-> IMAGE EVALUATION TEST TARGET (MT-3) 1.0 I.I 11.25 itt IM ly 12.2 SI |£0 12.0 U 1 1.6 Hiotographic Sdences Carporation 33 Wnr MAIN STtHT WIUTM.N.V. t4SN (7U)I73-4S03 CIHM/ICMH Microfiche Series. CIHIVI/ICMH Coliection de microfiches. Canadian Inatituta for Hiatorical Microraproductiona / Inatitut Canadian da microraproductiona hiatoriquaa :\ Tachnical and Bibliographic Notaa/Notas tachniquaa at bibliographiquaa Tha Inatituta haa attamptad to obtain tha baat original copy availabia for filming. Paaturaa of tbia copy whieh may ba bibllographically uniqua. which may altar any of tha imagaa in tha raproduction, or whieh may aignificantiy changa tha uaual mathcd of filming, ara chackad balow. HColourad covara/ Couvartura da coulaur nn Covara damagad/ D Couvartura andommagia Covara raatorad and/or iaminatad/ Couvartura raataur^a at/ou pallicuMa n~| Covar titia miaaing/ La titra da couvartura manqua □ Colourad mapa/ Cartaa g4ographiquaa an coulaur D Colourad ink (i.a. othar than Wua or black)/ Encra da coulaur (i.a. autra qua blaua ou noira) r~~| Colourad plataa and/or illuatrationa/ D D D D Planchaa at/ou illuatrationa 9n coulaur Bound whh othar matarial/ RalM avac d'autraa docunanta Tight binding may cauaa ahadowa or diatortion along intarior margin/ LaraUura aarrte paut cauaar da I'ombra ou da la d ia toca l on la kHig da la marga intiriaura Blank laavaa addad during raatoration may appaar within tha taxt. Whanavar poaaibla. thaaa hava baan omittad from filming/ II aa paut qua cartainaa pages blanchaa ajoutiaa lora d'una raatauration appaidiaaant dana la taxta, mala, loraqua eala 4tait poaaibla. caa pagaa n'ont paa At* film4aa. Additional oommanta:/ Commantairaa auppiimantairaa: L'Inatitut a microfiimi la maiilaur axamplaira qu'il lui a *t* poaaibla da aa procurer. Laa details da cat axamplaira qui aont paut-Atra uniquaa du point da vua bibliographiqua. qui pauvant modifiar una imaga raproduite. ou qui pauvant axigar una modification dana la mithoda normaia da filmaga aont indiquia d-daaaoua. D n Thia itam la filmad at tha raduction ratio chackad balow/ Ca documant aat film* au taux da reduction indiquA ci-daaaoua. Colourad pagaa/ Pagaa da coulaur □ Pagaa damagad/ Pagaa andommagAaa □ Pagaa raatorad and/or Iaminatad/ Pagaa raataurAaa at/ou pailicuiAaa Pagaa diacolourad. stainad or foxad/ Pagaa dAcoloriaa, tachatAas ou piqui Pagaa dAcolorAaa, tachatAas ou piquAaa Pagaa datachad/ Pagaa dAtachAaa Showthrounhy Tranaparanca Quality of prin QualitA InAgala da I'impraaaion Includaa aupplamantary matarii Comprand du matArial aupplAmantaira Only adition availabia/ Saula Aditian diaponibia |~n Pagaa datachad/ EShowthrounh/ rn Quality of print variaa/ |~n Includaa aupplamantary material/ r~1 Only adition availabia/ Pagaa wholly or partially obscured by errata slipa. tissuea, etc.. hava been refilmed to enaura the beat possible image/ Lea pagea totalement ou partiellement obacurcias par un fauiiiet d'errata. una pelure, etc.. ont AtA filmAes A nouveau da fa^on A obtanir la mailleure imaga possible. 10X 14X 1IX 22X MX »x 7 12X IfX aox MX »X 32X Th« copy fllmcd hw hn b««n raproduead thanks to the aanaroaity off: MMlieal Library MoQill Univmity MontrMM Tho imogot appoaring hara ara tha posaibia conaidaring tha condition off tha originai copy and in Icaaping ffliming contract spacifflcationa. quaiity lagibility tha L'axamplaira ffllm* fut raproduit grica i la g4niroaitA da: MMUeii Library RMoQill Urrivanity Laa imagaa auivantaa ont 4t* raproduitaa avac la plua grand aoin, compta tanu da la condition at da ia nattati da I'axamplaira fiimA, at an confformitA avac laa conditiona du contrat da ffilmaga. Original coplaa in printad papar covara ara fiimad baginning with tha ffront covar and anding on tha laat paga with a printad or iiiuatratad impraa- slon, or tha back covar whan appropriata. All othar originai coplaa ara ffiimad baginning on tha ffirat paga with a printad or iiiuatratad Impraa- aion. and anding on tha laat paga with a printad or iiiuatratad impraaaion. I.aa axampiairaa origlhaux dont la couvartura an papiar aat imprimte aont fflintte an comman9ant par la pramiar plat at an tarminant aoit par la danMra paga qui comporto una amprainta dimpraaaion ou dlNuatration, aoit par la sacond plat, aalon la caa. Toua laa autraa axampiairaa originaux aont fllmte an commandant par la pramMra paga qui comporta una amprainta dimpraaaion ou dlNuatration at an tarminant par la damlAra paga qui comporta una taUa amprainta^ Tha last racordad fframa on aach microffieha shaH contain tha aymbol ^^ (moaning "CON- TINUED"), or tho aymbol ▼ (moaning "END"). whiclMvar appHaa. Un daa symbolaa auivanta apparattra aur la damlAra Imaga da chaqua microffieha, aaton la caa: la aymbola -^ signiffia "A 8UIVRE", la aymbola ▼ aigniffia "FIN". Mapa. plataa. charta, ate., may ba ffiimad at diffffarant raduction ratloa. Thoaa too larga to ba antiraly Inciudad in ana axpoaura ara ffiimad baginning in tha uppar lafft hand comar. lafft to right and top to bottom, aa many fframaa aa raquirad. Tha ffoliowtoig diagrama INuatrato tha mathod: l.aa cartaa. planchaa. tablaaux, ate., pauvam Atra ffilmAa i daa taux da rMuction diffffAranta. Loraqua la document aat trap grand pour Atra raproduit an un saui clicliA. 11 eet ffNmA A partir da i'angia aupAriaur gauche, da gaueha A droita. at da haut an baa. an prenant la nombra d'imagae nAceeeaira. Lea diagrammae auivanta llluatrent la mAthoda. 1 2 3 1 2 3 4 5 6 INFLAMMATION AN ARTICLE BY J. G. ADAMI, M.A., M.D., REPRINTED FROM PROF. CLIFFORD ALLBUTT'S NEW SYSTEM OF MEDICINE FOR PRIVATE CIRCULATION %|P THE MACMILLAN COMPANY NEW YORK J896 \ si- Copyright, 1896, By MACMILLAN AND CO. <• 3. 8. Cuihiitff 8i Co. - licrwick & Smltli Nurwodd MaflR. ir.R.A. \i / c / PREFACE Believing that it will be advantageous to the students attend- ing my course to be able to obtain for themselves this study or essay upon Inflammation, I have begged the publishers of Professor Allbutt's New System of Medicine to grant me reprints, especially for the use of McGill students. I would here record my apprecia- tion of the favour shown to me by The Macmillan Company in departing from ordinary usage and acceding so willingly to my request. . J. GEORGE ADAMI Patiiolooical Laboratory, McGiLL Univbrsity, September, 1896. INFLAMMATION* Part I. — A General Survey of the Process of Inflammation Chapter 1. Introduction. — Chapter 2. The Comparative Patliolo^y of Inflamma' tion. — Chapters. Tlie Main Forms of the Process of Acute Iiitiummatiuu it the Higher Animals. Part II. — The Factors in the Inflammatory Process Chapter 1, On the Part played by the Leucocytes. — Chapter 2. On tlio Inflamma- tory Exudation.— Chapter 3. On the Part played by the Blood-Vessols. — Chap- ter 4. On the Passage of Corpuscles out of the Vessels. — Chapter 5. On the Part played by the Nervous System. — Chapter 6. On the Part played by the Cells of the Tissue. — Chapter?. On Fibrous Hyperplasia and its Relationship to lutiam- mation. Part III Chapter 1. On Classification. — Chapter 2. On Systemic Changes accompanying Local Injury and Litlammation. — Chapter 3. Conclusion. — Biblioqrapuy. PART I. — A General Survey of the Process of Inflammation Chapter 1. — Introduction Definition of Inflammation. — It is usual to begin the description of a morbid process by defining that process. In the case of infianima- 1 The following article is an attempt to bring into order the very numerous recent researches upossible ; pyugeuesis must uot be cuufouuded with iutlammatiou. s« SYSTEM OF MEDICINE which occurs in a living tissue when it is injured, provided that the injury is not of such a degree as at once to destroy its structure and vitality." This definition includes too much. The haemorrhage that occurs in the liver when it is injured, and the changes that there occur in the extravasated red corpuscles, are scarcely to be classed among inflam- matory phenomena ; the atrophic changes which occur in the retina, when through injury it becomes detached, are due mainly to malposition and disuse racher than to the primary trauma. But, as Dr. Burdon Sanderson has pointed out, the definition has this great advantage, that stating the cause, it clearly recognises inflammation as a process and not as a state. The external manifestations of this process under favourable conditions — where the region injured is a loose and vascular tissue, and where the injury is sufficiently severe or extensive — are red- ness, swelling, and heat with pain : redness from the congestion of the vessels ; swelling from the exudation of fluid and corpuscles from the congested vessels ; heat from the increased amount of blood in the region, and pain from the pressure upon and irritation of the terminations of the nerves in the region. To these four symptoms may be added a fifth, disturbance of function brought about by this departure from the normal condition of the region. Under unfavourable conditions — where the region injured is dense or less vascular, or where the injury is less severe — one or all of these symptoms may seem wanting ; nevertheless a minute examination of the tissues will show the same succession of changes as in the former case. Chapter 2. — The Comparative Pathology op Inflammation Accepting, then, this working definition, in order to arrive at a due comprehension of the succession of changes which we take to constitute the inflammatory process, it will be well with Metschnikoff ' to institute a series of observations upon the reaction to injury exhibited throughout the animal kingdom from the lowest forms upwards to man. By this means we shall be enabled to determine what factors in the inflammatory process are from their constancy of primary importance ; what are com- mon and essential, and what are superadded in the higher animals. The Response to Injury among the Protozoa. — Beginning our study with the lowest and simplest forms of life — forms so lowly that they have been regarded both as animals and as plants — we find even here phenomena accompanying the reaction to injury which throw light upon the inflammatory process as seen in the higher animals. Taking as an example the amoeba, we find, in the first place, that the nucleus plays an 1 Tho succeodinp; paragraphs are of necessity very largely an epitome of sundry por- tions of M. Metschnikoft's most pregnant work upon the comparative pathology of inflam- mation. By comparing tliem with the work in question, it will, however, ho seen that they depart from it in several points ; more esi)ecially in dwelling upon the extracellular activity of the wandering culls, and in hriiiging more pruminontly forward tho rospousu to injury on tho part of tho llxed cells. INFLAMMA TION 57 important part in this reaction. If, as Metschnikoff lias shown, one of the larger amoebae be cut in two, the region of injury becomes rapidly indistinguishable — the protoplasm of each moiety closes up, leaving no mark or scar : but of the two parts that which retains the nucleus grows and proliferates ; the