Scurvy Past and Present Part 3

=Age Incidence.=--Scurvy may occur at any age if the diet does not furnish sufficient antis...o...b..tic factors. As a matter of fact, it is encountered most often among infants and adults, not because these two age-groups are particularly susceptible, but because there are peculiar attendant circ.u.mstances. In the case of the infant, it is due to the fact that for almost the entire first year of its life it is dependent entirely upon milk, a foodstuff poor in antis...o...b..tic vitamine, and containing, under favorable conditions, barely enough to meet its requirement. If, therefore, the potency of the milk is weakened, or if an insufficient quant.i.ty is fed, and more particularly when both of these factors are involved, a s...o...b..tic condition will ensue. The reason why older children, those over one and a half or two years of age, do not develop scurvy is largely due to their varied and liberal diet, which is amply provided by the mother or guardian, so that even in times of want they receive more than their due share of the available food supply.[17]

[17] It would seem, however, that the growing infant requires relatively more antis...o...b..tic vitamine than does the adult. We know that its caloric requirement is fully a quarter to a third greater. In regard to vitamine, judgment cannot be based on experimental evidence, but on comparative figures. For example, unless we take this viewpoint, we must believe that, as an infant of six months weighing 15 pounds requires 15 c.c. of orange juice daily to furnish its antis...o...b..tic quota, an adult weighing 160 pounds requires 180 c.c. daily--the juice of three good-sized oranges. On this basis the adult would require six quarts (6000 c.c.) of fresh milk daily, twelve times the minimum requirement for an infant, which is one pint (500 c.c.) a day. These figures are manifestly too high.

From a clinical standpoint scurvy may be said to occur in infants during the second half year of their lives. There is general agreement on this point; it is borne out by the investigation of the American Pediatric Society and by the statistics of various individuals. On the basis of a large experience, Still states that nearly eighty per cent. of the cases appear between the ages of six and ten months, and that in no case did the disorder occur before the age of five months. It is of importance from both the etiologic and the therapeutic standpoint to distinguish clearly between the age when infantile scurvy is commonly diagnosed, and the earlier stage when it appears as a general nutritional disorder. We must remember that scurvy generally takes from six to nine months to become manifest, this developmental period varying mainly in proportion to the degree of the dietary deficiency. It is evident, therefore, that there must be a prolonged period of nutritional failure which precedes the diagnosis. This stage consists of two early phases, the first months where the faulty diet causes no apparent change and seems to have no deleterious effect on the infant, and the second, of latent and subacute scurvy. The "latent" condition is one merely of unsatisfactory nutrition and r.e.t.a.r.ded growth, which it is not possible to interpret; "subacute scurvy," which develops subsequently, is distinguished by characteristic signs and symptoms. We shall not review their symptomatology, as it is given in the chapter devoted to this topic. The subject is brought forward in this connection to emphasize the fact that the s...o...b..tic condition occurs far earlier than is generally realized, and furthermore, that if the earlier and more subtle symptoms of scurvy were comprehended, the age incidence would fall earlier than the current figures indicate. The earliest instance of this disorder which we have seen occurred in a baby four and a half months of age.

Age does not seem to play a definite role in regard to the incidence among adults. Scurvy frequently has been encountered among old men, and is of common occurrence among the most vigorous of the nation, the young soldiers and sailors. Some have stated that it takes place less often among soldiers in the twenties than among those in the thirties, but this has not been demonstrated. The fewest cases have been reported among children over two years of age. It was due to the apparent immunity of this age-group that, until very recently, German writers doubted the ident.i.ty of infantile and adult scurvy. The exclusion of children of this age is merely fortuitous and, moreover, is by no means absolute. One of the earliest cases of scurvy in children, reported by Montfalcon, occurred in a child six years old. Bateman in America described a case in a child of about this age. Barlow, in one of his first articles, reported scurvy in a small group of older children. The case so frequently quoted by German authors in this connection is that of Fraenkel, who described both clinically and pathologically a case of scurvy in a boy eight years of age. These cases by no means exhaust the number which are reported. Recently, Tobler has given us an account of scurvy, occurring during the war, in a Viennese foundling asylum which harbored children between the ages of two and fourteen.

