The Intestinal Phase in Urologic Disease II lhe Role of the Colon in Uroinfections By ROBERT TURELL, M.D. N E W YORK, N E W Y O R K

another paper (1), attention was directed to the I Nembryologic, a n a t o m i c , and physiopathologic relationship that exists between the intestinal and the urinary systems. It was also shown that the colon, as well as the entire intestinal tract, could act as a wide potential portal of entry for organisms into general circulation, or act as a serious focus of infection. Reiman (2) also considers "the various inflammatory states of the digestive tract such as appendicitis, cholecystitis, colitis, as well as constipation and hemorrhoids," as important focal infective factors in uroinfections. It is certain that, in infections of the urinary organs and passages caused by the colon bacillus group, a large percentage of these organisms come from the intestinal tract. M. Solis-Cohen (3) presented evidence from the literature in support of this view. He directed attention to the preponderance of infection with colon bacilli; bacilluria among females during attacks of gastro-enteritis; the more frequent occurrence of right-sided lesions on the theory of direct lymphatic extension from the adjacent cecum; colon stasis of fecal current; damage to the large intestine as by constipation, and to colonic focal infection. Kretschmer (4) found that 30 per cent of his patients with renal infection of the colon bacillus type gave a history of constipation. Some of his patients suffered from inflammatory and suppurative disease of the colon and anorectum. He firmly believes that these lesions produce and perpetuate uroinfection. Of great importance in these studies is the knowledge of Nissle's work, which established the fact that different strains of colon bacilli differ qualitatively and possess different antagonistic colon bacillus indexes. Utilizing Nissle's results, Peretz and his associates (5) studied seventeen cases of uroinfection caused by the colon bacillus group. In fifteen patients they found associated intestinal disease or dysfunction. In all instances a definite qualitative relationship between the colon bacilli recovered from the urine and the feces of the same patient was found. Peretz concluded that there exists a definite relationship between infection in the urinary tract and pathologic states in the intestinal canal, as well as between the types of colon bacillus present in the urinary tract and the colon. The therapeutic deductions are of course self-evident. The recent study by Baehr, Shwartzman and Greenspan (6) on B. friedlander infections is of vast importance. They showed that this organism is a common intestinal habitant, and that it may be recovered from suppurations due to the perforative lesions of the appendix and colon. Their views are supported by Dudgeon (7), who found B. friedlander in the feces of 5.5 per cent of his cases, but felt that "these organisms were m o s t commonly found in association with Submitted February 4, 1939.

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an abnormal condition of the intestinal tract such as diarrhea, colitis, and in the later stages of typhoid fever." Like other enteric organisms, B. friedlander may gain entry into the general circulation and be excreted by the kidneys. It is the contention of Baehr and his collaborators that in the presence of obstruction, the urinary passages and organs may become infected. However, no obstruction existed in six of their fifty cases of urinary tract involvement. Another interesting study is that of Neter (8, 9, 10, 11) who reported three cases of uroinfection caused by the dysentery bacillus, two of which were carriers. Dietrich (12) recently reported four cases of pyuria caused by dysentery bacilli. It is believed that uroinfection may follow or accompany an attack of intestinal bacillary dysentery, or it may occur in patients who present neither a history nor clinical evidence of intestinal bacillary dysentery. Neter (13) also reported two cases of infection of the urinary tract due to Shigella alkalescence. Stewart (14) reported a case of pyelitis of pregnancy due to the Flexner type of the dysentery bacillus. In his case the stool cultures were negative for the Flexner dysentery bacillus. Another recent case of pyelonephritis of pregnancy caused by dysentery bacilli was reported by Neter (9). In this instance the ~ame organism was found in both the feces and the urine. The foregoing studies suggest that infection in the urinary tract with B. dysentery and allied species, originates in the intestines, notwithstanding the fact that bacillary dysentery has been regarded as an essentially localized intestinal disease. In the consideration of urinary tract infections, it is surprising to note how little significance has been attached in the past to the inflammatory and suppurative ano-recto-colonic lesions. The terminal portion of the colon is continuously bathed in bacteria coming from the upper respiratory and the upper digestive tracts. It has been established that many people possess preformed anal ducts which empty into the crypts, but lead to racemose multi-glandular structures situated in the perianal tissues (15). Embryologically, these anal ducts appear at the time the prostate and the paraurethral glands do and possess a histologic resemblance to them (16)~ These ducts are lined with a secreting columnar epithelium, which in the branches becomes cuboidal (16), and are believed to be natural incubators for bacteria. The invading organisms may spread into the surrounding tissues producing inflammatory and suppurative states of local and focal significance. Hirschman (17) and others (18), have called attention to the significance of the crypt infections as foci. These observations have been amply substantiated. Hemorrhoids, have as a rule been looked upon as innocent lesions, and have

