By Alwin M. Pappenheimer, MD
Summary: A fascinating snapshot of some of the early animal research testing vitamin E deficiency. In this 1940 lecture, Dr. Alwin Pappenheimer details the grave and varied muscular and neural dystrophies that result in different species fed a diet lacking vitamin E. The young are particularly susceptible, he notes, often showing no symptoms for months after birth before being suddenly struck with neural or muscular dysfunction—the latter a condition he terms “nutritional muscular dystrophy.” In perhaps the most disturbing finding, a partial vitamin E deficiency in the diet of pregnant rats was shown to affect only the offspring—not the mothers, suggesting that what we today attribute to genetic inheritance is actually a problem of inherited malnutrition. In the words of Dr. Pappenheimer: “The fact that a partial deficiency of vitamin E in the mother may manifest itself only in the offspring seems to me to be one of the most significant lessons that one can draw from this work. May not similar things happen in human diseases and help explain the supposed hereditary or familial character of certain nervous and muscular disorders?” From Journal of the Mount Sinai Hospital, 1941. Lee Foundation for Nutritional Research reprint 57.[The following is a transcription of the original Archives document. To view or download the original document, click here.]
Certain Nutritional Disorders of Laboratory Animals Due to Vitamin E Deficiency
Delivered at the Blumenthal Auditorium, the Mount Sinai Hospital, New York City, May 14, 1940, as part of the Symposium on Vitamins.
In his Welch lecture last October, Dr. Evans1 presented a masterly review of the current status of the problems centering about the deficiency of vitamin E. It was obviously with some misgiving that I accepted the invitation to speak on a similar topic. However, having yielded to the temptation, I had best concentrate on the pathology of the various disorders that one may, with more or less assurance, ascribe to vitamin E deficiency. The chemical aspects of the problems, which are of course the really fundamental ones, I must, to my regret, leave to others.
I should like to preface my talk by emphasizing that I am speaking for my colleague, Dr. Marianne Goettsch, as well as for myself. We have been working in close collaboration on these nutritional diseases for the past ten years, and it has been, for me at least, a delightful and profitable association.
I. Nutritional Encephalomalacia of Chicks
About ten years ago, Dr. Goettsch and I2 set out to study the effect of vitamin E deficiency on reproduction in fowl. We placed day-old chicks on a simplified diet of skimmed milk powder, casein, lard, cornstarch, cod-liver oil, yeast, salts, and roughage. They throve nicely for the first three weeks or so and then began to show a variety of symptoms pointing to some grave disorder of the central nervous system—tremors, forced movements, head retraction, muscular weakness, somnolence. These symptoms often came on very suddenly, and many of the chicks died. Some, however, recovered, and as we became more familiar with the disease, we found many instances in which the symptoms were transient or even imperceptible, and yet definite lesions were found when the animals were killed. The incidence of the disease in several thousand chicks on our experimental diet has been about 60 percent, and we have not succeeded in finding out why all the birds did not succumb. We have tried four different breeds, and all are equally susceptible. But as the chicks grow older, the incidence becomes progressively less, and the adult bird is completely resistant.
The underlying pathology of this disease proved to be interesting. The cerebellum was most often affected, then the cerebrum, less often the midbrain and medulla. The essential lesion is an ischemic necrosis—often so extensive as to destroy four-fifths of the cerebellum of one or both hemispheres. Necrosis of ganglion cells, edema, hemorrhages, and the constant finding of hyaline thrombi in the small vessels—these were the characteristic features, which pointed unmistakably to a circulatory blockage as the cause of the lesions. Ink or dyestuff could not penetrate the affected areas, even in the earliest stages. However, we have never been able to determine whether the vascular occlusion was primarily functional or due to the capillary thrombi.
In chicks that survived this acute phase of the disease, reparative changes occurred—gliosis, new growth of blood vessels and reticulum fibers, and calcification. Such spontaneous healing, even in the absence of supplemental treatment with vitamin E, is comparable to the spontaneous recovery that occurs in young rats with muscular dystrophy due to vitamin E deficiency. There appears thus to be a critically susceptible period.
We did not at once recognize this nutritional encephalomalacia of chicks as a manifestation of vitamin E deficiency, in spite of the fact that our experimental diet was purposely lacking in this factor. We were led astray by the observation that a diet of natural foods in which vitamin E had been destroyed by treatment with ethereal ferric chloride, after the method of Waddell and Steenbock,3 failed to evoke the disease; also the addition of various foods supposedly rich in this factor did not always afford protection.