=Season and Climate.=--Many of the older writers laid great stress on the influence of season on the occurrence of scurvy, which they believed broke out particularly in the cold and damp months of the fall, winter and early spring. It is true that most of the epidemics have occurred at these seasons of the year. This is merely what should be expected, considering that the disease depends mainly upon the supply of fresh fruits and vegetables. Where conditions are abnormal, as in war, there have been notable exceptions to this seasonal incidence. In the "Report of the War of the Rebellion" there is an instructive graph ill.u.s.trating the occurrence of scurvy in our Civil War and in the Crimean War, which shows that this disease prevailed to the greatest extent during the winter months in the former, whereas in Crimea, the season of greatest frequency was the summer time. One of the severest outbreaks of scurvy on record is that which occurred at the siege of Thorn in Germany in the year 1703. During the months of July and August, when the weather was excessively hot, scurvy ravaged the besieged army. There are, furthermore, many reports of scurvy in the tropics during the dry season. In the island of Aruba, in the Dutch West Indies, which has been visited by scurvy year after year, and which is referred to elsewhere, the disease is endemic during the dry, hot season. Formerly it broke out on the men-of-war and vessels of the mercantile marine while they were in southern waters. As regards infantile scurvy, it has always seemed to us that season played a slight role; that cases which occurred in the summer tended to be less severe and to be characterized by periods of intermission rarely observed in the winter time.

The effect of _climate_ has been accorded a variable place in the etiology of scurvy. Lind believed that a damp, cold climate, such as that of the Low Countries, was conducive to scurvy. On the other hand, since it is realized that diet is the essential element, all other factors have been regarded as of no moment whatsoever. It is difficult to pa.s.s judgment on this question, since scurvy is now endemic in such a limited area of the world. It seems quite possible that a damp, cold climate, which depresses the various functions of the body, may exert an influence where the quota of antis...o...b..tic foodstuff is not quite adequate. Exposure to infection is also greater under such climatic conditions.

Economic status has to be considered in connection with infantile scurvy. Numerous writers have drawn attention to the fact that scurvy is seen relatively more frequently among the infants of the well-to-do and the rich than among those of the poor. This curious and paradoxical situation is due to the zealous care which the former receive--the extreme precautions in sterilizing the milk, the addition to the formulas of expensive proprietary foods, the watchfulness to avoid the child's obtaining a chance bit of fruit or vegetable. Since the popularization of commercially-pasteurized milk in the larger munic.i.p.alities, and the advertising propaganda for the sale of "baby foods" which has extended their use among the ma.s.ses, this distinction in the social status has been largely obliterated.

s.e.x seems to play no part in the etiology of scurvy. Several writers have claimed, however, that there is a certain degree of racial immunity. For example, Sheppard reports that the Zhob Kakai seldom develops scurvy, although he naturally excludes vegetables from his diet, and Boerich noted among the prisoners of war that the Slavs, especially the White Russians, were more susceptible.[18] Of course a lack of susceptibility of this nature can be merely relative. Such a racial distinction may seem far-fetched, but if we admit that disposition and habits of life can play a role, it is quite possible for races to vary in their predisposition to this disorder. Moreover, we shall see that individuals differ markedly in this respect. Lind and others repeatedly emphasize the fact that the indolent and slothful sailor was stricken with scurvy far oftener than the one who was active, and claimed that physical exercise even tended to bring about a cure.[19] Those who have had a large experience with scurvy in adults are almost unanimous in believing that a _psychic element_ enters into its etiology. In this way, in a measure, they account for the frequency of scurvy among defeated troops, in besieged armies, and among men depressed by homesickness, fatigue, and discouragement. This point of view cannot be lightly disregarded, bearing in mind that depressed mental states alter the functions of the organs and markedly affect secretion. The many cases and epidemics in inst.i.tutions for the insane cannot, however, be attributed to this cause, but are probably almost entirely due to a want of supervision of the dietary. Among infants, the question of the influence of race and of the mental state needs but little consideration.[20] For some time we have carefully observed the course of scurvy among happy and contented infants compared with those of an unhappy and fretful disposition; in some instances the former, although the diet was similar, seemed to develop scurvy less readily than the latter.