TURELL--THE INTESTINAL PHASE IN UROLOGIC DISEASE r a r e l y been t h o u g h t of as foci of i n f e c t i o n . H o w e v e r , R e i m a n (2), K r e t s c h m e r (4), and o t h e r s , have recognized t h e m as possible loci of infection. M a l m g r e n ' s (19) pathologic s tu d i e s of h e m o r r h o i d a l t i s s u e removed at operations, showed some evidence of inf ect i o n in all sections. T h r o m b o s i s was f o u n d by him almost c o n s t a n t l y in all t y p e s o f h e m o r r h o i d s . Th e f a c t t h a t t h r o m b o s i s is an e x p r e s s i o n of an inflammat o r y process has be~n g r e a t l y u n d e r r a t e d . I t is of i m p o r t a n c e to r e p o r t case h i s t o r i e s of p a t i e n t s seen d u r i n g t h e p a s t n i n e y e a r s , w h i c h illust r a t e e x e m p l a r y t y p e s of th e p a t h o l o g i c processes discussed in t h e p r e c e d i n g d i s s e r t a t i o n , and w h i c h s u g g e s t effective t r e a t m e n t . It should be observed t h a t n o t all s y m p t o m s and o b s e r v a t i o n s may, however, be f o u n d in any single case. T h e t e r m fecal stasis, as used in t h i s paper, denotes the evidence of feces in the colonic circuit, especially in the cecum and ascendin g colon, a f t e r th e t a k i n g of 30 to 45 cc. of c a s t o r oil wh i ch is followed by two or m o r e bowel e v a c u a t i o n s . This evidence was elicited r o e n t g e n o l o g i c a l l y in t h e s u r v e y films of t h e a b d o m e n w h i c h w e r e t a k e n on s e v e r a l d i f f e r e n t occasions. M a n y of the p a t i e n t s had had complete urologic s tu d i e s as well as v a r i o u s f o r m s of accepted urologic t r e a t m e n t w i t h o u t p e r m a n e n t beneficial effects. H o w e v e r , th e s e p a t i e n t s r esp o n d ed well to t h e r a p y described in this paper, and have rem a i n e d well. Case 1. S. T., a physician, 26 years old, had had an attack of right renal colic with u r in a r y frequency in April, 1929, when he required morphine. Several similar episodes occurred in the past which had always been relieved by enemata. The only other pertinent point in the history was constipation of long standing with occasional blood streaked stool. Physical examination was normal throughout except for spasm of the anal sphincter. Routine urinalysis showed a moderate number of leucocytes, colon bacilli, and streptococci. A survey roentgenogram of the abdomen showed evidence of stasis of fecal current in the cecum and ascending colon. No abnormalities in the urinary tract were observed. Immediate therapy consisted of castor oil catharsis and colonic irrigations. Subsequently, regular bowel habits were established with the aid of a proper diet and agar. During this regime there was a continuous diminution of the pathologic elements in the urine. In April, 1937, following a period of anxiety, there was a recurrence of constipation. Right renal pain and pathologic elements in the urine followed. The immediate therapy consisted of colonic irrigations and castor oil catharsis. The response was prompt and dramatic. Since then constipation has been avoided with the aid of acidophilus milk and agar. An excretory urogram, done in November, 1937, was normal, as was the urine. Case 2. A white man, 30 years old, was seen by a uro-

