Scurvy Past and Present Part 7

[Ill.u.s.tration: 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 antis...o...b..tics 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 role in the pathogenesis of scurvy in the guinea-pig, and that antis...o...b..tics 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 s...o...b..tic, 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 pleurae. 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 const.i.tutes 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 t.e.s.t.i.c.l.es, 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 ca.n.a.l is frequently very empty, especially the stomach and the small intestine, due to the lack of appet.i.te 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 caec.u.m, 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 caec.u.m will be found full and perhaps impacted, whereas if hay and oats have been fed, the caec.u.m 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 succ.u.mb 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 quant.i.ty 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 a.s.sociation 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 pa.s.sing, 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 s...o...b..tic diet on the foetus_. This investigation was carried out on a large series of guinea-pigs by Ingier (1915). The following comprise her conclusions:

"1. p.r.o.nounced cases of Barlow's disease may be produced in the foetus 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 s...o...b..tic changes in the skeleton are greatest in the earlier embryonic stages. The foetuses of that period, with practically no exceptions, die and show marked traces of impeded growth.

"2. Foetuses 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 s...o...b..tic mothers, and later on oats and water, is sufficient to change the latent scurvy into a highly-p.r.o.nounced case.

"4. The foetus 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 s...o...b..tic 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" a.s.sociated 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 h.o.m.ogeneous 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 trabeculae 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 trabeculae 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 s...o...b..tic "beading" or "rosary" of the ribs. Recently Delf and Tozer have described these changes, cla.s.sifying 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 antis...o...b..tic 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 antis...o...b..tic 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. 9) 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 antis...o...b..tic food the ossified band breaks down, the junction becomes deformed and disorganized, and a condition of "chronic scurvy (acute)" is stated to have developed.

[37] These changes are not found in every specimen, so that in order to be able to exclude scurvy definitely, it is necessary to examine a considerable number of ribs; several may be normal, only one or two showing the characteristic microscopic changes.

[Ill.u.s.tration: FIG. 9.--Diagrammatic representation of guinea-pig scurvy (copied from Delf and Tozer by the courtesy of the Cambridge Press).

1. Diagram of normal rib-junction.

2. Diagram of rib-junction to ill.u.s.trate "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 trabeculae. (_e_) Increased amount of blood in the marrow cavity.

3. Diagram of rib-junction to ill.u.s.trate "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 trabeculae 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 ill.u.s.trate "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 s.p.a.ce is filled with a ma.s.s of connective tissue; this is very characteristic in cases of fracture. A condition in which the trabeculae 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 ill.u.s.trate 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 trabeculae 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 interst.i.tial 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 antis...o...b..tic 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 s...o...b..tic 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 antis...o...b..tic vitamine, whether this may not play a role 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 dent.i.tion. 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 interst.i.tial 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 a.s.sociated with the degenerated muscle fibres--a collection of granules staining deep blue with haematoxylin 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 const.i.tuting evidence in favor of the microbic origin of scurvy. They show merely that the tissues of s...o...b..tic 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 antis...o...b..tic 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 alb.u.men 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 antis...o...b..tic 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 a.n.a.logy 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 s...o...b..tic 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 k.n.o.bs may persist indefinitely, const.i.tuting the sole residual sign of a former s...o...b..tic 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 appet.i.te remains good, and the dietary is complete except for antis...o...b..tic 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 ill.u.s.trate 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 r.e.t.a.r.d the gain.