La pression barométrique: Paul Bert's hypoxia theory and its critics

Respiration Physiology (1978) 34, 1-28 © Elsevier/North-Holland Biomedical Press

LA PRESSION BAROMI~TRIQUE: PAUL BERT'S HYPOXIA THEORY AND ITS CRITICS 1,2

RALPH H. KELLOGG Department of Physiology, Universi O, ~[ Cal~[brnia, San Francisco, CA 94143, U.S.A.

Abstract. Just one hundred years ago, Paul Bert published his most famous book, La Pression barom~trique .... summarizing his work on the physiological effects of altering barometric pressure. After a summary of Bert's life and contributions, this paper focuses on his experimental demonstration of the hypoxic etiology of altitude sickness. Bert showed that functional impairment or death occurred in each of a variety of species at a certain inspired oxygen pressure regardless of what combination of barometric pressure and oxygen percentage was used to achieve it. He further showed that the oxygen pressures impairing function were those producing arterial hypoxemia, and that raising the inspired oxygen percentage protected against the effects of altitudes that would otherwise endanger life. For the next several decades some other physiologists were unable to confirm these points. The criticisms of Setschenow, of Cyon, of Fraenkel and Geppert, of Mosso, and of Kronecker are analyzed in the light of modern knowledge. History Hypoxia

Mountain sickness Paul Bert

Exactly 100 years ago, Paul Bert (1833-1886) published his most famous book, La Pression barom~trique: recherches de physiologie exp&imentale (Barometric pressure: researches in experimental physiology) (Bert, 1878) (fig. 1). This book contains an extensive historical review of the literature dealing with the effects of AcceptedJbr publication 9 May 1978 I Based on a lecture presented in Srinigar, Kashmir, India on 10 October 1974 upon the centennial of Paul Bert's research monograph (Bert, 1874b). Unfortunately, a suitable manuscript was not completed in time for publication with the proceedings of the International Satellite Symposia of which that lecture formed a part (Paintal, 1976; Paintal and Gill-Kumar, 1977). 2 Some material was collected during support by USPHS Grant HL-13841 from the National Heart, Lung and Blood Institute of the National Institutes of Health, U.S.A. I am indebted to Professor Pierre Dejours of Strasbourg for much helpful information. ~lFig. 1. Title page of Bert's 1878 book on the effects of barometric pressures. (Bert, 1878) 3

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high altitude and high pressure, followed by presentation and discussion of Bert's own experiments and conclusions on these subjects. Although this book describes many important discoveries by Bert including the toxicity of high oxygen pressure and the production of decompression sickness by bubbles of nitrogen coming out of solution, I would like to celebrate the centennial of its publication by discussing Bert's experiments demonstrating for the first time that altitude sickness is caused specifically by the low oxygen pressure and can be avoided by raising the percentage of oxygen in the air breathed at high altitudes. Bert's attribution of altitude sickness to hypoxemia was untbrtunately disputed by a number of prominent physiologists for several decades before it finally gained universal acceptance. I will therefore attempt to analyze these conflicting experiments in the light of modern knowledge.

Theories before Paul Bert's research

Mountain sickness was first clearly described by Father Joseph de Acosta (1590), upon his return to Spain from his travels in the Peruvian Andes as a Jesuit missionary in the latter part of the 16th century. In the subsequent centuries, many travelers and balloonists described their own experiences with this illness. Many theories were proposed as to its etiology, without any clear conclusion until Paul Bert undertook his studies. Perhaps the best summary of this history before Paul Bert's contributions is that published by a Zurich physician, Conrad Meyer-Ahrens (1854), in the first book devoted to mountain sickness: Die Bergkrankheit, oder der Einfluss des Ersteigens grosser Hdhen auf den thierischen Organismus (Mountain sickness, or the influence of climbing great heights on the animal organism). The most important etiological theories discussed by Meyer-Ahrens and by Bert (1878) may be summarized as follows: (1) Low barometric pressure on the body surface. Albrecht von Haller (1761), citing Johann Friedrich Schreiber (1757), had supposed that the barometric pressure played an important part in supporting the superficial blood vessels. When the barometric pressure was reduced, these vessels would dilate, letting blood come out from the internal vessels, and would even rupture (nosebleeds, etc.). This seemed to be supported by the ideas of David Barry (1825, 1826) on the role of barometric pressure in venous return, (2) Increased volume of gastrointestinal gas. The increase in gas volume due to the decreased barometric pressure was supposed to interfere both with diaphragmatic action in breathing and with venous return through the abdomen to the heart. (3) Weakening of the coxo-femoral articulation. It was supposed that the barometric pressure played an important role in pressing the head of the femur into its socket. With reduced barometric pressure, the neighboring muscles would have to provide the necessary tension to hold the hip joint together, thereby accentuating the fatigue of walking. (4) Cold, over-excitement, over-exertion, and fatigue. These were believed to play

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a prominent part, the latter especially in the ascent of mountains as opposed to balloon ascents. (5) Increased evaporation. It is now known that increased evaporation rate is indeed characteristic of the high altitude environment, both because of the generally lower humidity and because of the greater mean free path of molecular movement that facilitates diffusion of water vapor from the surface of the skin and mucous membranes. (6) Increased light. It was a search for an effect of the increased ultraviolet light at high altitude on the control of breathing that led Hasselbalch and Lindhard (1911) serendipitously to discover the shift in ventilatory response to CO~ inhalation characteristic of high altitude acclimatization. (7) The decreased amount of oxygen per liter of air. Horace-B~n~dict de Saussure (1796) had suggested that rarefaction of the air had caused his increased breathing on the summit of Mont Blanc during his historic ascent in 1787, and Alexander von Humboldt (1803, 1838) had more specifically attributed mountain sickness to lack of oxygen. (8) Noxious gases from minerals in the mountains. This was believed to play a role especially in the Andes, where there were numerous bodies of ore being mined, and to help explain the obsevation that the severity of mountain sickness did not always correlate with the altitude of the pass being traversed.