We were further influenced by the current view that vitamin E is concerned primarily—and as was then believed, exclusively—with reproduction. It turned out that we were wrong. The chicks could be regularly protected by a variety of vegetable fats when these were substituted for an equivalent amount of lard in diet 108 [sic]. The activity was found to reside in the nonsaponifiable fractions of the alcoholic extracts, even after removal of the sterols, and a very considerable concentration of the active factor was thus effected. Following the chemical isolation of vitamin E by Evans, Emerson, and Emerson5 in 1936 and its identification as alpha-tocopherol, it was an obvious experiment to test its efficiency in the prevention of this disease.
This has been done by us6 and independently by Dam, Glavind, Bernth, and Hagens7—indeed the publicational priority belongs to those workers. It has been found that complete protection may be obtained by the daily administration of 0.2 mg of either the natural or the synthetic alpha-tocopherol or the tocopherol acetate. It is of course possible that other tocopherols or their derivatives may prove effective, but this has not yet been tested. The observation that the protective effect of natural foods against encephalomalacia is not destroyed even when the antisterility factor is rendered ineffective by ethereal ferric chloride treatment also demands further explanation. Ni8,9 has also obtained partial protection by the addition of 2 percent donkey skin gelatin (Ah-Chiaco) to an encephalomalacia-producing diet, but the protective factor in this substance has not been chemically defined.
It was interesting to find that this chick disease—manufactured in the laboratory—had its counterpart in the field. “Crazy chick disease,” as it is called, had been familiar to New England farmers for a number of years. Its identity, as far as symptoms and lesions are concerned, with the experimental encephalomalacia was established by Jungherr in 193610 and by others since. There is little reason to doubt that it will be found to be preventable by proper dietary supplement.
Before leaving the subject of vitamin E deficiency in chicks, I should refer to the recent paper of Dam and Glavind11 on “Alimentary Exudative Diathesis.” An extreme subcutaneous edema appeared in some of their chicks, and this they regard as a characteristic manifestation of vitamin E deficiency, indeed suggesting that it might afford a method of biological assay since it was preventable by wheat germ oil and by alpha-tocopherol. In our monograph “Encephalomalacia” (Bulletin 229 of the Storrs Agricultural Experiment Station), we have noted the rare occurrence of edema—most often, as was the case in the experiments of Dam and Glavind, on a low-fat diet. It was seen but once on diet 108, and there was no correlation between the generalized edema and the cerebral lesions.
II. Nutritional Myopathy of Ducklings
When the encephalomalacia-producing diet 108 was tried on ducklings, it produced effects quite different from those found in chicks.12 Clinically, the chief symptom was muscular weakness, so extreme in the last stages that the animals could not stand erect or even hold their heads up from the table. Symptoms of brain injury, such as tremors, forced movements, coma, etc., were never observed. And indeed in the duckling the brain and other parts of the central nervous system were found to be unaffected. The skeletal muscles, however, showed definite lesions. There was hyaline necrosis of the fibers, with rupture and segmentation, followed by a cellular reaction of leucocytes and histocytes and attempts at regeneration by the activated myoblasts. The lesions are thus practically identical with those produced in guinea pigs, rabbits, and young rats by vitamin E deficient diets. Although we have obtained protection with Crisco and partial protection with the nonsaponifiable fractions of soybean oil, the crucial experiment with alpha-tocopherol has not yet been carried out. This laboratory disease also proves to have its counterpart in the enzootic muscular dystrophy of ducklings described by Seifried and Heidegger13 in Bavaria.
III. Nutritional Myopathy of the Gizzard in Turkeys
The turkey reacts to vitamin E deficient diets in a very individual manner. The nervous system and skeletal muscles escape; it appears to be the smooth muscle of the gizzard, as Jungherr first observed, that is peculiarly vulnerable. There appears a patchy hyaline necrosis of the smooth muscle fibers, attended at first by an acute inflammatory reaction and followed later by fibrosis and attempts at regeneration of the muscle fibers. Dr. Jungherr and I14 have been able to lower the incidence of the disease by administering soybean oil or wheat germ oil but have not as yet tried out alpha-tocopherol.
Similar lesions have been found in young turkey poults obtained from commercial hatcheries.
