·No text on this page.

·DE SARD Aatonal and Metabolic Aspects of Infection ANDER ANNALS OF THE NEW YORK ACADEMY OF SCIENCES VOLUME 63, ART 2, PAGES 145-318 October 28, 1955 Editor ROY WALDO MINER NUTRITION IN INFECTIONS Conference Chairman and Consulting Editor WALAN RIGHT HLE and System Fortified Brons By JOACHIM RUAN CONTENTS Critical Evaluation of the Role of Nutrition in the Prophylaxis and Treatment of Disease By SEYMOUR LIONEL HALPERN Implications of Observations Vlade During I'xperimental Deficiencies in Man By 11 165 Autrition and Intestinal Parasitism By ll ILLI 4X H FRYE 175 The effect of Iligh Levels of Vitamins on the Resistance of Chicks to Tow? Typhoid By c 186 The brother and Vitamins in the Treatment of Swine Ententis By RW LUECKE 193 ByA E AXELROD AND J PRUZANSKY 202 Flard Balance During Infection with Reference to Protein and lineral Metabolism En Ohseruations on Infection and Certain Vitamins By BENJAMIN V KACAN o Pocong the Aged and the Debilitated Patient By AARON PRICOT AND AUDRE By LAL RINCE I KINSELL 240 and Nutrition in Infections By MAX B VILBERG AND MAX MICHAEL JR 252 Nutritional Deficiency as It Predisposes to Infection and the Role of Vitamin Deficien cies By ROBÉN LOrez TOCA Problems of Surgical Patients By Jo ATHAN E RROADS AND CHARLES E 268 Certain Infections By ELMER II LOCCHLIN AND WILLIAM G MULLIN Autritional Disorders an Bilharzial Cases with llepatosplenic Affection By A 1 MODSA A EL Norty KHATTAB I EL DEED AND M I ASHEM Altered Prognosis in the Diabetic with Infection By HERBERT POLLACK 311 Recapitulation and Prospects By Hon 4RD A SCHSEWER 314 TiZhis ser es of Napers in the result of a conference on Wirel on sa lwfedens held by the Section of Roingy of The New York Academy of Sciences Vay 24 and 25 1055 214 220 230 258 276 301 145 ·Copyright 1955 by The leto York Academy of S sences ·CRITICAL ETAT VATION OF THE ROLF OF NUTRITION IN THC PROPHYLAXIS AD TREAT VIENT OR DISEASE By Seymour Lionel Halpern Vew York Vedical C llege Flower Fifth trenue llespital Afw Hork !! Whenever significant advances have taken place in a phase of science, it is important periodically to assess critically the degree of accomplishment, to An c 1 1 T may expose previous overenthusiasm, censure unwarrantable pessimism and clarly new problems that have been created Statistically significant con clusions can be demonstrated after a relatively brief inter al with some forms of clinical and basic research Conversely the effects of an experimental maneuver may be so subtle, and may not reach a patent maumum for such a Jengthy period of time as to make hazardous the drawing of any early con clusions This situation prevails in nutrition research Premature over optimism with an unrealistic and improper application of some of the recent important advances in the field of nutrition and metabolism has led to some drcrediting of the findings among many individuals who otherwise are in the most advantagous position to apply them Since ancient times it has been suspected that an individual must have adequate nutrition to be well It has been recognized, to a lesser extent, that the well! is only steady food nutrition, and metabolism that a scientific foundation for many empirical beliefs has been constructed Biochemists physiologists physicians micro biologists nutritionists veterinarians, food technologists and other specialists have contributed to these studies The vast amount of accumulated data has led to much confusion with conflicting opinions and interpretation of the data Perhaps nou here in the realm of biology has there been gathered such A mass of facts that needs to be correlated and systematized as in the field of nutrition A considered rey lew of much of the pertinent blished data indicates that no reasonable doubt cin be entertained regarding the catholic role performed by nutrition in the maintenance of a positive state of high grade health and in the prophylaxis and therapy of disease The nutrients supplied to the tissues exert powerful direct influences not only as structural essentials for synthetic processes hut as regulators of all those biochemical processes that constitute the sum total of body metabolism The ability of a patient to recover from an illness injury or operation is closely related to his previous and current nutrient supply Rare indeed is the patient who cannot be aided by proper nutritional guidance since nutrition is probably the most important environ mental factor affecting health and disease 147 ·toss 148 Annals New York Academy of Sciences Some of the recent and current research that forms the basis for these conclusions is reported elses here in this monograph by the original investiga As it is impossible in the brieł space allotted to me to discuss more than a limited phase of this last subject only certain salient areas in the forest of nutrition will be explored in this presentation, and some of the major problems relevant to the role of nutrition in the prevention and treatment of disease will be underscored Developments en Arnthon Rescarch The infinite number of factors invohed in metabolism males research in this field, of necessity, very difficult to evaluate The number of permutations and combinations of biochemical reactions feasible from the known intermediary chemical metabolites is almost beyond calculation In the neophy te stages our know ledge of metabolism, it was considered that the metabolic pathwa, of protein, carbohydrate, and fat metabolism were separate and distinct the present adolescent stage of our knowledge, we know that this is not true Studies using compounds labeled with radioactive elements have proved conclusn ely that the intermediary pathways of metabolism for carbohydrates, protein, and fat frequently merge for several steps and cross at numerous inter sections The vitamins and minerals acting on numerous enzymatic and synthetic processes may act through their adequacy or insufficiency as red or green lights all along the metabolic rondway Evaluation of basic research in nutrition is quite complex because, in the evolution of a problem, one laboratory often fails to duplicate the findings of another Reported results of nutrition and metabolic studies by different research teams may even be contradictory Multiple factors influence the apparent mechanism of action of a compound apd the alterations produced by deficiency These factors include difierences in the management of animals or handling of tissues, small variations in other seemingly unimportant or unrelated nutrients, a divergency in type of tissue, organ, or organ system studied, and a different experimental approach The external conditions influencing clinical research are even more numerous than with basic research When determining the effects of experimental deſ ciences, for example, it must be ascertained whether any associated insufi ciency is present, whether all other environmental factors have been excluded 's a cause of observed results, and whether abnormalities detected are primary secondary "The latter pitfall is illustrated by the macrocytic anemia of corbic acid deficiency in infants This condition responds to either folic d or ascorbic acid, the hematopoietic defect in this case apparently being to a conditioned folic acid deficiency, for ascorbic acid appears to be neces sary for the conversion of folic acid to its active form, folinic acid When determining the positie results consequent to administering nutrients to healthy men, deficient humans, or sich individuals, psychologic influences that subjectively bias the patient or observer musi be ruled out Rhenever possible, the double blind test method should be used in this plan of snyes Cigation, neither the patient por the obserier knows which medication is the nutrient element or combination and which is a placebo Overenthusiasm, a ·149 Halpern Nutntion in Treatment of Disease with an expectation of beneficial effects from a compound, as well as pre existing prejudices thus are ruled out as factors influencing the interpretation of clinical signs and symptoms There are ample critical, statistically significant experimental studies to indicate that good nutrition is important for optimal resistance to infection, for a superior tissue capability to cope with disease and injury, and for max umum antibody production Good nutrition esll help to insure rapid wound healing after surgery, burns, or radiation exposure Normal blood protein lesels, osmotic pressure, and normal hematopoiesis will be maintained Ade quate nutrition will sustain tissue synthetic processes, secure correct hormone and enzyme activity and enable the liver and gastrointestinal tract, cardio vascular apparatus, nervous and other organ systems to function normally Proper nutrition thus is not only important in preventing teight disturbances and specific deficiency disease, but it has an equally vital role in maintaraing high grade health Thus, in a nonspecific manner nuention participates in the prophyla nas against most acute infections and when used as an adjuvant therapy, shortens the duration of convalescence of virtually all pathologic rocesses The term high grade health" is frequently used in this discussion rit seems quite clear that, even in the absence of all manifest disease, there are still varying levels of health The components of a good diel are well known There must be a sufficiency of calories, of proteins, especially animal proteins and of vitamins and min erals, including the electrolytes Therapeutic drets for acute infections and other diseases are extensions of the normal diet They not only must maintain the normal nutntional requirements but must provide for increased physiolog cal requirements for certain nutrients and increased losses of other nutrients Occasioned by the illness as well as for the replacement of any previous de pletions The requirements of each specific nutrient should be estimated separately for the )andividual The total nutrient needs also will vary from patient to patient In general, an attempt should be made to supply all necessary nutrients through the diet In major illness, marked metabolic alterations may be produced by physiological and psychological stresses, losses of nutrients from the body may be unduly large, and intake may be poor This will produce raped nutritional deficiency, which will be especially severe if there were preeristung depletions It is far more difficult to correct nutritional deficiency than to prevent it In an attempt to meet the nutritional demands of the ul individual, pharmaceutical preparations such as vitamin capsules and caloric concentrates are of great aid to the physician in the occasional case where all requirements cannot be met by the oral route, parenteral alimentation may be administered There is no substitute for clinical acumen to ensure the proper application of nutrition therapy It is unfortunate that too many people have the im pression that the benests of nutrition therapy can be accomplished through a mass effect by dumping into an individual the matumum possible amount of es ery knows nutrient In an attempt to do this attention may be focused on purified crystalline compounds and thus be diverted from the total diet ·150 Annals New York Academy of Sciences and nutrition of the patient There are so many unknowns in nutrition and metabolism that the focal alm of nutrition must be to supply a wholesome diet to insure an equate supply of all known and unknown factors Sup plemental vitamin capsules, for example, are unquestionably an important wd essential adjuvant to nutrition therapy, but it nlu ays must be remembered that they still art only i re enforcement for the diet and not a substitute cu problenis hrve been created by the injuclicious application of nutrition therapy Any mode of treatment, any In parut to the body, may act as a two edged swc benefits may be wrought Administe may be produced Such is the case harm, several factors should be considered when planning a chet regimen These are (1) The relation of nutrients to pharmacological agents The title of this paper reasonably could be extended to read "cvaluation of the role of nutrition in the prevention and treatment of disease and in the prevention and treat ment of the complications of pharmacological therapy " (2) The relation of nutrients to both the disease state and the stage of the disease process. The nutrient element that is so beneficial in one phase of an illness, can adversely affect, in the very sime dosage, the internal milieu of the body in another phase and produce toxic manifestations and death (3) The potentialities for toxicity of the nutrient element per sc Nutrients cannot be administered with complete impunity, even to normal persons Some clements essential for life may, in excess, produce sex ere tissue damage (+) The relation of the various nutrients to each other I or an optimal effect, there must be 2 proper balance and proportion among nutrients and all the nutrients utilized by the tissues must be simultaneously available to the cell This holds true whether the nutrient be classified as essential be cause the body cannot manufacture it, in which case it must be supplied from etogenous sources, or whether the cell can produce it in the in anabolic processes, more frey essential elements The Relation of Aulation to Pharm 1cological Agents The recent introduction of numerous new pharmacologic agents has made the problem of nutritional therapy more compler As examples of the manner in which pharmacologic agents superimpose additional dietary requirements se, diuretic drugs, antibiotics, hormonal ed used include various oral and parenteral mercunal compounds, carbonic anhydrase inhibitors (Diamot), and ion er change resins They either decrease sodium retention by the kidney with increased excretion of sodium in the urine (mercury, Diamox) or they may prevent intestinal absorption (1on exchange resins) and thus increase fecal losses of sodium Sodium chloride must be carefully adjusted in the diet Most patients requiring diuretics will beneſít by a sodium restricted dieta ·151 Halpern Xutntion in Treatment of Dreave low sodium syndrome, s bich us occasionalls fatal, may ensue nhen massive druresis with large losses of sodium : produced in a patient on 1 diet markedly restncted in sodrum This sindrome is corrected by replacing the depleted electrolytes The water soluble vitamins also are lost in abnormal amounts from the body during a huge diuresis This loss may be superimposed upon come previous nulntional depletion that many patients have while receni ing curetics, because of an anorexia associated with their intermits and often increased by a tastelen diet Some of the vague symptoms following frequent diuresis may be the valed by administering large supplements of the water soluble 31tamis Oral onhbolics non are prescribed unnsersalls for the treatment of man infections Infections raise the requirements for most nutrients because of the increased metabolic rate secondary to fever and toxicity and the phesiology changes produced in the tissues by the stress of the disease when nuser vomiting, diarrhes and excessive sweating scompiny the infection there are additional losses that must be compensated trores muy compound the difficulties Antibiotics often agyszate this deleterious state Some oral antibiotics and chemotherapeutic agents produce anorexn gastro- Intestmal upset manifested by vomiting and diarrhet occurs in as minis 25 per cent of patients receiving chlortetracycline and ory tetracycline The broad spectrum antibiotics destroy the normal barterial flora of the intestinal tract The biosynthesis of vitamins in the intestine normally in fairls considerable source of many B complex vitamins and of vimin The normal bacterial Nora also may be required for the utilization of some vitamins Sterzlization of the intestines by antibiotics increases the need for so erogenous source of vitamins It may be a factor in precipitating signs and symptoms of acute vitamin deficiency in subjects with infection W pruents at infection require nutritional support Idditional care must be estretsce when ra! broad spectum antibiotics are being administered to them These atients nould probably benefit from a vitamin supplement containing the compler factors, perhaps vitamin K and alco zitamin C, for which there a notably increased demand in situsions of stress Recenlly a combination w an antibiotic with these vitamins has been prepared in 1 single capsule This would appear to assure un adequate ant she of those vitamins that are especially needed in stress situations under treatment with antibiotics and may reduce the number of individuals who have 1 slela cd con le suence or other complication caused by nutriti naslequats Cortisone and reland compounds the subject at the interrelation of for mones nutritional elements 2002 en mes is local and f 5111ting on that in itself could be the besis for i monograph ( ut end related eumpoumis are nou leurs en andely used in poslans for the tre elment of rheumatore irthmus rheumati funer and other w Bied collige nous diseases inil fut mans serious alleryx disorekin luinyon il resultam bes locentri important In preventing and treating omple tas o torfisne lydrocortisone, ani adrenocorti otroju hormon These companies hist Hi common thur bility to sause i retention of tum audchloride with a concomitent incre ISE in weight and development of Assut com a loss of potassium with the ·152 Annals New York Academy of Sciences possible consequences of severe hypopotassemia, a rise in blood pH, a protein catabolic response with negative nitrogen balance and possible tissue wasting and increased glycogenesis with the development of hyperglycemua and glycosuria The incidence of these deleterious side effects is related to dosage, to treatment of the disease process, to previous nutritional status, and to current nutritional intake Dietary regulation has minimized the consequences of these side effects Weight gain and edema are decreased by restricting sodium intake Hypopotassemia is overcome by encouraging the intake of fruit juices and other foods high in potassium and possibly by potassium supplements The deleterious effects of negative nitrogen balance are counter acted by a high protein diet Adjusting the percentage of carbohydrate and the total caloric intake may control hyperglycemia if it appears A new synthetic derivative of cortisone, prednisone (metacortandracin, meticorten), though three to five tmes more effective as an anti inflammatory agent than cortisone or hydrocortisone, has only a slight effect on the serum electrolytes The need for sodium restriction and potassium supplementation is therefore not required to the same degree as with the other corticostero:ds Preliminary studies have indicated that the protein catabolic response is equally great and that negative nitrogen balance may be even more marked with prednisone than with the other compounds Adequate protein intake must be assured with all corticosteroids to prevent the deleterious consequences of protein disequilibrium Isoniazid Pyridoxine administration prevents the toxic effects of isoniazid which is used routinely at present in the treatment of tuberculosis Isoniazid adversely effects pyridoxine metabolism, as it forms a conjugate with the vitamin resulting in its inactivation and excretion Pyridoxine deficiency with neuritis develops If large doses of pyridoxine are given wth isoniazid, no neuritic symptoms occur Once neuritis has developed, however, it is necessary to discontinue the isoniazid in order to produce a remission Relation of Dietary Requirements to Disease Slage Each disease affects the requirements for nutrients to a different extent In many illnesses, the stage of the disease also has a profound influence on dietary requirements As examples of the varying requirements of different discases, ulcerative colitis, diabetes and congestive heart failure will be briefly discussed In ulcerative colitis, tremendous amounts of all nutrients are lost through the colon, thus causing a severe metabolic disturbance Fluid electrolytes, vitamins, and other nutrients are dissipated The problem of nutrition is rendered more difficult because food may not be retained in the intestinal tract for a sufficient length of time to permit its absorption There is usually an associated anorexia, and bland, low residue diets have to be continued for long periods of time In these patients, many serious complications can be I needed if there is a severe anemia Pellagrous tongues are not infrequent ·Halpern Nutrition in Treatment of Disease 153 because of poor absorption of vitamins Parenteral vitamin therapy may be indicated In diabetes, total calories are regulated upward or downward to achieve a normal weight The total amount of carbohydrate is regulated, as well as its distribution during the day, in order to prevent postprandial hyperglycemia The diet is coordinated with the type and amount of insulin administered In decompensated diabetes, there is a negative nitrogen balance and fluid, electrolyte, and vitamin losses Fluids sodium chloride insulin, and, at times, potassium will be required to restore compensation IIigh protein and high vitamin diets should be continued for some time following acute episodes to replace the depletions Many researchers believe that a large number of the signs and symptoms of congestie heart failure, shatever the underlying patholog), are due to the failure of the kidneys to excrete sodium in normal amounts In order to over core the deleterious affects of this sodium retention, it is necessary to place these patients on a sodium-restricted diet Though there may be a somewhat restricted choice of foods, and flavoring must be accomplished without salt, ut is rarely necessary to deviate greatly from the normal dietary pattern The nutntional deficiencies seen in patients with heart failure who are at home, arise rather frequently because the patient has not been told what foods he apeutic diet The importance of a high protein diet in the therapy ot 11er disease is now universally accepted Many clinical studies have confirmed the beneficial achievements from this therapy Experimental Iner disease is more readily induced when the diet us deficient in proteins Liver disease is associated with several abnormalities in protein metabolism Some patients with chronic liver disease are sensitive to high protein diets If such diets are used indiscriminately, hepatic coma may be initiated In the presence of hepatic coma, protein restriction must be practiced An attempt to force a high protein diet mły proyche a premature fatality among such patients Fat is not so harmful in liver disease as it was once believed to be Adequate caloric, protein, vitamin, and mineral nutrition is much easier to achieve it some fat is allowed Similar problems are present in treating kidney disease During the stage of massive proteinurua, protein intake my have to be doubled On the con trary, in the presence of renal failure suth uremia, the protein intakes should be reduced to the basic munimum In renal disease with edema, sodium restriction is necessary If a 'sodium losing 'nephritis is present, high sodium intales are to be cncouraged When the kidney is losing potassium, potassium replacement is necessary to prevent further kidney damage from hy popotas Conversely, in azotenua from acute inuna or chronic renal damage, hypxcrpotassemia may be the problem It may be appropriate at this time to note the influepce exerted by the caloric content of the diet on the requirements of many vitamins, especially those of the B comples The requireraents for some of these vitamins are minimal semil ·151 Innals New York Academy of Sciences When caloric intalc is greatly restricted It is rare to see maniſest vitamin deficiency discase in total starvation During refeeding after a period of stiriation overt vitamin deficiencies have been precipitated when the vitamin allowances were not increased suficiently to meet the increased metabolic demands of the high caloric schedule Toricily of Tarent Clemenís Certain nutrients in excess can be toric Continuous vitamin A administra tion in high levels muy produce multiple severe toxic symptoms especially in infants In hypcriitaminosis 1, there is an elevated concentration of vitamin I and alkaline phosphatase in the serum X rays of the long bones show a characteristic shell like bony hyperostosis An excess of vitamin A, as well as an absence of vitamin A in the feedings of pregnant rats will result in con genital anomalies in the ofispring It is seen thus that deficiency or excess of the same substance (ause major clinical and experimental abnormalities A prolonged greatly excessive intake of vitamin D will produce toxicity In hyperiilaminosis D anorexia nausea, vomiting diarrhea, weakness, head ache drowsiness, and weight loss may occur Such genitourinary symptoms as polyuria noctura and dysuria associated with metastatic renal calcification may characterize the syndrome I rays also may res eal calcification of vas cular organs and the prostate Iaboratory studies show an elevated serum calcium concentration, proteinuria eles ated blood urca nitrogen and other evidences of impaired renal function Both vitamin A and vitamin D toxicity syndromes are reversible, and they are cured by eliminating the supplementary vitamin Another potential danger of prolonged excessive intales of a nutrient supple ment lies in the possibility that the cells may accommodate themselves to the nutrient and then require the large amounts for normal function This phenomenon has been demonstrated repeatedly in microorganisms and is a basis of bactenal resistance to antibiotics Cases of a typical pyridoxine deficiency syndrome in infants precipitated by withdrawing large amounts of supplemental pyridoxine have been reported recently Restoring the large doses of the vitamin alleviated the symptoms It was then necessary to sean the infants aw2y from these excessive supplements Obesity also may be classified as an example of the deleterious results of Overnutrition In caloric insufficiency, functional impairments of the organs develop, the normal course of metabolic processes are interfered with, and the body in general deteriorates Anatomical changes will occur in most tissues of the deficiency of calories is severe anci prolonged Resistance to mrfection is markedly lonered and healing proceeds with difficulty Similarly, functional and anatomical disturbances also are induced by a caloric ou erabundance Obese individuals are more prone to develop degenerative cardiovascular diseases osteoarthritis diabetes, and other nietabolic disorders They often handle infections less well, have a lower endurance, and are greater operative risks than people of normal weight Obesity frequently results from the ingestion of naked calories te fools des ord of other dietary essentials It is ·Halpern lutrition in Treatment of Disease 155 not at all unusual to discover among the obese signs and symptoms of vitamin protein and other malnutrition that require active correction during the course of a reducing regimer Interrelationship among sirent Eletients Ibout 50 purited nutrients are ackno led,ed today as Indispensable for gronth and des elopment These include amino acids minerals vitamins fatty acids total calories and stater Strong interrelationships exist among these detary essentials For the most efficient utilization of any one dietary substance all metabolically related factors must be present simultaneously Failure to appreciate fully the necessity for the constantaneous presentation of nutrients lo the cells has been responsible for com reported achievements m h - F es> and rap»d tissue july atomic radiation and burns are contingent Up auequate protein supplies and normal protein metabolisms During the catabolic state that accompanies sei ere acute illnesses and injuries a negatie nitrogen balance may occur on a riet wich would be more than adequate during health The restoration of protein anabolism with a positive nitrogen balance requires astute attention to nutrition for the construction of proteins can proceed only when all component parts of the molecules being elaborated are ava lable simultaneously In incomplete amino aciel mixture cannot be utilized for the production of intermediary compounds of protein anabolism and will not be retained by the organism If all the amino acids necessary for protein synthesis are not present production at that moment is i mited by the one least available Amino acids not utilized immediately for protein con struction are lost for this purpose They enter the general metabolic pool and may be util zed in the production of other nitrogenous substances or else may be irreversibly further metabolized Two nutritionally incomplete foods or artificial mixtures supplement each other only when administered together Carbohydrates and fais have both a specific and nonspecific regulatorv effect on protein metabolism It is difficult to produce a positne nitrogen balance with insufficient calories though increasing the caloric intake abover critical level does not further promote the utilization of an adequate amount of protein When carbohydrates are fed simultaneously with roteins dietar am noacids are matımalls utilized for protein synthes is no need for the protein com pool to be used as a source of I carlinhsurate metabol sa Lursors for pc formation of nonessential a Lxperimental animals consumug ? Airtually fat free diet have 1 decreased nitrogen balance and excrete s gmt canth larger quintities of certain amino acids in both the urine ani feces than animals on an isocalori diet with average proporti ns of fat There by an increased deman 1 for mineral elements dunng periods of protein duis ·156 Annals New York Academy of Sciences anabolism, for potassium, sulfur, and phosphorus are laid down with nitrogen in the formation of tissue protoplasm The effectiveness of a high protein diet may be decreased by an insufficiency of mineral substances Normal protein metabolism also requires liberal quantities of vitamins, especially those of the B compler and ascorbic acid The vitamins act as biocatalysts in both synthetic and ovdative reactions Riboflavan is retained with protein, while negative nitrogen balance is accompanied by a negative riboflavin balance The poor wound healing and decreased rate of growth in experimental ariboflavinosis actually may be reflections of the injurous effect of riboflavin deficiency on protein metabolism The essential amino acid amino acid decarboxylases and is involved in protoporphyrin, antibody, and other protein synthetic processes Pantothenic acid is a component of co enzymes A, which is involved in the acetylation processes of intermediary protein metabolism Vitamin B1 has a specific role in nucleic acid and porphy rin synthesis, and will increase the utilization of marginal quality pro teins Cyanocobalamin and choline both function in the methylation process and spare the essential amino acid methionine Ascorbic acid is related to the metabolism of the amino acids tyrosine and phenylalanine The hepatic storage of completes containing folic acid, riboflavin, niacin, biotin, and pantothenic acid parallels the level of dietary protein Lastly, there is evidence that both ascorbic acid and pantothenic acid may indirectly influence protein metabolism through their effect on the adrenal cortex and their relationship to the secretion of adrenal cortical hormones In summary, it is apparent that protein metabolism is influenced by the total composition of the diet Virtually every element of nutrition has a role in assuring protein equilibriums that are favorable for the prophylaxis and treatment of disease The simultaneous presence of a sufficient amount of complete quality proteins, of carbohydrates, fats, and total calories, of minerals and of vitamins is needed if every phase of the metabolism of each individual dietary component is to proceed compatibly toward maximum health Problems of Islamin Therapy Even when all those working in the field of clinical nutrition have agreed that a vitamin supplement is indicated for a specific situation, there has been great difficulty in determining the qualitatre and quantitative composition of the preparatars Same clarification is now possible concerning this problem of vitamin therapy I. pared 1hc fruits or he use of vitamin K in terminal pregnancy or in the nex born intant, vitamin A in treating nyctalopia or follicular hyperkeratosis, and vitamin B, in pernicious ·anemia Halpern Nutrition in Treatment of Disease 157 There are numerous interrelationships between the vitamins One vitamin may promote the conversion of another vitamin into its active form or it may protect other vitamins from otidative destruction The metabolism of a specific vitamin is often greatly influenced by the adequacy of others in the diet Several vitamins often catalyze the same metabolic reactions Successful dietary management requires that the presence of all vitamins be assured There is a close association of many of the vitamins in natural foods In general, when a diet is deficient in one element, it will be found wanting in others It behooves the physician to prescribe a multiple vitamin preparation whether vitamins are administered for prophylaxis or for therapy Many commercial therapeutic vitamin preparations are lacking in pantothenic acid, of other vitamins, and all play & cogent role in certain specialized tissue func tions such as hematopoiesis, antibody synthesis, and corticosteroid hormone secretion It would seem logical that those chemicals, which are present in virtually all body tissues and are involved in a vast number of critical bio chemical rcactions, should be incorporated whenever supplemental vitamins are indicated, even though a recommended daily allow ance for them has not been ascertained While we await further increments of our knowledge concerning those recently characterized vitamins, it probably is best, at the present time, to follow the tentative recommendations of the Committee on Therapeutic Nutrition of the National Research Council, Washington, DC, concerning the qualitative and quantitative composition of vitamin prepara trons Because of the difficulty in ascertaining the essentiality and quantitative needs of vitamin substances, supplements must never be a substitute for a wholesome diet with its content of known and perhaps as yet unknown factors Iatrogenic maluurlion induced in a patient by a poorly concerved thers peutic diet has been observed with an alarming frequency So called thera peutic diets at tumes contain inadequate amounts of individual nutrients eten for the normal body and, in addition, they frequently neglect the superimposed demands of the disease process Iatrogenic malnutrition thus can be classified as a combination of primary and secondary malnutrition Therapeutic diets formulated especially for the treatment of particular signs or symptoms of a disease are most often lacking in total nutritional adequacy The most frequently inadequate nutrient is protein The de mands for protein commonly are not met in patients with ulcerative colitis and other darrheal diseases, in diets for peptic ulcer, especially during exacerba tions, in hidney diseases associated with massive proteinuria, and in diets for cirrhosis and hepatitis Diets for peptic ulcer usually are unduly low in calories and murheilly deficient in ascorbic acid In general, soft, liquid, and blind diets and postoperative regimens are apt to be nutritionally inadequate in vitamins, proteins, and calories Vinute attention should be paid to special diets, for tissue nutritional depletion is readily presented but often dullicult ·160 Annals New York Academy of Sciences choosing foods Education of the public, pointing out clearly what foods should be eaten and emphasizing the essential role of nutrition in the prophylaxis and therapy of disease, is necessary to increase the percentage of weil nourished individuals in the population and thus to maintain our nation in maximum productivity Summary and conclusions The nutrient supply to the body unquestionably exerts direct and powerful influences upon all the biochemical processes that constitute the sum total of body metabolism All research confirms that nutrition and health are in separable Overnutrition undernutrition, or an improper balance of the nu trient elements of the diet all have a detrimental effect Strong interrelations exist between dietary essentials The simultaneous presence of all nutrients is required for maximum tissue growth and synthesis Nutritional therapy is frequently of primary importance in the treatment of may be acclerated or retarded as a result of the diet pattern Autntional ther apy, whether by diet alone or in conjunction with special pharmacological sup plements must be correlated with other specific and nonspecific therapy of the illness The phase of the disease and the nature of specific tissue and organ pathology must be delineated in order that the potentialities and lunitations of therapeutic nutrition may be recognized Modern techniques, procedures, and preparations require responsible application Alost therapeutic nutritional regimens should be extensions and modifications of the normal Some new diets purported to prevent certain chronic illnesses of our scientific discoveries Extensive research is still necessary in que les of nutrition and metabolism of the full potentialities of lifelong nutritional guid ance are to be achieved The proper utilization of knowledge already gained requires perspicacity, good judgment clinical acumen, and a thorough under standing of the principles of nutrition Discussion of the Paper PROFESSOR TRA\CISCO GRANDE (University of Saragossa Vedical School Saragossa, Spain) It will be difficult for me to discuss at length the paper by Doctor Halpern because it has touched on so many problems This paper has given us such a clear idea of the present situation of nutrition that I do not think it is worth spending your time in discussing its general outlooh, with which I am completely in agreement I believe however, that it may be worthwhile to take a les points in particular and to try and sex them from a somen bat different angle especially on the basis of my own personal er perience ·We may Halpern Nutrition in Treatment of Disease 161 I am more interested in the public health point of view than in the clinical treatment of diseases I think we can discuss some of the problems of nutrition diseases from the point of view of prophylaxis If we know the role of an agent in the production of disease re are in a very good position for taking prophy lactic measures against the particular disease In the case of nutritional dis eases we can do very much rowadays in the matter of prophylaxis I believe that an analysis of our potentialities in relation to the prophy la ris of nutritional diseases is worth considering lle can classify diseases that we usually call nutritional--that is produced by changes of dietary onginanto four groups We have first of all a group of diseases which are produced by dietary deficit by lack of nutrients call them deficiency diseases or diseases oi malnutrition if you like lle have a second group which will be produced by disturbances in the normal proportion of the different nutrients that is imbalances Other kinds of nutritional diseases can be produced by overleeding by ex cess of total amount of food or of some of the elements in the food lle can call those diseases of overfeeding Finally we have another group of diseases which ne may call toxic ones re sulting from the fact that foodstuffs may be toxic or may contain some toxic substances Sone call these effects toxic effects and se may d scuss this problem a little more fully later Regarding the deficiency diseases I believe you will all agree that our situ ation today is quite satisfactory Our theoretical knowledge suffices I believe to eradicate most of the deficiency diseases if we have the economic and opera tional means to do so In other words we know enough to present scurvy to prevent beriberi If we are not able to do that it does not depend upon fack of hnowledge but upon the pure operational or economic difficulties There fore I think that our point of view as to the prophy la vis of deficiency diseases 13 completely sound and needs no more discussion The same may be true in the case of the imbalances those diseases-pellagra for instance--which are produced by alteration in the normal composition of the diet llehnok enough about the alterations of the diet that produce these diseases and therefore if we have the material means of changing or avoiding these alterations we can avoid the discase The problem of overfeeding is now attracting great interest in the world in some countries at least The problem of nutrition in the world at large is a problem of underſeed ng The great majority of the human race is of course ut derfed But there are countries in the world, the Inited States of course is a case--in which overfeeding may be a problem and we begin to realize non that overleeding can also be a medical problem and that a decrease of the amount of food that we are using may be important in the prevention of some types of diseases You knos as Doctor Halpern mentioned that our group in Minneapolis is interested in this problem and in the relationship between the blood cholesterol and the diet The relation between blood cholesterol and the incidence of coronary scleros s has been demonstrated It least Doctor heyes his collected a lot of evidence in this direction I am not in a position to dis cuss the question of whether high cholesterol is the cause of arteriosclerosis ·162 Annals New Yorh Academy of Sciences know that an increase of fat in the diet produces change in the blood cholesterol This is more important than the cholesterol content of the diet, as Doctor Halpern himself has already observed Of course the obvious prophylaxis of this type of disease if it is shown that the ingh fat content of the diet produces high blood cholesterol and that high blood cholesterol produces arteriosclerosis-ll be to decrease the amount of fat in the diet So the theoretical basis is clear, provided we supply the clear cut evidence My main interest will be to discuss the so-called toxic effect of diet, because I believe that insufficient attention has been paid to this problem I think we may distinguish three kinds of toxic foods First, toricity may result from con tamination and this is a problem of sanitation, which I am not going to discuss The second type of toxins are those already existing in the foodstuffs Thesc we may call the natural toxins Finally, there are the toxins produced in the foods by handling by the processing of foods during industrial and technoloical maneuvers These toxins are not produced naturally Of the natural toxins, we have a very nice, interesting example in the disease which you know as lathyrism For many years it has been known that the con sumption in grent amount of this leguminous seed, Lathyrus cicera, produces a characteristic difficulty of the nen ous system called Jathyrism, which is in short a spastic paralysis, from degeneration of the tract It has been impos suect pea whose tlower you know-which produce in rits a very typical picture This picture, however, is a bone diserse, with changes in the phosphatase of blood It has nothing to do with the human picture of lathyrism Therefore you liave two secds used as food that contain toxic substances producing very characteristic but different clinical pictures in man and in animals It may be that foodstuffs contain many other substances shich are able to produce toxic effects in the human body If, in the future, our know ledge progresses in this direction there is no reason why other substances we are using today as foods may not also be found to contain similar things that may be the cause of some of the discases for which we have no explanation today Of course, the prophylaxis of this type of disease is very simple if we know exactly the relationship between the particular foodstuff and the discuse In the case of Inthyrism it has been enough in my own experience in Spain to Tmat la tint not related somchos to the existence of toxic substances in the natural lovu stuffs Tlie nert problem that I should like to discuss connection with the toxic ·Halpern Nutrition in Treatment of Disease 163 effects of foodstufis is that of toxins produced by handling by the processing of foods lou all are familiar, I am sure with the effects of the bleaching of flour You know that certain chemical changes occurring during processing produce in the dog a condition characterized by running fits I wonder whether by similar chemical action on natural foodstuffs we are not also producing changes in other nutrients thich may eventually lead to noxious effects in the human body lle are concerned here chiefly with the problem of the relationship between nutrition and infection To put it better nutrition is important in the prophy latis not only of the poorly named nutritional diseases but also of other hands of disease Doctor Halpern has made clear the point that everything happen ing in the body is dependent upon the nutntional situation of the body There fore it is not necessary for me to go into more detail to convince you that nu trition is important for everything including infection Unfortunately we dont hnow much about the relationship about the mechanism of the relation ship between infection and nutrition In fact all our observations still lach scientific evidence I recall that during the Spanish Civil War I was very interested in trying to find out the relationship between for instance the increase of certain forms of clini al tuberculosis or the increase in cases of malaria and the nutritional situ ation of the population I collected much information but when I sat down and tried to put it into figures and to make a statistical analysis of the results I always found that my information was not sufficient to make such an appraisal of the relation. That is what is happening with much of our present know ledge in this regard If you take one of the classical books on nutrition the book by Doctor Jol liffe for instance you can find in two different chapters—the chapter by Doctor heyes and the chapter by the late Doctor Tisdall-two different opinions as to the relationship between the diet and the problem of infection Therefore I beleve that it is one of the fields in which our knowledge has to be expanded We need to look for the basic facts about the relationship between the two processes of infection and nutrition It has been claimed that the infection or rather the response of the human body to infection is a problem of protein nutrition After all the formation of antibodies is protein synthesis and it forms a part of protein metabolism The problem is not so simple as that I ou may have changes in one direction in the formation of antibodies and changes in another direction in the behavior of that particular disease in the clinical development of the disease Therefore I believe it is fair to say that we still need a lot of basic work in this held of the relationship between the infection and the nutritional situation of the host But there are still oti er problems in connection sith infectious diseases that I suppose must also be investigated an Ithat I am sure will għe important in formation for the future I few months ago Doctor DuBois of the Institute was in Vinneapolis dis cussing the present situation of infectious diseases He give what I thought vas a wonderful dress He pointed out a series of facts that for me here ·161 Annals New York Academy of Sciences certainly interesting He pointed out that with the use of antibiotics we nearly have son what we may call the war against bacteria lle have put a lethal end to infection lle have not prevented infection Besides, we are mainly in the light with bacteria We have saprophytes living in our body Some are doing things which are useful for us Some may also be producing substances of the nature of those toxins which may be harmful to our body and may also be inter fering with the host's nutritional processes The same thing happens with so called latent infection It is difficult to explain why, at one moment, a man who has been carrying some latent infection without consequence suddenly develops the clinical symptoms of the disease Is that related to some change in the chemical processes in the body? Is it related to some change in the nutritional situation of the nin? I believe this cold war against the bacteria is still to be won and that a lot of progress will take place if we know better which of the effects of these latent infections are an effect of the saprophytes on the nutritional processes of the body Therefore, our problem in dealing with the relationship between infection and nutrition is tuo fold On the one hand, ue nust start to study the actual process of infection On the other hand, we have to pay attention to the fact that infection is not the only thing that bacteria and other germs cause in the body, but that there may be important effects other than just the classical well known effects of infection ·IMPLICATIONS OF OBSERVATIO\S VIDE DIRIG EVPERIVF\TAL DFIICIE\CIES I\ 114\* By M Horwitt Bkle cul Research Laboratory Elgin State llasp lol Elgin TNI and Department of Biolog cal Clcmistry Lut erstly of Illinois College of Medicine Clicago III I or the past 14 years the Biochemical Research Laboratory of the 1 lgin State Hospital working under the sponsorship of the Food and Nutrition Board of the Vational Research Council Washington DC has been engaged in evaluations of the nutritional requirements of man in an effort to obtain basic information that could be related to physical and mental health In these in vestigations 10 to 13 subjects were mainta ned for approximately 2 years on specially controlled dietary regimens partially depleted in a single nutrient The game control ar - on infection and on other stresses as during the course of each experiment there were the usual number of intercurrent disorders and traumatic experiences that might normally be expected in 30 subjects over a 2 year period Attempts to evaluate the course of intercurrent infections and of one epidemic of a gastro intestinal disorder that required the use of sulfasuxidine gave data which were inconclusive Since it is not possible to relate the course of most infections with a gnen nutritional state the quantitation of an infectious state is difficult In the absence of specific data obtained from experiments specially designed for the study of infection this presentation may be a bit more philosophical than most After 25 years of rather intensive personal application attempting to obtain a better understanding of the science of nutrition houerer perhaps you will forgive me if I present an interpretise paper A few years ago 1 % as a consequence of observations made during our studies of riboflavin deficiencies in man we proposed the somewhat oversimplitied theory that some lesions of nutritional deficiency that we see in the adult are a consequence of the retardation of normal tissue replacement and repair or in other words the retardation of local growth This generalization is based not only on the well known inhibition of the growth phenomena in young animals on suboptimum diets but also on the realization which has been fortified by recent studies with isotopes on the turnover of tissue components that the for mation of new tissue components is almost as rapid in adult life as in the very young This simple statement was offered as a substitute for more complet explanations for the les ons of certain vitamin de ciencies Though the term growth is usually reserved for changes that we can see or weigh it is not incon sistent to consider the replacement of worn-out metabolic systems or of tissues damaged by the stresses of one s environment or activity as part of the general plenomenon of growth Both involve the sume fundamental process the for mation of new cells the ** supported On ! by grasts from the lat gal tam toundat an In 175 ·166 Annals New York Academy of Sciences If one thinks of infection as a type of environmental stress in which tissues may be destroyed by the ravages of an infectious agent or against which spe citic defenses such as antibodies and leucocy tes must be manufactured it is not difficult to understand why the common nutrilites have been gi en so much at tention in research on infection Unfortunately the general value of the thesis that good health and good nutrition are synonymous has led some to reach for interpretations of experimental data that may not be justified and as a conse quence the critics of vitamin prophylaxis and realimentation have had some specific things to criticize Though millions are spent with considerable fan fare in an effort to prevent the rare but more spectacular diseases attempts to achieve ? sane level of nutritional prophylaxis have been given the well known jaundiced eye The blame for this apparent discrepancy in public health edu cation may be an indirect consequence of the activities of a minority who have oversold the vitamins for selfish reasons but all too often the m sguided judg ment of sincere men has also led us astray Perhaps the most significant error made in nutritional research is in the use of an experimental plan in which one studies the effects of the total withdrawal of a nutr lite from the diet of a fast growing anımal sithout giving simultan eous attention to the effects of partial withdrawal By definition a nutrilite is a compound that the body cannot synthesize and is essential for the main tenance of the integrity of the living cell The complete withdrawal of this compound produces a kind of total deficiency and debility due to a combina tion of many primary and secondary effects that are not noted when the nutrilite in question is given to the animal in normal amounts Although many important scientific leads have come from total withdrawal experiments and though many imi estigators must be conscious of the need for grading the severity of a depletion study this technique of setting up a strw man to be hnoched down with ease has nos jumped the borders of pure nutri for reproduction tory experiments so that we can advance more quichly our hnowledge of the pair fed litter mate unless the intermediate levels of the deficiency in question are included in the experiment One of the complications of controlled research on the coursc of human d sease that may be pertinent to the subject of this monograph is the effect of bed rest ·Horwitt Experimental Deficiencies in Man 167 on the vitamin depleted patient It is now generally recognized that a patient immobilized in bed for a period of time tends to go into negative nitrogen bal ance. This is apparently true even though no acute infection or fever is I resent and when bed rest is prolonged the muscle atrophy which takes place becomes obxious The striking cure of the early stages of pellagra when a patent is placed in bed without supplementary therapy has been noted fre quently and, in the hight of our present hnow ledge of the curative effects of Iryptophan this is no longer the surprise it might have been I hat better source of tryptophan and niacin than one s onn flesh? Of some interest in this regard is the effects of bed rest on volunteers with experimental thiamine deficiency About 10 years ago . during studies on thi amine requirements of man 3 out of 11 subjects were confined to bed for ex tended periods as a precautionary measure following the appearance of neuro logical signs of thiamine deficiency in these subjects the lactic and pyruvic acid blool levels (determined in blood taken one hour after oral ingestion of 18 gm of glucose per kg body weight) decreased markedly despite the fact that they continued to obtain the experimental diet that provided only 0 2 mg of thiamine per day At that time we were at a loss to explain the mechanism of the improvement but the present knowledge of tissue catabolism during bed rest offers an acceptable theory to resolze the problem Before the components of muscle tissue can be excreted by the Ladneys they must appear in the blood stream This is true whether the bed rest follows partial nutritional deficiency Or surgery or traumatic experiences such as fever fractures or burns One may not yet be prepared to state dogmatically that this catabolic process is based on the need for its valuable functional effects but it is reasonable to conclude that the vitamins and other nutrilites so presented to the circulatory system may be as useful as long as the severe catabolic process continues as any synthetic mixture of similar composition injected to the blood stream at that time The part of this stress phenomenon of importance to this discussion lies in the recognition that the organism in good nutritional state has the reserve to meet the requirements of this protective mechanism satisfactorily What about the subject in poor nutritional state? Cuthbertson' has shown that rats in poor nutritional condition do not demonstrate this protein cata bolic process and there is one report of a patient in poor nutritional state with long stand ng rheumatoid arthritis who after multiple fractures falled to show any increase whatever in his protein catabolism Deciding whether the ex hausted adrenocortical mechanism is primary or secondary to the depleted state of the nutritional reser es is 100 reminiscent of the chicken and egg raddle so ne shall omst further comment on this question Obxervations of experimental riboflavin deficiencies in man have presented us with pecuhar opportunities to evaluate a possible relationship between environmental trauma and the type of lesion obtained in ariboflavinosis Certain areas of the body such as the shin at the oral angles are subject to much wear in i tear and subsequent danger of secondary infection Tissuring at the oral angles representin, mild cases of angular stomatitis are not uncom mon even in indiyaluals in a good nutritie state During the first Figin study on ribnilayın deficienci a high percentage of such lesions were noted in both the ·168 Annals New York Academy of Sciences depleted and the riboflavin supplemented groups The lesions however were relatively mild and transitory in the 24 subjects who recen ed riboflavin whereas 3 of the 13 subjects in the depleted group showed murhed exacerbation of the oral lesions that could not be healed by topical therapy until after ribo flavin was provided In a more recent study & a special attempt was made to evaluate the occur rence of these oral lesions In 6 out of 8 subjects on a diet that provided only 05 mg of riboflavin per day there were 16 instances of angular stomatitis Eight of these lesions with an average duration of about 4 weeks disappeared spontaneously before riboflavin supplementation The remaining & les ons were much more severe and required riboflavin supplementation to effect I cal ing In 23 other subjects who were receiving 2 5 mg of riboflavin per day and were being observed simultaneously 7 fissures were seen in 4 subjects These were considerably less severe than those observed in the riboflavin depleted subjects and they lasted an average of three and one half weeks To illustrate the course of these facial lesions and their possible relationship to infection the following example is given A 30-year old white man developed a small herpes simplex lesion in the left epiction the le ing the buccal mucous membrane lo therapy was applied Sır wechs later a sim: lar lesion appeared at the right oral angle without any preceding herpes inſec tion Treatment with zinc oxide ointment and later with camphor liniment was then instituted The never lesion the one on the right oral angle healed in about three weeks and did not recur The one on the left side continued in a fluctuating state of exacerbation and remission for several months Tuo months after the first appearance of the angular stomatitis the subject con two months later a fissure formed at the left nasolabial lobe As the lesions had been present for about four months supplementation with 6 mg of ribo flavın per day was instituted and the repair of the chronic facial lesions was quite definite and completed within one month I rcsh herpetic vesicles appeared subsequently on tuo occasions but there was no recurrence of severe lesions while the patient received riboflavin Some years ago Riddle Spies, and Hudson' showed that Staphylococcus aureus and Streptococcus hemoly/cus could be isolated from lesions of angular stomatitis This is not surprising as the open sound presents an excellent medium for bacterial growth In our experience the most characteristic sign of riboflavin deficiency in man has been the appearance of scrotal lesions and the only reasonable guess we can advance to explain this strange specificity is that this area is more subject to secondary infectious trauma Stannus, " in 1912, was the first to record that ·Horwitt Experimental Deficiencies in Jan 169 scrotal in ofsement may be the initial sign of deficiency in his pellagra patients Goldberget and Wheeler" reported that 6 out of 11 patients exhibited scrotal dermatitis before any other lesions of pellagra appeared and it should be noted that the diets of these patients provided less than 06 mg of riboflavin per day, which of course they do not know in 1920 llith this knowledge as a back ground, it was relatos ely simple for the Elgin group to isolate, identify, and study this part of the total pellagra syndrome An example of a relatn ely early phase of the scrotal dermatitis is gn en in FIGURE 1 Note the patchy redness associated with scaling and desquamation of the superhcial epithehum The mechan commissure is unmoked in most patients Thuis stage was observed in 12 out of 15 subjects on the riboflavin depleted regimen of the first nboflarza project and in 5 out of subjects in the second study Some of the subjects in the control groups exhibited signs of irritation and mild erythema, but in no case did any of these lesions approach the seventy of the average in the depletel groups TIGURE 2 shows a later stage in another induidual in which the scrotal lesion became quite tan and began to extend to the inner aspects of the thigh in another case not illus trated, some perinal inflammation sas noted tollowing which the scrotum be came tas, cozing, and inflamed to such an extent that the lesion extended up the shaft of the penis After the oral administration of from 2 to 6 mg of riboflavin per day the re covery from the severe lesions was dramatic Complete recovery was obtained n from one to five weeks I ILURE I is a photograph of the same scrotum shown n FICURE 2 sei en days after the diet of this patient was supplemented with 6 mg of riboflavin per day The counterpart of the scrotal dermatitis in the male may be found in the vaginitis and vulval dermatitis that have been reported as part of the pellagra syndrome in females 12 but it has been difficult to document this suppositions Since 1919 when experimentally produced scrotal dermatris was first pro duced and repaired by riboflavin withdrawal and subsequent supplementation, respectrely, we have tried to find some logical explanation for the phenomenon Why should more than half of all adult males who have subsisted for more than five months on diets containing less than 6 mg of riboflavin per dav shos such a specific lesion And this estimate includes Goldberger s subjects in whom the udentical' bilaterally symmetrical scals lesions separated by a median band of normal skin" were clearly described Here is a lesion Associated with a de ficiency of riboflavin that added nacin does not prevent hv should this dermatitis appear in this special tissue and not in others? Our guesses have included consideration of local hygiene, perspiration, friction from clothes, or from the inner aspects of the thighs, the effects of residual detergents in clothes and of a variety of fungal infections, but none of our guesses, nor those of a corps of dermatologists, has e been satisiying in the past All the factors mentioned, and more, may be contnbutory to the basic initial trauma The scrotum differs from other lissues in that it has a large number of oner Happing folds or rugae It is an elastic structure that espands and contracts with ortlinary body movemeats and the work of the dartos muscle, and there fore has numerous proinis of epithelial contact Lach point of contact within