logist in March, 1937, because of intermittent episodes of right renal colic, urinary frequency, and dysuria. Physical examination was normal. Urinalysis showed a trace of albumin, leucocytes, and colon bacilli. The survey fihn of the abdomen revealed evidence o f s t a s i s of fecal current after the administration of one ounce of castor oil, which was followed by two evacuations. Complete cystoscopic studies, including ureteral exploration with a wax tipped catheter, were n o r m a l . Periodic ureteral dilatations were of no avail. Distinct improvement was observed following castor oil catharsis and colonic irrigations, and has been maintained by the use of agar and an anti-constipation diet. Case 3. Mrs. L. M., 36 years old, was seen in February, 1935, because of frequent episodes of pain in the right renal region and loin, constipation, nausea, and occasional

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vomiting. Physical examination revealed poor nutrition, and tenderness and spasm of the sigmoid. Proctologic investigation showed a superficial posterior fissure, a deep crypt, hypertrophied papillae, and marked spasm of the anal sphincter. The urinalysis revealed a trace of albumin, numerous leucocytes, and colon bacilli. Survey films of the abdomen repeatedly showed evidence of stasis of fecal current. Gastro-intestinal roentgen ray films demonstrated evidence of retention of barium in the colon after seventytwo hours. Following palliative local t r eat me nt to the anal lesion, it was possible to resort to colonic irrigations and castor oil catharsis. Under this regime she improved rapidly and felt so well that she refused subsequent roentgen ray studies of the u r i n ar y tract. A urinalysis done in August, 1935, and in September, 1938, was normal. Th ese t h r e e cases i l l u s t r a t e a possible r e l a t i o n s h i p of fecal stasis to t h e i n i t i a t i o n and p e r p e t u a t i o n o f p y u r i a. T w o of these cases also had a n o r e c t a l disease of m o d e r a t e degree. Th e good r e s u l t s t h a t followed t h e r a p y d i r e c t e d to the colon alone a r e c l e a r c u t and definite. Cases n u m b e r 1 and 3 have been followed up f o r a long time. Case 4. Miss F. F., 22 years old, was seen in June, 1930, because of backache and constipation of long standing. Of more recent origin was a throbbing anal pain which was aggravated during defecation. Physical examination showed spasm of the ascending and descending colon, and two infected crypts of Morgagni accompanied by hypertrophied papillae. Routine urinalysis revealed numerous leucocytes and colon bacilli. After excision of the infected crypts and the hypertrophied papillae, a gradual disappearance of the pathologic elements of the urine was observed. A f t e r complete healing of the wound, and establishment of regular bowel habits, the urine gradually but spontaneously became normal. No recurrence was observed during a follow-up period of about eighteen months. Case 5. Mrs. T. N., 30 years old, was seen in December, 1937, because of intermittent left renal colic, diuria, nycturia, and dysuria. Constipation of long standing and the babituM use of cathartics were the only pertinent points in the past history. Physical examination was normal throughout. Proctologic investigation showed a posterior anal ulcer with an infected deep crypt and a sentinel pile, as well as marked spasm of the anal sphincter. Urinalysis revealed numerous leucocytes, staphylococci, and colon bacilli. The survey film of the abdomen showed stasis of fecal current in the entire colon. The excretory urogram revealed a normal urinary tract. The anal lesion was easily excised. The convalescence was uneventful. With the aid of diet, agar, and acidophilus milk, regular bowel habits were established. A f t er five months, the voided urine was found to be free from pathologic elements. She has remained well to date. Case 6. Mr. J. K., 86 years old, was seen in March, 1938, because of sharp pain on defecation and total hematuria. The past history was irrelevant. Physical examination showed signs of advanced senility, poor nutrition, suprapubic tenderness, and prostatic enlargement. Proctologic investigation revealed a posterior ulcer, deep crypts of Morgagni, and spasm of the anal sphincter. Residual urine measured 190 cc. Urinalysis showed numerous erythrocytes, leucocytes, and albumin graded three plus. Because of the age and general condition of the patient, a urologic study and anorectal operative interference were deemed inadvisable. The bladder was irrigated and the anal lesion treated palliatively. A f t er three weeks the urine was grossly clear and the anal lesion was much improved. Subsequently, after the passage of a hard stool, there was an exacerbation of the anal lesion with a prompt recurrence of pyuria. The residual urine then measured 100 cc. Again with the clearing up of the anal lesion, definite improvement of the urinary picture ensued.

