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Health Organisation of the League of Nations
324
TUDEUCLE
[April, 1936
OBITUARY. science have been truly epoch. making, IVAN PETROVITCH PAVLOV. opening up new lines of thought and February 27, 1936. new methods of exploration; and even THE death of Professor Pavlov in up to the time of his death he was the Leningrad at the age of 86 has mainspring of a " vast and stilI growing removed ono of the most outstanding organisation of ·research." Venerated figures in modern medicine. Although in his own country, he was no less· his work was primarily physiological, it • honoured by physiologists, neurologists bad an important bearing upon clinical and other scientists over the civilised medicine, including tuberculosis. Ilis world. interost in the natural sciences began at an early age. After graduating in 1879, be obtained in 1883 his M.D. degree in SEPTIMUS TRISTRAM PRUEN. hl.D.Dumr. St. Petersburg University for a thesis February 19, 1936. on tho efferent nerves to tho heart. For some thirteen years he carried on Dr. PnuEN, who died in Cheltenham his study of tho heart and blood circula- at thB age of 77, after forty years' work tion, this stndy being followed by his as surgeon to the Hospital for Sick well known investigations into the Children, Cheltenham, wiII bo rememphysiology of digestion, and this in bered by tuberculosis workers as one of turn by his study of nervous reflexes. the early followers in this country of He believed that all acquired habits Otto Walther's open-air treatment of and training depended on chains of phthisis. With his then colleague, Dr. conditioned reflexes, and his investiga- J. C. Braine.IIartnell, he founded in tion of the properties of these reflexes, 1897 the Cots wold Sanatorium, on the with his classical experiments on dogs, Cots wold Hills, seven miles from . are never pkely to be forgotten. ilis Cheltenham, which proved a popular services to physiology and to mental and successful venture.
HEALTH ORGANISATION OF THE LEAGUE OF NATIONS. TilE BLOOD-CULTURE OF THE TUBERCLE BACILLUS ACCORDING TO LOWENSTEIN . U:mER this heading thcre appcarcd in the lIIarch, HJ35, issue of the Quarterly Bulletin of the Health Organisation (see Tubercle, September, 1035, p. 568) three papers on experimental rcscarch into the value of Lowenstciu's mcthod of blood·culture. Professor Lowenstein, having taken exception to somc of thc statements in these three papcrs, it was agreed that he should answer them, and that to his answers replies should be given by Dr. A. S. Griffith, Dr. K. A. Jensen and Dr. A. Saenz. This exchange of views is published in the Quarterly Bulletin for December, 1935. PROFESSOR LilwENSTEIX'S VIEWS.
Tho idp.al would be, in an invcstigation of Lowcnstein's blood·culturo technique, to examino somo 1,000 cases of acuto polyarthritis, and to apply all threo methods of detecting the tubercle bacillus, i.e. : (1) Direct staining of tho h:cmoglobin-free deposit, (2) animal tests with the h:cmoglobin.freo deposits, and (3) Lowenstein's mcthod of culture. What actually happened whcn
samples of blood were submitted to Liiwenstein for examination was that only four instead of the expectcd 1,000 cases of rhenma' tism wcro inclnded, although acute rheumatism would ha\'c been the best subject of investigation. The proportion of positive tests on blood. culturo has been much higher in the hands of Lowenstein himself than in thoso of other laboratory workers whoso results" are naturally not as good as my own, for I have been working for thirty. three years on the question . . . and Lave, in the course of tLe last. six years, investigated more than 23,000 cases. . . . Professor Maresch himself pointed out that some thousand im·estigations nrc necessary for tho merc acquiring of the technique. Now that the ~Iaresch Institute has performed more than 14,000 tests, the results arc exactly the same as mine . . • . On December 31, 1031, I had made 2,889 blood-cultures during the preceding five years, and had obtnined 617 positive results in cases of polyarthritis." It is also suggested that the use of too powerful centrifuges may be responsible for the failure of Lowenstein's critics to obtain as high 0. proportion of positive results as he does. .. The work should be done with the same
April, H136]
HEALTH ORGANISATION OF THE LEAGUE OF NATIONS
centrifuge as I usc, which is supplied by Schulmcister, No.5, Spitalgassc, Vienna IX." It is also absolutely essential to remove the hremoglobin completely. for it may contain substances having an inhibitory efIect on tbe growth of tubercle bacilli. It is suggested by Lowenstein that Griffith" falls into the error of greatly overestimating the botanical difIerences between the human and bovine and, indeed, the avian type. Has not the English Tuberculosis Commission clearly and nnequivocally shown that no reliable difIerentiation can be arrived at between the human and bovine types, owing to the occurrence of so many transitional forms?" Lowenstein refers to five strains, cultivated from the blood of a polyarthritic paticnt, considered by Bruno Lange to be bovine and by Griffith to bc human_ Referring to Birkhaug's study of dissociation as "this extraordinarily thorough piece of work," Lowenstein emphasises Birkhaug's opinion that the avian, bovine and human strains do not present any fixed morphological features. As for the comparative valuo of his own positi vo findings and the negati ve findings of his critics, Lowenstein quotes Professor W. Neumann as writing: .. One single positive case proves a thousand times more than 1,000 negative cases." THE VIEWS OF PROFESSOR
LOWE~STEIN'S
CRITICS.