·170
Annals Neu York Academy of Sciences
FOUNCI Early phase of sc otal de ma
pe day subet US)
s obsc edal er 175 days on d et that pro dd041 mgr Lofta o
FGA2 Vo esec al on of, otum obseed no he na mnt ub LAS) al 749 duys on d at that
Tod dus ma bn la npe day The c was no apne ab e bea ng of th , les on un i olla I men
tal on wa ro d 21 days luc

·Hornutt Experimental Deficiencies in Man 171 Frut3 Demansta es reso ery of the same si rotum shown AGERE 2 se en days after sub A5 w** supplemented bome of botla a per day the rugae may be an area where friction presents more local sear and tear than is ordinarily surmised Scrotal erythema lahe angular stomatitis is not neces sarily a manifestation of ariboflavinosis If however as a consequence of local trauma, one obtains an infection or an insult to the tissue that must be repaired then the phenomenon of growth must come into play and a demand for ribo flavin for new tissue is made When the subject is depleted he can no longer Toh Peter to pry Paul te bring in riboflavin from some other part of the body The en thema therefore becomes a dermatitis the dermatitis becomes a more severe lesion and so forth Incidentally it may be proper to mention that there has been considerable confusion in our textbooks regarding what is or is not ariboflavinosis Indeed, the very existence of anboflavinosis has been doubted The reason for this confusion is simple to explain It can be dogmatically stated that no intesti gator who has ever obseri cd a group of adults on a daily intake of less than 06 mg of nicolaun for more than fise months has failed to see the signs of aribo- Navin 54 ufuch have I een described by Sebrell and his co vorhers' Con tersely those who have sought to produce this syndrome in adults in less time or have fed a daily level of intake of more than 0 8 mg per day for over a year have invariably failed to see any arbollas inosis'* This does not imply that 08mg per day is adequate or that much riboflavin could be stored for a future enteres cy on this intake but it does show that we may subsist for some time without obssous patholou) at this les el provided there are no major insults to the physical integrity of the indiv.lual in the meantime ·172 Annals New York Academy of Sciences If we extend our discussion of "reserse," or nutritional prophylaxis, to includle consideration of aged individuals, we get into another nutritional dimension that is not too well understood About a decade ago, It was the popular belief that the aged required more protein and vitamins than the young Thus notion developed as a consequence of finding a higher incidence of nutritional disorders in old people In order to check this notion an extensive collaborative study was inaugurated at the Elgin State Hospital by the l'ood and Nutrition board of the National Research Council 7 Among the general conclusions drawn from thus research was the conviction that the similarities between the nutn tional needs of the young and the old were greater than the differences, and that not simplify the problem very much I or a variety of social and physiological reasons, the quest for food may become a less satisfying experience with ad vanced age and, with the decreased caloric intake associated with a general de crease in activity, the margins of safety for the intake of proteins and vitamins are violated The loss of muscle mass usually noted in advanced age is by itself an indication of decreased nutritional reserve for defense against emergencies You are all acquainted with the difficulties encountered in attempting to reverse the long term calcium losses of the aged This long term calcium and nitrogen loss is very reminiscent of similar losses during short term bed rest, and one wonders whether the effects of decreased activity in advanced age is not plyst ologically related to the effects of decreased activity during bed rest 11 hat ever the explanation for this loss of stored nutrilites, it remains a fact that the Let us remember that many compounds that the body cannot use must be me tabolized or conjugated before they are excreted, and that added protein may cause additional unnecessary work for an already overtaxed circulttory system ser ennm. possible ef fec ccent work on huashiorkor'' and on experimental protein deficiencies in man' have clarified somewhat the earlier clinical observations of Jyver pathology produced on ileſicient diets While the possible relationship between liyer function and re sistance to infection cannot be stated simply, it cannot be denied At present, we are engaged in an attempt to determine whether adult men have a definite requirement for vitamin E To date, after over a year of the experiment, we have found it difficult to deplete the reserves of vitamin I in the average adult and conclusions on the place of tocopherol in the course of human disease cannot yet be made Roserer, se hase confirmed and elalia ·Horwitt Experimental Deficiencies in Man 173 rated in adult men previous observations made in rats and in infants that the red blood cell is more suscepuble to hemolysis by various agents when the tocopherol content of the plasma is decreased ll hether or not this phenom enou will prove to be of physiological significance remains to be determined A recent report by Mason and Bergel' showed that lobacterium leprac can sur sne in vitamin E-deficient rats to produce lesions typical of human leprosy This work will be watched with much interest as the onset of leprosy has usu ally been associated with a poor nutritional state In summary and conclusion se haie tried to present a plea for more critical evaluation of animal etperiments in which all or most of a gren nutrilite is withdrawn from the diet and we have elaborated on the suggestion that some of the lesions noted in vitamin deficiency are a locul manifestation of the re tardation of growth The concept that the cataliolic breakdown of tissue in stress may be a functional protectie mechanism has been discussed from the vient point of the need for adequate nutrite reserves 11 hile it is hoped that esery crached lip furrowed tongue sore gingna or conjunctivitis will nat be diagnosed as a nutritional deficiency it is also hoped that justifiable criticism of poor interpretations will not blind us from recogniz 1 d sease spectacle that we hope will immunize our children against a relatively rare As I approach middle age and lose some of the skepticism of youth ani I must confess to having been a strong opponent of vitamin overleeding- I cannot help but wonder in retrospect whether vitamin prophylaxis or the feeding of more than the minimum requirements of you will has not been at least as useful to the nation s health as the more obvious forms of immunological prophylaxis References I MITT AIXEC HAREY O # Hris & F LIEBERT 1950 Correlation of ur nars excretion of riboflavin with detary intake and symptoms of all oflavinsis MultiOR 41 247 2 Hills 01 I LIEBERT 1) L STEINBERC & UK JORWITT 1991 Clinical aspects of dietary deplet on ol miloflarin_Irch Internal Wed 87 632 3 DIETRICH ) GD HD) & E SUORR 1949 ficcts of immobilization upon arious metal olic an! physiological functions of normal men Am J Ved 43 11EDGDJE DIETRICK & SHORR 1949 Vodification of the effects of im motilization upon metabolic and physiological functions of normal men by use of an oscillating be Im ] Ved & 687 3 HOU GRD I 1 INTERVITE !! PARSON IS BACH'M & H TISENTERC 1944 Stu lies on fracture consalescence II The influence of d et on post traumatic nitrogen def cut exhibited by fracture patients Hull Johns llopkins Hosp 75 202 HOR UTT U K F LIEBERT O AREILER PITTUAN 1918 Investigations of human requ rements for B complessitsmuns Bull Mat Research Council U S 116 7 CC TABERTSON D 1942 fost traumatic metabol c response Iancet 1 6189 also 5th Coil on Consalescence # 1943 Josish Vac Ir Found ler Tork 8 fokuirt V In preparation 9 kmple ) NTD SPICE & PHUCO 1940 A note on the interrelationship of ele fciency diseix and relation to infectia Proc Soc Fxpul Biol Ved 45 301 10 Srants 11 S 1912 lellagra in Masaland Trans Roi Soc Trop Vat lys 6 112

·ለጎለ
1
SLSL
U
174
Annals New York Academy of Sciences
11 STAILS HS 1913 Pellagra in Nyasaland (second communication) Trans Roy
Soc Trop Med Hyg 7: 32
12 GOLDBERCER J &GAL
human subjects US PL
13 COLDSMITH, G H P SARET
requirements of man
and tryptophan J Chin
14 SEBRELL I II &R L BUTLER 1939 Riboflavin deficiency in man (ariboflavinosis)
Public Health Repts U S 54 2121
15 ILILLIANS RDH L MASON, P L Costck & RM WILDER 1943 Observations
on induced riboflavin deficiency and the ribolların requirements of min J Nutrition
26 301
16 BOEURER JJCE STANFORD & C RIAN 1943 reperimental riboflavın deficiency
in man Am J Med Sci 205 544
17 HORWITT M K 1953 Dietary requirements of the aged J Am Dietet Assoc 29.
413
18 SCRIMSI4W NSM BENAR M GOZYAN VITER & GARROYAVE 1955 Bio.
chemical and hematological findings in infantile pleuricarencial syndrome (kuashior
kor) Tederation Proc 14 449
16
23 MASON Kr&V BERCEL 1955 Iaintenance of 1/3obacterium leprae in rats and
hamsters ſed diets los in vitamin E and high in unsaturated fats Iederation Proc
14.442

·\UTRITIOVAND INTESTIVAL PARASITISV By William \l Irye Louisiana State Uni asily Scelo Vedicine 1c Oricons La The animal parasites that inhabit the intestinal tract of man and other ant mals present unique problems in relation to host parasite relationships These animal parasites represent a wide variety of forms from the single celled proto zoan parasites to the highly complex metazoa sith in many instances comph cated life cycles lo species of animal 15 susceptible to all parasites and no parasite is able to infect all hosts This discussion will be limited primarily to those parasites who as adults are primarily limited to the intestinal tract of the host In some instances the animal parasite in the adult stage remains in the lumen of the intestinal trict with no attachments to the tissue in others there will be direct invasion of the wall of the intestine The extent of tissue invasion will vary from a direct attachment as in honh worm disease to invasion of the wall of the intestine as in amebiasis and strongyloidiasis or as in ascariasis with the adult living in the lumen of the intestine with no direct attachment or invasion of tissue by the adult sorm There are many factors that may contribute to the relationships between tlie host and the parasite The food of the host is of extreme importance and 15 closely linked with the physiolo,lc state of the host In the intestinal tract, With changes in nutrition there may be a direct effect on the environment of the parasite and thus a possible alteration of the relationship between the host In general parasites that can establish themselves with the least damage to the host have the best chance for prolonged residence in that host since in such cases the host response to the presence of the parasite is meager or generally ineffectua! The best adjustment of parasite and host is usually found in parasites limited to the alimentary canal Humans ma har bor in their intestinal tract tapen orms such as Tarmo sagrata or Mules such as Fascrolopsis buske for many years with no physical effects so long as the diet is sufficient for both the individual and his parasite Likewise the intestinal flagellates as a group as well as the nonpathogenic amelue may persist in the intestine for years without the host being aware of the inſection since these forms are normally harmless commensals In animal parasitism the extent of damage produced to the host tissue :ll vary greatly and there are many com plex factors which must be considered in attempting to explain the pathogenesis of the various forms The capacity of a host to resist the destructive action of a gen parasite is sometimes due to the natural resistance of that host In some instances this files complete protection of the host from the parasite Such natural resist ance is not always present a birth but somermes it is developed against certain parasites only after the host has neared maturity In contrast to this type of resi tance the host in some instances remains susceptible to infection with certain animal parasites during an entire lifetime In such instances there sleyclops in surh a su certible lost on first exposure to a specific parasite an and the parasite 15 ·178 Annals Neu Vorh Academy of Sciences creased The results of this extensive series of experiments furnished further evidence that specific vitamins are important factors in host resistance to hel minthic infections These experiments while not permitting a blanket statement that deficient host diets react to the benefit of the parasite, do indicate that resistance is low ered to helminthic infections, both in the somatic and intestinal phases, when omnis orous hosts are maintained on diets deficient in A, B complex or D or on rations with highly restricted sources of protein These various studies have also shown that the degree of natural and acquired resistance of a host to its helminth parasites is dependent to a large extent upon its diet, its genetic con stitution, and its age Diets of man and other omnivorous animals, to serve in developing the most potent resistance to helminth infections must include adequate specific vitamins, minerals, and other substances essential to a sell balanced ration In contrast to the helminths found in the intestinal tract the single celled protozoan parasites present a somewhat different problem A large number of protozoan parasites Ine in the lumen of the intestinal tract of man and other animals and depend essentially on the diet of the host for their food Nutri tronal factors do play an important part, honever, in the host parasite relation ships in that certain dietary changes may contribute to the decrease of resistance on the part of the host, thus contributing to the production of damage by the parasite Protozoologists have long recognized the effect of diet of the host upon the parasite Hegner" in 1921 suggested that a "carnivorous diet," one high in animal protein content, was unfavorable for certain intestinal protozoa of mam mals Hegner and Eskridge's showed that rats infected with the human flagel late, Trichomonas hominis, when fed a diet rich in animal protein produced an unfavorable condition in the cecum of rats for growth and development of this flagellate Hegner and Esbridge16 also demonstrated that the conditions in the cecum of rats were rendered more favorable for trichomonads when a liver diet was substituted for the normal diet which consisted largely of carbohydrates Trye and Meleney!7 found that lach of vitamin A in the diet was not the cause of the inability to establish or maintain infection with Endamoeba muris in the rat Neither the lack of vitamin A in the diet nor the condition of A deficiency in the rats rendered the lumen of the cecum unsuitable for the development of E marts Ratcliffe's showed experimentally that a lugh protein diet ſavonng proteolytic bacteria in the intestinal tract decreased the intensity of natural infections with Endamocba muris in mice hayy and Taust,'' Taust and hagy,20 and I rust Scott, and Swartzu elder" demonstrated that, in dogs, fulminating experimental amebic colitis could be controlled with raw inser, which at times es en produced cure Thust and Swartzwelder" demonstrated that Ixer extract, introduced parenterally, had - not as the narrar of t1o loc nne nr emntome This n marler con prevents erythropoiesis, or that its amebastatic action is inhabited when it is ·Trye Nutrition and Intestinal Parasitism 179 introcluced intramuscularly Faust, Scotl, and Swartzuelder21 noted that dogs resistant to infection on a normal diet could usually be infected if they were placed on canned salmon Kittens fed on salmon diet are also more susceptible to infection with F Msitlynca In the literature on amebiasis, McCarrison and Lagy and Faust." refer to diet as a factor in the development of the clinical manifestations of this disease It was noted by Trye and Veleney in studies of the pathogenecity of a num ber of strains of Codamoeba luistolzlıca that monkeys ſed on a normal diet did not develop lesions with certain strains of histolztica, although numerous amehre were found in the lumen and decp in the glandular crypts but with no evidence of tissue pathology or invasion One monkey in this study became emaciated and extremely il! At autopsy this animal was found to have tu lor Thai tapt na thea 1 la 1 1. resistance and the production of tissue pathology by the parasite VcCarri son's showed that monkeys that were chronic carriers of E histolytica des eloped certain instances they lecime completely parasite free Larsh showed that in dous kept on a blach tongue deficient diet the virulence of the infection with Cost lyrica is enhancel and that the lowered resistance of these animals was related to a deficiency of nicotinic acid Taylor and his co-workers" demon strated that guinea pus became highly susceptible to E histolytica infection when feil rat ration pellets and that they are even more susceptible when fed a - . set up a controlled study of the effect of ascorbuc acid def ciency in guinea pigs experimentally infected intracecally with Endamoeba histolytica trophozoites 1 effect on those fed a milly scorbutogenic diet of natural forustufts was inter mediate Ictueen ile tho groups The ascorbic acid deficiency in these experi ments seemed to render the disease much more fulminating in the guinea pig Tumcrous experimental and clinical observations have demonstrated the im francif ascorbic acul in the phenomenon of reststanie to infection Perla and Marm rston "slonce that the influu nce of this vitamin on resistance is dxen lent 11 least in part on its role in the production of intercellular sul Several investigators have su, sested that diet influences the inculence course ·180 Annals New York Academy of Sciences ind final outcome of amebic infection in man Alexander and Mſelencyht re ported the results of a dietary study in two rural communities in Tennessee in which studies of amebiasis had previously been made in one community acute amebic dysentery was common, in the other, it is very rare although 40 per cent of the people in the community harbored Endamoeba histolytica In the community with little or no acute amebic dysentery, the diet was more adequate in calories and vitamins than in the area where acute amebic dysen tery was common In the community si here the amcbae showed less patho genic activity milk, green vegetables, and fruit were more prominent in the diet It was also found that the distribution of protein, fat and carbohydrates in the diets was about the same in the two communities This study indicated that where the diet was more adequate, evidence of acute infection with E histolyrıca was rare Elsdon Dew-s observed that in Durban, South Africa, where indigenous Ban tus, Indians, and Europeans live side by side, amebiasis affects these three races in different ways Among the maize eating Bantus, acute fulminating dysen tery is common Among the Indians who traditionally eat curry and rice, acute amebic dvsentery is rare but liver abscess is often encountered Among the Europeans who have a full essentially balanced diet, severe amebiasis seldom As a result of his long experience Doctor Elsdon Dew suggests that dietetic deficiencies are responsible for these differences In comparing the incidence of amebiasis among the Africans in Durban and in Lorenco Marques (Mozambique) Lisdon Dew attributed the strikingly lower rates of amebic dysentery in the latter to a supplement of fishi, rice, and many vegetables Sau tet and his co workers's believe that food shortages and consequent deficiencies in essential elements of nutrition have been responsible for the increased inci dence of amebiasis and other intestinal parasitic diseases in Marseilles during and immediately after the end of the war occurs ܨܕ ܐ ܐ gatots Attempts have been made to determine why this parasite produces also demonstrated that interchange of bacterial associates between strains did nathagann rec Ten section of strain differences ·Inc Sutrition and Intestinal Parasitism 181 toms in those patients harboring only small race but that apparently healthy la 1 - - to severity of infections with E histolytica The classical experiments of Walker and Sellardsto intimated that natural resistance was responsible for the failure of some human Volunteers to exhibit dysentery with strains of amebae that caused disease in other individuals Acquired immunity has been considered by some 10 account for the decline of amebiasis as is seen in humans beyond middle life Veither is there a clearly demonstrabie lasting acquired immunity in man following infection and very litrie evidence in animals The test of such immunity en klence in animals is seen in the work of Swartzwelder and \vant el who found that dogs following spontaneous recovery or after removal of E histolytica by therapy were markedly resistant to reinfection The evidence now available indicates that in order for Enda moeba Instolyfua to produce gross tissue pathology in the intestinal tract there must be a minimal of host resistance together with the accessory action of the intestinal bacteria detary deficiency and other factors The ability to control tissue pathology by alteration of one or all of these factors in man has never been demonstrated The local condition of the host tissue certainly influences tissue insasion Dietary deficiency as has been demonstrated in INL animise 10 UREU DU Alients with no specihc therapy These patients were placed on dietary supplements and bed rest but no other therapy of any kind in this group of 66 patients 39 were assigned to a sy ecific treatment schedule before the cn of the sis weeks follow up period 11 of the th patients had no clinical or parasitological evidence of amebic infection These 11 patients ly the standards used in the study would be counted as successfully treated in addition five other patients with stools still positive for F kost lua had recoiered clinically This group of acute amet ac dysentery patients studied and followed along with specifcally trcate 1 1ses is the only such erim le fount in the laterature on amet rasis What wart the detary sut lements played in spontaneous recou cry cannot be Icterm ned from this study It seems quite possible that the deficient diet ht h anon ·182 Innals New York Academy of Sciences was a definite reduction in number of acute cases, although the prevalence of [ histolylıca was still very high In an epidemic of amebiasis stud:ed by Sappenfield el al" and traced to a possible contamination of a plant water supply, the number of clinically rec ognized cases were in marked contrast to the Korean prisoner group The beginning of this outbreak was obscure but probably occurred several years before it was recognized A concentration of recognized clinical amebiasis developed in the late winter of 1953 There were a few cases of amebic abscess of the liver The total number of recognized cases of acute amebiasis was small in comparison to the Korean prisoners A careful epidemiological study and a stool survey of this group revealed that over 50 per cent of the employees harbored e histolzlıca but at the time the stool survey was made, there was no clinical evidence of disease in any of these individuals Here we hive 2 group of humans infected with E Instolylıca having a well balanced diet, good housing and other living conditions, in murhed contrast to the Korean group following the administration of Terramycin and Tetracyn, given with vitamin supplements and milk, there are practically no side reactions A group of 73 children betueen the ages of 3 and 10 years has been treated for amebiasis with Tetracyn Tetracyn, dispensed as pediatric drops, was used in this series with a daily dose of 23 mg per kilogram given over a period of six days There were no side reactions to the therapy, and some patients actually had an increase in appetite and slight weight gain Stool eraminations one week and one month after completion of therapy showed ercellent results, but the final es aluation of therapy will be deferred until after a three months' follow up period Discussion It has been clearly demonstrated by controlled laboratory experiments that nutrition is an important factor in the defense mechanisms of the host against certain intestinal parasites It seems evident that the conditions necessary for invasion or infection of the intestinal tract differ only slightly from those necessary for infection of the skin or other host tissue Improper or inadequate food supply may produce changes in the tissue un favorable to the host and at the same time favorable to the parasite The adjustments between the parasite and host are often extremely delicate, and only slight changes may mean the difference between no evident pathology and marhed damage to the host tissue and gross pathology produced by the prisite The experiments showing the relation of dietary factors in various helminth infections is striking Specific vitamin deficiencies have been shown to favor the parasite and at the same time to produce definite interference with host resistance It has also been established by laboratory experiments that diet is a factor of singular importance in altering the ability of the host to com bnt certain intestinal helminth infections Investigators interested in the intestinal protozoa of man and of other ·183 Fre Nutntion and Intestinal Parautism animals have long recognized the effect of diet of the host upon these parasites Well-controllo erscriments have demonstrated the importance of dietary factors on the juthology of amebiasis Tigher infectant and murialny rates and 3 more severity of amebtasis has been demonstrated in animals fed a pursfied det deficient in spectfic vitamins There is little doubt that dietary factors, under certain conditions, play an important part in the futhat up of amebrasis in man In certain parts of the world, evidence ficates that dietetic differences account for variations in the severity of infection with L kestolytica A careful eplemological study of tro endemics of amebrasiz offer interesting possibuties as regards the importance of nutritional factors in relation to resistance of the host and Blumenthal di at sumgested that repeated bactersa? safections susta accompany mg travma to the intestinal mucosa may be an important fat for in the occurrence of amelic dysentery During the seven month period of 104 cstigation of diarrhea and dysenter) in the pizzsoner of war camp in Korra, there were approumately 200 cases of acute shigellosis and many other undiagnosed gastrointestinal iníections These infections may have been a contributing factor a predisposing the intestinal mucosa to invasion bv E kustolzlıca 1t «as evident, however that with a more adequate diet, com Lined with better sanitation, all the gastrointestinal infections decreased in number and in seversty flost resistance to invasion of the intestinal tract by certain an malparasites can le altered markedly by dietary changes The mistance of the various nutritional factors in the repair of damaged tissue and the tregiment of these infections has been demonstrated References 1 AC 2 Z. . ascun im llg 6 m 101 7 timu 190 On the rhylactx action of tanjin in helminthians Heiniinth 11 ) 21 8 Il Rult 11 i 1976 The relation of state ! drluccncy to accarlasis in the shg l'aristol 21 431 >>>) 11 198 Weey show at 20 de helt fantasy I arasitol 32 135 152 ? 14 AKTI 0,1 ILICAT1 &1 Į LLCKER 1931 hestanre to rals to sus infections Asth nematouse 119 151 Es wis an an aparently similar tesistance of buxos to super infection with nemaloles Wash Icad Sci 21 235-265 11 RUE BEATLE & A L440s 1934 Bookworm anemia etrology and treatment with especial (cletchce to iron. Am. ) llys 20 200 306 ·184 Annals New York Academy of Sciences 12 FOSTER, A O&IV CORT 1931 The effect of diet on hookworm infestation in dogs Science 73 681-683 13 TOSTER, A O&! W Cr - diet upon the resistance 14 HIECYER RW 19244 tions with intestinal pro 15 HEGNER, R & L ESKRI hominis in rats J Tarabatur - J riman 1927 han med fine 15 t. وام في JU SADUN LILJ I tolynca of human 3 I Arch Pathol 3 II Arch Patbol 3 rural communities +-730 3 'n J Trop Med 49 JJ J4V 35 SAUTER JR., SA&R Cow 1948 Infuence de l alimentation de disette sur le Tr - Dec 501 57 parasitisme intestinal a Marseille (1C 36 MELENEY HT & FRE 14 of a strain of small race of R 1935 Ameljasts con forms in Egyptrans Ann damebic dysenter; Philr pine ) Sa (bj 133-01 ·Fry. Nutntion and Intestinal Parasitism 185 41 SWARTZATLORIC&W II AVANT 1952 Ingunity to anebic infect on in dogs Tmc ft. art Avoc Jol lus5 103J 43 SAPTENFIELD RIIERN CARTER C CTLBERTSOV V A BROOKE K M TAYNE 1 45. 46 B, Drocksston of the paper DOCTOR II VOLS (hasr El Amni Foculty of Vedicine Cairo, Egypt I should be to add a few words to nhat Professor Fre has said about amebi ASIS The relation of malnutrition to intestinal in siseness of Endamocha heslo snea as well as to us exsasntestinal kepark localization was not found Gonzally high lxy Wfty and myself in a study of a group of malnourished excusants compared to a similar group of well nourished city dnetlers 1 Qust recorded the same observation ia the lest Indies, and be etplained it by the dificulty of ency sement of ametae in paticats truang mamly on a carbohydrate diet maize «hich produces an ausd ston! Professor Mogroch, in a personal communition demonstrated experimentally the importance of allergy in the development of lives abscess in animals Allergy is manifested in well wunished cases 10 a greater extent than in malnourished ones In important factor in the observation of other workers who have shown a higher incidence of imebic dy senters in mineurshed cases is based on the higher sncidence of busteriał dysentery in cyst passer this must be dif fcrentnited from cases of acute amebic dysentery or chronic amclic dysentery oth acute exacerbatman s both of which segetatione forms must be demon strated ·THE CITECT OI HIGH LIVEIS OF VITAMINS ON THE RESISTANCE or CHICAS 10 FOIL TYPHOID By C II Hill and H Il Garren Torth Colina Slate College Kale g! IC Studies throughout past ycars lase established clearly that the desclopment of resistance to discase is subject to both genetic and environmental influences It is fair to say that dict is the environmental influence that has been studied most extensively Since the discovery of vitamins and the recognition of their cssential role in the maintenance of normal cellular metabolism these suts stances are probably the most studied of the various constituents of the diet Indeed it is recalled that it was a study of the then supposedly infectious dis ease of beriberi by Eijkman that led to our modern concept of vitamins The studies on the relationship of nutrition to discase have been reviewed in recent years by Schneider' and Clark et al? The investigations on the role of vitamins in resistance to disease have been concerned in general with deficien cies of an individual vitamin or group of vitamins The correlation between a vitamin deficiency and resistance to disease has been found to be positie in some cases and negative in others For example Hooley and Sebrel!' have shown that riboflavin or thramine deficiencies decrease resistance of mice to pneumococcal infection On the other hand Reiner and Paton' found that rats on a vitamin B complex deficient diet were more resistant to Trypanosoma equiperdum, as indicated by a pro longation of the incubation time over that of controls fed a diet containing a vitamin B complex supplement Ihile the results of studies on the effect of vitamin deficiencies in response to disease are of fundamental importance, they are difficult to interpret in terms of resistance of the host animal There is little in our knowledge of on ise tion are not plentiful esen less data are available on the effect of high levels of vitamins In the studies of flooley and Sebrell? mentioned above, the ad ministration of 5 to 10 times the amount riboflavin or thiamine gen the control group did not increase the resistance of mice to pneumococcal infec There are a few other instances in which an exceedingly high level of an individual vitamin lias been tested To one to the authors knowledge hon ever has tested the effect of the inclusion at high levels of all the known ri quired vitamins on resistance to disease This is the approach that has been taken in the erpenments presented in this report In all the studies presented herein rapidly growing strains of les llamp- The ay ho sare dee lynd 1 ted to let kan Comjany In Rahway for most of the stam oru af wughout these studes and to the Lede le Labo ato ts Pearl R 11 IT Suryl es of fol ca 4 186 ·Hul & Garren Chich Resistance to Typhoid 187 here or lite Roth chicks obtained from a commercial hatcher nere used! Torty birds were used per treatment in each experiment The chichs here neighed wingbanded and placed on experiment the day they hatched Thc crperimental period was divided into two parts 1 porcinorulation period of four weeks and a postinoculation kriod of approximateh three weeks in order to minimize any cfiest that differences in total feed intake might me an ru Sist ince to distast the fese intake of all furs 13 equalizeut during the pre inoculation period Juring the postinex ulation period feed was supplied ad ltation Hater 375 suppued ad libitum throughout the esperimental persox! It lour seeks of age the birds were inoculated with a culture of Salmonella gullaartem, the foul typhoid organism The organism was gTON sernight on proteose Ao $ agar (Diſco) at 37°C The bacteria were washed from the Agar with sterile salıne (085 per cent) and diluted with sterile saline to a read ing of 8 to 12 per cent light transmission on a (oleman spectrophorometer mode! It using a PC ulter at wavelength 60) One ml of this suspensi was given orally to each chich The resultin, disease was allowed to run its natural course, and the experi ments were terminated when the chichens had ceased to die and appeared to le recovering rapally from the effects of the injection This was usually in proximately three acehs from the date of inoculation The exprenmental diets were fed from the day of batching The basal diet d throughout these experiments is presented in TIBLE 1 This diet is a simplified diet containing no animal protein Il meets the requirements for vitamins, amino acids and minerals that have been established by the \ational hesearch Council Washington DC for chicks in the disease free state The timin content of the diet 39 sell as that of the mixture is presented in TIBLE 2 or comparative purpxases the vitamin requirements of the chichen are included in this table it will be noted that with one exception all usta mins are present in excess of the requirements Bhile the vitamin B, content appears not to meet the requirement it has not been possible to show differ ince in requirements berseen the sand tw per pund lesel when chichs were hatched from ons land by hens fed commercial diets then multiples of vitamin levels are referred to throughout these studies the reference is to muluples of the vitamin supplement The vitamin supple ment * is mixed with ground yellos cort so that when the vitamin levels were increased the corn in the basal dret 1.5 decreased thus heepng the drets selentical ercept for the vitamin leve The rruse of the first experiment 75 merels to determine if hinh levels of the require mins had an effect on the resistance of chicks to fox post in this experiment ascorbox au was included in the vitamin supple inent This was done for two reasons Dirst although the chicken susy xsexlly cloxes not require a dietary source of ascorbi acid there have been reports ? that in some instances Lenchend effects have been obtained then this vitamin Is included in the diet Second in animals that do require a dietary source of #xori e 3cx some crente exists that it may be concerned in discase te tance The other vitamins were included at a les el 10 nines that of the bisal supplement The results of this study are presented in TABLE 3 ·1 SS Annals New York Academy of Sciences TABLE 1 BASAL DIET Ter ctot Soybean meal Yellow corn Phosphate Limestone Salt Methionine Vitamin DLX Choline chloride MinSO. 47 0 48 0 20 1 S 05 0 3 05 700 mg/lb 100 mg/lb) TABLE 2 VITAMIN CONTENT OF THE BASAL DIET Vitamin Supplement/Ib Total Requ red 13 13 12 O 42 0 25 40 Thiamine (mg) Riboflavin (mg) Niacin (mg) Pantothenic acid (mg) Folic acid (mg) Biotin (mcg) Pyridoxine (mg) Choline (mg) Vitamin B (mcg) Vitamin A (IV) Vitamin D(IU) Menadione (mg) Vitamin E (mg) 09 16 80 50 0 45 45 16 700 3 3000 180 10 10 21 25 17 0 84 1 55 81 8 7 1460 3 4100 180 10 10 600 1200 90 0 20 TABLE 3 INFLUENCE OF EXCESS VITAMIYS ON RESISTANCE OF CHICKS TO TOWL TYPHOID Det Avg days sursival time Per cent total survival Basal 10 X vitamins + C,01% 83 12 8 10 40 Note Survival time calculated from day of inoculation till day of last death in crperiment The inclusion of the high levels of vitamins increased the percentage of surviving animals from 10 to 40 and increased the average survival time Thus It was tentatively assumed, pending confirmation, that high levels of vitamins did enhance resistance to fowl typhoid It tas important to determine whether or not the enlianced resistance due to high vitamin levels was due to a single vitamin or group of vitamins, or whether the entire combination of vitamins was necessary for this effect Studies were undertaken, therefore, to determine the effect of groups of vita mins on resistance to fowl typhood for the purposes of this study, the vita mins were arbitrarily divided into the fat soluble group, the water soluble B vitamin group, and ascorbic acid Each vitamin in the various groups was ·Hill & Garren Chick Resistance to lyphoid TABLE4 INTLLENCE Or I XCESS WITAVINS ON RESISTANCE OF Cnicus to Fowz TYUPOID SES Det 189 KE A days survivalt me RECO Basal 10 X vitamins + C 019% 010 witamin C Water soluble vitamins IDEN Ter cent total sunniya! Vote Survi alt me calculated fiel y of meulat on t ) dar of last death nesprement 12 2 15 0 11 0 86 11 0 48 34 15 25 De Faper mental fed at the same high level as it was fed in the complete high vitamin supple ment The results of this study are presented in TABLF 4 Again, the feedling of high levels of all the required vitamins resulted in an acrease in total survival and average survival time The various groups sted however, showed no beneficial effect In fact the high levels of fat soluble vitamins, A D, E and considerably decreased both total survival and average survival time The importance of this finding awaits confirma tion and further work The results of this study clearly show that the effect of high lesels of vita mins on resistance to fowl typhoid is not due to a single vitamin but to some combination of vitamins distributed between the groups tested Studies were directed therefore toward determining wluch vitamins were necessary in this combination These studies were carried out using the high vitamin supplement of all sitamins except the one under test This vitamin was pres ent at the same les el as in the basal group Thus if the absence of a vitamin from the vitamin supplement did not lower the resistance from that obtained with the complete vitamin supplement, that particular vitamin was considered o be not essential for increased resistance to foul typhoid under the conditions mployed The results of these studies are presented in TABLE 5 It was observed that, of the first group of vitamins tested only choline could : omitted from the high vitamin supplement without lowering the resistance over that obtained from the complete vitamin supplement The fat soluble vitamins vitamin Buz pyridoxine and ascorbic acid were all required in the vitamin mature The results of the experiment on the second group of vitamins tested are more difficult to evaluate due to the fact that, eventually mortality reached essentially the same level in all lots The prolongation of the average suryis al time, however indicates that the complete vitamin supplement promoted Areater resistance carly in the postinoculation period 1 he absence of riboslaun or niacın from the complete utamin supplement lowered this early re kustance The absence of thiamine biotin, folic acid or pantothenic acid, however apparently increased the resistance of the chicks These results show that the absence of an individual vitamin from the com plete high level of vitamin supplement can express itself in three ways in rela fron to the resistance obtained with the complete high lesel supplement The alısence can lower the resistance it can apparently increase the resistance, or ·190 Annals New York Academy of Sciences TABLE 5 EFFECT OF INDIVIDUAL VITAMI\S OY THIE RESISTANCE OF CHICAS TO FOWL TYPHOID Det Days ang surusalt me Per cent sury ors Experiment I 61 83 30 Basal 10 X vitamins + 01% 10 X vitamins - C 10 X vitamins - K 10 X vitamins - E 10 X vitamins -- D 10 X vitantins - A 10 X vitamins B12 10 X vitamins - B. 10 X vitamins choline 129 13 1 12 2 12 2 12 8 12 7 10 1 12 4 11 8 15 0 Lxperiment II Basal 10 X vitamins + 01% C 10 X vitamins - riboflayın 10 X vitamins – niacin 10 X vitamins thamine 10 X vitamins - brotin 10 X vitam ns - folic acid 10 X vitamins pantothenic acid 8 2 8 8 74 76 95 10 3 10 0 97 19 16 8 8 21 20 29 25 TABLE 6 EFFECT OF OMISSION OF INDIVIDUAL \ ITAMIAS FROM 1 HIGH LEVEL VITAMIN SUPPLEMENT ON RESISTANCE TO FOWL TYPHOID Louers resistance Increases resistance Vitamin A (34) Thiamine (1 6) Vitamin D (2 01 Biotin (20) Vitam nE Tolic acid (62) Vitamin K (50) Pantothenic acid (20) Vitamin B12 (075) Pyridoxine (67) Riboflavin (19) No effect Niaçın (14) Choline (24) Ascorbic acid (--) Note Figures in parentheses and cate multiples of requ rements present in the basal d et it can have no effect on the resistance The results obtained are summarized in this manner in TABLC 6 The figures in parentheses in this table indicate the level of the vitamin in the diet in relation to its requirement This is the level that resulted when the vitamin was omitted' from ine nigh level vitamin supplement it albu seny sents, therefore, the level in the basal diet in relation to requirement The data obtained considered in this manner, present several interesting aspects It is apparent that the increased requirement for vitamins for in creased resistance is not merely a certain multiple of each vitamin requirement Vitamin K at 50 times the requirement, is not sufficient for maximum resist ince, while 2 4 times the requirement for choline is sufficient, and 2 times the ·- HJI & Garten Chick Resistance to Typhoid 191 biotin requirement apparently results in greater resistance than does 20 times the requirement Inother important aspect of these results is the finding that ascorbic acid was important in promoting resistance to typhoid when used with high levels of other vitamins although alone it had no effect on resistance Since the hichen supposedly has no dietary requirement for ascorbic ackl, this finding required further investigation It is well known that ascorbic acid inhibits the growth of certain organisms 19 Thus the effect of ascorbic acid might have been due to its antibacterial effect against the Salmonella organism in the intestinal tract of the chicks Inother possibility was that the effect of ascorbic acul was due to its antiondant properties and thus this effect might not be specific for ascorbic acid Experi ments were therefore designed to determine more precisely the role of as orbic acid in protecting the chicks against fowl typhord In these studies ascorbic acid nas ſed at the 01 per cent level in combination ith high levels of the rest of the sitamins as in the previous experiments addition a lot was fed a high level of all the vitamins ercept ascorbic acid Thes lot was injected with ascorbic acid starting at the third week in the prein oxulation period and continuing until the end of the experimental period The ascorbic acid was injected intramuscularly dails in the same amounts as were consumed by the birds recen ing the ascorbic acid in their diet Another lot was fed diphenyl pleny lenediamine (DPPD) another antioxidant which is eing used for vanous purposes in poultry feeds The results of these studies are presented in TABLF 7 1gain the high level of vitamins with oi per cent ascorbic acid increased the resistance of the chicks as measured by a prolongation of the average sur wal time The ascorbi acid injected was even more effective than the orally administered ascorbu acid increasing the percentage of sun is al from 19 to 16 I urthermore the other antioxidant used DI PD kas cien more effective than ascorbic acid in the diet DPPD alone che ascorbic aud alone was in effective in increasing resistance to foul typhoid I rom these results it is apparent that the effects of ascorbic acid are most probally due to some action in the body and not in the intestinal tract This effect is apprently due to the antioxidant properties of ascorbic acid since it con le replaced I v inother anuovxlant in the diet of the animal TABLY 7 rreto TABIC ICID AND DPPD ON RESISTANCE OF CHICKS TO IONI. TYPIOID ar Dars as +) Xifa +0 IX van n nitted Xamn DID) alt me CECODEREDE Per cent Y von & 2 Brut JtX an + ule! 10 19 10 46 38) YES X2 XX x) 33 ·192 Annals New York Academy of Sciences TABLE 8 EFFECT OF INCREASING LEVELS OF VITAMINS OY RESISTANCE OF CHICKS TO FOWL Paon Det Days avg jury valt me Per cent sur OTS Basal 25 X vitamins +01%C 50 X vitamins + 01%C 75 X vitamins + 01%C 100 X vitamins + 01% C 82 82 10 0 9 2 88 10 3 30 23 Another interesting aspect of the data presented in TABLE 6 is the observa tion that the omission of thiamine, biotin, folic acid, and pantothenic acid from the high level vitamin supplement apparently increased the resistance of the chicks A possible explanation of this finding is that the high level of vitamin supplement used throughout these studies may have been too high to obtain maximum resistance to fowl typhoid In order to test this possibility, a series of vitamin levels were fed containing 25, 50, 75, and 100 times the level of the vitamin supplement contained in the basıl diet The results of this study are presented in TABLE 8 The level of vitamin supplement 25 times that of the basal diet had no effect on mortality or average survival time The addition of five times the RIC difficult to interpret in terms of resistance of the host It is presumably possi 11 JJ t 1 Amne vitamın level of the diet has two effects in the disease system one on the host resulting in increased resistance to typhoid, and the other on the Salmonella organism, increasing its disease producing capacity Thus, five times the basal vitamin supplement level may produce the maximum resistance in the host that this particular dietary manipulation is capable of producing It might still be possible however, to increase the disease producing capacity of the organtsm by further increases in vitamin levels These further increases would result, then in a more acute expression of the disease not because of decreased resistance of the host, but because of the increised disease producing capacity of the infectious agent In order to evaluate this hypothesis, an experiment was conducted in which this experiment are presented in TIBLE 9 In this experiment the les el of the vitamin supplement 7 3 times that given the basal group resulted in the greatest percentage of survivors when the organism was gien orally 11 hen the level of the vitamin supplement was increased to 10 times that of the basal group, the percentage of survival was ·Hill & Garren Chick Resistance to Typhord TABLE 9 FTTECT OF INCREASING LEVELS OF VITAMINS ON RESISTANCE OR Chicas To FouL TYPHOID ees Utos DACE Desag varyf time 193 ..sa! SO X vitamina +0% C 75 X vitamns + 01 1 100 X vitamins +010, C Per cat sury vors CRIS Zajected Oral 10 S 11 6 140 12 2 Loyecto 7.2 6 S 85 17 9 27 3 52 5 37 S 3 100 53 22 S reduced over the 75 times level When the organista was inoculated intra muscularly howeser the highest level of vitamin supplement resulted in the greatest number of sun rors Since no plateau of response was reached in the groups inoculated intramuscularly, no conclusion can be draan in regard to the hypothesis testes These results, however, confirm the previous finding that it is possible to supplement the diet to a level of sitamins too high to pro duce maximum resistance to foul typhoid Furthermore, the effect of high levels of vitamins in increasing the resistance to this disease is apparent even when the organism is introduced intramuscularly Further studies will have to be conducted with stall higher les els of islamins to determine whether a plateau in response to vitamins can be reached when the organism is inoculated ntramuscularly If such a plateau is reachedi, aod if further increases i vita min levels of the diet do not result in lowering of the survval rate this may be presumed to be evalence that the apparent decrease in resistance occurring when the highest valamin le: els are fed to groups inoculated orally is due to the (flect of the highest levels of vitamins on the infectious agent and not on the host In summary the results of the studies presented in this report clearly dernon strate that high levels of all the known required samins increase the resistance of chicks to foul typhoid The enhanced resistance observed when high levels of vitamins are fed is apywrently not due to a uniform increase in requirement for a}} vitamins Some vitamins, such as vitamin must be increased over the requirement for grouth many times more than others such as choline, in trer to bring about increased resistance to typhoid In addition to the es entral vitamins at high levels an antiordant is required in the diet in order to increase the resistance of the chich lo forl typhoid This antiordant apparently exerts its infuence in the body of the chick Futher ascorbuc un or phenylphenylene ckamine can act as the required Intotidant I 1stly it is possible to oversupplement the diet #sth vilamins in w far is obtaining maximum resistance to oral snoculations of the Salmonello Arkanism The exact mechanisms of all the phenomena obserye in these tudies ant not known ind thes 1874 further study Rrforcues 1 1 1 4.16 Tutti sanires stance to al 24 The strafegic situatan Witamins an 1 11 wmones & 35 O (LARE PALIVO LIC HINTYY #JI PRICT & 17. STRIDER 1912 Influence of nutrition in caserimental infection Rar 10114 ·Annals New York Academy of Scienc ·ANTIBIOTICS AND VITAVINS IN THE TREATMENT OF SHINE EVTERITIS By RW Lueche Deporiment of Agriculturel Chemistry Michigan Slale College, East Lansing, Vich It is the consensus of patholngists specializing in swine that there are probably sceral forms of enteritis in swine Among these investigators, Doylc (1943) has shown that an acute hemorrhagic dysentery is a disease distinct from necrotic enteritis In addition to swine dysentery, the importance of cholera in suine enteritis was shown by Gibbs (1933) This investigator isolated the vurus of hog cholera from the intestines of runt pigs showing enteritis (button Ithe ulcers) as long as 94 days after an outbreak of hog cholera In this con nection, Doyle and Walkey (1946) proved experimentally that the feeding of viscera from pigs affected with what was commonly diagnosed as necrotic enteritis" to cholera vaccinated pigs produced no clinical symptoms of disease Il hen parts of the same viscera were fed to cholera susceptible pigs, horever, one hall of them shoned lesions of hog cholera and ententis The remaining pigs were unthrifty for some time This would indicate that the virus of hog cholera produced a form of enteritis The remaining forms of enteritis consist of a complex group of conditions characterized by necrosis of the intestinal mucosa, and sometimes of the submucosa While there were those who considered enteritis as & filth-borne disease attributed to an invasion by the organism Salmonella choleracsnis, a fex investigators recognized the possibility that nutritional factors might be involved I'ndet practical feeding conditions in the United States, the diet of the pig is made up largely of corn, a condition that has prevailed for a great many years ITirt and McCollum (1914) were among the first to study the nu tritional requirements of swine with special emphasis on corn It was early recognized by these investigators that pigs could not be raised on corn alone but that if such a diet were supplemented with minerals and feedstuffs high in protein, good growth could be obtained 1 few other studies were reported, but no particular studies were designed to study the needs of swine for vita. mins of the B group until work was undertaken by Chick and his associates of Ingland and Flughes of California Previously, honeyer, Willer and Rhoads (1935) had chosen pigs as experimental animals for the attempted reproduction of a condition similar to pernicious anemia since tests on dogs had failed to prosc satisfactory As far as this writer is aware these workers were the first to feed a modified Goldberger 11 hecler chet to pth> They reported that diarrhea was a frequent finding, long with loss of appelle stomatitis, achlorhydria, and anem It certainly should be consulere extremely interesting that they produced a syndrome in pages that the authors consulered to resemble in many respects, pellagra in man and blacktongue in dogs Pubt he nth the ass roval of the thrector of the bed aan gricultural lyer mest titwa East Laks ng MA 1 Jumat Artak a 170 193 ·196 Annals New York Academy of Sciences Viacin deficiency At about this time, studies were showing that the rat Has apparently not a suitable animal for the investigation of the pellagra pre ventive and blacktongue preventie factors which appeared to be identica! The English worhers (Birch et al, 1937) turned to the pg Modified Gold berger \l heeler diets were used and in general, these insestigators found that one or more substances were lacking and that the deficiency was in the B-com pler rather t of appetite of the mucc with a fibrinous adherent membrane In a subsequent paper, Chich al al (1938) reported that nicotinic acid both prevented and cured the deficiency symptoms This writer s interest in the nutritional aspects of suine enteritis was stimu lated by previous work carried out at the Michigan Experiment Station by Davis and his associates (Davis et al 1940) This work indicated that nacin deficiency in pigs was perhaps more prevalent under farm conditions than had hitherto been recognized Furthermore the work of the Wisconsin group (hreh) e al 1945 1946) in establishing the relationship between nacin and tryptophan in the rat explained why pigs fed high corn los protein drets de veloped severe niacın deficiency even though the same ration contained seemingly adequate amounts of the vitamin The work of Lueche el al, 1947 and of Lueche el al, 1948, established for the pig the role played by tryptophan in niacin deficiency This work in dicated that the niacin requirement of the pig could be at least doubled when fed high corn diets low in tryptophan Pantothenic acid deficiency Another vitamin of significance in practical swine nutrition is pantothenic acid 1lith the advent of synthetic calcium pantothenate both Hughes (1942) and Wintrobe et al (1912) demonstrated that the feeding of a pantothenic acid free ration to pigs resulted in a loss of appetite, lonered growth rate diarrhea accompanied by a severe enteritis, and a characteristic locomotor incoordination often referred to as goose stepping " One of the most charac teristic pathological findings in pantothenic acid deficient pigs is a diffuse con gestion of the large intestine with an excessive discharge of mucus The wall presents a thickened and edematous appearance Degeneration of the mielin sherth of the sciatic nerve is also characteristic of the deficiency The fact that pintothenic acid deficiency could not only be produced using purified diets but also in diets made up of commonly used feed ingredients was demonstrated by our own studies (Luecke d al, 1949 1950) Perhaps the most distinctive characteristic of pantothenic acid deficiency is the occurrence of locomotor incoordination as shown in FIGURF 1 Although the neurological changes are stresersible the animals will grow to maturity In severe cases however complete posterior paralysis results followed by death Vullipie B ulamin deficiencies The fact that deficiencies of niacin and pantothenic acid could be produced in the laboratory on diets of natural feeds ied the Vichgan workers to investigate the possibilities of vitamin supplemen ·Lucche Treatment of Swine Enteritis 197 ret! Locomotor incuordnat od due to pantothed ca d defic cory tation of practical swine rations The results of this work (VcVillen et al 1949) indicated that rations containing corn oats soy bean oil meal meat meal alfalfa, and minerals could be markedly benefited by the addition of niacin, calcium pantothenate, and riboflavin The results of this experiment are shown graphically in FICURE 2 In view of the alone results it seemed likely that B vitamin deficiencies were Some of these pugs were purchased and brought in for studs Onc pg from neinval Tag RC areno han duction of mucus were found upon histological examination The average leucocy tc count for the 80 deficient us treited as on cells per cu mm compural with a normil range of 16 000 to 20 000 cells per cu mm Because of poor petites injections of substantial quantities of the 13 mins were given intraperitone 3lly Doses of my thiamine, 50 mg nbollanin 20 mg calcium pantothenate 20 mg nun and 10 mg p ruciorine were used! In addition a 19 per cent protein ration supplemented *ith liberal amounts of the same vitamins used for the intraperitoneri injec

