ALIMENTARY TRACT
Gums.—Where it has been possible to examine the gums of early cases, where swelling, redness or bluish discoloration are the chief symptoms and before secondary infection has set in, the microscopic picture is very similar to that of the skin. Small hemorrhages, round-celled infiltration, increase of connective tissue, clumps of pigment containing cells, or a diffuse deposit of brownish granules complete the picture. Congestion and edema are usually evident. The changes are most pronounced in the deeper layers of the submucosa and about the muscles, leaving the superficial layers strikingly intact, beneath an apparently normal epithelium. In the later stages, erosion of the mucosa occurs, and the upper layers of submucosa become involved. Polynuclear cells appear in great numbers, abscesses and ulcers are formed, which with proper staining can be shown to harbor the various types of mouth bacteria, cocci, spirillæ, etc. The pigmentation becomes intense, and a marked increase of the newly-formed connective tissue takes place.
The lesions of the stomach are neither characteristic nor, as a rule, very striking. Hemorrhages occur, the larger ones generally in the subperitoneal layers, the smaller ones in any of the coats. Thickening of the wall follows or accompanies these hemorrhages. Superficial erosions of the mucosa or even ulcers may be seen.
The striking congestion of the duodenum has been fully discussed in considering the gross pathology. At any level in the intestinal tract hemorrhage may take place, with the resulting pigmentation and scar tissue formation. The lymphoid structures—solitary follicles and Peyer’s patches—are usually intensely congested and often the seat of hemorrhage. They constitute the sites of predilection for ulcerative processes of the gut. Bacteria can be demonstrated at times in the submucous layers; however, no type has been found to predominate, the flora being composed of the usual intestinal forms. Aschoff and Koch have demonstrated in these ulcers the spirilla and fusiform bacilli so commonly found in the mouth. These follicular ulcers may be found in any part of the intestine, and may be shallow erosions, or extend through the follicle into the deeper tissues. Hemorrhages are commonly located about the follicles. The epithelial layer is edematous, often showing an increased number of cells.
The lymph-nodes may be congested, or edematous and hemorrhagic. Pigment is usually present and in some cases the peripheral sinus is distended with pigment-loaded cells. Where secondary infection has occurred, extensive necrosis of the glands is seen. This is found frequently in mesenteric nodes where severe intestinal lesions are present. The nodes lying in the drainage paths of hemorrhagic areas, especially the inguinal nodes, show active resorption of blood and blood pigments, and, as noted above, may be the seat of infection.
Liver.—In this organ, likewise, no change is found with sufficient regularity to warrant its acceptance as a distinctive lesion of scurvy. Fatty infiltration is, however, very common in the centre as well as in the periphery of the lobules. It is frequently associated with congestion, which may be so great as to lead to atrophy. In one case of Aschoff and Koch the picture resembled that of primary liver atrophy. The organ frequently contains extravasated blood or depositions of old blood pigment. It should be noted that Boerich described early cirrhosis in several of his cases, and that Aschoff and Koch record that one of their severe, acute cases showed “a recent cellular cirrhosis.” An exceptional lesion is reported by Reinert—a “leucocytic” infiltration of the liver and spleen occurring in a three-year-old child, and resembling that seen in pseudoleukæmia. Finally, it should be remembered in this connection that Hart and Lessing found calcium deposits not only in the muscles and adrenal glands of their monkeys, but also in the liver.
The spleen shares the general congestion of the internal organs. Sato and Nambu invariably found large numbers of pigment granules in this organ. Hirschsprung noted many Malpighian corpuscles, Reinert describes a true hyperplasia of the splenic pulp, and others mention infarcts and subcapsular hemorrhages.
The kidneys are often normal. On the other hand, various forms of nephritis are found, with cloudy swelling or interstitial change—a not infrequent complication of scurvy. More typical of the primary disease are congestion and hemorrhages, the bleedings occurring either under the capsule, into the interstitial tissues, or into the lumina of the tubules. Hayem found fatty infiltration of this organ and Aschoff and Koch a slight change of this kind in one case.
Adrenals.—A new interest in the study of the adrenals in diseases of the “deficiency” group has been created by the recent work of McCarrison. This author found the adrenals increased in size and weight in guinea-pigs dying of scurvy, whereas the adrenalin content of these glands was markedly decreased. On section there was hemorrhagic infiltration, “usually circumscribed in extent and situated around the periphery of the adrenal cortex.” This was seen even in early cases before hemorrhage had occurred elsewhere in the body. He describes also “degenerative changes in the cellular elements of cortex and medulla” consisting of vacuolation and disintegration of the cells with disappearance or loss of staining reactions of their nuclei. Rondoni, some years previously, had called attention to this increase in size and hyperæmia of the adrenals in guinea-pigs fed exclusively cereal diets. He, as well as McCarrison, noted an increase, though much less marked, as the result of starvation. LaMer and Campbell recently have confirmed McCarrison’s report of an augmentation in the weight of the adrenal glands in guinea-pigs fed on diets deficient in the antiscorbutic factor.
Comparable lesions have as yet not been found in human scurvy. These glands have been found normal by Jacobsthal, Schoedel and Nauwerk, Ingier and Epstein. In the cases of Aschoff and Koch no abnormality was noted except an almost constant increase in lipoid content. In those of Boerich the glands were normal in all but one case; in this instance the medulla was somewhat increased in size. In passing, we may repeat that Hart and Lessing found calcium deposits in the adrenals of four of their five monkeys, a lesion which has never been recorded in man.
It is valuable in this connection to compare the adrenal in scurvy with that of beriberi. In this disorder, Albert found the adrenal normal in one case, and Andrews describes only congestion in his eighteen necropsies. Ono found an increased adrenalin content in nine fatal cases, and states that the medulla appeared “fatter” than normal. More data will have to be obtained before it can be determined whether characteristic changes occur in scurvy, and how to interpret the hypertrophy described by several authors as common to guinea-pig scurvy.
Pancreas.—Sato and Nambu appear to be the only investigators who have described lesions in the pancreas. They found hemorrhages in one case among thirteen.
Thymus.—This organ has rarely been examined. Aschoff and Koch found no abnormalities in adults, nor did Jacobsthal in a case of infantile scurvy. Boerich noted enlargement in one instance.
Other Organs of Internal Secretion.—Very little attention has been paid to these organs. Aschoff and Koch state that the thyroids and hypophyses were normal in their cases.
Generative Organs.—No abnormalities have been described.
Central Nervous System.—The most frequent abnormality of the central nervous system is, as would be expected, hemorrhage; this has been discussed in the section dealing with gross pathology. No specific changes have been found in nerve-cells or fibres of the brain.
In a case of fatal scurvy in an infant a “focal degeneration of the lumbar cord” has been described, extending for a distance of about a quarter of an inch (Hess). The lesion differed from that of poliomyelitis in the absence of round-celled infiltration and of the characteristic changes in the anterior horn cells (Figs. 3 and 4). The outstanding feature was a loss of cells in the lateral groups of the left anterior horn; there were also fewer nerve fibres in this region, but this diminution was less striking. No definite interpretation of this case can be made as the data are insufficient to permit a conclusion as to whether the lesion was truly scorbutic or the result of an associated process. Schoedel and Nauwerk found no change in the spinal cord stained by Marchi’s method.
Peripheral Nerves.—The sheaths of the large nerves as well as those of the vessels are very often invaded by hemorrhage. The extravasated blood is found to lie around but rarely among the nerve fibres, which do not show any pathological alteration. Ingier is one of the very few to describe a degeneration of the nerve fibres. In one guinea-pig in which scurvy was induced she found “many marked degenerated fibrillar bundles of both sciatic and peroneal nerves, slight degeneration of the phrenic nerves and one vagus and its cardiac branch.” Another animal is referred to as having shown “very marked and well-developed degeneration of the nerves of the lower extremities.” It is open to question whether starvation played a rôle in the causation of these lesions. Schoedel and Nauwerk, and Aschoff and Koch examined these nerves but failed to find any lesions; the latter directed their attention especially to the vagus of twenty-two cases.
Retinal hemorrhages were found by Jacobsthal, and by Kitamura, who records “decided edema of the retina, marked bleeding and circumscribed hypertrophy of the nerve fibres” such as is found in albuminuric retinitis. These changes are considered again under the symptomatology of scurvy.
Bones.—Our knowledge of the minute pathology of the bones is far more complete and detailed than that of any other structure. This was to be expected in view of the fact that this is the only tissue in which the lesions are diagnostic. In considering the microscopic pathology it must be remembered that all the bones are rarely affected by scurvy, and that those that are involved show the scorbutic changes to a varying degree. One of the peculiarities of the lesion is that it involves the end of the diaphysis or rather the junction of the diaphysis and the cartilage. The bones most apt to show typical changes are the ribs; we shall therefore describe a section made through a costochondral junction.
The costochondral junction is generally swollen, somewhat beaded, and when cut longitudinally shows on gross examination a transverse yellowish bar, corresponding to the area of disorganization which will be described below. Under the microscope the line of juncture is not sharp and straight as is normally the case, but presents a wavy or irregular contour, the cartilage jutting into the bony end of the rib, instead of abutting in neat apposition to it. The bone is hollowed out and irregularly concave, whereas the cartilage presents a convex appearance. At the site of the junction is the Truemmerfeld area, where the normal tissue is splintered and fragmented. Everything in a state of disorder—trabeculæ of bone of various shapes and sizes lie scattered about, the cells irregularly arranged and much distorted, signs of recent hemorrhage, unrecognizable detritus. The picture is that of weakened bone having been crushed by the pressure of the more compact cartilage. Higher magnification shows that there are few osteoblasts (generally associated with the deeper fragments of bone), a varying number of intact red cells, according to the occurrence of hemorrhage, and occasional spindle- and star-shaped connective-tissue cells. Covering this mass of detritus there is frequently, as Aschoff and Koch have emphasized, more or less protective fibrin which has undergone some hyaline or connective-tissue organization.