other disintegrates in a longer or shorter time. Or injury may induce changes in the protoplasm of the entire amoeba: thus, Miss Greenwood points out that, without necessarily bringing about death, the inLorrupted current or an aqueous solution of thymol leads to a process of exudation or extrusion of clear hyaline spheres, or of spheres holding crystals and granules, from the surface of the organism — a pro- cess resembling that occasionally seen in the cells of an inflammatory area in higher animals. Nor is this all; apart from changes in the structure of these unicellular animals, differences may be seen in the behaviour of amoebae towards foreign bodies. It would seem, accord ' . g to Le Dantec, that amoebse ingest non-irritating foreign substances in- differently, provided they be sufficiently small. Around each particle so ingested a vacuole is formed, and the fluid in this becomes increasingly acid, and at the same time digestive. Kiukenberg, lieinke and Miss Greenwood have conclusively proved these and similar food vacuoles in the amoeba and other Protozoa to contain a pepsine or digestive ferment, which, as Le Dantec has shown by very delicate tests, exerts its action in an acid medium (the general protoplasm of the cell body being alkar line); this digestive process leads to the solution of food stuff's, pre- paring them to be taken up by the protoplasm of the organism. If the foreign substances be incapable of digestion they are sooner or later ex- truded. It is by this fonn;ition of digestive vacuoles that the anutba acts upon and destroys bacteria, diatoms, and other microbes ingested by it. There are, however, microbic forms around which it would seem that no proper vacuolation is developed, or if developed, the acid digestive fluid is neutralised by substances discharged from the parasites ; where this is the case, instead of destruction there is continuance of vitality and actual multiplication of the invading or parasitic form, leading to the eventual death of the amct'ba. Metschnikoff has observed this chain of events in one of the anui'bie which ingests and becomes tlie host of a minute rounded form, the ^^licrospha'ra. IMienomena of like nature may bo observed among the ciliate and flagellate infusorifi. While these phenomena may primarily bo regarded as the method employed oy the IM'otozoa for the assiniihition of food stuff's, tlicy also are clearly the means whereby the Proto/oa defend themselves against living organisms which have gained entrance into them, and thus foriu tho reaction to possible injury ; for when in certain eases the means of defence are overcome, tlie parasitic organisms gain the upper hand and lead to death. There is yet another reaction to injvirious intluences exhibited by the Protozoa into which it is necessary that I sh<»nld enter at some length. This is exhibited by the anio'ltii. but (^an be and has been most fully investigated in the myxomyeetes — multicellular forms which 5« SYSTEM OF MEDICINE can with equal propriety be classed as animals or plants, although usually they are included among the latter. These organisms form large plasinodia (masses of protoplasm, that is), in which, under ordi- nary conditions, the nuclei are the only indication of the individual cells which by their fusion have formed the masses. They are to be met with in leaf mould, and on the surface of moist decaying wood over which they creep with an amoeboid movement ; and inasmuch as they may attain great size — some species attaining twelve inches or more in length — they form admirable material for biological study. Ten years ago Stahl, investigating one of these myxomycetes (the JEthaliiim septicuni, an organism found in tan pits), showed that if placed upon a moistened surface close to a drop of infusion of oak bark, the Plasmodium moved actively towards and into the infusion ; if placed similarly near to a solution of glucose (0'5 per cent) it moved with equal rapidity away, and so also in the case of solutions of various salts. These observations of Stahl were (if we except Engelmann's observations in 1881 upon the tendency of sundry bacteria to remove from regions poor in oxygen to those where oxygen is present in abundance) the first of a series of observations upon the attraction and repulsion of plants and portions of plants by chemical substances. To this property Pf effer, who has made the fullest series of studies upon it, has given the name of cheniiotaxis, in place of Stahl's narrower " trophotropism " ; and one speaks of a positive or a negfitive cheniiotaxis according to the attrac- tion or repulsion exerted. If, as Metschnikoff has pointed out, the advancing edge of one of these plasmodia (of Physarum) be injured by cauterisation, the region of injury dies ; the protoplasmic currents, which had been advancing, reverse themselves abruptly, and within an hour the plasmodium has moved away, leaving the debris of the destroyed region behind. These experiments are so simple, and the results obtained seem so natural, that it may be asked whether it be worth while to attach a name to this property of living matter. Yet the name is in itself an aid to bearing these properties in mind; and, as will be pointed out later, the recognition of them is of material help in solving certain of the difficulties that present themselves in the study of inflam- nuitiou in the higher animals. Among tlu'se myxomycetes another fact can be nuide out. Stahl observed tluit the ])lasniodium of Fuligo, which at hrst nuwes away from a two i)cr cent sohition of common salt, will after a tinte (more esiM'cially if it has sutt'ered from hick of water) adapt itself to the sohition, advancing its pseudopodiaor ))roto])lasmi<' processes into it. With other myxomycetes tlie same adaptation has been observed. That is to say, by use or adaptation a negative may be transformed into a i)ositive cheniiotaxis. To this change I shall have occasion to revert. The Response to Injury among the Metazoa. — Passing from the Protozoa to tlie iMetazoii, we reiich immediately (or almost immedi- ately) a series of beings in which the division of labour among the ct'lls has led to the development of three cell layers — an (»nter ectoderm, an inner endodurm, and an intermediate ht.yer of mesoderm. INFLAMMA TION 59 Even in the very lowest forms among the Metazoa it is noticeable that of these three layers there is one, the mesoderm, whose cells have the especial function of reacting when any irritant or injurious stimulation is applied to the organism. Taking what are perhaps the simplest forms in which to observe the relationship and properties of these layers, Metschnikoff has studied these results of injury in the larval forms of astropecten and other echinoderms. At one well-recognisable stage these larva) resemble little more than the gastrula stage of the embry ologist ; the endoderm or hypoblast appears as a cul-de-sac — an invagination of the ectoderm or epiblast — while the mesoderm is repre- sented by amoeboid cells, budded oif from the endoderm, lying or float- ing in the semiliquid substance tilling the general body cavity. The ectoderm is so delicate that any sharp substance can readily penetrate into the body cavity ; and, when this happens, it is noticeable that the wandering mesodermal cells make their way to the foreign body, attach themselves to it, and fuse into plasmodial masses, thus forming a wall, as it were, around the invading substance, and cutting it off from the general body system. Here, then, in an organism possessing neither nervous nor vascular system, the reaction to injury, where that injxiry has not been sufficiently intense to cause destruction of the outer layer of cells, is simply and solely confined to the wandering cells of the body ; there is no effusion of fluid ; there is not necessarily phagocytosis on the part of these cells ; any digestive and destructive action on their part — any attempt in this way to remove the forei^ body — must then be by excretion, hy extracellular action. At the same time, this fusion of the cells and formation of a plasmodium around foreign substances of greater diameter than the individual mesodermal cells may bo looked upon as a mechanism whereby the equivalent of intracellular digestion is gained. But, as among these low forms cases occur in which, without the formation of plasmodia, the cells perform their destructive action upon bodies of larger size than themselves we do not lack examples of what must be considered as excretory destructive powers on their part. That these cells in the echinoderms are also capable of destroying minute foreign bodies by intracellular action, that is, by phagocytosis, lias been denumstrated in the larger transi)arent larval form known as Uipinnaria Asterigera; on introducing l)acteria under its ectoderm the nu'sodermal cells are seen to api)roach, and by their long i)seudopodia to adhere to and ingest the still living motile bacteria, whicli are rapidly digested. liesides this reaction to injury on the part of the mesodermal cells, a further response is exhibited to a remarkable degree among the lower Metazoa — I refer to the great i)ower of regeneration of lost i)arts, of cell lu'oliferation leading to the re])rodu(^tion of destroyed regituis. This ])0wer is l)est seen in the classical example of the Hydra, which may be cut into many pieces, each one of which is cai)able of glowing, so that in a relatively short tinn^ it becomes a fully formed individual. It is interesting to note in rcliition to tlie frecpient ten- dem-y towards hyperpliusia and excess growth following upon injury in 6o S VS ' :if OF MEDICINE h the higher animals, that iiiiong low forms, such as Hydra and Ceri- anthus, the same tendency is yet more strongly marked. Thus, as Loeb points out, if an incision be made in the stem of a Hydra, a whole new oral pole, provided with tentacles, will branch out from the region of cell destruction. In the actinian Cerianthus the process is not quite so extensive ; yet from the lower lip of the lateral incision a set of tentacles develops in all respects similar to those around the mouth. Ascending to the Worms, we find that the protective agency devolves upon mesodermal cells suspended in the perivisceral fluid, and again forming the peritoneal endothelium. We arrive, that is to say, at a state in which a lymphatic system may be said to be present ; for the spaces in which the free corpuscles lie are strictly homologous to the lymph-containing spaces of the vertebrate organism, and these corpuscles may be regarded as lymph corpuscles ; the peritoneal endothelium cor- responds with the mesodermal peritoneal endothelium of vertebrata. Among the annelids the process of reaction to injury may be well followed in the earth worm by studying the sequence of changes that occur around the gregarines which infest the male genital organs. While these parasites are active by their movements they prevent the adhesion of the wandering cells; but so soon as they pass