·198
Annals New York Academy of Sciences
STUDIES WITH RATIONS OF NATURAL FEEDSTUFFS
100
CONTROL
PA
90
PA + RIBO
PA.+ RIBO + NA
PA + R180 + NA + Th + Be
90
70
60
WEIGHT IN POUNDS
50
40
30
20
2 3 4 5 6 7
9 10
WEEKS ON EXPERIMENT
FIGORE 3 Growth response of D Ex fed va qus am n supplements Note thatna a cukuman
enste und r botlar supplements appea to be the im ng facto s

·I ueche Treatment of Sune I nteritis
199
+ x) (ecum olunan lomah from show me moms of ene
mu tu s ruda The myrna of the orda bi Onked
lucth kenne hea foll
before treatment
In 104 group Pas de TIERE
dess of age and in 1910.ods body of the
Then an erst sproumately 0

·200 Annals Nen York Academy of Sciences > FIGURE S P go from the same group afer 3 days of treatment The an maly a c aged 41 pound body we ght fententis trons was fed The period of treatment varied from 30 to 40 days and resulted in the complete recovery of approximately 80 per cent of the animals treated FIGURE 4 shows a group of pigs as they were brought in from a Michigan farm and FIGURE 5 shows the same group after 34 days of treatment The results of these experiments demonstrate that a nutritional type of enteritis does occur under practical feeding conditions involving a multiple B vitamin deficiency Niacin and pantothenic acid however appear to be par ticularly involved Antibrotrcs in the enterilts complex Il bile all of the foregoing has demon strated that deficiencies of certain members of the B complex are involved in the swine enteritis do not respond to v under farm conditic but rather a pathological condition caused by a number of factors Certainly the organism Salmonella cholerdesuis belonging to the paratyphoid groups most frequently found in pigs with enteritis This same organism however is also frequently found in apparently normal pigs It thus seems logical 1 view of what is now known concerning the effects of deficiencies of certain mem bers of the B compler on antibody production that a def ciency of one or more of these nutrients may be important predisposing factors 11 hether the above is true or not remains to be determined recent use of antibiotics in the treatment of infectious enteritis where certain organisms of the paratyphoid have been found has had a remarkably beneficial effect in reducing mortality and morbidity A great many reports have apo peared concerning the use of antibiotics for the treatment of enteritis The However the ·Luecke Treatment of Shine Enteritis 201 method usually employed for treatment involves the addition of the antibiotic to the feed at levels of from 50 to 200 gm per ton If the animals are not eating significant amounts of ſeed, however, the method of choice appears to be by way of the drinking water This latter method is not used extensively The use of antibiotics for the treatment of saine enteritis has virtually elim inated the disease, at least in certain areas where it was causing greater losses than all other diseases combined nicolin References BIRCH THI Chick &CJ MARTIN 1937 Fxperiments with pigs on a pellagra producing d et Biochem J 31 206.5 (MICK II TF MACRAE J) P MARTIN & CJ MARTIN 1938 Curative action of acid on pags sulering from the effects of a diet conseling largely of maize Bochem J 32 10 DALIS GKVA I REEVAN &L L VADSFY 1910 The relation of nutrition to the des clopment of necrolic enteritis in suine Vich State Coll AgExp Stat Bull 170 DLE IT 1947 Sanne dysentery J Am let Med Issoc 102 419 DIT I P&FL WALKEY 1946 Attempts to reproduce enteritis in S* 1510 J Am Het Wed Issoc 109 280 GIBT es 83 220 11AR ations restrictel to the Ilic J 1gr Research 64 185 RFIL HIIJ TIL PS SARYA &C I T'IVFIJEM 1945 Gronth retarding effect of corn in Dilatinic aci 1 low rations and its counteraction by tryptophane Science 101 449 Rent 1 IPSC 1 | Trẻ r 6 ۳ T MY TIRAL HUKI JRMMC MILLEN 194) Iantothenic acid deficiency in pirsfuldets of natural feedstuffs J Animal Sa 8 461 Teren Ne VIILLEN & F THORP JK 1950 Further studes of pantothenic MI MILLEN HR LUFCHEF TORP J& 1949 The effect of liberal B vitamin acu defilency in weanling mis _Inimal Sci 978 sus lementation on growth of wcanling pigs fed rations containing a sorts of feed stulis J Animal 8 518 Vu LFR 1 KALI KIBO 1915 Fxperimental production of loss of hematopoietic elements of gistrIC KC reit n and of liver in swine with achlorhywirua and anemia Clin Invest 14 153 WOSTKORE 11 V VII VILL# RIFOLLIN JR 11. J STEN VLATT It wrREY 1942 Sensory neumn degeneralın in 118 11 Trotection al ined by cakun pantothenate and syndorine J Nutntion 94 345 ·THE ROLE OF THE VITAMINS IN ANTIBODY PRODUCTION By A E Axelrod and ) Pruzansky Brochemistry Department School Wedicine Uni esiły of Pittsburgh Pillsburg) Pa Introduction Many researchers have been intrigued with the possibility of a relationship between nutritive state and resistance or susceptibility to in fection As a result, the search for dietary factors that could influence the resistance susceptibility of a host to infectious disease has been prosecute! graph attest to the mass of voluminous and often conflicting data in this fiel! The preponderance of efforts in these endeavors has been directed toward the possible relationship between diet and "natural' or innate resistance Such miestigations have been concerned with the ability of the host to survie the attack of a given virulent agent It is well known that numerous factors many of which are but poorly understood, may be involved in determining re sistance to infection Therefore, by this operational procedure, the effect of diet is conditioned by the interplay of these various factors It would seem that a study of the delineated components of this complex phenomenon would offer promise of some interesting and perhaps useful information The class c antigen anubody reaction is generally considered to be a significant facet of this intricate mechanism It seems appropriate therefore to inquire into the interdependence of any between nutrition and antibody formation or actuely acquired immunity A word of caution at this point it must be stressed that an immune response may not necessarily correlate with the degree of re sistance to an infectious process A review of the older literature in this field reveals an extensive olume of conflicting data with no unequnocal evidence to indicate that any specitic vitamin deficiency invariably leads to impaired antibody production An accurate assessment of many of these earlier researches is difficult because of the questionable speciicity of the deficiency under study, as well as the fatlure 10 utilize adequate inanition controls These studies have been summanzel elsewhere by lelrod and Pruzansky' The present paper will be confined to a discussion of our own experiments on the role of the vitamins in antibody response Etperimental Our investigations were designed to study systematically the effects of specific individual vitamin deficiencies upon antibody production in the albino rat In our first experiments human erythrocytes were employed as the antigen and the resulting serum antibody content was determined by the hemagglutination procedure More recently we have utilized purified diphtheria torond is the antigenic stimulus in this case serum antiboth titer was determined hy a hemagglutination reaction in olving the use of There su 1 es ha e beep sul gwrted by a grant in a d from the \1! saltam a Joundst on lo hori 202 re ·Arelrod & Pruzansky Antibody Production 203 TABLE 1 SU WARY OF THE DELETERIOLS EMTCTS or Ivoryt AL VITAMIN Dergingits to INT;BODY KESHOYEE to Humay TRUTHOCYTES N TVE RITZ RAT Syere Pantothenic acid Pyridoxine Pirroziglutamic ani! Moterste Long Thuamine Boten Riboflayan can trypte hanc Vitamin D Vitamin B1 TK acid treated sheep erythrocytes coated with the diphtheria foxand forts were directed toward producing indusidual deficiencies specific for ,itamin under study is controls, paired weighed, paired lets, and ad Ibufum fed rats were utilized All control animals received the same diet as the corresponding deficient group plus the crystalline ustamın in question The early exxnments with human erythrocytes as the antigen demonstrated that antibody synthesis was markediy impaired in certain vitamin deficiency states These results are summanized 10 TABLF i, shere it is esident that the most pronouncerl impairment of antibody response was noted in pantothenic aud prulovine and preraylglutamic acid descuencies I wish to reiterate That Wentical immunological procedures were employed in all of these studies the failure of simple inanition to mochfy the antibody response has been demonstrated repeateilly in these studies Further no cortclation Letueen the inhibiting efect of a vitamin deficiency upon fronth rate and upon anti Inals response could be shown Thus certain deficiencies eg. tumine Juscil sery mathese grouth inhibition without greally affecting an body re wunsc In other debciencies & prero Iglutamic acid a marked decrease in itbords response was noted although the growth inhibition was relativels shught This lack of any inanition effect on erperimental animals es reminiscent of the observations made by Balch' and (ell d als in malnounshed bumans Balch observed that prolonged nutricional depletion did not interfere with phtheria anutan production in Schich negative human subjects injector with purthed diphtheria fotok! Similarly Gelld al noted a relatively small chifferente in any production between well fed British soldiers and mal muneti frerman ensins These vissertations are of interest in ups of the tendency to assoch InanOn with a diet rased resistance to iníection It shouk le pointed out that no ruidente far the existence of andevulval vitamin deficiencies in thess liumor subjects was presented by Ibalch and Giella al Thus it would apļxar that the inhul tion of antibiy response cas de demonstratel only in specific men aluat timin-dehotenci stales comparable with those produced in the <<XTI : animals in this connection Vorty and Spuest have aliseneda lemse mantly remains to immunization with Pusicurella Iisrensis in 1778 with nine thrrmine, and rfn en deficu nues In order to investigate further the specificity of these vitamin effects there studies were extended to include ynfiel dihtheria fotout as the antigen' ·THE ROLE OF THE VITAMINS IN ANTIBODY PRODUCTION By A C Axelrod and J I'ruzanshy Brochemistry Department, School of Vedum, Unnusly of Pillsburgh, Pittsburgh Po Introduction Many researchers have been intrigued with the possibility of a relationship between nutritive state and resistance or susceptibility to la fection As a result, the search for dietary factors that could influence the resistance susceptibility of a host to infectious disease has been prosecuted vigorously for many years These studies have been motivated by the fervent hope that suitable manipulation of diet might influence the incidence and course the possible relationship between diet and "natural" or "innate" resistance Such investigations have been concerned with the ability of the host to surynt the attach of a given virulent agent It is well known that numerous factors many of which are but poorly understood, may be in oh ed in determining resistance to infection Therefore, by this operational procedure, the effect of dret is conditioned by the interplay of these various factors It would seem that a study of the delineated components of this complex phenomenon would offer promise of some interesting and perhaps useful information The classic antigen antibody reaction is generally considered to be a significant facet of that an immune response may not necessarily correlate with the degree of resistance to an infectious process A review of the older literature in this field reveals an extensive volume of conflicting data with no unequrlocal evidence to indicate that any specific vitamin deficiency invariably leads to imprired antibody production An accurate assessment of many of these earlier researches is dificult because of the questionable specificity of the deficiency under study, as well as the failure to utilize adequate inanition controls These studies have been summarized elsen here by Axelrod and P'ruzanshy! The present paper will be confined ! a discussion of our own experiments on the role of the vitamins in angebodes response Erperimental Our iniestigations were designed to study systematically the effects of specific indaidusi vitamin deficiencies upon antibody production in the albino rat Jn our first experiments, human erythrocytes were employed as the antigen, and the resulting serum antihody content was determined by the hemagglutination procedure More recently, se haie utilized purified diphtheria toroul as the antigenuc stimulus In this case, serum antibody trter sas determined by a hemagglutination reaction in oluing the use of *These «ut es have beep supported by a grant in and from the Vational Vitam o Foun'ation Inc ** Sota 202 ·Axelrod & Pruzansky Antibody Production 203 TABLE 1 SCBX 4RY OF THE DELETERIOUS EFFECTS OF INDIVIDCAL VITAX DEFICIENCIES I POV ANTIBODY RESPONSE TO HEWAN ERYTHROCYTES IN THE WHITE RAT Sesere Moderate lone Pantothenic acid Pyridoxine Pieroylglutamsc acid Thiamine Biocan Riboflavin Atacan tryptophane A Vitamin D Vitamin B2 tannic acid treated sheep erythrocytes coated with the diphtheria toroid 4 efforts were directed toward producing jadividual deficiencies specific for the vitamin under study As controls, paired weighed, patred fed, and od libulum fed rats were utilized All control animals received the same diet as the corresponding deficient group, plus the crystalline stamin in question The early experiments with human erythrocytes as the antigen demonstrated that antibody synthesis was markedly impaired in certain vitamin deficiency states These results are summarized in TABLE 1, where it is esident that the nost pronounced impairment of antibody response was noted in pantothenic cid, pyridoxine, and pteroylglutamic acid deficiencies I wish to reiterate that identical immunological procedures were employed in all of these studies The failure of simple inanation to modify the antibody response has been demonstrated repeatedly in these studies Further no correlation belkeen the inhibiting effect of a vitamin deficiency upon growth rate and upon antı body response could be shown Thus, certain deficiencies, eg, thiamine, caused very marked growth inhibition sithout greatly affecting antibody re sponse In other deficiencies ex pteroylglutamic acid, a marked decrease in antibody response was noted, although the growth inhibition was relatively slight This lack of any inatution effect in experimental animals is reminiscent of the observations made by Balch” and Gell et al. in malnourished humans Balch observed that prolonged nutritional depletion did not interfere with diphtheria antitoxin production in Schich negatne human subjects injected with purified diphtheria toroid Similarly, Gell et al noted a relatively sma}} ifference in antibody production between well fed British soldiers and mal- Jurished German civilians These observations are of interest in hex the tendency to associate panttion wah a decreased resistance to mfection It should be pointed out that no evidence for the existence of indi dual vilama deficiencies in their human subjects was presented by Ralch and Cell et al Thus it would appear that the inhibition of antibody response can be demonstrated onls in specific mdn dual vitamin deficrency states comparable with those produced in the experimental animals In this connection Morey and Spies have observed a decrease in anubody response to immunization with Pasteurella tularensis 27 patients with uicin thiamine, and riboflavin deficiencies In order to investigate further the specificity of these vitamin effects, these studies were extended to include purified diphtheria toroid as the antigen ·201 Annals New York Academy of Sciences PYRIDOXINE RIBOFLAVIN TITER$ 6,4007 PANTOTHENIC ACID 3200 4600- 800- 400- 200 20 O CONTROL DEFICIENT CONTROL DEFICIENT CONTROL DEFICIENT ICCRL 1 C rulat ng ant boly product on to d phther a toro din vlam o defic entrals Figues on the ord nate represent rec procal t ters With this antigen a closer correlation could be drawn with the effects of the vitamin deficiencies upon resistance to infection Again, individual deficien cies were produced in the rats and the anuals immunized with the toroid when a well defined deficiency state had been produced Three weeks after immuni zation serum antibody titers were determined as described above The re sults are shown in FICURES 1 and 2 The marked impairment of antibody synthesis in the following deficiencies is apparent pantothenic acid, pyridoxine riboflavin biotin and vitamin D Not shown in these data is the marked inability of pteroy Iglutamic acid deficient rats to fabricate antibody On the other hand the thiamine deficient rats were fully capable of normal antibody synthesis Sot shonn is the fact that good antibody responses were observed in many vitamin A deficient rats Thus, these experiments demonstrate the extreme effects of certain vitamin deficiency states upon antiboly production to diphtheria toroid in the white rat Ilith the exception of the marked deleterious action of the vitamin D deficiency, the trends observed with diph, theria toxoid were similar to those previously noted when red blood cells serve! as the antigen This difference in the effects of a vitamin D deficiency with the two antigens is interesting Investigative pathways of this type may lead us ·Axelrod & Pruzansky Antibody Production 205 TITERS 6,400- BIOTIN VITAMIN D THIAMINE 32001 46004 1.1.11 CONTROL DEFICIENT CONTROL DEFICIENT CONTROL DEFICIENT FIOURE 2 C roula oxant body produto od phther a toto do am n defic ent rats Fgures on th ord na recent rec pralt ers to an understanding of the mechanisms of antibody synthesis and the precise role of the vitamins in this process The effects of a lack of pantothenic acid upon the various phases of the anamnestic (booster) response to diphtheria toxoid were next considered The results are given in FICURE 3 The primary response to the toxoid was obtained three wecks after immunization in the usual manner As previously noted this primary response as low in the deficient rats and high sn the con trols At this time a booster shot of the toxoid was gnen and the secondary response was determined one week later in the deficient rats no secondary response was apparent Therapy with pantothenic acid during this secondary phase was ineffective in producing a response Therefore the mechanisms normally developed in the primary phase that are necessary for the establish ment of a booster response fail to materialize when pantothenic acid is lacking In contrast the controls shox a marked anamnestic response These data emphasize the need for an adequate intake of pantothenic acid during the pri mary phase » a booster response is desired The value of this observation in clinical practice remains to be determined The concern of this laboratory with the interrelationships between dietary components and resistance susceptib lity to disease led to an investigation of the effects of vitamin deficiency states upon serum complement which is recognized as an important factor in certain immune phenomena. The te ·206 Annals New York Academy of Sciences TITERS 81920- PANTOTHENIC ACID - DEFICIENT CONTROL 40,9604 20,480- 10,240- 5,120 2,5601 4280 640- 320- 160- PRIMARY SECONDARY PRIMARY SECONDARY FIGURE 3 Anamnestic responses to d phther a toxo d in pantotben c ac d dec ent and control rats 1 ures on the ord note represent rec procal titers sults of this study are shown in FIGURC 4 A decreased level of compleme was noted only in the rats deficient in pyridoxine and ribolavin These fects, however, could easily be attributed to the concomitant state of inanıtı in these deficiencies The low complement titers of the riboflavin inanit controls is evident This lack of a specific vitamin effect upon serum cor plement was further demonstrated in a study of the rate of serum compleme regeneration in vitamin deficient rats In this experiment, the serum cor plement was depleted In lilo to a negligible value by the successive admin tration of Type 3 pneumococcal polysaccharide and the homologous rabt antiserum The rate of complement regeneration was then determined bo in deficient and control rats As seen in FIGURE 5, the deficiency states had 1 significant effect upon serum complement regeneration Discussion The need for certain vitamins in the biosynthesis of antibodi is clear that can be said about the mechanism of their action? Let us fir analyze the difficulties involved in attempting to answer this question are asking for information on the role of biological factors concerned in tl mechanisms of the synthesis of a protein when se actually know so little protein synthesis To complicate matters further, this protein is one whic is not normally present in the body but is fabricated mainly through the stim lus of a foreign protein With the recognition of these difficulties, I shou ) ·Iselrod & Pruzansky Intibody Production 207 PGA PGA BIOTIN B OTIN PYROONE PYRIDOXINEREOFLAVNIRIBOFLAIN CONTROL DEFICIENT CONTROL DEFICENT CONTHOL DEFCIENT CONTROL DEFICIENT 300 .. . : 250 200 50% UNITS 150 100 50 * Pored red win noofrovn del crent group I CORY+ Indiv dual serum complement & ters tam -def edt aty like to discuss some of our experimental approaches to this problem At this point it becomes apparent that we have been stimulated to study the relation ship between diet and antibody formation by the belief that nutritional tech miques may prove of service in eluc: lating the complex mechanisms of antibody synthesis There are many factors that might influence the biosynthesis of antibody protein First there is the possibility that the metabolism of the antigen might be altered in the deficiency state ery httle is known about the role of nutritional factors in antigen metabol sm and we have only recently under Cahen such studies with labeled antigens Second se must gre consideration to the possibility that the antibody synthesizing cells whatever they may be are deranged in the deficiency state Such damage may be minuested either by structural changes demonstrable by histological techniques or by disturb ances in functional actis Erperiments in our laboratory have indicated a disturbance in the functional activity of splenic cells from pantothenic acid deficient rats amunized ith diphthera toroid In studies conducted in as sociation with Doctor Abrim Stayıtsky it was shown that spicnic cells from immunized pantothenic acid deficient rats in contrast to thosc from normal immunized rats were unable to fabricate antibody when cultured 11 tilro or when yssively translerted to normal zats With Doctor Leothenberger evidence was obtained that the mean DIA content of isolated splenic nuclei from immunized pantothenic aud deficient sats has loner than that from com parable controls These results may be interpreted to mean that the deficiency ·208 Annals New York Acndemy of Sciences PGA BIOTIN PYRIDOXINE PYRIDOXINE RIBOFLAVIN CONTROL CONTROL CONTROL DEFICIENT DEFICIENT 2004 150- 50% UNITS - . • 100) 501 Complement Levels Attained 22 Hours After Th rd Success ve Daily Depletion PERU 5 Serum complement teyene at onnd wual v tam n-dercrest rats interfered with the acceleration of cellular division that normally accompanies antibody production in the spleen Since cellular division is always preceded by an increase in DNA content, the participation of pantothenic acid in D\4 synthesis becomes an intriguing possibility Thurd there is also the distinct likelihood that the vitamins by virtue of their close interrelationship with various enzy me systems function directly in the enzymatic reactions invoked in antibody synthesis Our complete ignorance of these reactions constitutes an effective barrier against any attempt to implicate the vitamins in specific enzymatic mechanisms We do possess however, a few bits of evidence bear ing on this question Our studies, utilizing electrophoretic measurements have shown a normal serum gamma globulin content in vitamin deficient rats that are incapable of synthesizing antibody globulin? If we accept the sche 1 1 vitamin deficiency Finally it must be recognized that the serum antibody level that is utilized as a measure of antibody response probably reflects an equilibrium between the rate of antibody synthesis and release from the sites of synthesis on the one hand and the rate of destruction of circulating antibod) on the other A change in any one of these factors could obviously affect the content of circulating antibodies Thus it becomes important to evaluate the effects of a vitamin deficiency upon antibody release and degradation befort any positive statements can be made regarding any direct relationship between vitamins and antibody synthesis We have carried out certain esperiments in ·SASA E TXELROD 1955 Proc Soc Lupel Biol Med 89 323 64397 Axelrod & Pruzinsky Antibody Production TABLE 2 SCHEMATIC REPRESENTATION OY ANTIBODY FORMATION 209 Antica Amino acus Serum antibody I recursor Serum globulin this direction Without going into detas] se can state that the results ob tained have suggested that the decreased level of circulatrag antibody in the vitamin deficiencies cannot be attributed to a faulty release mechanism or to excess se destruction of antibody It seems more likely that there has been a disturbance in the processes of antibody synthesis Summary In conclusion, it can be stated that the data presented have dem onstrated clearly that an antibody response can be markedly inhibited 12 vari ous vitamin deficiency states ile have made an attempt to indicate the re search pathways we are following in our efforts to understand the role of these tamins The possible application of nutritional techniques to studies in the biosynthesis of antibody has been pointed out In assessing the value of these olsenations to the relationship of diet to resistance to infection it must be stressed again that an immune response is only one facet of a compler mecha nism determining resistance to disease The decreased immune response in a Vitamin deficiency will obviously be significant in the phenomenon of resistance to infection only in those cases where the importance of antibodies has been defimtely established References 1955 Vitamins and Hormodes 13 Io press 2 BALCI HI 11 1950 CELL P G H I PARR) & Z A LETTER 1948 Proc Roy Soc Ved 41 323 ALORES G R XTD Sets 1912 Proc Soc Expei Biel Ved 45 519 1933 Iroc Soc Expti Bol Med 88 179 E&J PRI ZAUSAY 1954 Symposium on Protesa Velabol sm Aau Vitamin Found Inc 8 26 8 LUDOUICY PPF AXELROD & BB CARTER 1951 Proc Soc Fxpt) Biol Wed 76 665 Discussion of the Paper DOCTOR KENTU BIETZFL (Foculty of Medicine Unifcsity of Adelarde Ideluide Australia) Doctor Lxelrod has presented in the nork that he has been doing in recent years, further enxlence of the relation beca een vitamin deficiency states and antibody production Like other people he has noticed that it is not inanition per se but the specific effect of vitamins in deficient supply that results in this deficient antibody production le did mention something that is nex, and that is the effect of vitamin D on antibody response ·210 Annals New York Academy of Sciences nosing diseases 10 diphtheria tovoid that is the deleterious effect of vitamin D deficiency on antibody production He has mentioned that, in his work he is using red blood cells and diphthena toroid He mentioned also that in human beings Spies and others have found there was a deficiency of antibody production in response to the injection of Pasteurella fularensis in people with pellagra There is some supporting evidence from the infection standpoint some work done in the Pathological Department of Columbia Unis ersity by Zucker and by Zucker and Zorand who found that in young deſicient rats Corynebacterium lethal to mice only killed off the rats in three weeks from infection The rats showed both pleurisy and pericarditis and multiple abscesses in various parts of the body Then certain Italian workers worhing again on rats showed that Salmonellu lyphosa and Brucella melitensis again in pintothenic acid deficient rats failed to produce very good agglutinin responses whereas the animals on the same diet plus pantothenic acid showed very high titer to both of these organisms Doctor Axelrod has stressed that measuring the resistance to infection by antibody response to injections represents of course, only one facet of this immune reaction Of course it does become of importance in clinical medicine when we use the presence of high titers to determine immune response in diag Also when we are watching the progress of an infection in the patient a rising titer does mean something of significance to us It then would appear from this evidence that Doctor Axelrod has presented and from other evidence that the utimins, especially of the B group seem to be definitely necessary in the elaboration of antibodies and agglutinins in the infections I have mentioned These days in clinical medicine, I think probably most people expect too much of antibiotics and fail to realize that it is ultimately the cell of the body that has to deal with the infection That is the metabolism of the cell has to be such that it can produce what is necessary to combat the toxin, so that phagocytosis and other cell reactions can ultimately deal with the infection While the antibiotic does much in curtarling infection the ultimate conquest of the infection is through the actual body cell In view of this and of the increased metabolism under conditions of infection and the increased needs in all body cells adequate supplies of these vitamins must be given lle have been doing that in clinical medicine for some time I should say not entirely with the idea of speeding up antibody production but for controll ng certa n of the side effects that we have seen with antibiotics Antibiotics lend to disturb both production and absorption in the gut especially when administered van gastro ntestinal route So it becomes necessary at least to give the stated requirements of the vitamins, or even to give more than what is considered a normal requirement to the individual with the increased metabolism and under the conditions of stress It was interesting that Doctor Axelrod generally found that the production ) of complement did not conform to the experiments on antibodies and that he thought perhaps the failure in reaction might have been explained by simple inanition I cannot gue any opinion on that But, of course, it is still possi ble that there may be a member of the complex vitamin family that might be ·Axelrod & Pruzansky Antibody Production 211 responsible At the moment the one that seems so essential from work that has been described thus far in these pages seems to be pantothenic acid I think too the work on the booster response to the diphtheria toroid was extraordinarily interesting in that one does not get the booster response unless there is a primary response I am afraid I cannot quite say why that happened DOCTOR ABRABI B STAVITSK (Department of lucrobiology II estern Resente I Betersity Claeland, Ohio) In discussing Doctor Axelrod s paper I shall concentrate on the joint experiments that he mentioned briefly Vany times during the day it has become obvious that it would be desirable to have more fundamental information on the basic aspects of both nutritional deficiency and antibody production Therefore, the experiments that have been de scribed are the result of a very happy coincidence for many years my laboratory has been engaged in studies of the basic mechanism of antibodies During the same period Doctor Axelrod has been studying the relationship of vitamins to antibody formation When he came to li estern Reserve University several years ago it was quite natural therefore for us to plan etperiments which combined the nutritional biochemical immu nological techniques we previously had used independently While the multidisciplined approach certainly has not solved the problem of the anamnestic reaction or of what nutritional deficiencies do I think it does offer a promising approach to a fundamental understanding of these problems It might be helpful first of all to summarize the two experimental systems that Doctor Axelrod and I used Doctor Axelrod has mentioned the booster response This is the classical reaction study by Grennie and Sydnerson in England 20 years ago One gives toroid There is a small rise in antitonin If honeser about three weeks later one gives torord again there is an accel crated production of antibody reaching a peak in about 10 days or two weeks later lle have taken cells in the middle of this anamnestic reaction We have done two things with these cells First we have cultured them and second we have made homotransplants as it were of them If one cultures splenic cells from a rat thus inoculated one finds that these cells continue to elaborate antibody 11 til If one takes these cells and transplants them al this time to normal rats the process of antibody production apparently con tinues in the normal animal What we have done then is this we have used simply both normal and pantothenic-deficient donors as a source of these ells and have compared the antibody response As Doctor Axelrod indicated ke have found that whereas splenic cells from normal animals continue to elaborate antibodies under these normal conditions cells taken from pantothenic-deficient animals were actise by neither method The other approach to the problem was to take cells from normal animals und transfer them to pantothenic acid deficient animals There was a very menger response upon transplant of normal cells into normal animals On the other hand unexpectedly there was a very good antibody response when one transferred normal cells from immunized rats to pantothenic acid-deficient animals The ceils derned from normal animals were able to produce antibody in a deficient animal I think it would be desirable at this point since we have made so much of ·212 Annals New York Academy of Sciences these experimental systems, to sunimarize rather quickly some of the evidene for the validity of the use of these systems for studying antibody formation Actually, there is good evidence that synthesis of antibody occurs when tissues from immunized animals are placed in a suitable medium tu titro I can sum marize this evidence briefly as follows disruption of these tissues by any means abolishes intibody formation If one incubates these ttssues at zero instead of at 37°C for instance or uses any inlubitors of oxidatne processes such as cyande dinitrophenol, or arsenate, the antibody production is inhibited Moreover the sites of antibody production in tilro parallel completely the sites of antibody production 111 1110 If one injects, we know the spleen elaborates antibody and only the spleen is active among the tissues cultured in tilro Nou to go over to the passive transfer reaction Again there is considerable esidence that this passie transfer or homotransplant actually involves the synthesis of antibody at least related to the synthesis that occurs in the intact animal There are three possible explanations of the homotransplantation reaction that one could visualize I think I neglected to mention just what the possibility homotransplant is When one transplants cells from immunized animals sex eral days after the transfer of these cells, the antibody appears in the recipient anımıl It can be shown that this is actual synthesis One can visualize this as actual transfer of antigen or antibody or, finally, that it represents active synthesis The transfer of antigen with these cells can be eliminated rather easily One knows that if one injects a large dose of an antıgen into an animal it takes several weeks before an appritiable amount of antibody results Moreover, any of the disrupting methods that I just discussed in connection with the int zitro reaction will result in disruption of the transfer action as well So you cannot damage the cells If it were simply a transferred antigen this would not be expected Interestingly enough these cells must have the proper metabolic environment You cannot transfer cells from one animal to another As we just indicated, the transfer may be successful in recipients that are unable themselves to make antibody by virtue of irradition dministration of cortisone immaturity, elc In other words a young animal that does not make antibody will nevertheless support the transfer I inally, in pantothenic acid deficient animals you can exclude passive transfer due to the transfer of antibody to the cells because you cannot extract enough total protein Jou cannot extract enough gamma globulin from these cells to account for the amount of antibody that appears in the recipient animal appeared in the recipient animal Moreover, of one administers a radioactive labeled amino acid to the recipient animal shortly after the cells are trans ferred, this amino acid is incorporated into the antibody that appears shereas the amino acid is not incorporated in the passively injected antibody There fore, both of these methods appear to be a good measure of active antibody synthesis As Doctor Axelrod mentioned, and as I have mentioned when we applied ·213 Ixelrod & Pruzansky Antibody Production hese techniques to the elucidation of the role of sitamins an antibody formation it was found that the cells derived from normal animals were actue under these conditions whereas cells derned from pantothenic acid deficient animals were not active These results provide a good deal of evidence as Doctor Hetzel has suggested for the autonomy of the cells themselves in other words one could transfer cells from immunszed animals in the inde dual in the environ ment where antibodies could not be made by sirtue of deficiency radiation at yet these cells did lead to the appearance of antibody Is to why the ransfer reactions occurred in deticient animals whereas they did not occur in ontrols the only reason I can give is the inability of the recipient to destroy transplanted cells since the pantothenic acid deficient animal males anti bodies very poorly if at all It hen it comes to explaining Doctor Arelrod s results however I must admit that we are still far from correct and complete ansuers Doctor Ixelrod has given most of the obisous explanations of the effects of vitamin deficiency on antibody formation I have very little to add in this contection I do think however that the experiments with the cells in panto thenic acid deficient animals male it quite unlikely as Doctor Axelrod has already indicated that the inability of the deficient anmals to make antibody is entirely due to their failure to release these antibodies We were also completely unable 10 extract any antibody from the tissues Tou might say that the bemagglutination method that we employ is as far as I hnou the most sensitie in turo method for the detection of antibody little as 100 n{ a microgram or a thousandth of a unit of diphtheria antatosin an be detected So if any active antibody 15 there we should detect it These Is did not yield any antibody whereas we could readily abstract such antı kly derred from the nondeficient animals The only other possibility that . wish to discuss is that there may be some disruption of the antibody synthetic mechanism in these cells Obviously it is too early to say that this is the reason but in this connection I think our experiments indicate some point of minor disagreement with Doctor Axelrod s indication that there might be some cilliculty of conversion of a precursor to antibody The experiments we hale done indicate that there is no appreciable amount of such a precursor in the transferred cells that in fact free amino aculs rapidly find their way into the antibody Therefore if there is any precursor it does not accumulate but is turned over and converted to antilody very readily I Doctor Arulrod desires to change his word precursor to some sort of enzyme system or enzymes I can concur In any case I should think that the buth of the evidence at this dilmittedly ser early stage of information favors some distuption of the anti body synthetic mechanism in these cells In any erent I think the possibilities of such sistems for further study in fundamental mechanisms of antiborts 1 rmation and possibly in the other problem of profein synt) esis are obs sous ·OBSERVATIONS ON INFECTIOV AND CERTAIN VITAMINS By Benjamin M Kagan Kunstadler Laboratories for Pediatric Research and Department of Pediatrics Sarah Blorris Hospital for Children, Jihad Reese li ospital Chicago III Most obseryers find that severe deficiency of vitamin A is accompanied by decreased resistance to infection This appears to be true in spite of the fact that formation of specific circulating antibodies is not disturbed in vitamina deficiencies, as shown so nicely in Doctor Axelrod s paper An example of an experiment demonstrating the influence of vitamin A deficiency was that re about 80 per cent survived on an adequate diet' Similar experiments with mice and measured doses of mouse typhoid bacıllı show differences in mor tality rates of 80 to 100 per cent in the deficient animals, as compared to 10 10 20 per cent in the controls Doctor Frye has pointed out that, on vitamin 4 deficient diets fowl develop more and larger worms, and that the resistance of rats and dogs to ascariasis is decreased on vitamin A-deficient diets A relatively long period of depletion is necessary before the influence of vitamin A deficiency on susceptibility to infection becomes significant This is most likely due to the fact that large amounts of vitamin A are stored in the liver An average human liver contains about 1,200 units per gram, or a total of between one half and one million international units of vitamin A: If all of this were available and at the rate of the recommended minimum allowance this would be sufficient to last the normal human for about three months Parenthetically, the infant, especially the new born, does not have such a large store upon which to drar In spite of this large reserve of vitamin A there is some evidence that its administration in excess of that contained in the average diet may have a beneficial effect on the course of infectie processes Thus, Vellanby and Greene reported that the administration of vitamin A in amounts above that wi the usual diet increased resistance to puerperal sepsis and septicemia Elis. before the days of antimicrobial agents, found that vitamin A reduced the mortality of postmeasles pneumonia in a controlled senes by 50 per cent Donaldson and Tasher also, in the same era, found that it reduced the mortality in a controlled series of adult patients with pneumonia by 44 per cent Other observers, honeser, have not been able to duplicate these results or to demon strate increased immunity to infection as a result of the administration of vitamin A in excess of that provided in the diet One of the best controlled studies was that by Shibley and Spies 1. These investigators studied a group of students selected by random sampling 10 The author wides to expreso s deep appreciat on to becomb ke botor Elizabeth Ka ser for bem To s work was supported a part by a grant from the Wat omall tam a Foundat mn lac News tance in all the crystimentat sort nited Wartor Kaikos Research Associate the shepartment of Ped. 14* Revarch 31 chael Rere Host ta! Chago I! 214 ·215 hagan Infection and Certain Vitamins subject knea to which group he belonged A careful tecord of respiratory infections was maintamed One group received 200 000 units of vitamin ! and 4000 units of vitamin D per week Another group recen ed 400 units of > } amin A The third group recented maize os! The seasonal incidence of colds and their severity were alike in all groups The duration of colds how eter, mas significantly shorter in those students who received the added vita min The later reported findings of (ameron uere similar Information was sought therefore on the neerl lor and the role of vitamin A during acute infection It has been bnou for some time that blood levels of Vitamin 1 decrease during acate iníection, in spic of the lare amounts in the leer This has been observed particularis in pneumonia abscesses and arute rheumate feierli This suggested certain questions in the presence of acute infection is there an increased tissue demind for this vitamin or an increased utilization? In the absence of either of these where does the blood vitamin I go? Is absorp tran impasteel? Is the rate of her uptake and release different in the presence of infection? These are some of the questions which stimulated our expery ments, which are still going on and which I art about to describe Il introbe s group and others's showed that injection of lurpentie or of sweet almond oil into rats produced abscesses which resembled bacterni ab blesses in the histologic appearance Be therefore used these spustances to simulate infection in rits and studied the vitamin 4 changes in the blood urine and tissues Mature al no male rats of the Sprague Danley strun weighing about 20 Am each were used Control ammals were fert the same standard feeding as experimental animals There i as no significant dierence in the mean weight Lain of the experimental and consrol groups during the period of study TAF 1 shows the eflect of the abscesses on serum levels Bloods taken to fays after the first injection shou changes in the same iliser ton though not as marked as those seen two days after the third and fourth injections Blood then seven days after a single injection may shou further lowering thin two days after injection though in some animals there is some recovery toward the preinjection level These results are thus similar to those ofasersed in bacterial infection in huntas Since they mai has been specifually due to turpentine per se rather thin to the abscesses similar experiments were dost using 911 cet almond ! (riu) 2) The results with this oil are similar to those kit turpentine Tit) SFRtX 11) I our injetan oli Turgentine in Kats ai licells iniersals It al It! 2 ++ + OX 3 2) + 7+ 2 ·216 Annals New York Academy of Sciences TABLE 2 SERUM VITAMINA Two Injections of 1 ml Sweet Almond Oil in Rats at Weekly Intervals Serum vitam n A (Vean) (48/100 mg USD) To rats Before insect on 2 days after 2nd inject on Experimental Control (not injected) 27 + 10 30 + 8 13 + 7 29 + 10 The next step was to determine whether absorption and liner deposition of the vitamin are decreased Blood levels following a standard orally adminis tered test dose of vitamin A alcohol were therefore determined The test doses were given by gavage to experimental and to control animals in doses of 12,000 units per hilogram body weight Blood levels were determined before the test dose 3 or 6 hours later, and 24 hours later The animals were studied in groups of six These studies were done in different groups of animals at different intervals of time after the injections, two days after a single injection of turpentine, two days after a single injection of sweet almond oil, two days after a second weekly injection of turpentine, and two days after a third injec tion of turpentine In all of these studies, there were no significant differences in serum vitamin A at three hours or at six hours after the test dose At 24 hours, however, the serum levels in the experimental animals fell lower than the serum les els in the control animals The 24 hour levels in the experimental animals fell to the same low levels as before the test doses The results of one such experiment are shown in TABLE 3 These data suggest that gastrointestinal absorption and liver storage were not modified by the abscesses That the 24 hour lesel in the experimental animals fell so low suggests that the liver stores are low The concentration of vitamin A in the livers was then studied TABLE + shows that the mean reight of the livers of the experimental animals was not significantly different from that of the controls Honever, the liver vitamin 1 TABLE 3 SERUM VITAMIN A Four Injections of 1 ml Turpentine in Rats at Weekly Intervals Fflect of Oral Dose of Vitamin A Alcohol 12 000 kg body wt Given two days after Fourth Injection Serum vitamin A) (g/100 gm. + SD) la rais Before 1st Beiose duse inject on LA turpent ne 3 hours after dose 24 buurt ufter ons Ftperimental Control 3 14 + 9 5 32 + + 37 + 5 12 + 2 168 + 3+ 41 + 6 203 109 8 5 ·hagan Infection and Certain Vitamins TABLE 4 LIER VITIN 1 Three Days after Fourth Injection of 1 urpentine 217 sorats L ver lame A of ver I sperimental Control Mom SD Hotelliver USD 12 0 12 101 + 11 1 092 140 10 914131 E 16 1 1 406 + 124 concentration and the total vitamin A content of the invers of the erperimental animals were significantly lower than those of the control animals These findings are similar to those found in humans who die with infection In the humans, however there has always been the additional question of inanstion during the infection which led to death It will be recalled that the test dose studies suggested that intestinal absorption and the mechanics of liver deposition during the simulated infection Sere not impaired This suggested the question as to what the liver concen tration would be if vitamin A were to be given in excess of that provided by the diet Ininals were therefore similarly injected and 24 hours before being sacrificed, they «ere given by gavage one large dose of vitamin A alcohol (12 000 units per kg body weight) TABLE 5 shows that the concentration of vitamin A in the lives of these animals was higher and that there was no diference between the experimental and control animals This conhrms the impression that hver storage of vitamin A proceeds normally in spite of the simulated infectious process We now attempted to determine where the serum and lover vitamin A were going under these conditions Determination of the vitamin A concentration in the central purulent portion of the abscesses, compared to the adjacent tissue and to the tissue of normal rats, revealed no significant differences The vitamin levels in these tissues were very low The center of the abscesses had mean levels of 2 wg per you the periphery 3 ug per gin, the normal subcutaneous tissue 2 ug per gm Studies of the vitamin concentration in other tissues including the hidney TABLE LIVER ITAXIS ! Shree Days alter I ourth Injection of Turpentine and One Day after Oral Dose of 12 000 tu kg body wt 15 ut of Ivec L ver am A Ierimentai (ntrol /SD/totallyez tU G 6 94+1 206 +1111 950 193 10 4+2 203 = 23 2 127 453 ·218 Annals New York Academy of Sciences TABLE 6 URINE VITA I our Injections of 1 ml Turpentine in Rats at Ilockly Inter als Crine Collected for Three Day Periods Beginning Two Days after lach Injection Tao days before Ist inject on After injection lo rats Lr net! Urine sol ml/24hrs ESD Urine at A 3/24hrs +SD tr ne rol ml/21 hrs USD USD 1 xperimental Control ܒ ܩ 45 + 1064 +07 52 1649 +33 106 + 38 42 7 + 360 78 + 19 11 2 spleen and intestinal wall also revealed no significant differences between the experimental and control animals The mean value for vitamin A concentrs tion in the kidneys, however, was more than twice as high in the experimentar as in the control group, but the variation is so great that the difference is mol statistically significant The urine (TABLE 6) revealed much higher levels of yıtamin A in some of the experimental animals as compared to levels before injection and as compared to urine levels of control animals However, because of the marked variation in urinary excretion of vitamin A in the individual experimental animals there is no significant difference in the mean Normally there is no detectable vita min A in the urine of humans, whereas, in some patients with pneumonia apa preciable amounts of it appear scesses, however, there is a difference in that in the kidney vitamin A 15 an creased, if anything, and not decreased Interestingly, Reichstein's compound L acetate has been reported's to loner the blood and hidney vitamin A of rats .1? LU 4114 VUSLI humans that, in acute infectie processes, both blood and liver stamin A are decreased They show that some loss may occur through the urine, but that ·Jis 3 WENDY II FC 1927 1 xperimentelle Untersuchunger aber die Wirkungs VABER Djection of o ls J Lab Cun vote on cysts and abscesses induced in 219 Dom Assoc 9 61 HALDSON JESS vitamin hagan Infection and Certain Vitamins References | Tisdul I 1950 In Cinica! Vutrition follvie Tisdall & Cannon da Chap 29 Hoel er Tev Jork 2 RALLI E PP CRIVY & DV SHORT 1935 Vitamin I and carotene content of buman lner Am J Med Sci 189 571 MELLANBY I & HIV GREENL 1929 tam n I as an anti infects e agent (its use ELLISON J B 1932 Intensive vitamin therapy in measles Brit Ved J 2 708 S & TASHER 1930 (Feb Mar) Iroc Transsaal Vine Vied Officers IFT LEWIS&L BARRENBERG 1933 Does our detary requ re 1 supplement J Am Med Assoc 101 657 \AchAY MV N 1934 Vitamin A deficiency in children vitamin 1 requirements of hab es khen les ons and vitamin 1 deficiency Arch Diseases Childhood 9 133 RENSTEN I 1932 (\ov 12) Vitam n A in treatment of pneumoma s Ifrican AUSEX Š ! 1934 (Fel 15) The explotation of vitam A VI State J Med 10 SUBLEY G S&T D Spies 1934 (Dec 29) The effect of vitamin I on the common cold J Am ved Assoc 1032021 11 CAMERON HIC 1933 (Sept) The effect of vitam n A upon inc dence and severity of 12 KAGAN ods among studentski dom Directie Assoc : 189 VE KAISER & VOCLAIU Vitam metabol sm in infection in LZA LFINNER T VOORE &I V SILARMAN 1954 Vitamin I in rheu matic fever Cin Mutrition 2 155 F COBURN L V Moore &C HOAGLAND 1914 The level of vitamin d and e in plasma c 289 es Ł MATTHEWS 1943 A by AVTROBE 1949 Anema of injection I Influence of adrenal cortical hormone on 1 and other bloo changes associate with inject on of turpentine J Lab Chn Vled 33 $32 (LARK 1 & & R 1 COLBURN 1955 A selationsh p between vitamin 1 metabolism an! cort sone Endocrinology 66 232 BODANSKY O&B VARLARDT 1951 Effect of Re chstan s compoun : L acetatc on plasma Iver and kidney vitamins a J Bol Chem 190 83 13 utnit on 14 SITAN* 5 EMERY C ·ILUID BALANCE DURING INFECTION WITH REFERENCE TO I'ROTTI\ A\D MICRAL METABOLISH EVZYVE SYSTEMS By Joachim Kuhnau Insti le of Plys olog cal Clemistry Un ersily of Ila nburg llamberg Germany Although reactions of water balance to infectious diseases may vary s dels according to the nature of the infective agent and the localization intensis and course of the infection the statement is possible that changes in flud ast th com ime! and then may be excreted by urine and sweat thus causing a more or less sesere state of dehydration On the other hand if a regime containing I beral amounts of salt is maintained during the course of infection large quantities of water may accumulate in the extracellular tissue gaps and the resulting water retention finds its expression in local or general edema The seemingly op posite phenomena of dehydration and water retention may thus be expla ned on the same basis 11. the loss of intracellular water This loss is accompanied by a corresponding loss of cell potassium which finds its say into the bloo? plasma and the inflammatory exudates of the infected organism and sub sequently is eliminated in the urine ! The fact that protein stan ation 100 may result in either dehydration or edema depending upon secondary con ditions and in losses of potassium points to a common origin of the changes in water economy caused by infections and by a lack of protein Indeed metalolism in acute infections is marked by the well known phenomenon of toxic destruction of proteins that is independent of body temperature and nutrition and leads to increased nitrogen excretion of the diuresis is large or to a rise of nonprotein nitrogen in blood of kidney functions are poor? 7. Destruction of proteins as well as dehydration is followed by liberation and leakage of entrs cellular potassium which is first accumulated in the extracellular fluid and after wards excreted in the urine. The release from the cell interior of potassium equivalent to the destroyed protein frees another portion of cellular water which leaves the cell. These facts justify the conclusion that increased break down of intracellular protein is one of the ultimate causes of the water and potassium drain from inside the cells during infection and at the same t me raise the question whether the status of protein nutrition might have an in fluence on the course of infections and the accompanying changes in water and mineral balance The intimate connection of the changes in protein metabolismi with disturlances of water and potassium equilibrium during infections makes it necessary to trace the mechanism producing the fundamental protein catabolic responses of the host organism to infectious stimuli The complexity of this mechanism is best shown by the fact that protein starvation which is apt to accentuate the toxic destruction of proteins may have quite opposite effects on the course of 220 ·221 Kuntu Fluid Balance Dunng Infection lectious diseases It is well known from the work of Cannon lo al and others that lack of protein in food deteriorates the status of an infected animal by suppressing antibody formation and thus diminishing the resistance of the organism against infection This effect concerns excluskely the host's organism On the other hand there is ample evidence gained from European experiences during and after World llar II that estreme protein slarvation contrary to expectation does not increase but actually decreases the incidence of infectious diseases (wath the exception of tuberculosis the morbidity of which obeys special lans) to a very conskerable extent Incidence and mortality figures in typhus, typhoid fever diphtheria scarlet lever theumatic fever and bacıl lary dysentery were greatly reduced by lack of proteins in food in Central and Western Furope during the years from 1971 to 1949 17 # and endemic outbreaks of some of the above mentioned diecases vanished spontaneously under these conditions In addition protein stantation increases resistance against in fection with vaccsnia and Heine, who first described polomietis mentions the fact that incidence of this disease is highest in children of well to do families This apparent contradiction may be emplained on the basis of the assumption tbar protein mtake inNuences the course of infections in two opposite ways first by enhancing the defense mechanisms in the host which are mainly meda nied by highly specialized proteins and second by providing the invading bacteria with the nutritne materil necessary for growth propagation and invasiveness Protein deficiency may thus damage the host by withholding the building stones essentia} for formation of antibodies but may at the same time inkubut multiplication of microorganisms and snthesis of bacterial toxins The presalence of one or the other of these two mechanisms determines whether lach of protein has a detrimental or a favorable effect on the infected organisms The complicated interplay of these tno modes of protein action in the field of the host parasite relationship and their repercussion on water and mineral metabolism recurre a more detailed discussion Prolin economy of the exfected organtsm as trifluenced by the pataste There is a great deal of experimental as well as clinical euidence that the invading parasite in generalized snfections deptakes the host of proteins or amino acids using them for is own growth and mustaplication and that protein staration stops microbiological grou th by inhibiting this withdraual or pwotein from the host This holds true for viruses as well as for bacteria Certain amino Heads derived from the protein of the host cells are indispensable for growth of viruses and pinges to v and lack or imbalance of amino aculs us aric ether w suppressing the sequelae ol sirus infection at all or in totigating its clinical The tendency of viruses to accumulate amino acids or peptides 11 the expense of the host tell points to a competition for protein letsees virus und host * 'The lace of rue particles to the cell surface 15 an enzymatic poconcesscatalyzed by a sirus enzime (amaluse) and competitively inhibited by certain muceproteins"occurring ruler aha un kuman milk 25 The potectie at een of human mith against neurotropie viruses may lie of practical salue ** (oram positive bacterit (Siaphosince its Quiksi are capable ul acumulating imino acids thin their cytoplasm aguinst the concentratum kradlient to such in amount that the ratio of internal to external concentration lies between turse ·222 Annals New York Academy of Sciences 10 (tyrosine) and 1670 (proline) This accumulation of free amino acids as to be looked upon as the first step of protein synthesis Gale and his « workers have gained evidence that the process of intrabacterial amino acid assimilation and protein synthesis is the point of attack of many antibiotics The accumulation of amino acids is inhibited by penicillin, the ensuing protein synthesis by chlortetracycline and oxytetracycline The protein losses incurred by the host, brought about by these processes of fixation, growth, and mulu plication of viruses and bacteria, are accentuated by the action of bacterul enzymes, which not only in themselves represent another kind of heterologous hostile protein but, in addition act in propagating infection by destroying dissolved host proteins as well as membranes and other structural elements of the host cells This deleterious effect, which manufests itself more or less exclusively at the protein matter of the host's organism, is brought about by protein splitting enzymes or proteaselile torms Among the numerous bac terial proteases, those of streptococcal origin have been studied extensively my In producing reactions of toxic protein breakdown, they are supported by the enzyme streptokinase, 38 at which combines teversibly with the plasminogen proactivator of the host's blood, thereby giving rise to a peptide splitting enzyme (plasminogen activator) This enzyme transforms plasminogen mto the fibrinolytic enzyme plasmın 2 Several peptides formed by bacteral pro teases are themselves endowed with toxic properties of a hormonelike nature the substances (leukotarın erudin, Pyrexin, “LPP") producing inflammatory reactions in infected tissues are peptides 33 * Simple peptides that may originate from toxic tissue proteolysis in infected areas exhibit permeability increasing properties, acting as pacemakers for the invading microorganisms Their action is supported by a great number of species specific bacterial hy aluronidases that enhance virulence and the spreading of bacterias 37 by in creasing permeability of the host cells, and that propagate inflammation phe , nomena (leukocytosis fibroblast proliferation, formation of exudates and granulomas?) A direct relationship erists between hyaluronidase elaboration by streptococci and their virulence as whereas microbiological hy aluronidases are mainly produced by gram positive bacteria (micrococci staphylococci streptococci) gram negative bacteria are the sources of other enzymelihe in vasive substances with an enormous biological activity These toxins which recently have been isolated from bacteria of the Escherichia coli, Salmonello Eberthella and Shigella groups 63 62 are protein bound lipopolysacchandes acting not only as highly effectne pytogens but also by increasing membrane per meability and capillary fragility with the result of hemorrhagic necroses (Shwartzman phenomenon). In addition, they induce certain host reactions such as leukocytosis, increases in phagocytic actusits, and activation of the pituitary adrenocortical system It is highly probable that the bacterial pro duction of these catalytically active agents represents the essential humusa! mechanism by which the well known response of the adrenal cortex to infer tions and the above mentioned toxic protein destruction in the host are med ated All these effects are clicited by extremely low quantities of bacterial lipopolysaccharides (1 to 3 ug/g), injection of 0 1 & E coli lipopolysat ·Kuhnau Flud Balance During Infection 223 charide, corresponding to 1019 to 10" molecules in an adult min, will produce Intense pyrogen reaction, leukocytosis, and adrenocortical stimulation Prolein economy of the infected organism as tafluenced by odaptation reactions on the host side The most important protein-consuming reaction of the host to infectious stimuli, represented by formation of antibodies from gammı globulins, proceeds along two different lines If it is elicited by toxins that in themselves are of protein nature, it depends upon the action of adaptive en zymes created by the primary action of toxins (Burnet), whereas nonprotein toxins (es pneumococcus polysaccharides) produce antibodies by direct tem. plete action (Haurowitz Breinl) in amounts surpassing the quantity of priming torin by more than a million times However the protein requiring reaction of the host organism to bacterial or virus infections is not limited to antibody production from gamma globulins but, in addition, consists in a formation of a series of speculic proteins and peptides, including members of the arglobulin group (haptoglobın) representing degradation products of mesenchymal glyho. proteins " lysozyme," some thermostable bactertoly sins," "and a great number of nonantibody enzyme inhibitors directed against bacierial enzymes upsetting the host's protein and fluid balance by cell destruction or invasion the great variety of these inhibitors formed under the pressure of the chemical attach comprises a trypsin inhibitor of a globulin character, a trypsin plasmin inhibitor in the arglobulin fraction," " and several antiproteases that are also found in serum in infections and after injection of bacterial proteins 60 61 These antiproteases (for the first time characterized by 1bderhalden") are not antibodies, since they can be proluced by nonantigenic bacterial proteins (topoids) Their relation to the other, mentioned protease inhibitors is still obscure Besides them, the infected host organism is able to elaborate a great number of antihyaluronidases that are partly heat stable and of a peptidelike structure, partly heat tabule and true proteins Large amounts of both types of antihyaluronxases are present in the serum of subjects with acute infectious (liseases, especially in pneumonia and rheumatic fever" " The heat stable streptococcal antihyaluronklases are species and group-specific peptides, thus resembling true antibodies, while the thermolabile antihyaluronidases do not neutralize specificalls the various bacterial enzymes The hyaluronidase inhiltors are of a special interest as regards water and protein metabolism in en for the + 1 na maul-ann AL1 43 4K VILIJAIS LE U u ulju Unu the lidt ellmunt copper takes part in the regulation of serum (p/1501) antihyaluronidase activity, obviously by forming a copper protein complex with strong inhibiting quality 11 here is sonized coprer inhibits valuronal se opls to a limited extents and, in vers los concentrations, even increases hyaluronid ise actiuity copiar in compler bunding especially as a compound containing 1 vitamin P like substance ullavonol or anthocyanin) may reduce blurondise ctitly vers eficiently cien at rather los concentrations (FIGURE 1) The indubition of hyaluroni