Paul Bert's background First, let us consider Bert's background and how he became involved in this problem. Bert (fig. 2) was the son of a lawyer in Auxerre, the chief city of the D~partement de l'Yonne in the chablis-producing section of Burgundy (Olmsted, 1952). He went to Paris to study law, but became interested in zoology as a result of attending a lecture by Gratiolet. As a result, after he had completed his law degree in 1857, at the age of 23, he proceeded to study natural sciences, passing his examination for the licentiate in 1860 and then completing his M. D. degree in 1863 with an important thesis on the transplantation of animal tissues (Bert, 1863), where among other things his invention ofparabiosis was described. Plastic surgeons applied his findings in repairing mutilated soldiers in the Franco-Prussian War of 1870, and today's renal transplant surgeons might consider him the father of their field for his study of tissue acceptance and rejection, just as he is considered the father of high altitude physiology. Claude Bernard had been a member of Bert's examination committee in 1860 and was so impressed that he took him into his own laboratory for two additional years of work, at the end of which, in 1865, Bert (1) received the degree of Doctor of Natural Sciences, (2) received the prize in experimental physiology from the Acad6mie des Sciences for a second thesis on tissue transplantation (Bert, 1866), (3) married Josephina Clayton, a Scottish lady who was studying French in Auxerre,

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Fig. 2. Oil portrait of Paul Bert in the Musee Paul Bert in Auxerre, France. (Allonymous, 1977)

and (4) moved to the University of Bordeaux as Professor of Zoology. As he lacked laboratory facilities at the University, he worked instead at the nearby marine biological station of Arcachon on the comparative physiology of respiration. Soon Bert was recalled to Paris as a substitute for the aging Professor Pierre Flourens at the Museum of Natural History to relieve him of the task of giving the course in comparative physiology in the winter of 1867--68. He took as his subject the comparative physiology of respiration. The publication of his lectures (Bert, 1870), a classic in its field, established his reputation as a respiratory physiologist. This book included studies on animals asphyxiated by breathing in confined chambers. After Flourens died in December 1867, Claude Bernard was appointed to succeed him in 1868 as professor at the Museum of Natural History. Finding his lectures at the Sorbonne increasingly burdensome, Bernard then resigned his chair there and arranged for it to be given to Paul Bert, who assumed responsibility for the physiology course in the Faculty of Sciences. There was at this time a Paris physician, Denis Jourdanet, who had gone out to Mexico in 1842 but had returned after 19 years and had published several books expressing the ideas he had [brmed about the influence of high altitude on people

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Fig. 3. The pressure room in the physiology laboratory at the Sorbonne. At extreme left, Jourdanet's human chamber for hyperbaric and hypobaric therapy. In the far corner, Bert's horizontal animal chamber for high pressures. Along the right-hand wall, Bert's double vertical human chamber. In the center, the Lenoir gas engine with large flywheel that replaced Bert's original steam pump. (Regnard, 1897)

and their diseases (Jourdanet, 1861a,b, 1862, 1863a, 1864). Jourdanet became convinced that the effects of high altitude were due to a reduction of oxygen in the blood, and indeed he coined the term anoxy~mie to describe this condition. He compared the 'barometric anoxemia' of altitude residents to the 'hypoglobular anoxemia' of anemic patients at sea level (Jourdanet, 1863b), believing both suffered from hypoxemia but from different causes. When Paul Bert became famous as a respiratory physiologist, Jourdanet persuaded him to undertake the laboratory study of high altitude physiology and provided him with a decompression chamber for his experiments (fig. 3).

Bert's experiments Bert's physiological work was rudely interrupted by the disastrous defeat of the French Army and capture of the Emperor Napoleon III in the Franco-Prussian War of 1870 (Anonymous, 1977). In the scramble to organize a republican government to save the country, Bert volunteered his services and was made secretarygeneral to the prefect of the D6partement de l'Yonne in his home town of Auxerre, where he played an important role in mobilizing the citizens to harass the invaders.

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Subsequently, Bert was sent to Lille to become prelect of the Departement du Nord. Nevertheless, he managed to present his first and perhaps most important report on hypoxia (Bert, 1871) to the Academie des Sciences in Paris on 17 July [ 871. just a few months after the fall of Paris (28 January 1871) and the Commune (18 March-27 May 1871). The title of this report was "Recherches exp6rimentales sur l'influence que les changements dans la pression barometrique exercent sur les phenomenes de la vie" (Experiments on the influence that changes in barometric pressure exert on the phenomena of life). This was followed by 12 subsequent reports under the same title, all published as notes in the Comptes Remhts' de l'Aead~mie des Sciences in 1871 1874. The lethal Po: threshoht is the same regardless q f barometric pressure or oxy,~en percentage In this first note, Bert (1871) summarized the combinations of barometric pressure and inspired oxygen percentage that just proved fatal for animals of various species. Figure 4 reprints his graph of the results, with the inspired oxygen percentage at death plotted as a function of barometric pressure for the sparrow, guinea pig, and frog. Bert recognized that the resulting curves resembled rectangular hyperbolas such that the product of the ordinate and the abscissa should be essentially constant. Replotting the data in terms of this product, which is the partial pressure of oxygen in the atmosphere at death, showed that his impression was correct (fig. 5). All the sparrows died when the partial pressure of oxygen had ['allen to between 3.2 and 4.2 percent of an atmosphere, or as we would now say, an inspired oxygen I!~

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Fig. 4. Results of letting sparrows (M), guinea pigs (C), and frogs (G) use up tile oxygen in a chamber at various barometric pressures. Ordinate: The percent oxygen at which death occurred. Abscissa: Barometric pressure in crn Hg. decreasing from sea level pressure at the left, and the corresponding altitudes in meters. (Bert, 1871 )

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Fig. 5. The bird data of fig. 4, recalculated in terms of partial pressure of inspired oxygen. Ordinate: Oxygen pressure at which birds died, expressed as percent of an atmosphere. Abscissa: Barometric pressure in cm Hg, decreasing from sea level pressure at the left. Note that throughout the wide range of barometric pressures, birds died at inspired oxygen pressures that were all within the relatively narrow range of 3.2 to 4.2 percent of an atmosphere. (Bert, 1878,fig. 18) pressure between 22 and 30 mm Hg. He therefore concluded that it was the partial pressure of oxygens not the barometric pressure nor the oxygen percentage~ that was crucial in causing death from high altitude exposure.