IV. Nutritional Muscular Dystrophy in Guinea Pigs and Rabbits
The generalized degeneration of the muscles in these animals, for which Dr. Goettsch and I suggested the term nutritional muscular dystrophy, was first observed by us in 1931 to develop following an ethereal-ferric-chloride–treated scorbutic diet supplemented by adequate amounts of orange or tomato juice.15 Since then it has been studied by a number of other workers—among whom I may mention Morgulies and Spencer;16 Ni;17 Woodward and McKay;18 Chor and Dolhart;19 Shimotori, Emerson, and Evans;20 Mackenzie and McCollum;21 Morris;22 and Madsen,23 who have found little difficulty in producing the disease. Although the course, duration, and intensity vary considerably in individual animals, their clinical behavior is on the whole quite characteristic. After a period of normal growth, which may range from two weeks to six months or more, there is an abrupt cessation, followed usually by a precipitous muscular weakness. The animals become lethargic and develop increasing muscular weakness to the point of almost complete helplessness, so that they cannot right themselves when placed on their back and cannot reach their food pans. In this state, they die, and we have never observed spontaneous recovery.
The skeletal muscles throughout the body are found to show extreme lesions, which however are not usually symmetrical and do not of necessity affect a muscle in its entirety. Both the gross and microscopic appearances depend on the duration and intensity of the lesions. In the very early and acute stages, which may develop within a few hours, the muscles are somewhat pale and watery, and the contractility is lost. Microscopically, there is extreme hyaline necrosis and fragmentation of the fibers as well as much interstitial edema. Very soon, however, there is a violent cellular reaction. The necrotic fibers become invaded by polymorphonuclear leucocytes and by histocytes, which often fuse to form plasmatic multinucleate masses about the necrotic remnants. These may become calcified. Particularly in young animals, the muscle nuclei, which escape destruction, early become activated. They divide mitotically and arrange themselves in rows; new myofibrils are formed on the surface; and the cytoplasm, which at first stains purplish, becomes red as the myohemoglobin is regenerated. This regeneration is sometimes extraordinarily active, even while the degenerative alterations are in full blast.
The dystrophic changes are not always as fulminating as I have depicted them, and the disease may run a chronic course. In such animals comparatively few fibers are destroyed at any one time, but their gradual loss and replacement by fat and fibrous tissue brings about a picture identical to that of an advanced case of human muscular dystrophy. Such animals may survive for many months, dying finally of inanition or of a terminal pneumonia. There are several points in the pathology that I should like to stress. One is the excellent preservation of neuritis and end plates in the midst of the necrotic muscle cells.21 With Dr. Wolf’s assistance, we have studied the brain and spinal cord quite thoroughly in some of our animals and have seen no alterations that seemed to be of significance. The histological evidence, therefore, favors a primary muscular lesion rather than a neural one. (Ekblad and Wohlfart [Zisch. I. Gos. Neurol. U. Psych.: 168: 145, 1940] have recently described sclerotic changes in the ganglion cells of the spinal cord. These have not been present in our material.)
Another point is the striking selectivity of the lesions for the skeletal muscles. Madsen,23 working in our laboratory, found degenerative changes in the heart muscle of a few rabbits and guinea pigs, but I am not wholly convinced that these lesions are referable to the vitamin E deficiency. They are certainly not a usual finding in this disease. The smooth muscle is never affected. Most of the animals die before the age of sexual maturity, and we have not been able to study the effect of vitamin E deficiency on reproduction in the rabbit or guinea pig. One of our rabbits, however, gave birth to two young while she was still in the incipient stage of the disease, as shown by biopsy. The young were scrawny and weak and survived but a day. Their muscles were found to show extreme degeneration, so that the development of the disease in utero was certain, and the normal transference of vitamin E to the embryo through the placenta may be assumed.
Since the preliminary report of this observation in 1936,25 we have been able to study twenty young born of mothers maintained on diet 48, in which 8 percent of soybean oil was substituted for the lard in diet 11. This sufficed to protect the mothers against muscle dystrophy for periods up to 958 days. It was not sufficient, however, to prevent the development of muscle dystrophy in the offspring during late intrauterine or early postnatal life. Sixteen of the twenty young, born dead or surviving less than 5 days, showed lesions of varying intensity in the muscles. The remaining four, with normal muscles, were all first litter animals.
An interesting feature of the disease in newborn rabbits is the accompanying edema of the subcutaneous tissue and intramuscular connective tissue, which is perhaps analogous to the “exudative diathesis” regarded by Dam and Glavind as a manifestation of vitamin E deficiency in the chick.
There is also an analogy to the muscular dystrophy of young rats born of mothers partially deprived of vitamin E, with the difference that in the rabbits the disease is present at birth, while in the rats it appears only at the end of lactation.