into the resting stage antecedent to spore formation, the cells form a thick mass around them. The parasite on its part forms a thick cyst wall ; never- theless, it may not unf requently be observed that, despite this protection, the parasite changes its appearance under the action of the surround- ing i)lasmodium, and in fact is killed. While this is happening no change could be detected by Metschnikoff in the neighbouring blood-vessels ; these appear to remain completely inactive : no exudation is noticeable nor any recognisable change in volume. While among the Worms a well-developed and closed vascular system is not unfrequently present, in other animal forms, which in most respects present a much more complex and advanced develop- ment, namely, in the Arthropods and Tunicates, this is not the case. In these the blood pours from tlie tubular heart sooner or later into the liic'iuue of the general body cavity ; and whether veins be absent (as is most usual), or present (as in the Cephalopods), the blood is sucked back from the body (Uivity into the heart. Tliis incomplete circulation, interesting as it is in connection with the development of the vertebrate circulation, is interesting also from the fiu^t that its incompleteness in these large and wide-si)read classes )f animals prevents reaction to injury from being associated with vascu ar changes. TIh^ blood in these animals, circulating through the ramilications of the body cavity, is evidently a mesodermal fluid, if it may l)o so termed. Its corpuscles are clearly mesodermal; and without going into lull details as to the properties of tliese (M)rpuscles, it may be said that tliey rc^present an liitiM-esting series of stages in the subdivision of laliour, Kor exam|»le, ■is Mr. Hardy has shown us in a low form of crustacean like Uaphuia ;the INFLAMMA TION 6l water flea), but one form of cell is present, whereas in the highly- developed Astacus (the cray fish), there are three distinct forms of leucocytes (no red corpuscles being present), each of which appears to have distinct functions. The one form in Daphnia has the property of taking up fat globules and food particles from the alimentary tract, foreign particles, such as granules of carmine or Indian ink, and the spores of parasites (Monospora, Metschnikoff) ; it is granulated, con- taining minute spherules which stain with basic aniline dyes (basophils granules), and under certain circumstances it may be seen to explode with lightning-like rapidity. In the higher Astacus there are in the circulating haemal fluid two varieties of cells: one is extraordinarily explosive ; when removed from the body cavity it gives off fine blebs or vesicles of its substance with such rapidity that, unless the greatest care be taken, nothing is seen of the cell save its nucleus ; this form is phagocytic : the other form is far more stable, and is loaded with large spherules which have a great affinity for acid dyes — they are eosino- philous — may be actively extruded, and undergo decomposition ; these cells never act as phagocytes. The third form, with basophile granules, is rarely found in the blood, and then only as the result of special stimuli ; but it is present in considerable numbers in the peculiar tissue which forms a sheath around certain of the arteries — Haeckel's " Zell- gewebe ; " this form is phagocytic, and can be seen to contain globules of ingested fat. As Metschnikoff demonstrated, in his most remarkable study upon a disease of Daphnia caused by the entry of the spores of a yeastlike organism (the Monosiwra) into its body cavity, its one form of leuco- cyte can be seen to react swiftly towards the spores; the cells ap- proach them, form a plasmodium around and eventually digest and destroy them. If, on the other hand, in consequence of their great numbers or the relative paucity of the leucocytes, certain of the spores be not attacked and develop uninterruptedly into mature torulaj, the leucocytos show no tendency to approach them — in fact, their neigh- bourhood leads to the explosion of the leucocytes — and the torulie, multiplying, }ead to the death of the organism. Often, again, brown eschars may be recogni^tid ujwn the transparent carapace of a Daphnia, due to injuries by other individuals; beneath these scars are to be found masses of leucocytes whicli remain in the region of injury until the cells of the tissue have ])roliferated, and there is complete union and repair. In addition, then, to the immediate reparative and protetitive re- action ot the leucocytes, there is exhibited among the higher invertebrata a later reaction in the shape of proliferation of the fixed cells. This proliferation, while not so extensive as among the lower invertebrates, can nevertheless be very great; and cells of all forms, whetlier of hypo-, meso- or epiblastic origin, and tissues so highly developed as the muscular and nervous, may participate in it. In illustration of tlie ample power of tissue reproduction after injury possj'sscd by these animals, I need but mention the trite examples of the reproduction of the hinder segments 6t 62 SYSTEM OF MEDICINE of divided worms, and in crustaceans the restoration of injured and cast off claws and appendages. Many more instances might be given to show that the reaction to injury remains essentially a reaction on the part of the wandering and fixed mesoblastic cells of the organism, followed in sundry cases by proliferation of the fixed epi-, meso- and hypoblastic cells, and by repair where these have been destroyed. Although these arthropods, molluscs and tunicates have a vascular system, yet, inasmuch as this is open, its changes, if they occur, could scarcely modify the inflammatory process. The Response to Injury among the Vertebrata. — If now we pass to the vertebrates, the picture presented is far more complex : not only do these present a highly-developed nervous system, but, moreover, the blood is enclosed in a complete vascular system. We shall now consider at length the results of an injury of an organ in one of these higher animals. Chapter 3. — The Main Forms op the Process op Acute Inplam- MATION IN the HiOHER AnIMALS The Experimental Production of Inflammation in Non-Vascular Areas. — Let us begin with the succession of changes that occurs in the sim- plest case, namely, in a non-vascular area, in one of the lowest vertebrate forms — for instance, in the embryonic axolotl ten to fifteen days old; let us curarise it, and apply a minute crystal of silver nitrate to the side of its flattened transparent tail fin, washing away the remains of the crystal with salt solution; or again, we may pass into the tail a small needle filled with finely-powdered carmine. l>y either procedure a certain number of cells is destroyed. The neighbourhood of tlie injury now becomes swollen (it may bu l)y imbibition of water through the wound), and the surrounding cells tumefied, vacuolated and less refractile. This is the^ns^ starje — that of injury and modification of the surrounding tissue. In a little time a few wandering cells (leucocytos) approach the injured region; by the next day these are present in fair numbers, and can be seen to have taken up the particles of carmine or debris of the destroyed tissue. This is the second stage — that of immigration of leucocytes. There are no vessels in the transparent fin of these young axolotls, no dilation of those nearest to the fin, and no diapedesis. All the leucocytes that pass to the part are pre- existing wandering cells of the connective tissue, — a fact of some little importance in connection with the origin of certain of the pus cells in the suppurative process of higher animals. The third stage is that of repair, of prolif(>ration of tlie injured epithelium, return of the fixed cells of tlie tissue to their jjrevious state, and emigration of the wandering cells. A very similar jjrogress of events occurs if the experiment be re|)eated upon the tail fin of the yovuig newt. Tlic^ same rapid alteration in the large branched connective tissiu' cells (wliich become vacuolated as their INFLAMMA TION 6S Ions processes are drawn in and shortened), and the same immigration of motile cells from the surrounding connective tissue are to be seen ; biit here we now find the earliest evidence of vascular participation, for, according to Metschnikoff, complete arrest of the circixlation may occur in the nearest vascular loop, liy the next day the parts have returned to the normal condition. If from these cases wo pass to mild inflammatory disturbances affecting the non-vascular regions of animals far higher in the scale, wo again discover a like process of events. For this purpose the. cornea affords an excellent ojjportunity ; in health it is absolutely non-vascular ; it is perfectly transparent, and is so thin that it can readily be examined microscopically. The cornea of mammalia, and indeed of vertebrates in general, is formed of fibres which run in layers parallel to the surface. These fibres, while roughly arranged side by side and parallel to one another in any given layer, are placed at an angle to the fibres of the layers above and below. Although free from blood-vessels the cornea is far from being devoid of channels along which lymph freely passes. Between the several layers there exist spaces in which lie the flattened connective tissue cells of the organ ; and, by means of numerous fine channels, these spaces around the cells are connected with similar spaces lying anteriorly, posteriorly and laterally. Through this rich anastomosis of channels there is a free flow of lymph. These channels arc really continuations of the body cavity of the animal ; they repre- sent, and in fact play the same part as the single body cavity of such a simple form as the larva of Astropecten, while the cells lying in the spaces are mesoblastic cells which have become fixed. Few studies are better calculated to impress the ir .stigator with a sense of the depth of the well at the bottom of which truth lies, than a research into the abundant literature dealing with observations upon the stages of the inflammatory process as it occurs in the cornea, and with the deductions therefrom. One after another the adherents to succes- sive forms of inflanuuatory belief have found in experiments upon this simple tissue ample support for their particular creeds. Selecting from among the many observations those which have stood the test of time, I will begin with the simplest, and pass on to those dealing with an increasing intensity of the inflammatory process. If, as Senftlobon first pointed out, the centre of the corniM of a rabbit bo washed with a strong solution of zinc chloride, then, in favour- alile cases, although the epithelial covering be gravely injured, there may bo no actual rui)ture of the outer layers of the tissue. Such a cornea ienu)ved twenty-four hours later may show no sign of migration of leucocytes — no sign, again, of congestion of the vessels at the peri- ])hi'ry. The only