Increasing the oxygen percentage protects animals J?om more severe decompression F r o m this conclusion, Bert reasoned that increasing the percentage oxygen in the inspired gas above that of atmospheric air should protect against still greater decreases in barometric pressure. To test this hypothesis, he developed a very simple apparatus, shown in fig. 6. A sparrow was placed in a bell jar, and air was pumped out until the sparrow fell over, apparently dead. He then admitted oxygen from the adjoining bag, raising the oxygen percentage and reviving the sparrow. Resumption of pumping then resulted in collapse of the sparrow at a lower barometric pressure than before, in accordance with his hypothesis. The rescue and further decompression could be repeated. Bert reported these results to the Academie des Sciences on 1 July 1872 (Bert, 1872a).

Hypoxia causes arterial hypoxemia in dogs at altitudes that produce mountain sickness These results pointed to the conclusion that mountain sickness or altitude sickness was due to lack of oxygen; but Bert felt it necessary to ascertain whether, in fact, there was less oxygen in the arterial blood under these circumstances. The answer

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P,. H. K E L L O G G

J)

_=:~. L

Fig. 6. Bert's apparatus for testing birds at decreasing barometric pressures and increasing oxygen concentrations. The bell jar (A) was progressively evacuated by a vacuum p u m p through stopcock (B). When the bird fell over, the pressure relative to atmospheric was read from the mercury manometer and converted to barometric pressure. The bird was then revived by purc oxygen admitted through stopcock (D) from the bag (O), and the cycle was repeated. (Bert. 1878, fig. 55)

to this question was not immediately obvious, for it was already known that oxygen did not come out of blood simply in direct proportion to a decrease in pressure (Meyer, 1857). Bert's fifth note, presented 8 July 1872, described his experimental demonstration that hypoxemia did indeed result (Bert, 1872b). He used a big double chamber operated by a steam pump (fig. 7), which was later replaced by the Lenoir gas engine shown in the middle of fig. 3. A large dog was tied down on a circular frame that would fit in the chamber. A 3346 ml sample of arterial blood was drawn as a control while the dog breathed atmospheric air. A carotid artery was then cannulated and connected with tubing through the wall of the decompression chamber to a specially constructed leak-proof syringe outside, into which blood could be aspirated despite the decompression of the chamber. To avoid the need for anticoagulants or flushing, the clamp on the artery was kept closed, with the connecting tubing clean and dry, until time for the experimental sample to be drawn (fig. 8). Later I will explain why I think this experimental detail was important

R

Fig. 7. Bert's double human chamber for studying low pressures. Chambers (A) and (A') could be independently decompressed into the vacuum reservoir (tank B), or they could be connected by opening an inner door. The steam pump at left was later replaced by a Lenoir-type gas engine. (Bert, 1878, fig. 27)

Fig. 8. Bert's apparatus for anaerobic sampling of arterial blood. The clamp on the artery (A) was first opened at the moment of sampling by pushing rod (S) from outside the chamber wall (P). Blood was aspirated into the special air-tight syringe (S), with all intervening connections immersed in water to avoid leaks. (Bert, 1878, fig. 30)

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R. 11. I~1.;I.1 ( ) ( i ( ;

Fig. 9. C'oncenlrcltioNs of C'()~ (~ibo,:c) ;Had ()_~ (bcloxx) in ~trtci'i~tl blood of dogs dccompcesscd ",,chile breathing ~lir Icirclcs aild zilloril~iling dots ~illd d~ishcs) or sul2jecled lo simil;lc hyl'~oxi~/ I-~5' i'cbrccllhing air through tl CO~ ~bsorbcr ~1 sec~ le','cl prcsstH-e (crosses ~md dolled lilacs). E~ch blood g~.l~,cot~centr;ttion has been multiplied b s tt t'~lclor to bring il<; control ",'zllue Io 4(I ~111'100 ml l'or ('(), or to 20 ml. 101) ml for O,. The absciss~t represc~ts b~ll'O111011"ic pt-cssurc in Cln Hg in the docolnt'~l-cssion cxpci-imclals ;Had pcrcetai oxygen illspircd il~ Ihc rcbl'ctllhing expct'imcllts. (BcI'I. 187~. !ig. ~,?)

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for his success. The chamber was then closed and decompressed to the desired effective altitude and held there for half an hour for a steady state to develop before the arterial clamp was released by remote control through the chamber wall to allow the arterial sample to be aspirated. The control and experimental arterial samples were then analyzed for total extractable oxygen and carbon dioxide and compared. Each sample was analyzed by heating it to nearly 100 °C with a water bath, while a mercury pump created a vacuum into which the oxygen and other gases would be drawn off. The use of ferricyanide for releasing these gases from hemoglobin was still unknown. The volume of the extracted gas was then measured in the mercury burette before and after absorption of carbon dioxide by alkali and of oxygen by pyrogallol. Figure 9 shows Bert's graph of the results. To normalize the data from experiments with different control values, he multiplied all oxygen data from each single experiment with a factor that would correct the control arterial oxygen concentration to 20 ml/100 ml and did likewise with a factor for carbon dioxide to correct its control value to 40 ml/100 ml. The open circles and dot-dash lines show the values in the experiments in which inspired oxygen pressure was lowered by decreasing barometric pressure. The crosses and dotted lines show the experimental results in the experiments in which inspired oxygen pressure was lowered by having the dog rebreathe air through alkali to absorb carbon dioxide. The results from the two sets of experiments agree quite well, although the data from the rebreathing experiments are relatively scant. More important, the arterial oxygen concentration seemed to fall significantly at the inspired oxygen pressures that correspond to the altitudes that produce mountain sickness.

Inspiring oxygen protects human subjects against severe decompression As final confirmation of his theory and its practical application to human function at high altitude, Bert reported in his last note in this series (Bert, 1874a) experiments on himself and two balloonists, Joseph Croc6-Spinelli and Th6odore Sivel. It is somewhat ironic that these were the first balloonists ever to die from the hypoxia of balloon flight. Their companion on the fatal flight of the Z6nith on 15 April 1875, Gaston Tissandier, survived (Tissandier, 1875a, 1875b). In one form of experiment, Bert was decompressed until he experienced the nausea, tachycardia, etc. of altitude sickness at the effective altitude of Mont Blanc (4807 m). He then inhaled oxygen and found that each breath of oxygen relieved both his tachycardia and his symptoms, which returned after inhalation of oxygen was stopped. Figure 10 shows another form of experiment, in which breathing oxygen continuously kept his pulse rate down despite further decompression to one-third of an atmosphere, equivalent to the altitude of the highest Himalayan peaks.