·224
25 Faipator
CAPIos tramme DODIE
Ithoixant plex
poosiso, color
prepareetfas complement
Ayersgo normal plus copper
concentration
PIATRA Copper Coricentration may
avate intections
pribyaluronidas
Pese feat Untuda 100
601
DELIRITION
YIOURE
OP VALORIIDEBB BY COPPER
Annals New York Academy of Sciences
Hyaluronic ac free andis.
cond) 5.5 €
Cu 2 compounds 1 ladicated on
TE ABDOBA
Rydzaronite! 1$0 120
0.067 a Terond-cotat mrtar
المفعولهام
FI
Donean
-19
TIE 1

·Kuhnau Fluid Balance During Infection 225 by 100 to 200 per cent The rise of lasma copper in infections may therefors le looked up on as an important defense mechanism against untoward effecte of bacterial hyaluroni lase The phagocytic activity of granulocytes represents another type of defense mechanism operated by the host It depends upon protein intake in so far as the available body protein determines the absolute number of phagocytes as well as their state of ripening phagocytic activity being proportionate to the quantity of granulocytes and the degree of their maturation Phagocytosis itself consists mainly of a series of enzymatic reactions by which the mem brane material and the cytoplasmic proteins of the parasite are stepwise de graded Phagocytes contain highly active proteases and peptıdases of several hunds especially tri and dipeptidases ! Vost of these peptide splitting enzymes display full activity only in the presence of cobalto 6 89 and there is some evidence that cobale offered to the organism mainly as vita min B1 plays a significant role in phagocytosis and defense against infection Indeed the almost complete disappearance of vitamin Bu from the urine in connection with moderately lowered serum Byz values* in patients suffering from febrile infections with leukocytosis (TADLE 1) points to a definite tissue retention of this cobalt containing compound in infections and to an increased requirement for cobalt of the body during fever and enhanced phagocytic actus The ity of the teukocytic enzyme stores, which are greatly increased during in Section This seems to be vahl for serum peptidases too since most of them are also activated by cobalt The degree of protein consumption brought about by the defense mechanisms against infection on the hast s skle must not be overestimated Ilthough there is no doubt that food protein is needed for the compensation of the above men tinnol. IT re ILLIU IL sujustments ( nila minima ) probably hormonal in nature and that it does not interfere generally with the humoral hematological and im The subnormal xtum ke els cost a t shantly. the b ghly read Balucs n myelund leukem a nere ng tono e thatphaporyt CC of leukorytes a thd kax in a boormally low ·228 Annals New York Academy of Sciences 29 SIEDLOS SKY, T&SD ELLIOTT 1951 An electrophoretic study of a streptococcal proteinase and its precursor J Exp Med 94.363 30 C In. h 31 S UI u. IVJI PCCT 10 39 it The art tanahmenlaanant The role of some higher peptides in indammation J Patbal 35 SPECTOR 1 G 1951 Bacteriol 63 93 36 37 38 39 40 schaften 34 59 41 WESTINAL, O LO LLDFRITZ 1954 Chemische Erforschung von Lipopolysacchariden 01 erris er de tellen I 1 # F vi. 45 MOLFF F 19344 On thermostal le bactericidal substance demonstrated in human . AL! 48 CLIPFTOY E I رلیں ورنا ، of serum sone J L. 49 JACOBSSOR serum Sca 50 ABDERIT ALDEN Leipzig Germany 51 MERTEV R 1918 Abucheiermentreaktionen gegen Bakterieneiweiss und Bakterien torn Biochem 7 318 198 52 D CANDIT DPI dorna etrentococcal bra T in- C. 53 111 20a* 56 B Biol Chem 172 347 5. FREEMAN S T F S IT FI & A DURFMAN 1919 Vagnegum and baluroni lace inhibitor of blood serum Proc Soc Tanti Bro! Ved 70 524 6 VIEWER K&V V RAPPORT 1991 The inhil ition of testicul ir hialuronidanel heavy metals Biol Chem 188 485 57 RENANTS A 1931 Untersuchungen uber die inwarkung von Kupferionen und ·66 14 299 o damage and AXIAI STEVENSOY 1944 Some metab kc aspects hematopoietic and immunoclectro horetic circulating piasma protein hematologic huhnau Fluid Balance During Infection 229 llambomplex bildenden Stoffen auf de Hyaluronidase Inaugural Dissertation Dons if SFELDT F ELECTER & HEAT 1955 Unpubhshers TRONE Monatsschr 2 37 03 WEISS 8054 A 1932 Gerne ber die Warkung von Stoffen dir kitam n P Gruppe auf de liya luron, lase Diplomarbeit Hamburg Germany 5) BREYDSTRUP P 1953 On the unsaturated copper dinding capacity of blood serum Scand J Clin Lab Invest 6 18 W KREBS II 1928 lber das Kupferim menschlichen Blutserum Xin Hochschr 7 584 le taux de cuivre du sang dans les infec Compt rend soc biol 139 81 12 CARTU RICHT GE VI LAURITSES P JOXES IN VERRILL&V V INTROBE 1946 The anemia of infection Hysoferremia hyfarcupremua and alterations in morphyrin metabolism in patients ) Cin Invest 2€ 3 LEIDERLING 1948 risen und Kupfer als Markstoffe im Organismus Wed 04 BREV FR W 1948 Bertrage zur Kenntnis des lisen und Kupferstoff vechsels im Serumetsen und Serumkupfer bei akuten und chronischen Infektionen 2 EISS CZARVETRAS 1935 Proteolytic enzymes of monocytic and pok honuclear plural exudates Arch Pathol 30 233 1931 I roteolytische Enzyme in den Leukozyten des Venschen z hysiol Chem 194 137 + FLEISCHER G1 19-5 leptidases in human leukocytes Ann Icad Sci 59(5) 1012 SMITH EL 1948 Studies on dipeptidases III Hydrolysis of methylated peptides the role of cobalt in the activation of glycylgly ane d peptidase J Biol Chem 176 21 VERTEN R 1919 und D-D pxeptidasen in den Formelementen des menschlichen und fierischen Blutes Biochem z 318 185 & HC j) DCBiH S R I HREYS HASHENBRL CNYR WORTHI 1947 Inema of infection Influence of cobait on anemia associated with inflammation Blood 2 323 ROWE JSLY ETCOPY D 13 IL SCANLOX & F STARF 1949 Nutritional status c responses to Sel nonells lyphimurtum infection on a protein deficient diet Lab Clin Ved 33 47 74 RICH fection Bull Johns lloj kins lloer 19 fecular dypetof a dreno cortical damage associated with acute in S TONETTI 1941 Ixperimentelle Bcolachtungen über das Prot dem der Tovinurrkung auf zellulare Substrate 1 harmazie 4 441 76 (OPE CL GARCH LLALRADO 1934 Occurrence of electrocortin in bunan Brit Wel jam 1290 MrNANI 1953 The signibcance of cortisont in an inflamed arca Brit J Ext: Pathol 34 412 8 TROST I V&L SMITH 1953 Influence of polascium salts on efficiency of par enteral protein alimentation in the surgical patient Vetabol sm 2 529 ol DARLING lin urine ·FORTIFIED BROAD SPECTRUM ANTIBIOTICS AS ADJUNCTS IN THE TREATMENT OF SURGICAL INFECTIO\S OF THE 1011G THE AGED, AND THE DEBILITATED PATIENT By Aaron Prigot and Aubre de L Maynard Department of Surgery Ilarlem II ospilal Department of llespills o lock 1 1 The introduction of the broad spectrum antibiotics in the treatment of surgical infections has placed in the hands of the surgeon potent anti inferint agents Because the duration of the acute phase of such illnesses has been considerably reduced, a certain laxity in the total care of the patient has resulted. It is to be remembered that once the acute phase of an infection has been overcome, the reparative process is still in operation and, in large measure s dependent on the nutrition of the patient and on nutritional therapy This latter factor is of even greater importance in the young in the aged, and to the debilitated Since the water soluble vitamins are not stored, the disease process in itsel disrupts the nutritional equilibrium by a reduction in the available nutriert factors through decreased absorption, decreased utilization, increased demand and increased loss of nutritional elements The decrease of nutritional elements available to the patient results from decreased intahe decreased absorption, decreased utilization, and increased loss The loss of appetite produced by inactivity, fever, pain, general malaise gastrointestinal lesions, and antibiotics causes a reduction in the available nutritional elements Gastrointestinal lesions and special diets may also re sult in decreased intake Absorption of nutritional elements from the gastrointestinal tract may be decreased by disease of the tract or by alteration of the bacterial population of the intestinal tract incidental to the prolonged use of antibiotics In a large number of diseases, the efficiency of the liver is considerably im paired, thus preventing normal vitamin metabolism The increased nutritional requirements in stress have been thoroughly documented? ? ? 4 and this knowledge should be utilized in order to avoid such complications as secondary infections and delay in wound healing and con valescence Ilth elevation of the body temperature, metabolic processes are accelerated, and thus greater amounts of the nutritional elements are required Finally, the increased loss of vitamins through the vanous body fluids and exudates makes it imperative that a thorough supportive regime be instituted for the patient The role of antibiotic therapy in the treatment of surgical infections has been firmly established In our hands, orytetracycline and tetracyclinet hare zielded satisfactory results in the treatment of surgical infections, whether used alone or as adjuncts to indicated surgery in They hase shortened appreciably the clinical course of some infections and markedly reduced the • Tb s invest sat on was supported a part by a grade from Chas Pf zer & Co Inc Brooklyn and the * The trade names at Char Pazer & Co Ince for the set to constetracycl se and tetracyd se are Terra myc n and Tetracyo respect rely 230 ·Prigot & Vaynard Antibiotics in Infections incxlence of surgical mtervention Not infrequently, with the judicious use fit these and bonus, the surgical proceduses kere of lesser magnitude than 25e usust in such cases Postsurgical complications have been greatly reduced in lases in which the 2014 otrs nese vsed either for the treatment of established micution or as a prophylactic measure I brief revier of the necessity for nucational therapy in styrss and disease and the pros en orth of anty OLICS IN the prophy lass and treatment of sorgical iníocirans indicast aby a combination of ittamins and antibiotics would supply Lamprehensuely the therapeutic requirements of the patient The anabolics employed on this study were oxyictracycline and retracycline, vulalle both ia capsule formand in a suspetision for padaing use Lach dose < mained 250 mg of the ani.bjotic fortified with the follos ing vitamins ascorbic acid is mg thuasne hydrochlonde 25 mg stolarin, 2. mg, Wscinamsde 25 mg, pyridoxine hydrochloride, 5 mg calcium pantothenate mg, riamo Ne meg falir acid 0375 mg, and menadione (vitamin k alog) 05 mg Adults recented four doses daily and children proportionately less The combination 39 kell tolerated by all patients Is no case were any side reactions obseſsed, nor was wakdrawal of mercation necessitated by allergic or toxic manifestations The addition of the vitamins in no way altered the absorption of the antibiotic 1 The results obtamed indicate sig ficaat yatuma sith the choice of antibiotic 1}} the patients made an eminently satisfactory recovery, wah many re alanrant feruumis being brought promptly under control The ease of ad 33 inistration of the anzbrauc and the nutritional elements, at the same time reduced the number of pills taken by the palent decreased she number of medications to be administred by the nutsing service, and decreased the inct cence of fatlure by the patient to take the presenbed medicalion Despite ተyu { I Tuigny Frve CASES TREATED KITU AV AYTIBIOTIC STAU CONTROV Dagnon ARKT ARE TAPET ol C# Dhuts Team leg Wacants Carbuncie Celluntss of an lacerations biles 1 CNS Brillars a learns Tersirala keputus Vrets reclute o femur Isacfure of his 50-60 20-35 54-05 2.05 1234 58 52-61 Daletes Drug Addictus Chronic myocarditu Chronic myocarditis Dabetes Ricoholm Tenhole Val and sufriren Burns 31 SB Diabetes arteryoeclerotus heart disease sensats to ) ·232 Innnls lex lork lendemy of Sciences malaise pain and other manfestations of severe illness the patients ap» petites and general condition were sitisfactory Complications such as pul monary infections decubitus ulcers and delayed wound healing nere not Encountered Harlem Hospital draws its patients from 1 section of the population economically depressed and living in 1 densely populated area Hence they do not have the advantages of adequate rest sunlight fresh air and good nutrition Mot infrequently on admission to the hospital they present in addition to the acute illness varying degrees of avitaminosis and malnutrition To no group of persons are the words of Pollach and Halpern more applicable In orde to administer marinally effective therapy to all patients the physician fout assume that all patients are somewhat nutritionally depleted 1 Frerne se srely onn nuled fracture of the teleb peal sed olid maled treated by opens red tion auf orytet . ys de tam A comb Da on as prophylax saga nt ne on ·Prigot & Vaynard Antibiotics in Infections 233 The 35 patients chosen for this study presented problems either of severe infection or stress, or a combination of both The cases were selected from among the young, the aged, and the debilitated The various types of surgical cases treated are listed in TABLE 1 Twenty-five patients suffered from various surgical infections Nine cases were complicated by diabetes, six by chronic myocarditis, and three cases by drug addiction Two cases were human bites in teen agers, and three were infected lacerations in elderly people The following case is typucal of the latter group Case lo i JP, a 19 year old man, had sustained a severe laceration of the right forearm six months previously The laceration was sutured, but became infected and had continue to drain This patient was a diabetic on 60 units truztIntett, AV PACOTE DI LO imur wyrar-ok max 1 Letrarul de turn arom! 1 dl on imged to suit Implaint analtheatergraphy kusan est plecen ·234 Annals New York Academy of Sciences of insulin daily The physical examination was noncontributory except for the severely infected laceration of the right forearm a culture from wh ch revealed Staplıylococcus aureus Within 72 hours after initiation of therapy the thick yellos discharge became thin and healthy granulations began to appear At this time excision of a necrotic tendon was performed and there after healing was uneventful In cases of severe fractures in the aged where open reduction is contemplated and a relatively long period of immobilization of the patient is necessary 10 have found that the antibiotic vitamin combination is most excellent It acts both as prophylaxis against infection and at one and the same time supplies the daily vitamin requirement The medication is instituted before operation and continued as long as necessary 1 LEFT 1834 FICTRE? Infe ted fracture of the ne k of the left femu (5 year old dabetc female) treated w his rets jort hed ant botc Snustat nected th Ipadol ·235 Pagot & Vaynard Antibiotics in Infections Illustrative of the good results secured in such cases are the following Case to 2, 3 L, an 8! year-old male, fell out of bed injuring his hap pi (use 1, RII a 38 year-old male, kas struck by an auto on Apni 11 1993 sustainin, a dislocation of the shoulder, a fracture of the left femur tibu and tabula Open reluction of the fracture of the femur was performed anii held in position by an intermedullary nail (FIGLFE 2) Convalescence has been unesentrul Case O HAN 1 58-year-old diabetic female sustained a fracture of the nech of the femur in 1953 She was treated consenatrely, and the head of the femur begin to undergo aseptic necross Two years ago, the area became infected and the patient des eloped a draining suus (FICURE 3) Under therapy, The patient has improvedl and the tract is now almost closed The final group consists of three patients who have endured severe stress and in whom at the same time large portals of entry for infection have been established These patients ranging in age from 7 months to 11 years were CP Al 1 Т. 3 mg scalding with boiling water Physical examination revealed second and third degree burns of the abdomen and left thigh (FIGURE 4) (se lo SV, an 11 year old I ov entered the hospital on Aprs † 1995 INT. * 72 Seven month-old boyth burn ested with fort ett nyelse oral een on ·23.1 Annals New York Academy of Sciences of insulin daily The physical examination was noncontributory except for the severely infected laceration of the right forearm a culture from which re vealed Staphylococcus aureits Ilithin 72 hours after initiation of theraps the thick yellox discharge became thin, and healthy granulations began to appear At this time excision of a necrotic tendon as performed and there after, healing was uneventful In cases of severe fractures in the aged where open reduction is contemplated and a relatively long period of immobilization of the patient is necessary me have found that the antibiotic vitamin combination is most excellent It acts both as prophylaxis against infection and, at one and the same time supplies the daily vitamin requirement The medication is instituted before operation and continued as long as necessary 1 1 LEFT 1834 FICÇEL 3 Iofe ted fracture of the ne 1 of the left femu (55 jear old d abet c female) treated to fort hed ant bot Sous tract nected thl podol ·Ingot & Maynard Antibiotics in Infections 233 Illustrative of the good results secured in such cases are the following Case No 2, J 1, an 81 year old male, fell out of bed, injunng bis hip r! 1) Convalescence was uneventful Case \o 3, R 11, a 38 year old male was struch by an avto on April 11, 1981 sustaining a kislotation of the shoulder, a fracture of the left femur, tibia tric fibula Opxn reluction of the fracture of the femur was performed and hield in [kysition by an intermedullary nail (FIGLRE 2) Convalescence has been uneventful Case lo nech of the the femur be infected and the pattent developed a drawing sinus (FICURI 3) Under therapy, the patient has improved and the tract is now almost closed The final group consists of three patients who have endured severe stress and in whom at the same time, large portals of entry for infectxon have been established These patients, ranging in age from 7 months to 11 3 ears, were Thalaiinternl no 6 il DL. WI. FLIR. 1 month old boy th bound treated oth fort bied cloneckoe org! Call ·234 Annals New Iorh Academy of Sciences of insulin daily The physical examination was noncontributory except for the severely infected laceration of the right forearm a culture from uh ch re vealed Staphylococcus aureus Within 72 hours after initiation of therapy the thick yellow discharge became thin, and healthy granulations began to appear At this time, excision of a necrotic tendon was performed and there after, healing was uneventful In cases of severe fractures in the aged, where open reduction is contemplated and a relatively long period of immobilization of the patient is necessary me have found that the antibiotic vitamin combination is most excellent I acts both as prophylaxis against infection and, at one and the same time supplies the daily vitamin requirement The medication is instituted before operation and continued as long as necessary 21 LEFT 1834 FIGURE 3 Infected fracture of the neck of the left femar (58 year old d abet e female) treated u th st fort med ant bos Snus tract nected wth Ipodo!

