@Copyright i985 bv The Humana Press Inc. All rights of any nature whatsoever reserved. 0163--4984/85/0705-0153502.00
Multiple Sclerosis A Multielement Survey N. I. WARD AND D. BRYCE-SMITH*
Chemistry Department, University of Reading, Whiteknights, Reading, Berkshire, RG6 2AD, United Kingdom M. MINSKI
Imperial College Reactor Centre, Silwood Park, Sunninghill, Ascot, Berkshire, SL5 7PY, United Kingdom W. ]3. MATTHEWS
The University Department of Clinical Neurology, The Radcliffe Infirmary, Oxford, OX2 6HE Received September 14, 1984; Accepted November 20, "1984
ABSTRACT Levels of 35 elements have been measured in whole blood and ultrasonically washed scalp hair from multiple sclerosis patients ond matched control subjects from Oxford, England. Among the significant differences found, the low levels of vanadium and the high levels of barium in the patients were most marked and consistent. Although the etiological significance of the observations is unknown, the low hair-vanadium levels are in qualitative agreement with a previous Canadian report. Hair- and blood-lead levels in the patients and the controls were virtually identical. Index Entries" Multiple sclerosis, and trace elements; vanadium, in multiple sclerosis; barium, in multiple sclerosis; copper, in multiple sclerosis; lead, in multiple sclerosis; trace elements, and multiple sclerosis; sclerosis, trace elements and multiple. *Author to whom all correspondence and reprint requests should be addressed. Biological Trace Element Research
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INTRODUCTION Disorders in mineral metabolism have been among the many suggested etiologies of multiple sclerosis. Warren in particular has drawn attention to apparent relationships between soil mineralization and the marked variations in geographical incidence of the disease (1-4). Most of the reports have related to elevated lead levels (5-7), though Westerman et al. found no such elevation (8), and there have been scattered reports of raised exposure to zinc (3,4), and to copper (7) and its antagonist molybdenum (3,4). Ryan et al. have described a study of 13 elements in scalp hair of Canadian multiple sclerosis patients and control subjects, and reported significant differences in the levels of copper, iodine, manganese, sulfur, selenium, and vanadium (9). These persistent scattered reports, coupled with the known primary, roles of copper, molybdenum, and lead in certain neurological diseases of farm animals characterized by demyelination or myelin aplasia (e.g., "swayback" in lambs) (10), prompted the present pilot study in which the levels of 35 elements, including those mentioned above, have been determined in whole blood and scalp hair of a group of multiple sclerosis patients and matched controls from the Oxford (England) area.
MATERIALS AND METHODS There were ten subjects in each group, matched for age and sex. All the patients had clinically definite multiple sclerosis in accordance with accepted criteria (11). Venous blood was collected in vacutainers. Proximal scalp hair (ca. 1 cm) was collected from the nape of the neck midway between the ears, washed twice with double distilled water in an ultrasonic bath, and dried under an infrared lamp within an airtight enclosure. All analyses were conducted blind to the clinical classification, using a neutron activation procedure similar to that of Ward and Ryan (12) for all elements except lead, in which case electrothermal atomic absorption was employed. Cadmium, cobalt, chromium, copper, magnesium, manganese, and zinc were analyzed by both methods; the results were in good agreement ((_+12%), although the figures quoted in this paper are those obtained by neutron activation. The procedures for all the elements were initially checked by analysis of NBS-SRM bovine liver standard reference material, and for AI, Sb, As, Ba, Br, Cd, Ca, Cs, Cr, Co, Cu, I, Pb, Mg, Mn, Hg, Mo, Ni, Rb, Sc, Se, Ag, Sn, V, and Zn by analysis of pooled blood plasma from ten individuals before and after addition of amounts of each element corresponding to ten times the limit of detection. Recoveries of these standard additions ranged from 90% (Hg) to 102% (Ca and Se). In view of the low levels of vanadium, and the emphasis on this element in the present report, the following more detailed information is provided. Biological Trace Element Research
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Vanadium N e u t r o n activation analysis (naa): "y-ray energy used 1434 keV, detection limit on Currie's criterion (13) 0.0008 p.g/mL. Analysis of pooled blood plasma from 10 individuals (mean -+ standard deviation of 10 replicates): naa 0.0064 -+ 0.008 ~g V/mL; eaa 0.0065 +- 0.0016 jag V/mL. Recovery by naa of standard addition of V, 98%. Great care was taken to avoid contamination during collection and analysis of samples. The data are given in the units ~g/g for hair and txg/mL for blood.