indications of injury and reaction may be the destruc- tion of the corneal corpuscles immediately beneath the cauterised area, and the apivarance of a zone surrounding this in which the corneal corpuscles appear enlarged, tlistinct and tunu^lied. The ])rocess may 64 SYSTEM OF MEDICINE continue and advance insensibly to repair without the intervention of leucocytes ; the hypertrophying cells of the " granular " zone eventually undergoing karyokinesis, and thus by multiplication replacing the cor- puscles destroyed. Here, then, necrosis and new growth of the fixed cells of the tissue are the only recognisable factors in the process of repair of injury. It must be confessed that the conditions permitting this simplest form of reaction are of rare occurrence ; it is worthy of attention that they can exist. By a slight modification of the preceding conditions another factor may be brought into play. If, after cauterisation in the manner above described, a break be made into the cauterised surface; or if again, without cauterisation, a little of the corneal tissue bo removed, then in a few hours a small whitish opacity is to be noticed within the corneal tissue in the immediate neighbourhood of the break in the continuity, and upon examination this opacity is found to be due to a massing of small round cells. As there is at this moment no sign of proliferation of the connective tissue cells of the cornea, these newly-collected cells can only be leucocytes ; and further examination of their properties proves them to be such : there is, however, no evidence of dilation of the peripheral vessels, no indication of diapedesis through their walls. The leucocytes, therefore, can only have entered into the wound from the cornea itself and from the conjunctiva and the lachrymal fluid bathing it. In this experiment the inflammatory process is represented by destruction of tissue and immigration of leucocytes, followed by repair ; neither the vascular nor the nervous system play any part in it. We are forced to the conclusion that the leucocytes have massed themselves in the injured area purely on their own initiative ; and that there must be an attraction, a chemiotaxis or chemiotropism, leading them actively to approach the region of cell destruction. The observations made upon these two simple cases help us materi- ally to understand the series of events which occur in more intense inflammation of the cornea, such as that produced by injuring the surface and causing the entrance into the injured region of a small quantity of a pure culture of the Pyococcus aureus. This may be accomplished by injecting the culture into the centre of the healthy cornea by means of the needle of a Pravaz syringe (Jacobs). The micrococci so intro- duced grow rapidly, the growth so extending along the lymph spaces that a branched mass of the microbes is produced, having the spot of inoculation as centre. Around the growth as it extends may bo seen a sharply-marked area in which the corneal corpuscles show evidences of degeneration ; the nuclei stain faintly, and the corpuscles, speaking generally, have a shrunken appearance. Here, again, the first effect of a microbic, as of a simple chemical injury, is to bring about degeneration of the fixed cells of the tissue. Within eighteen hours the zone of pro- liferating cocci and cell degeneration is well marked; and now the second stage begins to bo clearly manifest, namely, the determination INFLAMMATION 6S of leucocytes to the seat of injury. Within twenty-four hours there is a dense packing of these corpuscles around the central degenerated area, and great nmnbers of leucocytes may be seen converging along the lymph spaces from the periphery of the cornea. This is the second stage of the process, the first stage of reaction to the injury inflicted by the invading micro-organisms. If, as by Cohnheim ' in his original experi- ments upon the injury to the cornea, more careful examination be made into the stages of the determination of leucocytes, it can be seen that this determination is closely related to changes set up in the vessels at the periphery of the cornea; they become more prominent, the region has a congested appearance, the smaller as well as the larger vessels are dilated, and there is abundant evidence that the leucocytes are passing out from the contained blood into the surrounding lymph spaces. In- deed the accumulation of leucocytes shows itself first at the periphery of the cornea near the vessels, and gradually approaches the region of injury. Into the mechanism of this diapedesis, and into a fuller descrip- tion of the changes that take place in the blood-current in these distended vessels, I shall enter later when discussing the changes in highly vascular regions. Suffice it to say here that no distinction can be made out between the behaviour of the leucocytes in the previous experiment, when they entered the wounded area from the external surface, and in this where the majority) find their entrance from the blood; as in the previous case the part played was evidently active, so must it be here also. We cannot arrive at any other conclusion than that some attractive force leads to their determination towards the inflammatory focus. As we can easily show, by repeating the experiment, many of these leucocytes take up and contain numerous cocci, while other cocci remain free in the tissue spaces. Many of the leucocytes degenerate and present a broken down appearance ; and, as at the same time an increasing area of the corneal tissue becomes disintegrated, an ulcer appears. According to the viru- lence of the culture and the reaction on the part of the organism, the process may now extend, a larger and larger portion of the corneal tissue becoming affected ; or, on the other hand, there may be an arrest of the progress, the massing of the leucocytes preventing, as a barrier, the further extension of the micrococci into the lymph spaces ; '^ while at the same time there is an advance of newly-formed capillary vessels into the previously non-vascular tissue. It is to be noticed that the blood-vessels at the periphery of the cornea are prominent and dilated, and from them fine new vessels with very delicate walls pass towards tlie injured region. At the same time many of the corneal corpuscles, outside the area of destruction, can by appropriate staining be seen undergoing mitosis and proliferating. Thus the active repair of the tissue is initiated. ]' ( 1 There can bo no qiie.stion that Cohnheim In his experiments induced not a simple keratitis but one which in tlie absence of aseptic precautions rapidly became septic and suppurijtive. i< Into tbo details of this action I shall enter moro fully later. VOL. I F «5 ours there ^generated J along the cond stage sed by the lal expei'i- n be made n that this jels at the igion has a essels are ,re passing Daces. In- jriphery of region of er descrip- 5 distended ly vascular ut between when they this where Bvious case We cannot ee leads to can easily ake up and the tissue oken down le corneal the viru- anism, the le corneal B an arrest a barrier, es ; ^ while iry vessels 1 that the id dilated, s towards orpuscles, g be seen air of the lot a simple 10 soptic niid 66 SYSTEM OF MEDICINE { The Experimental Production of Inflammation in Vascular Areas. — From this study of inflammation, as it occurs in a region devoid of blood-vessels, let us now pass on to the more complicated process of inflammation in vascular areas ; and, as in the previous case we considered an ascending or advancing series of reactive changes, so here let us begin with the slightest injury associated with the mildest reaction, and pass onwards to states in which the inflammatory manifestations are more and more pronounced. If an incision be made with a perfectly aseptic instrument into the skin, also rendered aseptic, and be so made as to divide the dermis and tissues immediately below, without at the same time injuring any large vessel, it is the common experience of modern surgeons that repair takes place with the minimal amount of change recognisable as inflammatory. Repair takes place indeed so rapidly that, if the divided structures have come or have been brought into immediate contact, there may be firm adhesion at the end of twenty-four hours. This is primary union, or union by first intention, which, rare in the old days, commonly occurs in this era of aseptic surgery. The full sequence of events in these cases cannot, it is true, be well determined by continuous microscopic examination; but if the rabbit or dog be employed, and tissues, wounded in the manner described, be removed and examined at successive short intervals, we see that the changes which occur are mainly, nay almost entirely, related to the pre-existing cells of the part. The section divides a certain number of capillaries ; but in the very act of division the divided walls are apparently brought together ; and, partly by this means, partly by contraction, the lumina of these minute vessels become occluded, and the haemorrhage into the wound is altogether inconsiderable. Within an hour after the operation it is evident to the naked eye of a careful examiner that the immediate neighbourhood of the wound is slightly reddened and tumefied, but only very slightly ; and, associated with this, there is a feeble exudation between the apposed surfaces. But the exudation is not great, and even within this first hour after the infliction of the wound there may be development of fibrin and coagulation of the exudate, leading to the formation of a provisional cementing together of the opposed surfaces. In this exudation, and in the tissues in the immediate neighbourhood, the leucocytes that have undergone diapedesis may be few and far between, and may scarcely attract attention. The reaction, then, on the part of the vessels and of the leucocytes is of the slightest. Study of sections shows that the main role is played by tlic pre-existing cells of the part ; of these a certain number (not so many as might d priori be expected) are destroyed immediately, and show all the signs of disinte- gration ; a number relatively large have been injured only, their nuclei remaining intact, though their processes or some portions of the cell bodies have been cut through. It is ditticult to determine these injuries in the small cells of the cutaneous tissues ; they are better seen in the peritoneum when slight inflammatory changes have there been F INFLAMMATION 67 induced. This, however, can be made out that the cells in the immedi- ate neighbourhood of the wound became enlarged, and, without showing signs of division, prolong themselves (that is to say, send out prolonga- tions) into the region of the provisional fibrinous cicatrix. In this way, before the end of the second day, there may be a more or less complete replacement of the primary unorganised cementing substance by organ- ised growing tissue, — formed, in the first place, by the interlacing of processes