Paper - On certain early malformations of the embryo

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Windle BC. On certain early malformations of the embryo. (1893) J Anat Physiol. 27(4): 436-53. PMID 17232048

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This historic 1893 paper by Windle describes early malformations of the embryo.

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On Certain Early Malformations of the Embryo

By Bertram C. A. Windle, D.Sc., M.D., M.A.,

Professor of Anatomy in Mason College, Birmingham. (1893)

For some years I have been engaged in the study of the earlier malformations produced by various methods of disturbing the process of incubation in hens’ eggs. A preliminary note on this subject was published in the Proceedings of the Birmingham Philosophical Society (40), the researches having been carried out With the aid of a grant from the Endowment of Research Fund of that Society. In the present communication, it is my intention to give an account of some of the early malformations of the human embryo, and to examine them in the light of the results obtained by artificial teratogeny. In doing this, I propose first to describe the more important recently described human cases, and then to discuss the experimental evidence with its bearing upon the instances in point.

Section I. Early Malformations of the Human Embryo

It has long been recognised that early human ova when opened may exhibit either an apparent or real. absence of any contained embryo, or a more or less‘ ill-shaped, nodular, or cylindrical mass representing the product of generation. Although these conditions have been recognised, it is only recently that careful inquiry has been directed into the nature and causes of the malformations, and an accurate microscopical examination made. In his great Work on the human embryo, His examined a number of these malformed cases, and classified them (20) into Nodular, Atrophic, and Cylindrical groups, a division which he uses also in a most suggestive paper (21), to which I shall have to allude more fully at a later period. This classification was, however, avowedly based only upon external characteristics, which, as will shortly appear, are or may be highly misleading, since the outer form affords scanty information in the less developed cases of the condition of the internal organs. Giacomini, who has studied carefully some of these forms with the aid of an exhaustive microscopic examination, proposes a classification founded upon the characters thus revealed. He divides them (14) into Nodular embryos, which are those in which microscopic examination reveals no trace of organs; and Atrophic embryos, in which the organs, or some of them, though profoundly altered, are still recognisable. Acting in the main upon this classification, it will be convenient here to give a brief account of some recently described cases. Before doing so, it will be necessary to note two points. (1) There is a group of vesicular forms, the exact position of which is difficult to be ascertained. Such vesicular formations in the interior of the chorion have been described as normal embryos at an early period of development (Reichert), as monstrous embryos (His), or as productions of the chorion (Giacomini, Chiarugi). I have, therefore, thought it better to place them in a class by themselves provisionally. (2) It is evident that in the remaining groups there must be many cases the classification of which is doubtful, since it is difficult to say Whether the organs are completely unrecognisable or not. Giacomini goes so far as to say that a nodular embryo described by him is the unique example of that class so far recorded. I have ventured to include two others with this in the following list.

Early Malformed Human Embryos

A. Vesicular

  1. Reichert (32) described a very young human ovum without embryo, which was provided on the exterior with a chorion and villi. He regarded it as being a normal embryo of very early age, but Kolliker (23) is doubtful on this point, since the villi are not formed until after the amnion, and therefore the embryo, has developed.
  2. Giacomini (14). An ovum at the end of the first month, provided with villi, containing a small distended vesicle in its interior. On microscopic examination, this was found to consist of two strata, viz., externally of connective tissue, and internally of a single stratum of flattened epithelial cells. The author considers this to be a pathological production of the chorion.
  3. Giacomini (15). 2% months. A small amniotic vesicle, in Which the product had entirely disappeared, from defect of development.
  4. Giaeomini (19). 1st month. Ovum covered with villi, and containing no trace of embryo.
  5. Lachi (25). Ovum of 1-2 month. Choriou covered with villi, and containing two small vesicles. The author believes the atrophied embryo to have been represented only by its umbilical vesicle.
  6. Chiarugi (4). A bilobed vesicle, one portion of which might be considered as an embryo much atrophied. In a note to another paper (5) the author states that Giacomini (14) has described a case similar to this, which he regards as a pathological formation. To this view Chiarugi gives his adherence, and believes his case to bear a similar interpretation.