·Prigot & Vaynard Antibiotics in Infections 235 Tlustrative of the good results secured in such cases are the following Case lo ? JL an 81 year old male fell out of bed, injuring his hip Thusıcal eramination revealed senihty arteriosclerotic heart disease and a Omminuteil intertrochanteric fracture of the femur The fracture was reduced and held in position with a Smith Peterson nail and a VicLaughlin bar (FICURY Con alescence was unes entful Case lo 3 RH a 38 year-old male was struck by an auto on Apsal 11 1 1) sustaining a dislocation of the shoulder a fracture of the best femur tiba and fibula Open reduction of the fracture of the femur was performed and Ield in position by an intermedullary nas! (FIGLRF 2) Convalescence has been uneventful Case To HAV a 58-year-old diabetic female sustained a fracture of the nech of the lemur in 1953 She was treated conservatively and the head of the femur began to undergo aseptic PCIOSIS Two years ago the area became infected and the patient developed a dramning smus (FICURF 3) Under therapy the patient has improved anrl the tract is now almost closed The final group consists of three patients who have endured severe stress ani in si om at the same time large portals of entry for infection have been establishedi These patients ranging in age from 7 months 10 11 years were Camel 1 nat Then ક ng scaiding with inoxling water Chysical eramination revealeri second and third degree burns of the aldomen and left thigh (FirURE +) Case 1 OS Y nn 1 year old boy entered the houputal on April 4 199) FGRE & en fronth J boy #th bara fret edith for ed Estrary I ne on a xotion ·236 Annals Neu York Academy of Sciences FIGLZS Ee en year old boy r th burn of chest teated * h tetrag cunts tam no alsu non after his clothing caught fire He sustained 19 to 20 per cent second degree burns and 1 per cent third degree burns of the chest and abdomen (FIC CRF 5) Case lo 7I H 15 year old boy, was admitted on April 21 1933 having received a 2 to 3 per cent second degree burn and a 6 to 7 per cent third-degree burn of the night leg when his clothes caught fire (FIGURE 6)

·Prigot & Vund Antibiotics in Infections
237
FC16 Fyea olluny h burn tres edote > I ne
Lam Domb na or as an oal up on
Summary
The role of nutritional therapy in stress and disease has been throughly
established
The broad spectrum antibiotics orytetracycline and tetracycline
have proved their worth as adjuncts in the sure cal treatment of established
1
1
In our experience the addition of the vitamins in no way interfered with the
absorption and antibacterial action of the antibiotic The combination was
well tolerated No allergic or si le reactions were observe!
TE
or injection or a combination of stress and infection These patients made
fapid recovery without complications of secondary infection delay in sound
healing or retarded convalescence
The case of a Iministration of the combination of vitamins an antibiotic
.
1
(5)
The combination of the antibi tics orytetracycline and tetracycline with
Sitamins represents a decided advance in the total care of the young the aged
and the debilitated suffering from diseises insolving stress an i infection

·38 Annals New York Academy of Sciences References 1 SELTE 11 1930 Stress Acta Vontreal I l. Canada 2 SELYE HI 1916 General adaptation syndrome and d seases of adeptat on J Cin Endocrinol 6 117 * TEVENSON SIW GREEN TIL TASLOR P ROBINSON R C PAGE, R E JONSON & CO LUND 1916 Ascorbic acid ri oflavin thiamine and n'cotine acid in relation to sciere injury hemorrhage in 1 infect on in the human Inn Surg 124 810 4 ANDREAC A&J SL BROWAF 1946 Vitamin metabolism following trauma Can Vedt Assoc j 66 425 5 A1 TT 11 1. Inr: r w 1 61 7 PEREIRA Nieves L ist Tetracycline hydrochloride as an adjunct in the surgical Discussion of the Paper Doctor \\ ADRIAN FREEMAN (Department of Surgery, Ilarlem Ilospital, do ork, \ I ) I wish to thank Doctor Prigot for the privilege of reading and discussing his fine paper on supplementary vitamins in the infected and debil tated patient Many of the facts he has presented here have been observed on our service This is a well balanced study and will stimulate interest in the profession to study more thoroughly nutritional problems in health and dis ase For many years at Harlem Hospital, we have given supplemental vitamins by mouth intramuscularly or intravenously, to all patients on the Fracture service To name a few that have been used throughout the years breners erst, hematinic capsules thiamine hydrochloride, B complex, vitamins A B O G, folic acid tablets, Berroca C, and injectable liver extract Our patients are drawn from an overcrowded and cconomically depressed ection of the city In addition to patients from the immediate area, we also eceive indigent elderly patrents from other hospital districts These patients Elo not have adeguate diet, fresh air, or rest It is therefore inevitable that they are already suffering from borderline nutritional deficiency and secondary inemia fall from Many of time Hlespite all our efforts for early ambulation The increase in the age of the general population is reflected in the large number of our patients who are over 20 years of age ·Prigot & Maynard Antibiotics in Infections 234 finally, many of our cases are admitted with many forms of assallat discase-diabetes generalized arteriosclerosis, peptic ulcers for Clamp which have been long neglected because of economic factors Ilarlem Hospital is a very busy hospital On our fracture wards we ni hare as many as 15 to 20 patients with severe fractures This throws Liet strain on the nursing facilities The stress fortified antibiotics given in medication thus reduce the amount of work required from the nurses diir 1 assure the proper functioning of certain enzyme systems invoked in the re live process DOCTOR ARTHUR L GAR ES (Department of Stergery Ilarlem ll I ork, I ) The comments made by Doctor Freeman concernin 11 (T are equally true of the plastic surgery service le see a large nun! H1-1-1 4 Oral - 1 ill, suffering from pain, general malaise, debility and loss of valuable ! ut surface and body fluids These factors necessitate prolongeel jurt bed It is therefore of paramount importance that every available her! a supportive nature be administered in these cases lle have found that the stress fortified antibiotics, especially stress fortified tetracycline as all oral sus pension are extremely valuable in the treatment of our pediatric cases With the use of this combination, there have been ferver instances of secundary infet tion and no delay in convalescence The combination is well tolerated and thus se are assured that the patient receives and retains the medu ston ·VUTRITIONAL AND METABOLIC ASPECTS OF INTECTIOV By Laurance W Kinseli Institute for etabolic Researc) Highland llameda Co inty Hospital Ouklond Cold Many of the contributors to this monograph are vastly better qualified than I to discuss nutrition in relation to resistance and immunity to infection Ms remarks are confined to tuo fields (1) the place of corticoids* in resistance to infection in particular and stress in general, and (2) the relation of specific nutrients to pituitary adrenal function Infection and the Pulurtary Adrenal Axis Tour major sets of observations exist in regard to the place of the adrenal cortex in the over all picture of resistance to infection (1) It has been well established that the resistance of the Addisonian patient or the adrenalectomized animal to infection in particular, and to stress in gen eral, is markedly diminished 1 (2) This resistance is changed very little in animals or humans maintained with desoxycorticosterone Maintenance with cortisone or hydrocortisone however, brings the resistance essentially to a normal level 2 (3) Under appropriate experimental conditions, the administration of phar macologic amounts of corticoids to experimental animals receiving inoculations of pathogenic microorganisms results in increased mortality a (4) The combined administration of corticoids plus indicated antibiotics to critically ill patients under properly controlled conditions, appears to result in diminished morbidity and mortality On the basis of superficial evaluation, the above statements would appear to be confusing and contradictory Actually, shen properly evaluated, they are neither (see below) Established Physiologic and Pharmacologic Effects of Corlisone and Related Compounds (1) Regulation of energy metabolism In the absence of the adrenal cortex, there is major impairment of neoglucogenesis, hepatic glycogen storage, carbo hydrate oxidation, and, probably, fat oxidation's (2) Regulation of cardiovascular renal dynamics In the absence of the adrenal cortex, there is progressive diminution in the blood volume, contractile power of the heart and glomerulotubular function Corticoid administration cor rects such abnormalities (3) Modificalton of the inflammatory reaction Pharmacologic amounts vi $ art cone ficial or extremely dangerous (see below) (4) Inhibition of the effects of certain bacterial endolo rius This effect appears The term cort codsused in th s paper to Laclude ACTH cort sone and hydrocort sobe 240 ·Kinsell. Nutritional and Metabolic spects 241 to be well established? It is probably a major component of the over all "non specific antitoxic effect" of administered corticoids (5) Inhibtion of bacterial growth such an effect is a produced by any corti coid (6) Inhibition of specific antibody production Inder appropriate experi mental conditions, such an effect can be clemonstrated! \\hen corticoids are used properly in the management of infectious decise in the human such an effect either does not occur or is of such minimal legree is to be of no clini cal importance Vany other effects of cortisonelihe compounds may plas some part in the Over all picture of resistance to infection The present rise ussion, however, will be limited to the above The Use nf Corlicords in the Clinical unig ment Patients with Infectious Diseu There are three types of application of corticoils in patients (1) Replacement therapy in the patient with knew pintarv » adrenal insuf ficiency, 1 e, in the patient with Sheehan saundrome rllions dease In such individuals, one uses constant maintenance there the average dosage being 25 mg of cortisone acetate and 2 mg of buual de corticosterone ace tale daily, or 300 to 1500 ug of Ia fluorohydrocortis ne du Such medica tion in the Addisonian patient produces a state cila e to infection com parable with the normal 11hen infection actually occurs in these patients the longe of corticoids must be increased, on the average, to 100 mg ortisone lul or its equna lent Increase in the dosage of desory corticosterone in rarely required \\hen the infection has been controlled with antibodies the list is gradually reduced to the preinfection les el over a period of three to seven days (2) Prophylactic corticoid administration in indırduils eithe suspected partial be in the form of infectinn, operative trauma thermal dimage or the like That some individuals respond less sell to stress than others is common hnowl edge Whether such differences in response at least on occasion may be the result of relative pituitary adrenalinuclequicy - by no means clear It seems highly probable that this phase of the problem will be clanited during the nett fuo cars in the interim, one has occasion at times to answer the question Should John Smith, aged 65, who is less than 1 rugged individual, receive some supportive therapy to help him withstand a severe infection and or a major surgical procedures" lo unequivocal answer is possible at the present It would seem to us howeser, that one might set up the following tem porary "ground rules" (1) Jormally robust indispluals should not recente cupplemental corticoid therapy, except in the presence of dsre and overshelming emergency conditions time (see below) ·242 Annals New York Academy of Sciences (2) In patients such as the John Smith noted above, the use of a modest dos age of corticoids, eg of the magnitude one would administer to an Addisonian patient exposed to stress, has little likelihood of producing harm, and may be of some real value (assuming that the patient has been well screened for the presence of contraindications to corticoid therapy) Casual use of corlicords :s contraindicated in any induidual under any circumstances (3) Corlicoid administration in the presence of overwhelming anfechor This +421 2 circumstances, intensive corticoid administration, as the result of its antishock effect and nonspecific antitoxic effect, enables one to "buy time" until such time as the specific antibiotics have a chance to eradicate the offending organisms and the body has an opportunity to produce specific antibodies The standard emergency programs used in such patients are shown in FIGURC 1 The details of such therapy are discussed elsew here * Relationship of Specific utrients to Pilulary Adrenal Funchon One would anticipate that relative or absolute deficiencies or ercesses of spe cific nutritional factors would bear some relation to endocrine function Well known examples would be the changes in thyroid structure and function associ ated with iodine deficiency the change in functional activity of the B cells of the islets of Langerhans with variation in the relative and absolute concentra tion of carbohydrate in the diet, and the hyperplasia and hyperfunction of the parathyroids that can be produced by prolonged calcium and phosphorus der rivation From the standpoint of response to stress, the importance of knowing the effects of specific nutrients upon the functional activity of the pituitary adrenal axis is of obvious importance In FIGURE 2 is shown diagrammatically the relationship of some of the im portant exogenous and endogenous factors to the cell exposed to infection or other stress Nutritional entities play a double role Their availability in the proper amount is essential to the integrity of the body cells per se 'They are equally essential to the normal structure and function of the pituitary adrena) axis which in turn constitutes part of the major defense machinery of the body One must preface any discussion of the relationship of specific nutrients to adrenocortical activity with the statement that the total body of knowledge is still far from complete The following statements, however, appear to be rea sonably well documented (1) Sodium and potassium are vitally concerned with the level of adrenocorts cal function sodium deficit or potassium excess everting a stimulating elect and vice versa' (2) A diet adequate nutritionally, but containing small amounts of carbohydrale and large amounts of protein, results in adrenocortical stimulation' (3) Prolein deficiency results in diminished adrenocortical function The adrenal cortices of protein-deficient animals, however, are normally responsive to erogenous ACTH & ·Kinsell Nutritional and Metabolic Aspects 243 "SHORT PROGRAM FOR COMBINED HORMONAL ANTIBIOTIC THERAPY 401 IM ACTH 20 USP UNITS/DAY GIVE ANTIBIOTICS THROUGHOUT AND FOR 3 DAYS AFTER LAST DOSE ACTH 40 IV ACTH 201 USP UNITS/DAY 1 LM CORTISONE 300 ACETATE 1501 MGM/DAY IK HYDRO- CONCENTRATION-1OOMGM/500CC * CORTISONE 100 MAMBAY RATE (ADULT)-250 CC/HR DAYS 2 3 "LONG PROGRAM FOR COMBINED HORMONAL ANTIBIOTIC THERAPY 40 IM. ACTH 20 USP UNITS/DAY 40 GIVE ANTIBIOTICS IV ACTH THROUGHOUT AND 20 FOR 3 DAYS AFTER USP UNITS/DAY LAST DOSE ACTH TV HYDRO 2007 CORTISONE 1001 * MGM/DAY IM CORTISONE 300 ACETATE 200 MGM/DAY 1001 COTCENTRATION-ROOMGM/500CC RATE-250CC/HR-FIRST 500 CC LADULTH-100CC/HR-SECONO 500CC DAYS 1 2 3 4 5 6 7 PROPER APPLICATION CAN BE LIFE SAVING IMPROPER USE CAN BE LETHALI * IN ADDITION TO FREE HYDROCORTISONE BY INFUSION, HYDROCORTISONE (AS THE HEMISUCCINATE) MAY BE GIVEN STAT -100 MGM DISSOLVED IN 2CC OF WATER Standart hormonal antibot c therapy The Inur das imam ved in more than o ser Firtis 1 cent of patinis enous \CTII Quile marked morphologic changes have also been demonstrated in the ad renal cortes in choline deficient rats during the period of actre renal patholog). The adrenal corter tends to return to normal as resolution of the renal patholog occurs 10 ·244 Annals New York Academy of Sciences (nutritional) FACTORS EXOGENOUS Calories Amino Acids A NHL "Vilaminy unsaturated Telly Acids N N Electrolytes (NK, ci etc) Minerals ots essertsal t. popiration (F. MA HORMONES INFLAMATIUN Specific Immune Boditt Antiarn antibody ENDOGENOUS FACTORS Infection - Factors concerned in the protection of the cell FIGUIE 2 Exogenous and endogenous factors that cond to the ab I ty of the cell to w tbstand njury min A 12 (5) l'rlamın 1 deficiency can be associated with a significant decrease in abı ity to withstand stress It is still to be established whether cortisone will pri tect vitamin A deficient animals against the effects of stress An increase in adrenal weight has been reported in rats fed large doses of viti On the other hand, adrenal hypertrophy has been reported in tł presence of vitamin A deficiency 3 (6) Atrophy and reduction in the fat content of the adrenal cortex apparent! associated with impaired ACTH secretion, has been reported for ratsut hypervilaminosis D 14 (7) The relationship of zitamin C to adrenocortical function is considerably less than clear The following points, however, appear to be established (a) Under normal conditions, vitamin C is present in unusually high concen tration in the adrenal corter 15 (b) The cortical steroid content of the adrenals is markedly diminished in the scorbutic guinea pig 16 (c) Scorbutic animals have adrenals which are markedly depleted in ascorbic acid but normally responsive to ACTH " (d) There is some esidence suggesting that ascorbic acid improves the utiliza ·Kinsell Nutritional and Metabolic aspects tron of cortical hormones, and hence may decrease the requirement for ACIH stimulation under stress 18h 18 Thatever the final answer may be to the relationship of vitamin C and adre nal steroids, there would appear to be no question that ascorbic acid is not ry sential to a high level of adrenocortical function (8) Thramine deficiency appears to be associated with increased pintary adrenal activity The magnitude is greater than that which occurs et smple caloric deficit 19 with dimimushest ici luco corticoid adm (10) Pantothenic acid deficiency results in reproducible histolul al norn ties in the adrenal cortex These changes are most marked under enli of acute stress 19% 39 The mechanism of these changes and their lun! sgnificance is still unclear (11) Pyridoxine deficiency is associated with diminished resistance ! but again, as in the case of riboflavin, it is still to be establishe i shether attributable to a specific effect upon adrenal activity ulrltonal Requirements During Intensite Corincond Therapi T! tion The special principles that apply to nutritional management under these conditions, center about some of the efects of pharmacologic dosage of the coricoids-namely, increased protein catabolism sodium retention potassium diuresis, disturbance in carbohydrate metabolism and the production of ostea porosis Consequently, the diet of the patient receiving corticoids is high in protein, relatively high in calcium and phosphorus low in carbohydrate ade quate in calories low in sodium, and very high in potassium Since detasled the normal requirement of all these entities We have some observations that suggest that lire amounts of nucleoprotein slould be administered routinely to these patients This statement rests on 1 In meno catabolic effects of the corticoxs ire crerted most particuliers upon tissues ou ahh ratio of nucleus tn citoplasm teę tle thymus) Whether the use of pharmacologic amounts of sitamur J) wilt leven the tenu ency to net calcium and phosphorus depletion is still undetermine! pausal women anal in older men analle sterorts should alwais le coadmin stered to attempt to present such depletion Intensne corticoul therapy should not be ena luzeal in jutients with mutually fmor nutritional status unless such therapy is mandatory licorticoid therapy ·246 Annals Nen York Academy of Sciences is unavoidable (as in the case of fulminating periarteritis, dermatomyositis etc) prophylactıc" broad spectrum antibiotic therapy should always be co administered in addition to the use of the nutritional program noted above The increased hypersusceptibility to infection that characterizes malnourished patients who are receiving corticoids is probably attributable to a variety of factors which include prominently the inhibition of the inflammatory reaction diminished production of antibodies, partly as the result of the increased pro tein catabolism (this statement applies only to malnourished patients) in creased tissue edema with consequent tissue anoxia and diminished cellular resistance Summary The pituitary adrenal axis has been shown to play a major role in the indu vidual s response to infection, as well as to other forms of stress A variety of nutritional factors are concerned in both a specific and nonspecific fashion, with the functional activity of the pituitary and the adrenal, as well as with the metabolic effects of the corticoids Until our knowledge in this field is more precise it may be well to accept the thesis that a diet is compatible with optimal ACTH and adrenal steroid production if high in protein, adequate in calories moderate in carbohydrate, and adequate in as orbic acid and members of the B complex with particular reference to pantothenic acid In the individual with increased endogenous adrenal cortical activity as the result of infection and even more in the individual with infection who requires supplemental corticoid therapy, it is of the greatest importance that full at tention be paid to proper nutrition and antibiosis Under these conditions proper nutrition, in addition to the entities noted above, includes also hmitation of sodium and intensive supplementation with potassium chloride References 11 P1 1 SC 2 R r . 34 л 41201 3h ( 3c1 315 +1 } I ncycloped a Inc Ten ork ! 5 MINSELL 1GD VICHELS S V HRCES HPIRTRIDTE I BOLING & E. Всін 1937 The case for cort cal steroid hormone accelerat on of neon lucogeness from fat in diabet c subjects A summary of fie scars imestigatnes urh i chon In locrinol and Metabol sm 14 161 176 ·Kinsell Nutritional and Metabolic Aspects T 107 1 b pe tension of subtotally nephrectom zed rats Am J Ph vol 1623 10 OLSON RE & DELE 1949 Physiological and cytochem cal tud and adrenal cortex dur ng acute choline defic ency in seanl ng rals 31 SS 11a 3 11b ment of rat T 11c ER. HOPF BI Proc Soc Lept 12 SADI U DP 1 ptu tary Amst you 2W UU 13a weights of en 131 ndohr nen Dru nahot 174 339 31 Hartge ebe un 14 28 494) 1 SEVI GORGY 1 1928 Observat ons on the funct on of the chem stry of the ad enal corter Descr pt on of nesc Bochem J 22 1387 1409 162 GIROLD AXN SANTA 1939 Absence d hormone cort ca e 191 -- h - VA D SANTA MARTINET & VI BELLON 19 1ҹп 18h 1 18 ( Il sur II 135 19 DEAVE HI & JH STAW 1947 Cytochem cal stul o regronses of adrena cortex of rat to tham ne boflavin and pr dor ne d fic e ces | Autre on 34 1 19 196 SXT T na nry - 20 7 1 1 1 R Cont on 3 F X UTC ·248 Annals Nen York Academy of Sciences Discussion of the Paper DOCTOR MOSES M SUZNAN (Johannesburg General Ilospital, Johannesburg, South Africa) In a consideration of the problem of nutrition in infections, one of the first questions to be answered is that pertaining to the susceptibility and resistance to infection in the presence of malnutrition In other words, is a malnourished individual more susceptible to infection than the normally nour ished person, and, having contracted an infection is he less able to withstand ut? All other contributors to this monograph hase pointed out by anımal ex perimentation that certain dietary deficiencies increase or diminish suscepti bility to certain infections, thereby influencing resistance According to some investigators, this can be explained, at least in part, on biological and genetic considerations and characteristics of the particular species, or cien of different strains of the same species So that, in my opinion, these findings on the whole can hardly be applied to man Trom experience with people suffering from frank deficiency diseases as pellagra, I have gained the impression they are not particularly susceptible to infectious disease and that they are able to combat infection once established-1f not better than, at least as well as normally fed subjects I should Ishe to illustrate this point by describing two cases of pellagra The first patient was rather badly involved with pellagra, and he also hap pened at the same time, to have a very large postpneumonic lung abscess, as seen by X ray examination Despite this, he did not appear to be particularly ill clinically and he made an unes entful complete recovery in a short time on treatment with nicotinic acid and sulfapy ridine It might have been thought that, having severe pellagra, his recovery would have been delayed, or that he might not have recovered at all His resistance had been goor The pellag rous lesions disappeared, or largely so He showed very severe pellagrous lesions on his face, lips nose, and eyes, and yet he wathstood a severe infection indeed The second case had deep lesions such as are found on the feet of pellagrans Despite being exposed to the infection of the roadway while walking barelooted the lesions of this patient failed to show any signs of secondary infections Cultures made from scrapings of the rau surface, which were deep and extended down to bone, were sterile In nutritional deficiencies involving the B complex, endocrine glands and putuitary have been shown to be depressed, and it could be reasonably expected that systemic effects would be increased This is not the case One must er plain the increased resistance and diminished susceptibility of the patient on the basis of low cred virulence of invading organism due to change of environ ment In other words in some dietary deficiency diseases, it seems that the essential nutrients lacking for the host's well being are also those that are needleil to maintain the growth of invading organisms It may be argued that, by correction of the deficiency of the host and anal vertently of the invader, the infectie process would be encouraged It seems that this might be the test In other words, by improving the subject's nutri tional state can his resistance to infection le increased" ro go further, one may ask whether, in a patient harboring infection and considered to be-or thought likely to become-nutritionally deficient, us it ·Kinsell Nutritional and Vſetabolic Aspects 210 or justifiable to prescribe essential dietary supplement without appropriate antı brotic cos erage? That represents the symposium in reserse and cannot be answered but warrants future study This leads to a more important problem namely, the intluence of infect: >n nutritional status of the patient Although it cannot be shown that malnuts tion favors infection since under certain circumstances it may even disc unul or present it there is little doubt that infection itself intensifies poor nutrition that is that it favors the development of dietary deficiency states 132 year-old Bantu male in August 1939, was admitted with very breathlessness, palputation edema, and signs of advanced cardiac failure examination he was found to have consolidation of the right si le of! LI 1) dine, with improvement in the lung condition This case indi cipitation of acute beriberi heart failure may occur in the infection especially in that, previously, he had been on an u a le u therefore was on borderline nutrition state young Chunese boy, aged 15 had advanced and severe failure for which no cause could be found At the time te! 1 unknown cause The diagnosis of beriberi heart failure was a los treated with thiamine hydrochlonde, with marhed diuress in few days later it was realized why he had ſever is malar al found in the blood This was an example of a boy prew uslys quate diet precipitated into acute beriberi beart failure by 11 Lint It can be seen therefore, that in the presence of borderline nu TE acute detary deficiency state and replacement therapy are id st! development of such deficiency may be anticipated however 113 11er prevented by prior administration of vitamin supplements and extr nutra! especially when a borderline state of nutrition is suspected be ause 1 thels tory of dietary inadequacy, the erressis e consumption of alcohol perts Other examples of acute nutritie failure precipitated by infettions includle tis and in some 11 age or other causes ho at the onset sually insæl ous of nutritional deficiency syndrome unless preventive measures are adopted The mechanism for the development of nutritonnal failure in the presence of depletes the host of its los scores of available nutrients also perhaps because the pat ent s level of metabolism has been raised us the infection thereby in strasing the requirements of essential nutrients beyond the body s avulable supply ·250 Annals New York Academy of Sciences This brings me to the last point which I want to discuss, namely, the hor monal status of the patient with particular emphasis on adrenal cortex, already referred to by Doctor Kinsell, with whose remarks I am in complete agreement In the course of infections, although the inflammatory reactions-that is re activity and production of immunc bodies-re two essential protective mecha nisms they do not always succeed in preventing irreparable damige to tissues or organs not infrequently, fatal results Tlus damage is due not necessar ily to direct destructive effects of the invading organism or its tosin, but to the continuing and persistent excessive reactivity set up by the host s tissues to degree and extent far in ercess of what ordinarily should suffice to withhold the ravages of the infectious agent In other words the reparative process itself may prove to be the lethal factor Thuis heightened degree of inflammatory activity may occur despite the fact that antibiotics, in seemingly adequate dos nge are being administered, and the identity and sensitivity characteristics of the causative organism are known This ineffectiveness of antibiotic therapy is not necessanly due either to nat ural or acquired resistance of the causative organism to specific antibiotic agent or to insufficient dosage Some other intrinsic factor or factors must perforce exist through which are determined the degree and persistence of the tissue hy perreactivity as well as the accompanying exaggerated systemic and consti tutional effects Trom available data and from Doctor Kinsell's studies, it would appear that in some way the adrenal cortical function is involved There is either lack of hormone production or relative insensitivity of the inflamed tissue to existing amounts of circulating adrenocorticoids, amounts which in normal circum stances would be sufficient Whatever may be the nature or cause of tissue hyperreactivity and the marked systemic manifestations so frequently seen in these severe infections the use of ACTH cortisone, or hydrocortisone and, more recently, of the dela 1 dehydrocortisone preparations, which, incidentally, have a sery high anti inflammatory effect, will frequently succeed in affording sufficient suppression of these exaggerated reactions Needless to say whenever possible, appropriate antibiotic therapy in a de quate dosage and for a sufficient period of time must be used in conjunction with adrenal corticoid medication The latter, however, can be resorted to, i need be and relied upon as the main therapeutic measure when the spectfic antibiotic agent for the particular infection is not available or when the causatile in fectious agent has not been determined or is unknown Foretample, in various virus infections and other inflammatory diseases of unknown cause, when the life of the patient is threatened by an overwhelming or uncontrollable infection or from its complications adrenal cortical therapy should not be withheld on the theoretical grounds of the presumed consequent danger of the spread of the infection Under these circumstances the infection has already spread This applies no less to tuberculosis of the miliary, meningitic, or bronchopneumonic type than to any other type of severe infection It must be appreciated in regard to tuberculosis, that effective antibody coverage is fortunately available and this should meet any objection offered Besides, the principle is no of

·No text on this page.

·Untershy of Vetol ork College of V[edicine Yato 1 orkledicine Sla ANTIBIOTICS AND NUTRITIOV IN INFECTIOUS By Max B Milberg and Max Michael, fr 1edical Services armonides Hospital Brooklyn 11 and Department There is a voluminous and conflicting mass of data concerning interrelations between antibiotics and nutrition in various infections, both acute and chronic Since the subject is of extreme interest from clinical and biological standpoints it seems worthwhile to appraise the known facts and to focus attention further on some of the lines of thought currently being pursued All avarlable data implicate the seriousness of vitamins A and B compler deficiencies that have occurred with prolonged use of chemotherapeutic agents and antibiotics These deficiencies could result from (1) elimination of intesti nal bacteria that normally synthesize the vitamins and B-compler group (2) the diarrhea and vomiting that may result from antibiotic administration or (3) the anorexia and subsequent diminished food intake that can result from the infection itself or from antibiotic therapy Thus, it is possible that in certain chronic debilitating diseases such as urinary tract infections, pulmonary infection, ulcerative colitis, bacterial endocarditis, tuberculosis osteomyelitis elc, where normal nutrition has already been threatened, further protracted antibiotic therapy could cause greater nutritional havoc Only during the past quarter of a century has our knowledge of nutritional therapy progressed be yond the empirical recommendation of a "nutritious diet" in certain debilitating diseases A concept. * of disease that emphasizes the phenomena common to all mals dies irrespective of etiological considerations and that accounts, in part, for the nonspecific effects on metabolism that are essentially the same in all diseases whatever the nature of the primary etiologic factor, is concerned with stress This concept of disease describes a tripartite reaction-alarm, resistance, ex rodromal and or TL cause of the dissemination of bacterial toxins, the febrile reaction, and the at traction of defense cells The defensive and reparative processes that are mobilized whenever systemic stress is imposed are mediated by increased pituitary elaboration of adrenocorticotropic hormone (ACTH) which, in turn stimulates the adrenal cortex to elaborate its hormones, chiefly the gluco corticords or antiphlogistic bormones These endocrine functions depend to some degree on the nutritional status of the individual Conversely, the results of endocrine action profoundly affect the absorption, utilization, and ercretion of nutrients as well as the requirements for specific dietary factors * Body requirements may also be significantly increased by the increased metabolic demands increased metabolism of carbohydrate to provide energy calls for an increased caloric in take and an increased intake of all nutrients concerned with carbohydrate me tabolism It is desirable to provide sufficient carbohydrate capable of sparing pro- 252 ·Vilberg & Michael Antibiotics and Vutrition 253 1 1 some question as to whether a positive nitrogen balance can be restored by these means There is much experimental and clinical evidence to support a belief in the value of a high protein intale in conditions of stress As a corollary it may be stated that those vitamins known to be of importance as units in enzymes con cerned with protein metabolism must also be provided in increased amounts because of their greater utilization in this function. These vitamins include riboflavin macınamıle pyridoxine pantothenic acid folic acid and Br '13 Thiamine and niacinamide play a role in carbohydrate metabolism and they are recommended in greater than normal amounts for use in acceleration of this function " 15 Because of the interrelationships between almost any two of the essential vitamins 1it is probable that the optimal effect of a single vitamin given in large doses cannot be exerted unless the supply of all others is propor tionally increased Both ascorbic acid and pantothens acid ' appear to be essential in the met abolic functioning of the adrenal cortex If their intake is not increased suffi ciently during periods of stress it is theoretically possible that response of the adrenal cortex may be impaired* • lanous nutritional deficiencies notably of ascorbic acid and pintothenic acid may themselves constitute causes of stress The in urro synthesis of essential vitamins of the B-complex group and of vitamin his well documented 19 " In recent years there has been a growing realization that the commonly employed antimicrobial agents can interfere with the synthesis of the B complex vitamins and oi vitimin Dalt and Sebrell have reviencil this subject as it related to the sulfonamides and have recorded many instances of vitamin K and folic acid deficiencies occurring in patients treated with these agents Deficiencies of this kind resulting from the ad ministration of sulfonamides have been observed in normal subjects receiving d normal diet, indicating that vitamin production in the body is important to its economy Deficiencies have resulted from administration of other anti microbul agents I encilhn has resulted in the precipitation of niacin defi ciency and chloramphenicol in nacin folxc acid B, and vitamin A deficien Crytetricycline and chlortetracycline bave also resulted in deficiencies of vitamin riboflavin niacin Bir and folic acid 2577 By replenishing vita mus in such drug induced deficiencies it has been possible in many instances correct these manifestations ? Ilhat role this pliss in the ultimate re str from the infectious process in manis dullicult to assens 11 loc reson 1, woull-ulet that it is important In this forelimary studs we were nterested in caluiting the clinical cl luctueness is well as ans ontos ir reactions that might be encountered with We www.sav of my limizcline wide with hersker sowie Siimins originalls designatel a Terramycin formula \o 1 and 1ctracın Immuli \o I now entitied as Terrimycin Sl and Tetracın ST reactivels Is antiupatel (see TIRLF 1) the addition of the water soluble vitamins did (les - ·254 Annals New Yorh Academy of Sciences TABLE 1 CLINICAL RESPO\SE TO TETRACI SF Response Dagno lo of pas ents treated Aserare Joxe gm /day lo of days treate Sat factory nate Inde Coal term islactory 1520 57 man 20 5 12 2 20 7 10 20 10-14 Icute pharyngitis and tonsillitis Streptococci Others Laryngotracheobronchitis (no culture) I'neumonia Pneumococcic Bronchopneumonia (no culture) Viral Urinary tract infection Salb is E col: P's aeruginosa Proteus garis Soft tissue infection (Saurens) Cellulitis (no cultures) Pyoderma One culture-s aureus Soft tissue abscess (with I & D) S albus Saureus No culture Perrapical tooth abscess (no culture) 1 2 20 20 7 7 10 5 3 1 520 8 10 3 1520 7 بها 20 Total 45 39 5 not alter the clinical or antunicrobial effectiveness of the contained tetracycline The responsiveness is comparable to our previous studies with tetracycline alone and to those of other investigators 13 8" It is to be noted that the stra) pneumonias did not respond Three patients with urinary tract infections, tuo with Proteus and one with Pseudomonas aeruginosa had received, on previous occasions all of the broad spectrum antibiotics singly or in combination The infecting organisms were resistant to all the broad spectrum antibiotics One patient with a Proteus infection, Weyer, had a successful clinical course, be comin asymptomatic and afebrile, and with a diminishing pyura, in spite of persistent positive urine cultures for Proteus with demonstrable in tilro re sistance to tetracycline The patients with acute clinical illness resulting from either indefinable or sensitive pathogenic organisms responded satisfactorily within 24 to 48 hours In these patients with acute allness, there was no inci dence of a better response or of a better clinical status at the conclusion of therapy than would be expected with Terrimycin or Tetricn alone Is seen in TIBLE 2 33 patients were gren 1 5 10 2 gm of Tetracy n St 1x to 14 days orally In most instances antibiotic therapy was indicated and in those patients tho responded promptly, medication was administered Dier the indicated prolonged period in order to evaluate drug intolerince Forty nine of the patients had no untoward effects and four had complaints referable ·Milberg & Jfichael Antibiotics and Nutrition TABLE 2 I VTOWARD FEFECTS or TETESC SI THERAPY Dosage gm 15-20 OD Route oral Length of time administered 5-14 days Total number of parents treated 53 Results 19 To adverse effects Gastrointestinal complaints Inoretin Anorexia and bully stools Tausea and vomiting Abdominal cramps an Ieructatin 1 (dis 5) 1 day 8) 1 day 3) 1 day ) to the gastrointestinal tract Two of these had mild anorevia and, in addition, one of these two had bully stools starting on the cighth day This did not present continuation of medication and completion of therapy The two patients who had the more serious complaints refused medication The onc patient with bronchopneumonia, who had abdominal cramps and eructation, wis also receiving ammonium chloride as part of the regimen for congestive heart failure She refused all therapy at the end of the fourth day, but went on to a clinical remission It is our distinct impression that we dealt with paucity of complaints in view of dosage and length of time of drug administra tion Although acute vitamin deficiencies have been further implicatel in the anorectal syndrome, thereby complicating antibiotic therapy, no satisfactory TCMissions have been observed with the use of vitamins in certain limitel studies Jt is to be noted in this present small series that the anorectal syni clrome did not occur This can be compared with the figure of 7 of 90 patients recently reported on 1 lower dosage schelule of tetracycline ** Whenever a climcal evaluation of the tetracycline group of antibiotics is made the untonati gastrointestinal effects are almost always well described In evaluating the recent literature on tetracyclinc, -3 10-13 these effects have been of eviremely variable incidence Theoretically, the intable focus «cerns in le peripheral in mechanism (usalse factors could be many, including alteration in the lowel flora, competition of the antibiotics with essential nutritive factors in the gastrointestinal tract, or precinc drug allergy Specific drug allers woulil appear to Ise of minor importance as, not infrequently, Allients with almost the first orally ingested dose may become solent reactors \««! in his quia lex demonstralel gastrointestinal sale effects with fuirenteral tetruecline Sullicient medication could le sercled in the lonel i prolute the complaints nole! Isroup of 10 patients (see TAL 3) ucre treatal sath ternamycin ST, 2 um 1011 for 5 to 11 days Of this group ino hd untos ir gastrointestinal In tomurin our preliminary results of telraci dine combined with the valor soluble vitamins and presious studies with tetracycline alnne, it maakt ·254 Annals New York Academy of Sciences TABLE 1 CLINICAL RESPONSE TO TETRACIN SI Respons Average of lay Diagno No of pat ents treated done km /day troete! Sats Inde te m factory nate TE 1 3-2 0 5-7 9 2 20 S 12 2 2 20 7 10 NN Acute pharyngitis and tonsillitis Streptococci Others I aryngotracheobronchitis (no culture) I'neumonia Pneumococcic Bronchopneumona (no culture) Viral Urinary tract infection S albus cols Ps aeruginosa Proteus zulgaris Soft tissue infection (5 aureus) Cellulitis (no cultures) Pyoderma One culture-s aureus Soft tissue abscess (with I & D) S albus 5 aureus Mo culture l'erlapical tooth abscess (no culture) 20 10-14 20 20 inos 7 10 3 1520 8 10 3 I 1 S-2 0 7 3 1 20 14 1 Total 45 39 1 S not alter the clinical or antimicrobial effectiveness of the contained tetracycline The responsneness is comparable to our previous studies 28 with tetracycling alone and to those of other investigators 28 32 It is to be noted that the vual pneumonias did not respond 'Three patients with urinary tract infections, tuo with Prolens and one with Pseudomonas aeruginosa had recened, on previous occasions, all of the broad spectrum antibiotics singly or in combination The infecting organisms were resistant to all the broad spectrum antibiotics One patient with a Proteus infection, however had a successful clinical course, be comin asymptomatic and afebrile, and with a diminishing pyuria, in spite of persistent positive urine cultures for Prolous with demonstrable in a resistance to tetracycline The patients with acute clinical illness resulting from either indefinable or sensitive pathogenic organisms responded satisfactorily within 24 to 48 hours In these patients with acute illness, there was no inci dence of a better response or of a better clinical status at the conclusion of therapy than would be expected with Terrimycin or Tetracy n alune - Si for ind! ser I only the indicated prolonged period in order to evaluate drug intolerance nine of the patients had no untoward effects and four had complaints referable ·Vilberg & Vichiel Intibiotics and \utntion TABLE 2 LYTON AXD FFECTS OI TETACY SF THERAPY Dosage gt 1 5--20 OD Route oral Length of time a ima sleted 5-11 days Total number of patents treated 53 Reu 42 Toalverse effects Castro ntestinal com la nts Anoret 2 Anorer a and bulky ston's Tausea ani som t ng AY lom nal crants an Ieru tat on 1 (lay 5) 1 (day 8) 1 (lay 3 1 (lay +) GS & L I eart failure She refused all therapy at the end of the fourth day, but were on to a clinical remission It is our distinct impression that ne dealt maha paucity of complunts in view of dosage an l length of time of drug adm *** tion Ilthough acule vilamın dieticiencies lave been further implicated in the anorectal syndrome thereby.complacaling antit qotic therapy, no sat izen my to sul listinal is pro T un iteral tetriline Sulf cient ma cation coul I be stato rrr raluce the com lzins notael it ut 10 uut tents (see tu!!! ?ere trental wisdom Wilay rito il dess of the group (xo bid untone - In enmar our įrel muiry ruls tetracid xer wyler « lu? le vitam ns in presimus stules with tetracy*yzer 1 1 ·>56 Annals New York Academy of Sciences TABLE 3 LTON 4RD EFFECTS OF TERRUICIN SF TIER 4PX Dosage 2 gm daily Route oral Length of time administered 5 14 days Total number of patients treated 10 Results 8 To adverse eflects astrointestinal complaints Nausea and milky stools 2 (day 47 eem that a los incidence of significant untoward effects were noted lo ecording all of these reactions, we encountered 7 per cent adverse effects of both positive and probable cause due to the medication It is our impression that a higher incidence of reaction occurs in patients reated with Tetracyn or tetracycline alone than when combined with the vater soluble vitamins A much larger series, however, must be investigated under comparable conditions If this should hold true, it would be of signif ance in the prolonged therapy of such protracted disease states as ulceratne olitis, recurrent urinary tract infection, chronic pulmonary infections, bacterial ndocarditis, osteomyelitis etc The significance in these conditions where nutrition has already been threatened is apparent Summary The combination of water soluble vitamins with tetracycline or pry tetracycline has been administered to 63 patients Preliminary findings ndicate a lower incidence of side reactions, but this must be evaluated in arger series Il hether or not the addition of vitamins contributes to the stimate recovery of the patient and is a factor in the total body economy hould be further investigated References 1 SELIE H 1950 Stress cta Inc Montreal P Q, Canada 2 SELYE H&G HEUSER 1954 Fourth Annual Report on Stress Acta Inc Mont real PQ Canada 3 ERSCHOFF B IL 1932 \utrition and the anterior pituitary with special reference to the general adaptation syndrome Vitamins and Hormone 10 79-140 4 POLLACK H&SL HALPER 1952 Therapeutic nutrition Bull Natl Research Counal US 5 SPIES TDR 11 VILTER & G DOUGLAS JR 1914 Nutrition in convalescence and rehabilitation Southern Med J 37 560-572 Cp te TTD Motection and treatment of sciere 52 753 H LAIETIS & P PETERS nuest 24 523 531 Vitamins and Hormones 7 11-1+U VITCHELL HI H 1943 The chemical and physiolog cal relationsh p between vitam ns thess of purines and B , in metabolic proc 6 10+1 1970 H BABCOCK 523 524 ·Vilberg & Michael Antibiotics and Vutrition 257 18 LETEXSOV, S VR Gaen IL TAYLOR BS KOBINSON RCI AGE RF Jo {\Sov &CC LD 1916 Iscozinc actu ruroflavin thumine and mounic acid in relation to cevere injuri hemorrhage and infection in the human Ann Surg 126 810-856 14 JUXFY B C 1949 The rhs stalogs of thumine tamns ari 11 xmones 7 81 110 1S VOORT T 1945 the nterrelation of vitamsos Sitamins and Hormones 3 16 o tot Yh 1 13 $9 20 21 22 Lancet 1 432 1.32 28 DAT IS & WISESRELL 1945 Sulfonames and van deficiencies 13 21 dminis 25 315) 71 73 26 H**R7511 190 Tureom un an 1 (blam bersol in sucere! Im Ves ASBOX 142 161 166 27 GEWIY&G ) FRIUL 1950 Vansfestations of stain lehesency duringute mycs and chloramphen cul therapi oi en card us due to Naplucoccus aureus lale ) Boland A11 23 332 33x # VlDFXL 3 V Bivos TSS 1954 harmesham hera xu « efficacs at eetracych ne Inte al ca & Chemothera 1086 10% 29 14LAZZOU GVEREBRE L L OLTZ MES & H1 Furry 1954 Terracd ne ihrain on meumcaocal seumania Lostols & (hetsberajw$ 1075 27Xt 30 EISENBORG VI kvxs PAL 14& }} F SITES 1952 latafors and din cal nl servations on sercacs el se Intl Otics Inn 1914 1933 615-01K Viert cal Lactcored a inc Ten opk NUTA "SO 1997 Spies B DOWLING YI ( EPFX & CO JACA. 1961. Tetrarchar therap Vrch Internal Vert 91 351 303 #2 FLAN VIM FURLELL SS WACHY D B LA JR T Vons &L HISH 1954 Simca and tal praters plxersassons of a new stills fetracychre im Vei tuvK 154 661 563 hoh!! *** BJ QEMON I BODIAS SL BECAM4.59* &RII 1431 Icinical evaluatinn of letrar cline in justular lermatoses 1. tura in 1954 1955 665 $rn 1sprical Encychada inc Tow or ) inct ·256 Annals New York Academy of Sciences TABLE 3 UNTOI ARD EFFECTS OF TERRAVECI SF THERAPY Dosage 2 gm daily Route oral Length of time administered 5 14 days Total number of patients treated 10 Results 8 No adverse effects Gastrointestinal compla nts Nausea and milky stools 2 (day 4) seem that a low incidence of significant untoward effects were noted I recording all of these reactions, we encountered 7 per cent adverse effects both positive and probable cause due to the medication It is our impression that a higher incidence of reaction occurs in patient treated with Tetracyn or tetracycline alone than shen combined with th water soluble vitamins A much larger series, however, must be investigate under comparable conditions If this should hold true, it would be of signif cance in the prolonged therapy of such protracted disease states as ulcerata colitis recurrent urinary tract infection chronic pulmonary infections bacteri: endocarditis, osteomyelitis, elc The significance in these conditions when nutrition has already been threatened is apparent Summary The combination of water soluble vitamins with tetracycline ory tetracycline has been administered to 63 patients Preliminary find ng indicate a lower incidence of side reactions, but this must be evaluated ... larger series Whether or not the addition of vitamins contributes to the ultimate recovery of the patient and is a factor in the total body economy should be further investigated References SELYE H 1950 Stress Acta Inc Montreal P Q Canada 2 SELYE H&G HEUSER 1954 Fourth Annual Report on Stress Acta Inc Tont real P Q Canada 3 CRSCHOFF B H 1952 Nutrition and the anterior p tuitary with special reference to the general adaptation syndrome Vitamins and Hormones 10 79 140 4 POLLACK H & SL HALPERN 1932 Therapeutic nutrition Bull Mat Research Council US S SPIES T DRW VILTER & G DOUGLAS JR 1914 Nutrition in convalescence and rehabil tation Southern Med J 37 560 572 cction and treatment of severe 52 758 H LAVETIS & J P PETERS nvest 24 523 531 Vitamins and Hormones 7 MITCHELL II H 1013 The chem cal and phys ological relationship between vitam ng and amino acids Vitam ns and Hormones 1 137 194 10 SHIVE 11 The functions of B vitamins in the biosy nthesis of purines and 11 JO abolic proc 6 CDT Tn D 1044 n 7 11 146 1951 12 SF XK 1940 ·Mulberg & Michael Intibiotics and Nutrition 257 13 I ELESSON SVRK GREEN FIL TAYLOR BS ROBI SON RCI ACE RT Jounos &CC Luv 1916. Iscorbic acid nboflavin thlamine and nicotinic acil in relation to severe injury hemorrhage and infection in the human Ann Surg 124 810-856 14 JANEY BCP 1949 The physiology of thiamine atamins and Hormones 7 81 110 15 WOORE T 1945 The interrelation of sttamins Vitamins and Hormones 3 1-22 16 VIEILLFJORN IP 1933 The physiolngy and I jochemistry of ascorbic aca! Vita mins and Hormones 11 62-96 7 T. Y) • T. 101 D A CN . n nu Lancet 1 432-434 23 Dart IS &* II SEBXFLL 1945 Sulfonami les an satamın deficiencies Vita mins and Hormones 3 49 72 24 ILIINGER &TV SHTATTOCA 1946 Vucotinamide deficiency after oral adminis Lration of penicillin Brit Ved ) ? 611 613 25 MORRIS 6 F 1954 (May) Tellagrous dermattus following use of antit sotics GI 9(5) 71-73 26 HARXIS J I 1950 Tureomy an ani chluram hericol in Irucellosis J Im Ved 1scoc 142 161 165 27 GEWIN ITV &GJ FRIOU 1930 Manifestations of vitamin deficiency during aureo myan and chloramphenicol therapy of end carditis due to sluphelencens aureus Vale J Bol and Ved 23 332 338 28 VILBERG V VRBN peutic efficacy of tetr 29 I ALAZZOLO ITGV Tetracycline theras 1075 1051 30 I SEVERO GILTZIJ L'ALAZLOTO &11 Flippt 1955 Lalvoratory ani clinical nt servations on tetracycline Intil notics Inn 1974 1935 011-618 31 II DALING MITTER & GG rch Internal Ve 1 94 331 363 12 B Inve Je T MORE &E IIMAS is of a new antil totic tetracycline J NHL BE DISS I Bt CX* XLTER & R 11 VEL 1155 clinical cu aluation of tetracycline in justular dermatos Into I 1ors Inn 1951 1955 563 46) Ve fical I neel pela Inc \ew York 1 IAS ·NUTRITIONAL DEFICIENCY AS IT PREDISPOSES TO INFECTION AND THE ROLE OF VITAVIN DEFICIENCIES* By Rubén Lopez-Tocat Department of General Pathology University of Natana Medical School Horana Cuba Since 1945, in association with Spies and Stone in Birmingham, Ala, and with Garcia Lopez, Milanes, Diaz Tellechea, Reborado, and Aramburu in Cuba, I have been studying nutritional deficiences When I was invited to submit a paper to the conference on which this monograph is based the ques tion immediately rose in my mind "What should my contribution be?' I decided that it should be none other than a discussion of the relationship be tween deficiency diseases and the incidence of infectious diseases in some of the patients we have been able to study over a long period of time Introduction Time was when the field of nutrition involved little more than the question of prescribing a well balanced diet Since then, this field of knowledge has not only grown remarkably but has become an actual science as intricate and intriguing as any other branch of the absorbing compler of sciences that man culis medicine One of the most important recent steps made in the field of nutrition has been, in my opinion, the involvement of this field in other spheres of medical science This development by no means should be considered strange, as it has been impressed on the mind of every medical student at least since my earliest days at medical school, that a human being is an entity and that we must consider it in that light and try to solve its mysteries accordingly It is the invasion by nutrition of the field of in fectious diseases that I shall consider in this paper Much notable work has been done in establishing the relationship between nutrition and infectious diseases but in my opinion it is the work of P R Cannon and his collaborators followed shortly by that of Berry and Spies and some others, using experi mental animals, and that of llohand his co workers, on human beings that established the basis for well directed research in this field We have come 1 long way since then, and many additional facts of significance have been brought to light One of the concepts in respect to the role of nutrition in infectious diseases on which much work has been done is that of antibodies Cannon and his Co-workers' demonstrated that when hypoproteinemia is produced in experi , mental animals the production of antibodies is diminished This seems natural if we accept antibodies as globulins modified by the presence of an antigen These authors postulate antibody mechanism as the keystone ol acquired resistance That the infant's resistance is greater in early life is something that has been obsers ed by everyone and the reason for it is supposedly the protec tion conferred by the mother's antibodies at birth In 10 years of observa tion, Hess" verified that the incidence of pneumonia among 1200 infants under * The work descr be lothaer was performed in the Spec al llard for cln cal Research Department of General Pathology Va sets ty of Hasana bool of Med cene la: 103 Cuba The author wishes to exp ex his grat tude to Professors Cullermo Garcia Lopez Femmedo y labes und Carlos a Diaz Tellechts indto Doctor Alfredo Retoredo for the invaluables d of the cit csm and d scuss on 258 ·López-Toca Role of Vitamin Deficiencies 259 1 year of age was 3 times as great in those 6 to 12 months old as in those under 6 months of age Studying 130 pellagrins Riddle, Spies and Hudson' found that Staplıylococcus aurens and Streptococcus ltemolyticus, isolated from chetlatıc and ocular lesions, disappeared following riboflavin therapy They noted also the disappearance of Vincent s organisms found in oral lesions under nicotinic acid therapy They found in previously deficient patients, that the complement titer and bactericidal activity of the blood returned to normal levels as the diet improved Berry Davis and Spies' working with rats found a deterioration of various defense mechanisms in animals fed a diet similar to that of persons in an area of malnutrition They did not test this diet in order to study isolated elements since single deficiency states seldom occur in Nature In conclusion, they postulated the working hypothesis that resistance to certain bacterial inſections may be depressed by inadequate nutrition Patients with various diseases were studied immunologically and chemically, for antibody response in relation to dietary supplementation by Hohl, Reinhold, and Roses In 102 patients a common factor was hypo albuminemia These authors found an appreciable impurment of production of antibodies that was increased under dietary protein supplementation but the improvement was not enough to reach the titer observed in subjects with normal blood protein values receiving the same antigen stimulation Undoubtedly, proteins are not the only factor involved in antibody forma tion or in the general defense mechanism There have been contributions to the literature on the effect of some blood cells and other body cells and of Vitamins minerals and caloric intake on these mechanisms I ately it has been found that the compler action of the endocrine system will of necessity be linked with all these factors for the role of the system is integrated with the adrenal medulla the hypothalamus the anterior pituitary and the adreno corter under stress situations Moreover some nutrients are required by the grunds-Vitamin C for instance by the adrenals Robertson and Tisdall in an ercellent work which has become a classic gasc a diet made deficient in one nutrient at a time and a measured amount of Salmonella tvphimurrum to a group of rats and to control group In this experiment they proved that a low intake of a number of vitamins a low intake of minerils and change in the quality of proteins can all lower resistance 10 infection The increasett susceptibility of animals deficient in vitamin I was mentioned long ago by ( 1stellanos and Bento who described the influence of the vitamin on fat metabolism cpithelial elements ojxonic Inder and the retu uloen Inthelial system as an explanation of the protectie action of the vitamin Ten years after (1stellanos Leah commented on some cffects of vitimus I and I) as for example diminished body temperature immediately ifter injection and the ducreased level of the bi xxl m the presence of infections phenoment which he ascribed to the ma binism of visceral storage and not the destruction 15 15 SUPnel preuously Liensan call central 1 study onsect on the role of some utimins and conclusal that large doses of 144470K cal thuimine rolls in ind n.cotinic acid may scrie 1 useful 1 urpose in the case of acutely all people Onks 11er ago Seltellstried that ·260 Annals New York Academy of Sciences the control of infections, of transmissible diseases and of materno infantile mortality, the decrease of which can be attributed at least partially to the improvement of nutrition, has resulted in a high longevity of the general population Of course, not everybody is agreed on the defensive role of good nutrition in combating infections Contributions disproving this theory have been numerous, and we accordingly find papers emphasizing the fact that nutational deficiencies augment resistance to infections and, on the other hand, other papers concluding that resistance is lowered when the nutrients in question are added to the diet Schneider, who ably explained these contradictory possibilities, summanzed examples from the literature as follows the severity of Plasmodium lophurae infection in riboflavin deficient chicks is decreased and the severity of the infection in riboflavin deficient birds is increased when riboflavin is administered ? An ascorbic acid deficiency in monkeys depresses the usual course of lasmodium kroulest infection, while supplementation with ascorbic acid results in increased parasitemia and death Schneider himself found in mouse salmonellosis, that withholding fat from the diet results in increased survivorship, and that adding fat results in decreased survm orship He gives a final answers to the conflict of opinions by saying that sometimes diet does not affect our resistance to infectious diseases, but that it has this effect chrefly in the laboratory and sometimes in the outside world The vast bull of the experience of the outside world is that diet does affect our resistance to m fections Tuberculous infection, of course, has been a cause of dispute in connection with the action of nutritional deficiencies Many valuable works have ap peared on this subject Getz et al ,16 for instance, have reported studies of a group of 1100 nontuberculous men observed over a period of years showing an incidence of 28 cases of tuberculosis These patients showed lower levels of vitamin A than the rest of the group Ancel Keys!" has stated that, in the case of tuberculosis, undernutrition seems to increase susceptibility and decrease resistance But for nesther animals or man is there good evidence for decreased resistance or increased susceptibility to infectious diseases in general that may be attributed to undernutrition Where reasonable sanitation and epidemic control is main tained, infectious diseases other than tuberculosis present no special diffi culties Commenting on the argument that poor nutrition is accompanied by poverty por satutzties, and mos bossing, Tisdall28 recalled that in Great Britain during World War II, housing deteriorated markedly while nutrition was at a higher level than before the war The prevalence of tuberculosis did not increase to any appreciable degree in contrast, the Germans, who long were considered to have a racial resistance to tuberculosis, have suffered since then not only from poor housing but also from poor nutrition and the incidence of tuberculosis has soared Vutrition in postuar German has had a profours! effect on resistance to infection ·Lopez-Toca Role of Vitamin Deficiencies 261 About 15 years have elapsed since the fundamental works mentioned at tools for work in this field and we hear new explanations of means used by the body to obtain cnergy from basic foodstuffs He even take into account new philosophical conceptions such as the ideas on resistance and susceptibility expressed by Schneider i Materials and methods It is well to emphasize that what I describe is based purely on clinical observation of deficiency diseases in Cuba The patients under study constituted a large contingent of undernourished people the majority of whom were patients with sprue and nutritional mac rocytic anemia A minority comprised cases of pernicious anemia hypochromic anema pellagra anemia of pregnancy beriberi and so forth in the order mentioned Vitamin deficiencies of every kind were present in the patients in the more complex cases their symptoms mingling with those of the main d sease diagnosed There were cases of nutritional macrocytic anemia that also had signs of riboflavin deficiency and thiamine deficiency One patient had sprue and pellagra and another was a chronic sprue case that developed anemia of pregnancy Most of the patients were underweight The records of the whole group were integrated with those of 180 patients whose records We took arbitrarily from our files The total comprised 123 males and 37 ſemales their ages ranging from 14 to 84 years (for details see TABLE 1) These patients were studied from many different points of view but only those aspects important to our present purpose will be considered here in addition to the history the physical examination and the usual laboratory and roentgen ray examination other procedures were used to study these cases in accordance with the clinical data recorded for each group As the complete records would be too long to list such data will be mentioned as needed With a few exceptions all of the patients had a history of eating food that contained little or no animal protein Such a diet common in the rural areas TABLE 1 \UTRITIONAL DenciesCY PATIENTS Mandagnos umbe of ats 80 1 Sprue Via nutr nal anem a us in ma lagra 1 x hrom canem a Incm of regnane Der ber rulotlar niss ckle cell anem a 180 ty dowBAN ·262 Annals New York Academy of Sciences 200 .40 14 20 PERCENT 00 ha 20 CALUT US CALCUM CUN V CAMNA TAM NE AHO LAV A ALI ALOCAL NAT ONAN. TACK FOME OVANCIS OP NVT PCOMINGO. COUNT ON FOOD NOW NV & ENT# • BY OOO TO TILA MM- NW LIW . .0 GP Po ITULAT FICCEE 1 of Cuba, high in carbohydrates and fats, and low in protein and vitamins "e regard as a factor of importance in the development of sprue (FIGURE 1) Many patients suffering from this disease were placed on such a diet and none developed a remission 20 These foods were also combined in the same pro portion as in the diets of the patients, then dried and fed to young white rats at a proper relative level of serght 20 The rats had an arrested sheletal and somatic growth, priapism, testicular atrophy, arrested spermatogenesis, and alopecia Clinical signs of autaminosis were present in no less than 80 per cent of the total number of patients, and a majority of them showed an appreciable loss of weight Serum protein levels were below normal in almost every patient, as formerly noted in a study of 121 cases of sprue, al of whom 80 per cent had total plasms protein levels of 6 gm or below, 3 gm being the lowest level In every case of sprue," and in a high proportion of cases of nutritional macrocytic anemia roentgenographic studies of the gastrointestinal tract with special search for nutritional disturbances, showed pernicious anemia and even in those malnourished patients with no specific chnical patterns the symptoms were those of nutritional deficiencies 21 These symptoms are intestinal segmentation with alternating intestinal spasm and dilatation intestinal hypomotility, and signs of the "stack of coins" and of the "com wheel” Lien though these symptoms may be present in every disease that may produce submucosal e«lemi, in these cises it is logical to accept the nutri tional etiologs A search for bacteria and parasites" of the intestinal tract was also carried out on material aspirated through a Miller Abbott tube and in material talen ·López foca Role of Vitamin Deficiencies 263 by curettage from the intestinal mucosa by means of rectosigmoidoscopy Parasites were also looked for in the feces of every patient Cardiologic investigations showed corresponding results in a few cases of beriber: * An electrocardiographic survey was made In 50 per cent of the cases of sprue,28 we found los voltage and QT inter al prolongation These t glucose tolerance tests, etc showed their results in accordance with every onc of the diseases esplored I rom these data we have come to the conclusion that all of these patients were affected by nutritional deficiency diseases of many kinds Since one of patients have developed later has been treated by us but the patients have received of course the help of other specialists in diseases other than those within the field of internal medicine This has offered us the opportunity of knowing what has happened to these people in addition to illnesses directly attributable to a nutritional deficiency which many of them have suffered for years with frequent relaxes Results Among our 180 patients many have had infectious diseases that occurred through the period of observation but only episodes occurring during relapses of their nutritional deficiency have been taken into consideration in the statistics herein geven All diseases suffered in times when no symptoms or signs of nutritional de ciency were present have lscen ignored Minor infections suffered by every body, such as the common cold, were not talen into consideration Under this plan, the following incidence was noted pleurisy 3 cases erudatne pulmonary tuberculosis 8, pneumofua and bron chopnieumonia 7 pulmonary abscess 1 sinusitis 3 urinary infection 1 bacılary dysentery 1, tuberculous lymphadenitis, 1 The total number of bacterial or viral infections 23 in number among the whole group of 180 patients represents an incidence of 138 per cent Inalyzing the etiology of these infections we can divide them into to groups tulerculous and non tuberculous as in TABLF 2 and ascribing to the former group the cases ( Strobrin sus fleurisies whose etiology was demonstrated and i case of tuler tulos I the lumi li noles this infection reached a total of 12 cases or 66 Trit of the IN) patients analyzed kontuberculous infections totaleil 13, ?XT cent I he distribution of the c infections imong the different deficiency discases under study as may be seen in TIBIF 3 showed no special predilection for any of them being more prevalent in those diseases having the higher number of cases even though pirnicious anemia had a high inci lence compared with that of nutritional macrocytic anemia cases Intestinal parasitic 013 crets or adult forms were present in the lects of T ·261 Annals New York Academy of Sciences TABLE 2 Infections bacterial or tiral \umber of cases Percentage of 180 put cols I rudative pulmonary tuberculosis Serofibrinous pleurisy tuberculous lymphadenitis 3 12 66 Pneumonia and bronchopneumonia Sinusitis Pulmonary abscess Urinary infection Bacillary dysentery 13 72 25 13 8 TABLE 3 DISTRIBUTION OP BACTERIAL OR VIRAL INFECTIONS TPPEARING IN DIERX DEFICIENCY DISFASE Man diagnosis \umber of infect on 11 8 Spruc Nutritional macrocytic anemia Ternicious anemia Hypochromic anemia Tellagra Inema of pregnancy Berberi Sichle cell anemi. Triboflavinosis 0 61 6 per cent of the group, as recorded in TABLES 4 and 5, which shows a high percentage of intestinal parasitic infestation Comments On reviewing the data collected, some clinical facts become more relevant as, for instance, the distribution of infections No special infection was observed In regard to the prognosis of infections in our patients it is to be emphasized that any patient admitted to the hospital with an in fectious disease and exhibiting symptoms of a ses ere relapse of their malnourish ment had a poor clinical course An example of this was a case of bacıllar) dysentery a patient who suffered from exitus letallis in spite of treatment, as did one of the cases of pulmonary tuberculosis, though it should be saul that this was before the discovery of streptomycin and the newer chemical com pounds so useful in the therapeutics of tuberculosis On the other hand, clinical signs of augmented resistance to infections scre exhibited by most of the cases when we had the opportunity of obtaining better nutrition for them Improved nutrition in addition to combating the infection, as shown by improvement of the general state and a decrease of the symptoms of infection was accompanied by reappearance of the appetite, an ascension of the weight cure, and disappearance of clinical symptoms of nutritional deficiency this confirms, I thinh, the experience of all clinicians ·265 López Toca Role of Vitamin Deficiencies TABLE 4 INTESTINAL PARASITIC I FESTATION Sumber of Cases f16 Paras tes found Iscaris mbrtcodes ecolor americants Trichopes trick ra Fidelimax nana Endumoeba cols Sirongiloides stercoralis Guardid sulestinalis Chalomgsliz mestad TABLE F INFECTIONS IN FERY DEFICIENCY DISEASE INCIDFILE Tube บ Pneu mon. Busts Pu) monary abscess Ba Hary dy so ety Cars nfect on 1 6 + Sirue Nutritional macroxytanem Pern cious anemia Tellegra 1 1 1 Analysis of tabir 2 shons an incidence of 138 per cent of infectious diseases in this group of 180 persons during a period of from 6 months to almost 10 cars the average period being 8 years I have not the pertinent data 10 express the relationship of this percentage to that of a group of normal twople of the same ages and general conditions but if I were obliged to state my opinion, I should say that this percentage seems somewhat higher than that 15 normal persons The incidence of nontuberculous infections resembles more or less that which occurs in normal people Then the responsibility of the augmented general percentage is laud upon tuberculosis which had a high incidence of we compare our figures with those appearing in statistics of the general population In (uba the inculence of this disc1'e is 16 per cent according to the dat? I have been able to obtain In the Lnited States the incidence is calculated from 0 to 1 per cent During Il orki War 11 in the United States ? 18 million men were examined for mitary service and of this Ital 201 out of every 10000 sere found to hase come lurm of tuberculosis Itut one thirl of those rejectel had the diverse in in active phase which makes n xrientage of 07 Intestinal parasitism hnd a higher percentage than that found in a suncy ilrendy mentivne tarned out by Valines and others of our group The ruords of mans of the jutrents etu lied by this group correspond in this respect o those of our present group of patients lll of our parasitized ratients miroval is dui thme in the above mentioneel group un ler as to nie therapy and the clinical signs of their deficiency disappeare! Their appetites ·266 Annals New Yorh Academy of Sciences improved they gained neight, improved in other respects and, in the cases of anemia their blood reached normal levels All of this improvement folloned despite the fact that no antiparasitic therapy was used In no case did the parasites disappear from the alimentary tract The hypochromic anemia cases showed also the same degree of improvement without treatment of the parasites vation of at lugher than that observed in normal persons Infectious diseases having an etiology other than tuberculosis did not seem more prevalent in these patients than in other persons Tuberculosis had a morbidity higher than in the general population Clinical treatment proved more difficult in all infectious diseases when severe undernourishment was present and less difficult when nutritional treatment was added to specific therapy Symptoms of nutritional deficiency disappeared under appropriate therapy despite the presence of intestinal parasitic infestation References 1 CANON PIE CHASE & RK VISSLER 1943 The relationship of the protein reserves to antibody production J Immunol 47 133 2 HESS 4T 1932 Diet nutrition and infection Acta Paediat 13 206-224 3 RIDDLE J 1 TD SPIES & N P HUDSOV 1940 A note on the interrelationsh pol deficiency and resistance to infection Proc Soc Cyptl Biol Med 46 361 4 BERRI L J P L Davis & TD SPIES 1945 The relationship between diet and J Lab Clin Med 30 685 Antibody response in per 6 and resistance to diseases Can Med Assoc J 40 282 7 CASTELLANOS A & J BETO 1941 La dosis de vitamina A en las infecciones agudas del nino Bol soc cubana ped 13 107 182 8 LEAK W N 1951 (lov 26) El papel de las vitaminas A y Den las infecciones 3 95- 3798 Dla Méd 9 LEVENSOS Vet al 1946 Ascorbic acid riboflavin th amine and nicotinic ac d 10 salud 11 m 3 no 12 se of 13 ts of e to 15 er 16 17 les ot 18 TISDALLT 1919 Fffect of nutrition on res stance to infection In Clinical Tutti 11on 748 Johfie | Tusdal & P Cannon is Hoeber Me 19 RAN1 LINCS VI 1949 1 elation of nutrition to infection in children Health 39 859 York ) Im Fullc

