1911 Encyclopædia Britannica/Pathology

PATHOLOGY (from Gr. πάθος, suffering), the science dealing with the theory or causation of disease. The term by itself is usually applied to animal or human pathology, rather than to vegetable pathology or Phytopathology (see Plants: Pathology).

The outstanding feature in the history of pathology during the 19th century, and more particularly of the latter half of it, was the completion of its rescue from the thraldom of abstract philosophy, and its elevation to the dignity of one of the natural sciences. Our forefathers, if one may venture to criticize them, were too impatient. Influenced by the prevailing philosophy of the day, they interpreted the phenomena of disease through its lights, and endeavoured from time to time to reduce the study of pathology to philosophical order when the very elements of philosophical order were wanting. The pathology of the present day is more modest; it is content to labour and to wait. Whatever its faults may be—and it is for our successors to judge of these—there is this to be said in its favour: that it is in nowise dogmatic. The eloquence of facts appeals to the scientific mind nowadays much more than the assertion of crude and unproven principles. The complexity and mystery of action inherent in living matter have probably been accountable for much of the vague philosophy of disease in the past, and have furnished one reason at least why pathology has been so long in asserting its independence as a science. This, indeed, holds good of the study of biology in general. There are other factors, however, which have kept pathology in the background. Its existence as a science could never have been recognized so long as the subjects of physics, chemistry and biology, in the widest acceptation of the term, remained unevolved. Pathology, in fact, is the child of this ancestry; it begins where they end.

Progress in the study of pathology has been greatly facilitated by the introduction of improved methods of technique. The Recent Progress. certainty with which tissues can now be fixed in the state they were in when living, and the delicacy with which they can be stained differentially, have been the means of opening up a new world of exploration. Experimental pathology has benefited by the use of antiseptic surgery in operations upon animals, and by the adoption of exact methods of recording; while the employment of solid culture media in bacteriology—the product of Koch’s fertile genius—is responsible for a great part of the extraordinary development which has taken place in this department of pathological research. The discoveries made in pathological bacteriology, indeed, must be held to be among the most brilliant of the age. Inaugurated by Pasteur’s early work, progress in this subject was first marked by the discovery of the parasite of anthrax and of those organisms productive of fowl-cholera and septic disease. Then followed Koch’s great revelation in 1882 of the bacillus of tubercle (fig. 22, Pl. II.), succeeded by the isolation of the organisms of typhoid, cholera, diphtheria, actinomycosis, tetanus, &c. The knowledge we now possess of the causes of immunity from contagious disease has resulted from this study of pathological bacteriology: momentous practical issues have also followed upon this study. Amongst these may be mentioned the neutralizing of the toxins in cases of diphtheria, tetanus and poisonous snake-bite; “serum therapeutics”; and treatment by “vaccines.” By means of “vaccination” we are enabled to induce an active immunity against infection by certain pathogenic bacteria. The value of such protective inoculations is demonstrated in the treatment against small-pox (Jenner), cholera, plague (Haffkine) and typhoid (Wright and Semple). Pasteur’s inoculation against hydrophobia is on the same principle. “Vaccines” are also used as a method of treatment during the progress of the disease. Sir A. Wright and others, in recent work on opsonins, have shown that, by injecting dead cultures of the causal agent into subjects infected with the organism, there is produced in the body fluids a substance (opsonin) which apparently in favourable conditions unites with the living causal bacteria and so sensitizes them that they are readily taken up and destroyed by the phagocytic cells of tissues. Before the discovery of the bacillus of tubercle, scrofula and tuberculosis were regarded as two distinct diseases, and it was supposed that the scrofulous constitution could be distinguished from the tubercular. It was always felt, however, that there was a close bond of relationship between them. The fact that the tubercle bacillus is to be found in the lesions of both has set at rest any misgiving on the subject, and put beyond dispute the fact that so-called scrofulous affections are simply local manifestations of tuberculosis. A knowledge of the bacteriology of scrofulous affections of bone and joints, such as caries and gelatinous degeneration, has shown that they also are tubercular diseases that is to say, diseases due to the presence locally of the tubercle bacillus. At a very early period it was held by Virchow that the large cheesy masses found in tuberculosis of the lung are to be regarded as pneumonia infiltrations of the air-vesicles. Their pneumonia nature has been amply substantiated in later times; they are now regarded simply as evidence of pneumonia reaction to the stimulus of the tubercle bacillus. The caseous necrosis of the implicated mass of lung tissue, and indeed of tubercles generally, is held to be, in great measure, the result of the necrotic influence of the secretions from the bacillus. Tubercular pneumonia may thus be looked upon as comparable to pneumonia excited by any other specific agent.

In the “seventies” of the 19th century feeling ran somewhat high over the rival doctrines concerning the origin of pus-corpuscles, Cohnheim and his school maintaining that they were derived exclusively from the blood, that they were leukocytes which had emigrated through the walls of the vessels and escaped into the surrounding tissue-spaces, while Strieker and his followers, although not denying their origin in part from the blood, traced them, in considerable proportion, to the fixed elements, such as fibrous tissues and endothelia. Our present-day knowledge prompts the adoption of a middle course between the two theories. The cells found in an inflamed part are undoubtedly drawn from both sources, but while the blood leukocytes have a great tendency to become fatty and to die, those cells derived from the fixed tissues incline more to organization; the latter are, in fact, the source of the cicatrix which follows upon the cessation of suppuration (fig. 23, Pl. II. and figs. 31 and 32, Pl. III.). Organization and healing have been keenly inquired into, with results which seem to point the lesson that all methods of healing are to be regarded as extensions of the natural phenomena of growth. Normal cytology, of late, has become a science of itself, and has had a direct bearing upon that which is pathological.

At no time has so much been done to advance our knowledge of diseases of the nervous system as during the last thirty years of the 19th century. The localization of function in the cerebral and in the cerebellar cortex has doubtless been the main cause of this progress, and has proceeded pari passu with an extended insight into the structure and connexions of the parts concerned. The pathology of aphasia, as worked out by a combination of the experimental, the pathological and the anatomical lines of inquiry is a favourable example of what has been accomplished. The origin, nature, and propagation of neoplasms of all kinds, especially of those which are malignant, are engaging much attention. Much light has been thrown upon the functions and diseases of the blood-forming tissues. The origin of the corpuscles, previously a matter of so much difference of opinion, is now pretty fairly set at rest, and has proved the key to the interpretation of the pathology of many diseases of the blood, such as the different forms of anaemia, of leucocythaemia, &c.

It is largely to researches on the bone marrow that we owe our present knowledge of the origin and the classification of the different cellular elements of the blood, both erythrocytes or red corpuscles, and the series of granular leukocytes or white corpuscles. Whatever be the ancestral cell from which these cells spring, it is in the bone marrow that we find a differentiation into the various marrow cells from which are developed the mature corpuscles that pass from the marrow into the blood circulation. The healthy bone marrow reacts with remarkable rapidity to the demand for more blood cells which may be required by the organism; its reactions and variations in disease are very striking. If the demand be for the red cells owing to loss from hemorrhage or any of the anaemias, the fatty marrow is rapidly replaced by cellular elements; this is mainly an active proliferation of the nucleated red cells, and gives rise to the erythroblastic type of marrow. If the white cells be required, as in local suppurating abscess, general septicaemia, acute pneumonia, &c., there is an active proliferation of the myelocytes to form the polymorpho-nuclear leukocytes, so that we have in this condition a leucoblastic transformation of the fatty marrow.

The cytology of bone marrow, with the technique of blood examination, is of great assistance in the diagnosis of different pathological conditions. The deleterious influence of high blood-pressure has engaged the attention of physicians and pathologists in later years, and the conclusion arrived at is, that although it may arise from accidental causes, such as malcomposition of the blood, yet that in many instances it is a hereditary or family defect, and is bound up with the tendency to gout and cirrhotic degeneration of the kidney. The pathology of intra-cardiac and vascular murmurs has also been inquired into experimentally, the general impression being that these abnormal sounds result, in most cases at least, from the production of a sonorous liquid vein. Pneumonia of the croupous type has been proved to be, as a rule, a germ disease, the nature of the germ varying according to circumstances. The structural changes occurring in the bronchi in catarrhal bronchitis have also been ascertained, and, as in the case of pneumonia, have been shown to be frequently excited by the presence of a microphyte. The vexed question of the diagnosis of diphtheria is now a thing of the past. Quite irrespective of the nature of the anatomical lesion, the finding of the diphtheria bacillus on the part affected and the inoculability of this upon a suitable fresh soil are the sole means by which the diagnosis can be made certain.

The part played by the thyroid body in the internal economy of the organism has also received much attention. The gland evidently excretes, or at any rate gets rid of, a certain waste product of a proteid nature, which otherwise tends to accumulate in the tissues and to excite certain nervous and tissue phenomena. It wastes in the disease known as “myxoedema,” and the above product gathers in the tissues, in that disease, to such an extent as to give rise to what has been termed a “solid oedema.” It is questionable if the substance in question is mucoid. The pituitary body probably subserves a like purpose. When the pancreas is excised in an animal, or when it is destroyed in man by disease, grape-sugar appears in the urine. The gland is supposed to secrete a ferment, which, being absorbed into the portal circulation, breaks up a certain portion at least of the grape-sugar contained in the portal blood, and so prevents this overflowing into the circulation in general. The transplantation of a piece of living pancreas into the tissues of an animal, thus rendered artificially diabetic, is said to restore it to health.

Pathological chemistry has been remarkable chiefly for the knowledge we have obtained of the nature of bacterial poisons. Certain of these are alkaloids, others appear to be albumoses. The publication of Ehrlich's chemical, or rather physical, theory of immunity has thrown much light upon this very intricate and obscure subject.

Pathology is the science of disease in all its manifestations, whether structural or functional, progressive or regressive. In Connexion with Biology. times past it has been the habit to look upon its sphere as lying really within that of practical medicine, and human medicine more particularly; as something tagged on to the treatment of human disease, but unworthy of being studied for its own sake as a branch of knowledge. Such a view can recommend itself to only the narrowest of minds. A bearing, and of course an essential bearing on the study of medicine, it must always have. A system of medicine reared upon anything but a pathological basis would be unworthy of consideration. Yet it may well be asked whether this is the final goal to be aimed at. Our starting-point in this, as in all departments of biological study, must be the biological unit, and it is to the alterations to which this is subject, under varying conditions of nutrition and stimulation, that the science of pathology must apply itself. Man can never be the only object of appeal in this inquiry. The human organism is far too complex to enable us to understand the true significance of diseased processes. Our range must embrace a much wider area—must comprise, in fact, all living matter—if we are ever to arrive at a scientific conception of what disease really means. Hence not only must the study of our subject include the diseases peculiar to man and the higher animals, but those of the lowest forms of animal life, and of plant life, must be held equally worthy of attention. Modern research seems to show that living protoplasm, wherever it exists, is subject to certain laws and manifests itself by certain phenomena, and that there is no hard and fast line between what prevails in the two kingdoms. So it is with the diseased conditions to which it is a prey: there is a wonderful community of design, if the term may be used in such a sense, between the diseases of animals and plants, which becomes singularly striking and instructive the more they are inquired into. Utilitarian, or perhaps rather practical, considerations have very little to do with the subject from a scientific point of view—no more so than the science of chemistry has to do with the art of the manufacturing chemist. The practical bearings of a science, it will be granted, are simply, as it were, the summation of its facts, with the legitimate conclusions from them, the natural application of the data ascertained, and have not necessarily any direct relationship to its pursuit. It is when studied on these hues that pathology finds its proper place as a department of biology. Disease as an entity—as something to which all living matter is subject—is what the pathologist has to recognize and to investigate, and the practical application of the knowledge thus acquired follows as a natural consequence.

Since pathology is the science of disease, we are met at the very threshold by the question: What is disease? This may Health and Disease. best be answered by defining what we understand by health. What do we mean when we talk of a healthy organism? Our ideas upon the subject are purely arbitrary, and depend upon our everyday experience. Health is simply that condition of structure and function which, on examination of a sufficient number of examples, we find to be commonest. The term, in fact, has the same significance as “the normal.” Disease we may define, accordingly, as any departure from the normal standard of structure or function of a tissue or organ. If, for instance, we find that instead of the natural number of Malpighian bodies in the kidney there are only half that number, then we are entitled to say that this defect represents disease of structure; and if we find that the organ is excreting a new substance, such as albumen, we can affirm logically that its function is abnormal. Once grant the above definition of disease, and even the most trivial aberrations from the normal must be regarded as diseased conditions, quite irrespective of whether, when structural, they interfere with the function of the part or not. Thus an abortive supernumerary finger may not cause much, if any, inconvenience to the possessor, but nevertheless it must be regarded as a type of disease, which, trivial as it may appear, has a profound meaning in phylogeny and ontogeny.

Classification.—From the foregoing it will be gathered that the problems in pathology are many-sided and require to be attacked from all points of vantage; and the subject falls naturally into certain great divisions, the chief of which are the following:—

I.	Morbid anatomy.
	(a)	Naked-eye or macroscopic.
	(b)	Morbid histology or microscopic.
II.	Pathological physiology.
III.	Pathogenesis.
IV.	Aetiology.
V.	Pathological chemistry.