[18] It would be of interest to know whether the negro infant is more susceptible than the white baby, in view of its markedly heightened susceptibility to rickets. There are, however, no reports or statistics to enlighten us on this point.

[19] "Where the indisposition is but beginning, and even when the gums have been pretty much tainted, there have been numerous instances of a perfect _recovery without having the benefit of fresh vegetables_; provided the patient is able to use due exercise.... When it is advanced to what I have called the second stage it is hardly to be cured without their (fruits and vegetables) a.s.sistance." (Lind.)

[20] Caille has described a case of scurvy in an infant suffering from Mongolian idiocy, and we have also seen a similar case.

There can be no doubt that there is _predisposition_ to scurvy, as there is, probably, to every nutritional disorder. Among soldiers and sailors a certain number develop scurvy on the same ration which does not harm others. Some years ago when scurvy developed among a group of infants fed on pasteurized milk, this idiosyncrasy was noted. The distinction, however, is rarely sharply defined. Careful clinical investigation will generally show that the infants which seem to be spared are not thriving quite normally; they are somewhat pale, and do not gain in weight as they should, and their appet.i.te is poor. The most interesting experience of this kind is the following which is frequently cited: In a family where the first child developed scurvy, Finkelstein took the precaution, in the case of the second child, to have the milk boiled for as short a time as possible, and to begin mixed feeding early. In spite of these precautions this boy also developed scurvy. Finkelstein states that once before he had met with a similar mishap. An experience which he relates, regarding a foster-mother, an excellent nurse, who had three infants in succession develop scurvy in spite of preventive measures, is also of interest in this connection. The latter occurrence evidently cannot be attributed to hereditary or family predisposition, and serves to emphasize the inherent difficulties of the subject. v. Starck's report of an instance where twins were fed on similar milk mixtures and one developed scurvy, whereas the other thrived satisfactorily, is a striking ill.u.s.tration of the role of idiosyncrasy. This case, as well as many others, fails to be absolutely convincing in view of the fact that the daily intake of milk is not recorded.

A predisposition to scurvy cannot be ascribed to a condition of general malnutrition. For example, among infants it has never seemed that those suffering from marasmus or atrophy were particularly p.r.o.ne to develop scurvy. Whether syphilis, tuberculosis or malaria tends to precipitate the onset of this disorder cannot be stated.[21] In view of the fact that prematurity is such an important factor in the pathogenesis of rickets, it would be of interest to know whether a similar relationship exists between infantile scurvy and prematurity. The only clinical condition which we have found predisposing to scurvy is the "exudative diathesis" of Czerny, a term which implies a tendency to develop exudations of the skin or of the mucous membranes. Probably it is not without significance that in this diathesis the blood-vessels may evince a decided weakness, an increased permeability, as demonstrated by the "capillary resistance test." (See Symptomatology.)

[21] Many of the older authors believed that mercurial drugs were especially prejudicial in cases of scurvy.

Nothing whatsoever is known regarding the possible influence of the fat, protein, carbohydrate and salt content of the diet on the development of scurvy. Is it entirely immaterial whether one or another food element largely predominates, or is the antis...o...b..tic factor to some extent modified by other components of the food? Influences of this kind, which at most are secondary, cannot be ascertained by the biologic test which at present has to be relied on to measure the development of scurvy and the potency of antis...o...b..tics. It is quite possible that the course of scurvy may be affected by the character of gastric and intestinal digestion, by the activity of the glands which pour their secretions into these organs, by the destruction or elimination of the antis...o...b..tic factor in the food. The frequent a.s.sociation of dysentery and scurvy noted during the recent war and referred to by many previous writers, shows the effect of intestinal disorders. These hypotheses are tentatively advanced because it is evident that some factor exists, apart from the mere antis...o...b..tic value of the diet, which at times exerts a potent influence on the development of scurvy. Cases developing in spite of a moderate amount of antis...o...b..tic food, and others not responding to the addition of vegetables or fruit to the diet--although not numerous--have occurred too frequently and have been reported by too experienced observers to be brusquely disregarded. For example, Neumann, one of the keenest clinical students of scurvy, stated that he had met with four instances of this nature. Hess and Fish reported two similar experiences.

