 Chapter 4 of Histology of the Blood This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org, recording by Anna Simon. Histology of the Blood by Paul Ehrlich and Adolf Lazarus, translated by M. Myers. Chapter 4, leukocytosis The problem of leukocytosis is one of the most keenly debated questions of modern medicine. An exhaustive account of the various works devoted to it, of the methods and results, could fill by itself a whole volume, and would widely exceed the limits of an account of the histology of the blood. We can only deal fully, therefore, with the purely hematological side of the subject. Verichov, designated by the name leukocytosis, a transient increase in the number of the leukocytes in the blood, and taught that it occurred in many physiological and pathological conditions. In the period that followed, particular attention was paid to the leukocytosis in infectious diseases, and to the investigators for the last 15 years in this province, we owe very important conclusions as to the biological meaning of this symptom. Above all, Medchnikov has done pioneer service in this direction by his theory of phagocytes, and, though his theory has been shaken in many essential points, yet it has exercised a stimulating and fruitful influence on the whole field of investigation. The sketch Medchnikov's doctrine in a few strokes is only possible by a paraphrase of the very pregnant words, phagocytes, digestive cells. These words express the view that the leukocytes defend the organism against bacteria by imprisoning them by the aid of their pseudopodia, taking them up into their substance, and so depriving them of the power of external influence. The issue of an infectious disease would chiefly depend on whether the number of leukocytes in the blood is sufficient for this purpose. This engaging theory of Medchnikov has undergone important limitations as the result of further investigation. Denny, Buchner, Martin Hahn, Goldscheide and Jacob, Leuhe and Richter, and many others, have demonstrated that the most important weapon of the leukocytes is not the mechanical one of their pseudopodia, but their chemical products, Alexine Büchhe. By the aid of bactericidal or antitoxic substances which they secrete, they neutralize the toxins produced by the bacteria, and thus render the foe harmless by destroying his weapon of offense, even if they do not exterminate him. An explanation of the almost constant increase of the leukocytes in the blood in bacterial diseases is given by the chemiotactic as well as by the phagocytic theory of leukocytosis. The principle of chemiotaxis, discovered by Phefer, asserts that bacteria, or rather their metabolic products, are able to attract by chemical stimulus the cells stored up in the blood-forming organs, positive chemiotaxis. In the cases in which a diminution of the leukocytes in the blood is found, it is the result of a repulsion of the leukocytes by the bodies mentioned, negative chemiotaxis. As the experimental investigation of leukocytosis was carried further, it was found that leukocytosis, quite similar to that occurring in infectious diseases, could also be brought about by the injection of various chemical substances, bacteria proteins, albimiosis, organic extracts, and so forth, and it became evident that the explanation of the process by chemiotaxis must be supplemented in many respects. Luit, for instance, found that when substances of this kind are injected, two different stages can be distinguished in the behaviour of the leukocytes. The first came a stage in which they were diminished, leukopenia, luit, and in such a way that only the polynuclear cells were concerned in the diminution, whilst the number of the lymphocytes was unchanged. After this came the phase of increase of the white blood corpuscles, and here too exclusively of the polynuclear cells, the polynuclear leukocytosis. This behaviour seemed to indicate that during the first period a destruction of white blood corpuscles brought about by the foreign substances took place, and that it was only at the dissolved products of the latter which caused the emigration of fresh leukocytes by chemiotaxis. But new objections were raised against this view. Goldshireder and Jacob in particular showed by exact experiments that the trenchant leukopenia of the blood was not true but merely apparent, and was caused by an altered distribution of the white blood corpuscles within the vascular system. For whilst in the peripheral vessels from which the blood for investigation was usually obtained, there was in fact a diminution of the leukocytes, hypoleucocytosis, in the capillaries of the internal organs, especially of the lungs, a marked increase of leukocytes, hyperleucocytosis was found. There are other objections to the great importance that luit has given to leukopenia. A priori it is quite incomprehensible that the various substances which in the fundamental test tube experiment are able to exercise a distinct chemiotactic influence on leukocytes should under other circumstances need the intervention of the products of decomposition of the white blood corpuscles. Moreover, clinical experience speaks in general against Luit's theory. However in infectious diseases hyperleucocytosis is very common, and a trenchant leukopenia is equally rare. This contradiction to the experimental results obtained by Luit is easily explained when one reflects how different from the natural processes of the disease are the circumstances of experiment. In this case the animal is by intravenous injection fluttered at once with a morbid substance and a violent acute reaction of the vascular and blood systems is a natural consequence. In natural infection insidious and increasing amounts of poison come quite gradually into play, and for this reason perhaps hypoleucocytosis in a normal course of infectious diseases is much rarer than in the bruised conditions of experiment. Upon the clinical importance of leukocytosis, particularly for the infectious diseases and their various stages, an enormous mass of observations has accumulated. Selecting pneumonia as the best studied example, in the typical cause of this disease the constant occurrence of leukocytosis is undisputed. The increase usually continues up to the crisis and then gives place to a diminution of the leukocytes until a subnormal number is reached. Of special importance are the observations on an absence of leukocytosis in particularly severe or lethally ending cases, Kikotse, Settler, von Jax, Tristovic, Türk and others. In many other diseases as well the observation has been made that hyperleucocytosis as a rule is only absent in specially severe or in some way atypical cases. Several observers, Löwe and Richter, M. Hahn, Jakob, have been able to demonstrate experimentally for various infections that artificial hyperleucocytosis influences the cause of an artificial infection most favourably. The question in what way does this process contribute to the protection of the body is at the present time under discussion and introduces the most difficult problems of biology. The morphological character of leukocytosis is certainly not simple and we must sharply separate various groups according to the kind of leukocyte increased. The most important consideration is whether cells capable of spontaneous movement and of active emigration into the blood are increased, active leukocytosis, or whether the number of those cells is raised to which an independent mobility cannot be ascribed which therefore are only passively washed into the bloodstream by mechanical forces, passive leukocytosis. The passive form of leukocytosis corresponds to the different kinds of lymphemia including that of leukemia. In the section on the lymphatic glands we have established this view in detail and we have particularly insisted that a separation consisting of lymph cells does not occur. In sharp contrast to this form there are for every specific kind of active leukocytosis analogous products of inflammation, pus, exudations, composed of the same kind of cell. We divide active leukocytosis into the following groups A. Polinuclear leukocytosis 1. Polinuclear neutrophil leukocytosis 2. Polinuclear eosinophil leukocytosis B. Mixed leukocytosis in which the granulated mononuclear elements take part, myelemia A. One. Polinuclear neutrophil leukocytosis is the most frequent of all forms of active leukocytosis. Verhof, the discoverer of leukocytosis, advocated the view that it resulted from an increased stimulation of the lymph glands. The stimulation of the lymph glands consists in that they are engaged in an increased formation of cells that their follicles enlarge and after a time contain many more cells than before. The swelling of the lymphatic glands has as a consequence an increase of the lymph corpuscules in a lymph and through this an increase again of the colorless blood corpuscules. This standpoint had to be abandoned when Erlich showed that it is chiefly the emigration of the polinuclear neutrophil cells which brings about leukocytosis. Exact figures on this point were first given by Einhorn who worked under Erlich and were later generally confirmed. Corresponding with the increase of neutrophil blood corpuscules alone there is always a relative decrease of lymphocytes, often to 2% and even lower. It must here be borne in mind that the percentage of the lymph cells may be much diminished without change in their absolute number. It has, however, been conclusively demonstrated that occasionally in polinuclear leukocytosis the absolute number of the lymphocytes may decrease. Einhorn had already described a case of this kind and recently Tuerk has for the first time established the fact by an abundance of numerical estimations. Footnote? Naturally an ordinary leukocytosis may be combined with a lymphemia. We have already mentioned elsewhere that in the leukocytosis of digestion or of diseases of the intestine in children such a coincidence occurs. The eosinophil cells are as a rule diminished in ordinary polinuclear leukocytosis as Erlich had already mentioned in his first communication. The diminution is often considerable, often indeed absolute. A few diseases show, besides the neutrophil leukocytosis, an increase of the eosinophils as well as we shall describe in detail in the next section. Polinuclear neutrophil leukocytosis, leukocytosis kateksogen, may be divided to the several groups according to their clinical occurrence. We distinguish a physiological leukocytosis, which appears in health as an expression of changes in the physiological state. To this group belongs to leukocytosis of digestion, the leukocytosis from bodily exertion, Schoenburg & Zunz, or from cold baths, and further the leukocytosis of pregnancy, b. pathological leukocytosis, b. one, the increase of polinuclear cells occurring in infectious processes, often called inflammatory, after the principle apotheori fit denominatio. The majority of febrile infectious diseases, pneumonia, ericipolas, diphtheria, septic conditions of the most varied etiology, perititis, acute articular rheumatism, etc., are accompanied by leukocytosis of greater or less extent. In this connection, uncomplicated typhoid fever and measles occupy a peculiar position. In them, the absolute number of white blood corpuscules is diminished and chiefly at the expense of the polinuclear neutrophil cells. For the details we have quoted and for the course and variations of leukocytosis in infectious diseases, we refer to the thorough monograph of Tuik. Of Tuik's observations, we will mention only that in the final stage of