RESULTS For the following elements,t no significant differences (p > O. 1) were found b e t w e e n multiple sclerosis patients and control subjects: Whole blood:
Hair:
Ag, A1, Au, As, Ca, Cd, CI, Co, Cr, Cs, Hg, I, La, Na, Mn, Mo, Ni, Pb, Rb, Sb, Sc, Sn, Sr, Ti, W, and Zn Ag, Ca, Cd, CI, Co, Cr, Cu, Fe, Hg, K, La, Mg, Na, Ni, Pb, Rb, S, Sc, Sn, Sr, Ti, and W
In view of the previous reports linking lead with multiple sclerosis
(5-7), the following data for lead are provided (patients, controls respectively; arith.mean - SD, ~.gg-~); hair Pb (washed); 10.44 m 2.18, 10.69 -+ 2.37: hair Pb (before washing); 13.36 m 3.20, 14.20 -+ 2.55: blood Pb; 0.115 +- 0.017, 0.115 ~ 0.020. Table 1 lists those elements for which significant (S) or borderline significant (BS) differences were found between hair levels in patients and controls, and Table 2 gives the corresponding data for whole blood: BS = 0.1 > p > 0.05; S = 0.05 > p > 0.01: 2-tailed t-test. Table 3 provides a comparison between the geometric means for the 13 elements in scalp hair reported by Ryan et al. (9) and those found in the present work. (The use of geometric means explains why some of the data in Table 3 differ slightly from those in Table 1).
DISCUSSION The present study does not support previous reports of associations between lead, zinc, or m o l y b d e n u m and multiple sclerosis (1-6,9). Any associations found are of borderline significance at best, and not apparent in both hair and blood. Although the two groups were carefully matched, the numbers involved were rather small, and the results do not t D a t a are available from the authors on request.
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TABLE 1 Element Levels (lag/g, Arithmetic Mean • Standard Deviation) in Scalp Hair from Multiple Sclerosis Patients and Controls Element
Multiple sclerosis, MS
Aluminum 6.61 Antimony 0.075 Arsenic 0.643 Barium 3.373 Bromine 9.81 Cesium 0.146 Gold 0.0113 Iodine 0.70 Manganese 0.553 Molybdenum 0.060 Selenium 0.64 Vanadium 0.0144 Zinc 172
= 1.42 = 0.038 • 0.651 • 2.919 • 4.12 • 0.031 = 0.0122 = 0.49 = 0.112 !- 0.013 • 0.16 --+ 0.0068 • 18
Controls, C 8.32 0.054 0.382 1.677 13.68 0.174 0.033 0.89 0.602 0.066 0.57 0.0288 182
• 2,70 • 0.022 • 0.230 • 0.713 • 3.92 • 0.063 -+ 0.0334 • 0.56 • 0.126 • 0.019 • 0.13 • 0.009 • 12
Relationship Significance C MS MS MS C C C C C C MS C C
>MS >C >C >C >MS >MS >MS >MS >MS >MS >C >MS > MS
S BS BS S S BS S~ BS BS BS BS S BS
'q'he difference between geometric means is nonsignificant, but for the other elements the use of geometric means does not alter the indicated significance. e x c l u d e the possibility that n e u r o l o g i c disorders associated w i t h o n e or m o r e of the above e l e m e n t s m a y s o m e t i m e s p r e s e n t as m u l t i p l e sclerosis. The q u e s t i o n of c o p p e r deficiency in relation to multiple sclerosis m e r i t s special c o n s i d e r a t i o n , (a) because the c y t o c h r o m e oxidase r e q u i r e d for b i o s y n t h e s i s of the p h o s p h o l i p i d s that largely c o n s t i t u t e m y e l i n is a c o p p e r - d e p e n d e n t e n z y m e (10), a n d (b) because of the large d i f f e r e n c e r e p o r t e d by R y a n et al. (9) b e t w e e n the hair c o p p e r levels of m u l t i p l e TABLE 2 Element Levels (l~g/mL, Arithmetic Mean - Standard Deviation) in Whole Blood from Multiple Sclerosis Patients and Controls Element Barium Bromine Copper Iron Magnesium Potassium Selenium Sulfur Vanadium