The secondary etiologic factors are mainly predisposing; a few words, however, must be added concerning what may be termed _exciting factors_.

Infection is the most important condition which may suddenly and precipitously induce scurvy. This fact was brought to our attention in 1912 in connection with the outbreak of scurvy among infants receiving pasteurized milk. Its explanation was not clear at the time, but was elucidated by subsequent experience, and was described in 1917 as follows: "Latent scurvy was prematurely changed to florid scurvy by the presence of a ward infection; an epidemic of 'grippe' precipitated an epidemic of scurvy exceptional in its hemorrhagic tendency." The a.s.sociation of scurvy and infection has been recently emphasized by McCarrison and others, and seems to hold good for the other so-called deficiency diseases. In this connection one other exciting cause of scurvy may be mentioned, namely, trauma. The older writers noticed that following a fall or an accident, a sailor frequently developed scurvy, and Barlow in 1894 remarked on the influence of trauma in connection with infantile scurvy. As might be inferred, its effect is mainly to induce premature rupture of the weakened blood-vessels; in infants we have seen this occasioned by pressure exerted on the lower end of the thigh to ascertain the presence of tenderness. Viewing the situation broadly, it must be acknowledged that except for the realization that scurvy is due to a new food factor--a vitamine--our fundamental understanding of its pathogenesis has advanced but little, in spite of the employment of experimental methods and the availability of modern technic.

It is doubtful whether mere clinical studies will contribute in a large measure to the solution of the pathogenesis of scurvy. Much may, however, be learned by investigations of the metabolism in human scurvy--an aspect of the problem which, as will be brought out in a subsequent chapter, hardly has been explored. By this means may be acquired a clearer understanding of the effect of an antis...o...b..tic deficiency on the tissues and on cellular activity. Much may be expected from physiologic and pharmacologic studies of the specific vitamine, although it is not yet available in a pure state. Finally, it is probable that the solution of similar questions relating to the pathogenesis of cognate disorders--a study which is engaging the best efforts of so many workers throughout the world--will shed light on this particular disease.

CHAPTER III

THE ANTIs...o...b..TIC VITAMINE[22]

[22] Vitamine is used throughout this monograph as synonymous with "accessory food factor" or "food hormone" as a convenient descriptive term, without any intention of connoting a definite chemical substance.

We shall not discuss the subject of vitamines in general, but confine ourselves to the more limited field of the antis...o...b..tic vitamine. The recognition of the "accessory" dietary factors is of such recent date, however, that it will be well to consider briefly how attention came to be directed to them and how their existence was ascertained. As in the case of so many scientific discoveries, it is difficult to point to the exact time when the advance was made. On looking back we find that Lunin, in 1881, noting that mice were unable to live on a diet consisting of protein, fats, carbohydrates, salts and water, came to the conclusion "that other substances indispensable to nutrition must be present in milk besides caseinogen, fat, lactose and salts." This work did not stimulate similar investigations, nor did Lunin, as might have been expected, allude to scurvy. The work which focussed attention on this novel aspect of dietetics was the report of Eijkman, in 1897, to the effect that when fowl are fed decorticated rice, they develop a disease resembling beriberi, and that the paralytic symptoms disappear on feeding them rice polishings or its alcoholic extract. Here, for the first time, was a positive rather than a negative experiment, and one capable of simple verification. The subject was placed on a scientific basis by the cla.s.sic investigation of Hopkins, who experimented with purified food substances, and demonstrated how diets which were deficient could be rendered adequate. As early as 1906 he wrote "the animal body is adjusted to live either upon plant tissues or other animals, and these contain countless substances other than the proteins, carbohydrates and fats." "In diseases such as rickets, and particularly in scurvy, we have had for long years knowledge of a dietetic factor, but though we know how to benefit these conditions empirically, the real errors in the diet are to this day quite obscure." The work of Osborne and Mendel, and McCollum and Davis in this country, of Schaumann, Funk, Stepp and others, all led to the conclusion that purified diets are unable to satisfy the nutritive requirements of rats or mice, and that extracts of the natural foods suffice to render the diet adequate.

The same rule holds for man, who, when deprived of these vitamines, develops the so-called deficiency diseases--typically modern disorders.

