1565

sum score than those with low concentrations. These

findings suggest that any beneficial effects of a high serumvitamin A concentration on the early outcome in ischaemicstroke may be due to an interaction of the vitamin with the

early damaging chemical events that begin when ischaemiadisturbs normal brain function.

Oxygen deficiency due to ischaemia prevents oxidativephosphorylation and curtails production ofATP, the energysource of cellular ionic pumps. The result is a rapid loss ofpotassium from the cell, and the subsequent depolarisationof the cell membrane allows uncontrolled calcium entry intoneurons.1-3,15 During ischaemia there is also an increase inextracellular glutamate.16 Uncontrolled calcium entry intoneurons, partly mediated through overstimulation of N-methyl-D-aspartate-type glutamate receptors ’16 impairsmitochondrial function leading to a further reduction ofATP, and activates enzymes that degrade proteins, nucleicacids, and phospholipids.12 Phospholipid degradation leadsto formation of other products that are believed to causeneuronal damage-eg, arachidonic acid, eicosanoids,platelet-activating factor, and highly destructive freeradicals.1-3,17Vitamin A could interfere at any stage of this ischaemic

cascade of damaging biochemical interactions. One

explanation is that this vitamin protects neuronalmembranes from lipid peroxidation by free radicals.

However, if free-radical scavenging is the proposedmechanism, how can one explain the lack of difference inneurological outcome between patients with high and lowserum concentrations of vitamin E? Vitamins A and E arefat-soluble antioxidants that readily cross the blood-brainbarrier. Since we compared physiological concentrationsabove and below the mean serum vitamin E concentration ofthe study population, a protective effect against ischaemicbrain injury occurring only at very high vitamin Econcentrations cannot be excluded. In-vitro experimentswith rat brain tissue have shown that vitamin A is a far more

potent antioxidant than vitamin E.8 Moreover, vitamins Aand E may differ in their mode of antioxidant action. It hasbeen suggested that both intra-ischaemic and postischaemic(reperfusion) lipid peroxidation reactions occur. Vitamin Eseems to interact only with postischaemic reoxygenation-induced peroxidation.3 Vitamin E is effective at high oxygenconcentrations. By contrast, antioxidants such as

&bgr;-carotene, the precursor of vitamin A, are effective at lowoxygen concentrations.18 We do not know whether vitaminA is an effective antioxidant during ischaemia. Finally, theeffect of vitamin A could result from functions other thanfree-radical trapping. Vitamin A also plays an importantpart in preserving the structural integrity and normalpremeability of the cell membrane and the membranes ofsubcellular particles such as mitochondria and lysosomes.19

REFERENCES

1. Schmidley JW. Free radicals in central nervous system ischemia. Stroke1990; 25: 7-12.

2. Editorial. Treatment for stroke? Lancet 1991; 338: 1129-31.3. Yoshida S. Brain injury after ischemia and trauma. Ann NY Acad Sci

1989; 570: 219-36.4. Silvia RC, Piercey MF, Hoffmann WE, Chase RL, Braughler JM, Tang

AH. U74006, an inhibitor of lipid peroxidation, protects against lesiondevelopment following experimental stroke in the cat: histological andmetabolic analysis. Neurosci Abstr 1987; 13: 1499.

5. Hall ED, Pazara KE, Braughler J. The 21-aminosteroid lipidperoxidation inhibitor U7400F protects against cerebral ischemia ingerbils. Stroke 1988; 19: 997-1002.

6. Yoshida S, Busto R, Watson BD, Santiso M, Ginsberg MD.Postischemic cerebral lipid peroxidation in vitro: modification bydietary vitamin. J Neurochem 1985; 44: 1593-601.

7. Yamamoto M, Shima T, Uozumi T, Sogabe T, Yamada K, Kawasaki T.A possible role of lipid peroxidation in cellular damages caused bycerebral ischemia and the protective effect of alfa-tocopheroladministration. Stroke 1983; 14: 977-82.

8. Das NP. Effects of vitamin A and its analogs on nonenzymatic lipidperoxidation in rat brain mitochondria. J Neurochem 1989; 52: 585-88.