Dr. A. S. GRIFFITH: Lowenstein is under a misapprehension regarding the conclusions of the British Royal Commission on Tuberculosis. In their second interim report, the commissioners divided the viruses which they had examined into three groups. With regard to the third group, they thought that the bacilli might be in a special condition of instability and in process of being transformed from one type into another. But the further investigations of the Commission convinced its members that all the viruses in this group were either mixtures of human and bovine bacilli or attenuated forms of these two types, and that transitional forms did not occur. As for the five strains considered by Bruno Lange to be of the bovine type and. by Griffith to be of the human type, Griffith remarks that he knew nothing of this alleged difference till he read Lowenstein's note, and that correspondence with Lange and Lowenstein on the subject has not yet solved this riddle. .. Although I have repeated my request for the information, Lowenstein has not yet (November, 1!l35) supplied me with the numbers of the strains which he asserts Lange Bnd I assigned to difIerent types." As for Lowenstein's complaint that, in Griffith's paper, he nowhere refers to the well· established fact of dissociation, Griffith replies that it never occurred to him that dissociation might be advanced as an explanation of the discrepant results. Dr.. K. A. JENSEN: In support of his argument that the findings of all the investigators, including Lowenstein himself, contrast sharply
325
with Lowenstein's own earlier findings, Jensen publishes a table summarising the findings of French, German, Austrian and Danish workers. "When we come to consider the individual results arrived at by the difIerent investigators, we note that the percentage ofpositiye findings is practically the same for the various diseases, whethcr tubcrculous or non-tuberculous. The figures suggest, to my mind, a merely accidental distribution." Jensen dismisses as quite unfounded Lowenstein's suggestion that the discrepancies between the results of bloodcultures made by Jensen himself at Vienna and at Copenhagen respectively may be due to his having employed an inexperienced assistant at Copenhagen. As for Lowenstein's suggestion that the discrepancies observed may depend on the use of difIerent centrifuges, Jensen says that he adjusted the centrifuge he used to the speed recommended by Lowenstein, and that .. in view of the enormous numbers of tuberculosis bacilli demonstrated in the blood samples in Professor Lowenstein's laboratory, it is entirely out of the question that small difIercnces of technique should accoun t for the practically negative results of the other investigators." Jensen disagrecs with Lowenstein's assumption that mixed infections with human and bovine types are frequent, for in Jensen's own material of about 3,000 type-determined strains there were only five cases involving both the human and the bovine types. Though Lowenstein may believe in the existence of an abundance of transitional forms, Jensen has found only eight strains which could not readily be classified. Jensen concludes: "I can think of no other explanation than that there must exist in Lowenstein's laboratory some serious source of error which it is his duty to trace." Dr. A. SAENZ: With reference to Birkhaug's work on dissociation and the implication therefrom that the morphological characters of different cultures are not sufficiently fixed to allow of a reliable discrimination between the human and bovine types, Saenz remarks that he at first came to the same eonclnsion. '.' Snbsequently, however, to the work of Birkhaug and ourselves, on the subject of dissociation, a new fact of the highest importance came to light, which showed that the conclusions which both Birkhaug and we ourselves had felt entitled to draw from our experiments were erroneous. Three years of research work enabled us to advance the new idea that fresh guinea-pigs in our experimental cages might be parasitised by two types of acidfast bacilli, without outward signs of illhealth." As for Lowenstein's claim that Claude, Valtis and van Deinse have found tubercle bacilli in the blood and cerebrospinal fluid in several cases of. dementia prrecox, Saenz refers to correspondence with Claude and his assistant, Coste, who write that .. The presence of tnbercle bacilli in the blood and cerebrospinal fluid of certain dementia pru:cox cascs remains to be demonstrated." Whcreat Saenz remarks: "Thus the experimenters to whom Lowenstein appeals to support his case destroy it completely."