Multiple sclerosis, MS 0.144 4.09 1.06 462 36.9 1780 0.080 1760 0.0092
Controls, C
• 0.019 0.126 • 0.62 3.70 • 0.22 1.28 - 28 480 • 6.2 41.2 + 115 1688 • 0.027 0.097 • 62 1810 • 0.0024 0.0114
Biological TraceElement Research
--+ 0.022 • 0.41 • 0.46 • 26 • 5.6 • 67 • 0.029 • 104 = 0.0026
Relationship Significance MS MS C C C MS C C C
>C >C >MS >MS >MS > C >MS > MS >MS
S BS BS BS BS S BS S BS
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TABLE 3 Geometric Mean Levels in Ultrasonically washed Scalp Hair (tJ-g/g, Except for S) This study Element Aluminum Bromine Calcium Chlorine Copper Gold Iodine Manganese Selenium" Sodium Sulfur, ~ % Vanadium Zinc"
Ryan et al. (9)
MS
Controls
MS
Controls
6.52 8.90 524 410 11.92 0.0228 0.630 0.543 0.64 20.5 4.19 0.0131 172
7.98 13.03 584 390 12.18 0.0243 13.706 0.589 0.57 19.8 4.17 0.0249 182
5 5.0 210 1050 9 0.012 0.422 0.403 0.513 14 3.23 0.036 166
5 4.6 264 690 29 0.014 0.143 0.596 0.44 16 3.49 0.062 161
" A r i t h m e t i c m e a n s for b o t h s t u d i e s .
sclerosis patients and controls (see Table 3). However, the hair c o p p e r level of 29 ~g/g for control subjects reported by these workers is probably highly unrepresentative. The values of ca. 12 p,g/g for proximal hair f o u n d for both g r o u p s in the present study are m u c h m o r e in line with literature reports, e.g. 11.8 I~g/g for healthy subjects (14), a n d also with the m e a n value 11.03 -+ 3.16 p,g/g f o u n d for 100 healthy parturient w o m e n from Barnsley, England (15). However, blood c o p p e r levels in the p r e s e n t g r o u p of patients were lower than in controls (Table 2), a n d in view of uncertainties about hair copper as an index of more general c o p p e r status, a n d the evidence from animal studies (10) on the therapeutic effect of copper in d e m y e l i n a t i n g diseases, the possibility that mild c o p p e r deficiency could be a contributo D' factor in d i s t u r b e d m y e l i n a t i o n in h u m a n s remains open. A l t h o u g h statistically significant differences are a p p a r e n t for a n u m ber of e l e m e n t s in blood and/or hair, the cases of b a r i u m a n d v a n a d i u m s e e m particularly interesting because differences in the same direction occur in both w h o l e blood and hair for each element: b a r i u m tends to be h i g h e r a n d v a n a d i u m lower in the patients than in the controls. N o n e of the patients h a d ever been given a barium meal for X-ray examination. Ryan et al. (9) also reported elevated h a i r - v a n a d i u m levels in multiple sclerosis patients (Table 3): the differences in absolute levels from those in the p r e s e n t s t u d y may reflect differing exposure levels in C a n a d a a n d the UK, a n d / o r slight differences in the hair w a s h i n g procedures.