The term “pathogenesis” has reference to the generation and development of disease, and that of “aetiology,” in its present bearing, has to do with its causes. The use of the term “pathological physiology” may at first appear strange, for if we define physiology as the sum of the normal functions of the body or organism, it may be hard to see how there can be a physiology which is pathological. The difficulty, however, is more apparent than real, and in this sense, that if we start with a diseased organ as our subject of inquiry, we can quite properly, and without committing a solecism, treat of the functions of that organ in terms of its diseased state.

Influences Working for Evil upon the Organism

(1) Malnutrition.—When the blood supply is entirely cut off from a tissue the tissue dies, and in the act of dying, or afterwards, it suffers certain alterations dependent upon its surroundings. Thus, when the circulation to an external part is obstructed completely, as in the case of a limb where the main artery has been occluded and where the anastomatic communications have not sufficed to continue the supply of blood, the part becomes gangrenous (fig. 24, PI. II.); that is to say, it dies and falls a prey to the organisms which excite putrefaction, just as would happen to any other dead animal tissue were it unconnected with the body. Fermentative changes are set up in it, characterized by the evolution of gas and the formation of products of suboxidation, some of which, being volatile, account for the characteristic odour. In the formation of these the tissues break down, and in course of time lose their characteristic histological features. The blood suffers first; its pigment is dissolved out and soaks into the surroundings, imparting to them the pink hue so diagnostic of commencing gangrene. Muscle and white fibrous tissue follow next in order, while elastic tissue and bone are the last to show signs of disintegration. The oil separates from the fat-cells and is found lying free, while the sulphuretted hydrogen evolved as one of the products of putrefaction reacts upon the iron of the blood and throws down a precipitate of sulphide of iron, which in course of time imparts to the limb a range of colour commencing in green and terminating in black.

The temperature at which the limb is kept, no doubt, favours and hastens the natural process of destruction, so that putrefaction shows itself sooner than would be the case with a dead tissue removed from the body and kept at a lower temperature. Nevertheless, gangrene is nothing more or less than the putrefactive fermentation of an animal tissue still attached to the body. If the amount of liquid contained in the tissue be small in quantity the part mummifies, giving rise to what is known as “dry gangrene.” If the dead part be protected from the ingress of putrefactive organisms, however, it separates from that which is living without the ordinary evidences of gangrene, and is then known as an “aseptic slough.” Should the portion of tissue deprived of its circulation be contained in an internal organ, as is so often the case where the obstruction in the artery is due to embolism, it becomes converted into what is known as an “infarction.” These infarcts are most common in organs provided with a terminal circulation, such as prevails in the kidney and spleen. The terminal branches of the arteries supplying these organs are usually described as not anastomosing but many, if not all, of Cohnheim's end-arteries have minute collateral channels; which, however, are usually insufficient to completely compensate for the blocking that may occur in these arteries, therefore, when one of them is obstructed, the area irrigated by it dies from malnutrition. Being protected from the ravages of the organisms which induce putrefaction, however, it does not become gangrenous; it is only where the obstructing agent contains these organisms that a gangrenous slough follows, or, in the case of the contaminating organisms being of a suppurative variety, ends in the formation of a so-called “pyaemic abscess,” followed by rapid dissolution of the dead tissue (fig. 24, Pl. II.). In ordinary circumstances, where the artery is obstructed by an agent free from such organismal contamination, the part becomes first red. This is due to intense engorgement of the vessels brought about through these minute existing collateral channels and results in a peripheral congested zone round the infarct. There may be haemorrhage from these vessels into the tissues. This collateral supply not being sufficient to keep up the proper flow of blood through the part the veins tend to become thromboses, thus increasing the engorgement. The central part of the obstructed area very soon undergoes degenerative changes, and rapidly becomes decolourized. This necrosed area forms the pale infarct. Absorption of this infarcted zone is carried on by means of leukocytes and other phagocytic cells, and by new blood-vessels. If absorption be not complete the mass undergoes caseation and becomes surrounded by a capsule of fibrous tissue—being sharply cut off from the healthy tissue.

Where the malnutrition is the effect of poorness in the quality of the blood, the results are of course more widespread. The muscles suffer at an early period: they fall off in bulk, and later suffer from fatty degeneration, the heart being probably the first muscle to give way. Indeed, all tissues when under-nourished, either locally as the result of an ischaemia, or generally as from some impairment of the blood, such as that prevailing in pernicious anaemia, tend to suffer from fatty degeneration; and at first sight it seems somewhat remarkable that under-nourished tissues should develop fat in their substance (figs. 26 and 27, Pl. II.). The fatty matter, however, it must be borne in mind, is the expression of dissimulation of the actual substance of the proteids of the tissues, not of the splitting up of proteids or other carbonaceous nourishment supplied to them.

A part deprived of its natural nerve-supply sooner or later suffers from the effects of malnutrition. When the trigeminus nerve is divided (Majendie), or when its root is compressed injuriously, say by a tubercular tumour, the cornea begins to show points of ulceration, which, increasing in area, may bring about total disintegration of the eyeball. The earliest interpretation put upon this experiment was that the trophic influence of the nerve having been withdrawn, the tissue failed to nourish itself, and that degeneration ensued as a consequence. The subsequent experiments of Snellen, Senftleben, and, more lately, of Turner, seem to show that if the eyeball be protected from the impingement of foreign particles, an accident to which it is liable owing to its state of anaesthesia, the ulceration may be warded off indefinitely. If the eyeball be kept perfectly clean and no organism be admitted from the outside then ulceration will not follow. If, on the other hand, any pathogenic organisms be present the results are disastrous because the tissue, deprived of its nervous trophic supply, has greatly lessened resistance. The bed-sores which follow paralysis of the limbs are often quoted as proof of the direct trophic action of the nerve-supply upon the tissues, yet even here the evidence is somewhat contradictory. Still, there are facts which, for want of a better explanation, we are almost bound to conclude are to be accounted for on the direct nerve-control theory. The common variety of bed-sore is the result of continuous pressure on and irritation of the skin, the vitality and resisting power of which are lowered by a lesion of the cord cutting off the trophic supply to the skin affected. The acute bed-sore is, in some cases, a true trophic lesion occurring, as it may, on parts not subjected to continuous pressure or irritation. Trophic disturbance in the nutrition of the skin may be so great that a slight degree of external pressure or irritation is sufficient to excite even a gangrenous inflammation. Again, a fractured bone in a paralysed limb often fails to unite, while another in the opposite sound limb unites readily, and an ulcerated surface on a paralysed limb shows little healing reaction. A salivary gland degenerates when its nerve-supply is cut off; and the nerves leading up to the symmetrical sloughs in Raynaud's disease have been found in an advanced state of degeneration (Affleck and Wiglesworth). It is just a question, however, whether, even in instances such as these, the nutritional failure may not be explained upon the assumption of withdrawal of the local vasomotor control. There seems to be little doubt, notwithstanding, that one of the chief functions of the nerve cell is that of the propagation of a trophic influence along its axon. When a nerve-trunk is separated from its central connexion, the distal portion falls into a state of fatty degeneration (Wallerian or secondary degeneration). That special trophic nerves, however, exist throughout the body, seems to be a myth. It is much more likely, as Verworn alleges, that the nerves which influence the characteristic function of any tissue regulate thereby the metabolism of the cells in question—in other words, that every nerve serves as a trophic nerve for the tissues it supplies. It is a significant fact that neoplasms contain very few nerve-fibres, even although growing luxuriantly, and there is a doubt whether the few twigs contained in them may not merely have been dragged into their midst as the tumour mass expanded (Young).

Overwork.—The effect of overwork upon an organ or tissue varies in accordance with (a) the particular organ or tissue concerned, (b) the amount of nourishment conveyed to it, and (c) the power of assimilation possessed by its cells. In the case of muscle, if the available nourishment be sufficient, and if the power of assimilation of the muscle cells remain unimpaired, its bulk increases, that is to say, it becomes hypertrophied.

It may be advisable to define exactly what is meant by “hypertrophy,” as the term is often used in a loose and insignificant sense. Mere enlargement of an organ does not imply that it is in a state of hypertrophy, for some of the largest organs met with in morbid anatomy are in a condition of extreme atrophy. Some organs are subject to enlargement from deposition within them of a foreign substance (amyloid, fat, &c.). This, it need hardly be said, has nothing to do with hypertrophy. The term hypertrophy is used when the individual tissue elements become bigger to meet the demands of greater functional activity; hyperplasia, if there is an increase in the number of these elements; and pseudo-hypertrophy, when the specific tissue element is largely replaced by another tissue.

There are conditions in which we have an abnormal increase in the tissue elements but which strictly should not be defined as hypertrophies, such as new-growths, abnormal enlargements of bones and organs due to syphilis, tuberculosis, osteitis deformans, acromegaly, myxoedema, &c. The enormously long teeth sometimes found in rodents also are not due to hypertrophy, as they are normally endowed with rapid growth to compensate for the constant and rapid attrition which takes place from the opposed teeth. Should one of these teeth be destroyed the opposed one loses its natural means of attrition and becomes a remarkable, curved tusk-like elongation. The nails of the fingers, or the hair of the scalp may grow to an enormous length if not trimmed.

True hypertrophy is commonly found in the hollow muscular organs such as the heart, bladder and alimentary canal. As any obstruction to the outflow of the contents throws an increased amount of work on the walls, in order to overcome the resistance, the intermittent strain, acting on the muscle cells, stimulates them to enlarge and proliferate, fig. 28, Pl. II., and gives rise to adaptive hypertrophy. Should there be much loss of tissue of an organ, the cells of the remaining part will enlarge and undergo an active proliferation (hyperplasia) so that it may be made up to the original amount. Or again, in the case of paired organs, if one be removed by operation, or destroyed by disease, the other at once undertakes to carry on the functions of both. To do so a general enlargement takes place until it may reach the size and weight equal to the original pair. This is known as compensatory hypertrophy.

Examples of physiological hypertrophy are found in the ovaries, uterus and mammary glands, where there is an increased functional activity required at the period of gestation. Local hypertrophy may also be due to stimulation resulting from friction or intermittent pressure, as one may see in the thickenings on the skin of the artisan's hands. The extreme development of the muscles in the weightlifting athlete and in the arm of the blacksmith is the result of increased functional activity with a corresponding increase in the vascular supply; this exercise may produce an over-development so excessive as to be classed as abnormal.

In atrophy we have a series of retrograde processes in organs and tissues, which are usually characterized by a progressive diminution in size which may even end in their complete disappearance (fig. 29, Pl. II.). This wasting may be general or local—continuously from the embryonic period there is this natural process of displacement and decay of tissues going on in the growing organism. The functions of the thymus gland begin to cease after the second year from birth. The gland then slowly shrinks and undergoes absorption. From atrophy of their roots, caused by the pressure of the growing permanent teeth, the “milk teeth” in children become loose and are cast off. The ovaries show atrophic changes after the menopause. In old age there is a natural wearing out of the elements of the various tissues. Their physiological activities gradually fail owing to the constructive processes having become so exhausted from long use that the destructive ones are able to overtake them. As the cell fails and shrinks, so does it become more and more unable to make good the waste due to metabolism. This physiological wasting is termed senile atrophy.

General atrophy or emaciation is brought about by the tissues being entirely or partially deprived of nutriment, as in starvation, or in malignant, tubercular, and other diseases of the alimentary system which interfere with the proper ingestion, digestion or absorption of food material. The toxic actions produced in continued fevers, in certain chronic diseases, and by intestinal parasites largely aid in producing degeneration, emaciation and atrophy.

Atrophy may follow primary arrest of function—disuse atrophy. The loss of an eye will be followed by atrophy of the optic nerve; the tissues in a stump of an amputated limb show atrophic changes; a paralysed limb from long disuse shows much wasting; and one finds at great depths of the sea fishes and marine animals, which have almost completely lost the organs of sight, having been cut off for long ages from the stimuli (light) essential for these organs, and so brought into an atrophic condition from disuse.

Atrophy may also follow from overwork. Increased work thrown on to a tissue may produce hypertrophy, but, if this excessive function be kept up, atrophy will follow; even the blacksmith's arm breaks down owing to the hypertrophic muscle fibres becoming markedly atrophied.

From these causes a certain shrinkage is liable to occur, more evident in some parts of the body than in others. Thus the brain falls off in bulk, and the muscles become attenuated, and in no muscle is this more notable than in the case of the heart. A tendency to pigmentation also develops in certain tissues of the body, such as the nerve and muscle cells. As a result of these various degeneration's the functions of the body deteriorate, the faculties become blunted, and the muscular energy of the body is below what it was in earlier life, while the secreting glands in certain instances become functionally obsolescent.

Continuous Over-pressure.—The tissues of an animal or plant are all under a certain pressure, caused, in the one case, by the expulsive action of the heart and the restraint of the skin and other elastic tissues, and, in the other case, by the force of the rising sap and the restraint of the periderm or bark. Under this normal amount of pressure they can live and grow. But whenever, from any cause, the degree of pressure which they are naturally intended to withstand is surpassed, they fail to nourish themselves, become granular, die, and, falling to pieces, are absorbed.

Deleterious Surroundings.—There can be little doubt that all unnatural and artificial modes of life tend to deterioration of the powers of resistance of the organism to disease. We see it exemplified in plant life in circumstances which are unnatural to the life of the plant, and the prevalence of certain constitutional tendencies among the inhabitants of crowded cities bears evidence to the same law.

