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Donovanosis of the Epididymis Complicating Tuberculous Infection
TnE .JouR~AL OF UROLOGY
Vol. 70, No. 5, November 1953 Printed in U.S.A.
DONOVANOSIS OF THE EPIDIDYMIS COMPLICATING TUBERCULOUS INFECTION MILTON MARMELL, REGINA ULTMANN
AND
SOLOMON WEINTRAUB
Prorn the Departrnent of Pathology, Harlern Hospital, Departrnent of Hospitals,
New York, N. Y.
A thorough search of the literature failed to reveal any recorded cases of donovanosis (granuloma inguinale) 1 of the male internal genital organs. The following case of this disease, involving the epididymis, diagnosed by the demonstration of Donovan bodies in biopsy material, is deemed of sufficient interest to be reported. Donovanosis is a chronic, specific infection manifested clinically by ulcerating granulomatous lesions involving most commonly, the skin and subcutaneous tissues. Although these manifestations are generally limited to the external genitalia and adjacent areas, the lesions may appear as primary infection, and as the result of auto-inoculation, in other parts of the body. These extragenital lesions are estimated to occur in up to 7 per cent of all cases of donovanosis. 2 • 3 Though predominantly a cutaneous and subcutaneous disease, donovanosis may, however, involve other tissues and organs, such as the internal genital organs (reported thus far in the female only) 4 and may become disseminated and affect the viscera and the bones. 5 , 6 Histologically, the disease is characterized by the presence of cytoplasmic inclusions, the Donovan bodies, within large mononuclear cells. These bodies were described by Donovan in 1905,7 and since that time are considered as pathognomonic of this infection. In 1943, Anderson 8 succeeded in cultivating the Donovan body in the yolk sac of the embryonated hen's egg. She and her associates characterized the organism as a gram negative bacillus, and named it Donovania granulomatis. 9 Anderson's work has been confirmed in a number of laboratories. However, experimental inoculation of these cultured organisms into man or the lower animals, does not produce the disease. 10 The antibiotics have replaced the antimony compounds in the treatment of Accepted for publication July 17, 1952. 1 Marmell, M. and Santora, E.: Am. J. Syph. Gonor. and Ven. Dis., 34: 83-90, 1950. 2 Fox, H.: J.A.M.A., 87: 1785-1790, 1926. 3 Chen, C.H., Greenblatt, R. B. and Dienst, R. B.: Arch. Dermt. & Syph., 58: 703-715, 1948. 4 Marmell, M., Fielding, W. L. and Weintraub, S.: Am. J. Obst. & Gynec., 63: 893--896, 1952. 5 Lyford, J. III., Johnson, R. W., Blackman, S. and Scott, R. B.: Bull. Johns Hopkins Hosp., 79: 349-357, 1946. 6 Lipp, R. G. and Bibby, D. E.: Western J. Surg. Obst. & Gynec., 58: 173-177, 1950. 7 Donovan, C.: Indian Med. Gaz., 40: 411, 1905. 8 Anderson, K.: Science, 97: 560-561, 1943. 9 Anderson, K., De Monbreun, W. A. and Goodpasture, E.W.: J. Exper. Med., 81: 2540, 1945. 10 Dienst, R. B., Chen, C.H. and Greenblatt, R. B.: Am. J. Syph. Gonor. & Ven. Dis., 39: 152-157, 1949. 776
DONOVANOSIS OF EPIDIDYMIS
777
donovanosis. The effectiveness of the various antibiotics 11 • 12 • 13 • 14 is bringing about a rapid disappearance of the disease in localities where it was formerly widespread. 13 • 15 • 16 With such excellent therapeutic results, a marked reduction of cases of donovanosis, if not the eradication of the disease, depends upon early diagnosis and prompt and thorough treatment. Diagnosis depends upon the demonstration of Donovania granulomatis in tissue smears or in sections of biopsy material. No other criteria, clinical, therapeutic, skin tests, etc., can conclusively diagnose the disease. The organism is best demonstrated with Giemsa or Wright stains. We have found the hematoxylin and eosin stains unsatisfactory. CASE REPORT