What is the evidence that this muscle disease of rabbits and guinea pigs is really a manifestation of vitamin E deficiency? This question was discussed very thoroughly by Dr. Evans in his Welch lecture. The evidence in favor of this view is accumulating.
In our original paper, Dr. Goettsch and I thought that we could eliminate the lack of vitamin E as a factor in the causation of the disease since daily doses of approximately 200 mg of tested wheat germ oil failed to protect guinea pigs. In addition guinea pigs and rabbits on the diet that had not been treated with ethereal ferric chloride and contained vitamin E in amounts adequate for normal reproduction in rats eventually developed dystrophy. In the light of subsequent work, it would seem that the dosage, [with] the particular diet used (containing lard and cod-liver oil), was probably inadequate.
Mackenzie and McCollum,21 using the creatine excretion as a criterion of the disease, have obtained curative effects with alpha-tocopherol. Morris,22 with doses of 18 to 25 mg, obtained definite symptomatic cures. Shimotori, Emerson, and Evans20 effectively prevented the disease in guinea pigs over a period of 200 days by supplementing the diet with 3 mg of synthetic alpha-tocopherol on alternate days.
Dr. Goettsch and I have also succeeded in producing remissions and, in a few instances, permanent cures in guinea pigs by feedings or injections of 20 to 25 mg of synthetic alpha-tocopherol. The progress of the disease in our animals was followed by repeated muscle biopsies, and we were amazed to find that severe lesions may completely disappear within a week following the injection or feeding of a single dose. The evidence then supports the view that vitamin E deficiency is the essential thing in the causation of this disease and does not substantiate the contention of Morgulies24 that there is an additional water-soluble factor (B4?) concerned.
The point of view advocated by Madsen, McCay, and Maynard27 that the toxicity of cod-liver oil for the herbivora is the essential factor in the production of muscular dystrophy cannot, we think, be maintained in the face of Cummings and Mattill’s28 demonstration that cod-liver oil brings about the oxidative destruction of vitamin E. The more recent findings of Davis, Maynard, and McCay29 show that the addition of 3 percent cottonseed oil to a synthetic dystrophy-producing diet prolongs [protection] and in some cases prevents the disease. This finding can also be explained by the vitamin E content of the vegetable oil.
A rather instructive illustration of the effect of cod-liver oil in precipitating muscular dystrophy was brought to our attention by Dr. Leonard Goss of the Bronx Zoological Garden.30 Four tree-kangaroos were placed on exhibition at the World’s Fair, and to make them especially presentable, they were given large amounts of fish liver oil. They sickened, and three of them died, [showing] extreme muscular dystrophy. The third one was brought back to the Bronx Zoo but continued to show muscular weakness in spite of the withdrawal of fish liver oil from the diet. He was then given alpha-tocopherol and made a rapid and spectacular recovery.
V. Muscular Dystrophy in Young Rats
This chapter of the story begins with the report of Evans and Burr31 in 1928 that the offspring of female rats partially depleted of vitamin E often became more or less completely paralyzed towards the end of the lactation. Some of the rats died, while others recovered, with or without residual weakness. But it was not until the publication of Olcott’s paper32 in 1936 that the pathology underlying these symptoms was made clear. Olcott found widespread necrosis of the skeletal muscles—lesions essentially like those in the more acute phases of the muscular dystrophy of rabbits and guinea pigs. We have confirmed and perhaps amplified Olcott’s observations,32 as have Telford, Emerson, and Evans.34 The disease often develops with almost explosive suddenness, and—what to us seems very remarkable—it appears to be self-limited if the young rats survive. Even without any vitamin E supplement, healing of the muscle lesions occurs with astonishing rapidity, so that after a week little trace of the original devastation can be found. This is one of the interesting problems in connection with this curious disease that remains to be investigated.
As was the case with the chicken encephalomalacia, the symptoms are not always a reliable criterion. We frequently find extensive muscle lesions in rats killed on the 24th or 25th day. These rats have shown none of the usual symptoms, such as clenching of the paws, rough fur, bloody crusts about the eyes, and paresis.
Dr. Goettsch and Dr. Ritzman,35 modifying Evan’s original procedure slightly, have induced the muscle disease in a high percentage of rats. There appear, however, to be individual differences in the amount of vitamin required by the mother rat to protect her children against the disease, and these constitutional differences, which may conceivably have a bearing on the incidence of muscle dystrophy in humans, are being studied further.