the process of leukocytosis, which occurs at the time of the crisis in diseases which run their course critically, mononuclear neutrophil cells and stimulation forms as well often make their appearance in the blood. In still later stages, in which the blood has once more a nearly normal composition, a moderate increase of the eosinophils, gradually waxing and again waning, is very frequently found, zappert and others. Stienon, who has likewise devoted special researches to the occurrence of leukocytosis in infectious diseases, shows this point very well in his curves. B2. Toxic leukocytosis occurring in intoxications with the so-called blood poisons. This important group has not yet received adequate treatment in literature. In general, the majority of blood poisons, potassium chlorate, the derivatives of phenyl hydrazine, pyridine, phenacetin, call forth even in men a considerable increase of the leukocytes besides the destruction of the red blood carpuscules. This has been observed experimentally by Reader. We observed marked increase of the white blood carpuscules after poisoning from arsenirated hydrogen from potassium chlorate further in a fatally-ending case of hemoglobinuria, sulfonal poisoning, as well as after projected chloroform narcosis. B3. The leukocytosis which accompanies acute and chronic anemic conditions, especially post-hemoracic. B4. Cerectic leukocytosis in malignant tumors, phtesis, et cetera. Footnote. The so-called agony leukocytosis, we do not regard as a true leukocytosis, but only as the expression of a stoppage of the circulation caused by that condition. This produces an accumulation of the white carpuscules on the vessel walls, especially in the peripheral parts of the body which are as a rule used for clinical investigation. A leukocytosis is thus simulated. And footnote. To enter here more precisely into the special clinical importance of blood investigation in different forms of disease would lead us too far, and we refer for this subject to the excellent and thorough monograph on leukocytosis by Reader and to the papers of Zappert and Türk. In this place we will only touch on the most weighty points. A. The importance for differential diagnosis of the leukopenic blood condition in typhoid fever as compared with other infectious diseases, and in measles as against scarlet fever. B. The prognostic importance of the enumeration of the blight blood carpuscules, thus, for example, the absence of leukocytosis influences the prognosis of pneumonia unfavorably. Cricots and others. And the appearance of numerous malicides in bacteria is ominous as demonstrated by C. S. Engel. Finally, we may dismiss in a few words the origin of polynuclear neutrophil leukocytosis and refer to what has been said in another place on the function of the bone marrow. In agreement with Kerlov's researches, Erlich formulated, on severe anemic conditions 1892, his views on this subject as follows. Quote, the bone marrow is a breeding place in which polynuclear cells are produced in large numbers from mononuclear pre-existing forms. These polynuclear cells possess above all other elements the power of emigration. So soon as chemiotactic substances circulate in the blood, which attract the white elements, this power comes into play. This readily explains the rapid and sudden appearance of large numbers of leukocytes, which so many substances bring about, and particularly the bacteria proteins recognized by Buchner as leukocytic stimuli. I regard leukocytosis therefore in agreement with Kerlov as a function of the bone marrow. End quote. Of great theoretical interest is the contrast between eosinophil and neutrophil cells. At the height of ordinary leukocytosis, the number of eosinophil cells is diminished often to disappearance. Whilst during its decline, they occur in abnormally high numbers. Hence it follows that the eosinophil and neutrophil cells must react towards stimulating substances completely differently and in a certain sense, oppositely. Footnote. It is also of interest to notice the behavior of the eosinophil cells in the passive form of leukocytosis, lymphemia. A priori, both conditions could be combined. As C.S. Engel has established, in the congenital syphilis of children, a simultaneous marked increase of lymphocytes and eosinophil cells is found. The lymphocytosis in these cases is probably due to the anatomical changes of the lymph glands and the eosinophilia to specific chemotactic attraction. End footnote. It seems, generally speaking, that the bacterial metabolic products formed in the human diseases which are positively chemotactic for the polynuclear neutrophil cells are negatively chemotactic for the eosinophils and vice versa. The explanation of the individual clinical forms of leukocytosis is self-evident from the above description. The occurrence of physiological and inflammatory leukocytosis is exclusively to be explained by chemotaxis. In the other forms, however, other factors also come into play. In particular, the increased activity of the bone marrow or the extensive transformation of fatty to red marrow, causing a large, fresh formation of leukocytes. Our knowledge of eosinophil leukocytosis is still of comparatively recent date. After Elich demonstrated the constant increase of the eosinophil cells in leukemia, a considerable time elapsed before an eosinophilia was found in other diseases. An eosinophilia, however, that differs in its essential traits from a leukemic type. To Friedrich Müller, we owe the first researchers in this direction, at whose suggestion Golasch investigated the blood of persons suffering from asthma, in which he was able to demonstrate a considerable increase of the eosinophil cells. This was followed by the researchers of H. F. Müller and Rieder, who discovered the frequency of eosinophilia in children and its presence in chronic splenic tumors. Further, by the well-known work of Ed Neuser, who observed a quite astounding increase of the eosinophil elements in penfiges, and by the almost simultaneous analogous observations of canon in chronic skin diseases. From amongst the flood of further papers upon this condition, we will only mention the comprehensive account of the subject by Zapart. By eosinophilia, we understand an increase only of the polynuclear eosinophil cells in the blood. Confusion of this form of leukocytosis with leukemia is quite impossible, because a good number of characteristic signs are necessary for the diagnosis of the letter, as we shall have to explain in the next section. The presence of mononuclear eosinophil cells in the blood should not be regarded, as is the case in many quarters, as an absolute proof of leukemia, for they are also found in isolated cases of ordinary leukocytosis. The increase of eosinophil cells is not always relative, but may be absolute. The relative number, normally 2 to 4% of all leukocytes rises in eosinophilia to 10, 20, 30% and over. In a case described by Gravitz, 90% indeed was found. The thorough researchers of Zapart, carried out on moist preparations by a suitable method, are particularly instructive with regard to their absolute number. As the lowest normal value, he gives 50 to 100 eosinophil cells per cubic millimeter, as mean value 100 to 200, as a high normal value 200 to 250. The highest absolute number he has ever found was 29,000 per cubic millimeter in leukemia, the highest number in simple eosinophil leukocytosis, 4,800 in a case of Pemphichus. Reinbach indeed once found about 60,000 eosinophil cells per cubic millimeter in a case of lymphocerchroma of the neck with metastasis in the bone marrow. Polynuclear eosinophil leukocytosis, apart from the form observed in healthy children, occurs in varied conditions, and for comprehensiveness, we divide them into several groups. We distinguish eosinophilia, one in bronchial asthma. Increase of the eosinophil cells of the blood, often considerable, amounting to 10 and 20% and more, has been regularly found, first by Gholash, later by many other observers. For the special clinical course of the eosinophilia in asthma, see below. Two, in Pemphichus, Neuser first recorded that an extraordinarily great, indeed a specific eosinophilia was found in many cases of Pemphichus. This interesting observation has been confirmed on many sites, in particular by Zappert, who once observed 4,800 oxafil per cubic millimeters. Three, in acute and chronic skin diseases. Canon was the first to notice that in a fairly large number of skin diseases, especially in perigo and psoriasis, the eosinophil cells are increased up to 17%. The observation of Canon is worthy of attention, that the increase of the eosinophils is connected with a degree of extension of the disease, rather than with its nature or local intensity. In a case of acute, widely distributed urticaria, A. Lazarus found the eosinophils increased to 60% of the leukocytes, a number which, after the course of a few days, again sank to normal. The first observations on the occurrence of eosinophilia in helmintheosis, we owe to Mule and Rieder, who obtained fairly high values, 8.2 and 9.7%, in two men suffering from ankylostomum duodenala. Shortly afterwards, Zapod stated that he had found a considerable increase of the eosinophil cells in the blood, reaching 17% in two cases of the same disease. At the same time, he demonstrated Charcot's crystals in the feces. In a third case of ankylostomiasis, Zapod found no increase of eosinophil cells in the blood, nor the crystals in the feces. Almost simultaneously, Siege made similar observations. For a detailed working out of this important branch, we are greatly indebted to Leichtenstein. Under his direction, Büchleus established the interesting fact that ankylostomiasis, in its relation to eosinophilia, does not occupy a special place in diseases caused by worms. All kinds of helminthites, from the harmless oxyurus to the pernicious ankylostoma, may bring about an increase of the eosinophil cells in the blood, often to an enormous extent. Footnote. In his monograph on Botherocephalus anemia, Shaman, with reference to the behavior of the eosinophil cells, states that he has found them in but few cases of this disease. And footnote. Büchleus reports an observation of 16% eosinophils in oxyureates, of 19% in escharides, and Professor Leichtenstein, as we learned from a private communication, has quite recently found 72% eosinophil cells in a case of ankylostomiasis, and 34% in a case of tinium mediocanolata. It is well worthy of note that Leichtenstein was able to observe numerous eosinophil cells in the blood, in those cases where Charcot's crystals were abundantly contained in the thesis, since eosinophil cells and Charcot's crystals have elsewhere been observed to be interconnected phenomena. For example, in bronchial asthma, in nasal polypy, in myelemic blood and bone marrow, one must fall in with Leichtenstein's supposition that eosinophil cells ought also to be found in the intestinal mucus in cases of ankylostomiasis. Positive observations on this point as yet are wanting. T.R. Brown, who worked on the direction of Thayer, has lately communicated the interesting observation that in trigonosis there is constantly an extraordinary relative increase in the oxyphil leukocytes in the blood up to 68%. The absolute figures are also much raised and attained values, 20,400 for example, which are by no means frequent, even in leukemia. Brown regards this astonishing phenomenon as pathognomic for trigonosis, so much so that in a case that was clinically obscure, he made from the marked eosinophilia the diagnosis of trigonosis, which was later fully confirmed. 