The cartilage is also not normal. Its cells do not present an orderly arrangement, the proliferating columns having disappeared in the central convex portion, and being present to a varying extent near the periosteal borders. If we judge from sections of early scurvy in guinea-pigs, this disturbance of the columnar formation of the proliferating cartilage is one of the early signs of scurvy, and is associated with an unevenness and irregularity in shape and size of the bone trabeculæ. In young individuals, where cartilage activity is great, these changes are most marked and the entire zone of active cells may be somewhat widened.
Fig. 5.—Infantile scurvy. Epiphyseal junction of lower end of femur: (a) calcified cartilage at “Truemmerfeld” (b) hemorrhage in the fibrous marrow (Gernest-mark). Bone cortex and trabeculae abnormally thin. McCallums’ Text Book of Pathology. W. B. Saunders Co.
Below the Truemmerfeld is the Geruestmark or framework marrow, another distinguishing feature of scurvy. This extends for about 5 to 10 mm. toward the lymphoid marrow, where it ends more or less abruptly. It is composed of a loosely-constructed fibrillar tissue on a gelatinous-appearing groundwork, of sparsely scattered cells, and bony trabeculæ which are markedly thin and weak. Here and there are hemorrhages and blood pigment, especially adjacent to the “Truemmerfeld.” Another feature which strikes one at first glance is that the entire marrow area is incompletely filled by the thin and greatly-depleted trabeculæ of the spongiosa. The question has been raised whether this rarification is to be considered entirely of scorbutic origin. It is due evidently to a lack of function of the osteoblasts, which are diminished in number, and are represented by a layer of shrivelled spindle cells along the walls of the atrophied bony columns. They may fail almost entirely, as may its osteoid border, which is significant of active bone tissue. The lack of bony structure and rarification clearly is not due to an increase in the number or the function of the osteoclasts, for these do not appear in excess. It is mainly the result of normal bone resorption with a lack of normal bone regeneration. Aschoff and Koch suggest that the framework marrow may be able to manufacture bone, but cannot accomplish this because there is a lack of material from which to make osteoid tissue. This, they believe, constitutes the primary deficiency—a lack or faulty development of cement substance, which in turn may depend on an alteration of colloid material. Regarded in this light, the lesions of the bones resulting in fracture and those of the blood-vessels resulting in rupture and hemorrhage are dependent on a deficiency of the same basic material.
Hemorrhage occurs in the bone as elsewhere; it is almost never lacking. It appears either as large hemorrhages in the spongiosa, especially where the normal marrow joins either the Geruestmark or the Truemmerfeld, or merely as scattered cells, possibly the result of diapedesis. The blood-vessels in these areas are narrow and extremely thin-walled. The most typical site of hemorrhage is beneath the periosteum, a lesion widely known on account of its clinical significance ([Fig. 16]). Here the blood may extend for a considerable distance along the shaft, but rarely beyond the epiphyseal line. The clot forms readily, demonstrating that the nature of the hemorrhage is not a defect in coagulation, and in its midst may be seen fibrin, pigment, granulation tissue, and more or less firm connective tissue—constituting the callus. The inner surface of the periosteum is frequently lined with newly-formed bone and with a more or less dense deposition of lime salts, which becomes heavier in the course of the healing process, and is readily observed in radiographs. This periostitis ossificans may result in the clot being surrounded by a perfect shell of bone, with bony columns penetrating the deeper layers.
As the result of the lack of bone formation and the consequent weakening of the corticalis and the spongiosa, frequently a separation of the diaphysis from the epiphysis results. This lesion should not be regarded as a true separation, for, as Barlow pointed out, the line of cleavage is not at the junction, but below it, involving the uppermost region of the diaphysis. It is therefore correct to speak of a fracture or infraction. This lesion is generally accompanied by a deformity of the surface contour of the junction, due to a displacement of the cartilage, as a result of which “angular beading” of the rib is brought about. In some instances the cartilage is “telescoped” into the crushed end of the bone. To a varying extent fibrin covers the end of the fractured bone; the angles adjacent to the periosteum contain blood which becomes organized into dense connective tissue, thus serving as a splint for the fractured parts. In the course of healing a large number of foreign body giant-cells appear, blood-vessels sprout from the periosteum as well as the bony surface, and the necrosed tissue gives place to an active formation of callus, which generally leads to complete regeneration and restitution. It is remarkable how quickly and perfectly an epiphysis may become reunited to its shaft (Figs. 6 and 7). Sometimes, however, this takes place with resulting deformity, as in the development of coxa vara of the femur.
As Czerny and Keller have stated, it is difficult to define sharply the relation of bone fragility to scurvy. Histologically there is great similarity between the “osteotabes infantum” described by Ziegler and conditions sometimes found in infantile scurvy. The main distinction is that in the latter disorder the lesion is less generally distributed throughout the skeleton, and is particularly marked in a limited area of the bones (epiphyses). In considering this question it should be borne in mind that, experimentally, osteoporosis and scurvy can be brought about by diets which are absolutely dissimilar. For example, Bartenstein showed that young guinea-pigs develop osteoporosis and multiple fractures on a diet of raw milk containing an adequate quota of antiscorbutic vitamine.
Rickets and infantile scurvy are commonly found associated, although they bear no causal relationship to each other. The distinctive characteristic of rickets is the broad area of osteoid tissue which is formed at the epiphyseal junction, a broad band of incompletely calcified cartilage not found in scurvy. In the latter disease osteoblastic bone growth is greatly inhibited, but what growth does take place occurs in a normal and orderly manner. The osteophytes, for example, which so commonly develop at right angles to the axis of the bone in the subperiosteal hemorrhages, are composed of apparently normal bone. Another marked distinction between the two conditions is the paucity of blood-vessels in the cartilaginous area and in the marrow in scurvy, compared with the increased vascularity so generally encountered in rickets. It is evident, therefore, that although these two nutritional disorders bear a superficial resemblance to each other pathologically, they are radically different and almost antithetical.
CHAPTER V
EXPERIMENTAL SCURVY
There is no mention whatsoever of scurvy in animals previous to 1895, when Theobald Smith wrote: “When guinea-pigs are fed with cereal (it has been observed for some years in this laboratory), with bran and oats mixed, without any grass, clover, or succulent vegetable, such as cabbage, a peculiar disease, chiefly recognizable by subcutaneous extravasations of blood, carries them off in from four to eight weeks.” Smith did not pursue the subject further.
Coincident with the appreciation of the value of experimental methods, one would have expected attempts to produce scurvy in animals. The disorder had been recognized for a great many years, the fact that it was occasioned by a dietary deficient in fresh food was widely known, so that it would seem natural for clinicians or laboratory workers to have tried to induce the disease in animals by a similar restricted diet. There is, however, no suggestion of such an experiment in the voluminous literature on scurvy. The explanation of the neglect of an experimental study of scurvy appears to be that this was considered a disorder which required little investigation—its etiology, its prevention and its cure seemed thoroughly understood. It is strange that the mere fact that such a severe disturbance responded, as if by magic, to the administration of simple foodstuffs should not have awakened curiosity as well as wonder, and stimulated inquiry into the nature and significance of the curative agent.
In 1903 Bolle published the results of experiments on guinea-pigs which had been fed for various periods on raw or sterilized milk. He reported that the animals developed a marked fragility of the bones, varying in intensity in proportion to the degree of heat to which the milk had been subjected. These changes Bolle interpreted as typical scurvy, but it is difficult to decide whether the disorder was actually true scurvy, in view of the indefinite description of the bone lesions.
Bartenstein repeated Bolle’s work and described in detail the changes in the bones. From his work we learned that it was of little moment whether the animals were fed raw or sterilized milk—their nutrition failed within about the same length of time, and they died within a month. The chief pathologic change was a marked fragility of the bones, leading to spontaneous fractures, or to breaking of the bones in the course of ordinary manipulation. Bartenstein described the disorder as “beginning with the degeneration of the marrow, and secondarily leading to an atrophy of the bone due to increased absorption and deficient new formation of bone, especially at the endochondral lines of ossification. As the result of the osteoporosis, spontaneous fractures occur without noticeable hemorrhagic diathesis.” He found a deficiency of calcium in the bones of animals suffering from even a mild degree of this disorder. Hart and Lessing are of the opinion that we cannot accept Bartenstein’s diagnosis of scurvy. They compare this disorder to that described by Ziegler as “osteotabes infantum,” in which there is a more or less pronounced “jelly marrow” which has replaced the lymphoid cells in scattered areas. They sum up their analysis of the question with the statement that “the primary marrow changes in the diaphysis, the marked lacunar absorption by osteoclasts, the absence of subperiosteal hemorrhages, do not indicate typical scurvy.” Schmorl produced comparable lesions in dogs and came to the conclusion that the disorder was one “very similar” to scurvy but not identical with it, the essential difference being that in all animals there was a most marked absorption of bone by osteoclasts.
Similar results were obtained by others. In 1904 Peiper and Eichloff attempted to produce scurvy in dogs by means of a diet composed exclusively of raw or of sterilized milk. The following year we find a report by Esser of feeding goats on sterilized milk. None of these studies hits the mark; a condition of fragilitas ossium was produced rather than typical scurvy.