On December 12, 1950, H. H., a 39 year old man, was referred to the laboratory for a dark field examination of a penile lesion of 5 months' duration. The lesion had appeared 2 days following coitus. Self medication brought no relief. A month after the appearance of the penile ulcer, the patient noticed enlargement of the scrotum and sought medical advice. Treatment with "sulfa" drugs and penicillin, from August to December, by various physicians, had no effect upon the lesion or the scrotal swelling. The past history was significant only in that he had had gonorrhea in 1939 and chancroid in 1940. There was no history of trauma. Physical examination on admission revealed a thin, well developed man in moderate discomfort occasioned by the enlarged scrotum and penile ulcer. The temperature was lOlF. Both testes were felt to be enlarged, the left one markedly so. There was tenderness on pressure. The left testis was irregular in outline and firm in consistency. The lesion on the penis was a shallow ulcer with well demarcated edges. It was not painful and bled easily upon touch. It was 0.5 cm. wide, involved the corona and sulcus, and extended halfway around the circumference of the penis. The penis was swollen and edematous. There were no other abnormal findings. Dark field examination of the penile lesion was negative for Treponema pallidum, but the serologic tests for syphilis were strongly positive as were the Frei and Ito-Reenstierna skin tests for lymphopathia venereum and chancroid, respectively. No Hemophilus ducreyi or Neisseria gonorrheae were seen on smear. Tissue scrapings from the penile ulcer, stained with Giemsa, were positive for intracellular, encapsulated Donovania granulomatis. A chest x-ray taken during the patient's stay in the hospital revealed small, 11 Greenblatt, R. B., Dienst, R. B., Kuperman, H. S. and Reinstein, C.R.: J. Ven. Dis. Info., 28: 183-189, 1947. 12 Wright, L. T., Sanders, M., Logan, M.A., Prigot, A. and Hill, L. M.: Ann. N. Y. Acad. Sci., 51: 318-330, 1948. 13 Greenblatt, R. B., Wammock, V. S., Dienst, R. B. and West, R. M.: Am. J. Obst. & Gynec., 59: 1129-1133, 1950. 14 Whitaker, J. C., Wright, L. T., Beinfield, M. S., Wilkinson, R. S. and Marmell, M.: Antibiotics & Chemotherapy, 1: 208-210, 1951. 15 Thomas, W. L.: Am. J. Obst. & Gynec., 61: 790-798, 1951. 16 Hester, L. L., Jr.: Personal communication, 1952.
778
MARMELL, ULTMANN AND WEINTRAUB
nodular deposits at the lung apices which were suggestive of healed tuberculous lesions. Sputum examinations (6 concentrated specimens) were negative for acid fast bacilli. Terramycin was administered from December 6, 1950 to January 5, 1951 for a total of 23 gm. Under the influence of this treatment, the lesion healed and the temperature became normal. There was no effect upon the scrotal swelling. On January 8, 1951, a biopsy of the epididymis was performed. Sections of the organ showed replacement of a large part of the tissue by tuberculous granulation tissue with caseation. There were occasional tubular structures which were lined by one or more cuboidal to cylindrical cells with partly indistinct, ciliated borders. The cytoplasm was clear in some instances, and granular in others. The nuclei varied somewhat in size and position. These tubular structures were
Fm. 1. A, epididymis showing Langhans' cells. Small, dark staining bodies are cells containing D. granulomatis (see B). Giemsa stain, X 60. B, epididymis showing intracellular and extracellular Donovan bodies. Giemsa stain, X 450.
separated by a loose, vascularized granulation tissue containing a number of mononuclear cells which, in Giemsa preparations, were seen to be laden with pink staining intracytoplasmic Donovan bodies (fig. 1). Smears and cultures of the tissue were negative for acid fast organisms. Treatment with streptomycin was instituted (0.5 gm., b.i.d.), and on January 29, the patient was discharged "as improved." He was referred to the clinic for continuation of therapy. The patient failed to report to the clinic, but was re-admitted to the hospital on lVIarch 22, 1951 with meningeal symptoms. He had become ill a week previous to this admission, following a "drinking spree," and had been confined to bed during that period. When first seen on this admission, the patient appeared chronically and acutely ill. He was lethargic, but was rational as to time and place. The lungs, as on his
779
DO?-;OVA.c\OSIS OF EPIDIDYMIS
previous admission, \Vere clear to auscultation and percussion. The heart was normal. A positive Kcrnig ·was elicited. Spinal taps performed on March 22 and J\larch 29 showed the follm,·ing: ---
DATE
-------------
: TOTAL PROTEI;-; I
- - - - - ------- ------
200 monos.