B. Nodular

  1. Giacomini (18). Ovum of the second week, containing inside the chorion a small punctiform reddish body. There were no traces of blood-vessels in the chorion. There was a small solid body attached, which he regards as a unique instance of a nodular embryo. It contained no round cells such as are found in the atrophic forms. The explanation of this will be given in another place.
  2. Valenti (38). A two month vesicular formation containing masses of cells, but no traces of embryonic organs. The author is doubtful whether these cells represent an embryo or not, and perhaps the case may belong to the first category rather than to that in which it has been placed.
  3. Romiti (33). An oval vesicle covered with villi, and containing in its interior a small curved embryo. On microscopic examination, no traces of organs were discoverable, but two masses of cells at the extremity, supposed to be cephalic, might represent the optic vesicles, in which case the form would belong to the atrophic category. Many deeply staining cells were visible in the embryo.

C. Atrophic

1. Giacomini (14). Ovum at the commencement of the 2nd month. Microscopic examination showed the existence of a completely disorganised medullary canal and cerebral vesicles. There were no traces of blood-vessels in the cord or in the embryo, which latter contained masses of round cells.

2. Giacomini (17). A pyriform human embryo, resembling to the naked eye a. very small rod—like tubercle, divided by two sulci into three dilatations. The anterior and largest of these consisted of lymphoid cells and spaces containing epithelium (? nerve tube). The middle consisted of round cells, and the posterior was a vesicle with broken down contents (? an appendage of the umbilical cord). In the amnion there were traces of vessels as masses of deeply staining nuclei. He notes the close resemblance between this atrophic embryo and those artificially obtained in the rabbit (13).

3. Giacomini (16). Tubal pregnancy of about two months. Corsisted of a free cephalic and attached caudal extremities, and was reduced to a shapeless tubercle. The greatest volume of nervous system was observed in the cephalic extremity, b11t there was no trace of optic or auditory vesicles, nor of bloodvessels nor heart. ( N ote.—Lawson Tait (36) quotes a case of socalled ovarian pregnancy from Puech, in which, in a. cyst of the ovary, there was a villous body, which on incision showed in its interior a cavity distended by a clear fluid, and in the fluid floated an embryo, in the form of a vermiform body, 1 mm. long, curved in the middle and swollen at one extremity. It was enveloped in an excessively delicate membrane, by which it was fixed to the presumed chorion. Mr Tait adds, “Of course, the whole conclusion in this case depends upon the assumption that this vermiform body, only 1 mm. long, was an embryo. It may have been one, but there certainly is no proof advanced in favour of this view; and although I am by no means prepared to deny its accuracy, I am certainly very doubtful about it. If it was an embryo, it could only have been one of a few hours’ existence.” The case just cited seems to show that this may well have been an atrophic embryo, and of much greater age than Tait is prepared to allow.)

4«. Chiarugi (6). A two months embryo, with an amniotic sac, and a caruncle representing an embryo possessed of a rudimentary umbilical vesicle. Microscopic examination showed traces of a medullary canal and a rudimentary heart. Masses of deeply-staining round cells infiltrated the embryo. The author regards the specimen as one of an atrophic embryo of an exceedingly advanced stage.

5. Giacomini (15). Ovum of two months, containing a slightly curved tubercle with an umbilical cord. The embryo showed externally crystalline lenses, the first pair of branchial arches, a. tail, but no limbs. On microscopic examination, the medullary canal was visible, but no optic vesicles, two aortae, with traces of blood-corpuscles. There were no traces of bloodvessels in the cord.

6. Kollmann (24). An embryo with hydrops of the coelom, small ectopic heart, atresic veins and arteries of the heart, no blood-vessels on the yolk-sac, deficient development of the branchial arches and inferior extremities.

7. Kollmann (24). Embryo with partial ectopia of the heart, arrested development of head, eyes, nose, and branchial arches. No upper extremities. Blood-vessels very sparse, and none in the yolk-sac.