Man, like other animals, was naturally intended to lead an outdoor life. He was originally a hunter and a tiller of the ground, breathing a pure atmosphere, living on a frugal diet, and exercising his muscles. Whenever these conditions are infringed his powers of resistance to disease are lessened, and certain tendencies begin to show themselves, which are generally termed constitutional. Thus the liability to tubercular infection is far commoner in the midst of a depraved population than in one fulfilling the primary laws of nature; rickets is a disease of great cities rather than of rural districts; and syphilis is more disastrous and protracted in its course in the depraved in health than in the robust. Cattle kept within-doors are in a large proportion of cases tubercular, while those leading an outdoor life are much less liable to infection. The improvement which has taken place in the general health of the inhabitants of cities during recent years, concurrent with hygienic legislation, is ample proof of the above assertions. The diminution in the number of deaths from tuberculosis during the last forty to fifty years of the 19th century of itself points in this direction. Every living organism, animal and vegetable, tends to maintain a normal state of health; it is when the natural laws of health are violated that the liability to disease begins to assert itself. If, in these circumstances, the food supply be also insufficient, the combination of influences is sure, in course of time, to bring about a physical deterioration of the race. Certain avocations have a direct and immediate influence in causing diseased states of body. Thus workers in lead suffer from the effects of this substance as a poison, those who work in phosphorus are liable to necrosis of bone and fatty degeneration of the blood vessels and organs, and the many occupations in which dust is inhaled (coal mining, stone-dressing, steel-polishing, &c.; fig. 30, Pl. III.) are fraught with the greatest danger, owing to the destructive influence exerted upon the lungs by the inhaled particles. Among the most dangerous of the last class (the pneumokonioses) is perhaps that in which the dust particles take the form of finely divided freestone, as in stone-dressing and the dry-polishing on the grindstone of steel. The particles in this case set up a form of fibrosis of the lung, which, either of itself or by rendering the organ liable to tubercular infection, is extremely fatal. The abuse of alcohol may also be mentioned here as a factor in the production of disease.

Parasitism.—Of all external agents acting for evil, however, probably vegetable and animal micro-organisms with a pathogenic bent are most to be feared. When we consider that tuberculosis, diphtheria, cholera, tetanus, typhoid fever, anthrax, malaria and a host of other contagious diseases have each been proved to be of parasitical origin, an idea may be conveyed of the range of the subject. The living organism may be regarded as constantly engaged in a warfare with these silent and apparently insignificant messengers of destruction and death, with the result that too often the battle ends in favour of the attacking enemy.

Heredity.—The tendencies to disease are in great part hereditary. They probably express a variation which may have occurred in a far-back ancestor, or in one more recent, and render the individual vulnerable to the attacks of parasitic fungi, or, it may be, become manifest as errors of metabolism. The psychopathic, the tubercular, the rickety, and the gouty constitution may all be transmitted through a line of ascendants, and only require the necessary exciting agents to render them apparent. A distinction must be drawn between the above and diseases, like syphilis and small-pox, in which the contagion of, not the tendency to, the disease is transmitted directly to the foetus in utero. (See Heredity.)

The Cellular Doctrine in Pathology

The cellular pathology is the pathology of to-day; indeed, protoplasm—its vital characteristics under abnormal influences and its decay—will be regarded most likely as the basis of pathology in all time. According to our present knowledge of physiological and pathological processes, we must regard the cell as the ultimate biological unit—a unit of structure and a unit of function; this was first put forward by Schleidenin 1838, and by Schwann in 1839, but we owe to Virchow the full recognition of the fundamental importance of the living cell in all the processes of life, whether in health or disease. When Virchow wrote, in 1850, “every animal presents itself as a sum of vital unities, every one of which manifests all the characteristics of life,” he expressed a doctrine whose sway since then has practically been uninterrupted. The somatic cells represent communities or republics, as it were, which we name organs and tissues, but each cell possesses a certain autonomy and independence of action, and exhibits phenomena which are indicative of vitality.

Still, it must be borne in mind that this alleged autonomy of action is said to be founded upon an erroneous supposition, on the supposition that each cell is structurally, and it may be said functionally, separated from those in its neighbourhood. It is well known that in the vegetable kingdom the protoplasm of one cell frequently overflows into that of cells adjacent—that there is, as it were, a continuous network of protoplasm (idioplasm of Nägeli) prevailing throughout vegetable tissues, rather than an aggregation of isolated units. The same inter-communication prevails between adjacent cells in some animal tissues, and more particularly in those which are pathological, as in the case of the epithelial cells of cancer. Assuming, with Sedgwick and others, this amassed and bound condition of the tissues to be true, it would be necessary to reject the cell-doctrine in pathology altogether, and to regard the living basis of the organism as a continuous substance whose parts are incapable of living independently of the whole. Until, however, further evidence is forthcoming in support of this syncytial theory of structure, it would be unwise to regard it as established sufficiently to constitute a serviceable working hypothesis; hence, for the time being, we must accept the assertion that the cell represents the ultimate tissue-unit. Our present day definition of a cell is a minute portion of living organized substance or protoplasm.

The cells met with in morbid parts which are in a state of active Structure of Pathological Cells. vitality are built up of the same components as those found in normal tissues (Pl. I.).^[1] Thus they are provided with a nucleus which is the centre of cell activity; both of the reproductive and chemical (metabolic) processes which occur in the cell protoplasm. The executive centre varies in shape, but is usually round or oval, and is sharply defined by a nuclear membrane from the cytoplasm in which it lies. The nucleus in its vegetative stage shows a fine network throughout containing in the meshes the so-called nuclear-sap; attached to the network are the chromosomes, in the form of small irregular masses, which have a strong affinity for the “basic dyes.” Embedded in the nucleus are one or more nucleoli (plasmosomes) having an affinity for the “acid dyes.” The nucleolus shows an unstainable point at the centre known as the endonucleolus or nucleoluolus (Auerbach).

The cell body, or cytoplasm, is apparently composed of a fine reticulum or network, containing within the meshes a soft viscid, transparent substance, the cell-sap, or hyaloplasm, which is probably a nutrient material to the living cell. Within the cytoplasm are found manifestations of functional activity, in the form of digestive vacuoles, granules, fat, glycogen, pigment, and foreign bodies. Usually the cytoplasm shows a marked affinity for the acid stains, but the different bodies found in the cell may show great variation in their staining reactions.

The centrosomes which play so important a part in cell division may be found either lying within or at one side of the nucleus in the vegetative condition of the cell. Centrosomes may be single, but usually two are lying close together in the attraction-sphere. When mitosis is about to take place, they separate from one another and pass to the poles of the nucleus, forming the achromatic spindle. After the division and cleavage of the chromosomes of the original nucleus have taken place they pass from the equator to the poles of the spindle, rearranging themselves close to the separated centrosomes to form daughter nuclei.

The cytoplasm of the cell now undergoes division in a line between the two daughter nuclei. When complete separation has taken place, we have two daughter cells formed from the original, each being a perfect cell-unit. Some pathological cells, such as the giant-cells of tumours, of bone, and those of tubercle, are polynuclcated; in some instances they may contain as many as thirty or more nuclei. The only evidence we have in pathology of living structures in which apparently a differentiation into cell-body and nucleus does not exist, is in the case of bacteria, but then there comes the question whether they may not possess chromatin distributed through their substance, in the form of met achromatic points, as is the case in some infusoria (Trachelocerca, Gruber).

Although the methods of cell-division prevailing in normal structures are maintained generally in those which are pathological, yet certain modifications of these methods are more noticeable in the latter than in the former. Thus in the neoplasmata direct cell-division is more the rule than in healthy parts. In actively growing neoplasmata, certainly, the indirect method prevails largely, but seems to go on side by side with the direct.

A curious and interesting modification of the indirect method, known as “asymmetrical division,” occurs frequently in epitheliomata, sarcomata, &c. (Hansemann). It consists in an unequal number of chromosomes passing over to each of the daughter nuclei, so that one may becomehypo chromatic, the other hyperchromatic. When this happens the resulting cleavage of the cytoplasm and nucleus is also unequal. Several explanations have been given of the meaning of these irregularly chromatic cells, but that which most lends itself to the facts of the case seems to be that they represent a condition of abnormal karyorhexis.

In many pathological cells undergoing indirect segmentation, centrosomes appear to be absent, or at any rate do not manifest themselves at the poles of the achromatic spindle. When they are present, that at one end of the spindle may be unusually large, the other of natural size, and they may vary in shape. In pathological cell-division it happens occasionally that the segmentation of the cytoplasm is delayed beyond that of the mitotic network. The daughter nuclei may have arrived at the anaphase stage, and have even gone the length of forming a nuclear membrane, without an equatorial depression having shown itself in the cell-body. Sometimes the equatorial depression fails entirely, and the separation, as in some vegetable cells, takes place through the construction of a cell-plate. Intranuclear plexuses are not usually found in giant cells, but have been described in the giant-cells of sarcoma ta by Klebs and Hansemann, and in those of tubercle by Baumgarten. Some of the nuclei within multinucleated cells may occasionally be engaged in mitotic division, the others being in the resting state.

In the earlier accepted notion of direct segmentation, usually known as the schema of Remak, division was described as commencing in the nucleolus, as thereafter spreading to the nucleus, and as ultimately implicating the cell-substance. Trambusti, curiously, finds confirmatory evidence of this in the division of cells in sarcoma. Contrary, however, to the experience of others, he has never found that the attraction-spheres play an important part in direct cell-division, or, indeed, that they exert any influence whatever upon the mechanism of the process. Where pigment was present within the cells (sarcoma), the attraction-spheres were represented by quite clear unpigmented areas, sometimes with a centrosome in their midst.

Repair of Injuries

In the process of inflammation we have a series of reactions on the part of the tissues, and fluids of the body, to counteract the ill effects of irritation or injury, to get rid of the cause, and to repair its results. Injury and loss of tissue are usually followed by repair, and both the destructive and reparative changes are, as a rule, classified under the term inflammation. The irritants may be bacteria and their toxins, or they may be mechanical, chemical or thermic.

We do not now concur with the old view that inflammation was essentially an injurious process; rather do we look upon it as beneficial to the organism. In the various reactions of the tissues against the exciting cause of the injury we see a striking example of a beautifully organized plan of attack and defence on the part of the organism.

In some of the infective conditions the conflict fortifies the organism against future attacks of the same nature, as for example in the immunity following many of the acute infective diseases. This acquired immunity is brought about by the development of a protective body as a result of the struggle of the cells and fluids of the body with the invading bacteria and their toxins. This resistance may be more or less permanent. If the invasion is due to a pus-producing micro-organism which settles in some local part of the body, the result is an abscess (fig. 25, Pl. II.).

Abscesses.—One can easily demonstrate all the actions and reactions which take place in this form of acute inflammation. In such a conflict one can see the presence of these minute but dangerous foes in the tissues. At once they proceed to make good their hold on the position they have secured by secreting and throwing out toxins which cause more or less injury to the tissues in their immediate neighbourhood. These micro-organisms having found in the tissues everything favourable for their needs, rapidly multiply and very soon produce serious results. At this point one's attention is focused on the wonderful reactions possessed by the healthy tissues to combat these evil influences.

In a very short period—within three or four hours after infection—there appears to have been a message conveyed to the defenders of the body both as to the point of attack and the nature of the invasion. There is thus brought into play a series of processes on the part of the tissues—the vascular inflammatory changes—which is really the first move to neutralize the malign effects. We find at this early stage oedema of the part. This is an increased exudation of fluid from the engorged blood vessels which not only dilutes the toxins, but is supposed to contain substances which in some way act on these living micro-organisms and render them a more easy prey to the polymorpho-nuclear leukocytes (fig. 23, Pl. II.)—cells that are motile and extremely phagocytic to these bacteria. At this stage the rapidity of the blood circulation has become greatly diminished. The polymorpho-nuclear leukocytes are seen in great numbers in the blood vessels.

In health these cells, belonging to our first army of defenders, are found continually circulating in the blood stream in fairly large numbers; they are ever ready to rush to the point of attack, where they at once leave the blood stream by passing through the vessel walls—emigration—into the tissues of the danger zone. There they show marked phagocytosis, attacking and taking up into their interior and destroying the micro-organisms in large numbers. At the same time large numbers of these cells perish in the struggle, but even the death of these cells is of value to the body, as in the process of breaking down there are set free ferments which not only act detrimentally to the bacteria, but also may stimulate the bringing forward of another form of cell defenders—the mononuclear leukocyte.

To replace this cellular destruction there has been a demand for reinforcements on the home centres of the polymorpho-nuclear leukocytes—the bone marrow. This call is immediately answered by an active proliferation and steady maturing of the myelocytes in the marrow to form the polymorpho-nuclear leukocytes. These then pass into the blood stream in very large numbers, and appear to be specially attracted to the point of injury by a positive chemiotactic action. This phenomenon, called chemiotaxis, has been studied by several investigators. Leber experimented with several chemical compounds to find what reaction they had on these cells; by using fine glass tubes sealed at the outer end and containing a chemical substance, and by introducing the open end into the blood vessels he found that the leukocytes were attracted—positive chemiotaxis—by the various compounds of mercury, copper, turpentine, and other substances. That quinine, chloroform, glycerin, alcohol, with others, had no attractive influence on them—negative chemiotaxis. It was also found that a weak solution may have a marked positive attraction whilst a strong solution of the same substance will have the opposite effect. It has been proved that the pyo-genic bacterial toxins, if not too concentrated, will attract the polymorpho-nuclear leukocytes, but if concentrated, may have a repelling influence.