from the neighbouring cells ; in the second, and later, by a multiplication of these cells, together with a development of new capillaries, few in number, which branch off from the slightly-congested vessels in the neighbourhood. Thus in this case the process of repair is characteristically associated with hypertrophy and the new growth of the fixed cells of the tissue ; while vascular changes, exudation and leucocytosis, are relatively little marked. I have, however, never come across a case in which they have been entirely absent, save when the section has been truly extra-vascular — that is to say, when it has not penetrated into the vascular region of the skin, and has aCEected only the epidermis and outermost layers of the dermis. In such cases the response to injury may show itself purely as a proliferation of the epithelial cells. As I have said, observations of the above nature labour under the disadvantage that they must of necessity be discontinuous. I bring them in at this point, inasmuch as they represent the mildest condition of the inflammatory reaction. I have not personally observed this series of changes in tissues which permit of continued study under aseptic conditions; neither am I acquainted with any observations wholly fulfilling these conditions — made, that is to say, upon trans- parent vascular tissues subjected to the mildest aseptic injury and examined continuously under the microscope. The response to injury in the cases just mentioned was of the slightest. Let me now pass on to cases in which it becomes more pro- nounced; and in order to continue the comparative study of inflam- mation I would first describe the series of enenU in a highly vaseidar and transparent region in a low vertebrate animal, namely, in the tadpole's tail. If this be injured, either by the application of a caustic or by the introduction of a foreign inert body into its substance, a definite advance upon what was recognisable in the case of the axolotl, for example, is to be made out. Here the tail is very vascular, the wandering cells of the connective tissue are very few in number, while the blood is fairly rich in leucocytes which are small relatively to the size of the vessels. The results of injury are a congestion of the vessels, noticeable within fifteen minutes, and a well-marked determi- nation of leucocytes to the injured region. These cells, in the main, pass out from the vessels ; the few leucocytes pre-existing in the tissue appear to play a very small part. Compared with the axolotl experiment this observation is of considerable interest. Instead of a slight reaction slowly developing there is a rapid reaction ; instead of a slight accumula- 68 SYSTEM OF MEDICINE a LOn ila- tion of leucocytes theiv is a most pronounced accumulation. If there be any meaning in the determination of leucocytes to the region of injury, then evidently the active participation of the vessels of that region in the reactive process is fraught with benefit — it is a further important factor developed with the development and advance of the organism. The fuller details of this vascular interference in the inflammatory process have been followed by many observers, among whom first and foremost was Cohnheim ; and to this end the frog has supplied the most convenient means in regions at once vascular and fairly transparent, such as the web of the hind feet, the tongue, and the mesentery. Other observers passing higher in the scale of vertebrates have employed the mesentery of the cat, dog, and other mammalia. Suffice it to say that, with slight modifications due to local conditions in the tissue examined rather than to the animal selected, the process has been found to present the same features throughout the whole of the adult vertebrata, from the reptilia upwards. For general examination, perhaps, the best and simplest method of observing the succession of changes that follow injury of a vascular area is to be found in what I believe to be Coats' modification of Cohnheim's original experiment upon the frog's web (Coats' Pathology, 1889, p. 119). In order to reproduce as nearly as possible the conditions of an ordinary wound, instead of employing a caustic or chemical irritant, a small portion of the cutaneous surface is nipped off — the section being just deep enough to pass through the cutaneous layers without causing haemorrhage. For the experiment to proceed satisfactorily, it is necessary that the frog be curarised after having been pithed. The web of a small frog is so thin that the changes occurring in and around the vessels of the part can readily be followed even with a high power of the microscope. The first change noticeable in the immediate neighbourhood of the in- jured membrane is a dilation of the vessels, first of the arteries and then of the veins ; and in this first phase there is a very evident acceleration of the blood flow. At this early period the capillaries show little evidence of dilation, but in the course of an hour expansion is readily distinguish- able, and sundry capillary channels, previously invisible, become occupied by blood and show themselves. This first stage lasts for an hour, or in some cases perhaps two, and is followed by a phase of slowing of the blood current. While previously a well-marked axial stream of cor- puscles had been evident, with a peripheral zone of plasma devoid of corpuscles, the former now broadens out, the latter becomes less and less, and as it narrows an increasing number of the clearer rounded haemal leucocytes are to be seen in it travelling at a slower rate than the more axial stream, and every now and then stopping beside the walls of the vessels, and after a short stoppage passing on again. The leucocytes conduct themselves as if they have become " sticky." * As the current becomes yet slower all distinction between axial and 1 Even so low down in the scale as Daphiiia this same peculiarity is noticeable: there in health, as Hardy has pointed out, the leucocytes move freely ; but, if the slijjhtest injury be I NFL AM MA TION 69 peripheral streams is lost ; the corpuscles, closely packed together, fill the whole lumen ; the leucocytes in increasing number approach the vessel walls ; they adhere more firmly, and so long as a current is recognisable the action of the stream leads them to assume a pear-shaped appearance, the rounded ends pointing in the direction of the current. As the stream slows gradually the corpuscles may move at last in a series of jerks synchronous with the heart beats ; or frequently in the veins and capillaries the mass of blood may be seen moving slowly first in one direction, then in the other. Frequently one or other of these stages is followed by complete stagnation or stasis of the blood in the vessels of the injured area — I say frequently, for at other times little or no absolute arrest is seen in the vessels. Accompanying this stage, although observers employing other and chemical methods of inflicting injury have in general omitted to call attention to the fact, there is already a considerable oozing or exudation of clear fluid from the "'^ound ; there is, that is to say, an outpouring of lymph, and that apparently from the distended vessels. Now, with the slowing of the stream the leucocytes, accumulated next to the walls of the small veins and within the capillaries, pass from the interior to the exterior of these vessels ; and, if the process be studied carefully with a higher power, it can be seen that this mode of passage is of an active, or apparently active nature.^ A series of leucocytes can be distinguished some of which are rounded or flattened in immediate contact with the wall of the vein ; others possess a prolongation passing into the wall ; in others, again (or in the former if they be watched in the fresh specimen), the prolongation enlarges on the outer side of the small vessel while the portion of the leucocyte within the vessel becomes smaller. The final phase of this act of diapedesis is that the whole leucocyte passes through, and is found in the lymph spaces around the vessel wall. This process of diapedesis may be so general that in the course of five or six hours all the small veins of the region show a crowd of leucocytes situated along their outer surface. With these a greater or less number of red corpuscles may also make their escape. Although the capillaries, from the very smallness of their diameters, do not show the so-called " margination" of leucocytes, nevertheless this same process of diapedesis may occur at various points along their course, so that outside the capillaries also a fair number of the same small highly- refractile cells endowed with amoeboid movements can be observed. In this modification of Cohnheim's experiment a further stage is to be recognised. While at first the fluid exuded was clear and relatively free from cells and cell debris, now, as the inflammatory process continues, an increasing number of leucocytes is contained in the exudation. The inflicted upon the carapace, the leucocytes, previously unadhesive, soon show the tendency to adhere to the walls of the body cavity beneath the region of injury and elsewhere. 1 The process can be fully made out if at this stage the wounded region be removed, fixed immediately in weak osmic acid, aud prepared fur examination by the higher powers of the micruscupe. TO SYSTEM OF MEDICINE leucocytes > not remain in the immediate neighbourhood of the vessels, but many of them pass on to the injured surface ; still it would seem by active amoeboid movement. Thus at the end of six hours this surface may be covered by a serum or fluid in w bich are great numbers of these leucocytes. Here then we have the first step towards the formation of a scab or provisional protective covering to the wound. Further observations cannot well be carried out in the pithed and curarised frog ; but if an unpithed, non-curarised animal be taken, and the observations upon the earlier stage be neglected, it can be made out that if irritant matter do not find entry into the wound the process may be arrested at this point; the leucocytes upon the surface may break down, and with their breaking down and the formation of fibrin a soft scab be formed : the stasis of the blood in the distended vessels may be followed by a re-establishment of the current and slow return of the vessels to their former calibre, while beneath the thin, soft scab the epithelial cells rapidly proliferate. Within twenty-four hours there may be abuadant evidence of this new growth of the epithelium tending to. encx'oach upon and cover the wound. At the same time the region becomes less and less populated with leucocytes, so that — not to enter fully at this point into the reparative process — within sixty hours the region may show little sign of the injury and consequent inflammation. On the other hand, if irritants of a microbic nature enter the wound the process may extend, as in inflammation of the cornea. More especially