In 1907 the first systematic and convincing experimental study of scurvy appeared. In this year Holst and Froelich published a preliminary account of their classic work, undertaken in an endeavor to fathom the nature of “ship beriberi,” a disorder which disabled so many of the sailors in the Norwegian navy. We must remember that until recently attention has been focussed on the infectious diseases, and little thought given to the investigation of nutritional disorders. Although experimental investigation in this field may be stated to have been initiated by this work, it in turn had been stimulated by a conception of dietary diseases which had just begun to be realized. This new viewpoint was the result of the work of Eijkman. As has been mentioned in considering the pathogenesis of human scurvy, Eijkman demonstrated that hens developed polyneuritis, a disease resembling beriberi, when fed on polished rice, and that the simple change to a diet of unpolished rice, or the addition of rice polishings to the dietary, sufficed to protect or to cure. This work had been repeated and substantiated. It was evident to those who considered the question that the old lines of thought in regard to food and dietetics inadequately explained remarkable phenomena of this kind. It was also clear that nutritional disorders were subject to experimental investigation in a way similar to the infectious diseases, which were absorbing the interest of the various laboratories. It is unnecessary to review the rapid rise of investigative work in this field. It may be stated, in general, that during the past few years the investigations of scurvy have become so numerous that an established research technic may be said to have developed in connection with its study.
Attempts have been made to produce scurvy in various animals, but it has been brought about regularly only in the guinea-pig and in the monkey. Experiments on the dog are as yet too few to justify our regarding this animal as definitely available for this study. The nutrition of rats, mice, rabbits, hogs, pigeons, fowl, receiving a diet identical with that which regularly occasions scurvy in guinea-pigs, either progresses normally or a state of malnutrition develops which cannot be identified with scurvy. Recently Hart, Steenbock and Smith have reported that cattle can be reared to maturity on a diet which will produce scurvy in the guinea-pig in four to five weeks. We are therefore confronted with the remarkable and inexplicable phenomenon, a fact concurred in by almost all investigators, that a diet induces either normal nutrition or malnutrition, according to the experimental animal employed. A diet of polished rice, or other decorticated grain, will lead to the development of scurvy in the guinea-pig, to polyneuritis in the pigeon or fowl, or, according to Holst and Froelich, to a combination of these disorders in the hog.[35] The basis of these divergent results cannot be surmised, and is worthy of the most thorough investigation. It may well be that the elucidation of this problem—for example, why we are able to bring about scurvy in the guinea-pig but not in the rabbit, will shed light on the pathogenesis of this disorder. Are we to conclude that some of these animals have the power to synthesize the vitamine whereas others must depend upon the food for it, or are we to presuppose an ability to maintain normal life and function without any or with a minimal amount of this vitamine? The difference between these two groups, the susceptible and non-susceptible animals, probably is not as absolute as we have been wont to regard it. Recently Harden and Zilva have shown that although rats are able to thrive on a diet free from antiscorbutic vitamine, they show an appreciable gain in weight when this factor is added to the dietary. If such be proved to be the case, we must regard the non-susceptibility of the rat, the rabbit, etc., as relative rather than absolute.
From time to time a doubt has been raised as to whether we should accept guinea-pig scurvy as the counterpart of human scurvy. This question can be answered only by comparing the disorder in the one species with that in the other—as to mode of production, pathology, symptomatology, means of cure and all other phenomena. Viewed from these standpoints it is found that in almost every respect the disorder is identical in man and in the guinea-pig. The outstanding distinction is the difference in the length of time elapsing before the development of symptoms. In the child or in the adult it takes about six months of the deficient diet before clinical symptoms are manifest and a diagnosis can be established; in the guinea-pig the disorder can be recognized two weeks after restricting the diet. In the one instance we seem to be dealing with a nutritional disorder which is chronic or at least subacute, and in the other with a markedly acute condition. This distinction is open, however, to certain qualifications. In the first place, we must consider the duration of life of the two species, the comparatively short span of the guinea-pig compared with that of man. It must be borne in mind, furthermore, that the guinea-pig is placed on a diet absolutely devoid of all antiscorbutic vitamine, whereas this rarely obtains in human beings. For example, the diet which is most markedly scorbutic for infants is the “malt soup” previously mentioned, but even this food contains an amount of the antiscorbutic factor which is not negligible. But after taking these differences into consideration, it is nevertheless evident that the guinea-pig is far more sensitive to scurvy than man. This does not indicate that the guinea-pig is an unsuitable experimental animal, any more than the fact that the pigeon is more susceptible to polyneuritis than man indicates that it is unsuited to investigations of beriberi. It merely prevents our carrying out delicate quantitative experiments, and cautions against drawing too finely-spun deductions. In all nutritional investigations it should never be forgotten that conclusions drawn from experiments on animals are merely provisional, and must await substantiation on man, and, furthermore, that where differences in reaction are noted, the clinical data should be accorded full consideration.
Pathogenesis of Guinea-pig Scurvy.—From a pathogenetic point of view guinea-pig scurvy and human scurvy show remarkable points in common. Any diet that leads to the development of scurvy in man likewise brings it about in the guinea-pig, and contrariwise, any food which cures the disorder has the same beneficent effect on both species. This similarity extends so far that, as will be shown in the chapter on antiscorbutics, the relative potency of the various foods is approximately the same for man and for the guinea-pig. The parallelism generally is striking. The dietary which has been commonly employed in experimental scurvy has been that first suggested by Holst and Froelich, namely, oats, hay and water. Recently, however, this dietary has been enlarged in order to make it more complete, so as to include adequate protein, water-soluble and fat-soluble vitamine, and inorganic salts. To this end the group of workers at the Lister Institute (Chick and co-workers, Harden and Zilva) place their animals on a basal diet of one part of crushed oats and two of wheaten bran, and a daily ration of 50 to 60 c.c. of milk autoclaved for one hour at 120° C. This milk still retains a small amount of antiscorbutic vitamine. Cohen and Mendel have employed, apparently with good result, a “soy bean cracker,” containing soy bean flour which has been heated for 30 minutes at 15 pounds’ pressure (120° C.), 3 per cent. of sodium chloride, the same percentage of calcium lactate and of dried brewers’ yeast, and raw milk sufficient to supply 5 per cent. of butter-fat.
The use of raw milk was introduced by Jackson and Moore, and adopted by McCollum and Pitz and again by Pitz in a series of interesting experiments. The milk was given ad libitum. The results of these investigations were puzzling at first, until it was shown by Chick, Hume and Skelton that the dietary on which they were based contained a fundamental error which accounted for their lack of consistence. Although milk is not rich in the antiscorbutic factor, it possesses it in moderate degree, so that the outcome will be quite different according to whether a guinea-pig takes, for example, 50 c.c. or 100 c.c. daily. It is quite evident, therefore, that a food of this kind cannot be offered ad libitum, and that if this rule is not observed, most disconcerting results will follow.[36] This basic error in framing the dietary has made it impossible to accept the deductions of these authors. The conclusions of McCollum and Pitz are so striking and have led to such wide discussion, that they require consideration, in spite of the fact that the error in the dietary is now recognized. These authors found that the cæcum of their animals was greatly distended with putrefying fæces. As the cæcum is extraordinarily large and delicate in this species, they drew the deduction that the development of scurvy in the guinea-pig was due principally to the retention of fæces. “An impacted cæcum, the seat of putrefaction, may cause injury to the cæcal wall, sufficient to permit the invasion of the tissues by bacteria, or the animals may perhaps be injured primarily by the absorption of toxic products of bacterial origin.” Accessory dietary factors or vitamines, according to this theory, are supposed to play no part in the disorder, and antiscorbutics, such as orange juice, are considered to owe their efficacy mainly to their laxative properties, and to be replaceable by other laxatives such as phenolphthalein or oleum petrolatum. The efficacy of orange juice is supposed to be due to its content of citrates, and to be replaceable by what was termed “artificial orange juice,” a mixture composed of the various salts, citric acid and sucrose, in the proportions in which they are found in the natural juice.
These reports stimulated renewed interest in experimental scurvy, suggesting new aspects, and therefore directing attention to points requiring investigation. There were no data at hand on the consistency of the contents of the bowel in guinea-pigs, so that it was necessary to make appropriate observations in normal and in scorbutic animals. It was soon reported by various workers, Rappleye, Cohen and Mendel, Hess and Unger, and others, that there was no definite relationship between the occurrence of scurvy and impaction of the cæcum. In [Fig. 8] we see portrayed the stool output of a guinea-pig during the period in which it was developing scurvy, and during a subsequent period when it was being cured by means of orange juice. It is clear that there was no significant variation in the output during these divergent periods. A similar conclusion was arrived at by those who examined the cæcums of animals postmortem. Cohen and Mendel write: “Summarizing our experience with nearly one hundred scorbutic animals, we conclude that actual impaction of the fæces in the cæcum occurred in about one-quarter of the cases, and visible damage to wall, i.e., congestion or hemorrhage, or impaction, or both, was found in perhaps half of the cases. It should be noted that this statement covers all the diets we have tried.” We concur in this conclusion. Not infrequently we found the cæcums of markedly scorbutic pigs to contain semi-fluid fæces, the consistency of its contents depending on the character of the diet, quite apart from its adequacy and lack of the antiscorbutic factor. For example, a diet rich in milk, containing 100 c.c. or more, led to the formation of rather solid fæces; if oats were added to the milk diet the fæces in the cæcum were found to be still more solid, and this portion of the gut more often impacted. This condition could be detected by palpation even during life. Just as we encountered scorbutic animals on an oat, hay and water diet, who had semi-fluid fæces in the cæcums, so we met with others which were on a milk diet, and showed no signs of scurvy, although their cæcums were impacted with fæces of a putty-like consistence. Guinea-pigs do not seem to be able to tolerate a diet containing a large quantity of the fat of cow’s milk. Such a diet leads to impaction of the large intestine resulting in death, but does not induce scurvy. Jackson and Moore produced a condition of this kind by feeding pigs with cream containing 26 to 28 per cent. fat. “In every case,” they write, “the large intestine was distended with light mustard-colored semi-solid fæces.” This pathological condition is not understood, but is quite distinct from scurvy, and remarkable in view of the fact that the milk of the guinea-pig contains as high as 25 per cent. of fat. It is an interesting illustration of the marked biological difference in the butter-fat of various species.