Then we have the property of adaptation, in which the negative reaction may be changed into a positive; a given toxin may at first repel the cell, but by a gradual process the cell becomes accustomed to such a toxin and will move towards it.

On reaching the vicinity they leave the blood stream and join in the warfare—many performing their function of phagocytosis (q.v.), others falling victims to the toxins. The tissues of the part become disorganized or destroyed, and their place is taken by the mass of warring cellular elements now recognized as pus.

As soon as the fluids and the polymorpho-nuclear leukocytes have succeeded in diminishing the virulence of the micro-organism, the second line of defenders—the large mononuclear leukocytes (fig. 23, Pl. II.) make their appearance at the field of battle in ever increasing numbers. These are amoeboid cells and are extremely phagocytic, their power of digestion being greatly developed. Their principal function is to bring about the removal of foreign, dead or degenerating material. This they take up into their protoplasm, where it is rapidly digested by being acted on by some intracellular digestive ferment (fig. 31, Pl. III.). Where the material is too large to be taken up by an individual cell, the dissolution is brought about by the cells surrounding the material, to which they closely apply themselves, and by the secreting of the ferment, a gradual process of erosion is brought about with ultimate absorption.

If the abscess be deeply situated in some tissue and not able to open on to a free surface so allowing the contents to be drained off, the phagocytic cells play a very prominent part in the resolution of the abscess. They are seen pushing their way right into the field of conflict and greedily ingesting both friends and foes. The first defenders, the polymorpho-nuclear leukocytes, having performed their functions, are of no more use to the organism and are therefore removed by the mono-nuclear phagocytes as useless material (fig. 31, Pl. III.).

The tissues having now mobilized an army that completely surrounds the fighting zone, there is a gradual and general advance made from all sides. The vanguard of this advancing army is composed of a more or less compact layer of the mono-nuclear phagocytes (polyblasts) accompanied by numerous new vessels. These phagocytic cells carry out the complete removal of all the injured warring elements and the damaged tissues of the part. The vessels are only temporary channels by which is brought forward the food supply that is needed by the advancing army if it is successfully to carry on its function; they probably also drain off the deleterious fluid substances formed by the cellular disintegration that has taken place in the part. Closely on the advance of this army of phagocytes or scavenger cells follows the third line of defenders, the connective tissue cells or fibroblasts.

All these cells are probably of local origin and are now stimulated to make good the damage. The connective tissue cells or fibroblasts (fig. 32, Pl. III.) are seen in active proliferation around the phagocytic zone. First they are round or oval in shape; later they become spindle shaped, arranging themselves in layers. Then they develop definite fibrils which differentiate into fibrous laminae forming a zone which shuts off the abscess from the healthy tissue and so prevents the further invasion and injurious effects of the microorganism. By the aid of the new fibroblasts this fibrous tissue zone gradually encroaches on the pus area and replaces the phagocytic layer of cells as they proceed with the absorption of the pus mass (fig. 33, Pl. III.). When complete removal of the pus mass has been accomplished by the process of absorption, the damaged area is replaced by the new fibrous tissue, which later becomes condensed and forms the cicatricial or scar tissue (fig. 35, Pl. III.)—a healed abscess.

Wounds.—The healing of wounds is brought about by similar processes to that seen in the evolution of an abscess.

If the injury be a small incised wound through the skin and subcutaneous tissues without any septic contamination, there usually follows a minimum of reaction on the part of the tissues. As the edges of the wound are brought into accurate apposition there is little or no blood lodged between them, so that an extremely narrow strip of fibrin glues the cut edges together. This strip is rapidly replaced, mainly by the connective tissue cells of the adjoining tissue growing across the temporary filled breach and firmly uniting the two cut surfaces. The vascular changes are practically absent in healing by first intention.

Healing by second intention, or granulation, is usually seen where there has been loss of tissue, or extensive damage. The reactions of the tissues vary in degrees according to the nature and severity of the injury. In resenting such insults, a remarkable uniformity and regularity in the processes is brought about by the different cells and fluids of the healthy tissues of the body. Although we have not reached a stage of certainty regarding their origin, function and destiny, recent investigations have brought forward evidence to elucidate the importance of the part played by the different cells in the various types of the inflammatory process.

If there be a loss of tissue brought about by severe injury to the skin and the deeper tissues, there is usually an extravasation of blood from the severed vessels. Along with the exuded serum this fills up the breach in the tissues and the whole is rapidly formed into a fibrinous mass due to the disintegration of the polymorpho-nuclear leukocytes setting free their ferment. The ferment thus set free brings about the coagulation of the serum, which acts as a protective and temporary scaffolding to the injured tissues. Lying between the fibrin mass and the healthy tissues is a zone of injured and degenerated tissue elements, the result of the trauma.

As early as six hours after the injury the polymorpho-nuclear leukocytes are seen passing in large numbers from the dilated and congested blood vessels of the tissues at the margin of the wound into the injured zone, where they carry on an active phagocytosis. It is believed also that they secrete bactericidal substances and ferments which bring about the liquefaction of the fibrin and the damaged tissues—histolysis—and thus assist the process of absorption. They appear to prepare the injured zone for the coming of the next series of cells. Their function being at an end they give way to these cells which carry on the process of absorption.

In a period varying from twenty-four to thirty hours there is marked evidence of the removal of the degenerated cellular elements in the damaged zone by the mono-nuclear phagocytes. Numerous fibroblasts, together with polyblasts, are visible in the fibrin mass, and the vessels at the periphery of the damaged zone are now seen to be sending out offshoots which assist in the process of absorption. These vascular buds grow out in various directions as little solid projections of cells; they then become channelled and form the new but temporary meshwork.

After two to four days these processes are more clearly emphasized. By these processes we reach the stage where the fibrin mass and damaged tissues have been completely removed, and replaced by a temporary vascular and cellular tissue, known as granulation tissue (fig. 34, Pl. III.), which in turn has to give way to the more firm and differentiated fibrous tissue. By this time the skin epithelium may have grown over the wound.

After five to seven days we find the connective tissue cells taking the principal part in the building up of the new permanent tissue, for at this stage there is an active proliferation of the fibroblasts. These cells of various shapes are seen in large numbers, mainly lying in a direction parallel to the new vessels and capillaries, which all run at right angles to the wound surface. The branching processes of these cells apparently anastomose with one another and form a delicate supporting network. It is from these cells that the fine fibrillar substance is formed, and from this stage onwards—eight to fifteen days—there is a steady increase in the new fibrils, giving more density to the new tissue. At the same time there is brought about an alteration in the arrangement of the position of the fibroblasts. These become spindle shaped with their long axis more and more assuming a position at right angles to the vessels (fig. 34, Pl. III.); the two edges of the wound are thus more firmly bound together. As their fibrils become more developed they gradually form fibrous laminae which are laid down first in the deeper part of the wound. When this process has reached a certain stage and all the absorption necessary has occurred the new blood vessels, from the increasing pressure of the successive fibrous layers, gradually dwindle and become obliterated, i.e. at a period corresponding to the condensation of the fibrous laminae and the disappearance of the cellular character of the granulation tissue. Thus is formed in the damaged area a permanent tissue known as scar tissue (fig. 35. Pl. III.).

Fibrosis.—Where a chronic inflammatory process has taken possession of an organ, or, let us say, has been located in periosteum or other fibrous part, there is a great tendency to the production of cicatricial fibrous tissue in mass. Thus it is laid down in large quantity in cirrhosis of the liver, kidney or lung, and reacts upon these organs by contracting and inducing atrophy. The term “cirrhosis” or “fibrosis” is usually applied to such a condition of organs (figs. 36 and 37, Pl. IV.), that of “sclerosis” is used when such a deposition of fibrous tissue occurs within the central nervous system. Gull and Sutton asserted that in particular states of body, and more especially in the condition associated with cirrhotic kidney, such a fibrosis becomes general, running, as they alleged it does, along the adventitia of arteries and spreading to their capillaries. They supposed that it was accompanied by a peculiar hyaline thickening of the arterial wall, usually of the tunica intima, and hence they termed the supposed diseased state “arterio-capillary fibrosis,” and gave the fibrous substance the name “hyaline-fibroid.” They held that the cirrhotic kidney is simply a local manifestation of a general fibrous disease. Their theory, however, has fallen into disfavour of late years.

Tumours or New Growths

The various definitions of the term “new growth” leave us with a definite conception of it as a new formation of tissue which appears to originate and to grow independently. We have already compared the body to a social community, each constituent element of which—the cell—lives its own life but subordinates its individuality to the good of the whole organism. The essential characteristic of a new growth is that this subordination is lost and the tissue elements, freed from the normal mutual restraint of their interdependence, give way to an abnormal growth. All the hypotheses about the causation of new growths seek to explain the secret of this individuality or “autonomy,” as they recognize that the mystery of the origin of the great majority of tumours would be solved if we could trace how or why the tissue elements in which they develop first took on this abnormal growth.

Tumours are divided into two main groups—innocent and malignant. These differ only in degree and there is no hard and fast line between them. Innocent tumours are usually sharply defined from the surrounding tissues, and show no tendency to spread into them or to pass by means of lymphatics and blood vessels to neighbouring parts (fig. 38, Pl. IV.). Malignant tumours, on the other hand, invade the adjacent tissues and pass by lymphatics and blood vessels to distant parts, where they set up secondary growths (fig. 39, Pl. IV.).

Tumours appear to arise spontaneously, i.e. without evident cause; they may develop in association with prolonged irritation or injury (later referred to in more detail). To heredity, as an indirect or predisposing cause, has probably been assigned too great importance, and the many facts brought forward of the relative frequency of cancer in members of one family only justify the conclusion that the tissue-resistance of certain families is lowered.

At the present time we have still before us the question, what is the essential cause of tumours (q.v.)? This, one of the most difficult problems of pathology, is being attacked by many able workers, who are all striving from different standpoints to elucidate the nature of these new formations, which spring from the normal tissues in which they develop and which they destroy. In spite of all the valuable research work that has been done within the last few years, the essential cause of new growths still remains unknown.

To the work carried on by the Imperial Cancer Research Fund in England, and to investigators in other countries, are due the present day scientific efforts made to systematize investigation and clear away many of the hypothetical speculations that have gathered round this most difficult subject. Their investigations on cancers found in the lower animals, and the successful transplantation of such growths into a new host of the same species (mice and rats), have greatly advanced our knowledge of the etiology of this disease.

Many of the hypotheses of the past put forward to explain cancer must be discarded, in view of the facts brought to light by the comparative and experimental research of recent times. According to the hypothesis of Waldcyer and Thiersch there is perfect equilibrium between the normal epithelium and its supporting structure, the connective tissue, but with advancing age this balance is upset owing to the connective tissue gradually losing its restraining power. The epithehal cells are then able to pass from their normal position, in consequence of which they proliferate and at the same time revert to a more primitive type of cell. In this way they give rise to a malignant new growth.

Cohnheim's hypothesis of “embryonic residues” provides that early in the development of the embryo some of the cells, or groups of cells, are separated from their organic continuity during the various foldings that take place in the actively growing embryo. The separated cells become intermingled with other tissue elements amongst which they lie dormant with their inherent power of proliferation in abeyance. At a later date in the life of the individual, by some unknown stimuli, they resume their active power of proliferation and so give rise to new growths.

The “tissue-tension” hypothesis of Ribbert is a combination of the two foregoing. He holds that new growths arise, both before birth or at any subsequent period of life, by the separation of cells or clumps of cells from their normal position, and that in health there is a balance between the various tissues and tissue elements regulated by what he calls the “tissue-tension” of the part, i.e. that cells or groups of cells have a restraining power on one another which prevents any physiological over-activity.

From whatever cause the resisting power of the tissue elements is thus weakened, the invasion of other tissue elements is then allowed to take place. These being freed from the normal inhibiting power of the neighbouring elements, multiply and go on to the formation of a new growth. According to Ribbert it is the isolation, together with the latent capacity of isolated cells for unlimited proliferation, that gives rise to new growths.

Hansemann's “anaplasia” hypothesis seeks to find an explanation of the formation of new growths in the absence of the histological differentiation of the cell associated with a corresponding increase in its proliferative power and a suspension, or loss, of its functional activity.

The greater the degree of anaplasia the more the tumour cells conform in character and appearance to the embryonic type of cell and the more malignant is the new growth. A simple fibroma is a growth composed of fully formed fibrous tissue (fig. 40, Pl. IV.). The small round celled sarcoma is a malignant growth, and is composed of the primitive type of cell that goes to form fibrous tissue (fig. 41, Pl. IV.).

Then we have Beard's “germ-cell” hypothesis, in which he holds that many of the germ-cells in the growing embryo fail to reach their proper position—the generative areas—and settle down and become quiescent in some somatic tissue of the embryo. They may at some later date become active in some way, and so give rise to a cellular proliferation that may imitate the structure in which they grow, so giving rise to new growths.