if the water in which the frog is kept become foul, there is a tendency in the inflammatory processes to spread ; and in the cells of the central area, both flxed and migrated, to break down, leading to the formation of a spreading ulcer. The steps of this sequence of affairs it is difficult to follow by continuous microscopic examination, partly on account of the increased opacity of the region, partly because the process extends over days rather than hours. Here, therefore, I merely mention this possible extension of the change with its main naked-eye appearances. It is not possible by continuous observation to make out the steps of this more extensive inflammation characterised by excessive emigration of leucocytes and destruction of these together with the fixed cells of the tissue — the pyogenetic inflammation. Several observers, however, have followed its successive stages by means of examination of affected tissues at successive intervals after the infliction of injury. The Experimental Production of Suppurative Inflammation. — While, as shown by Councilman, Grawitz and de Barry, Straus, Leber and others, a suppurative inflammation may under certain conditions be brought about experimentally by the action of chemical irritants, such as mercury and turpentine ; yet under ordinary pathogenic conditions suppuration is induced by the growth of micro-organisms within the tissues. Hence it is better to study the conditions as induced by the inoculation of pus-producing microbes into one or other tissue. A very full series of observations upon the development of abscesses through the agency of the Staphylococcus pyogenes aureus has been made by Hohn- INFLAMMA TION 7» feldt. He employed rabbits, and incculated small quantities of pure cultures of the microbe subcutaneously. Four hours after inoculation the vessels of the region were found densely filled with corpuscles, and in them a commencing margination of the white corpuscles was discernible. Leucocytes were present within the tissue in numbers greater than normal ; although, compared with later stages, they were infrequent They were of two kiuf^s — the mono- nuclear in the majority, the polynuclear (or more truly the form with polymerous nucleus) in lesser numbers; both forms were congregated mainly around the line of entrance of the injecting needle. Many of the connective tissue cells were so swollen as to be rounded rather than flattened. The injected cocci, lying in the lymph spaces, were scattered through the tissue ; in part free, in part already ingested by cells, not only by the leucocytes, but also by connective tissue cells : the number within leucocytes was not inconsiderable. Preparations made at the end of ten hours showed the same conditions, but more distinctly. There was ample evidence of migration of the leucocytes, margination in the congested vessels, various stages of passage through the vascular walls, and large collections of the cells in the peri- vascular Ij^mph spaces ; from these they spread into the spaces between the bundles of connective tissue fibrils. The cocci lay in the lymph spaces and were increased in number, and the massing of leucocytes cor- responded in position to the accumulation of microbes. In these regions the leucocytes were mainly polymerous or multinuclear, but in the boun- dary zone away from the cocci the uninuclear form predominated. At the end of twenty hours there was further accentuation of these conditions. As yet an abscess proper had not formed, but enormous numbers of leucocytes were present, and also of mit.ococci; the fibrillao of connective tissue were widely separated by the collections of leuco- cytes, and these cells clustered round and hid the connective tissue cells. With the completion of forty-eight hours a well-defined abscess had formed, separated sharply from the surrounding healthy tissue. The centre of the abscess was seen to consist of densely-packed leucocytes mingled with largo growths of cocci. These leucocytes were almost entirely " miiltinuclear ; " and in this central area the nuclei of some showed fragmentation. Neither leucocytes nor connective tissue cells showed the slightest indication of mitosis. In the central area all traces of the previous capillaries had disappeared ; in the peripheral zone they were easily recognisable, being fully injected and showing a marginal disposition of their leucocytes, many of which could be seen (in osmio acid preparations) fixed in the process of diapedesis. The majority of the cocci lay in these leucocytes. Even whore the colonies of the microbes were thickest there the majority were intra- cellular. Passing towards the periphery the number of cocci became smaller and smaller. At the periphery they could Ix? seen not only to bo intracellular, but also free in the lymph spaces ; and Hohnfeldt, with other observers, saw them definitely grouped within the endothelial cells 72 SYSTEM OF MEDICINE of the peripheral vessels. Thus it may be noted that at this stage the proliferating microbes extended into the healthy tissues outside the abscess. In the centre of the abscess the original tissue had wholly disappeared ; nearer the periphery light streaks and bundles of the disintegrating fibrillae could be recognised between the leucocytes. Not till about the tenth day did new growth of tissue begin to show itself. During the preceding six days there had been more breaking down of the polynuclear leucocytes, characterised by fragmentation of the nuclei and by fatty degeneration of the cell substance. But by the tenth day the periphery had begun to assume the appearance of granulation tissue ; it contained numerous capillaries and new-formed connective tis- sue with characteristic epithelioid cells or fibroblasts possessing large oval pale staining nuclei. In these cells, as in the connective tissue cells of the surrounding healthy tissue, could the numerous steps of indirect cell division be made out. In this granulation tissue cocci were absent and leucocytes were infrequent. In the soft, cheesy central area masses of cocci were still present. Whether these were living or dead Hohnfeldt did not determine ; he inferred (what has since been proved by several observers to be an unsafe inference) that inasmuch as they stained well with aniline dyes they were alive. Thus, to sum up Hohnfeldt's observations, the processes occurring in a suppurative inflammation that ends in healing are the following : — 1. Congestion of the region of invasion, with marginatiou of the leucocytes. 2. Collection, in the region, of uninuclear leucocytes ; then diapedesis of leucocytes with polymerous nuclei : multiplication of the cocci. 3. Ingestion of large numbers of the microbes by the polymerous leucocytes and other cells, including the endothelial cells of the vessel walls. 4. Increasing immigration of leucocytes until the tissue becomes densely packed. This is accompanied by a yet greater proliferation of the microbes, whicli extend (i.e. are carried by lymph streams or by cells) into the region outside the developing al)sces8. 6. Destruction of tlu! tissue of the aft'ectiMl part. 6. Degeneration of the leucocytes within the sharply-defined abscess. 7. Eventual proliferation of the connective tissue at the periphery of the abscess ; formation of fibroblasts in the highly vascular surrounding zone; cicatrisation and encapsulation of the debris of the leucocytes and micrococci. There are not a few points in connection with these observations of Hohnfeldt that deserve discussion ; very possibly ho has misinterpreted certain of the appearances seen by him. On the whole, however, he draws a ftill and accurate picture of the successive stages of suppurative inflammation, and I may defer discussion to a later review of the action of the leucocytes and of the formation of fibrous tissue respectively. However, before leaving this general description of the scries of INFLAMMA TION 73 anatomical changes induced by injury, there is another phase of the inflammatory process set up by pathogenic micro-organisms which must not be passed over — I refer to those cases in which, instead of ending in repair, there is extension and generalised disease. The stages pre- ceding extension vary with the nature of the microbe ; thus, in some cases, the reaction to the invasion of the microbe is mainly leucocytic (as with inoculations of the micrococci of suppuration), in others it is mainly exudative or serous, the congestion of the vessels being followed by abundant exudation of serum into the tissues. This is the case in inoculation of animals — such as rabbits, guinearpigs and fowls — with cultures of micro-organisms which are peculiarly virulent in their bo- haviouf towards these animals. Such a serous or exudative inflamma- tion is, for instance, well seen if the vibrio Metschnikovi be inoculated into the pectoral muscles of a fowl. Within twelve hours, it may be, the seat of inoculation becomes greatly swollen, and on section is found reddened and congested; while from it drains an abundance of relatively clear, faintly-reddish serum containing but a few leucocytes. In such a case as this the micro-organisms appear to pass with ease from the centre of infection into the surrounding tissues, and thence into the lymphatics and general circulation, whence they may be obtained within twenty-four homs. Where there has been a well- marked abscess formation in the region of invasion there, as already indicated, it is true that the microbes may be found outside the abscess at a fairly early period ; but, in the main, proliferation is limited to the abscess, and the blood remains free and sterile. Under certain condi- tions of great virulence of the pyogenic microbes it is found that as the abscess extends it becomes ill-defined — there is no shcarp demarcation between the collected leucocytes and the surrounding tissue; the columns of leucocytes spread indefinitely from the centre, and numerous micrococci are intermingled with them. Where this is the case there is a marked tendency for the microbes to find their way into the general circulation from this irregular peripheral extension along the lynipliatio spaces, and to set up a condition of septicajmia as in the more serous inflammation described above. Septicemia, or the passage of micro-organisms into the blood, with all the results of sucli a passage — the condition which sundry French observers have described as inflammation of the blood — is dealt with in another article. In septicemia we pass beyond the local response to injury, we deal with a state of general systemic disturbance. Never- theless certain phases of the septicajmic condition throw light upon tho inflammatory process. In the first place, it is of interest to note that when tho infective micro-organisms and their products are within tho vessels they fail to mduco the cardinal symptoms of inflammation. They do not lead to exudation of fluid from tlie blood or to wide-spread diapedesis of leuco- cytes. The