8. Phisalix (30). Embryo of six Weeks, theshape of which was fairly evident. He sums up his description by saying that it exhibited “ troubles of secretion between the chorion and amnion, With adhesions of the latter to the former and to the umbilical vesicle, absence of liquor amnii, stripping-ofi” of the ectoderm, disappearance of the medullary canal, with foldings of its walls and alterations of the nervous elements, absence of nerve ganglia, absence of the Wolffian duct at its lower end, and general alteration of the epithelia. He especially notes that the epithelia are the tissues most readily affected by pathological processes.

9. His (21). A malformed embryo, in which the nervous tube was distinguished by its being particularly swollen. Several of the organs were distinguishable, but these organs and the cavities of the body were infiltrated with numerous small round cells, with deeply-staining nuclei. The author concludes with regard to these and similar forms, that

  1. Embryos which for any reason are arrested in their development, can, without completely degenerating or being absorbed, remain for weeks or even months within the membranes.
  2. The first changes in dead embryos consist in a marked swelling of the nervous system, as a consequence of which more or less remarkable transformations of the head appear.
  3. Very soon afterwards, there takes place an infiltration of the tissues with small wandering cells. The original limits of the organs are thus obliterated: the cells of the organs may remain for a long time, but appear finally to degenerate.
  4. The externally visible consequences of these events are turbidity and whiteness of the embryo, and loss of definiteness of the original surface-markings.

With regard to these cases the most important points to be noticed in the present connection are (1) the absence of bloodvessels or their diminution in size (B. 1, C. 1, 3, 5, 6, 7).

(2) Infiltration of the tissues with small round deeply-staining cells (B. 2, 3, C. 2, 4«, 9). Both of these points will appear significant in connection with the observations made in artificial teratogeny, which it will next be necessary to discuss.

Section II. Early Malforliations Artifically Produced

Many observers have noted that it is possible to produce alterations in the area vasculosa, with consequent effects upon the embryo, by interfering with the process of incubation. Amongst these the work of Panum and Dareste first calls for notice. Panum (28), who lays especial stress upon the importance of examining early malformations of the embryo, gave in 1862 a careful description of the conditions which he had observed. Many of these are associated with more or less defective forms of the area vasculosa, coupled with deficient development of the embryo. A group called by him defective area vasculosa formations shows scanty blood-islands, Without sinus terminalis. There is generally no trace of embryo, or it is only represented by a heaped-up mass of cells. He believes that the abnormal development of the embryo is associated with and caused by that of the area vasculosa, and concludes— (1) That the development of the embryo is not always brought completely to a standstill by a primary disturbance of the nourishment and of the area vasculosa, but that it can still proceed even if the development of that part is deranged. (2) That the disturbed development of the vascular area is antagonistic to the normal development of the embryo, and produces malformations of the same. It should be mentioned that in another paper (29) the same author alludes to some of these changes, describing alterations in the embryo previous to the formation of the blood-vessels, which he calls parenchymatous inflammation, and others subsequent to their development, which he terms embryonic "inflammation". In either of these cases he says the results are the same, viz., (1) abortive atrophy, or (2) heterologous agglutination. It is, however, obvious that the term “inflammation” cannot be accurately applied to the changes which he describes.

As early as 1883, Dareste (7) stated his opinion as to the malformations now under consideration. In the earliest times of embryonic life, he says, the embryo perishes through a peculiar anaemia of which I have described the mechanism. When an arrest of development attacks the islands of Wolff, the blood-corpuscles which are developed in their cavities cannot penetrate the circulatory apparatus. The blood, deprived of globules, causes more or less oedema of the embryonic tissues, and, as a consequence, their disorganisation. These views respecting the connection of deficient blood-formation with oedema are supported by Wernitz (39), who believes that, as a consequence of such a defect, a. general anaemia of the embryo may be produced with subsequent hydrops. In the last edition of his classical work (8) Dareste develops the views above stated still further. In the account there given, he first shows that the simplest modification of the blastoderm is the formation of an elliptical instead of a circular figure. This is occasioned by so arranging the egg in an open incubator that its highest point and the point of contact with the source of heat do not coincide. This malformation is not in itself of much importance, save in so far as it serves as a simple example of a malformation of the annexes of the embryo, and the only one, according to the author in question, which can always be produced by a definite and distinct procedure. The more important deviations from the normal consist in a defective formation of the area vasculosa, with isolation of the blood islands from absence of anastomotic communications, and their consequent failure to communicate with the interior of the embryo. Hence the fluid circulating in the blood-vessels of the embryo is colourless. As a consequence of these circumstances, dropsy of the embryo takes place, with its subsequent degeneration, either total or into an amorphous mass.