3/22/.51 3/29/51
760 monos. I
--------------·-
- - - - - - - - - -
SL"GAR
1
CHLO.RIDES
1
--·--------
WASSERi\IA~i'\~
----1
COLL(JLDAL
GOLD
1--
228 mg. % 1: 2.5 mg.% ' 7()() mg.% 224 mg.% 1 :-l6 mg.% 664 mg.% ! N"egative ] 111122;-l:311 I
------
The patient ran a downward comse throughout his 9 day hospital stay. On March 29, there was evidence of a left hemiplegia, and on ::viarch the patii,nt expired Consent for autopsy \rns not obtained. DISCTJSSION
The purpose of presenting this case is to record the fact that the Donovall body may invade the internal genitals of the male. The lack of an autopsy makes disrnssion of the pathological changes produced by this organism impossible. The most. probable cause of the meningitis may have been the tubercle bacillus. V\T e are at a loss to account for the part played by syphilis and lymphopathia venereum upon the central nervous system of our patient. There is al,w the report of Thierfelder and Thierfelder-Thillot, 17 in which donovanosis caused a paralysis in 3 of their patiems. \Vith the demonstration of Donovania granulomatis in the spleen, 5 li\,er} 17 ovaries and tubes, 4 bone marrow, 5 bladder, 18 bony structures,6 and in this case, the epididymis, donovanosis can no longer be thought of as a cutaneous disease, but should be regarded as a systemic infection ,vith lesions of the skin as a prominent, and perhaps, early recognizable symptom. This view has been expressed previously.1'1 It is strengthened by the demonstration by Lyford, Scott and Johnson,1 9 • 20 that donovanosis can cause arthritis, and by the report of Thierfelder and Thierfelder-Thillot,1 7 just referred to, that donovanosis may presenl symptoms referrable to the central nervous system. The possible invasion of the internal organs by D. granulomatis must, therefore, be suspected whenever patients with cutaneous donovanosis present symptoms and complaints referrable to other parts of the Verification of this suspicion may be difficult, and at times, impossible. This is particularly so in patients in whom the symptoms involve organs inaccessible to biopsy. In such cases, the diagnosis may be inferred from the presence of cutaneous donovanosis, and the exclusion of other pos8ible diagnoses. Where is possible, the diagnosis may definitely be establishc~d upon the demonstration of the organism in Giemsa or ,vright stained section:,; of the biopsied specimen. 17
Thierfelder, M. V. and Thierfelder-Thillot, M.: Arch. f. Schiffs-u. Tropcn-Hyg. 28:
221-2:35, 1924. 18
Rhinehard, W. J. and Bauer, J. T.: Am. J. Roentgenol. & Radium Therapy, 57: 562--
567, 1947.
Lyford, J. Ill., Scott, R. B. and ,Johnson, R. W.: Am. Syph. Gonor. & Ven. Dis., 28: 588-610, 1944. 20 Scott, R. B., Lyford, J. III. and .Johnson, IL W.: Bull. .Johns Hopkins Hosp., 74: 213-19
217, Hl44
780
MARMELL, ULTMANN AND WEINTRAUB
The diagnosis in the present case was complicated by the tuberculous infection. From the hematoxylin and eosin stain, the double infection was not apparent and would have been missed if Giemsa stained preparation had not been made. Tuberculosis and donovanosis do not, of course, exclude each other, and cases of cutaneous donovanosis in tuberculous patients have been reported. 21 • 22 In view of the apparent low virulence of D. granulomatis, 3 • 10 it may be said that the tuberculous infection predisposed the tissue for invasion by this organism. SUMMARY
In a patient exhibiting cutaneous donovanosis, Donovania granulomatis was also demonstrated in the epididymis. Dissemination of this organism into the internal organs should be considered in all patients with cutaneous donovanosis who show systemic symptoms. We are indebted to Dr. Louis T. Wright, Director of the Department of Surgery, for permission to use the case records. We wish to thank Mr. Clement A. Constan for his unstinted efforts in preparation of the photomicrographs, and Mrs. Esther Sax and Miss Anna Frankel for their co-operation in preparing the histologic slides. Kuhn: Charite-Annalen, 30: 427-436, 1906. Greenblatt, R. B., Dienst, R. B., Pund, E. R. and Torpin, R.: J.A.M.A., 113: 11091116, 1939. 21 22
Vol. 70, No. 5, November 1953 Printed in U.S.A.