Regarded as a group, they are a consequence of our altered mode of life and peculiar civilization. They follow naturally upon the development of immense cities housing millions of people, who necessarily must receive perishable foodstuffs produced at a great distance. To even a greater extent they are the product of countless ingenious methods devised mainly to render foods stable--drying, heating, the addition of preservatives--most of which accomplish their object, but incidentally rob the food of its essential vitamine.

None of the vitamines has been isolated in a pure state. The nearest approach to this desired end has been the work of Funk, who obtained the water-soluble vitamine in a state of such concentration that about 3 mg.

sufficed to cure a pigeon of polyneuritis. In considering the attributes of the antis...o...b..tic vitamine, it must be borne in mind that this factor is referred to as it exists in various foods; for example, in orange juice or in cabbage, and furthermore, that the method of ascertaining its presence or concentration is limited to the crude biological test of animal feeding.

The antis...o...b..tic factor is distinguished by being the most sensitive of the three vitamines, the most unstable, the least resistant to physical or chemical processes. It may be regarded as one of the most delicate indicators of the biological integrity of foodstuffs; however, as Falk and his co-workers have shown, the enzyme property of living matter is still more readily destroyed. The antis...o...b..tic vitamine is soluble in water, and therefore is termed by some the "water-soluble C" factor. It is also soluble in alcohol, as shown by the experiments of Hess and Unger and of Harden and Zilva, and the therapeutic tests on infants of Freise and of Freudenberg.[23] It possesses, therefore, the solubility of the water-soluble vitamine. Some have suggested that it may be derived from this vitamine, others that instead of one there may be a series of antis...o...b..tic factors--suggestions based on pure hypothesis.

Holst and Froelich showed that this vitamine pa.s.ses, without appreciable loss, through dialyzing parchment, and Harden and Zilva (2) that it can pa.s.s through a porcelain filter. The latter, using the method of Seidell, demonstrated that this vitamine is not adsorbed by fine precipitates such as fuller's earth, differing in this respect from the water-soluble vitamine; and that in a mixture of equal volumes of autolyzed yeast and orange juice, the antis...o...b..tic vitamine remained unaffected, whereas the water-soluble A was entirely removed.

[23] Freise cured a case of infantile scurvy by giving about 2 c.c. of an extract obtained from turnips by means of absolute alcohol. Seven weeks were necessary to cause a disappearance of symptoms. Freudenberg employed an extract of carrots, prepared with 96 per cent. alcohol, and effected a quicker cure.

One of the most distinctive characteristics of the antis...o...b..tic factor is its _sensitiveness to even moderately high degrees of heat_. In this respect it differs markedly from the water-soluble or so-called "antineuritic vitamine" which withstands exposure to high temperature.

The reaction of the antis...o...b..tic vitamine in this regard is not a simple one, and cannot be expressed by a mere statement of the degree of heat and the length of exposure. Numerous other factors, especially the reaction of the medium, but also the physical environment, must be taken into consideration--for example, cabbage is more resistant to the action of heat than its juice. An understanding of the relation of antis...o...b..tics to heat may perhaps best be obtained by considering the subject in connection with some definite foodstuffs. The most exhaustive study from a quant.i.tative standpoint is that of Delf. She showed that when cabbage is subjected for an hour to a temperature of 80 to 100 C., 90 per cent. of its antis...o...b..tic vitamine is lost, and that 80 per cent. is lost when a temperature of 90 to 100 is maintained for twenty minutes, or a temperature of 60 for a period of sixty minutes. This experiment shows that the destructive influence of heat is enhanced to a comparatively slight degree by a rise of temperature, only about threefold when it is raised from 60 C. to the boiling point. This result points to a temperature coefficient of about 1.5 to 10 C. of temperature. It is suggested by Delf that this low coefficient of destruction is opposed to the enzyme or protein-like theory of the nature of the vitamine, and suggests a simpler const.i.tution. On the other hand, we must bear in mind that the proteins which have been used in experiments and found to possess a high coefficient of heat, have been tested in the pure state, whereas the vitamine of the cabbage is bound up in the cell.

Experiments with this vitamine as found in milk accord with the above investigation, demonstrating that intensity of heat is not as destructive as prolonged heating. This agrees with the clinical experience that milk which has been boiled for a few minutes does not induce scurvy as readily as pasteurized milk which has been heated for 45 minutes to 140 or 165 F. (Hess and Fish).