·fópez Toca Role of Vitamın Deficiencies 267
20 CTT DA
Sutr 1 on an Is ase lost gradu
11
ÓPEZ Toxa dal 194) The as
Sprue Im ) Ved i 21B
22 lei PEZ RF VILÉS XR LÓPEZ TOCI 1949 (Jul ) Tuest o ap te sobre
las a terac ones tal olig aus del ntest na delgado en el oruc tr rcal
Irch Hour
ener tar o Falana Cuba I +
23 ITERN DEZ R&T 1) Spes 1941 Roenigeno og etuies on the ctfect of sn
thet clolc acl on the gas rn test nalt act of pat nts u th trnt cal frue Im )
Roentgenol kad um Iheraps E6 337 342
21 V LAVES I I CLRBFLO I RODRICLE I KOERI &TD Sp Es 1946 Dott
23
26
$
2 MILANES I 1980) 1) arreas or lefcenc a le la nutr con 190 Ldtal Selecia
Habana Cuha
29 Ci LngFRG B 1942 Tul erculos (in ca 28 Sal al Ra celona San
29 Suth - REX VOLDS & HAND 1919 Im Key Tulxerc 60 7 3 Quoted!
RL Coc1 XRF Lnet
ils Saundrs Ph la lelph a la

·NUTRITIONAL PROBLEMS OF SURGICAL PATIENTS By Jonathan E Rhoads and Charles E Alexander School of Vedicine Unitersity of Pennsiliania, Philadephia, Pa Cases of starvation in the United States at the middle of the 20th century are largely surgical Such nutritional deficiencies are rarely due to lack of available foodstuffs in the environment, but rather to a series of conditioned deficiencies in individual patients Thus, starvation may be conditioned by carcinoma of the esophagus or other obstructing lesions of the alimentary tract It may be due to the rapid growth of a tumor that parasitizes the food supply of the body It may be due to overactivity of the endocrine system, with elevation of the basal metabolic rate Acute infections with fever may step up metabolic requirements, or chronic suppuration may drain away protein, as in the case of surface burns or chronic draining sinuses Intestinal fistulas may shunt needed nutriment to the outside, or a deficiency of digestive enzymes may permit food to run its course through the alimentary tract unabsorbed and be lost in the feces Hypermotility with diarrhea may have a similar effect Such patients pass through a series of screening eraminations, and many of them reach our surgical wards in the hope that obstruction can be relieved, fistulas closed, or suppuration controlled While surgical methods can often help in obtaining these objectives, the immediate effects of preoperative treatment, of operation, and of postoperative care may tend to accentuate these deficits Furthermore, surgery in itself is a form of trauma, and it often precipitates the catabolic reaction classically described after long bone fracture by Cuthbertson and his associates in 1935 The first three accompanying tables illustrate some of the nitrogen losses measured and reported in the literature I do not have comparable data for any of the other classes of food In the first are compiled data on preoperative losses, ?' in the second, losses of blood during operation, and, in the third, certain estimates of the further losses in the postoperative period An important aspect of such cases is the interference with the progress of surgical patients that may result from protein deficiency Examples of this have multiplied, and half a dozen are listed in TABLE 4 Certain patients undergoing gastroenterostomy used to develop persistent vomiting due to failure of the new stoma to function The transfusion of such patients often changed the picture within a few days, so that gastric emptying was prompt In the experimental laboratory, Mecray, Barden, and Rardin' found an inverse relationship between the serum protein level of dogs and the gastric emptying time after gastroenterostomy Furthermore, this finding was not limited to fresh postoperative animals, but was found to obtain in some oper ated upon a year earlier and, finally, in nonoperated animals Roentgenologic observations by Barden revealed that the effect was not limited to the stomach but was manifested in the small intestine too, where the time for the head of the water barium meal to pass from the pylorus to the cecum was sharply increased by hypoproteinemia 268 ·209 Rhoads & Alexander Surgical Patients TABLE : MIR XFN LOSSES I ARIOLS TPS SLRGICAL PATIENTS Losses Before Operation f'e AY 902 S Bleeding pent c ulcer 2 Thermal burn (2) Surface ooz ng Total loss Small lowel obstruction (9) Long bone fractures (1) Long hone fractures (5) 7 84 30 89 11 04 137 (X) 120 00 1 10 Varable wechs me) TABLE 2 VITROGEN LOSSES IN VARIOCS TYPES OF SURC CAL I ATITN75 Losses Dur ng Operat on Based on 3 gm of trogen Per 100 cc of Blood Als son Va mun Vas mum rd 55 3 6 9 135 21 12 . 24 11 {8) 12 12) 18 (3) 36 (3) (10 22 S (10) 31 5 21 0 21 0 240 42 0 1080 TABLT 3 VITROCEY LOSS IY VARIOCS TIPES OF St ECICAL PATENTS Losses Ver Operat on WA H 18 0 650 10 Werks 540 Ilern nomy (8) Subtrochanteric osteotomy 15) (astr crestin ()) (holer stect ny *) ( isiru reucl n (R ut Je Tisxr ton tus & Kur fer ratel port culcet ) Nal al mastutiny X 1140 175 0 420 136 0 150 10 10 10 10 10 4 1 ui 1 th: tci ·270 Innals New York Academy of Sciences TIBLE 4 DEMONSTRATED DANGERS OF HIPOPROTEIVEMIA SAS (2) T 1 (5) (6) Decreased resistance to infection levels by the administration of lyophilized dog plasnia on the day the te t wound was made led to prompt sound healing with a normal histologic appearince! Somewhat surprisingly, a similar effect folloned infusions of gum acacia 13 It is not known whether this is a physical effect, or whether the acacia permitted the body to draw further on its attenuated supply of serum protein Another effect of hy poproteinemia in dogs concerns the formation of callus after experimental fracture of the ulna, as visualized by serial roentgenographs ** Whereas callus formation was virtually absent in hypoproteinemic dogs for 60 days considerable callus formation was evident in 30 days in the contra latcral ulnas of the sime clogs the following year, when proteins had been restored It has long been known that chronically hypoproteinemic animals usually have reduced plasma volume, so it was not surprising that Ravdın McNamce hamholz and Rhoads's found that hypoproteinemic animals required an average of only 26 cc /kg blood loss to produce a degree of shock that was brought about in normal animals by the loss of 43 cc blood/hg of body weight of particular importance today are experiments done on the relation of hypoproteinemia to resistance to infection Doctor Paul Cannon, of the University of Chicago, showed that, in the rat, the build up of the antibody titer to sheep red blood cell antigen was sharply retarded in the hypoproteinemic animal and that restoration of this capacity required feeding com ch as zein or gelatin in patients were made at hold, and Rose 17 where it was demonstrated that the response was slower in hypoproteinemic patients Hou general a phenomenon tlus is has not been demonstrated It was of interest that many of the individuals suffering acute malnutrition in concen tration camps during World War II did not succumb to infection but appeared to clinicians to be quite resistant l'ossibly, some natural selection of the more resistant indruduals had already occurred by the end of the war, though this was not felt to explain the observations Ross and Robertson's showed that the resistance of rats to a Salmonella en terilidis infection was lowered not only by protein deficiency, but also by cer tain vitamin and mineral deficiencies as well There has been a considerable amount of work reported in the literature of the last 10 years on the question of a possible increase of infection among the malnourished Certainly, it has been a clinical impression for generations ·Rhoads & Alexander Surgical Patients 271 that this nccurs The British Medical Research Council's reported in 1931 that infections were greater in an African trbe that hned principalk on cereals than in one in which there was a large intake of meat Benditthas shown that two weeks on a protein deficient diet must clapse before he molysin titers ns iler pleen Tainio reported a decrease of several enzyme proteins in stanation with the exception of the cytochrome oxidases Il ork on such a basic level should prove fruitful in the future In 1931, Schneider questioned the general acceptance of the hypothesis that susceptibility to infection was increased by poor nutrition He states! The time honored ves that malnutrition decreases resistance has recchio some support, but is confronted by a substantial body of evidence in which malnutrition increases resistance Indeed for the same dascase virus pneu monitis of mice, the same deficiency (pyridorine) can operate both ways, de pending upon its duration Metcoft goes so far as to doubt an increased incidence of infection a poorer antibody production and an impaired bone marrow activity in undernourished rats I)elaunay and associates" provide an excellent discussion and bibliography of hos a deficiency state may diminish or increase the sensitivity of an organism to pathogens ( handler" has reviewed the problem in parasitism Schechter reviewed the report of a team of physicians in Warsaw in 1942 He noted that there is not always an appreciable increase in cpidemics of infectious disezse in wartime starvation Community sanitation is said to be the controlling factor Ile contrasts the conditions in Warsaw and the clein cities of Holland and Austru To consider a practical nutritional problem in clinical sur cry one might think of patient with a pyloric obstruction who might well reach a surgical service after a conswerable weight livs due to anorexia and vomiting A period of gastric suction to empty the stomach of accumulated debris adds its but to the process of starsation Then when operation is done, (X) to 1000 ut of blond may easily be lost and the operation is capable of initiating a catalımlı response of considerable proportions Unless methols capable of correcting this detuviency are brought into play the anastomosis may fail to function the sound may posibl dehisce, and various infections may super end a «quence of cients that complete a sort of vicinus circle, 79 these 1 ml ons tend to interfere further with nutntion In un furt tu ve what correlation there might be between hypoproteinemia 1st of rulise infertuins we have reviewed the charts of a series of general uredients at the Hopital of the University of l'ennsylvania, l'hila Jelphia la I le basis of selection of the cars for study is shown in TABLE 5 nie lower limit of normal taken was 6.3 gm of protein per 100 ml, and the wnies was doned into a normal' control group and a hytoproteinemic group on this 154 (Thu 6) The infectious complications are group as wound, urinary tract purator tract and miscellaneous Toninfectious complica Ttans were pot considered The incidence in each category as shown in per ·272 Annals New York Academy of Sciences TAPLE 3 POSTOPER TIL E VYFECTIONS AND HYPOPROTEINENI+ Ilospital of the University of Pennsylvania Crter a tor select on of cases 135 11 23 Those not operated on elc Patients included in analysis 102 TABLE 6 POSTOPERATIE INFECTIONS AND HYPOPROTEINEN Hospital of the University of Pennsy hania Criterion of hypoproteinemia-serum protein (sp) <03 gm /100 ml No of patients in hypoproteinemic group No of patients in control group (s p > 63 gm /100 ml) 00 TABLF 7 POSTOPERATIVE INFECTIONS AND HSPOPROTEISESTI Hospital of the Unuyersity of Pennsylvania Class ficat on of infect ons Control group Hymy role nem group Wound Urinary tract Respiratory tract Viscellaneous 13 O 0 0 17 29 6 14 2 95 95 (Vult pletes of infect on in the same patent were counted separately in th s table only 1 centage for the two groups in TABLE 7 It must be emphasized that this was not the incidence of complications among all patients but merely among those who had serum protein determinations recorded and who met the other re quirements for inclusion in the series The statistical analysis of these data is shown in TIBLE 8 using only those cases with clearly defined infections and those who seemed clearls unafflicted ath infection The chance of the correlation between low serum protein and infection being unrelated was less than one in 1,000 (T ABLE 9) Unfortunately, there was an intermediate group of patients who ran exces site fever or leukocytosis or both, who were suspected of having an infection but in whom this never became manifest Even if we assume that all of these in the control group were infected and! that all in the hypoproteinemic group were uninfected the probability that the correlation between the two groups is due to chance remains less than one This is set forth in TABLE 10 in 100 ·273 Rhoads & Alexander Surgical Patients Taple 8 POSTUPERATIVE I_FECTIONS AND II) POPROTEINENTA Analysis of Results To of patents Control Group (1) No iníction Bi Po silyle infection 1C) Difinite infection 6 10 Total ( Ton Protein Group (1) \o infection (1) Possit le infection (C) Def nute inletti n 12 7 23 Total 42 TABLF9 I OSTOLERATIVE INJECTION AND HIPOPROTEINEMIA Chi square Values and Probability of Vo Difference Between the Groups inlect on Definic infection Control low protein H (33 999 12 (22 02) 10 (20 02) 23 (1293) 56 33 899 Curt 1911 strat ability < 0/01 Ind 4lerer' lent values TABLF 10 POSTOPERATIVE INFECTION AND HYTOPROTEINEMI Chi wuare Values and Prol al ality of lo Difference Between the Groups Definle & print losnit on ble inition LP (ntrol Iaurtein 44 (370) 19 (2595) 16 122 95) 23 (16 (3) 00 42 03 39 102 Sf GTR CA 10*21robab 1 ty <a Intate prel ted values While these figures would indicate quite strongly that a correlation exists hou can we interpret such a correlation? Does the hypoproteinemia lower the resistance to infection? Does the infection lower the serum protein? tre both changes likely to occur from one or more common causes, such as extent af uthology, extent of operation, length of anesthesi3 or the like? lle atemptat to reluce the chances that the inſecinn lowered the serum protein ·274 Annals Nen York Academy of Sciences level by dropping out cases in which infection was known to exist prior to the protein determination, but it is not possible to eliminate subclinical or prodromal stages of infection In general, hypoproteinemia and infection tended to be more common among patients requiring the more extensive surgical procedures He cannot attempt to interpret the significance of the correlation found among the data lle belicve that, to conclude from them that the hypoproteinemir was the etiologic factor responsible for the infection would not be valid even though eventually, it may be shown to be true In discussing these data one may well ask why so much attention is focused on scrum protein concentration as opposed to total circulating albumin, esti mates of antecedent protein loss, elc Serum protein concentrations were selected because they were available on many charts, whercas the more ref ned measurements had not been made often enough to permit this type of study Trom a practical standpoint, restoration of nutritional deficits in surgical patients of paramount importance In too many of these cases, the oral route is not immediately available because of local disease or recent operation on the alimentary tract Preoperative correction must usually rest on intravenous methods and after operation, these may often be supplemented by feeding through tubes placed in the jejunum either directly (Jejunostomy) or through the stomach (gastrojejunal ſeedings) The experience of Riegel and her associates would indicate that food was a little more effectively used enterally than parenterally Trans, fusions of whole blood and plasma still play a basic role in the correction of hypoproteinemia and should not be lost sight of, especially as means of cor recting the most pressing deficits of many of these cases of conditioned protein deficiency among surgical patients Mineral and vitamin deficiencies may be hard to recognize but, as a rule, they are easy to correct by the intravenous route when the oral route is not available Summary Severe undernutrition is frequent among patients referred to surgical clinics Operation tends to accentuate protein deficiency There is some experi mental evidence that protein deficiency lowers certain of the defenses against certain infections The incidence of infectious postoperative complications is correlated with serum protein concentrations below 63 gm /100 ml The probability of this correlation being a matter of chance is less than 1 per cent in the series analyzed It is not possible to say from our chnical observations, however, whether the reduced rotem concentrations are causally related to the higher incidence of infectious complications The effect of hypoproteinemia is to increase the chance for a variety of operate and postoperative difficulties It is thus of tremendous importance to find ways of giving surgical patients sufficient foodstuffs by the simplest routes available, to supply their unusual

·No text on this page.