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Fig. 10. Effect of progressive decompression oil Bert's own pulse rttte. Upper scale: Barometric pressure in cm Hg. Lower scale: Pulse rate per minute. Abscissa: Clock time t?om 10:20 to 11:50. At (0). Bert began breathing a high-oxygen mixture instead of air. (Bert, 1878, fig. 591

Publication history As 1 have said, Bert first presented these experiments and others on barometric pressure to the meetings of the Acad6mie des Sciences, Paris, and published them in a series of 13 notes in its Comptes Rendus. Within a month of the last of these individual presentations, Bert published his assembled experimental evidence in a 170-page monograph, whose title differed from that used for the 13 notes only by changing one word: "Recherches exp6rimentales sur l'influence que les modifications dans la pression barom6trique exercent sur les ph6nom6nes de la vie" (Experiments on the influence that modifications in barometric pressure exert on the phenomena of life). This monograph appeared first in the April 1874 issue of the Annales des Sciences Naturelles (Bert, 1874b). It was then reprinted from the same type-setting, except for a new title page and other minor conforming changes, in the fall of that same year in the Bihlioth~que de l'Ecole des hautes Etudes (Bert, 1874c). Determining which of these was truly the first edition provided me with a pleasant bibliographic puzzle, because the title page of volume 10 of the Biblioth~;que.... in which Bert's paper was printed, bears the date 1873. However, 1874 appears on the printed wrapper of that volume and on the title pages of this paper and all the other individual papers in this volume as well as most of those in the preceding volume.

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But which publication appeared first in 1874 is made clear by the records of the Acad6mie des Sciences (Anonymous, 1874), which indicate that their copy of that issue of the Bibliothkque... was not received until October 1874. Four years later, Paul Bert (1878) published the monumental volume entitled La pression baromktrique: recherches de physiologie expOrimentale (Barometric Pressure." Researehes in Experimental Physiology) (fig. 1), the centennial of which we are celebrating this year. Publication of this book was subsidized by Denis Jourdanet, and it was issued by G. Masson of Paris with the price of 25 francs stamped on the spine of the publisher's cloth binding, a very small fraction of what collectors now pay for copies when they can be found. In this book Bert preceded the experimental sections by a very extensive historical introduction, in which he acknowledges his debt to the less extensive compilation in Die Bergkrankheit... by Conrad Meyer-Ahrens (1854) mentioned above. He also added new material, including a detailed discussion of the fatal flight of the Z6nith in which his former experimental subjects, Croc6-Spinelli and Sivel, had been killed. By this time, Bert had become a public political figure, elected to the National Assembly in 1874, and he was so severely criticized for his involvement with the tragedy that he felt it necessary to defend himself by recounting here how he had written to Croc6-Spinelli warning him that his proposed supply of oxygen was wholly insufficient for the flight. Unfortunately, La Pression baromOtrique.., has never been reprinted in its original form. In the year following its original publication, a greatly abridged version in Italian was published with an Italian abridgement of Jourdanet's Influence de la pression de l'air sur la vie de l'homme (Influence of the pressure of the air on the life of man) (Jourdanet, 1875, 1876) in a curious little volume (Mucci, 1879), which seems to be very little known. During World War II, the work was again translated for publication, this time in its entirety in English as a contribution to the war effort by Professor and Mrs. Hitchcock of Ohio State University (Bert, 1943). This edition has been reprinted in 1978.

Bert after 1878

Bert continued active in research despite his political activities. Among other things he demonstrated that nitrous oxide could produce deep anesthesia for long periods without danger of hypoxia. He did this by inducing nitrous oxide anesthesia in a hyperbaric chamber where the oxygen pressure could be well maintained (Bert, 1879). This method of administration was subsequently employed in human surgery and named for him (Blanchard, 1880). However, Bert devoted much of his energy to his political life as a member of the National Assembly, playing a major role in reforming the French system of public education and becoming Minister of Education when his party formed the Cabinet in 1881. He encouraged the teaching of science in the public schools and himself wrote a number of science textbooks (Bert, 1881, 1883, 1885, 1886). Some of these went through many editions, and at least one was

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translated into English by his Scottish wile (Bert, 1888). At the age of 53, he died of dysentery just a few months after arriving in Hanoi to become governor-general of French Indo-China charged with de-emphasizing the French military control and organizing a civilian government that would be acceptable to the Vietnamese. His last letter indicates that he remained a scientist at heart, for it concerned the possibility of generating electricity to light the city (Deprez, 1887). His death occasioned public observances (Berillon, 1887), and a bridge in Auxerre was named for him and adorned with his statue. In 1977, the city of Auxerre inaugurated a museum to his memory (Anonymous, 1977).

Early reactions to Bert's work

An example of the early favorable reactions to Bert's work may be found in the records of the meetings of the Soci6t6 M6dicale de la Suisse Romande of Lausanne, published in its Bulletin. At the 27 January 1874 meeting of the Section Diablerets du Club alpin, M. Dufour, the president of the society, had argued that mountain sickness was due to inanition of the tissues (Dufour, 1874a). At the 2 April 1874 meeting of the Soci6t6 Vaudoise de M6decine, M. Forel called the attention of the members to Paul Bert's new monograph (Challand, 1874). At the May 1874 meeting, M. Dufour (1874b) reported to the members that he was completely convinced by Bert that hypoxia and hypoxemia are important causes of mountain sickness. But he pointed out that Bert had not proven that low oxygen pressure is the only cause. He now believed that mountain sickness is a complex affair for the mountain climber. At low altitudes, the symptoms are due mostly to fatigue. At high altitudes, they are due mostly to hypoxemia, which probably accentuates the fatigue in addition to its direct effects. But he did not completely give up his own pet idea, for he still believed that inanition of the tissues as well as work contributes to the fatigue. He recognized, of course, that the effects of balloon ascensions are due to hypoxia without fatigue.