5. Post-fibril form of eosinophilia, after the determination of various infectious diseases. In the section on polynuclear neutrophil leukocytosis, we've already mentioned that at the height of most of the acute infectious diseases, with a single exception of scarlet fever, the eosinophils undergo a relative decrease and may even entirely disappear. In the post-fibril period, however, abnormally high values for the eosinophil cells are often found, or even a well-marked eosinophil leukocytosis, which generally attains but moderate degree. Tuik, for example, in pneumonia, found a post-critical eosinophilia of 5.67%, 430 absolute, after acute articular rheumatism, 9.37%, 970 absolute. Zapat, in malaria, one day after the last attack, 20.34%, 1486 per cubic millimetres. The eosinophilia observed as the result of tuberculin injections, we include in agreement with Zapat in the group of post-fibril leukocytosis, for it appears only after considerable rises of temperature. During the real reaction period, the number of eosinophil cells sinks and only goes up again after the determination of the fever. The rise may be very considerable. In one case of Zapat's, the number of oxafils increased to 26.9%. In another of his cases, the highest absolute figure formed after tuberculin injections was 3,220 per cubic millimetres. In the case of Kravitz, the eosinophilia was quite extraordinary. The most marked changes in the blood occurred some three weeks after cessation of the tuberculin injections, of which ate altogether, from 5mg to 38mg, were given. Investigation showed 4 million red blood corpuscules per cubic millimetres, 45,000 white. Amongst the latter, there were 10 eosinophils to one non-eosinophil. The total number of eosinophil cells amounted to some 41,000 per cubic millimetres, whilst the other cells as a whole made up some 4,000. In as much as the latter contained polynuclears, lymphocytes and other forms, it follows that in this case, the polynuclear neutrophils must have been very much decreased, not only relatively, but also absolutely, so that this case represents precisely the contrary condition to ordinary leukocytosis and the infectious form in particular. 6. Imolignum tumours. In the caractia from tumours, an increase of the eosinophil cells has been observed by various authors. It is, however, of moderate degree and does not exceed 7 to 10 percent. Out of 40 decided cases, Reinbach found the eosinophils increased only in four. In the case of sarcoma of the forearm, he found 7.8 percent. Of the thigh, 8.4 percent. Imolignum tumour of the abdomen, 11.6 percent. Besides these, he describes the case of lymphocercoma of the neck with metastasis in the bone marrow, in which in an example the increase of the white blood corpuscules and especially of the eosinophil cells was found. The absolute number of the letter amounted on one day to some 60,000. This is an increase of 300-fold the normal, which apart from leukemia has doubtless never before been found. 7. Compensatory eosinophilia. After exclusion of the spleen. We have entered in detail into this form in the chapter on spleenic function, and have there already mentioned that the increase of the eosinophils found in chronic spleenic tumours by reader, vice and others must also be referred to the exclusion of the spleenic function. 8. Medicinal eosinophilia. Under this group occurs only a single observation of van Nordens, who observed the appearance of an eosinophilia up to 9 percent in two chlorotic girls after internal administration of camphor. In other patients this occurrence did not repeat itself, but probably researchers specially directed to this province of pharmacology would bring to our knowledge many interesting facts. On the origin of polynuclear eosinophil leukocytosis authors have put forward various theories which we will hear critically discussed in succession. An experiment frequently quoted as explanatory is that of Mula and Ridas. These authors do not derive the eosinophil cells of the blood from the bone marrow, but assume, as very probable, that the finely granular cells grow into eosinophils within the bloodstream. This developmental process seems very improbable for many reasons. Since the polynuclear cells circling in the blood are all under the same conditions of nutrition, it is a priori inconceivable why only a relatively small portion of them should undergo the transformation in question. And it is quite inexplicable why in infectious leukocytosis where the number of the polynuclears is increased so enormously their ripening to the eosinophils should remain completely interrupted. But the fact that a transition from neutrophil to oxfil cells has never really been observed in the blood is decisive evidence against the hypothesis of Mula and Rida. Where the hypothesis true, transitional stages ought to be found with ease in every sample of normal blood. Rida and Mula themselves are unable to bring forward any positive result with this kind, else they would hardly have been contented to fall back on the authority of Max Schütze, who professed to show the transitional forms between the finely and causally granular leukocytes in the circulating blood. The authority of Max Schütze in morphological questions stands high and very rightly, but one ought not to rely upon it for support in problems that are really histochemical and which should be solved by their appropriate methods. As logical consequence of their view and in decided opposition to Ehrlich, Mula and Rida assume that the eosinophil cells of the bone marrow, quote, are far rather the expression of a storage than of a fresh formation there. The bone marrow, therefore, should be regarded in reference to the causally granular cells of the blood more as a storage depot, where these cells serve other purposes, which for the present cannot be more closely defined, end quote. The chief reason for this assumption, these authors, see in the fact that the majority of the eosinophils in the bone marrow are mononuclear, whilst those of normal blood possess a polymorphous nucleus. Mula and Rida should themselves have raised the obvious objection that the same holds good for the nucleus of the neutrophils. They would then have seen the fold in their theory, for according to it, the most important blood preparing organ constitutes, as it were, not the cradle of the blood cells, but their grave. The simplest and readiest explanation, based, too, upon histological observation, is surely this, that the mononuclear eosinophil cells grow into polynuclear in the bone marrow, but that the latter only reach the blood by means of their power of emigration. As this view has been accepted by the great majority of authors since Ehrlich's paper on severe anemic conditions, we believe we may content ourselves with the above objections to the Mula-Rida theory, although it has even quite recently found supporters, for example B. Lenhardt's. H. F. Mula, moreover, in his paper on bronchial asthma, 1893, takes position different from his earlier and approaching that of Ehrlich. In considering the production of polynuclear eosinophilia, we may best start from an experiment of E. Noysus. Noysus, found in a Pemphicus patient whose blood showed a considerable increase of the eosinophils, the contents of the Pemphicus Bulla consisted almost entirely of eosinophil cells. Noysus, now produced a nonspecific inflammatory Bulla in the skin by a fessigant and found that the cellular elements in it were exclusively the polynuclear neutrophil concerned in all ordinary inflammations. Exactly analogous conditions, occurring spontaneously, have been demonstrated by Lorette and Perrin in the so-called During's disease. The Bullae, which appear in this dermatosis, contain, so long as their contents are clear, chiefly polynuclear eosinophil cells. In a later stage, as is usually the case, bacteria affect an entrance into the Bullae, which now become filled with neutrophils. According to modern views on separation, the experiment of Noysus and the observation of Lorette and Perrin can only be explained by the hypothesis that the eosinophil and neutrophil cells, as we've already several times mentioned, are of different chemiotactic irritability. Hence, the eosinophil cells only emigrate to those parts where a specific stimulating substance is present. From this point of view, experiments and clinical observations known up to the present on eosinophilia may be readily explained. Noysus experiment, for instance, may be explained in the following way. In the Pemphicus Bullae, a substance is present that chemiotactically attracts the eosinophils. Hence, the cells normally contained in the blood emigrate into them, and produce the picture of eosinophilus separation. Should the disease assume from the first a localized distribution only, the essential feature of the process is excluded. A totally different appearance, however, is produced when the disease has attacked large areas. Under these circumstances, large amounts of the specific active agent reach the bloodstream by absorption and diffusion. Here it exercises a strong chemiotactic influence on the physiological storage depot of the eosinophils, the bone marrow, leading to an increase of the eosinophils of the blood to a greater or less degree. The bone marrow, according to general biological laws, is by the decreased emigration, now further stimulated to a fresh production, and during a protected illness, can hence keep up the eosinophilia. In this way, other clinical observations may be explained. Golash has found that the sputum of asthmatic patients contains, in addition to Charcoalidon's crystals, eosinophil cells only. One must therefore assume that within the bronchial tree there exists material which attracts the eosinophils. This supposition is also supported by the close connection that obtains, according to many observations, between the severity of the disease and the eosinophilia. Thus Van Norden records that the eosinophil cells are more numerous about the time of an attack. They accumulated in especially large numbers after attacks had rapidly occurred several days in succession. That the increase of the eosinophil cells in this instance is directly connected with the attacks, and is not the expression of a permanent constitutional anomaly, is shown by a case in which Van Norden found 25% eosinophils during the attack and a few days later could only observe one example in 12 coverslip preparations, a diminution therefore of this group of cells. The observations of Canon and skin diseases are quite similar, for he showed that the expression of the disease determines the degree of eosinophilia more than its intensity, and it is the former factor which directly determines the quantities of the specific agent that pass into the blood. To the Mueller-Reeder hypothesis and the chemo-tactic theory of eosinophil leukocytosis, a third has lately been added, which may be shortly called the hypothesis of the local origin of the eosinophil cells. A. Schmid has with special reference to Asthma raised the question, quote, whether in the extensive production of eosinophil cells in Asthma, local production in the air passages is not more probable than origin from the blood. One may well regard the increase of the eosinophil cells in the blood of an asthmatic as secondary, end quote. This view, which has also been advocated by other authors, rests more particularly on the following facts and considerations. One, that in various diseases of the nose, especially in mucous pulopi and hyperplasia of the mucous