As demonstrated by tests with orange and with lemon juice, the antis...o...b..tic vitamine is greatly protected from the destructive effect of heat when it is a.s.sociated with an acid. This was shown first by Holst and Froelich and has been confirmed by numerous observers. An excellent example of marked thermostability conferred on a food by its acid reaction is furnished by the tomato, which is strongly antis...o...b..tic even after it has been subjected to the canning process.

Conversely, Harden and Zilva have shown that the vitamine is destroyed by alkali even when dilute (one-fiftieth normal sodium hydrate) and kept in contact at room temperature; this alteration does not take place at once, but in the course of several hours.

It is true that the antis...o...b..tic factor is peculiarly sensitive to _drying_, but there are exceptions to this rule, so that it is incorrect to state, as does the British Report of the Medical Research Committee, that "it may be regarded as an axiom that dry or dried foodstuffs will not prevent scurvy." We have shown that fresh milk dried by the Just-Hatmaker process may retain by far the greater moiety of its virtue. In this regard rapidity of desiccation and subsequent protection from oxidative processes are important factors. The general rule holds true, however, that this vitamine, in contradistinction to the "water-soluble" vitamine, is readily damaged and destroyed by drying.

This vitamine is peculiarly sensitive to _aging_, especially when it is present in an alkaline or neutral medium; but even in an acid medium its potency soon diminishes. Harden and Zilva found this to be the case with lemon juice stored for a fortnight in the cold room, and our experience has been similar in regard to orange juice kept in the refrigerator under a layer of liquid petrolatum. In milk the antis...o...b..tic factor diminishes with age, especially following pasteurization, in the course of which most of the acid-forming bacteria have been destroyed. Aging has the least effect when the food with which the vitamine is a.s.sociated has been dried. This is true not only of lemon and of orange juice as demonstrated experimentally and clinically, but even of milk, which even after it has been dried and stored for months, may still possess marked curative value.[24]

[24] Reference is made to a milk dried by the Just-Hatmaker process, containing about 3 per cent. of moisture. The clinical data on which this conclusion is based are given in the previous chapter.

Experiments by Harden and Zilva showed that exposure of lemon juice to _ultra-violet rays_ for eight hours does not influence its antis...o...b..tic activity, that exposure of autolyzed yeast for the same length of time likewise does not impair its "antineuritic" potency, but that under identical conditions the fat-soluble factor in b.u.t.ter becomes inactivated. Similar tests carried out by the author with orange juice led to the same result. It thus appears that one of the vitamines--not the most unstable--manifests a peculiar sensitiveness to a certain form of physical or chemical action.

In view of the fact that _shaking_ partly destroys pepsin and rennin, as shown by Shaklee and Meltzer, it would be of interest to ascertain whether this process brings about any impairment of the antis...o...b..tic vitamine. Particular interest is attached to this question because it is generally recognized that milk loses some of its potency in the course of handling--whatever may be comprised by this term. In experiments on the fat-soluble vitamine Steenbock and his co-workers found that "somewhere in the course of the manipulation to which the b.u.t.ter fat had been subjected, factors had been introduced which were responsible for a vitamine destruction."

Before discussing the question of the manner in which the antis...o...b..tic vitamine functionates, it may be well to state briefly the type of the disturbance which its deficiency occasions. The chief manifestation is damage to the integrity of the endothelium of the vessels, resulting in hemorrhage--whether from diapedesis or from rhexis or both of these conditions, the microscope does not inform us. Nor can it be stated positively that the endothelium has not been injured by a secondary toxic or bacterial factor. However this may be, the end result of the deficiency is endothelial damage, a pathologic condition which may be demonstrated clinically in scurvy by the "capillary resistance test"

(chapter VII). The other marked functional alteration in scurvy is increased susceptibility to infection; but how a vitamine deficiency induces this vulnerability cannot be explained. Clinical tests show that the blood contains sufficient ant.i.toxin (diphtheria) to afford protection. Harden and Zilva found that "guinea-pigs fed on an unrestricted mixed diet, on a quant.i.tatively restricted mixed diet, and a s...o...b..tic diet showed no differentiation in amboceptor and agglutinin t.i.tres, and in the complement activity of the blood." If this is to be interpreted as indicating that the protective substances of the body undergo but little alteration, we must consider whether susceptibility to infection, as well as tendency to hemorrhage, is not due largely to alteration in the cement substance of the endothelial and epithelial membranes.