Setschenow

In 1880, however, a more quantitative consideration of Bert's work was presented by the great Russian physiologist, Ivan Michailovich Setschenow (1880a). He wondered why Bert found decreased arterial oxygen concentration during relatively mild decompression, whereas J. Worm-Miiller (1871) and others had found that oxygen did not come off hemoglobin until the oxygen pressure had fallen below 20-30 mm Hg. Setschenow confirmed the observations of Worm-Mtiller, equilibrating blood with air at various pressures down to 25 mm Hg at 15.2 C , observing little change when the blood was heated to 38 'C. Yet he did not doubt that Sivel and Croc6-Spinelli had died of hypoxia. He then carried out a hypothetical calculation

PAUL BERT AND HIS CRITICS

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that indicated to him that the oxygen uptake in decompression might be limited if breathing did not increase. He reasoned that Bert must have tied down his dogs so tightly that their breathing was restricted. Unfortunately, his calculations were incorrect, as Nathan Zuntz kindly pointed out to him in a letter. Setschenow (1880b) then re-derived his predictions of alveolar gas composition in the steady state by finding the limit of an infinite series representing successive breaths. He further generalized the calculations the following year (Setschenow, 1881), without further reference to Bert.

Cyon's attack A subsequent commentator was not so agreeable, l~lie de Cyon was a Russian who also called himself von Cyon when he was working in Germany with Ludwig. He had done some experiments with Bert's chamber in 1874 and apparently had formed bad opinions of Bert's apparatus and methods. It is not clear to me why he delayed putting his views in print; but in 1883, five years after publication of La Pression barom~trique .... he published a vitriolic attack on Bert (Cyon, 1883). To show the tone, I have translated the first few sentences of Cyon's paper: "If one takes it into one's head to introduce 50 kilos of meat into the stomach of a dog by force, the animal subjected to this treatment would be choked or would quickly succumb to rupture of the stomach. What would one say of an investigator who, after having tried this, concluded that meat is a poison for the organism? Yet it is experiments of this type that Paul Bert has instituted to study the action of high pressures on the animal organism; it is analogous reasoning which has led him to accept that oxygen is a poison for animals as well as for plants..." (Cyon, 1883) This introduction sets the tone of Cyon's paper, most of which is concerned with oxygen toxicity. But he attacked Bert's decompression experiments as well. His specific criticisms seem to be that Bert's gas analyses were not as precise as they could have been, and that Bert had not included in his publications the quantity of air in the chamber, the weights of his sparrows, and whether or not they were fasting. Cyon said all of these might have affected the rate at which they used up the oxygen. Cyon didn't present any experimental data in support of an alternative theory. Even though outspoken criticism in print was more common a century ago than it is now, I suspect that Cyon's attack tells us more about his own personality than about Bert's work.

Fraenkel and Geppert A more reasonable and convincing criticism was published in that same year by Fraenkel and Geppert (1883). The first author was Albert Fraenkel (1848-1916),

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better known as the discoverer of the pneumococcus. He should not be confused with another Albert Fraenkel (1864-1938), who also was active in Berlin at that time and is remembered for having introduced intravenous strophanthin into cardiology. The second author was Julius Geppert, who later collaborated with the great Berlin physiologist, Nathan Zuntz, in a classic study of the regulation of breathing during exercise (Geppert and Zuntz, 1888). Like Cyon (1883), Fraenkel and Geppert (1883) were worried about the accuracy of Bert's analyses of the oxygen content of arterial blood in hypoxia. Like Setschenow (1880a), they also were worried by the apparent discrepancy between the relatively high oxygen pressures at which Bert had found hypoxemia developing, compared to the much lower oxygen pressures that were then considered necessary to remove oxygen from hemoglobin in vitro. They were reinforced in the latter doubt by the appearance the previous year of Gustav Hiifner's first paper (1882) on the oxyhemoglobin dissociation curve of blood, which showed that the hemoglobin remained completely saturated down to nearly 20 mm Hg, while the amount of physically dissolved oxygen was very small and hardly changing. They therefore attempted to repeat Bert's experiments on the arterial oxygen concentration of dogs during graded hypoxia in a decompression chamber. They merely tabulated their numerical data, but in fig. 11 1 have plotted their results in comparison with those obtained by Bert (1878, p. 643). It is clear from this plot that Bert's data showed desaturation at an effective altitude of 2500 m, consistent with the onset of symptoms of mountain sickness, whereas Fraenkel and Geppert's data confirmed their suspicion that the arterial blood was not desaturated even at the effective altitude of Mont Blanc (4807 m). Thus they felt convinced that mountain sickness at such moderate altitudes cannot be the result of hypoxemia. How can we explain the discrepancy between the observations of Bert and those of Fraenkel and Geppert ? I think the explanation can be found in their technique. Bert usually withdrew a single control sample of 33-46 ml first, then a single experimental sample after half an hour of decompression, drawing the latter into clean, fresh, dry tubing that did not require any flushing. Thus I estimate the total blood loss from the dog to be perhaps 75 ml. Fraenkel and Geppert, on the contrary, were very anxious to achieve maximum analytical accuracy. They therefore drew larger samples, 50 ml each, and they drew them in duplicate each time, as a further check. Moreover, they used a complicated system of tubing through the wall of their chamber. Since this was initially filled with sodium carbonate solution as an anticoagulant, it had to be flushed out with blood for each sample. Thus I estimate that their experimental sample alone involved a blood loss of at least 125 ml. Furthermore, Fraenkel and Geppert did not take a control sample before their experimental decompression. Instead, they kept the dog until the next day, then put him back in the chamber without decompression to draw the control samples, another 125 ml hemorrhage in my estimation. Assuming a normal blood volume at the start, a hemorrhage of 125 ml during the experiment, and then restoration of the blood volume by formation of additional plasma during the 24-hour delay before

