B. NORMAL AND PATHOLOGICAL HISTOLOGY OF THE BLOOD.
In satisfactorily prepared dry specimens the red blood corpuscles keep their natural size and shape, and their biconcavity is plainly seen. They present a distinct round homogeneous form, of about 7.5 µ in diameter. They are most intensely coloured in a broad peripheral layer, and most faintly in the centre corresponding to their depression. With all stains mentioned above the stroma is quite uncoloured, and the hæmoglobin exclusively attracts the stain, so that for a practised observer the depth of stain gives a certain indication of the hæmoglobin equivalent of each cell, and a better one than the natural colour of the hæmoglobin in the fresh specimen. Corpuscles poor in hæmoglobin are easily recognised by their fainter staining, especially by the still greater brightness of the central zone. When somewhat more marked, they present appearances which from the isolated staining of the periphery Litten has happily named "pessary" forms. The faint staining of a red corpuscle cannot be explained, as E. Grawitz assumes, by a diminished affinity of the hæmoglobin for the dye. Qualitative changes of this kind of the hæmoglobin, expressing themselves in an altered relationship towards dyes, do not occur, even in anæmic blood. If in the latter, the blood discs stain less intensely, this is due exclusively to the smaller amount of hæmoglobin.
A diminution in the hæmoglobin content can in this way be shewn in all anæmic conditions, especially in posthæmorrhagic, secondary and chlorotic cases. On the contrary, as Laache first observed, in the pernicious anæmias, the hæmoglobin equivalent of the individual discs is raised.
To appreciate correctly pathological conditions, it must always be borne in mind, that in normal blood the individual red blood corpuscles are by no means of the same value. Step by step some of the cells are used up and replaced by new. Every drop of blood contains, side by side, the most various stages of life of fully formed erythrocytes. For this reason influences which affect the blood—provided their intensity does not exceed a certain degree—cannot equally influence all red corpuscles. The least resistant elements, that is, the oldest, will succumb to the effect of influences, to which other and more vigorous cells adapt themselves.
To influences, of this moderate degree, belongs without doubt the anæmic constitution of the blood as such, the effect of which in this direction one can best investigate in cases of posthæmorrhagic anæmia.
In all anæmic conditions we observe characteristic changes in the blood discs.
A. Anæmic or polychromatophil degeneration.
This change in the red blood corpuscles, first described by Ehrlich, to which the second name was given later by Gabritschewski, is only recognisable in stained preparations. The red blood discs, which under normal circumstances stain in pure hæmoglobin colour, now take on a mixed colour. For instance, the red corpuscles are pure red in preparations of normal blood, stained with hæmatoxylin-eosine mixture. But in preparations of blood of a chromic anæmia stained with the same solution, in which possibly all stages of the degeneration in question are present, one sees red discs with a faint inclination to violet; others which are bluish red; and at the end of the series, forms stained a fairly intense blue, in which scarcely a trace of red can be seen, and which by their peculiar notched periphery are evidently to be regarded as dying elements.
Ehrlich put forward the theory, that this remarkable behaviour towards dyes indicates a gradual death of the red blood corpuscles, that is of the old forms, leading to a coagulation necrosis of the discoplasm. The latter takes up, as is the case in coagulation necrosis, the proteids of the blood, and acquires thereby the power of combining with nuclear stains. At the same time the discoplasm loses its power of retaining the hæmoglobin, and gives it up to the blood plasma in ever increasing quantity as the change proceeds. Hence the disc continues to lose the capacity for the specific hæmoglobin stain.
Objection has been raised to these views from many quarters, especially from Gabritschewski, and afterwards from Askanazy, Dunin and others. The polychromatophil discs are not, they say, dying forms, but on the contrary represent young individuals. The circumstance, that in certain anæmias the early stages of the nucleated red corpuscles are variously polychromatic, was evidence for this opinion.
In view of the great theoretical importance which attaches to this subject, the grounds for regarding this change as degenerative, may be here shortly brought forward.
1. The appearance of the erythrocytes which shew polychromatophilia in the highest degree. By the notching of their margins they appear to eyes practised in the judgment of morphological conditions, in a stage almost of dissolution, and as well-pronounced degeneration forms.
2. The fact that by animal experiment, for instance, in inanition, their appearance in large numbers in the blood can be produced. That is, precisely in conditions, where there can be least question of a fresh production of red blood corpuscles.