Fig. 8.—Shows a period with the development of scurvy, and one where it was cured by giving orange juice. It will be noted that there was no marked constipation while the animal had scurvy. During a period of a few days the amount of stool was scanty, corresponding to the decreased intake of oats and hay on the days preceding. Broken line represents clinical course of scurvy.
Nor was it found, as McCollum and Pitz claimed, that antiscorbutics were replaceable by laxatives in the diet. Without entering into the details of this aspect of the subject, which will be considered in the chapter on symptomatology, it may be stated that attempts to prevent the occurrence of scurvy or to cure it by means of laxatives invariably failed. Chick, Hume and Skelton, as well as Hess and Unger, gave oleum petrolatum to a series of pigs without the slightest favorable effect. Hart, Steenbock and Smith recently reported that they had administered 1 c.c. of this oil on alternate days to one series of pigs, and 2 mg. of phenolphthalein on alternate days to another series, without relieving the scurvy. Cohen and Mendel, in order to test the adequacy of their diet as to roughage, supplemented it with additions of considerable filter paper and sawdust, “without averting the appearance of scurvy.” It is evident, therefore, that constipation does not play an essential rôle in the pathogenesis of scurvy in the guinea-pig, and that antiscorbutics are by no means synonymous or interchangeable with laxatives. These results accord with observations on infantile scurvy.
The Pathology.—The pathology of guinea-pig scurvy is essentially that of human scurvy. Hemorrhages and separations of the epiphyses or fractures of the long bones dominate the macroscopic picture. The hemorrhages are found rarely in the gums, but are common about the joints, in the muscles of the jaw or in those of the hind legs. They may be subcutaneous and appear as bluish discolorations at various parts of the body, especially if the disorder has resulted in death or if infection has been superadded. On stripping the skin we often note hemorrhages in the intercostal muscles, and beading of the ribs at the site of the costochondral junctions, least marked in the upper and in the floating ribs. This has been frequently described in connection with guinea-pig scurvy; its similarity to the rosary of human rickets has been drawn attention to recently by Jackson and Moore. It should not be regarded as “pseudo-rhachitic,” but as typically scorbutic, from a microscopic as well as a macroscopic viewpoint. On closer examination a yellowish-white transverse line may be seen at the epiphyseal junction of the ribs, and frequently some subperiosteal hemorrhage. Beading of this character has been reported by Ingier also in the “snuffles” of hogs and as the result of trauma. A similar enlargement of the chondral junctions of the sternum may be found on examining its posterior surface.
The joints of the body always show some changes. The epiphyses are enlarged to a variable degree, resembling the epiphyses typical of human rickets. As in infants, this change is met with most commonly at the wrist joint, involving the ulna and the radius. The knee-joint is likewise often involved, especially the ends of the tibia; the elbow, ankle, and the shoulder may also show an articular swelling of the bones. About these joints hemorrhages in the subcutaneous tissues may be seen, or edema extending along the extremities. Not infrequently a fracture of one of the long bones is found, which may or may not have been diagnosed during life. The common site of fracture is the lower part of the tibia or fibula. Much more frequent than fractures are separations of the epiphyses, which long since have been recognized as typical of infantile scurvy. Even gentle handling in the course of performing the necropsy may occasion a lesion of this kind—of the tibia at the knee, of the radius or ulna at the wrist, or indeed at any of the epiphyseal junctions. The infracted ends occasionally may be seen held insecurely by a delicate band of periosteum. The shafts of the bones are brittle, rarefied, and easily broken.
On opening the chest, slight hemorrhages may be noted in the pericardium and in the visceral and costal pleuræ. The heart is frequently enlarged, and the pericardial sac contains an excess of serum; the right ventricle, however, is not found disproportionately hypertrophied. Pneumonia is met with very frequently and constitutes a common terminal infection.
On opening the abdomen we may note subperitoneal hemorrhages of the muscular wall or of the coils of intestine. The liver and spleen are generally normal, as is the pancreas. The kidney frequently shows minute hemorrhages beneath the capsule and on section.
The adrenals not infrequently are large. This fact was first brought out by Rondoni and Montagnani, and is of added interest in view of its confirmation by McCarrison as well as by LaMer and Campbell. Its significance is discussed at length in the consideration of the adrenal gland in human scurvy. In view of the fact that fasting leads to a similar hypertrophy, and that guinea-pig scurvy frequently is complicated by fasting, these observations should be extended. In all investigations of this kind, bacterial cultures should be taken of the adrenals, or other organs, to be certain that there is no complicating infection.
There have been no reports as to the effect of scurvy on the size of the testicles, ovary, thymus, thyroid or parathyroid glands in the guinea-pig, such as have been made by McCarrison in relation to avian polyneuritis.
The alimentary tract occasionally shows macroscopic changes similar to the lesions found in man. The entire canal is frequently very empty, especially the stomach and the small intestine, due to the lack of appetite for some days previous to death. In the stomach we may find areas of congestion or numerous small superficial ulcers surrounded by congestion and covered with mucus; occasionally these ulcers are somewhat larger and deeper. The larger ulcers are more frequently situated in the first part of the duodenum, often proximal to the papilla of Vater. Holst and Froelich described this lesion in one of their early communications. More common than ulceration of the duodenum is a diffuse congestion of its upper part. This lesion is of note because it has been described frequently in the protocols of human necropsies, and is found in beriberi, in avian polyneuritis, and in pellagra in man. Its significance is unknown, and has indeed never been discussed.
Lower down in the bowel there are occasionally areas of congestion and ulceration, but no section seems particularly predisposed to these lesions. The contents of the bowel, especially of the cæcum, as mentioned above, depend more on the character of the food than on the existence of scurvy. If the diet has consisted of milk and oats, the cæcum will be found full and perhaps impacted, whereas if hay and oats have been fed, the cæcum will be less full and its contents semisolid.
In view of the fact that many of the animals have taken very little food for some days previous to their death, it will be well to describe briefly the macroscopic picture of simple starvation in guinea-pigs. When guinea-pigs are given only water they live about one week; if orange juice is added to this water diet they succumb a little later to starvation. Under all these conditions the striking pathologic change—absent in scurvy—is edema. It is true that the limbs may show slight edema in scurvy, and that the pericardial and the pleural sacs, and even the peritoneal cavity, occasionally contain a small quantity of serum, but it is comparatively an insignificant amount. Moreover it is difficult to decide to what extent this edema is due to scurvy, and to what extent to starvation. In typical starvation, on the other hand, such as occurs on the limited diets enumerated above, we find marked subcutaneous edema, sometimes a true anasarca, and frequently also ascites. We are reminded of the “war edema” and its frequent association with starvation. Another distinction between the two conditions is the fact that the marrow in starvation is yellow and not red as in scurvy. In passing, it may be mentioned that the ascites was greater when orange juice had been given than where the animal received only water.
In perusing the literature but one study has been noted on the effect of a scorbutic diet on the fœtus. This investigation was carried out on a large series of guinea-pigs by Ingier (1915). The following comprise her conclusions:
“1. Pronounced cases of Barlow’s disease may be produced in the fœtus as early as ten to fifteen days after the commencement of dieting pregnant guinea-pigs with oats and water. There are wide individual variations. The scorbutic changes in the skeleton are greatest in the earlier embryonic stages. The fœtuses of that period, with practically no exceptions, die and show marked traces of impeded growth.
“2. Fœtuses from the later period of pregnancy are born alive, and apparently fully developed, with comparatively slight changes in the osseous system.
“3. Even a short extension of the period of extra-uterine dieting on milk from scorbutic mothers, and later on oats and water, is sufficient to change the latent scurvy into a highly-pronounced case.
“4. The fœtus cannot be kept alive longer than the adult animal, about twenty-eight days, either by intra-uterine dieting alone or by combined intra- and extra-uterine dieting.
“5. The mothers show signs of the disease at an early period and are more severely attacked than non-pregnant animals. Death also occurs comparatively often in the first period of gestation.”
In these experiments intra-uterine fractures, premature births and still-born litters are frequently mentioned. This suggests naturally an inquiry as to whether similar occurrences have been observed in human scurvy. In considering the pathogenesis of human scurvy, we have remarked on the meagreness of the data on this most interesting aspect of this disorder. In view of the similarity between human and guinea-pig scurvy, we should expect not only miscarriages and still-births to result, but cases of congenital scurvy, especially of the latent or rudimentary type.
Scurvy Has Been Induced Also in the Monkey.—The most extensive investigation of this kind is that of Hart and Lessing, who brought about scurvy in several young Macaci Rhesi which had been fed for some months on boiled condensed milk with the addition of cooked rice and pig-nuts. Typical scurvy resulted in all but one instance, and in this case an old animal was used and a different pathological picture developed. These experiments require brief reviewing, as the clinical signs and gross pathology in monkeys differ somewhat from those encountered in guinea-pigs, and particularly as these distinctions render scurvy in monkeys and in infants practically identical.