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PAUL BERT AND HIS CRITICS

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Fig. 11. Comparison of the arterial blood oxygen concentrations from the experiments of Fraenkel and Geppert (1883, p. 47) and of Bert (1878, p. 643). Ordinate: The decrease in arterial oxygen concentration below the sea level control value in that dog. Abscissa: Barometric pressure in mm Hg, increasing from zero to sea level pressure on the right. The (o) in the upper right-hand corner represents the author's estimate of the true sea level control concentration of arterial oxygen in Fraenkel and Geppert's experiments obtained by correcting their data for the effects of hemorrhage.

the control samples were drawn, I have calculated the altered oxygen capacity of their dog's blood and hence what the control oxygen content should have been. This is, of course, greater than their observed sea level control value and is indicated by the (o) in the upper right hand corner of fig. 11. By comparison, their experimental points show hypoxemia in accordance with Bert's theory. How can we explain the discrepancy between these results in vivo and Hfifner's dissociation curves in vitro? First, it must be recognized that the difference between inspired and alveolar gas composition was not clearly understood in quantitative fashion, and some arguments suggest that the authors thought of them as identical. It was only the previous year that Zuntz (1882) had first clearly enunciated the concept of the respiratory dead space, which had been only vaguely understood at the time of La Pression barom~trique... (Voit, 1878). It is greatly to Bert's credit that he recognized that there would be a difference between inspired and alveolar oxygen pressure and that he carefully compared the blood oxygen content when it was equilibrated in vitro at room temperature, in vitro at body temperature, and in vivo plotted as a function of the inspired oxygen pressure (fig. 12) (Bert, 1878). Christian Bohr (1891) quantified the relation of dead space to alveolar gas composition some years later in his well-known formula. More important was Hfifner's lack of knowledge of all the factors affecting the

20

R.H. KELLOGG

Fig. 12. Oxygenconcentration (ml/100 ml) in dog blood as a function of lhc barometric pressure (¢m Hg) at which it has been equilibrated (A) with air hi vitro at room temperature, (B) ~ith air ilz vitto a! body temperature, and (C) in vivo in the lungs of dogs breathing air. (Bert, 1878. fig 43) oxyhemoglobin dissociation curve. He did compare the curves for intact blood cells (defibrinated blood) and for crystallized hemoglobin, but he found they agreed! He knew about the effects of hemoglobin concentration and temperature, but he didn't know ab6ut the effect of pH. He dissolved his hemoglobin crystals in 12 mM N a H C O 3 solution, and he equilibrated all his solutions and bloods with CO,-free air, guaranteeing that they would be quite alkaline. Furthermore, he assumed the presence of but a single reactive group per hemoglobin molecule, one that would follow a simple law of mass action. Therefore he measured only 3 or 4 points per sample and then fitted the best rectangular hyperbola to those data. This was a bad assumption, for the curves are now known to be sigmoidal. As for the effect o f pH, that was not clarified until the effect of carbon dioxide on the oxyhemoglobin dissociation curve was described by Bohr, Hasselbalch, and Krogh (1904).

Mosso Angelo Mosso, professor of physiology at Turin, began to work at high altitude in 1882. Study of his technician, Giorgio Mondo, on the Thdodule Pass at 3333 m

PAUL BERT A N D HIS CRITICS

21

showed an increased respiratory frequency. Mosso calculated the tidal volumes and came to the conclusion that the respiratory minute volume decreased at high altitude. His raw data show that ventilation actually increased (Mosso, 1886, 1898 p. 41); but he came to the opposite conclusion because he converted his volumes to standard conditions (0°C and 1 m Hg in his case), rather than to body temperature and pressure, saturated (BTPS). He reasoned that if hypoxemia actually existed, as Bert had thought, the breathing should be stimulated rather than depressed. Thus he began to doubt Bert's hypoxia theory. He supported his ventilatory measurements by comparing pneumographic tracings recorded at Turin and Monte Rosa from human subjects (Mosso, 1898, p. 34) and later from sleeping dogs (Mosso and Marro, 1904), which confirmed the decrease in breathing. Mosso was also worried about the lack of arterial hypoxemia at altitude shown by the observations of Fraenkel and Geppert in apparent agreement with the predictions from the data of Hfifner. He decided to repeat Bert's crucial human chamber experiment (Bert, 1874a), but using the protocol that Bert had used with sparrows (Bert, 1872a). With his faithful technician in the chamber, he pumped air out until Mondo indicated that he was about to collapse. He then measured the composition and pressure of the gas in the chamber, revived Mondo by admitting some pure oxygen, and started pumping again to a new collapse point, at which he again measured the gas composition and pressure in the chamber. According to his calculations, both the barometric pressure and the percentage oxygen were lower on the second measurement, so the oxygen pressure at the point of collapse could not be a constant. I believe he made two errors in these experiments. In the first place, to be scientific, he carefully converted all his gas analyses to percentage by weight instead of percentage by volume, before multiplying them by the barometric pressure in the chamber. This was a serious error, because the accumulation of carbon dioxide, which has a much higher molecular weight than nitrogen or oxygen, results in the calculated oxygen percentage and hence partial pressure being falsely low. However, recalculation of his data shows that this alone is not enough to account for his observations. I think his more important error was to use too small a chamber and omit any provision for removing carbon dioxide. His chamber was little more than half the internal volume of Bert's great double chamber (U. Mosso, 1896; Bert, 1878 p. 630). Certainly it had a much smaller ratio of volume to metabolic rate than Bert used in his sparrow experiments (fig. 6), so that effects of high carbon dioxide would be a much more serious problem. In his human chamber experiments, Bert had been careful not only to use a large chamber but to continuously admit flesh air to ventilate it, preventing carbon dioxide accumulation. Putting his observations together, Mosso (1898) developed a new theory of mountain sickness. He proposed that the effect of low barometric pressure was comparable to that of the mercury pump in a blood-gas analysis apparatus. The vacuum simply extracted carbon dioxide from the blood, and the lack of carbon dioxide in the blood made one sick. He coined the word 'acapnia' to describe this lack of carbon