3. The clinical experience, that in acute losses of blood in man, these staining anomalies, can be observed in numerous cells, within so short a time as the first 24 hours. Whilst in our observations, which are very numerous upon this point, embracing several hundred cases, and carried out with particular care, no nucleated red blood corpuscles in this space of time can be found in man[8].
4. The polychromatophil degeneration can frequently be observed in nucleated red blood corpuscles, particularly in the megaloblasts. This fact can be so easily established that it can hardly escape even an unpractised observer, and it was sufficiently familiar to Ehrlich, who first directed attention to these conditions. The fact that the normoblasts, which are typical of normal regeneration, are as a rule free from polychromatophil degeneration, gave the key for the interpretation of this appearance. And similarly for the nucleated red blood corpuscles of lower animals. Askanazy asserts that the nucleated red blood corpuscles of the bone-marrow, which he was able to investigate in a case of empyema, shew, immediately after the resection of the ribs, complete polychromatophilia. This perhaps depends on the peculiarities of the case, or on the uncertainty of the staining method: eosine-methylene blue stain, which is for this purpose very unreliable, since slight overstaining towards blue readily occurs. (We expressly advise the use of the triacid solution or of the hæmatoxylin-eosine mixture for the study of the anæmic degenerations.)
After what has been adduced, we hold in agreement with the recent work of Pappenheim, and Maragliano, that the appearance of polychromatophilia is a sign of degeneration. To explain the presence of erythroblasts which have undergone these changes we must suppose that in severe injuries to the life of the blood these elements are not produced in the usual fashion, but from the very beginning are morbidly altered. Analogies from general pathology suggest themselves in sufficient number.
B. A second change that we find in the red blood corpuscles of the anæmias, is poikilocytosis.
By this name a change of the blood is denoted, where along with normal red blood corpuscles, larger, smaller and minute red elements are found in greater or less number. The excessively large cells are found in pernicious anæmia, as Laache first observed, and as has since been generally confirmed. On the contrary in all other severe or moderate anæmic conditions, the red corpuscles shew a diminution in volume, and in their amount of hæmoglobin. This contradiction, which Laache first mentioned, but was unable to explain, has found a satisfactory solution in Ehrlich's researches on the nucleated precursors of the myelocytes and normocytes (see below).
The blood picture of the anæmias is made still more complicated in that the diminutive cells do not preserve their normal shape, but assume the well-known irregular forms: pear-, balloon-, saucer-, canoe-shapes. Nevertheless in good dry preparations the smallest forms usually still shew the central depression. The so-called "microcytes" constitute an exception to this statement. These are small round forms, to which was allotted in the early days of the microscopic investigation of the blood, a special significance for the severe anæmias. They are however nothing but contraction forms of the poikilocytes, as the crenated are of the normal corpuscles. Consequently microcytes are but seldom found in dried specimens, whilst in wet preparations they are easily seen after some time. It is further of importance to know, that in fresh blood the poikilocytes exhibit certain movements, which have already given rise to mistakes in many ways. Thus at one time the poikilocytes were considered to be the cause of malaria. More recently the somewhat larger sizes were regarded by Klebs, Perles as amœbæ and similar organisms. In agreement with Hayem, who from the very first described these forms as pseudo-parasites, a warning must be given against attributing a parasitic character to them.
The origin of poikilocytosis, previously the subject of much discussion, is now generally explained in Ehrlich's way. For the mere fact, that by careful heating, poikilocytosis can be experimentally produced in any blood, forces one to the assumption that the poikilocytes are products of a fragmentation of the red blood corpuscles ("schistocytes," Ehrlich). And correspondingly the smallest fragments shew the biconcave form in the dry specimen; for they too contain the specific protoplasm of the disc "which possesses the inherent tendency to assume the typical biconcave form in a state of equilibrium."
Qualitative changes in the protoplasm of the poikilocytes are not to be observed, even by staining; and one may therefore ascribe to them complete functional power, and regard their production as a purposeful reaction to the diminished number of corpuscles. For by the division of a larger blood corpuscle into a series of homologous smaller ones, the respiratory surface is considerably increased.
C. A third morphological variation which anæmic blood may shew in the more severe degrees of the disease, is the appearance of nucleated red blood corpuscles.
Though we do not wish to enter here upon the latest questions concerning the origin of the blood elements, we must shortly indicate the present state of our knowledge of the nucleated red corpuscles.