TUDEUCLE
[April, 1936
OBITUARY. science have been truly epoch. making, IVAN PETROVITCH PAVLOV. opening up new lines of thought and February 27, 1936. new methods of exploration; and even THE death of Professor Pavlov in up to the time of his death he was the Leningrad at the age of 86 has mainspring of a " vast and stilI growing removed ono of the most outstanding organisation of ·research." Venerated figures in modern medicine. Although in his own country, he was no less· his work was primarily physiological, it • honoured by physiologists, neurologists bad an important bearing upon clinical and other scientists over the civilised medicine, including tuberculosis. Ilis world. interost in the natural sciences began at an early age. After graduating in 1879, be obtained in 1883 his M.D. degree in SEPTIMUS TRISTRAM PRUEN. hl.D.Dumr. St. Petersburg University for a thesis February 19, 1936. on tho efferent nerves to tho heart. For some thirteen years he carried on Dr. PnuEN, who died in Cheltenham his study of tho heart and blood circula- at thB age of 77, after forty years' work tion, this stndy being followed by his as surgeon to the Hospital for Sick well known investigations into the Children, Cheltenham, wiII bo rememphysiology of digestion, and this in bered by tuberculosis workers as one of turn by his study of nervous reflexes. the early followers in this country of He believed that all acquired habits Otto Walther's open-air treatment of and training depended on chains of phthisis. With his then colleague, Dr. conditioned reflexes, and his investiga- J. C. Braine.IIartnell, he founded in tion of the properties of these reflexes, 1897 the Cots wold Sanatorium, on the with his classical experiments on dogs, Cots wold Hills, seven miles from . are never pkely to be forgotten. ilis Cheltenham, which proved a popular services to physiology and to mental and successful venture.
HEALTH ORGANISATION OF THE LEAGUE OF NATIONS. TilE BLOOD-CULTURE OF THE TUBERCLE BACILLUS ACCORDING TO LOWENSTEIN . U:mER this heading thcre appcarcd in the lIIarch, HJ35, issue of the Quarterly Bulletin of the Health Organisation (see Tubercle, September, 1035, p. 568) three papers on experimental rcscarch into the value of Lowenstciu's mcthod of blood·culture. Professor Lowenstein, having taken exception to somc of thc statements in these three papcrs, it was agreed that he should answer them, and that to his answers replies should be given by Dr. A. S. Griffith, Dr. K. A. Jensen and Dr. A. Saenz. This exchange of views is published in the Quarterly Bulletin for December, 1935. PROFESSOR LilwENSTEIX'S VIEWS.
Tho idp.al would be, in an invcstigation of Lowcnstein's blood·culturo technique, to examino somo 1,000 cases of acuto polyarthritis, and to apply all threo methods of detecting the tubercle bacillus, i.e. : (1) Direct staining of tho h:cmoglobin-free deposit, (2) animal tests with the h:cmoglobin.freo deposits, and (3) Lowenstein's mcthod of culture. What actually happened whcn
samples of blood were submitted to Liiwenstein for examination was that only four instead of the expectcd 1,000 cases of rhenma' tism wcro inclnded, although acute rheumatism would ha\'c been the best subject of investigation. The proportion of positive tests on blood. culturo has been much higher in the hands of Lowenstein himself than in thoso of other laboratory workers whoso results" are naturally not as good as my own, for I have been working for thirty. three years on the question . . . and Lave, in the course of tLe last. six years, investigated more than 23,000 cases. . . . Professor Maresch himself pointed out that some thousand im·estigations nrc necessary for tho merc acquiring of the technique. Now that the ~Iaresch Institute has performed more than 14,000 tests, the results arc exactly the same as mine . . • . On December 31, 1031, I had made 2,889 blood-cultures during the preceding five years, and had obtnined 617 positive results in cases of polyarthritis." It is also suggested that the use of too powerful centrifuges may be responsible for the failure of Lowenstein's critics to obtain as high 0. proportion of positive results as he does. .. The work should be done with the same
April, H136]
HEALTH ORGANISATION OF THE LEAGUE OF NATIONS
centrifuge as I usc, which is supplied by Schulmcister, No.5, Spitalgassc, Vienna IX." It is also absolutely essential to remove the hremoglobin completely. for it may contain substances having an inhibitory efIect on tbe growth of tubercle bacilli. It is suggested by Lowenstein that Griffith" falls into the error of greatly overestimating the botanical difIerences between the human and bovine and, indeed, the avian type. Has not the English Tuberculosis Commission clearly and nnequivocally shown that no reliable difIerentiation can be arrived at between the human and bovine types, owing to the occurrence of so many transitional forms?" Lowenstein refers to five strains, cultivated from the blood of a polyarthritic paticnt, considered by Bruno Lange to be bovine and by Griffith to bc human_ Referring to Birkhaug's study of dissociation as "this extraordinarily thorough piece of work," Lowenstein emphasises Birkhaug's opinion that the avian, bovine and human strains do not present any fixed morphological features. As for the comparative valuo of his own positi vo findings and the negati ve findings of his critics, Lowenstein quotes Professor W. Neumann as writing: .. One single positive case proves a thousand times more than 1,000 negative cases." THE VIEWS OF PROFESSOR
LOWE~STEIN'S
CRITICS.