The nature of this class of early malformation having been noted, it is next important to observe that these identical malformations of the area vasculosa and embryo are amongst the most common results following upon any of the various methods of disturbing development hitherto practised. The following observations will render this point clear :—

A. Varnishing the Egg

Varnishing or otherwise covering the shell either completely or in part with a coating impermeable to air, is a proceeding which has been practised by various investigators. Amongst others, it has been tried by Panum, Dareste, and Gerlach and Koch (12), the last—mentioned stating that the decrease of oxygen causes dwarfing of the embryo with delay of ontogenesis. This proceeding, according to Tarulli (37), not only hinders respiration, but also afi'ects pressure and temperature. The air-chamber regulates pressure, and the surface of evaporation regulates temperature It is only when these two conditions are naturally fulfilled that respiration can remain normal. It is unnecessary to enter fully into the observations of different experimenters, and I shall only briefly summarise my own results, of which a sufficiently full account has already appeared. The incubator used in these and the other experiments was at first the ordinary bacteriological form, furnished with ventilators and water-dish, and the temperature was regulated by Dr N ico1’s useful modification of the mercurial thermostat. Subsequently I used one of Hearson’s Champion Incubators, with which I have had every reason to be satisfied. The eggs were coated with an impervious varnish, the position and size of the uncovered patch being varied in dilferent experiments. Sometimes it was placed at the vertex, sometimes below; sometimes at the blunt end, at others at the sharp. I have left two or,more small patches uncovered and have varied the shape of the patch, but the results obtained do not seem to have been appreciably affected by these changes. The abnormalities with which I am concerned in this paper being those of the area. vasculosa, I shall not at present deal with any others. I divide-these into two classes—(1) irregular area vasculosa, without any evident embryo; (2) irregular area vasculosa, with a more or less illformed’ embryo, or an amorphous mass representing the embryo. In both these classes the area vasculosa consists of a more or less incomplete ring, often of abnormal size, of small blood-flecks occupying the position of the sinus terminalis. In its interior are other isolated blood-islands in greater or less number. Occasionally some of these are connected with one another, but not usually with the embryo itself. In other instances. a few are connected with the embryo, but the greater part of the area vasculosa is unconnected. The number of eggs experimented with in this manner was sixty-four. Of these, twentythree showed no sign of development, six had deficient areae vasculosae without evident embryo, and twenty-five defective area; vasculosae with a more or less altered embryo.

It would carry this paper beyond its proper limits if I were to describe the various modifications in the embryo, and I therefore reserve the consideration of some of the forms for the present. I will only say that sometimes it was represented by an apparently shapeless mass, and at others was dead, and showed that whiteness and loss of regular contour to which His has alluded in connection with human embryos. The defective formation of the area vasculosa which I have noticed as produced in these cases is so similar to that described and figured by Panum, Dareste, and Lombardini, that I need delay no longer over it, nor is it necessary to present any figure of the condition. The ten eggs not hitherto accounted for presented features not at present under consideration.

B. Electricity

So far as I am aware, the first experiments of this kind were made by Prévost and Dumas, but the account of their observations is too scanty to be of any value (31). It is otherwise with the researches of Lombardini (26), which are given at considerable length in his book. The last mentioned experimenter applied the constant current to the eggs of the hen and of the frog during development. In the former, the treatment led to a number of malformations, amongst which may be mentioned hyperaemia of the head, vascular tumor of the eye, with early anencephalus, deformity of the entire body, 850.