·274 Annals New York Academy of Sciences kevel by dropping out cases in which infection was known to exist prior to the protein determination, but it is not possible to eliminate subclinical or pro dromal stages of inſection In general, lipoproteinemia and infection tended to be more common imong patients requiring the more extensa e surgical procedures We cannot attempt to interpret the significance of the correlation found among the data We believe that conclude from them that the hypoproteinemia was the etiologic failor responsible for the infection would not be valid even though cientually it may be shown to be true In discussin, these data one may well ask why so much attention is focused on serum protein concentration as opposed to total circulating albumin, esti mites of intecedent protein loss, elc Serum protein concentrations were selected because i hey ucre available on many charts, whereas the more refined measurements hidn t been made often enough to permit this type of study I rom a practual i indpoint, restoration of nutritional deficits in surgical patients is of paramount importance In too many of these cases, the oral route is not immediately available because of local disease or recent operation on the alimentary tract Preoperatie correction must usually rest on intravenous methods and, after operation Wiesc may often be supplemented by feeding through tubes placed in the jejunuin either directly tjejunostomy) or through the stomach (gastrojejunal feedings) The prince of Riegel and her associates 25 would indicate that food was a little more cffectively used enterally than parenterally Trans fusions of wholu I loo l and plasma still play a basic role in the correction of by poproteine mit und should not be lost sight of, especially as means of cor recting the most ressing deficits of many of these cases of conditioned protein deficiency among surgical patients Aincral nnd vitamin deficiencies may be hard to recognize but, as a rule, they are easy to correct by the intravenous toute shen the oral route is not available Summary Sever undernutrition is frequent among patients referred to surgical clinics Operation tends to accentuzte protein deficiency There is some expert mental evidence that protein (leficiency lowers certain of the defenses against certain infections The incidence of infectious postoperative complications is correlated with serum protein concentrations below 63 g/100 ml The probability of this correlation being a matter of chance is less than 1 per cent in the series analyzed It is not possible to say from our clinical observations, however, whether the reduced protein concentrations are causally related to the higher incidence of infectious complications The effect of hy poproteinemia is to increase the chance for a variety of operative and postoperatore difficulties It is thus of tremendous importance to find ways of gising surgical patients sufficient foodstuffs by the simplest routes available, to supply their unusual needs ·cas 1911 S ficance of Rhoads & Alexander Surgical Patients 275 References 1 (LTHBERTSON DP 1933 further obsersations on the d sturtance of metabolism caused by tours with particular reference to the dietan eru rements of fracture Brit Surg 23 507 2 Borne III 1911 Castro-Interologs 1 Saun lers Philadelp his la i iliв игів і чинним і вват с EIFLLER VILLING Son nitrogen Iks in eru ile from surface furns Surgery It ich HINJAGFYDFL 1910 1 lasma transfusion in etperimental inlestinal Instruc 11 on Inn Surg 112 240 (correction bed 112 976) 5 f10 4RD JIN L'ARSONISTEN II EISENBERG & RFint 1911 Studies cture com alescence mer Есл metal olism after fracture and sheltal okratinna in bealthy miles Kul) Johns Hleyhins 11 xp 75 156 6 (ILLAR FI Cr CROX & 118 191 Blowl lose in surgical operativne ] Im vel issa 176 1 NELLER HULIGIBBON JR & F E \LBRITTEN Je 191) Blood volume and extracellular duu changes during thoracic «perati ns' Thincacic Surg 18 6 DI LARX & CBI 1912 Sympxxium on alwominal sur fers postopuratne nitrogen lies and studies on parenteral nitrogen nutrition n cans of cascind gest Inn Surg 115 1091 o Risori (CI ROOP J Derul Steve S&J I had 1917 The nutei tsonal requirements for nitrogen tralance in surgical patients during the carli postopera Lise perio J. CI n Insest 26 18 10 VERAV P VIR BARDF\ &IS RANDS 1937 Tutrita nal com its effect in the gastric empting time before and after gastric cerations Surgery 53 11 T) Ta on # BRL SCHWE men 11 T 1 12 T Ishule Irch 1932 13 Riro IVT ILLICELXAN&I V TAVZEX 1912 The mechanism of delavc1 wound hinl ng in the presence of hypx roteinemia. In vel lauk 118 21 14 RIAD JI AKANISK 45 1942 influence of hipoproteinemia in the formatın of callus in cyrimental fracture Surgers 11 38 15 RADNI11 6 VANES J | KAMIKIZAJI KH 1971 Iffect the rolernen 1 on sure totally in shexk resulting from bemorrhage Arch Surg 18 421 16 ANYAP Kat al 144 Relationship protein deficiency to curg cal infecus n Inn Surg 1:0 14 1. UVOJO REINTIOLO ASB hose 1919 Intata res ne in patients with hyroteiner 13 Irch Internal Vecl 83 402 18 RISK&DERTHY The elect of vitamin B comglet on lerr Jihyavs (hilfren 43 47 19 yer Kepe \o 155 20 - [RIDGE D' RowLF & H ETT I reluctants rats on 1 protein lets 21 ITC ICT UIT an 1 its leukocytac crne in protein ile (in Infect us Diseass B3 87 ? BEL II) IIHL p ITFLUTTAJILLE 1951 (x!tcrnames the I ser in rotein den let ) Vuintin 9 465 2 INFICE !!! 1951 Sutrit: 11 ani revstance is currents to infectin In J1r Met 31 1 VTV1 101) Influence on tein nutrition comental infection Tull. ticalch 30 kr 1111951 la notion du terra en muretul pe la lumière les de Nierre rentrs I (arer co nutriha nnelles el revitance aut infectns irreur mat E9Q 128 20 ADETRIC 1963 The relath n of nutrition to farasten ja Valls W 964 533 2 YICHTE 1903 Itealth entuckness in times of starvati nan 11 ww sh lake Harult llanti The lietrew vel al Journal) : 101 Air Thirt ILA (RICTE &VT BARYS 1947 Stulo oiry tan hs Erolutes frein latin an plurne in parenteral nutrition Surf Cecot ktet 84 105 1 ·CERTAIN ASPECTS OF DEFICIENCY DISEASES OI THIE TROPICS AND TREATMENT OF SOME RELATED INTECTIONS By Elmer II Loughlin and Hilliam G Mullin lex I ork Medical College and flower and Fiſk fremye llospals eu Jork, NY A surprising panorama of food deficiency diseases has unfolded in the tropics and, consequently, the importance of the classic deficiency diseases has gradually waned in most areas The symptom complexes arising from an in sufficiency of food are considerably more inclusive and far more widespread than such restricted deficiencies as beriberi, pellagra, scurvy, and tickets They may vary according to the kind, degree, and duration of the insufficiency from mild latent conditions through progressive stages to extreme inanition on the one side and severe protein malnutrition on the other, or they may have overlapping gradients from inanition to protein malnutrition They are influenced by age and sex, by certain anthropological factors, and by such stress factors as pregnancy, lactation, and intercurrent infection, as well as by geographical location They are so intricate and diverse that they might have been woven by Arachne, and so inclusive that they might have been contrved by Dido Until recently, these broad syndromes were scarcely noticed by workers in the fields of nutrition and tropical medicine, whereas deficiencies presumably caused by the lack of single factors recensed emphatic attention during the Arart cles of other vitamins, an even larger number of medical papers appeared on ever, scientific facts then had replaced speculation and fancy It would be improbable today that the term "protein" would be conferred on a district similar to "Limehouse" in London, nor is kuashiorkor heralded as a "menace in banner headlines of today's newspapers as pellagra was in the newspaper headlines of 40 years ago, although protein with its amino acid components and associated factors, is certainly more important, and kuashiorkor more ravag ing, globally, than pellagra Although interest in the problems of tropical nutrition has been awakened +1 -1.1 fac uld be sick, and that their lives usually are regulated by traditional customs and by religious and tribal taboos and superstitions It should be appreciated also that anthropopsychic disorders, resulting from malnutrition in early hiſe, parasitic infections, and subsequent endocrine disorders, contribute to their bach sardness, their seeming lon order of intelligence, and the underdevelop ment of the regions in which they live, and that this apparent inferiority should not be considered solely dysgenic Since the nation that the fetus is merely parasitic and des clops more or less 276 ·Loughlın & Mullin Deficiency Diseases 277 independently of its mother was discarded, it is non becoming endent that interrelated anthropological factors infections, and malnutrition also affect the unborn child long before it takes its first breath Thus, like specters, these factors haunt it virtually from conception through a to:lsome, inglorious, and fast withering hfe to the grase If it were possible, it would seem timely at this point to inquire of the human ry gote of the tropics, Quo tddis/" Although it is essential to consider the reciprocal dependence of anthropologi cal factors, infections, and malnutrition as causatıye of tropical deficiency sy'n dromes from the prenatal period onward it is nevertheless fundamentally im portant to consuler the maternal arc of the nutritional ambit before progressing to those of the infant ani chuid I urthermore, since the mother us an infegral part of the tropical community except for appreciable differences during early childhood, pregnancy, and lactation she is influenced by the same factors that affect other adults in the same environment Therefore, to provide an casier comprehension of the maternal role in tropical nutrition as well as to aloid duplication the aforementioned factors and their effects on adult tropical indigenes will be evaluated collectively and the notable erceptions as they pertain to the mothers will be mentioned or described briefly The nante tropical mother already may be grarely deplaed by nulniltonal pri ration accentualel by oreru ork and parasitic infection and therefore, is phasically unprepared to take on the met groeing burden of pregnancy and lactulton In the Jace of increased nutritional demands by pregnancy and luctation the fropical mother, unlike many of her temperale cone counterparts seldom gels a special supplementan in of her diet and instead certain high quality fools are made watatlable by seasonal deficiencies of may be interdicted by lubos lo 10 35 to 561er cent of the langue of \ations standard and in many impoverished pris of Asia Africa Central Imerica and the Il est Indies, they are equally On most of the l'acific Islands where the traditional diets consist of tish Innanas, breadcruit taros sucet potatoes Jams, fruit, green vegetables and cocoanuts there is little evidence of deficiency diseases. In certain te glons of Centrul Imienica although the diets of the children may be markedly Ichchent both in calories and protein the diets of the adult agricultural workers whe grow their own food are comparatively adequate (atorie, total protein alium in thiimine ani niacin requirements are met, but Intakes of tumal, rotein utimin mbxoplu in and ascorbic acid are much lower than mmende NO LUCK the staple fxul of more thin half of the world! qkupalatwin anul -199plies at 116 70 cent of ibeur duls calories it n un mobile!lt the keer mnt creal In Inii (unt and outlıcast su the daily diet con rlee lutis of animal origin are negligible In other countries of the tropies rue mui le completels et pork rejlico I» legume mave an imt cofx 111 uxne kountries it grown in limited amounts and mus legie for xfacul ·278 Annals New York Academy of Sciences feasts while, in others it may be imported and therefore, may be too expensive to include as a staple of the diet " In regions where rice is the staple of the diet, malnutrition is prevalent, and it is in these places that nutntion can be materially improved through the use of supplementary foods such as milk The methods of preparation of rice for eating are also vitally important from the nutritional aspect Because of the peculiar harvesting and storage prac tices, rice is the only cereal that is regularly washed and cooked in water before it is eaten Ranganathan el al found that losses from rau rice due to washing and cooking amounted to 15 per cent of the calories, 10 per cent of the protein 75 per cent of the iron and 56 per cent of the calcium and phos phorus 13 While Swaminathan" found that up to 85 per cent of the thiamine also was lost Although rice entichment programs have been successful in reducing beriberi substantially in certain parts of the Philippines where this deficiency disease was prevalent, they are considered by some investigators to be impracticable for large scale application" Food plants in different parts of the world may vary considerably in biological value Dean has noted that maize, which usually has a low lysine content and a lysine methionine ratio usually of 2 3 in Guatemala has a still lower content of methionine and the ratio accordingly is 4 236 In most areas of Central America maize is not only low in lysine and methionine but is es pecially low in tryptophane The deficiency of the latter amino acid accounts principally for the low biological value (usually below 50 per cent) of maize Fortunately it has been possible to develop new genetic varieties, some with adequate tryptophane and nacin contents as well as reasonably adequate meth: onine content !7 18 13 Moreover, in the regions where total intales of protein are los, thus de ficiency usually is aggravated by exceptionally lou intakes of animal protein although it is appreciated that high quality protein alone is not a substitute for an adequate quantity of total protein In China, there is only 5 gm of animal protein available daily per capita This figure is matcred by that ol 9 gm in India and 4 gm in Jaia and Madura: Similar los intakes of animal fra tein are the rule in many parts of Africa, Central America, and the West Indies 6 0 20 21 2* In a survey of four Nigerian tribes Nichols calculated that one tribe--the Dah2rkeri--consumed duly only 2 gm of animal protein per capita They offset thus low intake of protein of good quality, however by consuming a large quantity of vegetable protein, 85 gm per capita daily Another tribe--the Isokos--consumed only 40 gm total of protein daily per capita 20 gm of which was of animal origin Incidentally hepatomegals vas noted in 9 per cent of the Daharkerris and in 19 per cent of the Isokos and 3 per cent of the former had ascariasis while 31 per cent of the latter were found to be infected with thus prrasite In some parts of Africa, cattle are considered as measures of wealth and except for special feasts, are not slaughtered for ſoxu! In many other parts of the tropics, the peasants he cattle and seldom use them for their onn food requirements lahes, where fish are eaten animal pr higher and deficiency diseases are ! where transportation facıhtı elic s and along rivers and tein intakes are much In rural areas netcept occasionally ·Loughlin & Mullin. Deficiency Diseases 279 for imported expensive salt or dried fish Pond culture of fish is being attempted in some countries to eliminate this inadequacy. In parts of the tropics, the live weight of cattle does not ecceed 450 to 500 lb and the output of milk during a seven to eight months lactation does not exceed 145 gal Where better supplies of milk are available, peasants usually prefer to sell the milk when possible while, in other regions, because it is so highly contaminated, severe gastrointestinal infections frequently result from feeling it to infants In some areas, according to Davies, to it is given to some adults as a luxury food, and the idea that children, and pregnant and lac tating mothers require extra fond is alien to African concepts In still other areas, no mlis gnen after weaning 2 A formidable obstacle in some coun tries where milk is available is its cost, and in those countries where it is dis tributed frec to mothers and children, it can become a serious financial burden to the government. The substitution of dry shım milk has been attempted Deficiencies can result, however, when such milk is the principal or sole food of the infant (rde 1nfra) Dcan has observed also that in Cast Ifrica, food habits have changed in some parts because local supplies of certain foods have become exhausted, and that changes in agricultural schemes are brought about by the discovery of a new preference, by necessity, or by the completion of a government agrı cultural plan He recommends that a famine-resistant crop-cassava or olani When planning to improve the nutrition of tropical indigenes or to correct chronic protein malnutrition, it should be noted that dried milk, stored in cans on the shelf at ambient temperatures for one year, may lose three quarters of its hological value This loss is in amino acids--some of these acids are destroyed and others become biologically unavailable and in certain vitamins, particuharly pyridoxine Children fed chietly or exclusively on one of these milks 1 LU ALUNY), Quring the cultivating and har resting asons women are required to toil in the fields with primitive and melli ient implements from early morning through the heat of the day In wnie oes this work is done after only a brile suertened coffee or gruel has Ixın talen upon arising The meal of the dry is not eaten until evening l'regnames and tistation except for the first month or two after parturition, 13sually does not esempt them from this clu! In adultion to the clones es finale in this strenuous work, the aiult in the trans ml ·278 Annals New York Academy of Sciences feasts while in others, it mit heima to include as a staple of diet m 44 washed and cooked in water LIVIL IL IS eaten Ranganathan et al found that losses from raw rice due to washing and cooking amounted to 15 per cent of the calories 10 per cent of the protein 75 per cent of the iron, and 36 per cent of the calcium and phos phorus 13 hile Swaminathan" found that up to 85 per cent of the thramine also was lost Although rice enrichment programs have been successful in reducing beriberi substantially in certain parts of the 1 hilippines where this deficiency disease was prevalent, they are considered by some insestigators to be impracticable for large scale application 15 Food plants in different parts of the world may vary considerably in biological value Dean has noted that maize, which usually has a low lysine content and a lysine methionine ratio usually of 2 3 in Guatemala has a still lower content of methionine and the ratio accordingly is 4 2 16 In most areas of Central America maize is not only low in lysine and methionine but is es pecially low in tryptophane The deficiency of the latter amino acid accounts principally for the low biological value is! 1. 0 - Morcover in the regions where total intakes of protein are low, this de ticiency usually is aggravated by exceptionally low intales of animal protein although it is appreciated that high quality protein alone is not a substitute for an adequate quantity of total protein In China, there is only 5 gm of animal protein available daily per capita This figure is matched by that of 9 gm m India and 4 gm in Java and Madura: Similar low intales of animal pro tein are the rule in many parts of Africa, Central America and the West Indies 20 20 21 In a survey of four Nigerian tribes Vicholsa calculated that one tribe-the Dakarherri-consumed daily only 2 gm of animal proten per capita They offset this low intake of protein of good quality however by consuming a large quantity of vegetable protein 85 gm per capita daily Another tribe-the Isolos consumed only 16 gm total of protein daily per capita 20 gm of which was oſ animal origin Incidentally hepatomegaly was noted in 9 per cent of the Dakarherris and in 19 per cent of the Isokos and per cent of the former had ascariasis while 31 per cent of the Intter were foun 1 to be infected with this parasite In some parts of Africa, cattle are consı fere ! is measures of wealth and except for special feasts are not slaughtered for fon] In many other parts of the tropics the peasants sell the cattle and seldom use them for their own food requirements In coastal strips and along ters and tahes where fish are eaten animal protein and total protein intales are much higher and deficiency diseases are less common 6 10 13 26 27 In rural areas where transportation facilities are lacking little fish is eaten except occas onails ·Loughlin & Mulin Deficiency Diseases 279 for imported expensive salt or dried fish Pond culture of fish is being attempted in some countries to eliminate this inadequacy In parts of the tropics the live weight of cattle does not etceedi 450 to 500 lb and the output of mik during a seven to eight months lactation does not erceed 143 gal Where better supplies of milh are available peasants usually prefer to sell the mik when possible while in other regions because it is 50 1 the infant (urde infra) Dean" has observed also that in East Africa food habits have changed in some parts because local supplies of certain foods have become exhausted and that changes in agricultural schemes are brought about by the discovery of a new preference by necessity or by the completion of a government agri cultural plan He recommends that a famine resistant cror-cassavar 1 Lield veut lemperatures for one year may lose three quarters of its bolog cal value This loss is in ammo acids--some of these acids are destroyed and others become biologically unavailable and in certain vitamins particu larly pyridoxine Ch Idren fed chiefly or exclusively on one of thpes mit է u Lud vuuts are considerably lower than estimates based on average consumption of the family or community " allowances should be conswered for losses of nutrient content of foods during cooking In many tropical countries depending on Incal - sistence it is the custom of pensable to food production vesting seasons women are 44 T U LOLL in the helle thmefirin somet i cent w the 44is not eaten until esening I renfncy and lactation except for the first month or two after parturition usually does not exempt them in this duty In addition to the calories er fended in this strenuous or the adult in the tropics particularly when ·280 Annals New York Academy of Sciences exposed to the direct rays of the sun and swerting heavily, may lose in erress of 4 gm of nitrogen daily via the shin 16 It would be interesting to speculate on the amino acid pool nitrogen balance, and circulating proteins during work under these conditions Although intestinal helminths and other parasites affect young children more severely than adults (ride infra), in those areas where these infections are prevalent and consequently intense, the pregnant mother may manifest not only the residual elfects of such chudliood infections but also those of a current helminthiasis-ıf severe with accentuation of the existing malnutrition These dietary privations are further accentuated by crop failures caused by drought and by the sersonal reductions between harvests--the hungry months when diets may be reduced to les els of less than 1000 calories daily -substantially below the local energy requirements particularly those of the pregnant or lactating mother The deleterious effects of such dietary priva tion on maternal nutrition during the hungry months or during crop la lures are not limited to just these periods On the basis of observations on Africans in whom after prolonged periods of protein starvation it was found that ade. quate diets for at least three months were required to attain nitrogen balance >> it is obvious that these periods of aggravated maternal malnutriton may extend well beyond the harvests Diverse taboos are encountered in various countries of the tropics and although some may be beneficial many are undoubtedly detrimental to good maternal infant and child nutrition In India, according to Raodieran deficiencies are common among nursing mothers and children of even upper classes because of religious restrictions Protein of animal origin og meat fish or fertilized chicken eggs is not eaten by orthodor Hindus in many regions of Africa where tribal taboos forbid mothers to eit certain fish eggs and chichens the diets are made additionally defective in protein a while in others the pregnant woman is allowed to eat fish ?? Deficiency diseases of adult tropical indigenes may be latent and only become manifest clinically under stress I'regnancy and lactation are stress factors that in tropical women commonly accentuate and bring to light the ind catrons of malnutrition including anemia hepatic disease edema and even cardiac insufficiency The principal deficiency anemias of the tropics are iron deficiency, or hypochromic microcytic and megaloblastic macrocytic Iron deficiency or hy chomuc microcytic anemii may be the result of (1) insufficient detary iron chron Warrhea or L u ſection (clisease) csophageal varices associated with schistus III cirrhosis and portal cirrhosis These inemus occasionally are so severe especully when there is more than one factor responsible eg hooh norm disease and pregnancy that trans fusion of blood may be urgently required The majority of these anemble however will respond satisfactorily to iron therapy and an adequate intake al proten especially when the responsible factor eg hooks orm is rciluceri ar ·Loughlin & Mullin Deficiency Diseases 281 eliminated A great deal of discussion has been centered upon hookworm ane mia with some investigators asserting that Iron alone is sufficient to produce and maintain cute, while others contend that iron alone wall not provide cure and that, in order to maintain the therapeutic effects of iron, the intake of pro tern must be adequate or the hooh worm burden must be removed or signili cantly reduced 29 30 Vegaloblastic macrocytic anemias are (1) those probably caused by the dietary lack of such extrinsic factors as folic and folinic acids vitamin B1 and other B compler vitamins as well as protein" and include (a) tropical macrocytic anemia and (b) dimorphic anemia a variant of the former due to associated iron deficiency (2) those presumably caused by impaired absorption of extrinsic factors and include (a) anemia of sprue and (b) the anemia accompanying pellagra, which also may be due partly to a lack of extrinsk fac tor Diphyllobothritim lolam (fish tapeworm) anemia is confined chiefly to the Baltic littoral, over 70 per cent of cases being reported from Finland 16-1 Tropical macrocytic anemia is the term conferred by Wills on a megaloblastic anemia observed in indigenous populations of tropical and subtropical ch mates 10 42 This anemja originally considered to be associated only with pregnancy has been found to occur in nonpregnant women as well as in men It can be distinguished from pernicious anemia which it closely resembles by the fact that achlorhydria is no more frequent than it is in the rest of the local population, and spinal myelopathy does not occur The stress of the in creaser nutritional requirements of pregnancy in women in whom malnutrition as latent or imminent probably may be sufficient to precipitate manifest anemia In Costa Rica, a severe hypochromic macrocytic (dimorphic) anemia is fre quently observed, and is considered to be due to mainutrition multiple preg nancies and hookworm disease " Similar cases have been reported from Africa 4 Tropical hemolytic anemias, including those caused by infections such as malaria and Bartonella and the hypersplenism associated with hala azar and schistosomiasis (Bantis syndrome) as well as the faminal hereditary sickle cell stale are frequently conditioned or aggravated by protein malnutrition and iron deficiency In many countries as children grow into adolescence and adulthood they continue to maintain diets similar to those on which they previously developed huashiorkor *9 A high incidence of protein malnutrition in children usually indicates undernourishment and malnutrition of the general population in many instances the diets or adults are observed to be poorer in that they are cleficient un calories as well as protein Then as a consequence of illness, in testion pregnancy lactation of prolongesl severe esertion (long tres), acute kwastorkor may lie precipitated in the adult * * In certain regions of South America Central America and the West Indies however the diets of adults are better qualitatively as well as quantitatively Lesions of the liver with severe chronic protein malnutrition (kuashiorkor) can occur in adults (Davies') and in lactating mothers? These lesions resemble the fatty infiltration and necrosis cellular infiltration and fibrosis observed in the lasers of young children although, probably as a consequence ·282 Innals New York Academy of Sciences of conditioning during acute attacks of kuashiorkor in chudhood, there is a greater degree of fibrosis Pancreatic sclerosis due to periacınal, peritubular, and periductal fibrosis is obserı ed in adults, and associated atrophy of the enzy me secreting glands of the small intestine result further in disturbed di gestion and attendant impaired absorption Gillman and Gilberte reported that fatty liver disease occurs much more frequently in acute pellagrins than in other members of the general population in South Africa and that, in pellagra Iruer in adults is doubted, it is generally accepted that adult tropical uit rhosis, which is indistinguishable from Laennec's portal currhosis as observed in temperate zones is linked with chronic protein malnutrition ? 20 45 49 608 It would appear that kuashiorkor, after it has been cured, does not inevitably lead to continuing cirrhosis i the diet remains satisłactory (in many places this is unlikely, ride supra) and cirrhogentc factors or substances are not prevalent $ There is no significant sex difference in cirrhosis of the liver as encountered in Africans 56 The increased frequency of cirrhosis of the her ia certain tropical areas was noted many years ago Rogersbs in 1911 reported that cirrhosis of the Inter among native Indians un Ceylon was obseried in 6 9 per cent of postmortem examinations and thus was seven times more frequent than cirrhosis in Eu Tannt han terial infection and torias absorbed from bonel ulcerations were etiological factors in the production of the curhosis In the light of present-day knowl edge, however, it is probable that chronic protein malnutrition accentuated by chronic dysentery was the basic causatre factor Almost 40 years later, Fernandosi found the incidence of cirrhosis to be still high in Ceylon (death rate for cirrhosis was 22/100,000 m Colombo (1919), and 195/100 000 in England and Wales) Of 192 patients with hepatic cirrhosis 24 had 10%! cirrhosis and 168 had Laennec's cirrhosis It was considered that Laennec s cirrhosts, in most instances, was the consequence of malnutrition min tronis oiic cu ·Loughlin & Mullin Deficiency Diseases 283 thosis resulting from increased iron intake and storage under the term hemo chromatosis Walker and Arvidsson & after studying iron overload in the South African Bantus, have concluded on the basis of microscopic examination of liver tissue that iron overload in the Bantu does not lead to cirrhosis and that hemochromatosis is distinct from siderosis They point out that in sidero $ls in the Bantus pancreatic pigmentation shen it occurs is only slight that hepatic fibrosis is often absent that diabetes is rire and that in hemochromato sls iron storage even early is parenchymal Anomalous serum proteins are found over most of the tropics with total serum protein values of the indigenes being the same or greater than those of their temperate zone counterparts Before modern electrophoresis techniques were used for determining the patterns of serum protein fractions some investigators sought to show that there was no close relation between malnutrition and altered serum proteins It has become evident since that total serum protein values are deceptive inasmuch as the progressive decrease in serum albumin is often coupled with an apparent compensatory Increase in gamma globulin In malnutrition excluding the consideration of certain protozoan infections hy pergammaglobulinemia is thought to be due to liver damage Alterations of the serum protein with lowering of the albumin fraction have been reported from diverse parts of the tropics 9 3 616 Although it has been decided that hypoalbuminemia and the hunger edema of Europe were not closely asso ciated it has nevertheless been considered highly probable that there is an almost invariable relation between hypoalbuminemia and edema in protein malnutrition as it occurs in the tropics? 70 61 65 66 Tropical ulcer and malnutrition are commonly associated in impoverished It is probable that the conditions leading to its development are those associated with poverty tiz malnutrition dirt trauma and invasion by common shin bacteria fusiform bacill and spirochetes The extent of the causative role of malnutrition in the development of tropical ulcer has not been determined It is recognized however that protein malnutrition materially interferes with healing in Uganda I oesenthal" observed that tropical ul cers did not occur in natives who consumed milk and meat Rao reported that tropucal ulcer was most common in those areas of India where malnutrition and anemia accentuated by malaria and hooh norm were prevalent especially on the tea plantations in Assam" and on coffee plantations in South Africa 69 1 ropical ulcer became even more prevalent during World War I when poverty and food privation worsened in Calcutta 10 7 Poindextera considered that an insull ciency of protein and vitamins was a factor in determining the chronicity (tropical ulcer In lut we ofered that where there was a heavy seasonal ramfill minutrition dirt trauma and infecti ns were the principil factors that acted jointly in preluce the ulcer as well as to contribute to the chronicity ind extent' In patients with extensic chronic ulcers the malnutrition was apparently aggravated by continuous seep ng of protein rich serosanguineous fluid from the base of the ulcer Since the fetal cco only is deperlent on tle stules of maternal health the infoni born of a malnouris/ed nadire frapical mother is likely to be immature and under wcigli The tropical infan' endused auth only meager resources IS areas ·IL 284 Annals New York Academy of Sciences 1911mical entironment uhere a succession of merciless adresaries 15 Quailing til Thus shortly after beginning its mundanc erisience, 11 must compele for surtirol where only the most lenacious can suriite An opportunity to observe the effects of maternal nutritional privation on the economy of the fetus was provided by the recent war in Lurope In ll upper tal, 11 art roman by not wer birt Uganda, birth weights were found to match those of European babies, whereas in the Congo, they were reported to be 400 to 500 gm less In India, birth weights of infants of malnourished mothers averaged about 700 gm less than those of babies of European mothers. In parts of Central America, children born at term are usually premature in appearance" Similar observations have been made in India and other parts of Asia where maternal malnutritional is prevalent Although it is usually impossible to ascertain the length of gestation in tropical countries, it is generally recognized that these low birth weights are not necessarily due to prematurity but rather to immaturity Despite the fact that native tropical mothers may have lower serum albumin values than their European counterparts, the serum albumin values of African infants match those of their European contemporaries & The values of all of the constituents of blood serum, particularly vitamin A and carotene, were lower in newborn children in Guatemala City than those of new born children in the United States 74 Although anemia is usual in malnourished tropical mothers the hemoglobin values of new born infants in East Africa are comparable to those of European newborns 75 76 It is inconceivable that severe anemia in the woman would L reflected in the infant at birth, anemia may become manifest at a later date when deficient fetal iron stores (a result of maternal deficiency) are not ade. quate to hold pace with rapid growth during the first several months of life 78 70 Contrary to previous notions, the quality of breast milk of malnourished mothers in the tropics, ercept for a higher fat content in some parts of Africa compares favorably with that of their American and European counterparts Jelliffe in 1952 noted that the breast milk of Nigerian mothers had an average protein content of 104 (range 0 59 to 1 76), despite poor diets inadequate in protein, and he confirmed similar observations made by Trose!!?' in Uganda The breast milk of Indian mothers of the poorer class in the Nilgiris u hose children were suffering from kuashiorkor, was found by Shrinvasan and Ramanathan" to contain 1 59 per cent of protein compared to 1 27 per cent in the breast milk of healthy mothers 304 mg per cent of methionine and 26 1 mg per cent of cystine, compared to mg per cent, respectively Ilalker, Arvidsson, and Drapero ascertarned that the breast milk of 31 poorly nourished, 190 average, and 45 self nourished In 1918 1 mg per cent and 190 ·Loughlin & Mullin Deficiency Diseases 285 South African Bantu mothers, eating diets based on maize, bread, and legumes did not differ materially from that of their American and European counter parts except for a lower content of vitamin C and niacin In places where beri ben is endemic the breast milk is also deficient in thiamine Although the nutritional status of the mother is often poor, tropical snfants usually continue to grow satisfactorily during the early months of breast feeding and growth weight curves are comparable to those of infants in the United States and England ? 11 10 81 At six to eight months, sometimes suitable Diarrhea which frequently results from such supplementary foods accentuates the insufficiency of the diet roportionately higher re Dean" points out that ely with growth during these early months since the infant receiving an adequate quantity of breast milk will continue to grow satisfactorily Ithou there is no correspondin increase in the available quantity of breast milk The optimal amount of protein required for satisfactory growth is not known according to Dean On the basis of temperate zone standards however the requirement of protein increases from a probable amount of 11 gm daily (supplied in 1 200 gin of breast milk) providing a protein hg ratio of about 2 1 at five to six months to 10 gm at tuo years to 50 to 60 gm by seven years and 70 to 90 gm there alter in a good mixed diet with two-thirds animal protein and one third plant protein It is appreciated that in many underdeeloped countries of the tropics the daily protein intahes do not erceed 30 grm and often are no more L An 1 investigations in Central America ? * based on studies on child feeding with plant protein made by Dean's in Germany would seem to show that an ade quate quantity of protein from any source provided the intake of calories and certain vitamins is suficient is more tmportant than the animal protein content of the det Tutni nal deficiencies in infancy and childhood usually become manifest 11 tle time when the supply of breast milk is failing and supplementary feeding » 1 ring to Brock and futret'the most serious and mulespread of theve lutritional lisorders as huashiorkor which is also known varuus pirts of the world as sindrome policorencial infantil Culebrille and ercept for pigmentary disturbances 38 distrofia de farinac' Jystrophic de furieuse nacl probably chladhrschodem huashiorkor is defined as a nutritional chinorder associated with a los protein diet occurring particularly cluring the age period between six months and five years It is apparent that the term 'protein' is not restrictive, and that the deficiency must include B illܬܙlx ܙܕ ·284 Annals New Yorh Academy of Sciences inimical enlironment where a succession of merciless aduersaries is availing it Thus shortly after beginning ils mundane eristence, 11 must compete for surnal u here only the most tenacious can suriile An opportunity to observe the effects of maternal nutritional privation on the economy of the fetus was provided by the recent war in Europe In Il upper tal, West Germany, although average birth weights had been reduced slightly by 1939, there was a further decline of 210 gm by 1945 This reduction was not as great as that in Rome in 1911 and in Vienna in 1915, where buth weights were 400 to 500 gm less than in preceding years 24 Unfortunately, recorded birth weights are not available for much of the tropical world In parts of Uganda, birth weights were found to match those of European babies, whereas in the Congo, they were reported to be 100 to 500 gm less In India, birth weights of infants of malnourished mothers averaged about 700 gm less than those of babies of European mothers * In parts of Central America, children born at term are usually premature in appearance " Similar observations have been made in India and other parts of Asia where maternal malnutritional is prevalent. Although it is usually impossible to ascertain the length of gestation in tropical countries, it is generally recognized that these low birth weights are not necessarily due to prematurity but rather to immaturity Despite the fact that native tropical mothers may have lower serum albumin values than their European counterparts, the serum albumin values of African infants match those of their European contemporaries 6 The values of all of the constituents of blood serum, particularly vitamin A and carotene, were lower in newborn children in Guatemala City than those of newborn children tn the United States 74 Although anemia is usual in malnourished tropical mothers, the hemoglobin values of newborn infants in East Africa are comparable to those of European newborns 75 76 It is inconceivable that severe anemia in the woman would not affect the blood of the fetus, and it is highly probable that women with very low hemoglobin values usually do not conceive but that, if they do they will abort Though a low maternal hemoglobin of the mother may not be reflected in the infant at birth, anemia may become manifest at a later date, when deficient fetal iron stores (a result of maternal deficiency) are not ade quate to hold pace with rapid growth during the first several months of life " 76 Contrary to previous notions, the quality of breast milk of mainourished mothers in the tropics, except for a higher fat content in some parts of Africa compares favorably with that of their American and European counterparts Jelliffe in 1932 noted that the breast milk of Nigerian mothers had an average protein content of 104 (range 0 59 to 1 76), despite poor diets inadequate in protein, and he confirmed similar observations made by Tronell7 in Uganda in 1948 The breast milk of Indian mothers of the poorer class in the Nilgiris whose children were suffering from kwashiorkor, was found by Shrinvasan and Ramanathan? to contain 1 59 per cent of protein compared to 1 27 per cent in the breast mill of healthy mothers, 30 4 mg per cent of methionine and 261 mg per cent of cystine, compared to 291 mg per cent and 190 mg per cent, respectively Walker, Arvidsson, and Draperse ascertained that the breast milk of 31 poorly nourished, 190 average, and 45 well nourished ·Loughlin & Vullin Deficienci Disease 285 South African Rantu mothers cating dets based on maize, bread, and legumes, dd not differ materially from that of their lmerican and European counter parts except for a lower content of vztamin C and nacin In places where beri beri is endemic, the breast mill is also deficient u thuamine Although the nutritional status of the mother is often poor, tropical infants usually continue to GTON Satisfactorils dunog the early months of breast feeding and growth seight curves are comparable to those of infants in the Lnited States and England' l* * At su to eight months sometimes eather, the growth of the tropical infant begins to lag behind that of the tem Jxrate zone infant indicatiog that there is probably an insufficiency of breast milk and that foods given to supplement the infant's diet-chiefli carbohy drate and at times, adult foods sath curry and spices are inadequate and un suitable Diarrhea which frequently results from such supplementary foods accentuates the insufficiency of the diet It is acknowledged that the young infant has a proportionately higher re quirement for rutrogen than older children and adults Dean' points out that the nitrogen requirements must diminish progressively with growth during these early months since the infant receiving an adequate quantity of breast mith wall continue to gros satisfactorily although there is no corresponding increase in the available quantity of breast milk The optimal amount of protein required for satisfactory growth is not known according to Dean On the basis of temperate zone standards however the requirement of protein increases from a probable amount of 14 gm daus (supplied in 1 200 gm of breast milk) providing a protein hg ratio of about 2 1 at five to six months to 40 gmn at two years to 30 to 60 gm by seven years and 70 to 90 gm there after in a good mured diet with tso-thirds animal protein and one third plant protein It is appreciated that, in many underdeveloped countries of the been settled whether animal protein is indispensable for growth Current investigations in Central Imerica" » based on studies on child feeding with plant protein made by Dean" in Germany sould seem to show that an ade quate quantity of protein from any source provided the intake of calories and certain vitamins is sufficient is more important than the animal protein content of the diet Sutritional dehciencies in infancy and childhood usually become manifest at the time when the supply of breast milk as fading and supplementary feedling islegun Iccording to Brock anel Autret, the most serious and we lespread of chese nutritional disorders ishlashiorkor which is also known in various parts of the worll as sindrome placarencial in nisl culcbrilla and elept for pigmentary disturbances 35 distrofia de farindent' dystrophe de fartneuse and probably Hekludhrschakes Asashiorkor is slefined as a nutritional disorder associated with a low protein diet (curring particularly during the age period between six months and five years It is apparent that the term protein is not restrictive, and that the deficiency must include i ·286 Annals New York Academy of Sciences compler vitamins, vitamin A in some areas and, possibly, vitamin C In localı tres in Haiti, where ku ashiorkor was prevalent, we were impressed by associated vitamin A deficiency, particularly among aduits Furthermore, the syndrome is not limited to these age groups in Central America, cases are seen in children through 12 years and, in Africa, adult cases have been reported and the pathol ogy has been described 45 It has been generally accepted that kuashiorkor is the result of prolonged consumption of a diet that is deficient in protein, as well as other essential factors, and in which the proportion of animal protein is low while that of carbohydrate is usually high Such diets have a low protein calorie ratio and a very low animal protein calorie ratio In Central America, Autret and Behar" found many cases in shich the calorie intake had been inadequate from an early age and in which there were mantiestations of undernourishment as well as of malnutrition In Djakarta, where rice is the mainstay of the diet and malnutrition is prevalent, Ooman" has observed that malignant malnutri tion (huashiorkor) is the result of a reduction of total calories and total protein with animal protein absent or minimal The intake of food is aggravated by anoreta and occasionally by vomiting and the digestion of food and absorption of nutrients are hampered by duar rhea Of these three symptoms associated with the syndrome, the last named desenes special mention, since most of the children with kuashiorkor hase diarrhea In some cases, diarrhea occurs as a consequence of alteration of pancreatic and intestinal enzyme functions and must be viewed as a result of The protein deficiency In other children, diarrhea can be ascribed 10 parasite or bacterial infection or to an unsuitable diet In the opinion of Autret and Behar,'' parasitic and other infectious diarrheas are most common in Central America and frequently precipitate a true deficiency disease in children who already are on the verge of malnutrition At this stage, there is decreased utilization of food, partly due to atrophy of the acini of the pancreas and of the enzyme secreting cells of the small intestine, * & and to consequent reduction of amylase, lupase, and tryps??? in the small intestine 21 85 86 In children that recover but probably have ad ditronal attacks of the malnutrition syndrome, fibrosis or sclerosis of the pancreas is usual in later life These pancreatic and intestinal lesions are coupled with atrophic changes in the parotid and lacrimal glands, and are viewed as the primary lesions of kuashiorkor 20 59 They are attended by the characteristic fatty infiltration of the cells of the penphery of the liver lobules lymphocytic infiltration of the portal triads, and a thichening of the retaculum in the same part of the Jobules 5 * Thece early changes of the her are follosed by increased fatty infiltration, which progresses in a centrolabular direction, cellular necrosis, and collagenization and fibrosis of the thickene! reticulum in and around the portal triads--the so called "stellate fibrosis" of Darjes 50 Davies viells the stellate fibrosis” as the stamp of hwasharhor which, although it is not found before the weaning penod, is common subse quently In two other widely separated regions of the tropics, other forms of nutri tronal liver disease occurring in infants and children have been described ·Loughlin & Mullin Deficiency Discases 287 serous hepatosis in Jamaica, in the li est Indies, by Hill, and hepatic cirrhosis in infants and young children in India and Ceylon This cirrhosis apparently is encountered as two distinct types (1) a portal cirrhosis of the Laennec type and (2) a form of biliary cirrhosis first described by Gibbons" in 1891 The latter usually is rapidly progressive, commonly affecting children one to three years of age of middle and high class Hindu families Both are frequently accompinied by jaundice and are fatal The role of viruses and of Escherichia col in the etiology of the latter is uncertain po Walnulti/ion and infechons in the tropics are 1 sseparably linked and make up lle uary and reſt of the fabric of disease of many tropical indigenes Tropical infections contrast with those of temperate clunates in so far as more of them are caused by animal parasites Although many are caused by the sime organisms that produce infections in temperate climates resistance and susceptibility to these as well as to animal parasites are more profoundly in fluenced by environmental ecologic and anthropological factors and by natural racial inherited and acquired immunity Fien though protein malnutrition is generally accepted as the fundamental determinant in kuashiorkor and although acute bacterial or viral infection especially pneumonia bronchitis and diarrhea can precipitate the syndrome there is no unanimity of opinion regarding the role of parasıtıc infections Brock and Autret' point out that hwashıorhor occurs imong Africans in Jo hannesburg the majority of whom have never been exposed to such tropical parasitisms as malaria schistosomiasis filariasis leishmaniasis and ancy los tomiasis They refer to Ilatt and McGregor (loc cul) who emphasized the importance of parasitism particularly malaria in the Gambii anil to the fact that the age of marimal incidence of Luashiorkor and the age of relative absence of immunity to malaria are the same Broch and lutret conclude whereas tropical parasites are probably always contributory to the etiology of kuashiorkor in the area surveyed and may sometimes play and important pirt it is likely that the dietary factor is always dominant Autret and Behar :0 in discussing the etiology of sindrome policarencial infantil in Central Amenca state that while the etiological influence of intestinal parasitism may be admitted it should be regarded as an indirect or secondary cause They also call attention to the fact that injudicious vermifuging may precipitate the heIn nulis parti (larls Iscarts lumbricoides play a significant role in aggravat 11 hsisl rhor in many areas of the tropics Investigators in India have tressed the interrelation of malnutrition and infection particularly maları and hookuorm infektion " They cons der that while malnutrition pre d spores to infection infection is a Lon litioning factor that nggravates the nuintal deficiency In Indonesia ? the prevalence of honk worm disense mong indigenes with indications of proltın malnutrition bas lel to energoin programs to combat this parasitism Williatns calls attention to the fict that ascarlasis is common in miny arts ·288 Annals New York Academy of Sciences of the world where washiorkor is found and is an important factor in a large proportion of the cases of this syndrome 93 She believes that too little attention has been directed to the devastating effects of ascariasis, and notes that one or two male Iscaris in the intestine of a young infant, though they may produce no eggs and therefore reman unrecognized, may create havoc in the digestne system and even cause death le think that infections with virgin female Iscars, which may be more prevalent and possibly more serious than male in fections, can also be missed, since their bizarre eggs either may not be recog nized or are not recovered in the yields of some diagnostic techniques a 180 Williams also points out that in areas where there is a high incidence of ascara sis, even though the adults may harbor them in apparent symbiosis, the effect of 1scaris on children who have not yet acquired an immunity is quite differ ent When a child develops an acute febrile illness (tide supra), the ascards often depart via the mouth nose, or rectum and, in chronic disease, they may already have left before the child is brought for examination Ascaris, there fore, may be a factor in a of kwashiorkor although all the worms have departed Infections with Iscaris may deprive the host of nutrients by high metabolic requirements (40 per cent of dry weight is protein formed from essential amino acids and content of thiamine, niacin, pantothenic acid, pyrı doxine, and vitamin B:2 in the worm's tissues is high), secretion of trypsin in hibitor (for protection against dissolution in intestinal canal), mechanical interference by heavy worm burden, mucosal irritation and increased secretion of mucin, and, at times, fever and diarrhea In two rural areas of Haiti, where malnutrition was prevalent, we found In localities in Haiti, however, where vitamin A deficiency and prolem mallu trition were prevalent, we found that ascariasis was uncommon and that the incidence of all intestinal helminth infections was less than 6 per cent On the other hand, we noted that intestinal protozoan infections, as well as malaria were common The incidence of Endamoeba hrstolylıca infections was 45 per cent, and of Guardia lamblia, 33 per cent Hookworm usually does not significantly affect the child who is younger than two years inasmuch as infants and young children are seldom exposed to infection until they crawl or toddle in spots infested with larvae Loughlın and Stoll (1946), however showed that sei ere and even fatal hooh worm disease in young children and infants in an age group considered relatively free from infection, could be contracted from fomites 20. After hookworm disease has an lo riced by increased protein hookworm burdens increasing the need for protein for blood regeneration and by interfering with food and protein intahe, may further reduce already los serum albumin lesels and thereby precipitate or aggravate edema 2: Truncao et al, I in a study of the bloul proteins in cases of ancylostomiasis in Portuguese Africa, found that the blood ·Loughlin & Mullin Deficiency Diseases 289 albumin was relatively lowered and that the gamma globulin was at least 50 per cent higher than normal The close association of hooks orm and pellagra 2n Eopt was pointed out by Khalil,10 sho found that pellagra was six times more common in hookworm patients than in the general population, and by Robertson and Doyle,164 who observed that 46 per cent of 300 hookworm pa - bacterial origin may reduce the ability of the African infant to withstand infections such as hookworm ascarlasis bronchitis and pneumonia to which it is exposed In holoendemic regions Garnham105 remarks that children almost from buth are in contact with the malarial parasite and that, apparently due to passive immunity acquired from the mother the infection rate during the first two or three months is only 10 per cent whereas half of the infants are infected by the suth month and practically all are infected by the ninth month This apparent relative immunity in breast fed infants also may be due to an antiplasmodial effect of milk, similar to that demonstrated by Maegrarthtos in Plasmodium berghez infections of milk fed rodents as confirmed by others 107 The reduction in the quantity of breast milk at five to six months (ride supra) may be associated with this significant rise in the incidence of malarial infections at that time Since the metabolic requirements are raised by fever due to malaria as well as other infectious agents it is highly probable that latent chronic protein malnutrition can be precipitated into manifest hwashnorhor or that once established, the latter can be aggravated Brock and Autret' Autret and Behar' and Thompson" have called at tention to the interrelation of kuashiorkor and diarrheas of protozoan or Although the protozoa giving rise to diarrhea are not spec fied we should suppose that most cases are due to infection with Endamoeba histolytica Giardia limbia also can cause durrhea as well as steatorrhea and leghelyit has stressed the association of steatorrhea and impaired absorption in giardiasis The mechanisms whereby huashiorkor and other multiple deficiencies are precipitated by diarrhea are intricate but may be constructed as follows the hurried passage of food through the intestinal canal interferes with di gestion and absorption of nutrients and results in increased loss of nutrients including B comples vitamins as well as fluid and electrolytes, anoretra limits the intake of nutrients leser associated with these infections aggravates the climinished intake and increased loss of nutrients by rusing the protein vita min C and B compler vitamin requirements intestinal irritation ulceration, and bleeding incxlent to the infection cause losses of fabricated protein in en 74 mes mucin crudate and blool the feeling of starchy diets that are sull further reduced in calories acerastes all of the aforementioned factors until a vere multiple deficiency syndrome is finally reachert I bese views regarding the role of parasitisms in precipitating or apgravating ftficiency diseases are not without esperimental support Chandler,tº on the basis of animal and human investigations, has remarked that the physiological welfare of the host 15 i contributes to the balance in host parasite relations, ·200 Annals New York Academy of Sciences is particularly affected by diet He considers that the diet, under certain cu cumstances, influences the ability of the host to develop specific immunity in infectious diseases, whether caused by bacterii, protozoa, or helminths Poor diets, particularly those deficient in protein or containing proteins of poor biological value, eventually will interfere with the production of antibodies that are modified globulin formed from essential amino acids When growth and antibody production must compete in a malnourished and parasitized young animal, both are adversely affected and, unless this is corrected by im proving the quality of the diet with regard to its content of biologically good protein or by removing part or all of the parasite burden, the young animal is unable to suruite because there is insufficient material to supply both Interest in the association of parasitic infection and malnutrition has been active for many years (ride supra) It was astonishing, however, to find a reference by Sambon (1908) to the Ebers papyrus written in 1550 BC, in which the dad disease, an endemic anemia, was ascribed to an intestinal worm--the Heltu worm " While, in 1906, Shipley and learnsides!! remarked that it was in children who require every gram of their food for growth that the loss is appreciable, and that we have passed from the day since Jordens in 1803 (loc cul) called intestinal worms "the good angels and unfailing helpers of chil dren" The treatment of helminthic and protozoan infections, when they are as sociated with severe chronic protein malnutrition (washiorkor), has generally been considered as unnecessary and even dangerous until the malnutrition has been significantly improved This trend in therapy has evolved from the fol lowing premises (1) infants and young children suffering from severe malnu trition that is associated with parasitic infections, particularly ascariasis hoohsorm, amebrasis, and malaria, seldom tolerate commonly used parasiti cides, (2) treatment of parasitic infections without simultaneous improvement of the diet does not ameltorate the manifestations of malnutrition, (3) the belief that certain deficiency diseases can be cured by merely supplying the deficient substances, eg, hookworm anemia "cured" by administration of iron, (4) the comparatively high percentage of cases of malnutrition in which helminthic and protozoan infections are not found at the time of examination, (5) the unavailability of efficacious nontoric parasiticides, (6) the failure to realize that such parasitic infections intensify the effects of the deficiency of vitamins and other nutrients, that "nonspecific stress" reactions resulting from combined infection and deficiency can cause adrenal cortical changes, and produce changes in those organs with high metabolic activity, especially the small intestine and incr The commonly used parasiticides (santonin, oil of chenopodium, carbon tetrachloride, emetine, certain 8 aminoquinolines) have low therapeutic ratios even in persons who ar fore, that such toric dr infant or young child and purgation are also prescribed to complete the treatment with certain anthelmintics Nevertheless, despite the introduction of new parasıtıcıda! agents--including the broad spectrum antibiotics orytetracycline and tetra TA Inut happ ·Loughlin & Mullin Deficiency Diseases 291 cycline, the piperazine compounds, and never aminoquinolines-most of the aforementioned toxic drugs are still being used in many areas either because they are readily avadable, are inexpensive, or because sorkers in the tropics are more familiar with their use Williams" has remarked that although ascariasis is prevalent in parts of the world where kuashiorkor is found the ascards already may have departed from the intestinal canal of the sick child before it is brought for examination In these cases, even though the infection may be intense enough to aggravate the dietary insufficiency or to precipitate a severe state of malnutrition, the interrelation of the parasitism and the malnutrition is generally overlooked Thus the absence of Ascaris in such cases does not lessen the need in other cases for treating ascariasis when it is associated with malnutrition, provided an ef fective and nontoxic drug is available Other severe helminthic and protozoan infections may be similarly regarded It should be realized that, when malnutrition has resulted from dietary insufficiency accentuated by parasitism even though the depletion caused by the parasites may be severe, the entire picture of malnutrition cannot be entirely reversed by merely removing the parasites Thus treatment of the parasitism and simultaneous improvement of the diet are required to ameliorate the mal nutrition Although the anemia of hooh sorm disease can usually be corrected by giving iron it has become event that unless a significant part of the hook worm burden is removed the relief is only temporary and cannot be maintained after the increased intake of iron has been stopped Tropical infections caused by metazoan protozoan and some bacterial parasites may be manifested either as chronic or as acute or fulminating dis eases In these infections particularly when they are chronic and are asso ciated with chronic malnutrition there is sufficient time for serious deficiencies of the B complex vitamins and of vitamin C to develop Although it is not generally realized, there is reason to believe also that many of these cases have progressed to a stage comparable to the exhaustion phase of the general adaptation syndrome" (Selye) 1120 b. It is under these conditions that the treatment of parasitic infections associated with deficiency diseases should be directed toward (1) speedily correcting the protein malnutrition and/or undernutrition (2) rapidly arresting the critical depletion by parasıtıc infcc tron(s) with orally or parenterally administered efficacious nontoric chemo therapeutic or antibiotic agents (3) correcting the depletion of thiamine, certain B complet vitamins and vitamin C that has resulted from infection as well as from dietary deficiency, and the consequent "nonspecific stress 'reactions caus mng adrenal cortical damage, and injury to those organs with high metabolic activity especially the intestine and the laer It thus would seem to be 1 sine qua non that these vitamins should be administered simultancously with anti infective therapy and not delay at until later when further systemic and intestinal depletion undoubtedly will have xcurred! Beginning in 1990 we have lind occasion to study delicienxy dresses and in terrelated parasitic infections in the Republic of Ilanti Ilthough Ilatt is com partively small--less than 11 (70 square miles in arca-deficiency diseases and parasitisms are not unvaning throughout the country Contrariise, thes ·292 Annals New York Academy of Sciences differ according to localities or regions as they might be affected by topical climatic, environmental and, possibly, by anthropological factors Conse quently, it would be impossible, after surveying a few limited areas, to generalize about the diseases affecting the entire population In certain localities, chronic prevalent, at least 75 per cent of the natives being infected In others, hook worm disease is a problem and, in still others, both of these parasites, as well as Trichuris, are prevalent In certain localities where chronic protein malnutrtion and vitamin A deficiency are common, less than 6 per cent of the natives have these helminthiases, and 33 per cent respective tions of prevalence Bac treponematoses --yaws and pinta---vary in regional prevalence or distribution In a locality where vitamin A deficiency is common, pinta is prevalent while yaxs is rare Tropical ulcer also is regional in its prevalence (ride supra) and is found frequently in areas where yans is prevalent Although the treatment of these diseases in Haiti obviously must be individualized according to the hind of deficiency and parasitism, the objectives outlined above, nevertheless have continued to be generally applicable Accordingly, we have treated mal nutrition and/or undernutrition associated with ascariasis, hookworm, malaria, amebiasis, yaws, and tropical ulcer, and have used certain new chemothera peutic compounds and broad spectrum antibiotics as antı infectie agents 1scartasis In the treatment of ascariasis associated with malnutrition, we have found certain piperazine compounds, including diethylcarbamazine (Hetrazan) and piperazine calcium edathamil (Perin), to be innocuous These compounds are highly effectne, are available in syrups, and, with regimens of either one dose (45 mg/hg body weight) of piperazine calcium edathamıl, or four single doses administered on consecutive days (each dose, 15 mg/kg) of diethylcarbamazine, up to 94 per cent of Ascaris are expelled These pipera zines seldom cause toxic reactions, but these reactions, when they do occur, are usually mild Dietary restriction, fasting, and purgation are not required to increase their effectiveness or to diminish their toxicity 113 115 Hooku orm The piperazines are not effective in the treatment of hook However, Crysto.ds Anthelmintic (hexylresorcino!) can be given with comparative safety to children who can swallow pills Two or three doses given several days apart (0 1 gm for each year of age through 10 years to the adult | 11 worm empty, it should preferably be given with water in the morning and food souk be withheld for several hours Purgation is not required in the treatment of hookworm with hexylresorcinol I. 1 I - ·I oughlin & Mullin Deficiency Diseases 293 can be administered in single doses lle have found that a single dose of hy droxychloroquine (Plaquenil) caused 1 prompt clintcal response and a rapid disappearance of the parasitemia in falciparum malaria 16 These doses ranged from 10 gm for children less than su ycars and 15 gm for those Lietucen 6 and 12 years to 20 gm for adults 1 single dose of hy drorychloroquine has been found to be effective also in the treatment of par malaria 19 Under circumstances where oral administration is impossible, hy drorychloro quine can be administered parenterally in single doses of one sixth to one third the amount given orally Pyrimethamine because of possible folic acid antagonism 18-134 and certain 8 aminoquinolines are not recommended for treating malaria in debilitated anemic and malnourished indı duals In a recently published paper 121 se discussed the use of the broad spectrum antibiotic orytetracycline (Terramycin) in the treatment of some tropical diseases including amebiasis certain helminthiases the shigelloses donovano sis (granuloma inguinale) lymphopathia senerea the treponematoses yaus and pinta-and tropical ulcer Orytetracycline has been used in Haiti to treat amebasis, jaws pinta tropical ulcer lymphopathia venerei donovanosis (granuloma inguinale), and certain helminthiases including enterobiasts Although the first four are commonly associated with deficiency diseases lymphopathia donos anosis and enterobiasis usually are not causally related An earlier substantial part of this program was designed to study the efficacy of orytetracycline in the treatment of yans amebiasis and tropical ulcer white lately the program has been expanded in its therapeutic aspects to include tetracycline (Tetracyn) and oxy tetracycline and tetracycline combined with Stress Formula (ST) vitamins such as Terramycin SF and Tetracyn SF re spectively Dosage of Oxyfetracycline and Telrocycline These antibiotics are usually administered orally as follows to children less than 5 years of age 10 gm daily to children between 3 and 10 years 15 gm daily to those more than 10 years and to adults 20 gm daily Of course the dosages are modified according to the infection being treated In amebiasis and donovanoss these doses are usually administered once daily for 10 consecutive days In yaxs pinta and tropical ulcer they are given once daily for five consecutive days In enterobiasis a seven-day regimen is used and in lymphopathua venerea, a 28 day regimen is applied tnder certain circumstances where parenteral ad ministration is considered necessary orytetracycline and tetracycline can be cfiettivels a Inuinistere i bi intramuse ular injection in the following doses for any the above jerı xis or until oral administration can be instituted children less than cirs 11 10) my mnjected once daily chil iren between an 1 10 vein minje lect one duls children more than 10 years and adults 2-0 mg injected ontt du Four carrules of Terramycin or Tetracyn SI containing 10 gm of the until totic also supyls the following amounts of water soluble Stress I ormula vitamins 10 mg of thumine 10 mg of riboflavin 100 mg of nacinamide 20 mg of calcium pantothenate 2 mg of pilotine 1 mg of folic acid 4 mcg of amin B1: 300 mg of ascorbic acid, and 2 mg of vitamin . Thus S15*** ·291 Annals New Yorh Academy of Sciences capsules (1 5 gm of antibiotic) will supply one and one hall times the Stress Tormula, and eight capsules (20 gm of antibiotic) l supply two times the Stress Formula Amebaasis Oxy tetracycline has been found to be a consistently superior, relatively nontoric, safe therapeutic agent in acute amebrasis *** 125 Unlike some arsencal compounds and halogenated hydroty quinolines, orytetracycline is rapidly effectuat in controlling darrhea and eliminating Endomorba histolica from intestinal ulcers and the feces, and does not require preliminary control of the diarrhea with emetine to be effective Consequently, emetine, which is contraindicated in young children and is highly toxic for debilitated and mai noucished individuals, need not be admimstered Inasmuch as orj tetracycline has been found to be more effectual than other chemotherapeutic drugs and antibiotics in the treatment of shigelloses126 and since differential diagnosis may be impossible in areas where amebic and bacular dysenteries are both prevalent, the use of this antibiotic is currently recommended for treating acute In preliminary investigations of the comparative efficacy of oxy tetracycline and tetracycline we find that these antibiotics have essentially the same clinical effect in amebiasis when cases are observed for periods of sur neels post treatment As a consequence of experiments showing that a combination of equal parts of oxy tetracycline and tetracycline produced a fourfold increase in inhibitory effect on E histolzrica in viro, over that obtained when erther ants biotic was used sungly;' ,17 ke nere prompted to investigate this synergism clımı cally In 14 patients with intestinal amebiasis thus far treated with a combina tion of equal parts of orytetracycline and tetracyline-the total dose of both antibiotics being the same as nben either is used singly we have observed no relapses during sex weeks posttreatment periods Inasmuch as antibiotics tein malnutrition and they intensify the severity of the latter by fever and anoreria Malnutrition and anemiz commonly accompany late jass, par ticularly when fabricated protein is lost in the serosanguineous fuid that seeps from large ulcerous lesions or when destructive lesions in olving the oral cavity interfere with nutrition Orz tetracycline, administered either orally or parenterally has been found to be highly efficacious in the treatment of both lute and early yang 128-132 The tamd response of early yaxs to dry tetracyclinc c w and lace (gangosa) deforming osteoperiostitus, gummus and erfenste utc lesions of the ertremities is arrested with one or tso and, occasionally, courses of oxytetracycline therapy as outlined above Treatment of ·Loughlin & Vullin Deficiency Diseases 295 lesions of late jans with orytetracychne not only duectly improves the nutir tion of the individual but also improves the physical condition of the adults so that they can again become productive members of the community Al though we have olyserved Jarisch Iferxheimer reactions, particularly in infants and young children treated with procaine penıcıllın, we have not encountered malnutrition The fact that such reactions do not occur with og tetracycline therapy is especially important when considering the treatment of yaws asso ciated with latent malnutrition or with manifest kwashiorkor Tropical ulcer (phagedepic ulcer) le previously have indicated that the treatment of tropical ulcer should comprise systemic as well as local measures 121 The former included a diet high in calories high in protein content and having supplements of B complex vitamins and vitamin A Antimicrobial therapy systemically administered was considered optional but in Haiti, where yaws e andam to the base and margins of the ulcer nromnti in amb nad av It was noted that acute ulcers reacted 1 within six to eight weeks Those patients with very extensive ulcers that had failed to heal completely with this therapy nevertheless were sufficiently improved to be able to return home and resume gainful work Terramictn SF and Tetracya s The comparative efficacy of orytetra cycline and tetracycline i hen administered singly or simultaneously in the same capsules with stress formula vitamins is being currently investigated in amebia sis yaus pinta tropical ulcer donovanosis lymphopathia venerea and certain helminthases As noted before amebiasis yaus pinta and tropical ulcer in Haiti are commonly associated with debciency states malnutrition and/or un lernutrition These antibiotics--orytetracycline and tetracycline henen la u NUUS th 21S Ulthough the numliers of cases of individual diseases treated with oryteira clinc alone tetracycline tlone ory tetracycline with stress formula vitamins and tetracycline sith stress formula vitamins are still too fes to dras more بهراه Justs of Terramycin SI and Tetracyn SI are factual advantages (1) ulcerous lesions of late yans and tropical ulcer when treated with these antı biotic stress formula combinations manifestly heal more rapidly than when ·294 Annals New York Academy of Sciences capsules (1 5 gm of antibiotic) will supply one and one hall times the Stress Formula, and eight capsules (20 gm of antibiotic) will supply two times the Stress formula Amebiasis Oxytetracycline has been found to be a consistently superior, relatively nontonic, safe therapeutic agent in acute amebiasis ?" 15 Unlike some arsenical compounds and halogenated hydroxy quinolines, ory tetracycline is rapidly effectual in controlling diarrhea and eliminating Endamoeba histol!ıca from intestinal ulcers and the feces, and does not require preliminary control of the diarrhea with emetine to be effective Consequently, emetine, which is contraindicated in young children and is highly toxic for debuitated and mal nourished individuals, need not be administered Inasmuch as oxytetracycline has been found to be more effectual than other chemotherapeutic drugs and antibiotics in the treatment of shigelloses" and, since differential diagnosis may be impossible in areas where amebic and bacillary dysenteries are both prevalent, the use of this antibiotic is currently recommended for treating acute infectious diarrheas associated sith chronic protein malnutrition (kwashiorkor) Recent short term observations in South Africa base disclosed that tetracycline may be as effective as oxy tetracycline in the treatment of acute amebiasis 19 In preliminary investigations of the comparative efficacy of oxytetracycline and tetracycline, we find that these antibiotics have essentially the same clinical effect in amebiasis when cases are observed for periods of six weeks post treatment As a consequence of experiments showing that a combination of equal parts of orytetracycline and tetracycline produced a fourfold increase in inhibitory effect on C Instolzlıca, 11 muro, over that obtained when either antı hiotic w cally tion of antibiotics being the same as when either is used singly-we have observed no relapses during six weeks' posttreatment periods Inasmuch as antibiotics have little beneficial effect on hepatic amebaasis (hepatitis and abscess), chloro quine (not emetine) is the recommended drug, particularly for malnourished and debilitated adults, and for infants and young children 1 aus The early lesions of yays frequently are associated with chronic protein malnutrition, and they intensify the severity of the latter by fever and Malnutrition and anemia commonly accompany late yaws, pir ticularly when fabricated protein is lost in the serosanguineous fluid that seems from large ulcerous lesions or when destructive lesions involving the oral cavity interfere with nutrition Oxytetracycline, administered either orally nacin the treatment of both to orytetracycline ever, subsidence of ponemas from the surface lesions, as determined by phase microscopy, anu a remarkable im provement of appetite The progress of destructive lesions of the oral cavity and face (gangosa), deforming osteoperrostitis, gummis, and extensive ulcerous lesions of the extremities is arrested with one or tro and, occasionally, three courses of orytetracycline therapy as outlined above Treatment of these wanan anorexia L1 - ·Loughlin & Mulien Dehciency Diseases 29 lesions of late yans with oxy tetracycline not only directly improves the nutri tron of the individual, but also improves the physical condition of the adults so that they can again become productive members of the community 2011 though we have obsers ed Janisch Hertheimer reactions, particularly in infants and young children treated with procaine penicillin, ne have not encountered such reactions from orytetracycline therapy lle have seen such reactions, when they are accompanied by a sharp febrile response and anoreria precipi tate a sekere deficiency state oz aggravate an already manifest chronic protein malnutrition The fact that such reactions do not occur with ory tetracycline therapy is especially important then considering the treatment of yaus assocated ruth latent malnutrition or with manifest kuashiorkor Tropical ulcer (phagedenic ulcer) lle pres rously have indicated that the treatment of tropical ulcer should comprise systemic as well as local measures * The former included a diet high in calories high in protein content and having supplements of B complex vitamins and vitamin 1 Intimicrobial therapy systemically administered was considered optional but in that there sans is endemxc oxy tetracycline was administered according to the dosages used in the treatment of late yans Since ulcerous lesions of lite sans had re $ponded so favorably to topically applied oxytetracycline systemic therapy was supplemented with daily topical applications of crystalline osy tetracycline to the base and margins of the ulcer It was noted that acute ulcers reacted promptly to combined ory tetracycline therapy and to improved diet and that healing was complete within two or three sechs Chronic ulcers however were notably slower in their response with half of the ulcers healing completely within six to eight sechs Those patients with very extensic ulcers that had failed to heal completely with this theraps nes ertheless were sufficienth improved to be able to return home and resume gainful work Teramycis SF and Tetracy# SF The comparatne efficacy of orytetra cycline and tetracycline when administered singly or simultaneously in the same capsules with stress formula vitamins is being currently investigated in amebra * sans punta tropycal ulcer donos anosis lymphopathsa cherea and certain helminthases As noted before amebaasis yang punta and tropical ulcer in lartı arc commonly associated with deficiency states malnutrition and nr unlernutrition These antibiotics-orytetracycline and tetracycline when supplied in the same capsules aith stress formula vitamins have made it fossil le to determine whether there are definite advantages to administering the required and or previously deficient vitamins at cractly the same moment Is the antibiotics Ilthough the numers of cases of Indisidual diseases treated with or feira line ak ne tetracycline alonc oritetracycline with stress formula uttamins und tetracycline with stress formuli sitamins are still too len to draw more than generalized conclusions it might be possible neuert! cless to extrapolate Into the folal number rises of all the diseases Ifrute thus far reuman observations thisclose that what were consulered initially 1$ hypothetical advantages of Terrimycin si ani letracın sr are factual advantages (1) ukcrous lesions of late yans and tropical ulcer when treated with these antı biotic stress formula combinations manifestly heal more rapily than when ·296 Annals New York Academy of Sciences only the antibiotics are administered (2) ulcerous lesions of the large intestine either antibiotic to individuals with deficiency diseases associated with infection provide a safe balanced combination of these essential substances-a fact t1 at may be critically important in the treatment of infections when they are asso ciated with kwashiorkor (4) the stress formula vitamins exhibit no patent inhibitory effects on the antiparasitic activity of either antibiotic when they are used to treat the aforementioned infections (5) the absence of notable tovic reactions in 134 cases of bacterial protozoan and metazoan infections treated with Terramycin ST and Tetracyn ST in len Jork NY, as well as in Hartı is noteworthy (6) there is no apparent difference in the antimicrobial activity of either Terramycin ST and Tetracyn SF References 1 READ V 1948 Proc 4th Inter Congr Trop Ved an Ivalar a Intern Organ and Conf Ser I 5 1190 2 Postals S 1918 Proc 4th Intern Congr Trop Ved and Valaria Intern Organ and Coaf Ser 1 5 1210 3 W H 1943 Proc 4th Intern Cong Trop Vel and Malar a Intern Organ and Conf Ser I 5 1217 4 AYKROID WR 1948 Troc 4th Intern Congr Trop Ved and Malaria Intern Organ and Conf Ser I 5 1172 5 RAO NI 4 R 1918 I roc 4th Intern Congr Tror Med and Malaria Intern Organ and Conf Ser I 5 1202 6 T'LATT BS 19.17 Trans Roy Soc Trop Med Hyg 40(4) 379 BROCK JF & No 8 Rome 8 TRONELL HIC 1 9 TROWELL HIC & 10 AUTRET V&M BEJAR 195+ Sndrome Pol catenc al Infantil (kuashiorkor) and Rome South Taabc ndanVed P+ con ca) Seat: Ser No 12. Rome 10 DEAN RFA 1955 E African Med J 32 79 17 AGUIRRE T C CYRIQLE ROBLES & NS SCRBISHA 1953 Food Research 18 268 18 AGUIRRE F R BRESSAVI & NS SCRIMIS IAW 1933 Food Research 18 273 19 Institute of Nutr fion for Central America and Panama 1931 Innual Report 20 DAVIES I VP 1952 inn Rey Ved 3 99 21 THOMPSOV VD 1951 1 African Ved J 31 127 22 PAINE GC&1K PATVE 1927 im J Hy 7 73 23 MICHIOL B I 1954 Ann VI Acad Sci 67 761 24 DEAN RT 1 1954 J Trop Ved Hyg 67 283 25 TROU ELL HC 1945 [ Vrican Ved ſ 25 235 26 E Afr can Med Survey 1951 Departmental Ann Rest No 3 27 CHESTERN AV CC 11. 2017) 28 OTTO G H & J ! 29 CRUZ W O 1948 Lar 1 Interd 820 and Conf Ser / ·Loughlın & Mullin Deficiency Diseases 297 30 RHODES C P B 1 CASTLE GC PAYNE & II & LAWSOY 1934 Am J Hg 20 291 31 PAINE GCXFX PAYNE 1910 Am J Hyg 32 123 32 CHANDLER A C 1953 J Roy Fgypt Med Assoc 36 811 33 Atso J & B CASTLF 1946 Am J Med Sa 211 513 3+ DAS GUPTA CRJ B CHATTERJEE & P BASU 1953 Brt Med J 2 613-619 3> Fox II & 1 hondt 1954 Trans Roy Soc Trop Med Hyg 48 17 36 STOLL N R 1917 J Paras tol 33(1) 1 37 BELDING D L 1952 Textbook of Ci nica! Paras tology Appleton Century Croſts Mer York NY 38 TOTTERMAN C 1971 Acta Vel Scand 118 410 3 yo Juno) 1931 I URSANEX 15 193 Ley i Neuws 52 SRIRAMACHARI SAVDAN DICHAR: 1937 Ind an ) Wed Sci 8 31 53 BROCK JI 1955 Sutr! Revs 33 1 51 DAVIES J P 1952 Afr can led ] 1 141 55 ROCERS L 1911 Ind an Ve Gaz 46 47 $6 London England 58 los 535-501 59 GO Xoc Troy Ved lyg 47 536 61 STANIER VAI GIOVES 1954 Br J Nutnt on 8 155 02 TRENS L & BROCK 1954 SV can ) ( Sa 6 20 63 BERONIS WAYBEX E in Assnc it on th 11 Horst & C D SES VIV 1934 S AS can ] Cin Sci 6 35 61 BUSSANI I TRATET & T I Forg 1953 Vied trop 13 977 65 WILLS I ANT BELL 151 Lancet 1 82) 66 TROSELL HIC 194) Trans Roy Soc Trop Vied tyg 42 117 67 LOF ENT nplrg) G1 V tchell (9 Roy D 12 256 Butterworth & Co (9 HOTA YA ARA KRIS YAMA 012 Ind an Ve Gaz 77 139 70 TANJA DALMO 14 In an Vel Gas 79 17 1 R AAR vih VRHY COLUL & RA ALLE 1915 fod an Veel Caz 80 129 DEXTER HA 1960 1ch Drmitol Sysh lol 62 (24 UTIN E IL CIRCE I JOSEP 1953 Ant to Innual 1933 54 ი:ი legge + GOIERE 1952 Informe 76 8 We 25 311 J Yet Research 31 Tranu Ro Sr Tron Ved il 48 374 11 WFLD TRUHI 1 1 can let J 31 lt ·1 298 Annals New York Academy of Sciences 82 SCnnco + NCPR & Co Proc Scient Sessions 8th Ann Veet 83 D Chud Feeding British Ved Research Majesty s Stationery Office London England 81 OOBAN HAPC 1953 Documenta Med Geograph et Trop 6 193 85 DAVIES JAP 1931 Layer Injury Trans 9th Conf Jos ah Macy Jr Founda tion Melork NY 86 VECIIELU P 1950 Ann Paed at 176 319 87 THOMPSON MD &H CTROWELL 1952 Lancet 1 1031 89 HILL I 89 GIBBON 90 BAO P 91 WATERL Brit Office London England 92 WILLIAMS CD 93 WILLIAMS CD 94 JELLIFFE D B 95 SINTON JA 193 96 GUNASILARA S T 97 VICKERS J & 98 LOUGHLIN F H & 99 STOLL NR 1951 Paras tic Infections in Man Most EQ Columbia Un v Press Ne v York NI 100 Lorcytry EH&S HI SPITZ 1949 J Am Med Assoc 139 997 101 LOPCJILIN E INR STOIL 1947 Am J yg 46(2) 19) 102 TRINCAO CL GOUVEIA F PARRIERA & A I RAACO 1953 Bull soc pathol Exotique 46 440 103 KHALIL V 1921 Rep & Notes Publc Health Laborator es Vin stry of Inter or Lgypt 61 101 ROBERTSON SC&M C DOILE 1936 Proc Soc Trptl Bol Med 36 374 105 GARNIAM PCC 1954 E African Med J 31 155 106 VIAEGRAITJI BG 1952 Brt Med J 107 RAFFAELE G&P M CARRESCIA 195+ Rv malario) 33 47 108 VECHELYIP 1953 Bull mém soc méd hop Pars Nos 26 & 27 896 109 CHANDLER AC 1953 Roy, Egypt Aled Assoc 36 533 110 SATBOY LW 111 SIIIPLEY A I 112a SELYE 11 112b SELYE 1 ta Endocrinologica Vontreal I yol 112c SELYE H 1950 Acta Inc Montreal P Q Canada 113 LOCAL E I RAPPATORT VA JOSEPH W G MOLLI 1931 Lancet 261 1197 114 LOT GUILIN EN & HG VULLIV 1954 Ved Clin N Amer ca 98(2) 591 115 LOUCILIN I II & MULLIN The treatment of a scar ass with preraz ne call WELLS I RAPPAPORT & A JOSEPH 1952 J Trop Med Ilyg 3(5) 833 AVDER ERFF & CA FALCO 1948 J Bol 119 HITCITYGS G H Y SHERWOOD & II VANDERl El 120 Reports of Societ 121 LOUGHIIN EH 8(3) 150 122 VARTIN GIF 11 FRYE 1953 J Am 123 KILLOTGI J H 17 12+ ELSDON DEY R en York 125 VCHIARDY G & FRIE 1954 J im Vled csoc 164 616 126 HARD AIRT I 150\&GA VARTIN 1952 Ann VI Acad Sc 56 10 0 127 SENECA JI & C BERCENDAHL. 1954 Am J Med Sc 228 16 nno TT Fric cloped a ·Loughlin & Mullin Deficiency Diseases 299 129 LOECHLIN E H&A ! JOSEPH 1951 Antitotics & Chemotherap: 1 76 129 LOGHIN CHA A JOSEPH & DEVALIEX 1932 Caz med France 59 1035 130 LOLCELIV FHA A JOSEPH & F DEVALIER 1931 Ant botics & Chemotherat) 4 155 131 Cl. LV 4RAES F \EXY & TRAVASSOS 1950 Hostal Rio de Janexo Brazł 38 29 132 Avroro O&N HINDLAY 1931 Traps Rnt Soc Trop Ved lig 45 261 133 LOUCUN ETA A JOSEPH & SCHAEFFER 1991 Am J Trop led 31 26 Discussion of the Paper DOCTOR NORMAYR STOLI (Rockefeller Yusufnite ſ lledical Research Tea Jork, V 3 ) Toa parasitologist obviously there were many things in Doctor Loughlin's paper which are of interest I want to raise a point for Basley h Ashford in connection with hook worm You remember that hoohstorm which is an infection related to trematodiasis was described hy Batharz in Egypt about 100 years ago and about 10 years later by llucherer in Brazil The great interest the medical world tool in this disease occurred somen hal later first in the late 1870 s following the construction of the Simplon Tunnel in Europe and the miners anemia that spread from and then in the late 1820 s, with the discovery that anemia in Puerto Rico was essentially a hook worm anemia It was soon determined that the degree of severity of this disease and it tooh about three decades to make this decision-mas related to the number of worras that the individual had That made it very simple People with small numbers of norms had little manifestation of disease People with large numbers of vorms had a great deal of such manifestation Darling went so far as to say that the degree of depression of hemorlobin tad a linear relation to the number of worms As he said 100 norms representa such and such depression of hemoglobin llaving clanfied the problem in this way we then discovered that there were people trho theoretically should have had but dzů not have very deep anemias These cases occurred particularly in certain areas A general correlarion of the theory was obtainable in some parts of the world but not in others Thuis dificulty puzzled the hooh norm workers a great deal The discrepancy was ascribed to race It was ascribed more recently to the development of the experimental pattern of immunities a word we never used in connection trith norm diseases until alout 20 years ago The dulically was asenbed particularly to lad nutrition by Ishford agut due to the emphasis he put on the idea I think you would forgive me if I quote a les sentences from his autobiography published in 1934 the year of his death Ashford starts for the benefit of intelligent readers both lay and professional tout here and abroad ne amply achnowledge the very important place laken nutritional unbalance in producing the picture recognized all oser f'uerto hic is la unitu or in other words honk norm diseace But the undeniable fut remains that this was not a nutritional but a parasilk anemil That it scapable of curc and ol prevention by specií citrugs and the use of latrines refter incly is seen from the hxtory of the sensational transformation ni a helpless anem at deth s door to a ruddy si nous laborer simply on the expulsion of these tiny worms and without any alteration in his accustome! fool 11 then dres the influence of poor dit come in? Thus parasites lus {xorls falanced and bring fatahtes and serious gra les af anemia which thford om 194 Sold er in P. Monowil lewat