DONOVANOSIS OF THE EPIDIDYMIS COMPLICATING TUBERCULOUS INFECTION MILTON MARMELL, REGINA ULTMANN
AND
SOLOMON WEINTRAUB
Prorn the Departrnent of Pathology, Harlern Hospital, Departrnent of Hospitals,
New York, N. Y.
A thorough search of the literature failed to reveal any recorded cases of donovanosis (granuloma inguinale) 1 of the male internal genital organs. The following case of this disease, involving the epididymis, diagnosed by the demonstration of Donovan bodies in biopsy material, is deemed of sufficient interest to be reported. Donovanosis is a chronic, specific infection manifested clinically by ulcerating granulomatous lesions involving most commonly, the skin and subcutaneous tissues. Although these manifestations are generally limited to the external genitalia and adjacent areas, the lesions may appear as primary infection, and as the result of auto-inoculation, in other parts of the body. These extragenital lesions are estimated to occur in up to 7 per cent of all cases of donovanosis. 2 • 3 Though predominantly a cutaneous and subcutaneous disease, donovanosis may, however, involve other tissues and organs, such as the internal genital organs (reported thus far in the female only) 4 and may become disseminated and affect the viscera and the bones. 5 , 6 Histologically, the disease is characterized by the presence of cytoplasmic inclusions, the Donovan bodies, within large mononuclear cells. These bodies were described by Donovan in 1905,7 and since that time are considered as pathognomonic of this infection. In 1943, Anderson 8 succeeded in cultivating the Donovan body in the yolk sac of the embryonated hen's egg. She and her associates characterized the organism as a gram negative bacillus, and named it Donovania granulomatis. 9 Anderson's work has been confirmed in a number of laboratories. However, experimental inoculation of these cultured organisms into man or the lower animals, does not produce the disease. 10 The antibiotics have replaced the antimony compounds in the treatment of Accepted for publication July 17, 1952. 1 Marmell, M. and Santora, E.: Am. J. Syph. Gonor. and Ven. Dis., 34: 83-90, 1950. 2 Fox, H.: J.A.M.A., 87: 1785-1790, 1926. 3 Chen, C.H., Greenblatt, R. B. and Dienst, R. B.: Arch. Dermt. & Syph., 58: 703-715, 1948. 4 Marmell, M., Fielding, W. L. and Weintraub, S.: Am. J. Obst. & Gynec., 63: 893--896, 1952. 5 Lyford, J. III., Johnson, R. W., Blackman, S. and Scott, R. B.: Bull. Johns Hopkins Hosp., 79: 349-357, 1946. 6 Lipp, R. G. and Bibby, D. E.: Western J. Surg. Obst. & Gynec., 58: 173-177, 1950. 7 Donovan, C.: Indian Med. Gaz., 40: 411, 1905. 8 Anderson, K.: Science, 97: 560-561, 1943. 9 Anderson, K., De Monbreun, W. A. and Goodpasture, E.W.: J. Exper. Med., 81: 2540, 1945. 10 Dienst, R. B., Chen, C.H. and Greenblatt, R. B.: Am. J. Syph. Gonor. & Ven. Dis., 39: 152-157, 1949. 776
DONOVANOSIS OF EPIDIDYMIS
777
donovanosis. The effectiveness of the various antibiotics 11 • 12 • 13 • 14 is bringing about a rapid disappearance of the disease in localities where it was formerly widespread. 13 • 15 • 16 With such excellent therapeutic results, a marked reduction of cases of donovanosis, if not the eradication of the disease, depends upon early diagnosis and prompt and thorough treatment. Diagnosis depends upon the demonstration of Donovania granulomatis in tissue smears or in sections of biopsy material. No other criteria, clinical, therapeutic, skin tests, etc., can conclusively diagnose the disease. The organism is best demonstrated with Giemsa or Wright stains. We have found the hematoxylin and eosin stains unsatisfactory. CASE REPORT