membrane, laden, benolioi, and others, a great accumulation of eosinophil cells is found in these tissues, whilst they are apparently not increased in the blood. This objection is easily laid aside from the chemo-tactic point of view. For, if in the places in question substances are present which act chemo-tactically on the eosinophil leukocytes, in the course of time marked accumulation must occur without an increase of their number in the blood. One might as well conclude from Neumann's experiment in lymphatic leukemia, for example, where the artificial separation consisted only of polynuclear neutrophil cells, that the polynuclear cells were formed in the tissue, since in the blood they were present in very small percentage. For in this case, too, the same incongruity between the blood and the particular tissue exists. Two. Adolf Schmidt has urged the converse argument. He showed that in the sputum of patients with myelogenic leukemia, no more eosinophil cells were present than are commonly to be found in the peronchial secretion, although the blood was unusually rich in eosinophil cells. In our opinion, however, this observation does not support the hypothesis of local origin, but on the contrary, is clear evidence that not the larger or smaller number of eosinophil cells in the blood decides their immigration, but the presence of specifically active chemical stimuli. For we know from our observations on leukocytosis in infectious diseases that the bacterial stimulating substances act on the eosinophil cells rather in a negative than in a positive sense, and if ordinary sputum is not rich in eosinophils in spite of a marked eosinophilia of the blood, this only corresponds to our experience in general. Indeed, this phenomenon is quite similar to Noysus Pemphicus experiment, where the specific phototype of disease showed an eosinophilia whilst abscesses produced artificially, on the contrary, only neutrophil cells. Finally, we may employ to support our view another analogous experiment of Schmidt himself. He found numerous eosinophil cells in the sputum of an asthmatic patient, but only neutrophil cells in an artificially produced separation of the skin. Thus we see that the chief reasons brought forward by the supporters of the theory of local origin are not proof against the most obvious objections that can be raised from the chemiotactic standpoint. Moreover, neither histological nor experimental proof has been given for this theory in spite of numerous investigations in this direction. All the same, it should not be out of place to explain the possibilities that are given for a local origin of the eosinophil cells. First, the eosinophil cells might be the result of a progressive metamorphosis of the normal tissue cells. That such a process is possible is proved by the local origin of the mast cells. These may arise as Ehrlich and his school have always assumed by transformation of pre-existing connective tissue cells. Footnote. This view has lately received striking confirmation from the interesting experiment of Boymer who produced on himself by means of continued stimulation with urticaria urus a considerable increase in four days of the mast cells in the irritated portions of the skin. And footnote. But that the same holds good for the eosinophil cells as well has no wise as yet been proved. Secondly, it is conceivable that isolated eosinophil cells pre-existing in the tissues should rapidly multiply and so produce a local accumulation only. Numerous mitosis could be considered an adequate proof of this process. But so far no figures of nuclear division have been observed. Indeed, A. Schmid, who has directed special experiments there too from the standpoint of his theory, has found them entirely absent. As a third possibility for the local origin of the eosinophil cells, their direct descent from neutrophil cells is conceivable and is by many regarded as a kind of ripening. This assumption nevertheless must be described as unsound since the necessary condition of its foundation, namely the observation of corresponding transitional stages has not so far been fulfilled. By the inductive method then we conclude that a local origin of the eosinophil cells can hardly come under discussion. And this conclusion is strengthened by comparison with the behaviour of the mast cells which are related to the eosinophils in many points and only differ from them essentially in the nature of their granulation. The mast cells too, like the eosinophils, form a normal constituent of the bone marrow and occur regularly besides in normal blood, though in very small number. According to Canon, they amount to 0.28 percent of the leukocytes. We know that the mast cells are produced in large quantities locally wherever an overnutrition of the connective tissue occurs, for instance in chronic diseases of the skin, elephantiasis, brown induration of the lungs. In the case of the mast cells then, we see the conditions actually realized which the supporters of the theory of the local origin of the eosinophil cells only assume. We should therefore expect that an increase of mast cells in the blood or in certain inflammatory exudations would be by no means seldom. With this point in mind, Ehrlich has subjected the sputum in emphysema and brown induration of the lungs to exact examination for 20 years. Nevertheless, he has obtained entirely negative results. The special blood investigations of Canon have likewise proved to be practically negative. In 22 healthy persons, Canon entirely failed to find the mast cells on nine occasions. In the others, he found on the average 0.47 percent. The highest percentage number obtained was 0.89 percent. Only in a few cases of skin disease was a slight increase indicated. The average amounted to 0.58 percent. A number therefore, which is often to be found in healthy individuals. A leukocytosis of mast cells comparable with the eosinophil or neutrophil forms of leukocytosis has not been demonstrated in the cases of Canon or other observers. On the other hand, the mast cells undergo a considerable increase in myelogenic leukemia, in many cases equalling or even exceeding that of the eosinophils. We shall not err in deriving the mast cells of the blood, so leave the bone marrow on the grounds of this fact, or in conjecturing that their origin is not from the connective tissue, even when they are excessively increased. Footnote, that a well marked basophil leukocytosis has not so far been observed may be thus explained. The substances which tract the mast cells are very rarely produced in the body, much more seldom than the corresponding substances attractive for the eosinophils. In morbid conditions where substances attracting the mast cells were present, it might be possible to find a separation of mast cells or a mast cell leukocytosis as well. In this connection an observation of Albert Neisser is of the greatest interest. He met with private communication, one out of a numberless cases of gonorrhea in which the periodant secretion consisted entirely of mast cells. And footnote, we think we have shown in the preceding paragraphs that the evidence so far brought forward for a local origin of the eosinophil cells does not withstand the objections that have been raised. The task now lies before us to produce positive proof that the accumulations of eosinophil cells in the organs and secretions must be explained by emigration from the blood. This proof offers great difficulties in as much as we normally find eosinophil cells in many places. Here then we cannot trace a process step by step but we have to deal with final conditions. Could we observe the genesis of eosinophil cells in organs, usually free from them, it would be easier to clear up this question. Up to the present but a single observation on this point is available. Michaelis established the interesting fact that on interrupting lactation in suckling guinea pigs in the course of a few days numerous eosinophil cells collect in the memory glands but not in the lumen of the canylicoli. The eosinophil cells are further polynuclear exactly corresponding to those of the blood and therefore to be regarded as immigrants. We may explain this condition according to modern views as follows. Under certain conditions the memory gland is capable of an internal secretion by means of which substances are produced that are specifically chemiotactic for the eosinophil cells. When the external secretion of milk is disturbed the internal secretion is abnormally increased. The fact too that in Michaelis researchers no eosinophil cells passed into the true secretion of the gland may be thus explained. Footnote. Unger has recently published completely analogous observations on the human breast for the mast cells. Under the influence of stagnation of the milk he saw an invasion of the gland tissue by typical mast cells. Footnote. Exactly similar observations have been made on pathological material first recorded in the brilliant and fundamental work of Goldman. In a case of malignant lymphoma Goldman found a considerable accumulation of eosinophil cells within the tumor and demonstrated atomically that it was brought about by an emigration of the cells from the vascular system. Hence Goldman concluded that the eosinophil cells pass over into the tissue in question at the call of certain chemotactic products. Goldman and later Kauter showed that these eosinophil cells were not merely due to an ordinary inflammation. For in a large number of other diseases of the lymph glands particularly the tuberculous they were entirely absent. Similarly Lorette and Perrin have shown in their investigations of Turing's disease that the eosinophil cells which are also present in the cutaneous tissue in large numbers apart from the contents of the bullae are due to an emigration from the bloodstream. Thus it is evident from a number of various facts that the eosinophil cells found in the tissues are not formed there but have immigrated from the bloodstream. It naturally often happens that this appearance is not preserved equally distinctly in all cases. For as has been seen in the ordinary polynuclear nucleocytes the immigrated polynuclear eosinophils may similarly change to mononuclear cells. They may perhaps settle down and approximate to the character of fixed connective tissue cells. Such appearances may readily give rise to the view that in this case the reverse nuclear metamorphosis has occurred. That is a progressive development from mononuclear eosinophil to polynuclear cells. In agreement with Goldman, Yarason and H.F. Mueller we believe that the only admissible explanation of the facts mentioned above is that the eosinophil cells obey specific chemiotactic stimuli. By this hypothesis we can easily understand eosinophil leukocytosis, the presence of eosinophil cells in exudations and secretions, and the local accumulation of this kind of cell. As to the nature of these chemiotactically active substances we can so far only surmise. From amongst the clinical phenomena capable of throwing light on this subject we mentioned once more the fact that the metabolic products of bacteria repel the eosinophil cells. The opposed behavior of eosinophil and neutrophil cells is very well illustrated by a case of Leuchtenstern. Quote, in a very anemic almost moribund patient with ankylostomias there were found 72% eosinophil cells in the blood in 1897. The patient contracted a crupus, pneumonia, and in the high fibro period of the disease the number of eosinophils sank to six to seven percent, and rose again after the termination of the pneumonia