Apart from general listlessness and lack of activity, the first sign is hemorrhage of the gums, the characteristic sign of infantile scurvy. This is stated to be constant; in the guinea-pig it is most exceptional. Another sign characteristic of infantile scurvy is the subperiosteal hemorrhage, which in the guinea-pig may be found as a small effusion near one of the larger joints or the costochondral junctions, but in the monkey consists of large effusions, similar to those described by Barlow. Subperiosteal hemorrhages of the cranial bones were constantly seen, and not infrequently involvement of the scapula and of the maxilla. Hemorrhage into the orbit leading to exophthalmos and to hemorrhagic discoloration of the upper lid—a lesion not infrequent in human scurvy—is also described; in guinea-pigs we have met with exophthalmos only in two instances. In all other respects scurvy in the monkey resembles that in the guinea-pig, even to the extent of the scorbutic rosary of the lower true ribs. Hart and Lessing describe the presence of the “white line” of Fraenkel, which is referred to at length in treating of the symptomatology of human scurvy. This is a shadow, seen by means of the X-ray, traversing the long bones near their epiphyses—a definite “shadow band” associated with a narrow light zone lying just beneath it. This “white line” has been noted likewise by Talbot, Dodd and Peterson in the scurvy of monkeys.
Microscopic Pathology.—Turning to the microscopic pathology, we find that the changes are similar to those described elsewhere in connection with human scurvy. It will be unnecessary, therefore, to give more than a general survey of the typical alterations. Little has been added to the description of lesions so carefully depicted in the first report of Holst and Froelich (1907). The bone marrow at the ends of the diaphyses in proximity to the epiphyseal junction loses its normal lymphoid character and is replaced by a reticular or fibrillated substance, the so-called “framework” marrow (Geruestmark of Schoedel and Nauwerk) containing a homogeneous mucoid tissue and only a few osteoblasts and marrow cells. The number of blood-vessels is considerably reduced and fresh hemorrhage or blood pigment is frequently seen. The osseous tissue itself shows marked changes, corresponding to the rarification and brittleness noted on gross examination. The osseous trabeculæ are fewer in number and those which remain are slender and irregular, and frequently appear as isolated islets. The cortical substance also becomes very thin. There are marked alterations in the intermediate cartilages, especially of the ribs.[37] Instead of the cells being arranged in orderly rows, they are irregularly placed, and frequently greatly reduced in size and number. The bone trabeculæ on which they abut are not well formed or of equal length, and do not present an even and transverse plane, but are misshapen, small, so that the line of junction with the cartilage is zigzag. In cases of marked scurvy the junction may be entirely disorganized and deformed, showing fractures of the rarefied bone and hemorrhages in the neighborhood. This leads frequently to a macroscopic deformity of bone, a bulging of the surface at the costochondral junction—the scorbutic “beading” or “rosary” of the ribs. Recently Delf and Tozer have described these changes, classifying them as those occurring in “incipient,” “definite,” “acute,” “chronic definite,” and “chronic acute” scurvy. [Fig. 9] shows these types in diagrammatic form. In this figure we see how varied may be the manifestations of this nutritional disorder, according to whether it has existed for a shorter or a longer time; in some instances the picture is very puzzling. The “incipient scurvy” corresponds to what we have termed clinically “latent scurvy” in infants, a condition which cannot be diagnosed and is manifested merely by a faulty nutrition which responds promptly to the addition of an antiscorbutic to the diet. There have been no histologic examinations in man at this incipient stage, but we may infer that they are similar to the bony changes found in the guinea-pig. When the scurvy has become chronic in an animal which has lived for months on a quota of antiscorbutic food sufficient to preserve life but insufficient to prevent the development of scurvy, we find a microscopic picture at the costochondral junction differing widely from that seen in the acute stage. Not only are the columns of cartilage cells represented merely by misshapen vestiges, but an ossified band (Fig. 95) is seen at the junction. It is probable that this is frequently the cause of the marked cessation of growth which has been described in connection with this type of scurvy in infants. Delf and Tozer interpret this ossified band at the junction as “an attempt to strengthen the junction in an abnormal manner, the normal process having broken down.” If the animal is again deprived of antiscorbutic food the ossified band breaks down, the junction becomes deformed and disorganized, and a condition of “chronic scurvy (acute)” is stated to have developed.
1. Diagram of normal rib-junction.
2. Diagram of rib-junction to illustrate “Incipient Scurvy.” This rib-junction is very nearly normal, but shows what may be regarded as the first recognizable signs of the onset of the disease; these are: (a) An appearance of general abnormality (when compared with the normal). (b) Unevenness of the junction and slight disorganization of the rows of cartilage cells. (c) Shortening of the length of the rows of cartilage cells. (d) Shortening, and decrease in number of the trabeculæ. (e) Increased amount of blood in the marrow cavity.
3. Diagram of rib-junction to illustrate “Definite Scurvy.” Histological signs vary considerably in these cases (according to the severity of the disease), and may approach in appearance those characteristic of the “Acute” condition. The rows of cartilage cells may be almost normal, but are more often noticeably shortened and usually somewhat disorganized or arranged in circular groups. The trabeculæ are usually about half the normal length and have a truncated appearance. The junction as a whole may present an uneven, slightly disorganized appearance and there is sometimes a certain amount of macroscopic deformity.
4. Diagram of rib-junction to illustrate “Acute Scurvy.” In these cases the junction and rows of cartilage cells are often completely disorganized, causing a marked macroscopic deformity of the bone. The bone of the shaft is frequently fractured. The marrow is no longer in contact with the edge of the junction and the space is filled with a mass of connective tissue; this is very characteristic in cases of fracture. A condition in which the trabeculæ have almost disappeared and the rows are much shortened is also found in “Acute Scurvy,” in those ribs in which no fracture of the shaft has occurred; usually, however, there is little or no ossification across the junction. There is frequently hemorrhage into the marrow cavity.
Diagrams 5 and 6 illustrate types of “Chronic Scurvy.”
5. May be described as “Chronic Definite Scurvy.” The rows are much shortened but not disorganized and an ossified band extends across the junction.
6. May be described as “Acute Chronic Scurvy.” The junction is deformed, and the rows are very disorganized; the trabeculæ have disappeared and an ossified band extends across the junction. There is no connective tissue to be seen and no existing, or recent, fracture.
It has been noted by many investigators that changes in the teeth take place in the course of scurvy. They become somewhat yellow and lose their glistening appearance, and occasionally break off. The molars commonly become loosened, so that they can readily be removed from their alveolar sockets; less frequently this is true of the incisors. Until recently, however, this subject has not been studied in detail, and no significant histologic changes in the teeth have been described. Jackson and Moore showed that with marked changes in the teeth there was often “great dilatation of the veins in the pulp attended by more or less hemorrhage into the pulp,” and that “in guinea-pigs fed on oats and hay there was almost complete necrosis of the pulp of the incisor teeth, also more or less necrosis in the pulp of the molars.”
Recently an intensive study of this subject has been made by Zilva and Wells, which is of special interest because it describes the first beginnings of these lesions, and particularly because we have no knowledge whatsoever of the dental changes which occur in human scurvy. These investigators found a fibroid degeneration of the pulp of the teeth, a pulpar fibrosis. “It is clear at once,” they write, “and it is an important fact that no trace of cellular organization, no trace of cell nuclei, no trace of interstitial cement substances can be found anywhere. Nerves, cells, blood-vessels, and odontoblasts have all shared the process of fibrication and are no longer recognizable.” These radical changes in the teeth, brought about by a deficiency of antiscorbutic vitamine, were demonstrated not only in guinea-pigs but also in monkeys. In some instances they were found where a histologic examination of the costochondral junctions showed nothing abnormal. “Profound changes were recorded where the scorbutic changes during life were so slight as to be almost unrecognizable,” and, they continue, “the mildest degree of scurvy which could just be discovered at the postmortem examination produced well-defined changes in the structure of the teeth.” If this work is confirmed, we must consider the teeth as one of the first tissues of the body to be affected by scurvy. The authors quite rightly raise the question whether the teeth of young children may not likewise be injured by a deficiency of antiscorbutic vitamine, whether this may not play a rôle in the dental caries so prevalent among civilized communities. It is evident, they state, that such transient conditions of infantile scurvy as have been described by Hess as “subacute” or “latent” scurvy, may occur more often than is usually suspected, and may reasonably be expected to influence dentition. It seems quite possible that the caries of the permanent teeth is due not only to infantile rickets but also to infantile scurvy.
Besides the typical histologic changes in the bones there are alterations in other organs which require mention. All investigators have found a degeneration of the muscles, showing a loss of their striations, swelling of the fibres, and the presence of irregularly-distributed vacuoles and granules. The interstitial tissue frequently is permeated with edema, as we should expect from gross appearances. Holst and Froelich have reported a fatty degeneration of the heart muscle, as well as of the epithelium of the mucous membrane of the glands of the stomach and of the intestine. Hart and Lessing, in their protocols of necropsies on monkeys, describe an interesting lesion associated with the degenerated muscle fibres—a collection of granules staining deep blue with hæmatoxylin and dissolving on the addition of acid. These granules, interpreted as being composed of calcium, were found in the muscles of the limbs, of the tongue, and in the heart. It is reasonable to attribute their formation to an absorption of bone throughout the body. Similar calcium deposits were seen frequently in the adrenal glands, in their cortex, or at the border of the cortex and medulla. This lesion gains special interest in view of the calcium deposits described so frequently in connection with mercurial poisoning, more particularly as the symptoms of scurvy and of this toxic condition have marked clinical resemblances.