Since the fundamental work of Neumann and Bizzozero, the nucleated forms have been generally recognised as the young stages of the normal red blood corpuscles. Hayem's theory, on the contrary, obstinately asserts the origin of the erythrocytes from blood-platelets, and has, excepting by the originator and his pupils, been generally allowed to drop.
Ehrlich had in the year 1880 pointed out the clinical importance of the nucleated red blood corpuscles, in as much as he demonstrated that in the so-called secondary anæmias, and in leukæmia, nucleated corpuscles of the normal size, "normoblasts"; in pernicious anæmia excessively large elements, "megaloblasts," "gigantoblasts" are present. At the same time Ehrlich mentioned that the megaloblasts also play a prominent part in embryonic blood formation.
In 1883 Hayem likewise proposed a similar division of the nucleated red blood corpuscles into two,
(1) the "globules nuclées géantes" which he found exclusively in the embryonic state, (2) the "globules nuclées de taille moyennes" which he found invariably present in the later stages of embryonic life, and in adults. Further, W. H. Howell (1890) found in cats' embryoes two kinds of erythrocytes, (1) very large, equivalent to the blood cells of reptiles and amphibia ("ancestor corpuscles"), and (2) of the usual size of the blood corpuscles of mammalia. And similarly more recent authors, H. F. Müller, C. S. Engel, Pappenheim and others, have adhered to the division of hæmatoblasts into normo- and megaloblasts. And it is on the whole recognised, that, physiologically, normoblasts are always present in the bone-marrow of adults, as the precursors of the non-nucleated erythrocytes; that the megaloblasts, however, are never found there under normal circumstances, but only in embryonic stages, and in the first years of extra-uterine life.
S. Askanazy on the contrary has expressed the view, that the normoblasts may arise from the megaloblasts, and thereby denies the principal distinction between them. Schaumann also holds that the separation of the two kinds rests on doubtful foundation, since occasionally it is questionable whether particular cells are the normoblasts or the megaloblasts.
We distinguish three kinds of nucleated red blood-corpuscles on the grounds of the following characters;
1. The normoblasts. These are red corpuscles of the size of the usual non-nucleated disc, whose protoplasm as a rule shews a pure hæmoglobin colour, and which possess a nucleus. Occasionally there may be 2-4 nuclei. The sharply defined nucleus lies generally in the centre, comprises the greater part of the cell, and is above all distinguished by its intense colour with nuclear stains, which exceeds that of the nuclei of the leucocytes, and indeed of all known nuclei. This property is so characteristic that the free nuclei, which occur occasionally in anæmias, and particularly often in leukæmia, may be recognised as nuclei of normoblasts, although surrounded by traces only of hæmoglobin, or by none at all.
2. The megaloblasts. These are 2-4 times as large as normal red blood corpuscles. Their protoplasm, which constitutes by far the chief portion of the body of the cell, very often shews anæmic degeneration to a greater or less degree. The nucleus is larger than that of the normoblasts, but does not form so considerable a fraction of the cell as in the latter. It is often not sharply defined, and is of a rounded shape. It is distinguished from the nucleus of the normoblast by its much weaker affinity for nuclear stains, which may often be so small that little practised observers perceive no nucleus.
Occasionally very large cells are present of the kind just described, which are therefore called gigantoblasts, but which are not distinguishable in other respects from the megaloblasts.
It cannot be denied that it is often difficult to decide whether a particular cell is to be regarded as a specially small megaloblast or a large normoblast. In such cases one would naturally search the preparation for perfect forms of hæmatoblasts, and for the presence of free nuclei or of megalocytes, in order to obtain an indirect conclusion concerning the cells in question.
3. The microblasts. These are occasionally present, e.g. in traumatic anæmias, but they are very seldom found, and have not so far attracted particular attention.
The question of the meaning of the normoblasts and megaloblasts has led to lively and significant discussions, partly in favour of, partly against the distinction between these two cell forms. After surveying the literature, we are forced to separate the megaloblasts from the normoblasts, in the first place because of their subsequent histories, and the peculiarities of their nuclei, and secondly because of clinical observation.
α. The fate of the nuclei. For some time past two views, almost diametrically opposed, have been in existence with regard to the nature of the change of the nucleated to the non-nucleated erythrocytes. The chief exponent of the one, Rindfleisch, taught that the nucleus of the erythroblasts leaves the cell, which thereby becomes a complete erythrocyte, whilst the nucleus itself, by the aid of the small remnant of protoplasm which surrounds it, takes up new material from the surrounding plasma, manufactures hæmoglobin and so becomes a fresh erythroblast. According to the second theory the erythroblasts change to non-nucleated discs by the destruction and solution of the nucleus within the cell body. ("Karyorrhexis," "Karyolysis.") The authors who support this view and also describe it as the only kind of erythrocyte formation are chiefly Kölliker and E. Neumann.