to 54%. After removal of the worm the number at once fell to 11%. In the year 1898 the patient harbored but a very few ankylostomata. Charcot's crystals were no longer present in the feces. The number of the eosinophils amounted to eight percent. End quote. The question what cells produce on their destruction actively chemiotactic substances is a very great importance but cannot be answered with the material at present available. The breaking up of ordinary pus cells or lymphocytes does not appear to give rise to any such substances but there is much evidence that the decomposition products of epithelial and epithelioid cells act chemiotactically. Thus we can explain the frequent occurrence of eosinophilia in all kinds of skin diseases. Again in all atrophic conditions of the gastric, intestinal and bronchial mucous membrane there occurs a local accumulation of eosinophil cells. Further this kind of cell is increased in the neighborhood of cartenoma. Additional support for this view is seen in the fact that in bronchitis and asthma the less the superative element of the secretion is developed the more numerous are the eosinophil cells. An observation of Yarrison is worthy of mention in this connection. He observed abundant eosinophil cells in foci of lupus after injection of tuberculin. In these foci then by the destruction of the epithelioid cells brought about by the tuberculin substances must have been produced which act chemiotactically on the eosinophil cells. The specific substances are absorbed and reached the blood and impart to it also the chemiotactic power. The direct cause then of most forms of eosinophilia seems actually to lie in a destruction of tissue and in the products thus produced. On the other hand it cannot be doubted that substances foreign to the organism circulated in the body may act chemiotactically on the eosinophil cells. Footnote. A very interesting observation of Goldmann's deserves mention here. Goldmann found in preparations of the pancreas of proteus sanguinis containing parasites that the eosinophil cells in the neighborhood of the encapsulated parasites were much increased whereas they were sought for in vain in more distant parts. And footnote. The observations quoted above of the well-marked eosinophilia in the different forms of helmintheosis may here be specifically mentioned. The action of the helminthides was formally regarded as purely local but the indications that they act also by the production of poisonous substances continue to increase. Thus Lindstow has pointed out that the general typhoid state and the fatty degeneration of liver and kidneys that is of organs which Trujjina does not reach necessitate the assumption of a poisonous substance and in several varieties of ankylestoma as well there is distinct evidence of the production of a poison. We gather from Hutumann's article on animal poisons Eulenberg's Realen encyclopæde 1867 that just as ankylestomum in man produces the well-known severe anemia, so ankylestomum triconosophylum in the dog and ankylestomum pernesiosum in the tiger causes analogous general effects. Both theosophilus latus II is now generally accredited with the production of a definite toxic substance and the common tapeworm even by no means infrequently brings about injuries to the body which are to be referred to the action of a poison. So much follows from these observations that the tapeworms cannot only absorb but also can give out substances that are absorbed from the intestine of the host and are able to bring about distant effects. One expression of these distant actions is as Leichtenstein insists the eosinophilia of the blood. We do not think we should assume on the evidence before us that the substance which attracts the eosinophil cells is identical with the cause of the anemia. Many observations, the absence for example of eosinophilia in both theosophilus anemia, showman, render probable the existence of two different functions. In any case the substance causing the eosinophilia is more widely distributed than that to which the anemic condition is due. End of section nine. Section 10 of Histology of the Blood. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer please visit LibriVox.org. Recording by John K. Thomas, John Thomas Kruskowsky. Histology of the Blood by Paul Ehrlich and Adolf Lazarus. Translated by B. M. Myers. Section 10 B. Leukemia. Mixed Leucocytosis. In spite of the enormous extent of the hematological observations of the last descener, which a very considerable portion deals with the problem of leukemia, the literature shows many absurdities and misconceptions even on important fundamental ideas. This is especially the case with the weighty question of the distinction between various forms of leukemia. From the purely clinical standpoint it is usual to describe a lino, a nino medullary and a pure medullary myelogenic form of leukemia, but the distinguishing characteristics in this classification are crude and purely external and they find no place in hematology. Newman first showed that the lymphoid proliferation in lymphatic anemia is not confined to the lymph glands but may extend to the spleen and bone marrow. These proliferative processes may give rise to a considerable enlargement, for example of the spleen without any change in the specific character of leukemia or the condition of the blood. In spite of the spleenic tumor we have to deal with a pure lymphatic leukemia. In customary clinical language a case of this would be described as lino lymphatic leukemia. The unreliability and incorrectness of this terminology is best illustrated by another form of leukemic metastasis. In lymphatic leukemia the liver may swell by lymphomatous growth to a large tumor and we ought then to speak of a hepatolymphatic form of leukemia. This term is by no means so misleading as lino lymphatic, for no one would conclude from the former that any liver cells passed into the blood whilst the latter implies the idea that specific spleenic cells take part in the blood changes. Further the assumption of a pure linole variety of leukemia is totally unwarranted from hematological investigations. The possibility of a specific blood change depending solely upon disease of the spleen appears a priori almost excluded after what has been said on the physiological participation of the spleen in the formation of the blood. Pathological data completely confirm this view. Aeroleic at least in an enormous number of cases has never once succeeded in confirming the existence of a purely spleenic form from the blood examination. The conditions in myelogenic leukemia are quite similar for foci of myeloid tissue may appear in the spleen or lymph glands according to the kind of metastasis as it is the proliferation of the myeloid tissue and not the accompanying swelling of spleen or lymph glands that is specific in the process. The nomenclature lino medullary or medullary lymphatic leukemia must also be described as illogical and misleading. We distinguish them from the histological standpoint but two forms of leukemia leukemia processes with proliferation of lymphoid tissue lymphatic leukemia to leukemic processes with proliferation of myeloid tissue myelogenic leukemia. The accompanying clinical phenomena may be indicated by simple unequivocal amplifications. For instance lymphatic leukemia with enlargement of the spleen or of the liver myelogenic leukemia with enlargement of the lymph glands. From our present knowledge which it may be remarked is still far from full we may assume that lymphatic and myelogenic leukemia have quite a different etiology. The recent discovery of Lewitt should be decisive on this point for he demonstrated in myelogenic leukemia the presence of forms like plasmidia within the white blood corpuscles but wasn't able to find them in lymphatic leukemia. The necessity of separating lymphatic from myelogenic leukemia is further shown by the fundamental clinical differences between them. Lymphatic leukemia falls clinically into two readily distinguishable forms. In the first place acute lymphatic leukemia characterized by its rapid course the small spleenic tumor the tendency to petitia and to the general hemorrhagic diethesis. By its startling course this disease has given all observers the impression of an acute infectious process. The second form of lymphatic leukemia is marked off from proceeding by its chronic and often very protracted course. The spleen shows its participation in the disease as a rule by a very considerable enlargement. We have at present no investigations adequate to decide whether chronic lymphatic leukemia represents a single disease or should be etiologically subdivided. Hematologically all lymphatic leukemias are characterized by a preponderance of lymph cells. In particular of the larger varieties it should here be expressly mentioned that richness of the blood in large lymph cells is by no means characteristic of the acute form of leukemia for chronic very slowly progressing cases show the same condition. Thus in a case of this kind under observation in Gerhard's wards all observers Grohwitz, Neuerdin, Ehrlich found the large cells during its whole course. In agreement with our remarks elsewhere so page 104 we assume with regard to the origin of lymphatic leukemia that the increase of the lymph cells is brought about by a passive inflow into the blood and not by an active emigration from chemical stimuli. Myelogenic leukemia presents a picture that is different in every particular. In former years the distinction between myelogenic leukemia and simple leukocytosis offered great difficulties. These conditions were regarded as different stages of one and the same pathological process and when the proportion of white to red corpuscles exceeded a certain limit 150 it was said that leukocytosis ceased and leukemia began. By the aid of the analytic color methods the fundamental difference between the two conditions was first disclosed. Leucocytosis is now recognized to be chiefly an increase of the normal polynuclear neutrophil leukocytes whereas myelogenic leukemia brings elements into the blood that are abnormal. The cells here introduced are so characteristic as to render the diagnosis of leukemia possible even in the rare cases where the total number of the white blood corpuscles is not to any extent increased. The best example of which we are aware is a case observed by V Norden in which the proportion of white to red was only one to two hundred. Although the blood picture of myelogenic leukemia has been so clearly drawn by Ehrlich misconceptions and obscurities still occur in the literature and they are due to great errors in observation. It has for instance happened that unskilled observers have regarded and worked up cases of lymphatic leukemia as myelogenic. The apparent deviations discovered in this manner are copied as especially remarkable from one book to another through insufficient mastery of the staining method, the characteristic and diagnostically decisive elements neutrophil myelocytes for example are frequently mistaken. A further source productive of misconceptions lies in the circumstances that the typical leukemic condition of the blood may essentially change under the influences of intercurrent diseases. Thus the intrusion of leukocytosis brought about by secondary infection is able to obliterate more or less the specific character of the blood. Such conditions must naturally be considered a part and should not be used to overthrow the general characteristics of the picture. No one surely would deny the diagnostic value of glycosuria