·300
Annals New York Academy of Sciences
Am. fram af ter nlane
ha
A
han the
.
Puerto Ricans and much more meat It is therefore no longer a medical
problem but a sociologic one of the very first water

·\UTRITIOTAL DISORDERS IN BII HIRZI IL CASIS WITH HI P41OSPI CVIC ALTECTIO\ Hy A H VOLS I Fi VofT. V huuT IB, I 11 DEFR 111 V 1 ASHEV hasr 111 Tacully / ed ine Cair I CYN one ova ol Bulhar.ja deposited in portal tracts Parenchy matous changes occur in these formations very late (FIGURE 1a) Although most Egyptian peasants do not consume alcohol they are fre quently subject to nutritional-deficiency diseases as their staple diet consists of carbohydrate mostly muze and their deficiency is conditioned by a heavy parasitism and by chronic intestinal infections accompanied by intermittent or prolonged diarrhea Their nutritional cleficiency is also precipitated or aggra Sated by hepatotoxic and antibacterial drugs used indiscriminately for treat ment (FICURE 2) It seems that patients hepatic bilharziasis are vulnerable to virus hepa titis becoming infected enterally or parenterally during the course of ant bilharzial treatment (FICERES 3a b and c) Such multiple etiological factors lead to a complicated type of cirrhosis in acldition to the predominant bilharział A unique opportunity was seized to study the nutritional aspects of three types of hepatic fibrosis and cirrhosis in a group of 96 pxatients living on the same diet and in the same environment The etiology of hepatic disorders as based on histopathological grounds' was predominantly parasitic in 40 per cent nutritional in 32 per cent and viral in 28 per cent all having urinary or intestinal types of bulharzial infestation or both In all of the cases studied specual stress was placed on the nutritional deficiency disorders as manifested clin.cally lochemically and radiologically In ad liti in histopathological changes in the later were studied through needle Dropsics uses in the prelomu a lly suurilta nal group were churacterized by 1) Likh inci lence of resuluil an i recurrent symptoms of pellagra (80 per entendemuc parotitis a few cases hung cnlarged lacrimals as well anix lasin me thout circumcorneal injectton and vitamin I deficiency Periph aral neuritis in fcd in most of these cases (FIC LRF fa) Irejuen of moulerite and kevere anema or prolonged larrhea Huler iniken of hejutomegals with smaller «pleens in only 5 per shrunken night I be of the liver with moderatels enlarged spleen was noiect (+) tarls arxearance of ana orci affecting both upper and lower extremities inian cffusion in one si le of the curl cauty ( [igher incidence of en Ixrinal imbalance in the form of dwarfism in int ·302 Annals New York Academy of Sciences Figut 1 (a) B tharzial periportal fibro is (b) B lharz a ora in portal tract 11 sh mag bustion antilism, alopecia of the trunk and pubic areas, as well as unilateral or bilateral y necomastia? (FIGURES 4b, c, and d) In one case, s) necomastia became fore apparent after Fuadın treatment administered in the hospital (6) In tuo cases, hypervolemia was noted, with engorged neck veins in the bsence of congestive heart failure or emphysema ·Mousa el al Disorders in Bilharzial Cases 303 ... FUEL 2 Nutritional fatty of Itrat on in Marzieller (7) Minimal symptoms and signs of portal hypertension whether mani fested by dyspepsia, hematemesis, or dilated abdominal veins Brochemically and radiologically, the nutritional group showed (1) A higher incidence of hypoallyuminemua and a low hemoglobin percentage conditions that are easily corrected by diet Thc dysproteinemia could be differentiated in three groups, as shown in TABLE 1 (2) Liver functions are less affected in the viral group and simulate their condition in the late stages of hepatic bilharziasis They showed mild hytoglycemia with relative insulin resistance, indicating earlier impairment of the carbohyxirate function of the liver (FIGURE )) (3) The 17 helosteroids were found ton in all cases, wlule the effect of adrenaline and of the ACTH test on cosinophils excluded primary hypoau renalism I strogenic inactivation is dependent on the availability of the Vitamin B complex and co is markedly more deficient in this group than in the other two groups (+) To hyperbilirubinemia nas met with, a condition that is constant in the viral group and terminal in some of the bilharzial group (9) Anth fluid is low in protein content and specific gravits, as well as in cellular count which contrasts with the higher figures for both in the other to grouris (6) Ilypochlorhidria, which responds to histamine, and defickt nt juancreatic juices, as cramined by a modific Viller Abbot tube alter injection with I'rostigmin, are higher in incuience than the other group They show marked improvement alter prolongeri dietetic therapy, especially shen vitamin is included ·304 Annals New York Academy of Sciences FIGURE 3 () Postinfective hepatit s cirrhosis in a case of bithartias s (7) A percutaneous lienohepatography showed milder grades of portal sein dilation and Linking of the splenic vein (FIGURES 6a and b) Visualized col laterals, however, were not met with in this group, while the intrahepatic portal venules were constantly filled, a condition seen in late bilharzial cases The portal circulation time is not differential, as the presence of collaterals compensates for the delay in cases with portal hypertension Hiatus hernia was found in the chronic ascitic forms of the three groups (FIGURF 7a) (8) The intestinal pattern, although slightly affected in the three groups was more apparent in the nutritional cases with a return to normal in the cases followed (FIGURE 8), affecting mainly the junction of the jejunum with the ileum (9) Steatorrhea was mild and infrequent, but no case of megalocytic anemia was met suth in either group (10) The incidence of toxic jaundice after Diodotrast injection during the recording of lienohepatographies was found to be commoner in cases with parenchy mal liver damage Summary and discus51013 The findings described above clarified sanations in the clinical picture and the course of endemic hepatic bilharziasts among

·305
Mousa et al Disorders in Bilharzial Cases
Ficht) () Poul ofert ve bertitus est. It is of Dharau
ta morrbage dittat al Care (viral bepat lu)
{E} Acelebratic Accrous with
'vices to us when treated collectively with antil
barzzal or common anthelmintic drugs it must be bome in mind that I

·300
Annals New York Academy of Sciences
Wie
Ficon 4 (a) Endemic parotius mith enlarged lacrimals (b) Gynecomastie developed durchs 317
barz al treatment and d) Gynecomaque ip bepatomegaly Bredominantly of postdutritonal type

·307 Mousa et al Disorders in Bilharzial Cases TABLE I PRE ral Autr tional Paras tc Bhul polen Allurin Duminished (easily correcter by dict) - a Gl butin & Globulin #lormal Dimuished (not easily cor 1) diet) ++ + ++++ ++ + ++ Globulin Joot 90 do 70 601 avat poote ) 30 CO 30 20 101 7 1 14 2 (la s hours > An aspte of inculis sitive (29) aod three on plus of Pelat11. 10 alin resistant cura, POLRES tas ng hypoglycem Anth insulin resistance and delayed return to normalan hepat e bithart as th nutrional del cen y d seases comited to a normal control dashed curve) F1G21 6 ) Lurer beretomby is b Durslalakes.

·30S Annals New York Academy of Science b с FIGURE 6 (6) L ver liepatography in nutnt onal cases (c) Mony sual zed portal venuley la 1 er bi harzial cases Collaterals are seen million peasants are so treated yearly in Egypt in accordance with the obliga tory scheme of the antibilharzial campaign In cases having clinical nutritional deficiency diseases with viral or bilharzial liver, the absence of fatty hepitic changes could be explained as follows (1) the diet may be deficient in certain vitamins, but sufficient in lipotropic factors, (2) a lack of nicotinic acid may bloch transformation of choline into betaine thus blocking the transmethylation function of choline but accentuating its lipotropic function and (3) a substarvation diet, as in cases with prolonged diarrhea is less apt to induce hepatosteatosis than a partually deficient diet

·Nousa et al., Disorders in Bilharzial Cases
309
2
b
) Esophageal ar X IR b aral at
Fretet? (a) latus hernia
In conclusion, the above studied cases could be grouped nutritionally as
cases in which (1) nutritional deficiency was the chief cause of liver invoke
ment, (2) hepatic involvement incapacitated the patient economically and
placed him on a lower nutritional rating, (3) hepatic disease or portal hyper

·310
Innals New Jork Academy of Sciences
Fick p mn shed leo ejunal pattern
tension interfered seriously with digestion and absorption (4) the liver, as the
heart of the metabolic processes showed the effect of acute or chronic injury
in its nutritional function
References
1 ERPAN VIH VOUS A Vofty V KHATTAD & V HASHEM 1935
Gaz l'aculty
Med Cairo In press
2 MANDY M&M BASALY 1955 VD Thesis Cairo Egypt
3 MAJDY V&H SENNA 1955 MDThess Cairo Egypt
4 RAGHIEB V HERPAN A DEES & M MAHFOUZ 1955 J Egypt Med Assoc 38 159
5 DEEB 1995 Gaz Faculty Mled Cairo In press

·ALTERED PROG\OSIS IN THE DIABFTIC WITH INFECTION By Herbert Pollach College of Physicians and Surgeons Columbia Unirersity Neo York ! Elsew here in this monograph Doctor Jonathan Fyans Rhoads has presented an etcellent discussion on the problems concerned with nutrition in relation to infection to surgical convalescence and to other clinical aspects of nutri tional disease as seen in hospitals Most of the worl that he has presented was based upon experimental work both in humans and in animals lle have in our medical practice a naturally occurring classical example of this relationship of nutritional disturbance to susceptibility to infection 10 diabetes mellitus Little attention has been paid to this interpretation of these phenomena by virtue of the acceptance of traditional authority The other aspect of the problem of the relation of infection to metabolism is dra matically presented in every case of ketotic acidosis precipitated by an infec tion This is a vicious cycle which must be understood Many readers will recall that before insulin and even in the early insulin era when regular insulin was first introduced statements were made that increased concentration of sugar in the tissues was the cause for the severity and frequency of infections This was d ctum This we accepted and no body questioned it The professor said so and that is the way it went The introduction of regular insulin enabled us to control the blood sugar levels to some extent This limited control of blood sugar concentration did not make Very much difference in the frequency and severity of infections Carbuncles of you will recall were very common in the days of regular insulin Death rate from sepsis was high in sp te of the fact we could control the ketosis and acidosis associated with the infection The mortality rates ran as high as 50 per cent With the introduction of protamine zinc insulin however the whole pcture has changed the long acting insulins have completely altered the prognosis of the infection in the diabetic As a matter of fact whether or not the patient has glycosuria or rigidly controls the glycosuria the immediate effect of the long acting insulins is essentially the same We know that these people on the so called free diet or free glycosuria group frequently have blood levels up to 300 mg per cent with glycosurias in the order of 100 gm a day as sho in by Tolstoi in his excellently controlled series Even in Tolstoi s group did occur it was quite ses ere Tl e typical type of tuberculos s in the diabetic In the preinsulin and early insulin era was the so-called galloping consumption m ka mn 1 311 ·312 Annals Neu York Academy of Sciences tic hormones and the destruction of insulin in the body, interference with glyco gen supply and a whole host of hypotheses that were purported to show why diabetics were so susceptible did not erplain this With the introduction of the long acting insulins and with a much better understanding of the whole problem of nutritional status today, we can I be lieve, interpret at least clinically if not experimentally, some of these facts One of the major duierences between the action of the protomine zinc insulins and water soluble insulins is to maintain positive nitrogen bilance even in the face of extensne glycosuria This is the key to the difference If you will recall some of the early work which was done by Hilder Boothby Atchley and Loeb in decontrolled diabetics, one of the major facts they all observed was the loss in protein that occurred with decontrol We repeated this work in our own metabolism ward and were able to show that the nitrogen losses within the first few hours after the precipitation of even a minor hetotic episode could be as much as 11 gm of nitrogen in a few hours Obviously this repre sents a tremendous protein dant regular use of protamine zinc insulin In the diurnal variations in the cc the positive nitrogen balance exists ut nours When the diabetic is treated exclusively with suort acting insulin this phenomenon does not exist Transient hetosis and the concomitant negatne nitrogen balance frequently develops in the long over night period and is detected in the early morning urines The hetosis disappears during the day under the influence of the injected insulin and reappears during the night when the effect of the last dose of insulin has been dissipated That meant there were periods of decontrol and ner and of control With the long action insulins we no lonnaand hence no diurnal per ad IS m 1 fo esoteric solutions that ha sussion of infections would be complete without recognition of the role of the antibiotics Once infection has dei eloped nti biotics play the same role as in the ing actinne! The c S . ul instin 1 2 lut ptas 1 It uu vien doma to some extent bolic rate physiolo I ne saving treatment its use acu Obviously a malnourished loving patient was better than a well fed dend one 11 hen insulin was introduced it was used in connection with these minimal diets The anxieties associated with the process of learning to use insulin most efficiently resulted in the retention in use of these minimal diets Is time went along and experience and con us ·Pollach Altered Prognosis in the Diabetic 313 fidence in the use of insulin nas gained larger and larger amounts of food sere prescribed The basic concept of undernutrition however persisted The attention of the physician was so sharply focused on the control of the carbo hydrate phase of the condition that he frequently lost track of the overall contents of the diet and the state of nutrition of his patient It was eas er to control glycosuria with limited food intales than wath expanded diets Fur thermore the majonty of patents being treated for diabetes in the early insulin day's were elderly people whose requirements as will be pointed out later L It is axiomatic that good health is dependent on optimum nutrition In order for the individual to have a sense of well being and be able to carry out his da ly work the food intake must assure an adequate supply of nutnents from calories to trace elements Variations in the body s ab iity to store cer tain of these essentials lead to a necessary margin between minimal daily re quirements and actual recommendations In addition one must provide for increased needs in 12mes of metabolic stress The dal etic as is well known is pecularly subject to these metabolic stress periods The problem is to set up recommended allowances of nutrients for the d abetic and to educate the phy's cian in their use This will insure grenter resistance to infection ·RECAPITULATION AND PROSPECTS By Howard A Schneider The Rockefeller Institute for Medical Research, Ac I ork, A I Nature, to be commanded, must be obeyed -- RACIS Bico Seven years have passed since a conference was held in the United States on the topic of nutrition and infection On that occasion, at a meeting held in Minneapolis, Mian, by the Society of American Bacteriologists, emphasis was ח + 1 5 what different and more heterogeneous base, concerned less with experiments and weighted more with clinical experiences and epidemiological concerns I think it is also fair to say that this conference itself was an experiment, almost a "preliminary experiment" And, like an experiment, it was the test of an hypothesis that, in turn, rested on certain assumptions Now, no one in these papers has explicitly said that this was so, and my mention of assumptions is an uninvited assumption in itsell I find this necessary, however, in order to epitomize the rather heterogeneous contents of the papers presented here That the papers presented are a heterogeneous lot is, I think, almost an historical necessity, for it is now more obvious than ever that there is no clear and simple connection between infection and nutrition that has won universal assent Certainly the experimenters were aware of this lack of assent before beginning their work and, now that we have studied their reports, assent us lacking still At best, I am afraid, we have made but a beginning A moment ago, I spoke of an unspoken hypothesis that brought us together for a fresh wrestle with this recurring hope and problem I think that the working hypothesis in these papers has been that, by a re-examination of the re examination Unfortunately, no matter hos meticulous this examination might be, it does not necessarily follow that a meaningful connection with another discipline, the study of infectious disease, is thereby established No, libe so much else in science, we are confronted with an ad hoc necessity of searching for ezidence of the supposed connection between nutrition and in fection On such an occasion, plausibility is not enough, the construction of possible and labyrinthine connections is not enough, only proof will suffice The strategic basis of modern nutrition rests on the operational consequences of the differences between plethora and deficit in the nutritional ens tronment The experimenter arranges these differences, the clinician and epidemiologist assess them as they make their appearance in the natural world With feu exceptions, the contributors to this monograph have leaned toward the vien Clark, P Fatal 1919 Bacteriol Rys 15 99 314 ·Schneider Recapitulation and Prospects 315 that in striving for an abundance, in the nutritional sense, ne are on the side of the angels, and that, when we come to contemplate the consequences for infectious disease of this abundance, only the happy end of an increased reststance confronts us Now, as experimenters in this field hase been aware, this just is not so For example, students of snfectious disease hase long recognized that in viral diseases it is only the well nourished host which has matimal susceptibility, and it is the malnourished host shich has an enhanced resistance The nutritionist must realize that it is an inadequate view to con sider the host as a fortress, staying of infectious invaders, and that nutrition can strengthen the metaphorical walls, heighten the toners, and reinforce the garnison To believe this would be to fall into the anthropocentricity that students of infectious disease have long abandoned If nutritionists wish to make an effective contact with the study of infection, they must recognize that the reasons are clear and cogent for regarding infectious disease as an open ecological system in which the opportunistic forces of evolution lead infectious agents to occupy, frequently only temporarily, the ecological niches which the hosts provide the satisfactory nature of this ecological niche is thus equated with susceptibility, and nutrition, then, is as positively implicated in sus ceptibility as it is implicated in these papers with resistance I think there is one more hidden assumption implicit in many of the papers presented here This is the silent acceptance of the myth of panresistance, the idea that "resistance to infection" is a status embracing resistance to all in fections That this has been shown to be not only a myth, but an incorrect myth, we owe to the geneticists who have clearly demonstrated, by inbreeding and selection, that it is possible to assemble into one and the same host sus ceptibility to one disease and resistance to a second This means that it must be anticipated that in relating nutrition to infection there must be introduced some notions of specificity, ie, specific nutrients must be examined in relation to specific infections In my view, the papers in this monograph do not adequately reflect this necessity So much for general comments Let us now turn to some of the papers them selves Among those addressed to the effect of nutrition on infection, I think five call for more than general comment Doctor Hill's paper on high vitamin levels and the resistance of chicks to fowl typhoid is illustrative of the dif ficulties in experimentation in the field of nutrition and natural resistance to infection The variance encountered in experiments of this kind demands a more complete statistical analysis than he has provided As his successive experiments show, more analysis is needed of the variance u sth his experi mental groups before we are justified in placing any reliance on the differences Belueen groups Indeed, in some of the later experiments some of the original differences have not been duplicated, or are ret ersed The paper of Doctor Rhoads on the association between hypoproteinemia and postoperative infections is an interesting attempt to probe clinically the ideas of Doctor Paul Cannon, so frequently alluded to by many speakers at the conference Doctor Rhoads is on sound ground it seems to me, when he points to the necessity of adequate restoration of protein in the surgical patient for gond surgical reasons I concur also in his reluctance, however, to conclude ·316 Annals New Yorh Academy of Sciences that the higher incidence of infectious complications is causally related to re duced protein concentrations Now that Doctor Rhoads has led the way, we may expect some definitie studies on the matter It is to be hoped that such studies will be designed to test directly the effects of various protein intales that are referable to purified protein, such as casein, in order to avoid the ambiguity of concomitant variations in the intake of other, unknown sub stances The protein question leads naturally to the question of antibodies Doctor Axelrod's thoughtful paper, by restricting los analysis to specific nutritional entities and to specific antigenic processes, has made a specific and important contribution If, as Doctor Axelrod has beautifully demonstrated, some of the vitamins are involved in antibody biosynthesis, one is tempted to inquire (1) whether this is an effect on the kinetics of antibody formation and deficient animals are merely slowed, but not stopped, and (2) whether deficiencies at levels lable to be encountered in human populations are likely to affect antibody synthesis significantly Doctor Axelrod is of course, quite correct in caution ing against a too facile transposition of his results into terms of the actual in fectious disease Indeed, it may well be that his methods may find their most important use in the understanding of the intricate processes of protein syn thesis In addition to considering the effect of nutrition on infection, there has also been some consideration of the etfect of infection on nutritional status It would appear, from the papers presented here, that in the prolonged episodes of parasitic infestations (infections?) the burden of disease increases some of the nutritional demands of the host Doctor Suzman's discussion brought forward some interesting data on the precipitation of nutritional deficiency signs by infectious episodes It is apparent that the whole subject needs more in vestigation No modern discussion of infection can be complete without consideration of the antibiotics As the paper of Doctor Milberg and Doctor Michael points out, the prolonged use of antibiotics is not without nutritional hazard due to diarrhea and anoreya It would seem that the clinician would best insure that these drains are compensated The alleged effect of such supplementation in reducing the incidence of undesirable adverse effects of antibiotic therapy is in dou The participants in this conference are indebted to Doctor Kunsell for a lems These nutritional problems of electrolyte balance, protein Lidou. etc are probably best met head on, as nutritional problems in themselves But in all candor, se still lach evidence that the nutritional manipulations thus un dertaken enable us to enter by the back door, so to speah, and that these manipulations by indirection via the mimicry of those end effects of the endo crines, which are presently known affect the issues of susceptibility and resistance to infection It has probably struch the reader, as I am sure it has the participants that ·Schneider Recapitulation and Prospects 317 in striking out to encompass the subject of these papers in its outline some details here and there have been lost from sight This may well be true If this has occurred it is probably due to the fact that when nutrition seeks to effect a junction with the problems of infectious disease it must take into account the fact that the feld of infectious d seases has a well established sys tem of values a hierarchial order of procedures that are recognized as im portant and effective ways of coping with infection High in this hierarchy for example are vaccination chemotherapy and antibiosis On the face of things as they are now it must be adm tted that nutrition finds a lower and lesser place in this hierarchy Indeed as our knowledge of nutrition and metabolism has groin we have been struck by the growing interrelatedness between its various items in the T think we shall also be anare that value judgments will have to be made and we shall insist on separating the demonstrable and important from the demon strable but trial In this search for valid bases of our value judgments I think that nutrition ists would do well to recall the great lesson non receding in the history of their science That lesson of 40 years ago was that nutrition was not then and may never be a closed deductively formulated science Torty years ago chemists wrestled with the problem of a diet supporting life and growth and found the solution to their problem not in quantiative manipulation of the items they hnen but in an appeal to the natural world for new qualitatively important items the vitamins Lest we commit the same blunder and the ultimate nutritional heresy let us be aware that nutrition embraces the whole world of natural foods and let us remember that there may lie in wait for us new nutritional entities that if ne but properly seek them out may well be the real bridge into the world of infectious disease Let us at least ask the question Fnally in such a clouded crystal ball as hes before us in these pages I think waters

·No text on this page.

·No text on this page.

·No text on this page.