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Barium a n d v a n a d i u m are both elements of potential neurological significance: the latter is n o w classed as an essential m i c r o n u t r i e n t . Barium is a calcium antagonist that induces m u s c u l a r paralysis in cases of acute p o i s o n i n g , and despite the very low solubility of b a r i u m sulfate it is evidently sufficiently mobile to appear in hair a n d blood. The essentiality of v a n a d i u m appears to be associated inter alia with its role in the regulation of (Na/K)ATP-ase activity, a n d thereby the s o d i u m p u m p . There is evidence that v a n a d i u m is u n d u l y elevated in manic depressive psychosis to a d e g r e e that correlates significantly with the severity of the mania, a n d falls o n recovery (16). The fact that two separate studies of g e o g r a p h ically distant subjects have n o w f o u n d v a n a d i u m levels significantly depressed in multiple sclerosis patients raises the obvious question w h e t h e r bringing the levels up to a normal range, possibly c o u p l e d with increased calcium and copper intake, w o u l d p r o d u c e any effect. It may be recalled that v a n a d i u m in the form of m e t a v a n a d a t e s was earlier in this c e n t u r y u s e d in the treatment of a n u m b e r of conditions, i n c l u d i n g n e u r a s t h e n i a , apparently with some success (17). On the other h a n d , the epidemiological evidence that multiple sclerosis has its origins in childh o o d or a d o l e s c e n c e - - b e i n g possibly the rare sequela of a c o m m o n infection in early life precipitated by some u n k n o w n s e c o n d a r y factor or factors ( / / ) - - m a k e s it unlikely that any trace e l e m e n t or other biochemical abnormalities f o u n d in patients some decades later could be of primary etiological significance.
ACKNOWLEDGMENTS We are grateful for financial s u p p o r t p r o v i d e d by the C o o p e r Trust, Sanity, the KIB Foundation, Foresight, Esso Petroleum, The Shave Trust, a n d the Trustees of the Greene Charitable Settlement.
REFERENCES 1. H. V. Warren, J. Coil. Gen. Practit. 6, 517 (1963). 2. H. V. Warren, R. E. Delavault, and C. H. Cross, Ann. N Y Acad. Sci. 136, 657 (1967). 3. H. V. Warren and R. E. Delavault, Geolog. Soc. Am. 123, 97 (1971). 4. H. V. Warren, ]. Roy. Coll. Gen. Practit. 22, 56 (1972). 5. A. M. G. Campbell, G. Herdan, W. F. T. Tatlow, and E. G. Whittle, Brain 73, 52 (1950). 6. P. R. James, Med. J. Aust. 1, 219 (1975). 7. H. V. Warren, J. Biosoc. Sci. 6, 223 (1974). 8. M. P. Westerman, M. Bruetman, and E. Pfitzer, Arch. Environ. Hlth. 29, 355 (1974).
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9. D. E Ryan, J. Holzbecher, and D. C. Stuart, Clin. Chem. 24, 1996 (1978). 10. Trace Elements in Human and Animal Nutrition, 4th edn., E. J. Underwood, Academic Press, London, 1977, pp. 77-80. 11. Multiple Sclerosis: A Re-Appraisal, 2nd edn.,. D. McAlpine, Churchill Livingstone, Edinburgh, 1972, p. 202. 12. N. I. Ward and D. E. Ryan, Anal. Chem. Acta 105, 185 (1979). 13. L. A. Currie, Anat. Chem. 40, 586 (1968). 14. K. M. Hambidge, Am. /. Clin. Nutr. 26, 1212 (1973). I5. D. Bryce-Smith, N. [. Ward, and R. Watson. Unpublished studies. 16. G. J. Naylor, Biol. Psych. 18, 103, (1983); G. J. Naylor, A. H. W. Smith, D. Bryce-Smith, and N. I. Ward, Biol. Psych. 19, 759 (1984). 17. Toxicity of Industrial Metals, 2nd ed., E. Browning, Butterworths, London, 1969, p. 343.
