised poisoned monkey 18 and from the sera of poisoned monkeys three to five weeks before the onset of proteinuria. 1 The aberrant proteins have been named minialbumins. It seems likely that these proteins arise in extra-renal tissues, and they pass into the urine only later when renal tubular reabsorption has become impaired by cadmium ions in the glomerular filtrate. All minialbumins so far analysed resemble one another in aminoacid composition, and they are deficient in lysine and cystine compared with normal serum-albumin. Both the tryptophan residues of normal monkey albumin are missing in the minialbumins of poisoned animals.19 Minialbumins aggregate readily to form molecules of the usual size (mol. wt. 66,000) 20 and even larger (up to 170,000) in low-salt media, including physiological fluids. Aggregation is partially reversible by inorganic salts, urea, edetic acid, and reagents such as mercaptoethanol which attack disulphide bonds. An equilibrium exists between aggregated and disaggregated molecules. Albumins of conventional size in the serum of cadmium-poisoned monkeys-and presumably man-seem to be a mixture of approximately equal numbers of normal molecules and of molecules 14. Rowe, D. S. Biochem. J. 1957, 67, 435. 15. Smith, J. C., Wells, A. R. Br. J. ind. Med. 1960, 17, 205. 16. Kekwick, R. A. ibid. 1955, 12, 196. 17. Kench, J. E., Gain, A. C., Sutherland, E. M. S. Afr. med. J. 1965, 39, 1191. 18. Gain, A. C., Kench, J. E. S. Afr. J. Lab. clin. Med. 1965, 11, 77. 19. Kench, J. E., Sutherland, E. M. Br. J. ind. Med. 1967, 24, 326. 20. Kench, J. E., Sutherland, E. M. S. Afr. med. J. 1966, 40, 1109.
formed by aggregation of minialbumin. 40-60% of the albumin molecules circulating in the serum of cadmiumpoisoned animals are abnormal in aminoacid composition, molecular weight, or both. Urinary albumin of such animals contains relatively fewer molecules (approximately 13%) which are aggregates. Normal human serum-albumin is a single polypeptide chain containing approximately 575 aminoacid residues,21 of which only 1 is tryptophan.22 23 With a similar structure, normal monkey albumin has 2 tryptophan residues only,19which clearly excludes the possibility of minialbumin (mol. wt. 5000) being a repeating unit of the albumin molecule as a whole. The size and aminoacid composition of minialbumins is consistent with some derangement at an early step in catabolism of serumalbumin, perhaps in the liver, by which a mixture of peptides (mol. wt. 5000) accrues by fission of the albumin molecule along its length.2° One or more fragments containing both tryptophan residues and rich in lysine and cystine are metabolically removed. The remaining peptides are then able to aggregate to form molecules which electrophoretically and antigenically are indistinguishable from normal albumin. Microheterogeneity of serum-albumin has been well established by FOSTER and his colleagues.24 25 If this hypothesis is valid, cadmium ions may play an important physiological role in regulating the biosynthesis of molecular variants of albumin and perhaps of other proteins, including enzymes, the prototype only in each case being dependent on a specific D.N.A. code.
Annotations PLASMA PHOSPHOLIPIDS AND PLATELET STICKINESS IN MULTIPLE SCLEROSIS
MULTIPLE sclerosis is
one
of the conditions in which the
blood-platelets stick more readily than normal to each other or to glass.26 27 One suggestion 26 is that a rise in the unsaturated-fatty-acid concentration of the plasma in multiple sclerosis might be the cause of the increase in platelet stickiness; but the in-vitro studies of Kerr et a1.28 showed that the unsaturated fatty acids, linoleic and linolenic, were the only free fatty acids which did not Linolenic acid and lecithin cause platelet aggregation. inhibited platelet aggregation in the presence of the saturated fatty acids. Other phospholipids, however, promoted platelet aggregation in vitro. The aggregation produced by phosphatidic acid, phosphatidyl serine, and phosphatidyl ethanolamine was reversible in suitable conditions, but sphingomyelin and lysolethicin seemed to cause irreversible platelet aggregation. On p. 99 Dr. Bolton and others report findings which indicate that the lysolethicin of the low-density lipoproteins in the plasma of patients with multiple sclerosis is the factor responsible for the increased platelet stickiness 21. 22. 23. 24.
Potgieter, G. M., Hines, M., Kench, J. E. Clin. chim. Acta, 1967, 18, 107. Ramachandran, L. K., Witkop, B. J. Am. chem. Soc. 1959, 81, 4028. Spahr, P. F., Edsall, J. T. J. biol. Chem. 1964, 239, 850. Foster, J. F., Sogami, M., Petersen, H. A., Leonard, W. J. ibid. 1965, 240, 2495.
25. 26. 27. 28.
Petersen, H. A., Foster, J. F. ibid. p. 2503. Caspary, E. A., Prineas, J., Miller, H., Field, E. J. Lancet, 1965, ii, 1108. Payling Wright, H., Thompson, R. H. S., Zilkha, K. J. ibid. p. 1109. Kerr, J. W., MacAuley, I., Pirrie, R., Bronte-Stewart, B. ibid. 1965, i, 1296.