stimulus, whatever it be, wliicl) leads to these phenomena at the point of iuvasioa is no lou^jor called into activity when the uoxa is 74 SYSTEM OF MEDICINE within the circulatory apparatus. This is the reverse of what might be expected if the inflammatory process were primarily due to a modification of the endothelium of the vessel walls by the irritant, a modification pas- sively permitting the exudation and passage outwards of the leucocytes. The statement that infective micro-organisms and their products circulating within the ulood fail to induce inflammatory changes, would seem to need modification when the development of metastatic abscesses is taken into account. But a study of the mode of pi-oduction of these abscesses shows that the statement still holds. Such abscesses originate round emboli of pyogenic micro-organisms in the capillaries. Sundry cocci are arrested in the capillary, proliferate and fill the vessel. It is only when a minute vessel is thus occluded that the abscess process begins, that is to say, when by this occlusion the vessel has become extravascular ; and while it is true that, primarily, the arrest of patho- genic microbes within the capillaries is often associated with a small accumulation of intravascular leucocytes and with degenerative changes in the vascular endothelium, the metastatic abscess, as such, forms not by accumulation of leucocytes in the occluded vessel, but around it ; the leucocytes emigrating from surrounding capillaries. Inflammatory Fever. — In the second place, through this study of advancing inflammation it is of interest to trace the very close relation- ship that exists between inflammation and fever. Besides the local changes here described, local injury is accompanied by systemic dis- turbances. These may be slight or grave. Take, for instance, progressive abscess formation, or follow the development of a malignant carbuncle in man. At first the reaction is purely local, but very soon, long before any of the micro-organisms are capable of detection in the blood, thero is exaltation of temperature and a slight febrile state, the fever becoming more and more evident as the local process becomes more and more extensive, until with the detection of the microbe in the blood the most severe fever, with con- stitutional disturbance, sets in. Local inflammation, then, without any other possible explanation than either tlie nervous irritation to which it may give rise, or the passage into the general circulation of the soluble products of bacterial growth and tissue destruction, or both, may load to the development of the febrile state. How large a share is l)laycd by these two possible factors it is difficult to say. That bacterial products injected into the circulation lead to the rapid pro- duction of the febrile state wo have ample evidence ; but whether those act directly by inducing increased cellular activity, or indirectly by stimulating the censbral centres, wo cannot absolutely say. As yet wo have little accurate knowledge of tlie ]iarts played by the nervous system in the devolo])mpnt of the febrile state. This, however, may safely be declared, that the more we study the continued fevers the more do we discover that these commence by a local inflammatory disturbance. The continued fevers are the continuance, or rather the extension, of a primarily localised inflammatory lesion. [Vule art. on " Fever."] INFLAMMA TION 75 Summary of the Facts thus far brought forward. The main facts gathered thus far concerning the inflammatory pro- cess, and the conclusions to be drawn therefrom, may now be placed in order before I discuss in detail the various factors in the process. They are — 1. Injury, when it is not so widespread and severe as to lead to the death of the individual, is followed by a reaction on the part of the organism. 2. In unicellular organisms the continued vitality of the individual after injury, and in multicellular organisms the vitality of the indi- vidual cells, are dependent primarily upon the persistence of the nucleus ; if this be destroyed or removed the rest of the cell is incapa- ble of complete restitution and continued growth. 3. In unicellular organisms the reactive process is twofold, and con- sists of (a) destruction or removal of the irritant; destruction being brought about by a process of intracellular digestion, removal by extru- sion of the irritant : (p) new growth of the organism. 4. This response to injury on the part of unicellular organisms is essentially reparative. 5. In multicellular organisms, with division of labour among ^e constituent cells of the individual, there is a separation of functions ; the twofold reaction to local injury is yet more clearly mai^ked ; but (a) The destruction or removal of the irritant is in the main accom- plished by the wandering cells of mesoblastic origin. (6) The new growth to replace the tissue destroyed by the irritant proceeds in the main from the fixed cells of the tissue. 0. Ascending the scale of multicellular organisms, a division of labour and differentiation of function is discoverable among the wander- ing mesoblastic cells. Whereas in the lower forms of the Metazoa one type of leucocyte alone is present, in the higher forms two or more varieties can be distinguished which possess different properties and act differently towards irritants introduced into the system. 7. According to the nature of the irritant causing the injuiy, the leucocytes are actively attracted in greater or less numbers to the region of injury, surround the irritant, and remove or destroy it by means very similar to those employed by unicellular organisms. Where the irritant is present in the form of discrete particles, there some at least of the leucocytes may incorporate the particles, and remove them or destroy them by a process of digestion. Others of the leucocytes in the higher Metazoa never act thus as phagocytes; nevertheless they are equally attracted to the focus of inflammation, and presumably tend to counteract the irritant by some other (extracellular) means. 8. While to the wandering cells appears to bo allotted the main duty of removing dpletori()\is and irritant matters, certain of the fixed cells of the orgatiism, notably the endothelial cells of the vcssj'Is, cnn also exert these functions. 76 SYSTEM OF MEDICINE 9. Among the very large number of Metazoan forms in which no complete vascular system is present, this attraction of the leucocytes to the region of injury is at first the sole response to injury. At a later period proliferation of the fixed cells occurs in the neighbourhood of the injury. 10. Among the higher Metazoa, in which there is a well-developed vascular system, the determination of leucocytes to the region of irrita- tion still continues, and is in fact markedly aided by the participation of the vessels in the inflamirntory process. 11. The vascular phenoraena in inflammation may be regarded as serving two main purposes — (a) the pouring out of increased fluid into the injured area ; (6) the afflux and diapedesis of leucocytes. 12. Even in the highest Metazoa, possessing fully-developed vascular systems, the response to injury in a non-vascular area, such as the cornea, may be associated with no change in the surrounding vascular areas, but purely with a determination to the injured area of leucocytes already free in the surround) :ig tissues. 13. The second phase of the inflammatory process, that of tissue repair, but very rarely occurs without evidence of previous migration of leucocytes and exudation from the congested vessels. 14. A comparative study leads inevitably to the conclusion that the determination of leucocytes to the region of injury is the most constant and most characteristic early response to injury recognisable through- out the Metazoa, and that it must be regarded as the most important factor in the first stage of the inflammatory process. The vascular phenomena noticeable in the higher Metazoa must be regarded as a second and highly important factor of later development and adjuvant. New tissue formation is the prominent characteristic of the later stages of the process. 15. As among the Protozoa, so in the Metazoa, the response to injury is consistently an attempt to repair the injury. This general survey of the response to injury throughout the animal kingdom demonstrates most clearly that the same broad principles, the same methods of defence and repair on the part of the organism, are called into activity from the lowliest forms to the higliest ; that, in fact, no line can be drawn to separate one set of phenomena as truly inflam- matory from another set which, while also a response to injury, are non- inflammatory. Although it is true that the term inflammation implies a reddening and congestion of the vessels, we find upon closer exam- ination that this reddening and congestion is not the fundamental but a superadded feature in the process of repair of injury — a feature super- added as the organism advances in its place in the animal kingdom. Thus if we are to comprehend the process satisfactorily we must pass beyond the narrower acceptation of the term. Having thns sketched broadly the general phenomena of the inflam- matory process, it will bo well now to describe in fuller detail the factors of this process among the higher vertebrata, and to bring together the INFLAMMA TION 11 more important results of the study of the respective functions of the wandering cells, the vessels, the fixed cells, and the nervous system in inflammation. PART 11. — The Factors in the Inflammatory Process Chapter 1. — The Part played by the Leucocytes The Leucocytosis of Inflammation. — As I have already shown, there is more than one form of leucocyte in the mammalian organism, and the several forms evidently possess different attributes, and act differently in the reaction to injury. Inasmuch as these forms have been variously classified — so variously, in fact, that it is often far from easy to collate the various descriptions, and to discuss the forms distin- guished by one observer in the terms of another — it is necessary to give the chief classifications of them, and their relations. The first to discriminate between the forms of white corpuscles in the blood was Wharton Jones so long ago as 1846. He drew a dis- tinction between A. GranuWlta jSr^"ar. B. " Nucleated " cells — Non-granular. His observations, together with those of Rindfleisch in 1861 and 1863, were confirmed and advanced by Max Schultze, who made out the following forms : — 1. Small round cells with round nucleus and little clear protoplasm. 2. Larger cells with round nucleus and more clear protoplasm. 3. Cells with finely granular protoplasm, and one, two, or more nuclei. 