for diabetes because in conditions of in a nation for instance the sugar of a diabetic may completely vanish although disease continues. And one does not deny the diagnostic value of the spleenic tumor in typhoid fever because of the enlargement of the spleen may occasionally subside under the influence of an intestinal hemorrhage. From these considerations it is obviously necessary to derive the description of leukemic blood from pure uncomplicated cases and to construct it with the aid of standard methods. In this manner a type is obtained so characteristic as to render diagnosis absolutely certain from the blood alone. It is needful here to emphasize this hundredfold repeated experience with special distinctness. For some recent authors do not even yet allow the full diagnostic importance of the blood examination. The Limbeck says in the latest edition of his clinical pathology of the blood that one should not regard the blood changes as an invariably reliable diagnostic resource in meledogenic leukemia and that the diagnosis of leukemia should not rest on of the presence or significance of one or more cells. Not only the general features of the case but the blood condition as well should be considered. To these remarks the objections must be made that up to the present no serious hematologist will have had to diagnose a leukemic disease principally from the presence of one or more cells. In the work of Ehrlich and his pupils at least it has always been shown that the character of a leukemic condition is only settled by a concurrence of a large number of single symptoms of which each one is indispensable for the diagnosis and which taken together are absolutely conclusive. With these premises it is indisputable that the microscopic examination of the blood alone on dry preparations without the assistance of any other clinical method can decide whether a patient suffers from leukemia and whether it belongs to the lymphatic or myelogenic variety. The microscopic picture of myelogenic leukemia disregarding the almost constant increase of the white blood corpuscles has a varied highly inconstant character. This arises from the cooperation of several anomalies namely a that in addition to the polynuclear cells their early stages the mononuclear granulated corpuscles likewise circulate in the blood. B that all three types of granulated cells the neutrophil eoceno fill and mass cells participate in the increase of the white blood corpuscles. C that atypical cell forms appear example dwarf forms of all the kinds of white corpuscles and further mitotic nuclear figures. D that the blood always contains nucleated red blood corpuscles often in great numbers. One we begin with a discussion of the mononuclear neutrophil cells eryx myelocytes they are present so abundantly in the blood of medullary leukemia as to impart to the whole picture a predominantly mononuclear character as we have frequently mentioned myelocytes occur normally only in the bone marrow not in the circulating blood their eminent importance for the diagnosis of myelogenic leukemia where there have been regularly found by the best observers is in no way diminished by their transitory appearance in a few other conditions cp to 77 78 though they have been occasionally found according to turks investigations in the critical period of pneumonia as parts of a general leukocytosis the danger of confusion with leukemic blood changes is non-existent this is guarded against by one the much smaller increase of the white cells to the diminution of the acenophil and mass cells three the fact that the myelocytes of leukemic blood are nearly always considerably larger for the preponderating polynuclear character of the leukocytosis which is not a faced by the small percentage amount of myelocytes at most 12 five the incomparably smaller absolute number of myelocytes in the most pronounced case of turks for example in which the percentage number of myelocytes amounted to 11.9 calculation of their absolute number gives at most 1000 myelocytes per millimeter cubed this is a figure which bears no comparison with that obtaining in leukemia where 50 000 to 100 000 myelocytes per cubic millimeter and over occur in cases that are in no way extreme two the mononuclear acenophil cells before the introduction of the staining method mossler had described large coarsely granulated cells marrow cells as characteristic for myelogenic leukemia these are to be regarded as for the most part identical with the mononuclear acenophil cells noticed by muhler and raider as peculiar and aptly described by them as acenophil analogs of a preceding group they appear as large elements with oval feebly staining nucleus undeniably a valuable sign of leukemia they're not nearly so important as the mononuclear neutrophil cells as follows from the numerical superiority of the latter to regard the presence of acenophil myelocytes as absolute proof of the existence of a leukemia is inadmissible since they are occasionally present in small numbers in other diseases the absolute increase of the acenophil cells in his first paper on leukemia erlich stated that the absolute number of polynuclear acenophils is always much increased in myelogenic leukemia this assertion of erlich has been received under some protest the limbeck in his textbook even speaks of an alleged increase of the acenophil cells the well-known work of muhler and raider has more particularly given rise to this opposition and thrown doubt on the diagnostic importance of the acenophil cells these authors however base their contradiction on false premises for erlich did not speak of a rise of the percentage of the acenophil cells but only of an increase in their absolute number in a case of leukemia only the normal percentage number of acenophils is found it indicates all the same a great absolute increase and muhler and raider with themselves have fully confirmed erlich statement had they only calculated the absolute figures in a few of their cases selecting from the seven cases in this paper those where it is possible from the given data to obtain the absolute number of the acenophil cells we get the following results case 29 3.5 percent eos 14 000 per millimeter cubed 33.9 percent 8 000 31 3.4 percent 11 000 the figure given by zappert as a high normal value is 250 in these cases there is an average number of 11 000 that is 50 times as great the observations then of muhler and raider themselves suffice fully to confirm erlich statement the absolute number of acenophil cells depends naturally to a certain extent on the relative proportion of white to red corpuscles and the greater the relative number of leukocytes the greater should be the number of acenophils zappert for instance found the following figures in his cases proportion of white to red corpuscles absolute number of acenophils 124 3 000 2 4560 11 18 3 300 11 15 7 000 11 13 8 700 12 11 6000 12 7.6 8 300 127.0 7600 127.0 29 000 125.0 14 000 1 2 3.8 3 4 000 apart from the approximate parallelism between the two rows of figures this abstract shows that the minimal value 3 000 acenophils with a proportion of white to red of 1 to 24 still amounts to 15 times the normal the maximal figure found by zappert of 30 000 is moreover by no means to be considered extreme cases of leukemia are not infrequent in which we find 100 000 acenophils per millimeter cubed and over from these figures it must be admitted that the absolute increase of the acenophil cells in medullary leukemia is not alleged the limbic but on the contrary is very real and considerable that the absolute and relative number of acenophil cells may markedly sink in certain complications of leukemia constitutes no exception to the law that the acenophil cells are increased in myelogenic leukemia in this connection the self-evident principle must be observed that only analogous conditions are comparable the standard of comparison for a leukemic patient suffering from severe sepsis is not the blood of a healthy person with normal numerical proportions but that of a patient similarly attacked by a severe sepsis now we know that in sepsis the number of acenophil cells is enormously diminished so that zappert in five cases of this nature was unable to recognize any acenophils in the blood in contrast to this stands a case of myelogenic leukemia described by writer and mewler complicated by a severe and legally ending super creative process in consequence of the acute neutrophil leukocytosis brought about by the septic infection and the number of acenophils sank rapidly from 3.5 percent to 0.43 percent four hours before death the absolute number of acenophil cells however in this terminal stage still mounted to 1400 to 1500 per millimeter cubed and was therefore in comparison with an uncomplicated sepsis very much raised writers should not have disputed the importance of the acenophil cells for the diagnosis of leukemia from cases like these on the contrary they should have seen in them a decisive confirmation of the constancy of the absolute increase of the acenophils in leukemic blood at the time when erlich formulated his proposition on the diagnostic importance of the acenophil cells in leukemia the simple acenophil leukocytosis cp 148 first discovered later by the investigation of asthma etc was unknown for no confusion can arise between leukemia and conditions accompanied by acenophilia as they can be distinguished on clinical grounds alone the blood moreover provides ample means for a differential diagnosis one the total increase of the white cells in this case seldom reaches degrees that remind one of leukemia two the acenophil cells are exclusively polynuclear three mass cells and neutrophil myelocytes are almost entirely absent in favor of the diagnostic value of the absolute increase of the acenophil cells are those cases too where with a blood condition closely recalling leukemia the absence of acenophil cells exclude the diagnosis of that disease in a case of carcinoma of the bone marrow described by epstein with an anemic constitution of the blood nearly always present it may be mentioned in leukemia there was found a marked increase of the white blood corpuscles numerous neutrophil myelocytes and nucleated red corpuscles anyone holding as mewler and writer do that the number of acenophil cells did not be considered in the diagnosis must in this case have diagnosed myelogenic leukemia this however was according to alex system impossible owing to the complete absence of acenophil cells from all these observations it follows that an absolute increase of acenophil cells is indispensable for the diagnosis of leukemia for the absolute increase of the mast cells the mast cells are always increased in myelogenic leukemia they may be counted in leukemic blood with the aid of the triacid or eocene methylene blue stain as shown by the former they appear as polynuclear cells free from granules since their granulation takes on no die of the triacid mixture in all cases of myelogenic leukemia the increase of mast cells is absolute and considerable generally they are equally or half as numerous as the acenophils occasionally they may exceed the latter in number hence it follows that the mast cells undergo an increase in number relatively greater than the acenophil cells for they normally amount only to some 0.28 percent they're perhaps of greater diagnostic value than the acenophils because up to the present time we know of no other condition in contra distinction to acenophil leukocytosis in which a marked increase of the mast cells occurs five a typical forms of the white corpuscles