Some workers regard certain appearances in dividing cells found in cancer as evidence of a reversion of the somatic cell to the germ-cell type (heterotypical), otherwise found only in the process which results in the formation of an embryo. These appearances are probably due to a pathological mitosis, commonly found in cancer, in which there is an irregular diminution in the number of chromosomes; some are cast out and become degenerated or some pass over to one of the daughter cells, leaving a reduced number in the other, and thus give rise to asymmetrical mitosis.

From the histological examination of tumour cells there is no evidence to show that they resemble the protozoa unicellular organisms in occasionally passing through a sexual process of reproduction, i.e. that nuclear conjugation between cells ever takes place.

In recent years the successful experimental transplantation of new growths, occurring sporadically in white mice and rats, into animals of the same species, has thrown a fresh light on all the features of malignant growths. From these experiments it is shown that cells taken from these growths and introduced into animals of the same species give rise to a cancerous growth, whose cells have acquired unlimited powers of proliferation. They are direct lineal descendants of the cells introduced, and are in no way formed from the tissue cells of the host in which they are placed and grow.

Not only is this true of epithelial cells, but the connective tissue-cells of the supporting structure of cancerous growth, after repeated transplantation, may become so altered that a gradual evolution of apparently normal connective tissue into sarcomatous elements takes place, these giving rise to “mixed tumours.” The sarcomatous development may even completely outgrow the epithelial elements and so form and continue to grow as a pure sarcoma.

The fact that it is possible to propagate these cells of one animal for years in other animals of the same species, without any loss of their vegetative vitality, suggests that this continued growth is kept up by a growth-stimulating substance present in the proper species of animal; this substance, however, has not the power of transforming the normal tissue into a cancerous one.

Henser, Bencke, Adami, Marchand and others have also put forward hypotheses to account for the origin of new growths. These observers maintain that the cells from some cause lose, or may never have had developed, their functional activity, and thus acquire the activity of growth. The descendants of such cells will become more and more undifferentiated, thereby developing an increased vegetative activity.

Oertel finds an explanation of this want of complete cell-differentiation, loss of function, and acquired vegetative activity in the non-homogeneous character of the nuclear chromatin elements of the cell, and maintains that the different properties of the cell are carried and handed down by the different orders of chromatin loops. We have analogies to this in the two nuclei of some of the protozoa, the one being solely for the purpose of propagation, the other being associated with the functional activities of the cell. Oertel thinks that in man we have these two different functions carried on by the one nucleus containing both chromatin orders. If, from whatever cause, any of the chromatin loops belonging to the functional order be lost the descendants of such a cell, being unable to restore these loops, will be minus the functional attributes associated with the lost elements. These, having the full equipment of the vegetative order, will now develop the inherent power of proliferation to a greater or lesser extent.

The foregoing hypotheses have all sought the origin of new growths in some intrinsic cause which has altered the characters of the cell or cells which gave rise to them, but none of them explain the direct exciting cause. The parasitic hypothesis postulates the invasion of a parasite from without, thus making a new growth an infective process. Many cancer-parasites have been described in cancerous growths, including bacteria, yeasts and protozoa, but the innumerable attempts made to demonstrate the causal infective organism have all completely failed.

It is well known that cancer may develop in places where there has been chronic irritation; an example may be found in cancer of the tongue following on prolonged irritation from a jagged tooth. Clay-pipes may also give rise to cancer of lips in males in England, while cancer of the mouth of both sexes is common in India where chewing a mixture of betel leaves, areca-nut, tobacco and slaked lime is the usual practice. In the case of the squamous epithelial cancer of the anterior abdominal wall found so frequently in the natives of Kashmir, the position of the cancer is peculiar to this people, and is due to the chronic irritation following on repeated burns from using the “kangri”—a small earthenware vessel containing a charcoal fire enclosed in basket-work, and suspended round the waist, to assist in maintaining warmth in the extreme cold of the hills of Kashmir.

The irritant may be chemical, as is seen in the skin cancers that develop in workers in paraffin, petroleum, arsenic and aniline. However close the relationship is between chronic irritation and the starting of cancer, we are not in a position to say that irritation, physical or chemical, by itself can give rise to new growths. It may merely act locally in some way, and so render that part susceptible to unknown tissue stimuli which impart to the cells that extraordinary power of proliferation characteristic of new growth.

At the present time we are quite uncertain what is the ultimate cause of new growths; in all probability there may be one or more etiological factors at play disturbing that perfect condition of equilibrium of normal tissues. A defect in co-ordination allows the stimulated active vegetative cellular elements, or the more fully differentiated tissue, to over-develop and so form tumours, simple or malignant.

Other Tissue Products

Mucoid.—In many pathological conditions we have degenerative products of various kinds formed in the tissues. These substances may be formed in the cells and given out as a secretion, or they may be formed by an inter cellular transformation. In the mucinoid conditions, usually termed “mucoid” and “colloid” degenerations, we have closely allied substances which, like the normal mucins of the body, belong to the glucoproteids, and have in common similar physical characters. There is neither any absolute difference nor a constancy in their chemical reactions, and there can be brought about a transition of the “colloid” material into the “mucoid,” or conversely. By mucoid is understood a soft gelatinous substance containing mucin, or pseudomucin, which is normally secreted by the epithelial cells of both the mucous membranes and glands. In certain pathological conditions an excessive formation and discharge of such material is usually associated with catarrhal changes in the epithelium. The desquamated cells containing this jelly-like substance become disorganized and blend with the secretion. Should this take place into a closed gland space it will give rise to cysts, which may attain a great size, as is seen in the ovarian adenomata. In some of the adenoid cancers of the alimentary tract this mucoid material is formed by the epithelial cells from which it flows out and infiltrates the surrounding tissues; both the cells and tissues appear to be transformed into this gelatinous substance, forming the so-called “colloid cancer” (fig. 42, Pl. IV.).

The connective tissue is supplied normally with a certain amount of these mucinoid substances, no doubt acting as a lubricant. In many pathological conditions this tissue is commonly found to undergo mucoid or myxomatous degeneration, which is regarded as a reversion to a closely similar type—that of foetal connective tissue (fig. 43, Pl. IV). These changes are found in senile wasting, in metaplasia of cartilage, in many tumours, especially mixed growths of the parotid gland and testicle, and in various inflammatory granulation ulcers. In the wasting of the thyroid gland in myxoedema, or when the gland is completely removed by operation, myxomatous areas are found in the subcutaneous tissue of the skin, nerve-sheaths, &c.

Colloid.—This term is usually applied to a semi-solid substance of homogeneous and gelatinous consistence, which results partly from excretion and partly from degeneration of cellular structures, more particularly of the epithelial type. These cells become swollen by this translucent substance and are thrown off into the space where they become fused together, forming colloid masses. This substance differs from the mucins by being precipitated by tannic acid but not by acetic acid, and being endowed with a higher proportion of sulphur.

In the normal thyroid there is formed and stored up in the spaces this colloid material. The enlarged cystic goitres show, in the distended vesicles, an abnormal formation and retention of this substance (fig. 44, Pl. V.). Its character is readily changed by the abnormal activities which take place in these glands during some of the acute fevers; the semi-solid consistence may become mucoid or even fluid.

Serous degeneration is met with in epithelial cells in inflammatory conditions and following on burns. The vitality of these cells being altered there is imbibition and accumulation of watery fluid in their cytoplasm, causing swelling and vacuolation of the cells. The bursting of several of these altered cells is the method by which the skin vesicles are formed in certain conditions.

Glycogen is formed by the action of a ferment on the carbohydrates—the starches being converted into sugars. The sugars are taken up from the circulation and stored in a less soluble form—known as “animal starch”—in the liver and muscle cells; they play an important part in the normal metabolism of the body. The significance of glycogen in large amounts, or of its absence from the tissues in pathological conditions, is not clearly understood. It is said to be increased in saccharine diabetes and to be greatly diminished in starvation and wasting diseases.

Fat.—Fatty accumulations in the tissues of the body are found in health and in pathological conditions; these are usually recognized and described as fatty infiltrations and fatty degenerations, but there are intermediate conditions which make it difficult to separate sharply these processes.

The fatty accumulations known as infiltrations (figs. 45 and 46, Pl. V.) are undoubtedly the result of excessive ingestion of food material containing more neutral fats than the normal tissues can oxidize, or these, as a result of defective removal owing to enfeebled oxidative capacities on the part of the tissues, become stored up in the tissues.

In acute and chronic alcoholism, in phthisis, and in other diseases this fatty condition may be very extreme, and is commonly found in association with other tissue changes, so that probably we should look on these changes as a degeneration.

Adiposity or obesity occurs when we have an excessive amount of fat stored in the normal connective-tissue areas of adipose tissue. It may be caused by various conditions, e.g. over nutrition with lack of muscular energy, beer-drinking, castration, lactation, disturbed metabolism, some forms of insanity, and may follow on some fevers.

Fatty degeneration is a retrogressive change associated with the deposit of fatty granules or globules in the cytoplasm, and is caused by disorganized cellular activity (figs. 26 and 27, Pl. II.) . It is frequently found associated with, or as a sequel to, cloudy swelling in intense or prolonged toxic conditions. Over and above the bacterial intoxication's we have a very extreme degree of fatty degeneration, widely distributed throughout the tissues, which is produced by certain organic and inorganic poisons; it is seen especially in phosphorus and chloroform poisoning. The changes are also common in pernicious anaemia, advanced chlorosis, cachexias, and in the later stages of starvation. In diabetes mellitus, in which there is marked derangement in metabolism, extreme fatty changes are occasionally found in the organs, and the blood may be loaded with fat globules. This lipoemic condition may cause embolism, the plugging especially occurring in the lung capillaries.

Fatty degeneration is common to all dead or decaying tissues in the body, and may be followed by calcification.

Autolysis is a disintegration of dead tissues brought about by the action of their own ferments, while degeneration takes place in the still living cell. The study of autolytic phenomena which closely simulates the changes seen in the degenerating cell has thrown much light on these degenerative processes.

These conditions may be purely physiological, e.g. in the mammary gland during lactation or in sebaceous glands, caused by increased functional activity. It may follow a diminished functional activity, as in the atrophying thymus gland and in the muscle cells of the uterus after parturition.

Any of the abnormal conditions that bring about general or local defective nutrition is an important factor in producing fatty degeneration.

The part played by fats and closely allied compounds in normal and abnormal metabolism need not here be discussed, as the subject is too complex and the views on it are conflicting. It will be sufficient to state briefly what appears to be the result of recent investigation.

The neutral fats are composed of fatty acids and glycerin. In the physiological process of intestinal digestion, the precursors of such fats are split up into these two radicles. The free fatty acid radicle then unites with an alkali, and becomes transformed into a soluble soap which is then readily absorbed in this fluid condition by the epithelial cells of the mucous membrane. There it is acted on by ferments (lipases) and converted into neutral fat, which may remain in the cell as such. By the reverse action on the part of the same ferments in the cell, these neutral fats may be redissolved and pass into the lacteals.

Many cells throughout the body contain this ferment. The soluble soaps which are probably conveyed by the blood will be quickly taken up by such cells, synthetized into neutral fats, and stored in a non-diffusible form till required. The fat in this condition is readily recognized by the usual microchemical and staining reactions. As fat is a food element essential to the carrying out of the vital energies of the cell, a certain amount of fatty matter must be present, in a form, however, unrecognizable by our present microchemical and staining methods.

Some investigators hold that the soaps may become combined with albumin, and that on becoming incorporated with the cytoplasm they can no longer be distinguished as fat. If from some cause the cell be damaged in such a way as to produce disintegration of the cytoplasm, there will be a breaking down of that combination, so that the fat will be set free from the complex protein molecule in which it was combined as a soap-albumin, and will become demonstrable by the usual methods as small droplets of oil. This splitting up of the fats previously combined with albumin in the cell by the action of natural ferments—lipases—and the setting free of the fats under the influence of toxins represent the normal and the pathological process in the production of so-called fatty degeneration.

Calcification.—Calcification and calcareous deposits are extremely common in many pathological conditions.

There are few of the connective tissues of the body which may not become affected with deposits of calcareous salts (fig. 47, Pl. v.). This condition is not so frequently seen in the more highly differentiated cells, but may follow necrosis of secreting cells, as is found in the kidney, in corrosive sublimate poisoning and in chronic nephritis. These conditions are quite distinct from the normal process of ossification as is seen in bone.

Many theories have been advanced to explain these processes, and recently the subject has received considerable attention. The old idea of the circulating blood being supersaturated with lime salts which in some way had first become liberated from atrophying bones, and then deposited, to form calcified areas in different tissues will have to be given up, as there is no evidence that this “metastatic” calcification ever takes place. In all probability no excess of soluble lime salts in the blood or lymph can ever be deposited in healthy living tissues.

At the present day both experimental and histological investigations seem to indicate that in the process of calcification there is a combination of the organic substances present in degenerated tissues, or in tissues of low vitality, with the lime salts of the body. From whatever cause the tissues become disorganized and undergo fatty degeneration, the fatty acids may become liberated and combine with the alkalies to form potash and soda soaps.