Biological Trace Element Research
Vol. 7. 1985
Multiple Sclerosis A Multielement Survey N. I. WARD AND D. BRYCE-SMITH*
Chemistry Department, University of Reading, Whiteknights, Reading, Berkshire, RG6 2AD, United Kingdom M. MINSKI
Imperial College Reactor Centre, Silwood Park, Sunninghill, Ascot, Berkshire, SL5 7PY, United Kingdom W. ]3. MATTHEWS
The University Department of Clinical Neurology, The Radcliffe Infirmary, Oxford, OX2 6HE Received September 14, 1984; Accepted November 20, "1984
ABSTRACT Levels of 35 elements have been measured in whole blood and ultrasonically washed scalp hair from multiple sclerosis patients ond matched control subjects from Oxford, England. Among the significant differences found, the low levels of vanadium and the high levels of barium in the patients were most marked and consistent. Although the etiological significance of the observations is unknown, the low hair-vanadium levels are in qualitative agreement with a previous Canadian report. Hair- and blood-lead levels in the patients and the controls were virtually identical. Index Entries" Multiple sclerosis, and trace elements; vanadium, in multiple sclerosis; barium, in multiple sclerosis; copper, in multiple sclerosis; lead, in multiple sclerosis; trace elements, and multiple sclerosis; sclerosis, trace elements and multiple. *Author to whom all correspondence and reprint requests should be addressed. Biological Trace Element Research
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Vol. 7. 1985
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Ward et al.
INTRODUCTION Disorders in mineral metabolism have been among the many suggested etiologies of multiple sclerosis. Warren in particular has drawn attention to apparent relationships between soil mineralization and the marked variations in geographical incidence of the disease (1-4). Most of the reports have related to elevated lead levels (5-7), though Westerman et al. found no such elevation (8), and there have been scattered reports of raised exposure to zinc (3,4), and to copper (7) and its antagonist molybdenum (3,4). Ryan et al. have described a study of 13 elements in scalp hair of Canadian multiple sclerosis patients and control subjects, and reported significant differences in the levels of copper, iodine, manganese, sulfur, selenium, and vanadium (9). These persistent scattered reports, coupled with the known primary, roles of copper, molybdenum, and lead in certain neurological diseases of farm animals characterized by demyelination or myelin aplasia (e.g., "swayback" in lambs) (10), prompted the present pilot study in which the levels of 35 elements, including those mentioned above, have been determined in whole blood and scalp hair of a group of multiple sclerosis patients and matched controls from the Oxford (England) area.