Speaking generally of his experiments, he says that the efiects of the disturbance may be either general or local, and that in the former case there follows total atrophy, mummification, and death after a short period. He also remarks that the commonest occurrences at an early period are hydraemia, accompanied by atrophy. Processes of hypertrophy, atrophy, and necrobiosis may occur in the embryo, dependent solely upon changes in the material of nutrition. His most important remark in connection with the subject of this paper is, that he has not seen any malformed case in which the albumen, vitellus, and blood were not more or less altered. In his experiments, as in mine, the frequency of occurrence of vascular lesions, whether of anaemia or of hyperaemia, is especially noteworthy. I have not dwelt upon the former condition, because it is foreign to the purpose of this paper, in which early anaemia is the defect under consideration. It is, nevertheless, one of great importance, and I hope to deal with it on some future occasion when my observations on this point are more complete. In my experiments I used a battery which was devised for me by my colleague Professor Poynting, which he calls a sawdust Daniell. He was good enough to ascertain for me that such a battery was capable of transmitting a current through an egg, which could be distinctly recognised by its effect upon a Thomson galvanometer of low resistance. The egg-shell was perforated at its extremities by two extremely small holes, into which were introduced the platinum wires used for making connections between contiguous eggs and the battery. The wire in each case perforated the albumen for about one-quarter of an inch. The apertures being exceedingly small, were almost entirely closed by the wires, but in order to complete the closure, I used, in the earlier experiments, a. drop of sealing-wax. In the later series, in case the heat of the wax should prove a disturbing factor, I substituted canada balsam dissolved in chloroform, which answers the purpose very well. I did not, however, notice any particular difference between the series conducted under the former as compared with the latter conditions.

The results obtained were briefly as follow. Not including batches which failed from one reason or another, chiefly on account of the difficulty of obtaining really satisfactory eggs in the centre of a large city, thirty-two eggs were submitted to the influence of the current from the commencement of incubation, in four series. Of these, five presented defective area vasculosa; with malformed embryos, and one Without embryo. A number did not develop, and a larger proportion proceeded to normal development than in the varnished series.

There were other malformations noticed, notably one case in which the eye and orbit of one side were totally absent, whilst the other was normally formed There did not -seem to be any relation between the development and the position of the eggs with regard to the positive or negative poles or the centre of the circuit. It should be mentioned that of sixteen control eggs used in these experiments, two presented defective area; vasculosm with malformed embryos. I have tried one small series with the interrupted. current. The eggs were wired as in the former experiments, and allowed to develop for twenty-four hours in the incubator without further disturbance. At the end of this period a weak current, unappreciable to the finger, was transmitted for fifteen minutes from a small single-cell bichromate battery. Four days afterwards the eggs were opened. The first showed a small defective area vasculosa without trace of embryo. The second, a small embryo, with umbilical vessels and blood-islands, well-developed, but small, white, turbid, and with small haemorrhages at the posterior end. The third had no visible area vasculosa; the embryo was small, but to the naked eye normally developed. The heart and aortae were full of blood, and a few twigs entered the body. The embryo was dead, turbid and white. The other three eggs had not developed. I hope to continue this class of experiments further. In connection with these electrical experiments, the well-known efiects of currents upon blood-corpuscles under the microscope should be remembered. Dr Fell (10) states also that blood taken by himself from the temple of William Kemmler (electrocuted at Auborn prison in 1890), the first man executed by electricity, seven minutes after the electric force had been turned off, presented marked peculiarities. Fully one third of the field presented granular particles of protoplasm ranging from the full-sized corpuscle to the size of ordinary granules. Protrusion of the protoplasm from the corpuscles was frequently noted. He also states, “without further consideration of the influence of the electric current upon the lower forms of life, it may be seen that the influence is positive in its character; that we have with the Weaker currents an undoubted electrolysis produced, and with the stronger or a long continued influence of the current a lowered vitality of the protoplasm.”