amongst these are to be mentioned a dwarf forms of the polynuclear neutrophils and of the acenophil elements respectively as a rule they resemble normal polynuclear cells on a small scale b dwarf forms of the mononuclear neutrophil and acenophil leukocytes which correspond to the pseudo lymphocytes described elsewhere see page 178 the importance of these dwarf forms for leukemia is as yet insufficiently explained and it is difficult to decide whether they are already small forms on reaching the blood stream or whether they are there produced by division of a large cell see cells with mitosis formally particular weight was laid on the observation of mitosis for they were regarded as evidence that the increase of white blood corpuscles was brought about in the circulating blood itself an assumption specially supported by law it a large number of authors hf mewler wartime writer have demonstrated mitosis particularly of the mellocytes in the circulating blood in leukemia no diagnostic importance of any kind can however be as scribed to them they are found in all cases only in very small numbers thus mewler says that he generally must look through many thousand of white cells before meeting one mitosis only in one case did he find the figures of nuclear division somewhat more abundant where there was one mitosis only to several hundreds of leucocytes these really negative observations show that the mitosis play a complete negligible part in the increase of the cells in the blood itself for the diagnosis of leukemia they are valueless six nucleated red corpuscles form a constant constituent of leukemic blood in different cases their numbers very varying in one case they occur extremely sparingly and another every field contains very many the normal plastic type is found most frequently but side by side with it megaloblasts and forms transitional between the two are occasionally found mitosis within the red blood discs have been described by different authors but possess no theoretic or clinical importance the appearance of erythroblasts in leukemia may be either a specific phenomenon or merely the expression of an anemia accompanying the leukemia we are inclined to the first supposition since the occurrence in such numbers of nucleated red cells is hardly ever observed in other anemias of the same severity so much for the characteristics of leukemic blood upon which the diagnosis of the disease is made we must add that although in any case of medullary leukemia each particular factor described is to be recognized yet the same manner of its appearance its numerical relation to the others and to the total blood varies extremely apart from the degree of increase of the leukocytes no one case is the same as another with regard to the other anomalies in one case the blood bears a large-celled mononuclear neutrophil character and another the increase of the acenophil cells predominates in a third the nucleated red blood corpuscle preponderate in a fourth we see a flooding of the blood with mass cells and hence results in multiplicity of combinations and each single case has its own individual features it is of special importance to study the changes due to certain intercurrent diseases in the blood picture of medullary leukemia this point has recently been the object of detailed investigation in particular by a franco like chime and others according to these authors under the influence of febron diseases the total number of leukocytes may be enormously decreased the blood moreover is altered so that the mylamic characteristics become less marked and the polynuclear neutrophil elements largely preponderant the latter may attain the percentage numbers of common leukocytosis up to 90 percent and over we will hear mention a few rare cases demanding special attention showing the alterations leukaemic blood may undergo and occasionally presenting almost insuperable difficulties in diagnosis we find but a single case of this kind mentioned in the literature zappert reported a patient who in february 1892 had shown the typical signs of myelogenic leukemia amongst others the relation of white to red cells was found to be 1 to 4.29 and 1400 acenophil cells per millimeter cubed 3.4 percent were counted at the end of september of the same year the patient was brought in a miserable condition to the hospital where she soon died with gradually failing strength during this period of observation the proportion of white to red was 1 to 1.5 the percentage of acenophils 0.43 the mononuclears most of which had no neutrophil granulation amounted to 70 percent of the leukocytes zappert expressly mentions that these mononuclear cells were in no way similar to the lymphocytes in general appearance at the autopsy zappert found the bone marrow studded with non-granulated mononuclear cells and the acenophil cells were much more scanty than is usually the case in leukemic bone marrow blasstein under alex direction investigate a second case of this kind this patient had also been the subject of exact clinical investigations for some time on account of myelogenic leukemia during the time he was last in hospital the blood could only be examined a day before the fatal termination the direct consequence of a septic complication with a markedly leukemic constitution of the blood there were found 62 percent polynuclear cells 17.5 percent mononuclear cells about the size of the ordinary myelocyte 0.75 percent acenophil cells nucleated red blood corpuscles in moderate amount the preponderance of polynuclear and the small number of acenophil cells is readily explainable from the septic infection on the other hand the absence of granules in the mononuclear cells is most surprising these two observations can only be interpreted by assuming a loss in certain terminal stages on the part of the organism of its power of forming neutrophil substances similar conditions occur in non-lechemic conditions for example in a striking case of post hemorrhagic anemia described by Ehrlich it is of great importance to direct attention to these cases which up to the present have been practically disregarded for ignorance of their occurrence may easily give rise to gross errors concerning the nature in origin of the mononuclear cells and to the manufacturer of a linear form of leukemia finally we have to discuss the important question how the origin of myelomic blood is to be explained according to our conceptions two possibilities come under consideration either we have to deal with a passive inflow of bone marrow elements or with an active emigration from the bone marrow into the circulation this important and difficult question is certainly not fully ripe for discussion the most weighty objection to be raised against an active emigration of the bone marrow cells is derived from the behavior of the white blood corpuscles on the warm microscopic stage these investigations have been performed by a number of authors of whom may be mentioned B. S. Deckey, Newman, Hayam, Loet, Mayot, Gilbert, and particularly H. F. Mueller on the ground of his summary of the subject concerning the behavior of the forms of cells here involved all authors are agreed that under no conditions do the lymphocytes show the smallest spontaneous movement whilst the polynuclear neutrophil cells always exhibit vigorous contractility with regard to the forms most characteristic of leukemic blood the statements are partially contradictory some authors deny all spontaneous movement of these cells but most of them report observations from which it follows that a certain power of spontaneous movement is not to be gained it'll be admitted that in questions of this kind negative results are weakened by positive data thus Jolly recently described similar observations as follows visibles dans les observations et appartenant surtout un des globules de grand taille it is naturally impossible to decide if these minute movements suffice for a spontaneous locomotion but one cannot exclude offhand this opposition that they do it is indeed supported by a further observation of Jolly on the mononuclear isenophil cells of the marrow hitherto it was taken for established that these cells are completely devoid of spontaneous movement Jolly however was recently able to examine a specimen from a case of typical leukemia in which nearly all the isenophil cells showed active movement he says ces globules granuleaux actifs présentant des mouvements des progressions et des changements des formes caractéristiques et rapides c'est pendant je n'ai pas vu ces globules présentaires des pseudopods et fils des plus les comptes restiants presque toujours assez nettement arrêtes ces particularities correspondant exactement à la description qu'on donne depuis longtemps machutes des mouvements des cellules granules des sangs normal examination of dry specimens from the same case showed as Jolly expressly mentioned that the blood contained as the chemo blood always does polynuclear and mononuclear isenophil cells in contrast then with all earlier observations Jolly has demonstrated an active spontaneous movement of the mononuclear asenophil cells the amoeboid movement of the mononuclear cells is so seldom seen not because they lack this function but obviously from defects in the methods of investigation which as is manifest are rather rough and wholly unsuited for delicate biological processes there are many instances in the literature of the failures of this method even in the case of cells with undisputed mobility thus writer failed to observe any contractility in the majority of polynuclear leukocytes in a case of malignant lymphoma whereas according to other observations they possess this property without exception we think then we must draw the conclusion that the feeble mobility of the mononuclear cells both eosinophilus and polynuclear is only apparent and is owing to the gross method of investigation in reality they doubtless have mobility sufficient for emigration a further but much less weighty objection to the view that myelogenic leukemia is an active leukocytosis is that pus artificially produced in leukemic patients has nearly always the histological constitution of normal pus but from our previous detailed remarks we should only expect a myelemic constitution of the pus if the specific morbid agent of leukemia were present in a concentrated form at the place of inflammation just we saw in Pymfigus Neusers eosinophilus separation occurred only in the specific Pymfigus bule but not in the foci of separation that were artificially produced we know that the myelocytes are in no way positively influenced by the chemiotactic stimuli of ordinary infectious agents on the contrary it clearly follows that the above mentioned observations on the transformation of leukemic blood under the influence of infectious diseases that the common bacterial poisons act in a negatively chemiotactic sense both on the eosinophil and on the neutrophil mononuclear cells under these circumstances we should indeed expect that artificially produced separation in leukemic patients would have not a myelemic but a polynuclear neutrophil character it will be the task of further investigations to examine accurately inflammatory products example pleuritic exudations in leukemic patients with the object of elucidating the question whether under special conditions of disease all the leukocyte it's characteristic for leukemia may not be able to wander from the blood thus in a case of pleurisy in a leukemic patient Ehrlich received the impression from the preparations that a myeloid emigration had in fact occurred carrying all of