There has been but little histologic investigation of the nerves in experimental scurvy. In fact, the only systematic study of the kind is that of Holst and Froelich, whose attention was drawn to this field in an attempt to solve the relationship between scurvy and ship beriberi. These writers found a true Wallerian polyneuritis in only two pigs, one of which had been fed on wheat bread made with yeast, and the other on decorticated barley. In many instances, however, there was extensive degeneration of the axis cylinders without degeneration of the sheaths. They do not, however, attribute great importance to these changes, as the same lesions were found in the nerves of animals fed on cabbage and fresh potatoes. In view of the confusing reports on the nerves of birds in experiments on polyneuritis, one cannot be too careful in drawing conclusions from histologic studies of this kind.
In the study by Jackson and Moore on experimental scurvy in guinea-pigs, the histology of the blood-vessels is carefully considered. “Marked thinning of the wall” was found and depicted; “the wall as a whole had partially melted away, leaving few traces.” These parts of the wall contained many small round bodies resembling cocci, which were stained a deep blue by the Wright and the Giemsa methods. These bodies were present also in the lumen of the vessel and in the inner layers of the more normal portions of the wall. In addition to such changes in the veins, “lesions having the shape, location, and characteristics of infarcts, were found in the ends of the diaphyses of the long bones.” As a result of this pathologic picture the authors are of the opinion that they may have been dealing with a mild infection. This is quite possible, as scurvy tends to render the tissues less resistant to the entrance of bacteria. We believe, however, that even if such were the case, the phenomenon must be regarded merely as secondary in its relation to the pathogenesis of scurvy.
Following the study on the pathology of experimental scurvy, Jackson and Moore undertook to determine primarily whether the small stained bodies seen in the sections of the scurvy lesions were bacteria. This investigation has been cited frequently as presenting cogent evidence in favor of the infectious nature of scurvy, so that it will be necessary to consider it fully; the general question of whether scurvy is a bacterial infection is discussed under the consideration of etiology.
As is well known, Morpurgo, a generation ago, claimed to have produced rhachitic lesions in young rats by means of artificial infection with a gram-positive diplococcus. Pappenheimer brought about similar lesions in rats by the injection of a suspension of bone marrow from a rhachitic animal. Koch injected a streptococcus longus intravenously into young dogs, occasioning gross bony changes of the epiphyses and costochondral junctions, and microscopic changes resembling scurvy—an irregular line of ossification and “a framework” marrow, which, however, showed regions of osteoid. Jackson and Moody were able to isolate from the crushed tissue of their guinea-pigs “a diplococcus of low virulence with a tendency to form chains and produce green (color) on blood agar.” Pure strains of these organisms inoculated into the circulation of guinea-pigs and rabbits, living under ordinary conditions (a mixed diet consisting of green vegetables, hay and oats), gave rise in most instances to hemorrhagic and other lesions in the bones, joints, muscles, lymph-glands or gums. Hemorrhages were found beneath the periosteum in the region of the lower incisor teeth and the acetabulum and ribs. These results are far from constituting evidence in favor of the microbic origin of scurvy. They show merely that the tissues of scorbutic animals frequently harbor bacteria, and that injections of these bacteria will bring about hemorrhages which may be subperiosteal in character. They are open to the specific criticism that scurvy was produced readily in the rabbit, an animal which otherwise does not develop scurvy, and, furthermore, they differ from feeding experiments in inciting scurvy notwithstanding the fact that the animals were receiving an antiscorbutic diet (green vegetables). Cultures of the hearts’ blood of the affected animals were sterile in every instance; a result obtained likewise by Holst and Froelich.
Further studies of this kind should be carried out and should include cultures of the blood and tissues of guinea-pigs in the various stages of scurvy, especially the early stage. In addition, a histologic study should be made of the bones of animals injected with bacteria (preferably streptococci), in order to ascertain whether notwithstanding an unrestricted diet, typical lesions can be produced by this means.
For further details of the pathology of scurvy, the reader is referred to the chapter on human pathology.
Symptoms.—Let us consider the symptomatology of guinea-pig scurvy. In the course of an observation of many hundreds of animals we have been struck by the striking uniformity of the signs and symptoms. The animals made use of were almost invariably of moderate size, weighing from 200 to 300 grams. Where heavier pigs were employed the disease progressed less rapidly, but the signs were the same; they were, however, more difficult to elicit, owing to the subcutaneous fat. Most of the animals were on a diet of hay, oats and water ad libitum, but there was no variation in symptoms where fat and fat-soluble vitamine were supplied by an addition of egg yolk or of cod liver oil, or where egg albumen was fed to render the protein adequate, or where the inorganic salts were supplemented by additions of sodium or calcium chloride.
There is a variability in the sign which signalizes the onset of the disorder—sometimes it consists of a flattening of the weight curve, at others of an inordinate excitability of the animal, or frequently of a tender joint, generally a wrist. The joints almost invariably become tender early in the disease, causing the animal to wince and cry when it is examined. Accompanying this tenderness there is often slight swelling due to edema, or perhaps some hemorrhage, which alters the sharp, clean-cut contour of the joint. This edema may extend upward along the tendon sheaths. Soon the animal becomes lethargic rather than nervously active, and may look ill, as manifested by a roughness of its coat and its unnatural posture. Frequently it sits on three legs with the tender hind leg drawn upward and outward so as to escape pressure—a posture termed by Chick, Hume and Skelton (1918, 2) “the scurvy position,” and indicative of hemorrhage into the joints or muscles. At times it lies curled up, with the side of its face resting on the floor, as if to support its painful or sensitive jaw; this they have termed the “face-ache position.” The two diagnostic signs, however, are the hemorrhages about the joints and the loosening of the teeth. The diagnosis frequently can be established by the twelfth to the fourteenth day; the earliest diagnosis was made on the eighth day. Hemorrhages appear somewhat later than tenderness, and are situated at the joints, most frequently at the knee, which may be markedly swollen and show a bluish or reddish discoloration, extending upward or downward for some distance. Other joints are often involved, frequently the wrist, the ankle or the shoulder. In other cases hemorrhages into the muscles are noted, especially of the leg or of the thigh, and later, especially toward the end, hemorrhages from the bowel. Fractures or separations of the epiphyses may be found on examination or may be occasioned by the physical examination. A frequent site of this lesion is at the wrist or at the knee, involving the head of the tibia or the lower end of the femur. These fractures knit rapidly when an antiscorbutic is given, but result at times in deformity.
Loosening of the teeth is another typical sign. It is, however, one which does not appear early and is somewhat difficult to elicit. The molar teeth are generally involved, especially those of the upper jaw, which may be so completely separated from their alveolar sockets that they can readily be removed by forceps. It is, however, impossible to examine the molar teeth satisfactorily during life. Far less frequently an incisor tooth becomes loosened; more often it loses its glistening appearance and looks dull and yellowish. Occasionally an incisor tooth fractures. The gums are rarely altered sufficiently to aid diagnosis; not infrequently they are congested or bluish, rarely hemorrhagic, and never ulcerous or spongy. This is the chief difference between the symptomatology of scurvy in the guinea-pig and in man, and probably is the result of lesser susceptibility of the former to infection by pyogenic bacteria. In general, however, the disorder in the guinea-pig bears a closer analogy to infantile than to adult scurvy; due to the fact, possibly, that young pigs are generally used for the experiments.
A sign of great interest, although not of diagnostic importance, is the “beading” of the ribs noted by many observers, and emphasized by Jackson and Moore. It has been described also in monkeys by Hart and Lessing. This is an enlargement or swelling of the costochondral junctions of the ribs, especially of the lower true ribs. It corresponds clinically to the “beading” and the “rosary” so characteristic of infantile rickets and mistakenly termed the “rhachitic rosary.” As pointed out, in discussing the symptomatology and pathology of human scurvy, this sign must be regarded as truly scorbutic in animals as well as in infants. The “rosary” is difficult to palpate in pigs which have considerable subcutaneous tissue; in thin animals, however, its course can be followed, the gradual development and subsequent disappearance. In this connection the enlargement of the epiphyses must be mentioned, another sign supposed to be characteristic of rickets in infants. Marked swelling of the wrists is frequently encountered in guinea-pigs suffering from scurvy—a bony enlargement involving the lower epiphyses of the ulna and of the radius. This is met with far more commonly in chronic scurvy than in the usual acute case. Where the disorder has existed for a long period, these bony knobs may persist indefinitely, constituting the sole residual sign of a former scorbutic condition.
The relation of loss of weight to the development of the scurvy requires consideration. In experiments carried out on rats to test the diets in respect to the water-soluble and the fat-soluble vitamines, the weight curve is used as the main criterion to judge whether the foodstuff is adequate. In guinea-pigs we cannot employ the weight curve as a criterion. Not infrequently an animal develops scurvy, and nevertheless does not lose in weight, but even gains slowly and steadily. This occurs when the appetite remains good, and the dietary is complete except for antiscorbutic vitamine. The same holds true for human scurvy, as we have noted in connection with the symptomatology. We have attempted to make up for this defect by adding to the charts a curve representing the clinical course (Fig. 10). Although this curve is computed on an empirical basis, it gives a comparatively true picture of the disease and is far more exact than attempting to portray the disease by means of a weight curve.[38] Indeed, when we rely on the latter method it is impossible frequently to illustrate graphically the reaction of guinea-pigs to various influences. Another disadvantage of the weight curve is that it is influenced by factors having no direct relation to scurvy, especially infections of various types which retard the gain.