22

R.H. K E L L O G G

dioxide in the blood. By this acapnia theory, the breathing would naturally be depressed at high altitude by the lack of carbon dioxide stimulus, and the accumulation of carbon dioxide in his chamber experiments (shown by his analyses) would naturally be protective, allowing decompression to lower barometric pressures. Hereasoned further that hyperventilation at sea level should also produce hypocapnia, and he noted that it produced cerebral symptoms similar to those of decompression. We now realize that hyperventilation hypocapnia produces cerebral symptoms similar to hypoxia because it does in fact make the brain hypoxic, by inducing cerebral vasoconstriction, while inspiring carbon dioxide protects against hypoxia to some extent both by dilating the cerebral vessels and by stimulating the breathing. The former brings the brain tissue oxygen pressure closer to that of the alveolar gas, while the latter brings the alveolar gas pressures closer to those being inspired. It is only fair to say that some physiologists did not believe Mosso's acapnia theory, recognizing that the laws of pulmonary gas exchange required that a depression of alveolar ventilation at a constant metabolic rate would mean that the alveolar carbon dioxide pressure would rise, increasing its pressure in arterial blood. In fact it was hypoxic stimulation of breathing that was accounting for the decreased arterial carbon dioxide observed. Adolf Loewy (1895) seems to have understood this and attacked Mosso's acapnia theory strongly (Loewy, 1898). Mosso and Marro (1903) themselves subsequently observed hypoxemia in decompressed animals, but they were unable to understand it. The following year, they were reassured in their erroneous view by additional experiments that showed no change in arterial oxygen with altitude (Mosso and Marro, 1904). Joseph Barcroft (1925, p. 8) recalled that he became convinced of the error of Mosso's acapnia theory in 1910 by taking along Haldane's gas analyzer (Haldane, 1898) and alveolar sampling technique (Haldane and Priestley, 1905) and measuring the alveolar carbon dioxide and oxygen pressures in the various members of the expedition that Nathan Zuntz led to Mt. Teneriffe. Barcroft found that he hardly hyperventilated at all and hence had the most nearly normal carbon dioxide pressure (38 mm Hg) and the lowest alveolar oxygen pressure and was quite sick at altitude. Douglas, at the other extreme, had a large fall in alveolar carbon dioxide pressure (to 32 mm Hg) and hence a relatively high oxygen pressure and was essentially well. Certainly sickness did not correlate with hypocapnia, as Mosso would have predicted, but with hypoxia.

Kronecker

Perhaps the last major opponent of Bert's hypoxia theory of mountain sickness was Hugo Kronecker, Professor of Physiology in Berne and the organizer of the first International Physiological Congress. In 1890, the commission that was considering the possibility of building a cog railway up to the summit of the Jungfrau asked him to advise them as to the physiological problems that such a tourist railway might entail. Kronecker, familiar with the still-prevalent theory that mountain

PAUL BERT AND HIS CRITICS

23

sickness was mostly due to fatigue and over-exertion (Longstaff, 1906), recognized that tourists carried up the mountain in a railway carriage might react differently from mountaineers climbing the mountain under their own power. He therefore organized a party of 7 persons ranging in age from a boy of 10 to a 70-year-old peasant and including two ladies aged 20 and 30 as well as doctors and professors aged 30, 40, and 50. He arranged for this group to ascend as far as they could on mules and then be carried on litters from Zermatt to the Breithorn, 3660 m, while he studied their pulse rate, sphygmographic pulse tracings, depth of respiration, and blood hemoglobin concentration. He reported his findings in a report to the Jungfrau railway commission (Kronecker, 1894), followed by a paper in the Revue Scientfique (Kronecker, 1895a), then an English version in the Medical Magazine of London (Kronecker, 1895b). In the latter he says that his observations 'will be found in detail in the Reports of Swiss Medical Institutes' (Mitteilungen aus schweizerischen medizinischen Instituten in the French version of the paper). I have never been able to find this detailed paper and suspect that it was never published. For lack of original data, therefore, I cannot do better to present his point of view than to quote from his London paper: "In my opinion all symptoms point to the hypothesis that mountain-sickness consists in a disturbance of the circulation. Those attacked by it have all the appearance of persons suffering from cardiac affections. Deep breathing is of no good. The malady may arise in this manner: As a result of the diminished atmospheric pressure the pulmonary vessels dilate, which, producing stasis in the capillaries, causes dilatation of the right ventricle. Vigorous stimulation of the skin may produce contraction of the vessels, hence the beneficial influence of a fresh but not too cold wind. Muscular exertion, on the contrary, increases the abnormal stimulation of the heart. The distended veins contain so much blood that arterial blood-pressure falls, and the brain is insufficiently supplied with blood, hence longing for sleep, faintness, etc. Stasis in the portal vein causes loss of appetite, nausea, and even vomiting. These inconveniences cannot be attributed to want of oxygen, for deeper respirations are no remedy, and besides, the symptoms do not increase in proportion to the diminution of oxygen..." (Kronecker, 1895b) In this he was harking back to the old mechanical theory of Schreiber (1757) presented by Albrecht yon Haller (1761), Kronecker's 18th century predecessor at Berne. Eight years later he extended his opinions in a monograph entitled Die Bergkrankheit (Mountain sickness) (Kronecker, 1903), which is really not very much more informative as to the observational basis for his views. In this book he did, however, specifically call the circulatory condition pulmonary edema, long before the general recognition of acute pulmonary edema as a relatively common complication of high altitude (Hultgren et al., 1961). Later, Kronecker (1911) reviewed various case histories, including a case diagnosed as pulmonary edema at autopsy, and reaffirmed his opposition to the hypoxia theory: "How essentially different are such illnesses from attacks of shortness of breath from hypoxia ! Mountain sickness arises from disturbance of the pulmonary

24

R.H. KELLOG(; circulation, passing away as soon as the atmospheric pressure in the lungs (lesser circulation) and the blood vessels in the rest of the body (greater circulation) have equilibrated." (Kronecker, 1911 )