C. Magnetism

The effect of incubating eggs laid between bar-magnets has been tried by Maggiorani (27). The eggs were exposed during incubation to the influence of powerful magnets. A similar set of eggs, hatched in the same manner, but kept away from all magnetic influence, served as controls. Cases of arrested development were four times more numerous in the former than in the latter group. Microscopic examination showed that the sterilisation of the germs was probably due to an intense vascularisation of the yolk-sac. After the birth of the chickens this increased mortality continued, deaths being three times more numerous in the magnetised group. In View of these experiments, Slater (35) tried the effect of magnetic influence upon the development of caterpillars. Of three caterpillars of the common large white (cabbage) butterfly, two did not develop and the third was a cripple. It had merely rudimentary stumps in place of antennae, the wings on the left side were expanded, and the legs on the same side were smaller than on the right. Three other caterpillars of the same batch, allowed to develop under similar conditions, but without the magnetic influence, exhibited no deviations from the normal. I have tried a few series of experiments with hens’ eggs, but on account, possibly, of the magnets not being strong enough, Without any very definite results.

D. Light

Blane (3) has tried the eflect of submitting the embryo during incubation to the influence of a bright, cold light. He finds that the embryo is sometimes normally developed, but smaller than normal embryos of a corresponding age. Sometimes the development of the embryo is accompanied by an imperfect development of the area vasculosa, which is sometimes too small, at other times its vessels contain only a colourless fluid, or the blood-islands develop in an irregular manner, containing corpuscles only at certain points, or finally, the arrest may be complete. These imperfect conditions of the _area vasculosa coincide frequently, but not always, with abnormal formation of the embryo or of the amnion, such as absence or atresia of the amnion, hydrops, heterotaxy, omphalocephaly, cyclops, atrophy of the head. finally, but very rarely, the embryo is unformed, rudimentary, or dead. He concludes, therefore, that white light has a destructive effect on the cells of the blastoderm in the hen’s egg.

E. Experiments on Rabbit Embryos

It may, lastly, be mentioned that Giacomini (13) has conducted several series of experiments on the embryos of rabbits, his method of procedure being described in the paper referred to. The disturbance has been produced by (1) withdrawal of fluid from the blastodermic vesicle, (2) puncture of the same, (3) introduction of a foreign body into the same, (4) puncture with pressure, (5) ligature of a part of the uterus. The general effect of these experiments was to arrest development. In some cases an atrophic embryo was formed, the resemblance of which to those found in human abortive ova has already been alluded to.

From these observations it follows that a common, indeed it might with reason be said the most common, consequence of early interference with the processes of development is a derangement of the growth and progress of the area vasculosa and of the elements arising with it from the region around the body of the embryo. Though this is not the only effect produced, it is a very common one, and the frequency of its occurrence in the experiments of different observers and under varying conditions is remarkable.

Section III. Primary Results of the Disturbance of the Developmentof the Area Vasculosa