The potash and soda is then gradually replaced by calcium to form an insoluble calcium soap. The interaction between the soaps, the phosphates and the carbonates which are brought by the blood and lymph to the part results in the weaker fatty acids being replaced by phosphoric and carbonic acid, and thus in the formation of highly insoluble calcium phosphate and carbonate deposits in the disorganized tissues.

Pathological Pigmentations.—These pigmentary changes found in abnormal conditions are usually classified under (1) Albuminoid, (2) Haematogenous, (3) Extraneous.

1. The normal animal pigments and closely allied pigments are usually found in the skin, hair, eye, supra-renal glands, and in certain nerve cells. These represent the albuminoid series, and are probably elaborated by the cells from albuminous substances through the influence of specific ferments. This pigment is usually intracellular, but may be found lying free in the intercellular substance, and is generally in the form of fine granules of a yellowish-brown or brown-black colour. In the condition known as albinism there is a congenital deficiency or entire absence of pigment. Trophic and nervous conditions sometimes cause localized deficiency of pigment which produces white areas in the skin.

Excessive pigmentation of tissue cells (fig. 48, Pl. V.) is seen in old age, and usually in an accompaniment of certain atrophic processes and functional disorders. Certain degenerative changes in the supra-renal glands may lead to Addison's disease, which is characterized by an excessive pigmentary condition of the skin and mucous membranes. This melanin pigment is found in certain tumour growths, pigmented moles of the skin, and especially in melanatic sarcomata (fig. 49, Pl. V.) and cancer. The action of the sun's rays stimulates the cells of the skin to increase the pigment as a protection to the underlying tissues, e.g. summer bronzing, “freckles,” and the skin of the negro.

The coloured fats, or lipochromes, are found normally in some of the cells of the internal organs, and under certain pathological conditions. This pigment is of a light yellow colour, and contains a fatty substance that reacts to the fat-staining reagents. Little is known regarding this class of pigment.

2. Haematogenous pigments are derived from the haemoglobin of the red blood corpuscles. These corpuscles may break down in the blood vessels, and their colouring material (haemoglobin) is set free in the serum. But their disintegration is more commonly brought about by “phagocytosis” on the part of the phagocytic cells in the different organs concerned with the function of haemolysis, i.e. the fiver, spleen, haemolymph glands and other tissues.

The haemoglobin may be transformed into haematoidin, a pigment that does not contain iron, or into a pigment which does contain iron, haemosiderin.

The haematoidin pigment may vary in colour from yellowish or orange-red to a ruby-red, and forms granular masses, rhombic prisms or acicular crystals. It can be formed independently of cell activity, nor does it require oxygen. These crystals are extremely resistant to absorption, are found in old blood clots, and have been known to persist in old cerebral hemorrhages after many years. Haematoidin in normal metabolism is largely excreted by the liver in the form of bilirubin.

Haemosiderin, an iron-containing pigment (probably an hydrated ferrous oxide), is found in more or less loose combination with protein substances in an amorphous form as brownish or black granules. Cellular activity and oxygen appear to be essential for its development; it is found usually in the cells of certain organs, or it may be deposited in the inter cellular tissues. Haemosiderin in the normal process of haemolysis is stored up in the cells of certain organs until required by the organism for the formation of fresh haemoglobin. In diseases where haemolysis is extreme, particularly in pernicious anaemia, there are relatively large quantities occasionally as much as ten times the normal amount of haemosiderin deposited in the liver.

In hepatogenous pigmentation (icterus or jaundice) we have the iron-free pigment modified and transformed by the action of

the liver cells into bile pigment (bilirubin). If the discharge of this

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pigment from the liver by the normal channels be prevented, as by obstruction of the main bile ducts, the bile will accumulate until it regurgitates or is absorbed into the lymph and blood vessels, and is carried in a soluble state throughout the tissues, thus producing a general staining—an essential characteristic of jaundice.

3. In extraneous pigmentation we have coloured substances either in a solid or fluid state, gaining entrance into the organism and accumulating in certain tissues. The channels of entrance are usually by the respiratory or the alimentary tract, also by the skin. Pneumonokoniosis is due to the inhalation of minute particles of various substances—such as coal, stone, iron, steel, &c. These foreign particles settle on the lining membranes, and, by the activity of certain cells (fig. 50, Pl. V. and fig. 30, Pl. III.), are carried into the tissues, where they set up chronic irritation of a more or less serious nature according to the nature of the inhaled particles.

Certain metallic poisons give rise to pigmentation of the tissues, e.g. in the blue line on the gums around the roots of the teeth due to the formation of lead sulphide, or in chronic lead poisoning, where absorption may have taken place through the digestive tract, or, in the case of workers in lead and lead paints, through the skin. Prolonged ingestion of arsenic may cause pigmentary changes in the skin. If silver nitrate salts be administered for a long period as a medication, the skin that is exposed to light becomes of a bluish-grey colour, which is extremely persistent. These soluble salts combine with the albumins in the body, and are deposited as minute granules of silver albumin are in the connective tissue of the skin papillae, serous membranes, the intima of arteries and the kidney. This condition is known as argyria.

Various coloured pigments may be deposited in the tissues through damaged skin surface—note, for example, the well-known practice of “tattooing.” Many workers following certain occupations show pigmented scars due to the penetration of carbon and other pigments from superficial wounds caused by gunpowder, explosions, &c.

Hyaline.—This term has been applied to several of the transparent homogeneous appearances found in pathological conditions. It is now commonly used to indicate the transparent homogeneous structureless swellings which are found affecting the smaller arteries and the capillaries. The delicate connective-tissue fibrillae of the inner coat of the arterioles are usually first and most affected. The fibrils of the outer coat also show the change to a less extent, while the degeneration very rarely spreads to the middle coat. This swelling of the walls may partly or completely occlude the lumen of the vessels.

Hyaline degeneration is found in certain acute infective conditions; the toxins specially act on these connective-tissue cell elements. It also seems to be brought about by chronic toxaemias, e.g. in subacute and chronic Bright's disease, lead poisoning and other obscure conditions. The hyaline material, unlike the amyloid, does not give the metachromatic staining reactions with methylene-violet or iodine. The chemical constitution is not certain. The substance is very resistant to the action of chemical reagents, to digestion, and possibly belongs to the glyco-proteids.

Amyloid.—The wax-like or amyloid substance has a certain resemblance to the colloid, mucoid and hyaline. It has a firm gelatinous consistence and wax-like lustre, and, microscopically, is found to be homogeneous and structureless, with a translucency like that of ground-glass. Watery solution of iodine imparts to it a deep mahogany-brown colour; iodine and sulphuric acid occasionally, but not always, an azure-blue, methyl violet, a brilliant rose-pink and methyl-green gives a reaction very much like that of methyl-violet, but not so vivid. The reaction with iodine is seen best by direct light; the reactions with the other substances are visible only by transmitted light. The name “amyloid” was applied to it by Virchow on account of the blue reaction which it gives occasionally with iodine and sulphuric acid, resembling that given with vegetable cellulose. It is now known to have nothing in common with vegetable cellulose, but is regarded as one of the many albuminoid substances existing in the body under pathological conditions. Virchow's conjecture as to the starchy nature of the substance was disproved by Friedrich and Kekule, who confirmed Professor Miller's previous finding as to its albuminous or protein nature. Oddi in 1894 isolated from the amyloid liver a substance which Schmiedeberg had previously obtained from cartilage and named “chondroitinic-sulphuric acid” (Chondroitinschwefelsäure). It also occurs in bones and elastic tissue, but is not present in the normal human liver. Oddi does not regard it as the essential constituent of amyloid, chiefly because the colour reactions are forthcoming in the residuum after the substance has been removed, while the substance itself does not give these reactions. Quite likely the amyloid may be a combination of the substance with a proteid. The soda combination of the acid as obtained from the nasal cartilage of pigs had the composition C₁₈H₂₅Na₂NSO₁₇.

Krawkow in 1897 clearly demonstrated it to be a proteid in firm combination with chrondroitin-sulphuric acid. As probably the protein constituent varies in the different organs, one infers that this will account for the varying results got from the analysis of the substance obtained from different organs in such cases.

This amyloid substance is slowly and imperfectly digested by pepsin—digestion being more complete with trypsin and by autolytic enzymes.

There is no evidence that this material is brought by the circulating blood and infiltrates the tissues. It is believed rather that the condition is due to deleterious toxic substances which act for prolonged periods on the tissue elements and so alter their histon proteins that they combine in situ with other protein substances which are brought by the blood or lymph.

Amyloid develops in various organs and tissues and is commonly associated with chronic phthisis, tubercular disease of bone and joints, and syphilis (congenital and acquired). It is known to occur in rheumatism, and has been described in connexion with a few other diseases. A number of interesting experiments, designed to test the relationship between the condition of suppuration and the production of amyloid, have been made of late years. The animal most suitable for experimenting upon is the fowl, but other animals have been found to react. Thus Krawkow and Nowak, employing the frequent subcutaneous injection of the usual organisms of suppuration, have induced in the fowl the deposition within the tissues of a homogeneous substance giving the colour reactions of true amyloid. When hardened in spirit, however, the greater part of this experimental amyloid in the fowl vanishes, and the reactions are not forthcoming. They were unable to verify any direct connexion between its production and the organism of tubercle. These observations have been verified in the rabbit, mouse, fowl, guinea-pig and cat by Davidsohn, occasionally in the dog by Lubarsch; and confirmatory observations have also been made by Czerny and Maximoff. Lubarsch succeeded in inducing it merely by the subcutaneous injection of turpentine, which produces its result, it is said, by exciting an abscess. Nowak, however, found later that he could generate it where the turpentine failed to induce suppuration; he believes that it may arise quite apart from the influence of the organisms of suppuration, that it is not a biological product of the micro-organisms of disease, and also that it has nothing to do with emaciation. It is a retrogressive process producing characteristic changes in the fine connective tissue fibrils. The change appears to begin in the fibrils which lie between the circular muscle fibres of the middle coat of the smaller arterioles and extends both backwards and forwards along the vessels. It spreads forwards, affecting the supporting fibres outside the epithelium of the capillaries, and then passes to the connective-tissue fibrils of the veins. The secreting cells never show this change, although they may become atrophied or destroyed by the pressure and the disturbance of nutrition brought about by the swollen condition of the capillary walls. The circulation is little interfered with, although the walls of the vessels are much thickened by the amyloid material (fig. 51, Pl. V.).

Amyloid Bodies.—These are peculiar bodies which are found in the prostate, in the central nervous system, in the lung, and in other localities, and which get their name from being very like starch-corpuscles, and from giving certain colour reactions closely resembling those of vegetable cellulose or even starch itself. They are minute structures having a round or oval shape, concentrically striated, and frequently showing a small nucleus-like body or cavity in their centre. Iodine gives usually a dark brown reaction, sometimes a deep blue; iodine and sulphuric acid almost always call forth an intense deep blue reaction; and methyl-violet usually a brilliant pink, quite resembling that of true amyloid. They are probably a degeneration-product of cells.

Spurious Amyloid.—If a healthy spinal cord be hung up in spirit for a matter of six months or more, a glassy substance develops within it quite like true amyloid. It further resembles true amyloid in giving all its colour reactions. The reaction with methyl-violet, however, differs from that with true amyloid in being evanescent.

Response of Tissues to Stimulation

A stimulus may be defined as every change of the external agencies acting upon an organism; and if a stimulus come in contact with a body possessing the property of irritability, i.e. the capability of reacting to stimuli, the result is stimulation (Verworn). Stimuli comprise chemical, mechanical, thermal, photic and electrical changes in the environment of the organism. A stimulus may act on all sides and induce a general effect without direction of movement, but in the production of movement in a definite direction the stimulus must be applied unilaterally. Stimuli applied generally, not unilaterally, in most cases induce increased divisibility of the cells of the part.

Thus the poison of various insects induces in plants the cellular new formation known as a gall-nut; a foreign body implanted in a limb may become encysted in a capsule of fibrous tissue; septic matter introduced into the abdomen will cause proliferation of the lining endo(epi)thelium; and placing an animal (salamander, Galeotti) in an ambient medium at a higher temperature than that to which it is accustomed naturally, increases the rapidity of cell-division of its epithelium with augmentation of the number of karyokinetic figures. Hair and some other like structures grow luxuriantly on a part to which there is an excessive flux of blood. Bone (e.g. drill-bones) may develop in a soft tissue with no natural bone-forming tendencies, as a result of interrupted pressure, or a fatty tumour may arise in the midst of the natural subcutaneous fat in the same circumstances.

Among stimuli acting unilaterally, perhaps none has proved more interesting, in late times, than what is known as Chemiotaxis. By it is meant the property an organism endowed with the power of movement has to move towards or away from a chemical stimulus applied unilaterally, or, at any rate, where it is applied in a more concentrated state on the one side than on the others, and more particularly where the concentration increases gradually in one direction away from the living organism acted upon. Observed originally by Engelmann in bacteria, by Stahl in myxomycetes, and by Pfeffer in ferns, mosses, &c., it has now become recognized as a widespread phenomenon. The influence of the chemical substance is either that of attraction or repulsion, the one being known as positive, the other as negative chemiotaxis.