Here he seems to have explained even acclimatization to himself on the basis simply of mechanical pressure changes, transmitted incredibly slowly through the body. End of the controversy Angelo Mosso died in 1910, and leading altitude physiologists of the 20th century adopted Bert's theory. I have mentioned Adolf Loewy and Joseph Barcroft already. Hermann von Schr6tter (1906) made his support of the hypoxia theory quite clear, as might have been expected from his association with Zuntz (Schroetter and Zuntz, 1902), who had long supported this theory (Schumburg and Zuntz, 1896). Haldane's student, R.O. Ward (1908), in describing experiments that he conducted in Mosso's laboratory on Monte Rosa, was careful not to take sides in the controversy; but the accompanying paper by Boycott and Haldane (1908) makes it clear that they were convinced of the etiologic role of hypoxia, although they considered the role of carbon dioxide still unclear. Five years later, however, when writing up the results of their famous expedition to Pike's Peak, Douglas, Haldane, Henderson, and Schneider (1913) stated explicitly that they attributed all the effects to hypoxia. Hasselbalch and Lindhard (1911), although they went to the Austrian Alps to study the effects of the increased ultraviolet light, seem to have been convinced of the primary role of hypoxia. Nevertheless, Kronecker's associates (Frumina, 1908 : Rosendahl, 1908) continued to publish papers opposing the hypoxia theory, and Kronecker (1914) himself gave a lecture to this effect just a few weeks before his death. However, the determined opposition seems to have died with him, and one can write a neat terminus to this view in his school; for three years later, his pupil Erwin Rippstein (1917) reported that he had repeated and confirmed Paul Bert's animal chamber experiments and announced himself finally convinced that Bert had indeed been right !

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Barry, D. (1826). Experimental Researches on the Influence Exercised by Atmospheric Pressure Upon the Progression of the Blood in the Veins... London, Thomas and George Underwood, 175 p. B~rillon, E. (1887). L'(Euvre Scientifique de Paul Bert. Paris, Picard-Bernheim; Auxerre, Georges Rouill& 115 p. Bert, P. (1863). De la Greffe Animale. Th~se, Facult~ de M6decine de Paris No. 118:110 p. Bert, P. (1866). Recherches Exp6rimentales pour Servir ~ l'Histoire de la Vitalit6 Propre des Tissus Animaux. Th6se, Facult6 des Sciences de Paris, Paris, E. Martinet, 96 p. Bert, P. (1870). Lemons sur la Physiologie Compar6e de la Respiration Profess6es au Museum d'Histoire Naturelle. Paris. J.-B. Bailli~re et Fils, 588 p. Bert, P. (1871). Recherches exp6rimentales sur l'influence que les changements dans la pression barom6trique exercent sur les ph6nom~nes de la vie. C. R. Acad. Sci. 73:213-216. Bert, P. (1872a). Recherches exp~rimentales sur lqnfluence que les changements dans la pression barom~trique exercent sur les ph6nom6nes de la vie. Quatri6me note. C. R. Acad. Sci. 75 : 29 33. Bert, P. (1872b). Recherches exp6rimentales sur l'influence que les changements dans la pression barom6trique exercent sur les ph~nom6nes de la vie. Cinqui~me note. C. R. Aead. Sei. 75: 88-92. Bert, P. (1874a). Recherches exp6rimentales sur l'influence que les changements dans la pression barom~trique exercent sur les ph~nom6nes de la vie. 13e note. C. R. Acad. Sci. 78:911-914. Bert, P. (1874b). Recherches exp~rimentales sur l'influence que les modifications dans la pression barom~trique exercent sur les ph~nom~nes de la vie. Ann. Sei. Nat. Zool. S&. 5, 20: 1-167. Bert, P. (1874c). Recherches exp6rimentales sur l'influence que les modifications darts la pression barom6trique exercent sur les ph6nom~nes de la vie. Bibliothdque de l'Ecole des hautes Etudes, Section des Sciences naturelles 10: 1-167. Bert, P. (1878). La Pression Barom6trique: Recherches de Physiologie Exp6rimentale. Paris, G. Masson, 1168 p. Bert, P. (1879). Anesth6sie par le protoxyde d'azote m61ang~ d'oxyg~ne et employs sous pression. C. R. Acad. Sei. 89: 132-135. BerL P. (1881). Leqons de Zoologie. Paris, G. Masson, 556 pp. Bert, P. (1883). Lectures sur l'Histoire Naturelle des Animaux... Paris, Hachette, 394 p. Bert, P. and R. Blanchard (1885). l~16ments de Zoologie. Paris, G. Masson, 692 p. Bert, P. (1886). Leqons d'Anatomie et de Physiologie Animales. Paris, G. Masson, 260 p. Bert, P. (1888). First Year of Scientific Knowledge. London, Relfe Brothers, 344 p. Bert, P. (1943). Barometric Pressure: Researches in Experimental Physiology. Columbus, Ohio, College Book C o , 1055 p. Bert, P. (1978). Barometric Pressure: Researches in Experimental Physiology, ed. by M.A. Hitchcock and F. A. Hitchcock. Bethesda, Md, reprinted by Undersea Medical Society, Inc., 1055 p. Blanchard, R. (1880). De l'Anesth6sie par le Protoxyde d'Azote d'apr~s la M6thode de M. le professeur Paul Bert. Paris, Aux Bureaux du Progrks MkdicaL 101 p. Bohr, C. (1891). Ueber die Lungenatmung. Skand. Arch. Physiol. 2: 236-268. Bohr, C., K. Hasselbalch and A. Krogh (1904). Ueber einen in biologischer Beziehung wichtigen Einfluss, den die Kohlens~urespannung des Blutes auf dessen Sauerstoffbindung (ibt. Skand. Arch. Physiol. 16: 402-412. Boycott, A.E. and J.S. Haldane (1908). The effects of low atmospheric pressures on respiration. J. Physiol. (London) 37:355 377. Challand, T. (1874), Soci6t6 Vaudoise de M6decine. S6ance du jeudi 2 avril. Bulletin de la Soci~tO MOdicale de la Suisse Romande 8: 149-152. Cyon, I~. de (1883). L'action des hautes pressions atmosph6riques sur l'organisme animal. Arch, (Anat.) Physiol. [1883] Suppl.-Bd. :212-239. Deprez, M. (1887). Correspondance. Revue Scientil~que (Revue Rose) (Paris) S6r. 3, 24~ ann6e, 1" semestre. 39: 59. Douglas, C.G., J.S. Haldane, Y. Henderson and E.C. Schneider (1913). Physiological observations made on Pike's Peak, Colorado, with special reference to adaptation to low barometric pressures. Phil. Trans. R. Soc. London Ser. B, 203: 185-318.

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