Fig. 10.—Hay, oats, and water ad libitum during period I resulted in a lack of gain in weight, and in a development of scurvy. During period II, 1.5 c.c. of orange juice were given daily, and as will be seen there was a marked gain in weight and disappearance of the scorbutic signs, although, as is generally the case, they continue to develop for a short while after an antiscorbutic is given. When the orange juice was discontinued in the third period, the weight once more fell and the scurvy redeveloped. The broken line represents the course of the scurvy, and is a composite formed on the basis of the aggregate of the scorbutic signs. Each square represents a 2-day interval.
Guinea-pigs generally die of scurvy after having lost about one-third of their body weight; occasionally the loss is greater, reaching almost 50 per cent. This loss is due partly to the scorbutic condition, but to a greater extent to starvation occasioned by a marked lack of appetite. In this connection it may be noted that guinea-pigs frequently lose for a few days following the addition of an antiscorbutic to the dietary (Fig. 11). This reaction is evident from a perusal of the weight charts of other investigators, and occurs likewise in human scurvy. This loss is accompanied, as Gerstenberger has pointed out, by diuresis, which may be so marked that it is evident to the casual observation of those caring for the animals.
Fig. 11.—These guinea-pigs developed scurvy in spite of receiving a large quantity of the water in which young carrots had been cooked for only 20 minutes. It will be noted, however, that although the pigs developed scurvy they did not lose weight, as is usually the case. After they had developed definite scurvy they were given in addition the equivalent of 80 c.c. of a dried milk prepared by being heated to about 116° C. for a few seconds. The addition of this milk to the diet cured the scurvy, showing that it had largely retained its antiscorbutic vitamine.
Exophthalmos may be mentioned again in this connection as a very rare sign of guinea-pig scurvy. Hæmaturia also occurs at times; it is not known how frequently it is present, whether it is an early manifestation in the guinea-pig as in the infant, or whether the source of the blood is the kidney or the bladder.
The superficial lymphatic glands are frequently palpable in scurvy, especially those in the inguinal region. This sign is emphasized by some pathologists. It has seemed to us attributable less to the nutritional condition than to the infections which so frequently complicate the disorder.
According to Jackson and Moore a rise of temperature does not accompany scurvy in the guinea-pig. As the result of an examination of nine guinea-pigs they conclude that “experimental scurvy is a non-febrile disease in the majority of affected animals.” Nor did they find a leucocytosis, the average leucocyte count of eight scorbutic pigs being about 8000.
As the data are meagre, a consideration of the chemical alterations associated with the scurvy of guinea-pigs and monkeys will be taken up in conjunction with the metabolism of human scurvy. The therapy of animal scurvy will also be deferred ([chapter VI]), as the reaction to dietetic measures is practically the same in man and in animals. In concluding this chapter we would call attention to the following interesting statement contained in the recent paper by Delf and Tozer: “In other experiments, however, where a liberal supply of an antiscorbutic was given and where the fat-soluble A growth factor was known to be deficient, the resulting histological changes in the rib-junctions of the animals examined were found to resemble closely those of ‘Definite’ or of ‘Definite Chronic’ scurvy. In these test cases the antiscorbutic chosen was, we believed, deficient in the fat-soluble A growth factor (for example, orange juice). This fact is mentioned because in the case of an animal not receiving an adequate supply of fat-soluble A the resulting changes in the junctions are not dissimilar from, and are likely to be confused with, those caused by scurvy alone.” If this observation is confirmed, it emphasizes the necessity in nutritional experiments, of constructing a dietary which is complete in every respect except the one under investigation; it also suggests the development of new pathologic entities in relation to other nutritional disorders resulting from a lack of the accessory food factors.
CHAPTER VI
ANTISCORBUTIC FOODS
Historical Review.[39]—It is impossible to state when and how the knowledge of the value of antiscorbutic foodstuffs came to be appreciated. It is probable that the potency of herbs and fruits in scurvy was known empirically to individuals and groups of people long before the fact gained general recognition. A most interesting history of antiscorbutics is given in the excellent work of Hirsch and in our great classic on scurvy by Lind. The first realization of the value of lemons and oranges seems to have been the result of a chance discovery. Budd tells us that in the sixteenth century sailors of a Dutch sailing vessel laden with these fruits were attacked with scurvy, and that, when they partook of the lemons and oranges in the cargo, a miraculous cure resulted. He narrates also the following striking incident, which is mentioned likewise by Lind:
In the year 1600 four sailing vessels left England for the East Indies. The sailors on three of these ships did not receive lime juice, whereas those on the fourth received their daily quota. The men of the first three ships suffered severely from scurvy, but those on the fourth escaped.
In an excellent work on “Scorvey,” published in 1685, Harvey wrote: “Wherefore most acids, especially spirit of salt marine, juice of sorrel, limons, citrons, etc., are so deservedly extolled in some scorbutic distempers and seconded with good success.” Thus we see that even at this early date it was taken for granted that citrous fruits possessed virtue in curing scurvy. Bachstrom (Observationes circa Scorbutum, 1734) evidently was well-acquainted with the antiscorbutic value of scurvy grass, and relates the story of a sailor severely disabled from scurvy who was put ashore to perish on Greenland, and crawled on the ground, grazed on scurvy grass like a beast of the field, and was able to return home perfectly recovered. (Cited from Lind.)
The credit for forcing a general acceptance of the antiscorbutic value of fresh food belongs to Lind. He did not, however, have an easy task, and in 1747, in order to convince those who still were skeptical, he resorted to an experiment on human beings. Twelve patients in his hospital were given the same diet, except that some received sea-water in addition to their dietary, others vinegar, or elixir of sulphuric acid, or a daily portion of cider, or oranges and one lemon daily. The last two groups, as we should expect, recovered quickly; one man who received cider improved, but in no other case was any alleviation noted.
Lind extols the value of lemons and oranges, of berries, of sour cabbage, of cider, and of all fresh fruits and vegetables. In spite of the fact, however, that Lind’s teaching was based on an experience with thousands of patients suffering from scurvy in the naval hospital, his ideas did not take root. It required an event which came directly under the official eye to bring about radical changes in the diet of the sailors. In 1795 the English Fleet suffered from a severe epidemic of scurvy, which was finally controlled by giving the sailors fresh vegetables and fruit. This therapeutic result was so convincing that thenceforth a daily ration of lime juice was ordered for the sailors and a regular issue provided for the navy. This marks the cessation of scurvy as a scourge of the British navy. From this time the disease appeared only sporadically. The sharp decrease in the incidence can be appreciated by Budd’s statement that 1457 cases of scurvy were admitted to the Royal Naval Hospital in 1780, whereas in 1810 an English physician reported that in the seven preceding years he had not treated a single patient in this hospital suffering from scurvy. In another marine hospital, between the years 1806 and 1810, only two cases of scurvy were admitted.
Nothing was done for the British merchant service until over half a century later, although scurvy continued to make its appearance among the sailors with varying severity. Smith states in the article on this subject in Allbutt’s System of Medicine: “In 1864 it was pointed out by Doctor Barnes that during the twelve years following 1851, 1058 cases of scurvy had been admitted into the hospital ship Dreadnought.” In 1854 a law was passed requiring every vessel to carry an adequate supply of lime juice. This law, however, failed in effect, due to the fact that a large part of the lime juice was adulterated. A new shipping-act was passed, therefore, in 1867, with the object of preventing adulterations, at the same time increasing the daily quota for each seaman from half an ounce to one ounce.
It may be of interest to add a few words concerning certain antiscorbutics which have been under discussion or recognized for so many years that they have acquired an historical aspect. One of these foodstuffs is sauerkraut, which was recognized by Lind in 1772 as having particular potency in this disease. It is interesting to note, in this connection, that this writer appreciated the close relationship of acidity to antiscorbutic virtue. “One quality,” he writes, “entering the most perfect antiscorbutic composition is a vegetable accescency.” He prized sauerkraut for its inherent value, and particularly, because he found that “sour cabbage will keep for an East-India voyage.”
The famous navigator Cook, whose voyages were remarkable for the freedom from illness which his sailors enjoyed and the absence of scurvy, always kept a large supply of sauerkraut on hand. It was believed by many that the immunity of the Dutch seamen to scurvy was due to their large consumption of this vegetable. As the result of this empirical knowledge, the English navy in 1780 introduced the use of sauerkraut into its ration. As just noted, however, this antiscorbutic was supplanted some few years later by an issue of lime juice.
It is common knowledge that outbreaks of scurvy follow closely upon a failure of the potato crop. This has been particularly the case in Ireland, where it was especially evident in relation to the great epidemic of scurvy in 1847. Holst and Froelich inform us that “all scurvy epidemics in Norway in the nineteenth and beginning of this century followed failure of the potato crop.” Nor is this danger past. In an article entitled “The Rôle of Antiscorbutics in Our Dietary,” the author recently reported that the partial failure of the potato crop in the eastern part of the United States led to the development of scurvy in numerous institutions, in one of which over 200 cases of definite scurvy developed in the spring (1916).