Dr. A. S. GRIFFITH: Lowenstein is under a misapprehension regarding the conclusions of the British Royal Commission on Tuberculosis. In their second interim report, the commissioners divided the viruses which they had examined into three groups. With regard to the third group, they thought that the bacilli might be in a special condition of instability and in process of being transformed from one type into another. But the further investigations of the Commission convinced its members that all the viruses in this group were either mixtures of human and bovine bacilli or attenuated forms of these two types, and that transitional forms did not occur. As for the five strains considered by Bruno Lange to be of the bovine type and. by Griffith to be of the human type, Griffith remarks that he knew nothing of this alleged difference till he read Lowenstein's note, and that correspondence with Lange and Lowenstein on the subject has not yet solved this riddle. .. Although I have repeated my request for the information, Lowenstein has not yet (November, 1!l35) supplied me with the numbers of the strains which he asserts Lange Bnd I assigned to difIerent types." As for Lowenstein's complaint that, in Griffith's paper, he nowhere refers to the well· established fact of dissociation, Griffith replies that it never occurred to him that dissociation might be advanced as an explanation of the discrepant results. Dr.. K. A. JENSEN: In support of his argument that the findings of all the investigators, including Lowenstein himself, contrast sharply
325
with Lowenstein's own earlier findings, Jensen publishes a table summarising the findings of French, German, Austrian and Danish workers. "When we come to consider the individual results arrived at by the difIerent investigators, we note that the percentage ofpositiye findings is practically the same for the various diseases, whethcr tubcrculous or non-tuberculous. The figures suggest, to my mind, a merely accidental distribution." Jensen dismisses as quite unfounded Lowenstein's suggestion that the discrepancies between the results of bloodcultures made by Jensen himself at Vienna and at Copenhagen respectively may be due to his having employed an inexperienced assistant at Copenhagen. As for Lowenstein's suggestion that the discrepancies observed may depend on the use of difIerent centrifuges, Jensen says that he adjusted the centrifuge he used to the speed recommended by Lowenstein, and that .. in view of the enormous numbers of tuberculosis bacilli demonstrated in the blood samples in Professor Lowenstein's laboratory, it is entirely out of the question that small difIercnces of technique should accoun t for the practically negative results of the other investigators." Jensen disagrecs with Lowenstein's assumption that mixed infections with human and bovine types are frequent, for in Jensen's own material of about 3,000 type-determined strains there were only five cases involving both the human and the bovine types. Though Lowenstein may believe in the existence of an abundance of transitional forms, Jensen has found only eight strains which could not readily be classified. Jensen concludes: "I can think of no other explanation than that there must exist in Lowenstein's laboratory some serious source of error which it is his duty to trace." Dr. A. SAENZ: With reference to Birkhaug's work on dissociation and the implication therefrom that the morphological characters of different cultures are not sufficiently fixed to allow of a reliable discrimination between the human and bovine types, Saenz remarks that he at first came to the same eonclnsion. '.' Snbsequently, however, to the work of Birkhaug and ourselves, on the subject of dissociation, a new fact of the highest importance came to light, which showed that the conclusions which both Birkhaug and we ourselves had felt entitled to draw from our experiments were erroneous. Three years of research work enabled us to advance the new idea that fresh guinea-pigs in our experimental cages might be parasitised by two types of acidfast bacilli, without outward signs of illhealth." As for Lowenstein's claim that Claude, Valtis and van Deinse have found tubercle bacilli in the blood and cerebrospinal fluid in several cases of. dementia prrecox, Saenz refers to correspondence with Claude and his assistant, Coste, who write that .. The presence of tnbercle bacilli in the blood and cerebrospinal fluid of certain dementia pru:cox cascs remains to be demonstrated." Whcreat Saenz remarks: "Thus the experimenters to whom Lowenstein appeals to support his case destroy it completely."