MATERIALS AND METHODS There were ten subjects in each group, matched for age and sex. All the patients had clinically definite multiple sclerosis in accordance with accepted criteria (11). Venous blood was collected in vacutainers. Proximal scalp hair (ca. 1 cm) was collected from the nape of the neck midway between the ears, washed twice with double distilled water in an ultrasonic bath, and dried under an infrared lamp within an airtight enclosure. All analyses were conducted blind to the clinical classification, using a neutron activation procedure similar to that of Ward and Ryan (12) for all elements except lead, in which case electrothermal atomic absorption was employed. Cadmium, cobalt, chromium, copper, magnesium, manganese, and zinc were analyzed by both methods; the results were in good agreement ((_+12%), although the figures quoted in this paper are those obtained by neutron activation. The procedures for all the elements were initially checked by analysis of NBS-SRM bovine liver standard reference material, and for AI, Sb, As, Ba, Br, Cd, Ca, Cs, Cr, Co, Cu, I, Pb, Mg, Mn, Hg, Mo, Ni, Rb, Sc, Se, Ag, Sn, V, and Zn by analysis of pooled blood plasma from ten individuals before and after addition of amounts of each element corresponding to ten times the limit of detection. Recoveries of these standard additions ranged from 90% (Hg) to 102% (Ca and Se). In view of the low levels of vanadium, and the emphasis on this element in the present report, the following more detailed information is provided. Biological Trace Element Research
Vol. 7, 1985
A fflultielement Survey of Multiple Sclerosis
155
Vanadium N e u t r o n activation analysis (naa): "y-ray energy used 1434 keV, detection limit on Currie's criterion (13) 0.0008 p.g/mL. Analysis of pooled blood plasma from 10 individuals (mean -+ standard deviation of 10 replicates): naa 0.0064 -+ 0.008 ~g V/mL; eaa 0.0065 +- 0.0016 jag V/mL. Recovery by naa of standard addition of V, 98%. Great care was taken to avoid contamination during collection and analysis of samples. The data are given in the units ~g/g for hair and txg/mL for blood.
RESULTS For the following elements,t no significant differences (p > O. 1) were found b e t w e e n multiple sclerosis patients and control subjects: Whole blood:
Hair:
Ag, A1, Au, As, Ca, Cd, CI, Co, Cr, Cs, Hg, I, La, Na, Mn, Mo, Ni, Pb, Rb, Sb, Sc, Sn, Sr, Ti, W, and Zn Ag, Ca, Cd, CI, Co, Cr, Cu, Fe, Hg, K, La, Mg, Na, Ni, Pb, Rb, S, Sc, Sn, Sr, Ti, and W
In view of the previous reports linking lead with multiple sclerosis
(5-7), the following data for lead are provided (patients, controls respectively; arith.mean - SD, ~.gg-~); hair Pb (washed); 10.44 m 2.18, 10.69 -+ 2.37: hair Pb (before washing); 13.36 m 3.20, 14.20 -+ 2.55: blood Pb; 0.115 +- 0.017, 0.115 ~ 0.020. Table 1 lists those elements for which significant (S) or borderline significant (BS) differences were found between hair levels in patients and controls, and Table 2 gives the corresponding data for whole blood: BS = 0.1 > p > 0.05; S = 0.05 > p > 0.01: 2-tailed t-test. Table 3 provides a comparison between the geometric means for the 13 elements in scalp hair reported by Ryan et al. (9) and those found in the present work. (The use of geometric means explains why some of the data in Table 3 differ slightly from those in Table 1).
DISCUSSION The present study does not support previous reports of associations between lead, zinc, or m o l y b d e n u m and multiple sclerosis (1-6,9). Any associations found are of borderline significance at best, and not apparent in both hair and blood. Although the two groups were carefully matched, the numbers involved were rather small, and the results do not t D a t a are available from the authors on request.