On December 12, 1950, H. H., a 39 year old man, was referred to the laboratory for a dark field examination of a penile lesion of 5 months' duration. The lesion had appeared 2 days following coitus. Self medication brought no relief. A month after the appearance of the penile ulcer, the patient noticed enlargement of the scrotum and sought medical advice. Treatment with "sulfa" drugs and penicillin, from August to December, by various physicians, had no effect upon the lesion or the scrotal swelling. The past history was significant only in that he had had gonorrhea in 1939 and chancroid in 1940. There was no history of trauma. Physical examination on admission revealed a thin, well developed man in moderate discomfort occasioned by the enlarged scrotum and penile ulcer. The temperature was lOlF. Both testes were felt to be enlarged, the left one markedly so. There was tenderness on pressure. The left testis was irregular in outline and firm in consistency. The lesion on the penis was a shallow ulcer with well demarcated edges. It was not painful and bled easily upon touch. It was 0.5 cm. wide, involved the corona and sulcus, and extended halfway around the circumference of the penis. The penis was swollen and edematous. There were no other abnormal findings. Dark field examination of the penile lesion was negative for Treponema pallidum, but the serologic tests for syphilis were strongly positive as were the Frei and Ito-Reenstierna skin tests for lymphopathia venereum and chancroid, respectively. No Hemophilus ducreyi or Neisseria gonorrheae were seen on smear. Tissue scrapings from the penile ulcer, stained with Giemsa, were positive for intracellular, encapsulated Donovania granulomatis. A chest x-ray taken during the patient's stay in the hospital revealed small, 11 Greenblatt, R. B., Dienst, R. B., Kuperman, H. S. and Reinstein, C.R.: J. Ven. Dis. Info., 28: 183-189, 1947. 12 Wright, L. T., Sanders, M., Logan, M.A., Prigot, A. and Hill, L. M.: Ann. N. Y. Acad. Sci., 51: 318-330, 1948. 13 Greenblatt, R. B., Wammock, V. S., Dienst, R. B. and West, R. M.: Am. J. Obst. & Gynec., 59: 1129-1133, 1950. 14 Whitaker, J. C., Wright, L. T., Beinfield, M. S., Wilkinson, R. S. and Marmell, M.: Antibiotics & Chemotherapy, 1: 208-210, 1951. 15 Thomas, W. L.: Am. J. Obst. & Gynec., 61: 790-798, 1951. 16 Hester, L. L., Jr.: Personal communication, 1952.
778
MARMELL, ULTMANN AND WEINTRAUB
nodular deposits at the lung apices which were suggestive of healed tuberculous lesions. Sputum examinations (6 concentrated specimens) were negative for acid fast bacilli. Terramycin was administered from December 6, 1950 to January 5, 1951 for a total of 23 gm. Under the influence of this treatment, the lesion healed and the temperature became normal. There was no effect upon the scrotal swelling. On January 8, 1951, a biopsy of the epididymis was performed. Sections of the organ showed replacement of a large part of the tissue by tuberculous granulation tissue with caseation. There were occasional tubular structures which were lined by one or more cuboidal to cylindrical cells with partly indistinct, ciliated borders. The cytoplasm was clear in some instances, and granular in others. The nuclei varied somewhat in size and position. These tubular structures were
Fm. 1. A, epididymis showing Langhans' cells. Small, dark staining bodies are cells containing D. granulomatis (see B). Giemsa stain, X 60. B, epididymis showing intracellular and extracellular Donovan bodies. Giemsa stain, X 450.
separated by a loose, vascularized granulation tissue containing a number of mononuclear cells which, in Giemsa preparations, were seen to be laden with pink staining intracytoplasmic Donovan bodies (fig. 1). Smears and cultures of the tissue were negative for acid fast organisms. Treatment with streptomycin was instituted (0.5 gm., b.i.d.), and on January 29, the patient was discharged "as improved." He was referred to the clinic for continuation of therapy. The patient failed to report to the clinic, but was re-admitted to the hospital on lVIarch 22, 1951 with meningeal symptoms. He had become ill a week previous to this admission, following a "drinking spree," and had been confined to bed during that period. When first seen on this admission, the patient appeared chronically and acutely ill. He was lethargic, but was rational as to time and place. The lungs, as on his
779
DO?-;OVA.c\OSIS OF EPIDIDYMIS
previous admission, \Vere clear to auscultation and percussion. The heart was normal. A positive Kcrnig ·was elicited. Spinal taps performed on March 22 and J\larch 29 showed the follm,·ing: ---
DATE
-------------
: TOTAL PROTEI;-; I
- - - - - ------- ------
200 monos.