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These three cases illustrate the possible relationship of anorectal inflammatory and suppurative lesions to urinary tract infection. These anorectal lesions were also responsible for sphincter muscle spasm with resulting constipation. Fecal stasis coexisted in case number 5 and was demonstrated roentgenologically. Roentgenograms were not done in the other two cases. The effects of the treatment directed to the anorectal lesions again speak for themselves. Case 7. Mrs. G. B., 27 years old, was known to have had chronic ulcerative colitis of long standing with periodic relapses consisting of bloody diarrhea accompanied by urinary frequency and dysuria. Physical examination showed definite u n d e r n o u r i s h m e n t , diffuse abdominal tenderness and spasm of the sigmoid, and percussion tenderness over both kidneys. The sigmoidoscopic and roentgen pictures were typical of advanced chronic ulcerative colitis. The urinalysis, during the periods of remission, showed an occasional leucocyte, and a few grampositive cocci in the sediment. During relapses the urine is loaded with leucocytes, gram-positive cocci, and gramnegative rods. Case 8. Mrs. A. S., 56 years old, was seen in May, 1938, because of bloody diarrhea. She had first observed diarrhea sixteen years ago, and a year later an appendicostomy had been performed which was kept open for one year. Periodically she develops bloody diarrhea which is associated with urinary frequency, tenesmus, and dysuria. The urinary and colonic symptoms usually subside simultaneously. Her past history includes a plastic vaginal operation, and a hemorrhoidectomy. Her son died of "colitis," and one daughter has chronic bacillary dysentery. Physical examination was normal throughout. Rectosigmoidoscopic examination showed a uniformly reddened and easily bleeding mucous membrane. Examination of the stool revealed numerous leucocytes, erythrocytes, and streptococci. No dysentery organisms, amoeba, or cysts were found in the stool, mucosal scrapings, or crypts aspirations. The urinalysis showed a moderate number of leucocytes and a trace of albumin. The culture was sterile. During remission, the urine was free from leucocytes on two occasions. Her blood serum agglutinates Flexner dysentery antigens V and Z in 1:320 dilution. Case 9. Miss G. M., 11 years old, developed "colitis" in March, 1925. Eight years later she developed left renal colic and spontaneously passed a small calculus. Cystoscopic studies were normal except for leucocytes with few clumps in the urine from the bladder and the left kidney. The cultures were sterile. The left pyelogram showed a normal kidney and ureter except for a constriction without obstruction at the level of the fifth vertebra. A culture of the bladder urine repeated on April 19, 1932, showed B. coli and short chained streptococci. Her blood serum agglutinates the Duval-Sonne antigen in dilution of 1:320. In November, 1936, a permanent ileostomy with exclusion of the distal portion of the ileum was performed by Dr. Marino at the Brooklyn Hospital, because of a continued upgrade progress of the colonic disease, which was complicated by polyps of the colon, and polyarthritis. On several subsequent occasions the polyps were fulgurated uneventfully. Five or six days following the last fulguration which was done on April 3, 1938, she developed sharp pain in the left kidney and loin with an elevation of temperature which persisted for several days. Cystoscopic studies were done on April 25, 1938. The left pyelogram showed dilatation of the pelvis and the upper portion of the ureter. The bladder urine contained hyaline and a few granular casts, a moderate number of erythrocytes and a few leucocytes with rare clumps. The right kidney urine showed amorphous urates. The urine from the left kidney revealed many red blood cells, a moderate number