The female organs of certain cryptograms, for instance, exert a positive chemiotactic action upon the spermatozoids, and probably, as Pfeffer suggests, the chemical agent which exerts the influence is malic acid. No other substance, at least, with which he experimented had a like effect, and it is possible that in the archegonium which contains the ovum malic acid is present. Massart and Border, Leber, Metchnikoff and others have studied the phenomenon in leukocytes, with the result that while there is evidence of their being positively chemiotactic to the toxins of many pathogenic microbes, it is also apparent that they are negatively influenced by such substances as lactic acid.

From a pathological point of view the subject of chemiotaxis must be considered along with that of phagocytosis. Certain free mobile cells within the body, such as blood-leukocytes, as well as others which are fixed, as for instance the endothelium of the hepatic capillaries, have the property of seizing upon some kinds of particulate matter brought within their reach. Within a quarter of an hour after a quantity of cinnabar has been injected into the blood of the frog nearly every particle will be found engulfed by the protoplasm of the leukocytes of the circulating blood. Some bacteria, such as those of anthrax, are seized upon in the same manner, indeed; very much as small algae and other particles are incorporated and devoured by amoeba. Melanine particles formed in the spleen in malaria, which pass along with the blood through the liver, are appropriated by the endothelial cells of the hepatic capillaries, and are found embedded within their substance. If the particle enveloped by the protoplasm be of an organic nature, such as a bacterium, it undergoes digestion, and ultimately becomes destroyed, and accordingly the term “phagocyte” is now in common use to indicate cells having the above properties. This phagocytal action of certain cells of the body is held by Metchnikoff and his followers to have an important bearing on the pathology of immunity. Phagocytes act as scavengers in ridding the body of noxious particles, and more especially of harmful bacteria.

A further application of the facts of chemiotaxis and phagocytosis has been made by Metchnikoff to the case of Inflammation. It is well known that many attempts to define the process of inflammation have been made from time to time, all of them more or less unsatisfactory. Among the latest is that of Metchnikoff: “Inflammation generally,” he says, “must be regarded as a phagocytic reaction on the part of the organism against irritants. This reaction is carried out by the mobile phagocytes sometimes alone, sometimes with the aid of the vascular phagocytes, or of the nervous system.” Given a noxious agent in a tissue, such, let us say, as a localized deposit of certain bacteria, the phagocytes swarm towards the locality where the bacteria have taken up their residence. They surround individual bacteria, absorb them into their substance, and ultimately destroy them by digestion. The phagocytes are attracted from the blood vessels and elsewhere towards the noxious focus by the chemiotaxis exerted upon them by the toxins secreted by the bacteria contained within it. The chemiotaxis in this instance is positive, but the toxins from certain other bacteria may act negatively; and such bacteria are fraught with particular danger from the fact that they can spread through the body unopposed by the phagocytes, which may be looked upon as their natural enemies.

Natural Protection against Parasitism

The living organism is a rich storehouse of the very materials from which parasites, both animal and vegetable, can best derive their nourishment. Some means is necessary, therefore, to protect the one from the encroachments of the other. A plant or animal in perfect health is more resistant to parasitical invasion than one which is ill-nourished and weakly. Of a number of plants growing side by side, those which become infected with moulds are the most weakly, and an animal in low health is more subject to contagious disease than one which is robust. Each organism possesses within itself the means of protection against its parasitical enemies, and these properties are more in evidence when the organism is in perfect health than when it is debilitated.

One chief means employed by nature in accomplishing this object is the investment of those parts of the organism liable to be attacked with an armour-like covering of epidermis, periderm, bark, &c. The grape is proof against the inroads of the yeast plant so long as the husk is intact, but on the husk being injured the yeast-plant finds its way into the interior and sets up vinous fermentation of its sugar. The root of the French vine is attacked by the Phylloxera, but that of the American vine, whose epidermis is thicker, is protected from it. The larch remains free from parasitism so long as its covering is intact, but as soon as this is punctured by insects, or its continuity interfered with by cracks or fissures, the Peziza penetrates, and before long brings about the destruction of the branch. So long as the epidermis of animals remains sound, disease germs may come in contact with it almost with impunity, but immediately on its being fissured, or a larger wound made through it, the underlying parts, the blood and soft tissues, are attacked by them. A very remarkable instance of an acquired means of protecting a wound against parasitical invasion is to be found in granulations. Should these remain unbroken they constitute a natural barrier to the penetration of most pathogenic and other forms of germ-life into the parts beneath. Bacteria of various kinds which alight upon their surfaces begin to fructify in abundance, but are rapidly destroyed as they burrow deeply. This is accomplished by a twofold agency, for while numbers of them are seized upon by the granulation phagocytes, others are broken up and dissolved by the liquid filling the granulation interspaces (Afanassieff). This latter, or histolytic, property is not confined to the liquid of granulations; normal blood-serum possesses it to a certain extent, and under bacterial influence it may become very much exalted. Jürgelünas makes out that when an animal is rendered immune to a particular micro-organism this histolytic property becomes exalted.

Dropsy

During conditions of health a certain quantity of lymphy liquid is constantly being effused into the tissues and serous cavities of the body, but in the case of the tissues it never accumulates to excess, and in that of the serous cavities it is never more than sufficient to keep them moist. When any excessive accumulation takes place the condition is known as “hydrops” or “dropsy.” A “transudate” is a liquid having a composition resembling that of blood-serum, while the term “exudate” is applied to an effused liquid whose composition approaches that of the blood-plasma in the relationship of its solid and liquid parts, besides in most cases containing numbers of colourless blood-corpuscles. Exudates are poured out under inflammatory conditions, while none of the truly dropsical effusions are of inflammatory origin; and hence the class of exudates, as above defined, may be rejected from the category of liquids we are at present considering. Where the dropsical condition is more or less general the term “anasarca” is applied to it; if the tissues are infiltrated locally the term “oedema” is employed; and various names are applied, with a local significance, to dropsies of individual parts or cavities, such as “hydrothorax,” “hydro-peritoneum” or “ascites,” “hydrocephalus,” and so on. In “anasarca” the tissues which suffer most are those which are peculiarly lax, such as the lower eyelids, the scrotum, and the backs of the hands and feet. It is invariably the result of some cause acting generally, such as renal disease, valvular defect of the heart, or an impoverished state of the blood; while a mere oedema is usually dependent upon some local obstruction to the return of blood or lymph, or of both, the presence of parasites within the tissue, such as the filaria sanguinis hominis or trichina spiralis, or the poisonous bites of insects. Dropsy of the serous cavities is very commonly merely part of a general anasarca, although occasionally it may be, as in the case of ascites, the sequel to an obstruction in the venous return. Dropsical liquids are usually pale yellow or greenish, limpid, with a saltish taste and alkaline reaction, and a specific gravity ranging from 1005 to 1024. They all contain albumen and throw down a precipitate with heat and nitric acid. None of them, in man, coagulates spontaneously, although they contain fibrinogen. The addition of some of the liquid squeezed out from a blood-clot, of the squeezed blood-clot itself, or of a little blocd-serum, is sufficient to throw down a fibrinous coagulum (Buchanan), evidently by these substances supplying the fibrin-ferment. The proteid constituents are very much like those of blood-serum, although they never come up to them in amount (Runeberg). The quantity of proteid matter in a purely dropsical effusion never amounts to that of an inflammatory exudation (Lassar). Certain peculiar substances, probably degenerative products, some of them reducing copper, are occasionally met with. The liquid of ascites sometimes contains chyle in abundance (hydrops lacteus), the escape having taken place from a ruptured receptaculum chyli.

In a given case of anasarca due to a cause acting generally, it will be found that the liquid of the pleural cavity always contains the highest percentage of proteid, that of the peritoneal cavity comes next, that of the cerebral ventricles follows this, and the liquid of the subcutaneous areolar tissue contains the lowest. The reason of this is apparently that the negative pressure of the pleural, and partly of the peritoneal, cavity tends to aspirate a liquid relatively thicker, so to speak, than that effused where no such extraneous mechanism is at work (James).

The subject of the conditions under which dropsical liquids are poured out opens up a very wide question, and one about which there is the greatest diversity of opinion. It turns in part, but in part only, upon the laws regulating the effusion of lymph, and physiologists are by no means at one in their conclusions on this subject. Thus Ludwig was of opinion that the lymph-flow is dependent upon two factors, first, difference in pressure of the blood in the capillaries and the liquid in the plasma spaces outside; and, secondly, chemical interchanges setting up osmotic currents through the vessel-walls. His results, so far, have been confirmed by Starling, who finds that the amount of lymph-flow from the thoracic duct is dependent upon difference in pressure. It varies with the increase of the intracapillary or decrease of the extracapillary pressure, and is also in part regulated by the greater or lesser permeability of the vessel-walls. Heidenhain, on the other hand, rejected entirely the filtration view of lymph-formation, believing that the passage of lymph across the capillary wall is a true secretion brought about by the secretory function of the endothelial plates. Starling does not accept this view, and cannot regard as an article of faith Heidenhain's dictum that normally filtration plays no part in the formation of lymph. Lazarus-Barlow, again, looks upon the pouring out of lymph as evidence of the demands of the tissue-elements for nutrition. An impulse is communicated to the blood vessels in accordance with this demand, and a greater or smaller outflow is the result. He traces various local dropsies to the starvation from which the tissues are suffering, the liquid accumulating in excess in accordance with the demand for more nourishment. It may be asked, however, whether a dropsical tissue is being held in a high state of nutrition, and whether, on the contrary, the presence of lymph in excess in its interstices does not tend to impair its vitality rather than to lend it support. According to Rogowicz and Heidenhain, certain substances increase the quantity of lymph given off from a part by acting upon the cells of the capillary wall; they hold, in fact, that these substances are true lymphagogues. Heidenhain recognizes two classes, first, such substances as peptone, leech extract and crayfish extract; and, secondly, crystalloids such as sugar, salt, &c. Starling sees no reason to believe that members of either class act otherwise than by increasing the pressure in the capillaries or by injuring the endothelial wall. The members of the first class influence the endothelial plates of the capillaries injuriously, inducing thereby increased permeability; those of the second class (sugar, &c.), on injection into the blood, attract water from the tissues and cause a condition of hydraemic plethora with increased capillary pressure. The increased flow of lymph is due to the increased pressure in the abdominal capillaries.

It is now coming to be recognized that increase of blood pressure alone is not sufficient to account for all dropsical effusions. Much more important is the effect of the alteration in the amount of crystalloids in the tissues and blood and therefore of the alteration in the osmotic pressure between these. Loeb found experimentally that increase of metabolic products in muscle greatly raised its osmotic pressure, and so it would absorb water from a relatively concentrated sodium chloride solution. Welch produced oedema of the lungs experimentally by increasing the pressure in the pulmonary vessels by ligature of the aorta and its branches, but this raised the blood pressure only about one-tenth of an atmosphere, while in some of Loeb's experiments the osmotic pressure, due to retained metabolic products, was equal to over thirty atmospheres. Thus differences in osmotic pressure may be much more powerful in producing oedema than mere differences in blood pressure.

Now differences in the amount of crystalloids cause alteration in osmotic pressure while the proteid content affects it but little; and of the crystalloids the chlorides appear to be those most liable to variation.

Widal, Lemierre and other French observers have noted a diminution in the excretion of chlorides in nephritis associated with oedema; Widal and Javal found that a chloride-free diet caused diminution in the oedema and a chloride containing diet an increase of oedema. Oliver and Audibert published some cases of cirrhosis of the liver with ascites in which they got results comparable to those of Widal. Some other observers, however, have not got such good results with a chloride-free diet, and Märishler, Scheel, Limbecx, Dreser and others, dispute Widal's hypothesis of a retention of chlorides as being the cause of oedema, in the case of renal dropsy at all events; they assert that the chlorides are held back in order to keep the osmotic pressure of the fluid, which they assume to have been effused, equal to that of the blood and tissues. Certainly not all cases of renal dropsy show diminution in the excretion of chlorides. Bainbridge suggests that a retention of metabolic products may cause the oedema in renal disease, Bradford having previously shown that loss of a certain amount of renal tissue caused retention of metabolic products in the tissues. As sodium chloride is one of the most permeable of crystalloids it seems strange that damage to the renal tissue should impede its excretion. Cushny has shown experimentally that slowing of the blood-flow through renal tissue causes less sodium chloride to appear in the urine while the excretion of urea and sulphates remains unaffected; apparently the chloride, being more permeable, is reabsorbed and so only appears to be excreted in less quantity.

In the dropsy of cardiac disease, owing to the deficient oxidation from stagnation of blood, metabolic products must accumulate in the tissues; also lymph return must be impeded by the increased pressure in the veins and so dropsy results (Wells).

The local oedema seen in some nervous affections might be explained on the hypothesis of increased metabolic activity in these areas due to some local nervous stimulation.

Thus, while increased pressure in the blood or lymph vessels may be one factor, and increased permeability of the capillary endothelium another, increased osmotic pressure in the tissues and lymph is probably the most important in the production of dropsy. This increased osmotic pressure is again due to accumulation of crystalloids in the tissues, either products of metabolism due to deficient oxidation from alteration in the blood or other cause, or, it may be, as in some cases of nephritis, owing to a retention or re absorption of chlorides in the tissues.

Practical Applications

Medicine and surgery have never been slow to appropriate and apply the biological facts of pathology, and at no period have they followed more closely in its wake than during the last quarter of the 19th century. When, for instance, the cause of septic infection had been revealed, the prophylaxis of the disease became a possibility. Seldom has it happened, since the discovery of the law of gravity, that so profound an impression has been made upon the scientific world at large as by the revelation of the part played by germ-life in nature; seldom has any discovery been fraught with such momentous issues in so many spheres of science and industry.