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TABLE 1 Element Levels (lag/g, Arithmetic Mean • Standard Deviation) in Scalp Hair from Multiple Sclerosis Patients and Controls Element
Multiple sclerosis, MS
Aluminum 6.61 Antimony 0.075 Arsenic 0.643 Barium 3.373 Bromine 9.81 Cesium 0.146 Gold 0.0113 Iodine 0.70 Manganese 0.553 Molybdenum 0.060 Selenium 0.64 Vanadium 0.0144 Zinc 172
= 1.42 = 0.038 • 0.651 • 2.919 • 4.12 • 0.031 = 0.0122 = 0.49 = 0.112 !- 0.013 • 0.16 --+ 0.0068 • 18
Controls, C 8.32 0.054 0.382 1.677 13.68 0.174 0.033 0.89 0.602 0.066 0.57 0.0288 182
• 2,70 • 0.022 • 0.230 • 0.713 • 3.92 • 0.063 -+ 0.0334 • 0.56 • 0.126 • 0.019 • 0.13 • 0.009 • 12
Relationship Significance C MS MS MS C C C C C C MS C C
>MS >C >C >C >MS >MS >MS >MS >MS >MS >C >MS > MS
S BS BS S S BS S~ BS BS BS BS S BS
'q'he difference between geometric means is nonsignificant, but for the other elements the use of geometric means does not alter the indicated significance. e x c l u d e the possibility that n e u r o l o g i c disorders associated w i t h o n e or m o r e of the above e l e m e n t s m a y s o m e t i m e s p r e s e n t as m u l t i p l e sclerosis. The q u e s t i o n of c o p p e r deficiency in relation to multiple sclerosis m e r i t s special c o n s i d e r a t i o n , (a) because the c y t o c h r o m e oxidase r e q u i r e d for b i o s y n t h e s i s of the p h o s p h o l i p i d s that largely c o n s t i t u t e m y e l i n is a c o p p e r - d e p e n d e n t e n z y m e (10), a n d (b) because of the large d i f f e r e n c e r e p o r t e d by R y a n et al. (9) b e t w e e n the hair c o p p e r levels of m u l t i p l e TABLE 2 Element Levels (l~g/mL, Arithmetic Mean - Standard Deviation) in Whole Blood from Multiple Sclerosis Patients and Controls Element Barium Bromine Copper Iron Magnesium Potassium Selenium Sulfur Vanadium
Multiple sclerosis, MS 0.144 4.09 1.06 462 36.9 1780 0.080 1760 0.0092
Controls, C
• 0.019 0.126 • 0.62 3.70 • 0.22 1.28 - 28 480 • 6.2 41.2 + 115 1688 • 0.027 0.097 • 62 1810 • 0.0024 0.0114
Biological TraceElement Research
--+ 0.022 • 0.41 • 0.46 • 26 • 5.6 • 67 • 0.029 • 104 = 0.0026
Relationship Significance MS MS C C C MS C C C
>C >C >MS >MS >MS > C >MS > MS >MS
S BS BS BS BS S BS S BS
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TABLE 3 Geometric Mean Levels in Ultrasonically washed Scalp Hair (tJ-g/g, Except for S) This study Element Aluminum Bromine Calcium Chlorine Copper Gold Iodine Manganese Selenium" Sodium Sulfur, ~ % Vanadium Zinc"
Ryan et al. (9)
MS
Controls
MS
Controls
6.52 8.90 524 410 11.92 0.0228 0.630 0.543 0.64 20.5 4.19 0.0131 172
7.98 13.03 584 390 12.18 0.0243 13.706 0.589 0.57 19.8 4.17 0.0249 182
5 5.0 210 1050 9 0.012 0.422 0.403 0.513 14 3.23 0.036 166
5 4.6 264 690 29 0.014 0.143 0.596 0.44 16 3.49 0.062 161
" A r i t h m e t i c m e a n s for b o t h s t u d i e s .
sclerosis patients and controls (see Table 3). However, the hair c o p p e r level of 29 ~g/g for control subjects reported by these workers is probably highly unrepresentative. The values of ca. 12 p,g/g for proximal hair f o u n d for both g r o u p s in the present study are m u c h m o r e in line with literature reports, e.g. 11.8 I~g/g for healthy subjects (14), a n d also with the m e a n value 11.03 -+ 3.16 p,g/g f o u n d for 100 healthy parturient w o m e n from Barnsley, England (15). However, blood c o p p e r levels in the p r e s e n t g r o u p of patients were lower than in controls (Table 2), a n d in view of uncertainties about hair copper as an index of more general c o p p e r status, a n d the evidence from animal studies (10) on the therapeutic effect of copper in d e m y e l i n a t i n g diseases, the possibility that mild c o p p e r deficiency could be a contributo D' factor in d i s t u r b e d m y e l i n a t i o n in h u m a n s remains open. A l t h o u g h statistically significant differences are a p p a r e n t for a n u m ber of e l e m e n t s in blood and/or hair, the cases of b a r i u m a n d v a n a d i u m s e e m particularly interesting because differences in the same direction occur in both w h o l e blood and hair for each element: b a r i u m tends to be h i g h e r a n d v a n a d i u m lower in the patients than in the controls. N o n e of the patients h a d ever been given a barium meal for X-ray examination. Ryan et al. (9) also reported elevated h a i r - v a n a d i u m levels in multiple sclerosis patients (Table 3): the differences in absolute levels from those in the p r e s e n t s t u d y may reflect differing exposure levels in C a n a d a a n d the UK, a n d / o r slight differences in the hair w a s h i n g procedures.