=The Mode of Action of the Vitamine.=--One of the most interesting as well as puzzling questions in regard to the antis...o...b..tic vitamine concerns the manner in which it prevents or cures scurvy. It is a subject which at present is in a state of flux, hardly having emerged from the realm of hypothesis, so that detailed consideration will profit little. At first the _modus operandi_ was explained and accepted as enzyme action, but it was soon evident, in view of the thermostability of the vitamine, that it could not be cla.s.sed as a ferment or enzyme in the generally-accepted sense of this term. In general, it may be stated that there are two main views: one that the vitamine acts directly, and the other that it acts indirectly through the function of the endocrine glands. _Direct action_, furthermore, may be accomplished in at least one of three ways. The vitamine may (1) serve as a source of nutriment for the tissues, (2) exert an ant.i.toxic effect on toxic products, or (3) function as a catalyzer. The first interpretation is evidently the simplest and conforms to the long-established knowledge of caloric food factors. That such small amounts as 2 c.c. of orange juice daily should suffice to protect an animal from nutritional disaster runs counter, however, to former conceptions of food nutrition. Further than this there is little against this viewpoint. In its favor is the fact that, up to a certain point, antis...o...b..tics act in direct ratio to the amount given; for example, 2 c.c. of canned tomato juice is insufficient to prevent scurvy in guinea-pigs, 3 c.c. will protect some but not all of a series, whereas when the amount is increased to 4 c.c. daily all animals will be saved. As we are considering new food factors it is manifestly unwise to judge them by old standards, and to decide offhand that they cannot possess such a high degree of nutritive power. This question must be regarded as still open.

The ant.i.toxic theory suffers from the fact that the toxic origin of scurvy cannot be established. Before this is possible, it is clear that it will be difficult to bring forward convincing evidence of a neutralizing substance. Against this theory is the fact that elimination therapy is of no avail in the treatment of infantile scurvy. Hess and Unger (1919) failed to alleviate the symptoms by means of catharsis, diuresis, sweating and repeated intravenous injections of normal salt solution. In its favor it may be advanced, in a general way, that the vitamine, in many characteristics, resembles an ant.i.toxin--in its extreme lability, its destruction by heat, aging and alkalies. On the other hand, ant.i.toxins also are readily destroyed by acid which, as has been shown, exerts a protective influence on the antis...o...b..tic factor.

The rapidity of action of the vitamines, one of the most impressive phenomena, calls to mind the neutralizing action of an ant.i.toxin, and probably has given rise to the a.n.a.logy. Williams suggests that the vitamines have "a general, non-specific, ant.i.toxic or eliminative action" on toxic substances resulting from the metabolic decomposition of food.

The theory has been advanced that the action of the vitamines is catalytic. Although this viewpoint has been taken regarding the water-soluble rather than the antis...o...b..tic vitamine, it will be well to review briefly the work on which it is based. Among the first to suggest this hypothesis were Vedder and Clark, who noted a relationship between the amount of vitamine required by fowls and their carbohydrate intake.

Funk in 1913 made a similar observation in regard to beriberi, and in the following year, with von Schoenborn, showed that a vitamine-free diet led to hyperglycaemia, with diminished amount of hepatic glycogen, and that the addition of water-soluble vitamine diminished the hyperglycaemia and increased the liver glycogen. The work of Burge and his co-workers on the catalase content of tissue led to a similar conclusion. Their results may be summarized by the statement that the oxidative processes are hampered and fail to balance the autolytic changes, and, furthermore, that a relationship exists between the catalase activity, acidosis and normal oxidative processes. This theory would presuppose that scurvy is due to the formation of toxins which are normally in process of continual destruction in the body. According to some, these catalyzed toxic substances are metabolic in character, originating from incompletely oxidized food; according to another interpretation, they are the product of autolyzed tissue cells (tissue toxins). The difficulty with this explanation is that scurvy cannot be prevented or cured by a diet containing food of high catalytic power.