The names of Pasteur and Lister will descend to posterity as those of two of the greatest figures in the annals of medical science, and indeed of science in general, during the 19th century. The whole system of treatment of tubercular disease has been altered by the discovery of the tubercle microphyte. Previously consumptive individuals were carefully excluded from contact with fresh air, and were advised to live in rooms almost hermetically sealed and kept at a high temperature. The treatment of the disease has now gone off in the opposite direction. Sanatoria have started up all over Europe and elsewhere for its treatment on the open-air principle. Individuals suffering from pulmonary phthisis are encouraged to live night and day in the open, and with the best results. The rapid diagnosis of diphtheria, by recognizing its bacillus, has enabled the practitioner of medicine to commence the treatment early, and it has also enabled the medical officer of health to step in and insist on the isolation of affected persons before the disease has had time to spread. The discovery of the parasite of malaria by Laveran, and of the method by which it gains entrance to the human body, through the bite of a particular variety of mosquito, by Manson and Ross, promises much in the way of eradication of the disease in the future. One of the most remarkable practical outcomes of germ-pathology, however, has been the production of the immunized sera now employed so extensively in the treatment of diphtheria and other contagious diseases. By the continuous injections under the skin, in increasing doses, of the toxins of certain pathogenic micro-organisms, such as that of diphtheria, an animal—usually the horse—may be rendered completely refractory to the disease. Its serum in course of time is found to contain something (antitoxin) which has the power of neutralizing the toxin secreted by the organism when parasitical upon the body. This immunity can be transferred to a fresh host (e.g. man) by injecting such serum subcutaneously. The modern system of hygiene is in great part founded upon recent pathology. The recognition of the dangers accompanying the drinking of polluted water or milk, or of those attached to the breathing of a germ-polluted atmosphere, has been the natural sequence of an improved knowledge of pathology in its bacteriological relationships. Skin-grafting and regeneration of bone are among not the least remarkable applications of pathological principles to the combat with disease in recent times; and in this connexion may also be mentioned the daring acts of surgery for the relief of tumours of the brain, rendered practicable by improved methods of localization, as well as operations upon the serous cavities for diseased conditions within them or in their vicinity.

For the special pathological details of various diseases, see the separate articles on Parasitic Diseases; Neuro-Pathology; Digestive Organs; Respiratory System; Blood: Circulation; Metabolic Diseases; Fever; Bladder; Kidneys; Skin Diseases; Eye Diseases; Heart Disease; Ear, &c.; and the articles on different diseases and ailments under the headings of their common names.

Authorities.—Adami, “Inflammation,” Allbutt's System of Med. (London, 1896), vol. i.; Afanassieff, “Granulation Tissue and Infection,” Centralbl. f. allg. Path. u. path. Anat. (1896), vii. 456; Arnold, “Finer Structure of the Cell,” Arch. f. path. Anat. (1879), lxxvii. 181; Beyerinck, Beobachtungen üb. d. ersten Entwicklungsphasen einiger Cynipidengallen (Amsterdam, 1882); Bordet, “Phagocytosis,” Ann. de l'inst. Pasteur (1895), x. 104; Buchner, “Chemiotaxis of Leucocytes,” Berl. klin. Wochenschr. (1890), xxvii. 1084; Cancer: synopsis of recent literature. See The Practitioner (1899), vol. ix.; Chatin, “Direct Cellular Division,” Compt. rend. acad. d. sc. (1898), cxxvi. 1163; Coats, Manual of Pathology (London, 1895); Cohnheim, Vorlesungen üb. allg. Path. Berlin (1877-1880); Cornil, “Organization of Clot within Vessels,” J. de l'anat. et physiol. (1897), xxxiii. 201; Davidsohn, “Experimental Amyloid,” Arch. f. path. Anat. (1897), cl. 16; Delage, “Studies in Merogony,” Arch. de zool. expér. et gen. (1899), vii. 383; Ehrlich, “Mastzellen,” Arch. f. mik. Anat. (1877), xiii. 263; Engelmann, “Chemiotaxis of Oxygen for Bacteria,” Arch. f. d. ges. Physiol. (1881), xxv. 285; Farmer, “Present Position of some Cell Problems,” Nature (1898), lviii. 63; Flemming, “Studies in Regeneration of the Tissues,” Arch. f. mik. Anat. (1885), xxiv. 371; Frank, Die Krankheiten der Pflanzen (Breslau, 1895); Galeotti, “Experimental Production of Irregular Karyokinetic Processes,” Beitr. z. path. Anat. u. z. allg. Path. (1893), xiv. 288; Grawitz, “Slumber Cells,” Arch. f. path. Anat. (1892), cxxvii. 96; Hahn, “Increase of Natural Resistance by Production of Hyperleucocytosis,” Berl. klin. Wochenschr. (1896), xxxiii. 864; Hamilton, “Process of Healing,” Journ. Anat. Physiol. and Path. (1879), xiii. 518, also “Organization of Sponge,” Edin. Med. Journ. (1882), xxvii. 385; Text-Book of Pathology (London, 1894); Hansemann, “Pathological Mitosis,” Arch. f. path. Anat. (1891), cxxiii. 356; Hartig, Text-Book of the Diseases of Trees (Eng. trans., London, 1894); Heidenhain, “Action of Poisons on Nerves of Submaxillary Gland,” Arch. f. d. ges. Physiol. (1872) v. 309, also, “Question of Lymph Production,” ibid. (1891), xlix. 209, also, “Central-Body of Giant-cells,” Morph. Arb. (1897), vii. 225; O. Hertwig, Die Zelle u. d. Gewebe (1898, also Eng. trans., 1895); Heukelom, “Sarcoma and Plastic Inflammation,” Arch. f. path. Anat. (1887), cvii. 393; Justi, “Unna's Plasma-Cells in Granulations,” Arch. f. path. Anat. (1897), cl. 197; Jürgelünas, “Protective Action of Granulations,” Beiträge z. path. Anat. u. z. allg. Path., Ziegler (1901), xxix. 92; Kickhefel, “Histology of Mucoid,” Arch. f. path. Anat. (1892), cxxix. 450; Krawkow, “Chemistry of Amyloid,” Arch. f. exper. Path. u. Pharmakol. (1897) xl. 195, also “Experimental Amyloid,” Arch. f. path. Anat. (1898), clii. 162; Krompecher, “Plasma-Cells,” Beitr. z. path. Anat. u. z. allg. Path. (1898), xxiv. 163; Labbé, La Cytologie expérimentale (Paris, 1898); Lazarus-Barlow, “Lymph Formation,” Journ. Physiol. Camb. (1895-1896), xix. 418, also, Manual of General Pathology (London, 1898); Loeb, “Certain Activities of the Epithelial Tissue of Skin of Guinea-pig, &c.,” Johns Hopkins Hosp. Bull., Balt. (1898), ix. 1, also “Artificial Production of Normal Larvae,” Amer. Journ. Physiol. (1899), iii. 135; Löwit, “Relationship of Leucocytes to Bacterial Action,” Beitr. z. path. Anat. u. z. allg. Path. (1897), xxii. 172; Lubarsch, “Experimental Amyloid,” Arch. f. path. Anat. (1897), cl. 471; Lubarsch and Ostertag, Ergebnisse der spec. path. Morphologie u. Physiologie des Menschen (Wiesbaden, 1896); Ludwig, Lehrbuch der Physiol. vol. ii.; Marshall Ward, Timber and some of its Diseases (London, 1889); Massart and Bordet, “Irritability of Leucocytes,” Journ. publ. par la soc. des sci. med. et nat. de Bruxelles (1890), vol. v.; Metchnikoff, Lectures on Comp. Path. of Inflammation (Eng. trans., London, 1893); Notkin, “Nature of Colloid in Thyroid Gland,” Arch. f. path. Anat. (1896), cxliv. 224 (Suppl. Hft.); Nowak, “Experimental Researches on Amyloidosis,” Arch. f. path. Anat. (1898), clii. 162; Oddi, “Nature of Amyloid,” Arch. f. Path. u. Pharmakol. (1894), xxxiii. 376; Paget, “Address on Healing,” Brit. Med. Journ. (1880), ii. 611; Pelagatti, “Blastomycetes and Hyaline degeneration,” Arch. f. path. Anat. (1897), cl. 247; Penzo, “Influence of Temperature on Cellular Regeneration,” Archivios per le scienze mediche (1892); Pfeffer, “Chemiotaxis,” Unters. aus d. bot. Inst., zu Tübingen (1884), i. 363; ibid. (1888); Pickardt, “Chemistry of Pathological Exudates,” Berl. klin. Wochenschr. (1897), xxxiv. 844; Plimmer, “Aetiology and Histology of Cancer,” Practitioner (1899), ix. 430; Ruffer and Plimmer, “Cancer Bodies,” Journ. Path. and Bacteriol. (1892-1893), i. 395; Runeberg, “Filtration of Albuminous Liquids,” Arch. f. d. ges. Physiol. (1885), xxxv. 54, also “Diagnostic Value of Proteid in Dropsical Liquids,” Deutsch. Arch. f. klin. Med. (1883), xxxiv. 1; Russell, “Fuchsin Bodies,” Brit. Med. Journ. (1890), ii. 1356; Salvioli, “Production of Oedema,” Virchow and Hirsch's Jahresbericht (1885), i. 252; Schottländer, “Nuclear and Cell Division in Epithelium of Inflamed Skin,” Arch. f. mik. Anat. (1888), xxxi. 426; Sczawinska, “Reticular Structure of Nerve-Cells,” Compt. rend. acad. d. sc. (1896), cxxiii. 379; Senator, “On Transudation,” Arch. f. path. Anat. (1888), cxi. 219; Shattock, “Healing of Incisions in Vegetable Tissues,” Journ. Path. and Bacteriol. (1898), v. 39; v. Sicherer, “Chemiotaxis of Leucocytes of Warm-blooded Animals outside the Body,” Münch. med. Wochenschr. (1896), xliii. 976; Siegert, “Corpora Amylacea,” Arch. f. path. Anat. (1892), cxxix. 513; Starling, “Mechanical Factors in Lymph Production,” Journ. of Physiol. (1894), xvi. 224, also a number of other papers bearing upon lymph-production, in same; Thorne, “Endothelia as Phagocytes,” Arch. f. mik. Anat. (1898), lii. 820; Thoma, Lehrbuch d. allg. Path. (1894), also vol. i. (Eng. trans., London, 1896); Trambusti, “On Structure and Division of Sarcoma Cells,” Beitr. z. path. Anat. u. z. allg. Path. (1897), xxii. 88; Verworn, General Physiology (Eng. trans., London, 1899); Weismann, Essays upon Heredity (Eng. trans., Oxford, 1891); also, The Germ Plasm (London, 1893); Welch, “Oedema of Lung,” Arch. f. path. Anat. (1878), lxxii. 375; Wilson, The Cell in Development and Inheritance (London, 1896); Ziegler, “Entzündung,” in Eulenburg's Real Encyclopädie, also Text-Book of Special Pathological Anatomy (Eng. trans., New York, 1897).  (D. J. H.; R. Mr.*) 

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1. ⁠DESCRIPTION OF PLATE I.

   Series of Figures illustrative of Irregular Division of Cells.

   Figs. 1 to 6 are from the epithelial cells of a cancer of the mamma. (After Galeotti.)

   Figs. 7 to 21 are from a sarcoma. (After Trambusti.)

   Fig. 1.—Resting epithelial cell.

   Fig.  2.—Asymmetrical diaster.

   Fig.  3.—Tripolar division in which the splitting of the loops has commenced.

   Fig.  4.—Tetrapolar karyokinesis.

   Fig.  5.—Another form of tetrapolar division.

   Fig.  6.—Cell in a state of degeneration and chromatolysis; the large rounded body in the cell is a cancer parasite.

   Fig.  7.—Polynuclcated cell with nuclei of normal size arising from multiple karyokinetic division.

   Fig.  8.—Pigmented cell with resting nucleus. The attraction-sphere and centrosome lie in the cytoplasm in the neighbourhood of the nucleus.

   Fig.  9.—Hypertrophic nucleolus.

   Fig. 10.—Large cell with a single nucleus; nucleoli in a state of degeneration.

   Fig. 11.—Multinucleated giant-cell, the nuclei small and produced amitotically.

   Fig. 12.—Karyokinetic figure, the one centrosome much larger than the other.

   Fig. 13.—Cell in process of karyokinetic division with retention of the nucleolus during the division.

   Fig. 14.—Division of the nucleolus and formation of nuclear plate. The nucleolus is elongated, and its longest measurement lies in the direction of the equatorial plane of the nucleus.

   Fig. 15.—Division of the nucleolus by elongation, construction, and equilateral division of the nucleus.

   Fig. 16.—Division of the nucleolus without any evidence of division of the nucleus.

   Fig. 17.—Nucleus with many nucleoli.

   Fig. 18.—Direct division of nucleus.

   Fig. 19.—Multiple direct division of the nucleus.

   Fig. 20.—Nail-like nucleolus.

   Fig. 21.—Fragmentation of the nucleus.