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Barium a n d v a n a d i u m are both elements of potential neurological significance: the latter is n o w classed as an essential m i c r o n u t r i e n t . Barium is a calcium antagonist that induces m u s c u l a r paralysis in cases of acute p o i s o n i n g , and despite the very low solubility of b a r i u m sulfate it is evidently sufficiently mobile to appear in hair a n d blood. The essentiality of v a n a d i u m appears to be associated inter alia with its role in the regulation of (Na/K)ATP-ase activity, a n d thereby the s o d i u m p u m p . There is evidence that v a n a d i u m is u n d u l y elevated in manic depressive psychosis to a d e g r e e that correlates significantly with the severity of the mania, a n d falls o n recovery (16). The fact that two separate studies of g e o g r a p h ically distant subjects have n o w f o u n d v a n a d i u m levels significantly depressed in multiple sclerosis patients raises the obvious question w h e t h e r bringing the levels up to a normal range, possibly c o u p l e d with increased calcium and copper intake, w o u l d p r o d u c e any effect. It may be recalled that v a n a d i u m in the form of m e t a v a n a d a t e s was earlier in this c e n t u r y u s e d in the treatment of a n u m b e r of conditions, i n c l u d i n g n e u r a s t h e n i a , apparently with some success (17). On the other h a n d , the epidemiological evidence that multiple sclerosis has its origins in childh o o d or a d o l e s c e n c e - - b e i n g possibly the rare sequela of a c o m m o n infection in early life precipitated by some u n k n o w n s e c o n d a r y factor or factors ( / / ) - - m a k e s it unlikely that any trace e l e m e n t or other biochemical abnormalities f o u n d in patients some decades later could be of primary etiological significance.
ACKNOWLEDGMENTS We are grateful for financial s u p p o r t p r o v i d e d by the C o o p e r Trust, Sanity, the KIB Foundation, Foresight, Esso Petroleum, The Shave Trust, a n d the Trustees of the Greene Charitable Settlement.
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9. D. E Ryan, J. Holzbecher, and D. C. Stuart, Clin. Chem. 24, 1996 (1978). 10. Trace Elements in Human and Animal Nutrition, 4th edn., E. J. Underwood, Academic Press, London, 1977, pp. 77-80. 11. Multiple Sclerosis: A Re-Appraisal, 2nd edn.,. D. McAlpine, Churchill Livingstone, Edinburgh, 1972, p. 202. 12. N. I. Ward and D. E. Ryan, Anal. Chem. Acta 105, 185 (1979). 13. L. A. Currie, Anat. Chem. 40, 586 (1968). 14. K. M. Hambidge, Am. /. Clin. Nutr. 26, 1212 (1973). I5. D. Bryce-Smith, N. [. Ward, and R. Watson. Unpublished studies. 16. G. J. Naylor, Biol. Psych. 18, 103, (1983); G. J. Naylor, A. H. W. Smith, D. Bryce-Smith, and N. I. Ward, Biol. Psych. 19, 759 (1984). 17. Toxicity of Industrial Metals, 2nd ed., E. Browning, Butterworths, London, 1969, p. 343.
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