For example, wheat embryos which, according to recent investigations of Crocker and Harrington, have a high catalytic activity, were found of no therapeutic value in relation to infantile scurvy (Hess, 3).

This problem has been approached from quite a different angle. As is well known, certain bacteria require serum, blood, milk, etc., in order to grow satisfactorily on artificial culture media. It has been established recently, primarily by the work of Lloyd, that this peculiarity in the cultivation of microorganisms is due largely to their requirement of vitamine. She found a relationship of the inverse order between the amount of amino acid present in the culture medium and the amount of vitamine required to stimulate the growth of strains of meningococcus. Reasoning from this experience, she suggests that the action of the accessory growth factors is to increase the reaction velocity of the proteolytic metabolism. Here we find the vitamines once more regarded as catalyzers. This author, however, a.s.sociates their activity with proteolytic rather than with carbohydrate metabolism.

Interesting and suggestive work of similar nature has been carried out in relation to the growth of protozoa and of yeasts (Eddy).

Investigations of this kind, dealing with unicellular organisms propagated on a simple food, have the advantage of greatly simplifying the problem.

The recent work of Dutcher falls under this caption, differing merely in the fact that he attributes to the vitamines an _indirect action_. He has demonstrated that the tissues of polyneuritic birds show a decrease in catalase activity to a point 56 per cent. below normal, and that this activity is largely restored when the birds are cured with vitamine.

According to this writer the vitamine functions as a metabolic stimulant, and its lack results in a depression of the body oxidations with an accompanying formation of toxic metabolic products, injurious to the nervous system. The action is regarded as coming about in an indirect manner, being accomplished through the hormone action of the vitamines on one or more glands of internal secretion.

The _endocrine hypothesis_, suggested by Funk in his monograph, is not without some corroborative evidence. In testing the pharmacologic action of the water-soluble vitamine, Uhlmann found that it stimulated the various glands of the digestive tract, in this respect acting like pilocarpine. Some years ago Albert expressed the opinion that the action of this vitamine was "vagotropic" like atropine, and recently Dutcher has reported definite relief and cessation of polyneuritic symptoms by means of pilocarpine (0.5 mg. subcutaneously). He claims equally good results from thyroxin, the hormone of the thyroid gland, from desiccated thyroid and from tethelin (pituitary). Voegtlin and Myers conclude, as the result of experiments with brewers' yeast, that the chemical and physical properties of secretin and vitamine are identical.

The early work of Funk and Douglas, which showed that various _glands of internal secretion_ diminish in size and undergo degenerative changes when the diet is vitamine-free, the newer work of McCarrison and of Dutcher to the same effect, clearly point to an intimate relationship between some of the endocrine glands and the vitamines. As regards scurvy, the only work is that of Rondoni, McCarrison and of LaMer and Campbell on the adrenal glands, which were found by all to be enlarged in guinea-pigs suffering from this disorder. These investigations must be regarded as tentative rather than conclusive until confirmed by similar necropsy reports in man. In this connection it should be noted that thyroid, parathyroid or suprarenal extract is of no avail in the treatment of scurvy. This failure may, however, be explained by the fact that the normal balance of glandular activity was not established. We must bear in mind, however, that although the vitamines may influence the secretion of the glands of internal secretion, this explanation does not satisfactorily account for the symptoms of the "deficiency diseases." These disorders do not in the slightest respect resemble the clinical pictures which we are accustomed to a.s.sociate with a lack of activity of the glands of internal secretion. If the polyneuritis of beriberi and the hemorrhages of scurvy are attributable to a diminished secretion of the endocrine glands, then it will be necessary to revise present conceptions of their physiologic functions.

=The Fate of the Vitamine in the Body.=--One of the most important questions in relation to the antis...o...b..tic vitamine, quite apart from its chemical nature, physiologic function, and its source, is its fate in the human body after it has reached the alimentary ca.n.a.l or been carried to the tissues. It can be readily appreciated that our knowledge of this aspect is very meagre. We shall endeavor, however, to detail what little is known of this subject, conscious of the fact that investigations of the next few years may contradict our present viewpoints.