of leucocytes with small clumps, and a few granular casts. All cultures of the urine were sterile. The foregoing three cases show the association of urinary tract infection with inflammatory states of the colon. Urinary frequency, dysuria, and pathologic elements in the urine accompanied each episode of diarrhea in cases number 7 and 8. The disappearance of the diarrhea and the urinary symptoms usually occurred simultaneously. Of special interest is the occurrence of fever, pain in the left kidney, and pathologic elements in the urine following fulguration of polyps in the defunctioned colon in the last case. DISCUSSION During the past nine years I have encountered thirty definite instances of uroinfection which were associated with i n t e s t i n a l disease or dysfunction. Fourteen of these cases were studied in detail. Additional cases are now under study. The urinalysis in each instance s h o w e d an acid reaction, leucocytes, either gram-negative rods, gram-positive cocci, or both, traces of albumin, and occasional erythrocytes. The urinary tracts were otherwise normal. This was corroborated in nine cases where complete urologic investigations were made. The survey films of the abdomen, taken in twelve instances, showed evidence of fecal stasis, usually in the cecum and ascending colon. In eleven patients proctologic disease was present. Crypt infection was found five times, anal ulcer four times, and pectinosis (contracted anus) twice. Stasis of fecal current, most frequently of proctologic etiology, was the most common intestinal observation. In association with ano-recto-colonic disease, it presents a source of both local and focal infection. It is possible that fecal stasis, if of long duration, could damage the colon (20). The colon then may act as an important portal of entry for enteric organisms into the blood and lymph streams. There is ample reason to believe that suppurative and inflammatory states about the anorectum (2, 4, 17, 18), with or without fecal stasis, have focal infective possibilities. Hence, proctologic lesions should be searched for and properly evaluated in all cases of uroinfection, especially in the acute and recurring types of pyelonephritis caused by the colon bacillus group. I t is noteworthy that even those who contend that foci of infection play little or no role in chronic uroinfections, agree with Von Lichtenberg (21) and Winsbury-White (22), that infection of the prostate gland or uterine cervix does cause and perpetuate uroinfection. These genital infections or inflammatory states are frequently kept active by distant foci of infection which must be eradicated. In bacteriuria and in some cases of renal infection where superficial tissues are involved, the removal of foci of infection have at times been followed by spectacular recovery (23). In this connection, one should remember M. Solis-Cohen's (3) recommendation, "to make sure that the bacterial focus, as welt as the diseased tissue, is removed, because so long as infecting germs are permitted to remain, a cure of the secondary infections they are producing cannot be expected." The treatment in this series of cases consisted of colonic irrigations, castor oil catharsis, agar, acidophilus milk, anti-constipation diets, and the eradication of ano-recto-colonic inflammatory and suppurative disease. The subjective complaints, renal colic and pain, disappeared promptly. The disappearance

SEGARD---OUR

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of the pathologic elements in the urine was gradual, but at times very slow, requiring several months. Treatment to the urinary tract was avoided except in case number six, but even in this instance, the influence of the anal lesion upon the pyuria was clear cut. The uroinfections encountered in my patients appear to have been of the moderate and subacute recurring types. Whether or not they have any relationship to the chronic forms has not yet been determined. On general principles, I feel that these infections should be eradicated promptly and permanently as a matter of prophylaxis against recurrence and chronicity. Special attention to derangements and disease of the intestinal tract, and to other loci of infection, if present, should be given in all cases of uroinfection, if only on an empirical basis. For the past quarter of a century, Beer (24) routinely administered castor oil to his patients suffering from uroinfections, with the idea of bringing about complete evacuation of the colon. Beer (25) found this simple therapy very elfective in many cases of renal infection. I had the rare opportunity to observe and study his material. I feel that where castor oil therapy is ineffective, the colobacilluria should be considered of secondary etiologic significance, as this therapy acts almost as a