the elements in the blood into exudation this observation does not prove the point for numerical estimation of the proportion of white to red blood corpuscles in the exudation was not made and these estimations are necessary in order to prove indisputably the active emigration of the white blood corpuscles into the exudation and to exclude their purely mechanical passage perrexine from the blood stream the hypothesis of the active origin of myelemia is considerably supported by a further train of argument in leukemia besides the myelocytes the polynuclear leukocytes are also enormously increased and their active emigration is beyond doubt and the view that the mononuclear cells are washed into the blood excludes that of a single mode of origin of the leukemic blood condition and commits us to a highly artificial explanation of its production the morphological changes of leukemic blood under the influence of infectious diseases can only be explained from the standpoint of the emigration theory or if the white blood corpuscles were mechanically carried out of the bone marrow as a whole it is incomprehensible that a bacterial infection should alter this process to a polynuclear leukocytosis this change of character is easily explained on the other hand as we have above shown more in detail by the assumption that ordinary bacterial poisons act positively chemo tactically only on the polynuclear neutrophil cells but negatively on the other forms we explain the origin of the chemic blood by the emigration into the blood under the influence of the specific leukemic agent not only of the form polynuclear elements but also of their mononuclear acenophil and neutrophil early stages and to classify myelogenic leukemia with the active leukocytosis end of section 10 leukemia recording by John Thomas Koosomarski www.validaturallife.com Section 11 of Histology of the Blood by Paul Ehrlich This is a LibriVox recording All LibriVox recordings are in the public domain For more information or to volunteer please visit LibriVox.org Recording by Morgan Scorpion Histology of the Blood by Paul Ehrlich and Adolf Lazarus Translated by M. Myers Section 5 Leucopenia Dimmunition of the white blood corpuscles Leucopenia Dimmunition of the white blood corpuscles plays comparatively with their increase a very unimportant role in clinical observations It occurs in but few groups of diseases and but seldom attains a market degree Koblanck has described a most marked fall in the number of colourless cells in the following remarkable blood condition In a strong man 25 years of age whose internal organs were found to be healthy short epileptiform attacks occurred in one of which death took place The autopsy gave no indication of the cause of death Two examinations of the blood were made in the course of the three days he was under observation In one of these out of 10 cover glass preparations not a single white blood corpuscle was found and in the second only one example We have mentioned this case here because it is remarkable as an extreme Leucopenia never before observed An explanation however is impossible owing to the obscurity of the general clinical condition For the rest of the conditions under which a considerable diminution of the leukocytes occurs are very well known We distinguish two chief groups One Leucopenia from destruction of a portion of the white blood corpuscles Blow it Two Leucopenia from deficient inflow of white corpuscles Alpha In infectious diseases from negative chemiotaxis Beta In anemia etc from defective action of the bone marrow We have entered more fully into the Leucopenia experimentally produced by Loet in the chapter on leukocytosis We there explained that according to present views we have to deal not with an actual destruction of the white elements but merely with an altered distribution within the bloodstream Amongst the infectious diseases where hypo-leucocytosis occurs typhoid fever must first be mentioned The diminution is cheaply at the expense of the polynuclear cells Uncomplicated measles too generally runs its course for the marked leukopenia especially distinct during the breaking out and at the height of the exanthem These cases of infectious leukopenia are to be explained not by a destruction of white corpuscles but rather by a diminished inflow brought about by the circulation of substances negatively chemiotactic for the polynuclear elements Leucopenia has still another meaning in certain cases of severe anemia where it indicates a highly unfavorable prognosis Erlisch has described Charité Analaine 1888 a case of post-hemorrhagic anemia ending fatally where an extreme diminution of the leukocytes occurred Exact figures showed that the greater proportion 80% of white blood corpuscles consisted of lymphocytes whilst the polynucleus amounted to 14% instead of 70 to 72% normally Eosinophil cells and nucleated red blood corpuscles were entirely absent Erlisch explained these phenomena by a deficient activity of the bone marrow which found expression in the insufficient formation of red and white blood corpuscles As the anatomical basis of this deficient activity he conjectured that in this case the fatty marrow of the big long bones could not have been changed to blood-forming red marrow as is the rule in severe anemias In two cases the autopsy fully confirms this diagnosis made during life The blood platelets the hemoconii The blood platelets were first described by Hayam later by Bidsor Zero as a third formed element of normal blood They are roundish or oval disks free from hemoglobin They are extremely unstable under mechanical, thermal and chemical influences Their size amounts to some three microns Specifically characteristic is their tendency the result of their extraordinary stickiness to run together into largeish clumps Grape clusters This circumstance greatly facilitate the distinction of the blood platelets from the other formed elements that renders their enumeration most difficult The apparatus usually used for counting the blood corpuscles is, for this reason, deceptive for the platelets rapidly cling to its walls and remain there All early authors, E.G. Bidsor Zero endeavored to obviate this error by some particular diluting fluid But a number of these elements still remained passant to the walls of the capillary tube of the mixing apparatus Recently Brody and Russell have recommended a new mixture in which the platelets remain quite isolated and are stained at the same time They allow the drop of blood as it comes from the puncture to enter a drop of the fluid and then estimate the relative proportion of red blood corpuscles to platelets Footnote 36 The physiological figures found by Brody and Russell with the aid of this method exceeded considerably those of earlier authors They found a proportion of platelets to erisocyte 1 to 85 or an absolute number of about 635,000 per millimetre and a footnote 36 The prescription for their solution is as follows Dahlia glisserin 2% solution of common salt equal parts Another method used by the majority of more recent authors is the relative enumeration of blood platelets in the stained dry specimen Erlisch found that the blood platelets were picked out by their deep red colour corresponding to the amount of alcohol they contain in preparations treated by the Iodine eryosine method C page 46 Ravel's new method is much more complicated and in no way more serviceable depending on a stain with iron hematogselin recommended by E. Haydnheim for demonstration of the centrosomes A process of rossins not yet published is more convenient It consists in fixing the dry preparation for 20 minutes in osmic acid vapour and staining in a concentrated watery solution of methylene blue With regard to the significance of the blood platelets most authors, of whom we should before all mention Haydn bitzotero, Laker assume justifiably that they are preformed in the living blood The view opposed to this advocated more particularly by Loet that these forms first arise in the blood after it has left the vessels we may describe on the grounds of our own extensive observations as inaccurate The blood platelets on the grounds of their small size and complete lack of nuclear substance are generally regarded as not analogous to real cells Whether they represent intravital precipitation of substances of the plasma or whether they are budded off from the cells cannot at the presently decided with certainty though many facts seem to support the latter assumption that they contain glycogen C page 45 marks them as descendants of the blood cells Moreover, appearances are often met with in dry preparations that arouse the suspicion that the platelets arise from the red blood corpuscles Kerper Arnold has further observed processes of budding in the red blood corpuscles and not only extravascularly but also intravascularly in the mesentery of young guinea pigs and has seen the elements that were cut off change into forms free from hemoglobin Our knowledge too of the physiological function of the blood platelets still needs much amplification The original view of Hayam who regards the blood platelets as early stages of the red blood discs and for this reason calls them hematoblasts is according to the judgment of most hematologists untenable Nearly all more recent papers on the other hand C.P. Lewis' compilation recognized the close connection of the blood platelets with coagulation first observed by Bidsodzero Whether the substance of the platelets directly yields the material for fibrin formation as Bidsodzero holds or whether according to the observations on thrombus production of ebboth and shimmelbush they play but a subordinate part is not yet decided To enter here into the chemical side of this complicated problem would lead us much too far and we will only refer to a few clinical observations which illustrate the relations between the clotting power of the blood and the number of platelets it contains marked increase of the blood platelets occurs in chlorosis, mure and in post-hemorrhagic anemia, hyum In both conditions there is a decided increase in the clotting power of the blood in contrast is the important observation of Dennis who found in two cases of proprora where as is well known the clotting power of the blood is always much lowered or may even be entirely destroyed only one morphological blood change a very marked diminution of the blood platelets Aelish likewise had occasion to examine a similar case in which the blood platelets were entirely absent H.F. Miller has described a fourth form constituent of the blood and given it the name of hemoconii or blood atoms, blood dust It is found in the plasma of the blood as very small granule or cocae like colorless corpuscles highly refractile with a very active molecular movement which keeps their shape under observation for a very long time without any special precautions According to Muller these bodies are not blackened by osmic acid and probably contain no fat They seem to have no connection with fibrin formation as they always lie outside the fibrin network Muller found them in every normal blood in varying numbers however much increased in the case of a morbid adisonii diminished in hunger and achexius More detailed observations are necessary to determine the chemical nature of these forms Experiments in this direction by extracting with aether or by the use of fat staining substances alcana, pseudon, dye and comparative investigations on the pymic blood should be successful End of section 11 End of Histology of the Blood by Paul Aelish and Adolf Lazarus translated by M. Myers