9. Mathew NT, Meyer JS, Rivera VH, Charney JZ, Hartmann A.Double-blind evaluation of glycerol treatment in acute cerebralinfarction. Lancet 1982; ii: 1327-29.

10. Mahoney FI, Barthel DW. Functional evaluation: the Barthel index.Md State Med J 1965; 14: 61-65.

11. Vuilleumier JP, Keller HE, Gysel D, Hunziker F. Clinical chemicalmethods for the routine assessment of the vitamin status in human

population. Part 1: the fat soluble vitamins A and E, and beta-carotene.Int J Vit Nutr Res 1983; 53: 265-72.

12. Allen CMC. Predicting the outcome of acute stroke: a prognostic score.J Neurol Neurosurg Psychiatry 1984; 47: 475-80.

13. Sundt TM, Grant WC, Garcia JH. Restoration of middle cerebral arteryflow in experimental infarction. J Neurosurg 1969; 31: 311-21.

14. Jones TH, Morawetz RB, Crowell RM, et al. Thresholds of focal cerebralischemia in awake monkeys. J Neurosurg 1981; 54: 773-82.

15. Sjiesjö BK, Bengtsson F. Calcium fluxes, calcium antagonists andcalcium related pathology in brain ischemia, hypoglycemia andspreading depression: a unifying hypothesis. J Cereb Flow Metab 1989;9: 127-40.

16. Rothman SM, Olney JW. Glutamate and the pathophysiology ofhypoxic-ischemic brain damage. Ann Neurol 1986; 19: 105-11.

17. Lindsberg PJ, Hallenbeck JM, Feuerstein G. Platelet-activating factor instroke and brain injury. Ann Neurol 1991; 30: 117-29.

18. Burton GW, Ingold KU. &bgr;-carotene: an unusual type of antioxidant.Science 1984; 224: 569-73.

19. Harper HA. The fat-soluble vitamins. In: Harper HA, Rodwell VW,Mayes PA, eds. Review of physiological chemistry. Los Altos: Lange,1979: 147-58.

From The LancetValue of medical degrees

"If a degree, in short, always has been, and, in spite of all theregulations which can be made, always must be, a mere piece ofquackery, it is certainly for the advantage of the public that it shouldbe understood to be so." Thus wrote Adam Smith in 1774, in aletter to Cullen, which has only recently seen the light. Thehypothesis is not new to the readers of The Lancet. We have alwaysenforced the doctrine practically, and, by dint of a little ridicule,have made many excellent men and scientific physicians ofindividuals who, without our aid, might have been "Dubs" (so wepleasantly designated them) and nothing better.... When he says,"There never was, and, I venture to say, there never will be, auniversity, from which a degree could give any tolerable securitythat the person upon whom it had been conferred was fit to practisephysic," it is evident from the context that his objection lies againstthe competency of the tribunal: he intimates that a degree, conferredby professors upon a "dutiful" pupil who had attended all theirlectures, taken notes of all the fine things they said, and paid them allthe fees which they chose to demand, could never be a safe criterionof competency. Again, when he reminds Cullen that "a degree canpretend to give security for nothing but the science of the graduate;and even for that it can give but a very slender security"; that "forgood sense and discretion, qualities not discoverable by anacademical examination, it can give no security at all"; he runs onthe verge of paradox in statement, but really means no more thaneverybody admits, that scholastic examinations are not absolutetests of the original powers of the mind, and that a man may get upand pass an examination without having all the qualities required forthe successful practice of physic, or the pursuit of any science.... Itmight be argued that one obvious advantage offered by the title of"doctor" would be its pointing out plainly to the public those whowere licensed to practise physic; but in that case it should beconferred on all who were licensed to practise; and the quackerycould only be got rid of by pretending to nothing more than thelicence to practise implied; for the essence of quackery consists in anunfounded pretension to superior knowledge, or to superiority. Theground on which the degree would be granted in such a case wouldbe that the title was a convenient designation of certain qualities, theappellative of a person possessing skill of a peculiar kind.

(Aug 27, 1842)