Although our own studies have been restricted almost entirely to young rats, others have found lesions both of the muscles (Knowlton and Hines36) and of the spinal cord (Einarson and Ringsted37) in older rats maintained for several months on a vitamin E deficient diet. The studies of the Danish observers are of particular interest [since] the degeneration of the pyramidal tracts and anterior cells as well as of the dorsal sensory tracts offer a resemblance to the lesions of amyotrophic lateral sclerosis in man. In two of a number of our older rats, Dr. Wolf has found similar changes. The therapeutic results recently reported by Dr. Wechsler38 and Bicknell39 in England at least offer the hope that the analogy between the rat and the human disease is not a superficial one.
It is now well established—through the work of Evans and Burr,31 of Morelle,40 of Barrie,41 of Demole and Pfaltz,42 of Goettsch and Ritzmann,35 and of Knowlton, Hines, and Brinkhous43 —that this muscular dystrophy of young rats is effectively prevented by wheat germ oil and by alpha-tocopherol, either natural or synthetic. A single dose of 0.5 mg administered on or before the seventeenth day regularly confers protection. Oil of wheat germ treated with ethereal ferric chloride was still antidystrophic in spite of the fact that 20 mg failed to prevent resorption in vitamin E depleted rats, and this discrepancy invites further study.
In the hope of learning something further of the pathogenesis of the muscle lesions, we have during the past winter performed some rather interesting though childishly simple experiments.44
The sciatic nerve to the left leg was resected, and the histological lesions of the gastrocnemius muscle on the two sides were compared. It was found, to our surprise, that the dystrophic lesions did not develop in the muscle deprived of its nerve supply when the operation was performed at any time between the fifth and the seventeenth day. When, however, the nerve was cut on the eighteenth day, the protection was no longer effective—either because the irritability of the distal segment persisted for a day or two or because the changes initiating the muscle necrosis were already underway, although there were at the time no visible symptoms or gross lesions (Table 1).
These results seemed to inculpate some obscure nervous influence in the production of the lesions. We have had the thought that the necrosis might be the result of angiospasm. The persistence of a shell of intact fibers on the surface of the muscle suggested that they might have been spared because of an additional blood supply from the fascial vessels. Loss of sympathetic innervation through section of the sciatic nerve might then have inhibited the vasoconstriction causing the necrosis.
This pretty idea received a rude shock when we found that section of the Achilles tendon leaving the nerve supply intact was equally effective in protecting the gastrocnemius (Table 2). It is therefore not the loss of nerve supply per se that is essential, but rather [it is] the loss of muscle tonus that affords protection. We have found further that mere inactivity of the muscle is not sufficient to prevent the lesions. We placed one hind limb in a molded copper splint, completely immobilizing the knee and tibio-tarsal joints in the extended position. Since the mother rat resolutely opposed this procedure and tore off the splints, it was necessary to feed the young rats on skimmed milk with a dropper. The splinting did not protect, and lesions were found on both sides. The effect of transection of the spinal cord at the lower dorsal or upper lumbar levels was also studied in a fairly large series, but the effects as regards the muscles of the lower extremities were not consistent, probably because of the varying extent of the destruction of the cord below the level of the section.[Table, with title:] Table 1. Effect of Section of Left Sciatic Nerve On Muscular Dystrophy of Young Rats on Vitamin-E-Deficient Diet. (See original for data).
The interpretation of such experiments is not easy, and it is obvious that much further work must be done before we can even guess at the precise role that vitamin E plays in muscle physiology. That the denervated or tenotomized muscle is less sensitive to the lack of vitamin E than the functionally active muscle seems proven. But we do not know why and have not been able, as yet, to formulate a plausible hypothesis.
One is tempted to conclude a lecture of this sort with some sweeping generalizations. But it is pretty obvious that we are only at the beginning of our knowledge as to the fundamental role that the tocopherols and related substances play in nutrition. As to the applicability of results obtained with laboratory animals to problems of human disease, one can make no forecasts, but the work has gone far enough, it seems to me, to justify a cautious empiricism. The fact that a partial deficiency of vitamin E in the mother may manifest itself only in the offspring seems to me to be one of the most significant lessons that one can draw from this work. May not similar things happen in human diseases and help to explain the supposed hereditary or familial character of certain nervous and muscular disorders?[Table, with title:] Table 2. Tenotomy of Left Gastrocnemius. (See original for data.)