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therapeutic test. Kretschmer (4) also long ago recognized the etiologic relationship of stasis of fecal current and of the inflammatory and suppurative lesions of the anorectum to uroinfections. He noted that the eradication of the intestina,1 lesions, or the correction of the existing colonic dysfunction materially hastened the eradication of the kidney infections. Bugbee (26) too, stressed the influence of stasis .of fecal current on the various forms of pyelonephritis. SUMMARY AND CONCLUSIONS 1. Stasis of fecal current and inflammatory and suppurative disease of the ano-recto-colonic tube, are capable of producing and perpetuating uroinfections. Cases of urinary tract infection caused by the colon bacillus group should especially have a careful intestinal survey for evidence of the aforementioned ano-colonic lesions or dysfunction. 2. These uroinfections usually disappear following the eradication of the intestinal lesions. They are not primary urologic problems. Illustrative case histories are presented. I am indebted to Dr. A. W. Martin Marino, Brooklyn Hospital, Brooklyn, New York, and to Dr. A. Hyman, Mount Sinai Hospital, New York City, for their valuable help and criticism.

REFERENCES 1. 2. 3. 4. 5.

6. 7. 8. 9. 10. 11. 12.

Turell, R. a n d M a r i n o , A. W. M . : I n t e s t i u a l P h a s e in U r o l o g i c Disease. I. General C o n s i d e r a t i o n s . To be published. R e i m a n , H . A . : I n f e c t i o n s of Kidney, in B e r g l u n d , H . ; Medes, G. a n d o t h e r s : K i d n e y in H e a l t h a n d Disease. P h i l a d e l p h i a , Lea & F e b i g e r , Chap. 20, pp. 301-329, 1935. Solis-Cohen, M. : B a c t e r i o l o g i c a l Studies S u g g e s t i n g Focal O r i g i n in M a n y I n f e c t i o n s ; T h e r a p e u t i c I m p l i c a t i o n s . Urol. and Catan. Bey., 40:231-249, April, 1936. K r e t s c h m e r , H . L . : T r e a t m e n t of Pyelitis. S. G. O., 33 :932-641, Dec., 1921. P e r e t z , L. H., S c h a p i r o , J . N., C h o m j e n k o . T. A. a n d Ptochoff, M. P. : U b e r die Q u a l i t a t s b e d e u t u n g d e r Bact. Coli bei Pyelocystitis in L i c h t e d e r L e h r e yon d e r Schutzrolle der N o r m a i l e n Mikroflora. Ztschr. f. Urol, Chir.. 41:262-274. 1935. B a e h r , G., S h w a r t z m a n , G. a n d G r e e n s p a n , E. B . : Bacillus F r i e d l a n d e r I n f e c t i o n s . Ann. Int. ned., 10:1788-1891, J u n e , 1937. D u d g e o n , L. S . : S t u d y of I n t e s t i n a l F l o r a U n d e r N o r m a l a n d A b n o r m a l Conditions. J. Hyg., 25:119-141, J u l y . 1926. N e t e r , E. a n d H o s t e r m a n , O . : I n f e c t i o n of t h e U r i n a r y Tr~,ct w i t h D y s e n t e r y Bacilli. Arch. Path., 24:272-273, A u g . , 1937. N e t e r , E . : I n f e c t i o n s of U r i n a r y T r a c t D u e to B a c t e r i u m Dysent e r i a e . J. Infect. Dis., 61:338-340, Nov.-Dec., 1937. N e t e r , E. a n d Rappole, F. : P a t h o g e n i c i t y a n d A n t i g e n i c S t r u c t u r e of Shigella A l k a l e s c e n s ( A n d r e w e s ) . Arch. Path., 25:298, Feb., 1938. N e t e r , E . : I n f e c t i o n s of t h e U r i n a r y T r a c t D u e to Shigella P a r a d y s e n t e r i a e a n d Allied Species. J. Bact., 35:202, Feb., 1938. Dietrich, H . F . : A c u t e P y u r i a Due to D y s e n t e r y Bacilli. A m . J. Dis. Child., 56:270-274, Aug., 1938.