Rindfleisch arrived at his theory by direct observation of the process described, as it occurred in physiological saline solution with the blood of fœtal guinea-pigs and teased preparations of bone-marrow.
E. Neumann regards Rindfleisch's doctrine as untenable, since the process which he observed is chiefly the result of a severe injury of the blood from the sodium chloride solution and the teasing. If a method of preparation be chosen which protects the blood as far as possible, and avoids every chemical and physical alteration, the exit of the nucleus as described by Rindfleisch does not occur.
The view of Kölliker and Neumann that the nuclei gradually decay in the interior of the cell is not supported by the observation of a process, but by the fact that in suitable material, for instance, fœtal bone-marrow, liver blood, and leukæmic blood, the transition from erythroblast to erythrocyte is shewn by all phases of nuclear metamorphosis. v. Recklinghausen professes to have directly observed the dissolution of the nucleus within the cell in rabbit's blood, kept living in a moist chamber. Pappenheim's opinion however, that in this case processes are concerned such as Maragliano and Castellino have described as artificial necrobiosis, seems in this connection worthy of consideration.
Just as with regard to the formation of erythrocytes the views differ one from another, so also with regard to the "free" nuclei which come under observation in numerous preparations. Kölliker has taught that these nuclei are not quite free, but are always surrounded by a minute border of protoplasm. On the other hand Rindfleisch regards these nuclei as having migrated from, or having been cast off by the erythroblasts; and Neumann explains them as the early forms of erythroblasts. Ehrlich was the first to endeavour to effect a compromise between the directly opposed views of Rindfleisch and Neumann. He taught that both kinds take part in the production of the red discs. From blood preparations which contain numerous normoblasts, for instance in "blood crises" (see p. 62), an unbroken series of pictures can easily be put together shewing how the nucleus of the erythroblast leaves the cell, and at last produces the appearance of the so-called free nucleus. It must be expressly mentioned that these pictures are only to be found in specimens in whose preparation pressure of any kind upon the blood has been avoided. Further, however rich a blood may be in normoblasts, the metamorphosis of the nucleus as described by Neumann, is practically never to be observed. It is quite otherwise with the megaloblasts. Amongst them, few examples are to be found in which traces at least of the destruction and solution of the nucleus are not shewn, and in a blood preparation of pernicious anæmia, which is not too poor in megaloblasts, one can construct step by step the unbroken series from megaloblasts with a complete nucleus through all stages of Karyorrhexis and Karyolysis to the megalocytes, as the process is described by Neumann[9].
From Ehrlich's observations it follows, that the normoblasts become normocytes by extrusion or emigration of the nucleus, the megaloblasts become megalocytes by degeneration of the nucleus within the cell.
M. B. Schmidt without making use of the principal distinction made by Ehrlich, also concludes from his researches on sections of the bone-marrow of animals in extra-uterine life, that both kinds of erythrocyte formation occur.
Quite recently Pappenheim, partly in conjunction with O. Israel, has carried out very thorough researches on these particular points. As the subject for observation he chose the blood of embryonic mice. He was able in the first place, like Rindfleisch, to produce the exit of the nuclei from the cells by the addition of "physiological" salt solution to fresh blood, and is of the opinion that the exit of the nucleus from the erythroblasts only takes place artificially.
In embryonic blood the metamorphosis to erythrocytes occurs exclusively by nuclear destruction and solution within the cell, be it in the case of megalo- or gigantoblasts or of cells of the size of the normal red blood corpuscle.
The free nuclei that are observed, whose appearance Pappenheim explains by a preceding solution of the protoplasm (plasmolysis), he regards, in opposition to Rindfleisch and Neumann, not as the beginnings of a developmental series, but as the surviving remnants of the degenerated dying blood cells. Clinical observation, certainly, does not support this conception of Pappenheim's; in as much as in suitable cases with numerous free nuclei (leukæmia, blood crises) transitional forms, which according to Pappenheim must necessarily be present, are not to be found. Moreover, in alluding to a case of leukæmia of this kind, this author himself admits that the appearance of free nuclei can be explained in this instance by the exit of the nucleus.