By Alwin M. Pappenheimer, MD, Department of Pathology, College of Physicians and Surgeons, Columbia University, New York City. Reprinted from Journal of the Mount Sinai Hospital, Vol. VII, No. 2, by the Lee Foundation for Nutritional Research.
1. Evans, H.M. “New Light on the Biological Role of Vitamin E.” J. Mount Sinai Hosp., 6:233, 1940.
2. Pappenheimer, A.M., and Goettsch, M. “A Cerebellar Disorder in Chicks, Apparently of Nutritional Origin.” J. Exp. Med., 53: 11, 1931.
3. Waddell, J., and Steenbock, H. “The Destruction of Vitamin E in a Ration Composed of Natural and Varied Foodstuffs.” J. Biol. Chem., 80: 431, 1928.
4. Goettsch, M., and Pappenheimer, A.M. “The Prevention of Nutritional Encephalomalacia in Chicks by Vegetables Oil and Their Fractions.” J. Biol. Chem., 114: 673, 1936.
5. Evans, H.M., Emerson, O., and Emerson, G.A. “The Isolation from Wheat Germ Oil of an Alcohol, Alpha-Tocopherol, Having the Properties of Vitamin E.” J. Biol. Chem., 113: 319, 1936.
6. Pappenheimer, A.M., Goettsch, M., and Jungherr, E. “Nutritional Encephalomalacia in Chicks and Certain Related Disorders of Domestic Birds.” Bull. 229, Storrs Agr. Exp. Station, June 1939.
7. Dam, H., Glavind, J., Bernth, O., and Hagens, E. “Anti-encephalomalacic Activity of dl-Alpha-Tocopherol.” Nature, 142: 1157, 1938.
8. Ni, T.G. “The Prevention of Nutritional Encephalomalacia by Gelatin.” Chinese J. Phys., 12: 281, 1937.
9. Ni, T.G. “Further Experiments on the Prevention of Nutritional Encephalomalacia in Chickens.” Chinese J. Phys., 13: 229, 1938.
10. Jungherr, E. “A Field Condition Resembling Nutritional Encephalomalacia in Chicks.” Science, 84: 559, 1936.
11. Dam, H., and Glavind, J. “Alimentary Exudative Diathesis and Its Relation to Vitamin E.” Skand. Arch. f. Phys., 82: 299, 1939.
12. Pappenheimer, A.M., and Goettsch, M. “Nutritional Myopathy in Ducklings.” J. Exp. Med., 59: 35, 1934.
13. Seifried, O., and Heidegger, E. “Untersuchungen uber eine enzootisch auftretende muskeldystrophie bei jungen enten.” Arch. f. wiss. U. prakt. Tierhlk., 70: 122, 1936.
14. Jungherr, E., and Pappenheimer, A.M. “Nutritional Myopathy of the Gizzard in Turkeys.” Proc. Soc. Exp. Biol. and Med., 37: 520, 1937.
15. Goettsch, M., and Pappenheimber, A.M. “Nutritional Muscular Dystrophy in Guinea Pig and Rabbit,” J. Exp. Med., 54: 145, 1931.
16. Morgulies, S., and Spencer, H.C. “A Study of the Dietary Factors Concerned in the Nutritional Muscular Dystrophy.” J. Nutrition, 11: 573, 1936.
17. Ni, T.G. “Effect of Donkey Skin Gelatin (Ah-Chiaco) Upon Nutritional Progressive Muscular Dystrophy.” Chinese J. Phys., 10: 237, 1936.
18. Woodward, J.W., and McKay, C.M. “Synthetic Diets for Herbivore.” Proc. Soc. Exp. Biol. and Med., 30: 241, 1932.
19. Chor, H., and Dolhart, R.E. “Experimental Muscular Dystrophy in the Guinea Pig.” Arch. Path., 27, 497, 1939.
20. Shimotori, N., Emerson, G.A., and Evans, H.M. “Role of Vitamin E in the Prevention of Muscular Dystrophy in Guinea Pigs Reared on Synthetic Rations.” Science, 90: 89, 1930.
21. Mackenzie, C.G., and McCollum, E.V. “Vitamin E and Nutritional Muscular Dystrophy.” Science, 89: 370, 1939; “The Cure of Nutritional Muscular Dystrophy in the Rabbit by Alpha-Tocopherol and Its Effect on Creatine Metabolism.” J. Nutrition, 19: 345, 1940.
22. Morris, S.G. “Synthetic Alpha-Tocopherol and Nutritional Muscular Dystrophy.” Science, 90: 424, 1939.
Joseph H. Globus, MD, Editor-in-chief
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