13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

23. 24. 25. 26.

N e t e r , E. : I n f e c t i o n s of U r i n a r y T r a c t Due to Shigella Aikalescens. J. Urol., 39:727-730, May. 1938. S t e w a r t , H . L . : P y e l i t i s of P r e g n a n c y D u e to Bacillus D y s e n t e r y F l e x n e r . A m . J. Obst. and Gynec., 35:887-889, May, 1938. Danicls, E. A . : A n t i F i s s u r e , A n a l S p a s m a n d A n a l Stenosis. A m . J. Digest. Dis. and Nutrit., 3:775-783, Dee., 1936. T u c k e r , C. C. a n d H e l I w i g , C. A . : A n a l Ducts. Arch. Surg., 31:521-530, Oct., 1935. H i r s c h m a n , L. J . : Focal I n f e c t i o n of A n a l O r i g i n . J . A. M. A., 97:1609-1611, Nov. 28, 1931. Blaisdell, C. P . : A n a l C r y p t i t i s . A m . J. Digest. Dis. and Nutrit., 3:188-190, M a y , 1936. M a l m g r e n , quoted by Buie, Louis, A. : P r o c t o s c o p i c E x a m i n a t i o n a n d T r e a t m e n t of H e m o r r h o i d s a n d A n a l P r u r i t u s . Philadelphi::, W. B. S a u n d e r s C o m p a n y , p p . 73-80, 1931. J e f f r e y s , cited by Solis-Cohen ( 3 ) . V o n L i c h t e n b e r g , A . : K i d n e y a n d U r e t e r a l L e s i o n s S e c o n d a r y to A d n e x a l Disease. J. Urol., 24:1-39. Jury, 1930. W i n s b u r y - W h i t e , n . P. : Influence of I n f e c t i o n of L o w e r U r i n a r y T r a c t a n d R e p r o d u c t i v e O r g a n s on K i d n e y s ; w i t h Special R e f e r ence to L i t h i a s i s a n d H y d r o n e p h r o s i s . J. Urol., 36:469-511, N o v . , 1936. B r ~ a s c h , W. F. : Clinical D a t a C o n c e r n i n g C h r o n i c P y e l o n e p h r i t i s . J. Urol., 39:1-33, J a n . , 1938. Beer, E . : P e r s o n a l C o m m u n i c a t i o n to the A u t h o r . Beer, E . : R e n a l I n f e c t i o n s . J. Mr. Sinai Hosp., 4:144-150, Sept.Oct., 1937. Bugbee, H. G. : I n f e c t i o n s of U r i n a r y T r a c t in Children. N c w York State J. Med., 25:1063-1065, Dec. 1, 1925.

Our Present Knowledge of the Action and Sources of Copper in Nutritional Anemia By CHRISTIAN P. SEGARD, M.D. LEONIA,

clinical picture of the use of copper and iron T inHEhaemoglobin formation as at present described, has been variously stated. These statements conflict to such an extent that a review seems timely. While there seems to be a wide difference of opinion among a few, there is the possibility of neglected factors that will reconcile all of them. Most medical men were taught and the literature states that the formation of haemoglobin depended S u b m i t t e d M a r c h 12, 1939.

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JERSEY

upon the presence of iron. They are also taught that massive doses (two to six gins.) are more effective than doses which approached the utilization level of the organism (15 to 50 mgm.). In all cases, large doses of iron were more effective than small doses. But iron is not the whole answer. (All physiological reactions are due to the presence of either an enzyme, hormone, vitamin or catalyst or other determiner). Though three-fourths or more of the "massive dose" was known to be excreted, yet results in haemoglobin