Although Pappenheim, as above mentioned, recognises no difference between megaloblasts and normoblasts in embryonic blood as far as the fate of the nucleus is concerned, he nevertheless decidedly supports Ehrlich's separation of the erythroblasts into these two groups, as two hæmatogenetically distinct species of cells. He does not regard as distinguishing characteristics, the size and hæmoglobin content of the cells—although as we have described above, these are in general different in normo- and megaloblasts—for these two properties undergo such great variations as to increase considerably under certain circumstances the difficulty of diagnosis of individual cells. The chief characteristic is, as Ehrlich has always particularly insisted, the constitution of the nucleus. The nuclei of cells which are with certainty to be reckoned among the normoblasts are marked by the absence of structure, their sharply defined contour, their intense affinity for nuclear stains. That is by properties which histology sums up under the name Pyknosis (Pfitzner) and recognises as signs of old age. The nuclei of the megaloblasts are round, shew a good deal of structure, and stain far less deeply.
β. The clinical differences. Normoblasts are found almost invariably in all severe anæmias that are the result of trauma, inanition or organic disease of some kind. They are however mostly rather scanty, so that a preparation must be searched for some time before an example is found. But occasionally, most often in acute, but also in chronic anæmias, and even in cachectic conditions, every field shews one or more normoblasts.
V. Noorden was the first to describe a case in which in the course of a hæmorrhagic anæmia normoblasts temporarily appeared in such overwhelming numbers in the circulating blood, that the microscopic picture, which at the same time comprised a marked hyperleucocytosis, was almost similar to that of a myelogenous leukæmia. And as in addition to this occurrence the number of blood corpuscles was nearly doubled, v. Noorden gave it the distinctive name "blood crisis."
The following procedure is to be recommended for the investigation of the blood crisis:
1. Estimation of the absolute number of red blood corpuscles.
2. Estimation of the proportion of white to red corpuscles.
3. Estimation of the proportion of nucleated red to white corpuscles by means of the quadratic ocular diaphragm (see page 31) in the dry preparation.
For instance if we find in a case of anæmia, 3-1/2 millions of red blood corpuscles, the proportion of white to red corpuscles = 1/100 and that of the nucleated red to the white = 1/10, then in 1 cubic millimeter there are 3500 nucleated red corpuscles, that is for 1000 ordinary there is 1 nucleated corpuscle.
Megaloblasts on the contrary are never found in traumatic anæmias. And in chronic anæmias of the severest degree, the result for example of old syphilis, carcinoma of the stomach and so forth, one looks for them almost always in vain, although they are sometimes to be found in leukæmia. On the contrary, the conditions, apparently much milder, in which from the clinical history, ætiology and general objective symptoms pernicious anæmia is suggested, are almost without exception characterised by the appearance of megaloblasts in the blood. Nevertheless in very late stages of the disease they are always scanty, and a very tedious search through one or more specimens is often required to demonstrate their presence. Hence follows the rule, that the investigation of a case of severe anæmia should never be considered closed, before three or four preparations at least have been minutely searched for megaloblasts under an oil immersion objective.
This clinical difference between the two kinds of hæmatoblasts admits of but one natural conclusion, which primarily leaves untouched the question, so much discussed at the present time, whether the megalo- or normoblasts can change one to the other. In all cases of anæmia, in which the fresh formation occurs according to the normal type, only in greater quantity and more energetically, we find normoblasts. Almost all anæmias resulting from known causes: acute hæmorrhages, chronic hæmorrhages, poverty of blood from inanition, cachexias, blood poisons, hæmaglobinæmia and so forth,—in short all conditions rightly called, secondary, symptomatic anæmias,—may shew this increase of normal blood production. In the conditions, which Biermer, on the grounds of their clinical peculiarities, has distinguished as "essential, pernicious anæmia" megaloblasts on the contrary occur, and represent an embryonic type of development. The extent to which this type participates in the blood formation in pernicious anæmia is most simply demonstrated by the fact that megaloblasts are present in all cases of pernicious anæmia, as Laache first shewed, and in some cases form the preponderating portion of the blood discs. Whilst, therefore, in the ordinary kinds of anæmia we find that the red corpuscles tend to produce small forms, in pernicious anæmia, on the other hand, and exclusively in this form, we find a tendency in the opposite direction. This constant difference cannot be a chance result, but must depend on some constant law: in pernicious anæmia excessively large blood corpuscles are produced. Ehrlich's demonstration of megaloblasts has sufficed for this logical advance. All researches, which try to obscure or totally deny the distinction between megaloblasts and normoblasts are wrecked by the simple clinical fact that in pernicious anæmia the blood is megaloblastic.