3/22/.51 3/29/51
760 monos. I
--------------·-
- - - - - - - - - -
SL"GAR
1
CHLO.RIDES
1
--·--------
WASSERi\IA~i'\~
----1
COLL(JLDAL
GOLD
1--
228 mg. % 1: 2.5 mg.% ' 7()() mg.% 224 mg.% 1 :-l6 mg.% 664 mg.% ! N"egative ] 111122;-l:311 I
------
The patient ran a downward comse throughout his 9 day hospital stay. On March 29, there was evidence of a left hemiplegia, and on ::viarch the patii,nt expired Consent for autopsy \rns not obtained. DISCTJSSION
The purpose of presenting this case is to record the fact that the Donovall body may invade the internal genitals of the male. The lack of an autopsy makes disrnssion of the pathological changes produced by this organism impossible. The most. probable cause of the meningitis may have been the tubercle bacillus. V\T e are at a loss to account for the part played by syphilis and lymphopathia venereum upon the central nervous system of our patient. There is al,w the report of Thierfelder and Thierfelder-Thillot, 17 in which donovanosis caused a paralysis in 3 of their patiems. \Vith the demonstration of Donovania granulomatis in the spleen, 5 li\,er} 17 ovaries and tubes, 4 bone marrow, 5 bladder, 18 bony structures,6 and in this case, the epididymis, donovanosis can no longer be thought of as a cutaneous disease, but should be regarded as a systemic infection ,vith lesions of the skin as a prominent, and perhaps, early recognizable symptom. This view has been expressed previously.1'1 It is strengthened by the demonstration by Lyford, Scott and Johnson,1 9 • 20 that donovanosis can cause arthritis, and by the report of Thierfelder and Thierfelder-Thillot,1 7 just referred to, that donovanosis may presenl symptoms referrable to the central nervous system. The possible invasion of the internal organs by D. granulomatis must, therefore, be suspected whenever patients with cutaneous donovanosis present symptoms and complaints referrable to other parts of the Verification of this suspicion may be difficult, and at times, impossible. This is particularly so in patients in whom the symptoms involve organs inaccessible to biopsy. In such cases, the diagnosis may be inferred from the presence of cutaneous donovanosis, and the exclusion of other pos8ible diagnoses. Where is possible, the diagnosis may definitely be establishc~d upon the demonstration of the organism in Giemsa or ,vright stained section:,; of the biopsied specimen. 17
Thierfelder, M. V. and Thierfelder-Thillot, M.: Arch. f. Schiffs-u. Tropcn-Hyg. 28:
221-2:35, 1924. 18
Rhinehard, W. J. and Bauer, J. T.: Am. J. Roentgenol. & Radium Therapy, 57: 562--
567, 1947.
Lyford, J. Ill., Scott, R. B. and ,Johnson, R. W.: Am. Syph. Gonor. & Ven. Dis., 28: 588-610, 1944. 20 Scott, R. B., Lyford, J. III. and .Johnson, IL W.: Bull. .Johns Hopkins Hosp., 74: 213-19
217, Hl44
780
MARMELL, ULTMANN AND WEINTRAUB
The diagnosis in the present case was complicated by the tuberculous infection. From the hematoxylin and eosin stain, the double infection was not apparent and would have been missed if Giemsa stained preparation had not been made. Tuberculosis and donovanosis do not, of course, exclude each other, and cases of cutaneous donovanosis in tuberculous patients have been reported. 21 • 22 In view of the apparent low virulence of D. granulomatis, 3 • 10 it may be said that the tuberculous infection predisposed the tissue for invasion by this organism. SUMMARY
In a patient exhibiting cutaneous donovanosis, Donovania granulomatis was also demonstrated in the epididymis. Dissemination of this organism into the internal organs should be considered in all patients with cutaneous donovanosis who show systemic symptoms. We are indebted to Dr. Louis T. Wright, Director of the Department of Surgery, for permission to use the case records. We wish to thank Mr. Clement A. Constan for his unstinted efforts in preparation of the photomicrographs, and Mrs. Esther Sax and Miss Anna Frankel for their co-operation in preparing the histologic slides. Kuhn: Charite-Annalen, 30: 427-436, 1906. Greenblatt, R. B., Dienst, R. B., Pund, E. R. and Torpin, R.: J.A.M.A., 113: 11091116, 1939. 21 22