From the area around the embryo-proper develops that part of the mesoblast which is known as the parablast or mesenchyme, and from which is developed the vascular and lymphatic systems and the connective tissues. This view put forward by His and the Hertwigs, in a more or less modified form, seems to be gaining general acceptance. Thus Ziegler (441) states that the blood and lymph vascular systems are phylogenetically derived from the lymph vascular system. In ontogeny it may be seen that some of the first vessels to arise are parts of the primary coelom, and are gradually shut off from it. The red-blood corpuscles arise ontogenetically from the solid venous rudiments, and in histological regeneration they arise similarly from the venous capillaries; the red-blood corpuscles belong both in origin and function to the blood-vascular system; they do not arise from the white corpuscles in the blood, but have a similar origin with them, insomuch as they are derived from the histological foundation of all the mesenchymatous tissues. Again, Van der Stricht (34) states that the first blood corpuscles appear at the level of the area vasculosa, and at the expense of its mesoblastic constituents. These all have the characters of red-blood corpuscles. The White-blood corpuscles arise later, and are also mesoblastic. Interference with the development of the region from which the mesenchymatous elements are derived, such as appears to take place in the experiments detailed above, will produce (1st) a failure in the development of the blood-vascular system in the manner described by Dareste; (2nd) irregular development of the connective tissue elements also derived from the mesenchyme. This second fact gives an answer, I think, to His’s question as to whence the round cells come which he noticed in such numbers infiltrating the tissues and filling the cavities of the embryo which formed the subject of his paper. That these round cells are derived from the mesenchyme will, I think, seem the most probable explanation. This has, indeed, in part been suggested by Giacomini in explaining the reason why his nodular embryo does not present the masses of round cells which are found in the atrophic forms. He says that at the period at which the embryo perished, the mesoblast had not arrived at the importance in development which it afterWards attains, and that consequently the small, round lymphoid elements which are mesoblastic in origin are not present in this embryo. These round cells have been found, as has already been noted, in a number of the malformed human embryos, and are regarded by His as of especial interest. I have also found them in microscopic sections of the atrophic chick embryos obtained artificially in the incubator. These embryos contain remains of the nerve-tube, of some of the organs, and masses of round cells. They thus belong to the class described by Giacomini as atrophic, and the similarity of the appearances presented under the microscope is another proof of the identity of the malformations and of the proximate causes which produce them. Summing up the facts of this section, it may be concluded——1st, that the amorphous (atrophic) embryos found in hens’ eggs as the result of a disturbance of some kind of the process of development are due to (a) an irregular development of the vascular elements which consists in imperfect formation and isolation of the blood—islands, their failure, either total or partial, to connect with the vascular system of the body of the embryo, together with (b) the formation in large numbers of round cell elements which infiltrate the tissues of the embryo ; 2nd, that similar causes lead to the formation of the irregularly shaped atrophic human embryos, as shown by the faulty development of the blood-vascular system in these forms, and their infiltration with numerous round cell elements.

Section IV. Later Malformations due to Deficient Vascularity

The cases which have been considered in this paper are those in which the interference with the development has been so early in date and so serious in nature as to lead to grave changes in the mesenchymatous tissues, having as a consequence the early death and degeneration of the embryo. I have, however, been able to make some observations which lead me to believe that a partial occurrence of similar changes, insufficient to cause the death of the embryo, may afford a clue to the etiology of some of the malformations exhibited by the embryo at term, or at least at a period when the various organs and parts have become fully differentiated. My observations on this point are not yet complete, but I hope that the experiments upon which I am now engaged will enable me to speak with more certainty upon this point in a later paper. At the present time, therefore, I will only note the following points as probably bearing upon this part of the question. (1) The probable association of a local dropsy with some of the forms of body cleft. (2) The existence of a single umbilical artery in cases of sirenomelia and its allied conditions, a fact now well established (Forster (11), Ahlfeld (1) ). (3) Wernitz’s collection of cases (39), showing that certain malformations may co-exist with arterial deficiencies, of which the following may be mentioned,—(a) Duncan (9), anencephalus, with carotid arteries ending at the base of the Skull; (1)) Budin (2), hydrocephalus, with small carotid arteries ; (c) Klebs (22), atrophy of right temporal and parietal lobes, with small arteries; (d) 736., hydroanencephalus, with no right internal carotid artery; (e) "£19., microanencephalus, with closure of vessels. To these might be added other cases which I reserve for the present.

Section V. Conclusions

It is necessary to exercise caution in drawing conclusions in so large a subject, and one where there are so many possibilities of mistake, but I think the following points may be at least tentatively put forward as following from the facts described in the foregoing pages :—

  1. That whatever the nature of the disturbance applied to the developing embryo, the results which follow are in many if not most of the cases absolutely identical.
  2. That these effects for the most part manifest themselves in connection with the area vasculosa and the mesenchymatous region.
  3. That they consist in faulty development of the bloodislands, and frequently to their failure to connect with the blood-vessels of the embryo.
  4. That, further, they lead to the irregular development of numerous round cell elements which infiltrate the tissues of the embryo.
  5. That the results are dropsy or degeneration of the embryo, which is found to present deficient vascular development and an infiltration with round cells, the embryo itself being illshaped, and many of its parts so ill-developed that its normal shape is not recognisable by the naked eye.
  6. That, finally, it is probable that partial failures of a. similar kind may lead to the production of some of the later types of malformation of the embryo.


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