The occurrence of scurvy in the navy and on sailing vessels has been associated in the minds of many with the large amounts of salted meat which necessarily was included in the dietary. It was evident that meat that was salted had no antiscorbutic value, but the query has been raised whether eating a considerable amount of salted meat did not induce scurvy. Lind mentions “flesh long salted” as leading to the development of scurvy. The question of the value of meat as an antiscorbutic is of importance at the present time, chiefly in connection with Polar expeditions and army rations. As the result of an outbreak of scurvy in the Polar expedition of 1875–6, a British Arctic Survey Committee was appointed to make an investigation. In 1877 it reported that “although the scurvy was due to the absence of lime juice from the sledge dietaries, meat in large amounts is able to prevent the disease.” Stefánsson also emphasized the value of meat in preventing scurvy in the Polar regions. In his expeditions he has found that raw meat, if taken in sufficient quantity, is able to afford complete protection. Jackson, who lived for some years among the Samoyeds, tells us that this tribe, owing to the fact that they consumed considerable reindeer meat, never suffered from scurvy in spite of the fact that they ate no vegetables or fresh fruit during the winter.
The following account, a personal communication from Dr. Harrison J. Hunt, who spent four years in the Arctic regions, is of interest in this connection:
“For some four years I was with the Smith Sound Eskimos, on the northwest coast of Greenland. These people get nothing but animal food normally, and have lived that way for many generations, yet are healthy, of good physique, and are normal in other ways. Scurvy was unknown to them as far as I could ascertain; certainly there was none while I was among them. Much of their meat is eaten raw, and the rest only partly cooked; that is, ‘rare done.’
“Whalers who were accustomed to winter in Hudson Bay practically always had scurvy in the crew. It was common knowledge among the captains that fresh meat was curative of scurvy, and it was their practice to obtain meat from the Eskimos whenever possible for that purpose. The last English expeditions to the South Polar regions were afflicted with scurvy which was entirely and quickly eradicated by the use of fresh seal meat in the place of salt meats and canned foods. They do not state that this meat was eaten raw or even rare cooked. On the Danish coast of Greenland, during seasons poor in game, scurvy is quite common, but the natives there live largely on breadstuffs (very coarse rye bread). Personally, during my four years in the Arctic, I took no fresh vegetables whatever, or other commonly-called antiscorbutics, relying solely on rare or raw meat. I never was stronger or more healthy in my life. I did have dried fruits and vegetables, and usually plenty of fresh bread. Usually the Eskimos eat their raw meat in a frozen condition, and I can attest that it is extremely palatable in that condition.”
We do not wish to discuss, in this place, the value of meat as an antiscorbutic; in passing, however, it may be said that, as in the case of the other antiscorbutics, its efficacy will depend largely upon the amount consumed. The British Mesopotamia Commission Report of 1917 shows that scurvy can develop on a ration which includes 28 ounces of meat a week. We must remember, however, that this refers to cooked meat, whereas in the Polar expeditions meat generally was eaten in a raw state.
Recently an historical inquiry has appeared in an article by Chick, Hume and Skelton as to the antiscorbutic virtue of limes and lemons. This sketch is of exceptional interest because it treats of the oldest and most cherished antiscorbutics, and particularly because it has unearthed a peculiar fallacy in their connection. As they state, there would appear to be every reason for believing “that the use of so-called lime juice was responsible for the disappearance of scurvy from the British navy in the first decade of the nineteenth century.” It would seem, however, that the lime juice which gained this great reputation in the navy some 125 years ago was in reality lemon juice, and that it was not until about 50 years ago that lime juice was really used. These authors show—by one of those striking human experiments which, occasionally, is available—that in a Polar exploration which was organized in 1850 lemon juice was issued to each man, and that no case of scurvy developed, whereas in a similar expedition which went out in 1875 lime juice was issued and scurvy developed the following spring with great severity among the sledge crews. This investigation, therefore, seems to prove that lime juice, the prototype of antiscorbutics, has been accorded a false position; that in reality the sailors of the past have been protected by lemon juice.
Antiscorbutic Foods.—As far as has been ascertained, the antiscorbutic food factor exists in all fresh vegetable and animal tissues, being present to a far greater degree in the former than in the latter. It is distinguished by being associated in nature with cells which are the seat of active metabolism, just as the water-soluble vitamine is associated mainly with cells which are in an inactive or dormant state. Vegetables or fruits may be mildly or highly antiscorbutic; there is indeed a remarkable difference in their content of antiscorbutic factor or vitamine. They vary widely also in the degree to which their potency is affected by physical or chemical conditions. In this chapter the most common animal and vegetable antiscorbutic foodstuffs will be considered and the effect which processes such as drying, canning, change of reaction, etc., exert on their specific value. Their therapeutic application in the prevention and cure of scurvy will be considered in a subsequent chapter. Until recently our knowledge of this subject was empirical and inaccurate; as the result of scientific work, however, carried out during the past few years in different parts of the world, quantitative and comparative figures of antiscorbutic food values have been evolved.
Milk.—It is important to have as accurate an idea as possible of the value of milk as an antiscorbutic, as the infant depends on it during the first months of its life for a supply of this essential factor. Considerable attention has been paid to this question in the last few years, and recent reports tend to confirm the former estimations which had been overlooked and forgotten. In 1847 Curran wrote that in the Irish epidemic of this year they had admitted to the Dublin Union Hospital 80 cases of scurvy which had been on a diet which included one pint of milk daily, but was deficient in vegetables. From this experience he realized that milk was not rich in the principles which protect against scurvy. In the following year Parkes came to the same conclusion, stating that 500 to 750 c.c. of raw milk did not always suffice to prevent scurvy. In addition to these opinions concerning adults, similar conclusions have been drawn from clinical experience with infants. Barlow (1894) realized that a small amount of milk was insufficient to protect against scurvy. Still writes: “The antiscorbutic power of fresh, unboiled milk is evidently slight.” In 1914 Hess and Fish pointed out that “milk must not be considered as having potent antiscorbutic properties.” Nevertheless, when this question was raised recently by the experimental work of Jackson and Moore, and that of McCollum and Pitz, it was not appreciated that, like other antiscorbutics, milk must be regarded from a quantitative standpoint, and that, as it is a weak antiscorbutic, its effect must depend largely on the quantity consumed.
The first laboratory work on this subject was that of Froelich in 1912, who showed that guinea-pigs could be protected by an exclusive diet of fresh milk, and that raw milk is more effective than heated milk. In his work, the amount of milk taken by the animals was not measured, so that it is impossible to glean from it more than these general conclusions. In the following year, as a result of some quantitative experiments, Funk stated that he was able to protect guinea-pigs with 50 c.c. of fresh milk in addition to an oat diet. This estimate, as subsequent workers showed, is too low. Chick, Hume and Skelton were the first, however, to investigate the antiscorbutic potency of milk in a systematic and convincing manner. They demonstrated that if the daily consumption of fresh milk was less than 50 c.c., a guinea-pig died almost as quickly as if it received no milk; if the daily quota varied from 50 to 100 c.c., a greater or less protection from scurvy was observed, varying proportionately with the amount consumed; if 100 to 150 c.c. were taken daily, which practically amounts to a complete milk diet, satisfactory growth and development occurred, and no symptoms of scurvy were observed. This represents in a general way the present conception of the antiscorbutic power of milk. In passing, it may be remarked that it is not altogether clear why 50 c.c. of milk do not afford partial protection, and prolong the life of the animal for a definite length of time. The authors conclude that “milk is evidently a food poor in the antiscurvy accessory factor, and a ration large in comparison with that of other antiscorbutic materials is necessary to afford satisfactory protection from scurvy.” The error must be avoided, however, of regarding milk as a standard article of diet containing a definite and specific amount of vitamine per cubic centimetre. It will be shown later that this point of view cannot be taken in regard to vegetables, and it is probable that it cannot be assumed for milk.
A general conception of the antiscorbutic potency of cow’s milk may be gleaned from the fact that it requires a minimum of about sixteen ounces (500 c.c.) daily to protect an infant from scurvy or to cure it. Twelve ounces have failed to effect a cure in several instances, although the milk was raw and of the best grade. If it is pasteurized, a larger quantity is required, depending upon various conditions connected with the heating process and upon the age of the milk, circumstances fully discussed in relation to etiology. Thus it becomes evident that pasteurized milk assumes a two-fold rôle, acting as an antiscorbutic if little of its vitamine content has been destroyed and if a large quantity is consumed, or leading to the development of scurvy when one or both of these conditions is unfavorable. The same holds true for milk which has been boiled for a short period. If the milk has been heated twice, it tends to produce scurvy; if it is condensed, the greater part of its antiscorbutic value is destroyed.
It seems necessary to emphasize again the important fact that dried milk may possess marked antiscorbutic potency, depending on the method of preparation ([Fig. 11]). As stated, sixteen ounces of milk dried by the Just-Hatmaker process cured scurvy promptly, in spite of the fact that the milk had been dried six months previously. Here, therefore, is a food of high caloric value, compact, antiscorbutic, and stable. The fact that milk, in spite of drying, retains this labile vitamine for so long a period, demonstrates that it is available in the most remote parts of the world, and that the possibilities of its transportation are unlimited.
Little is known regarding the antiscorbutic content of the milk of the various domestic animals. Some claim that goat’s milk is notably rich in this particular, but experiments with it are too few to warrant conclusions. Lind writes: “Goats, of all animals, afford the richest whey, possessed of the greatest antiscorbutic virtue . . . which in a singular manner restores the constitution when weakened and impaired by scurvy.” Human milk possesses about the same potency as cow’s milk, as mentioned in the discussion of the occurrence of infantile scurvy in countries where the adult form is endemic. Twelve ounces of human milk, from a woman on a liberal and varied diet, barely sufficed to alleviate the symptoms of a case of moderate intensity.