The appearance of megaloblasts and megalocytes is therefore evidence that the regeneration of the blood in the bone-marrow is not proceeding in the normal manner, but in a way which approximates to the embryonic type. The extreme cases are naturally seldom, such as that of Rindfleisch, in which the whole bone-marrow was found full of megaloblasts. It is sufficiently conclusive for the pernicious nature of the case, "if only considerable portions but not the whole marrow, have lapsed into megaloblastic degeneration." We can now say that the megaloblastic metamorphosis is not a purposeful process, and for the following reasons: 1. Since the fresh formation of red blood corpuscles by means of the megaloblastic method is clearly much slower. This is especially borne out by the fact that the megaloblasts are present in the blood always in small numbers only, whilst the normoblasts, as above mentioned, are often found in much larger quantities. In agreement with this, "blood crises" are not to be observed in the megaloblastic anæmias. 2. Since the megalocytes which are formed from the megaloblasts possess in proportion to their volume a relatively smaller respiratory surface, and so constitute a type disadvantageous for anæmic conditions[10]. This is still more evident when we remember that the production of poikilocytes is on the contrary a serviceable process.
The megaloblastic degeneration of the bone-marrow is no doubt due to chemical influences, which alter the type of regeneration in a disadvantageous manner. We do not for the most part yet know the exciting causes of the toxic process; consequently we are unable to put a stop to it, and its termination is lethal. The Bothriocephalus anæmias, which in general as is well-known offer a good prognosis, by no means contradict this view. They hold their privileged position amongst the anæmias of the megaloblastic type, only for the reason that their cause is known to us, and can be removed. As in many infectious diseases, individuals react quite differently to the presence of the Bothriocephalus. Some remain well; others show the signs of simple anæmia, ultimately with normoblasts; whilst a third group presents the typical picture of pernicious anæmia. For many years, so long as its ætiology was unknown, Bothriocephalus anæmia was not separated on clinical grounds from pernicious anæmia. Severe Bothriocephalus anæmia may be described as a pernicious anæmia, with a known and removable cause. Good evidence for this point of view is afforded by a case of Askanazy, who describes a severe pernicious anæmia, with typical megaloblasts, in which after the complete expulsion of the Bothriocephalus, the megaloblastic character of the blood formation quickly vanished, was replaced by the normoblastic, and the patient rapidly recovered. This observation is so unequivocal, that it is a matter of surprise that Askanazy chooses to deduce from it, the ready transition from megaloblasts to normoblasts; whereas it is clear and definite evidence that megaloblasts are only produced under the influence of a specific intoxication. And in this way the presence of megaloblasts in the pernicious anæmias is to be explained. The megaloblastic degeneration of the bone-marrow depends on the presence of certain injurious influences, of which unfortunately we are as yet ignorant. Were it possible to remove them, it is quite certain à priori that the bone-marrow—if the disease were not too advanced—would resume its normal normoblastic type of regeneration. Clinical observation supports this contention in many cases. In megaloblastic anæmias apparent cures are by no means rare, but sooner or later a relapse occurs, and finally leads with certainty to a lethal issue. These cases, familiar to every observer, prove with certainty that the megaloblastic degeneration as such may pass away, and that in isolated cases the conventional treatment by arsenic suffices to bring about this result. A definite cure however under these conditions is not yet attained, since we do not know the ætiological agent, still less can we remove it. For this reason, the prognosis of megaloblastic anæmia, apart from the group of Bothriocephalus anæmia, is exceedingly bad.
FOOTNOTES:
[8] Dunin, on the contrary, designates the appearance of nucleated red blood corpuscles within the first 24 hours after the loss of blood as normal and regular. This view does not correspond with the facts. A single case on one occasion may exhibit a rarity of this kind.
[9] Probably the dot-like and granular enclosures in the red corpuscles, which stain with methylene blue, and which Askanzy and A. Lazarus have observed in numerous cases of pernicious anæmia are also products of a similar nuclear destruction.
[10] It does not seem superfluous in this place expressly to emphasise, that what has been said on the diagnostic importance of the megaloblasts only holds for the blood of adults. For the conditions of the blood in children, which vary in many respects from that of adults see "Die Anæmie," Ehrlich and Lazarus, Pt. II. (Anæmia pseudoleukæmica infantum).