4. Cells with coarse granules in the protoplasm. . The distinctions drawn were, so far, purely morphological ; and very little notice was taken of these varieties for a long period until Ehrlich, in a notable series of papers extending from 1878 to 1887, drew atten- tion to the fact that the wandering cells of the organism react diversely towards the different aniline dyes and possess diverse tinctorial affinities indicating chemical differences in the nature of certain constituents of the cell bodies. The granules of the i)rcvious observers were found to bo variously affected by the dyes emjiloyed ; they were shown not to be fatty, but — as Ehrlich put it — of the nature of a glandular excre- tion ; * and comparing the effects of the two groups of aniline colours — that in which the dye is associated with the acid constituent of the salt, and that wherein the dye forms the base (the "acid" and ** basic" • .1. Woiss lias Btudlod tho micro-ohemlcal reactions of the oosinopbilous Rranulns, and coiinludcH that tlioy aro of allxuiiinoid nature ; asthoy were found not to be digested in gastric juicu ho would ally thum witli tho uucleins. 78 SYSTEM OF MEDICINE aniline dyes respectively) — lie made out the existence of five forms of granulation associated with as many varieties of wandering cells. His table of cells according to their granulation is as follows : — a. Granulation — Eosinophile. — Cells frequently in horse's blood, present con- stantly in small numbers in human blood ; numerous in medulla of bones of rabbits, dogs, guinea-pigs, etc. Stain deeply with acid aniline dyes. Granules large and coarse. /3. Granulation — Amphophile. — Cells frequent in rabbits and guinea-pigs in blood ; present also in medulla of bones. Stain both with acid and basic dyes. Granules fine. >. Granulation — Basophile. — Largo cells found in the connective tissue, from the frog upwards, "Mastzellen" ; in blood of man only in cer- tain cases of Leucaemia. Stain only with basic dyes. Granules coarse. 3. Granulation — Fine Basophile. — The "mononuclear" leucocyte of human blood. Granulation fine. Stain with basic dyes. e. Granulation — Neutrophile. — The most frequent leucocyte of human blood, " polynuclear." Stain only in neutral dyes — not in acid or basic. While Ehrlich and his pupils, and Rieder, have done much to throw light upon the relative numbers of the leucocytes possessing these different granulations in different diseases, they have accomplished little in dis- covering the origin of the various forms, their functions, or their relation- ships. We owe the first satisfactory studies upon the properties of the different forms to Metschnikott", who, at an early period in his long- continued and wonderful series of researches upon Phagocytosis, made out that the different wandering cells of the body act differently towards microbic and other foreign particles introduced into the organisms. Thus he was led to draw a distinction between — 1. Lymphocytes — immature leucocytes. 2. Large hyaline cells, mononuclear, phagocytic, "macrophages."* 3. Smaller neutrophile cells, polynuclear, *' microphages." 4. Eosinophile leucocytes — not phagocytic."'' Quite recently the admirable researches of Prof. Sherrington, and of Dr. Kanthack and Mr. Hardy, have appeared which, starting on the groimdwork laid down by the older observers, have made a notable advance in the determination oi the function of the various forms of wandering cells in inflammatory and other conditions. The observations 1 While acknowledging that a certain amount of convonicneo attends the employ- ment of these terms, " macrophage" and " raicrophago," I cannot but agroo with Pro- fessor Hurdon-Sanderson that they are utterly l)ai'l)aric. 2 While this article was passing through tlio press, M. Meanil, a pupil of Motschnikoff, has stated that eosinopliilous cells can occasionally act as pliagocytos. The statement is contrary to MetschnikofT's previous observations and, I may add, contrary to general experience. Until furtliur uuuliriuatury obtiurvatiuuu huvu buou uadu, I am uut prepared tu accept the statement. INFLAMMATION 79 of Kanthack and Hardy are especially full, and I shall have occasion to refer continually to their results. In the mfeantime it may be said that they materially simplify the classification given by Ehrlich, by dividing the leucocytes thus : — 2: ^fn^'SJaf ' } 0^P^« ««"«• Staining with acid dyes. 4:Rne^'^SM*'}Ba«)plulecell8. Staining with basic dyes. 6. Hyaline cells, i). Lymphocytes. Their coarsely granular oxyphile cells are the eosinophile cells of most writers ; their finely granular are the neutrophile and amphophile of Ehrlich. They prove conclusively that Ehrlich's neutral stain is in no sense to be regarded as such, but must be considered as an acid dye. It is now possible to collate these various classifications, and in this way to begin to study the functions of the various forms with a clear appropriation of the terms employed in the following paragraphs. Collation of the different Classifications of the Varieties of Leucocytes. Kanthack and Uardy. Ehrlich. Metschnikoff. Max SchulUe. Wharton Jonca. Lymphocyte. Lymphocyte. Lymphocyte. Small round cell I. (Non-granular t nucleated cells. Hyaline cell. Macrophogocyto. Large round cell H. Coarsely granular Eosinophile coll. Eosinophile cell. Cells with coarsely Grannie cells, oxyphile. granular proto- plasm. coarsely granular. Finely granular J oxyphile. ( Neutrophil ,^^ Amphophile Miorophogocyte. Cells with finely Granule cells, finely granular proto- granular. plasm. Coarsely granular Basophile cell with basophile. y granulation. Maotzellen. . Finely granular Basophile cell with Cells with finely ? Granule cells, finely basophile. J granulation. granular proto- plasm. granular. LymphocyU. — Immature leucocyte ; round nucleus deeply staining ; scanty pro- toplasm ; increased in number after food ; diminished after starvation ; indi&tii.guishable from small elements of lymphoid tissue. Not phagocytic ; variable in number ; not amoeboid ; may form up to 30 per cent of tho leucocytes present in human blood. Uyaline Cell. — Kound or kidney-shaped nucleus of slight staining power ; abundant protoplasm ; hyaline ; non-granulated ; actively amooboid and phagocytic ; rare in blood (2 per cent) ; abundant in coolomic fluid. Nuclei have been s». en to undergo mitosis. Coarsely Granular Oxyph 'le. — Large horseshoe-shaped nucleus (in man) ; rela- tively large spherules in protoplasm ; highly refractive ; staining deeply with acid aniliuo dyes ; abundant in cwlumic lluid, iu serous cavities, in inter 79 &> SYSTEM OF MEDICINE stices of areolar tissue (K and H), and in bone marrow (Ehrlich) ; rare in blood (2-4 per cent) ; amoeboid ; non-phagocytic. Finely Granular Oxyphile. — Smaller than last (in man) ; nucleus branching or polymerous, staining deeply ; granules very small and spherical ; feeble oxyphile reaction (Ehrlich's amphophile reaction in rabbit, neutrophile in man, etc.). Abundant in blood (20-70 per cent of all leucocytes) ; absent from ccBlomic fluid ; actively amcaboid and phagocytic. The most common form of pus cell. Coarsely Granular Basophile. — When found free in coelomic fluid, round nucleus staining very feebly ; spherules large and numerous, stain with basic dyes — somewhat similar cells are found stationary in connective tissue spaces — absent from human blood in health ; non-phagocytic. Finely GHranular Basophile. — Spherical ; smallest of the wandering cells ; tri- lobed nucleus ; clear cell substance containing great numbers of fine baso- phile dots. Found in human blood in small numbers (1-5 per cent) ; increased after meals. From this description of the character of the various forms of leuco- cytes (for which I am largely indebted to Kanthack and Hardy) it will be seen that certain forms are characteristically present in the circulating blood, namely, the finely granular oxyphile and the finely granular baso- phile ; others in the body fluid, namely, the coarsely granular oxyphile and coarsely granular basophile ; while the lymphocytes and hyaline cells are common to both fluids. It must be added that the eosinophile, or coarsely grantdar oxyphile, are also present in small numbers in the healthy human blood : it occurs in larger numbers, however, in diseased conditions which do not come within the scope of this article. Of the origin and relationship of these diverse cells we still know very little. As Gulland has pointed out, the blood of the embryo is entirely free from white corpuscles. The exact period at which each form makos its first appearance has not yet been studied, although in all probability such a study would throw a flood of light upon the origin of the different orders of cells. The most that we can say with fair certainty is that the lymphocytes, while representing the larval form of leucocytes in general, are in the main derived from lymphoid tissue ; that some of them develop into the hyaline cells (for, as Sherrington and others have noted, every gradation is observable between these two forms) ; and that what appears to be an immature eosinophile cell can often be detected in the peritoneal fluid, as also an immature coarsely granular basophile cell (Kanthack and Hardy). Beyond this we have not at present advanced.* Ehrlich's sug- gestion that the eosinophile cells are derived from the bone marrow may II quite understand that sundry obBGrv«.r8 rcKard all the various forms of leucocytes as modiiications one of another. It is true that all embryologically have the same origin ; BO, for example, have the corpuscles of cartilage and bone, yet this does not make carti- lage and bone one tissue. Evcrard, Gulland, RutTor, Dcmoor and Massart, state that all transitions are observable between the various forms ; I cannot but think that the methods of staining employed by these observers were insulHciont for these wide conclusions. It is interesting to note that these observers, like Kantliack and Hardy, fouud Ehrlich's «mphophilu and uoutrouhilu colls to utaiu with oouiu, i.e. tc bu oxyphile. INFLAMMATION 8i be partially true, but not entirely ; inasmuch as it is difficult to correlate the preponderance of these cells in the body fluid with so special and local an origin. Nor can the recent observation of Siawcillo, that eosinophile cells are abundant in the ray which possesses neither bone nor bone marrow, be regarded as favourable to Ehrlich's hypothesis. And again, the observations of MetschnikofE and his pupils render it eminently probable that some, at least, of the large hyaline cells are derived not from lymphocytes, but from proliferating endothelial cells of the lymph and blood-vessels and of serous surfaces. Finally, it is noticeable that the cells with multilobate nucleus (the finely granular oxyphile), the commonest of the haemal leucocytes, are not to be recog- nised in lymphoid tissue : yet, as Sherrington has pointed out, certain of their peculiarities, notably the contorted shape of the nucleus, may be regarded as acquired, inasmuch as if they be allowed to remain at rest in the living state outside the body the nuclei become more spherical. Of these varieties of wandering cells not all have, so far, been found to bear a part in the inflammatory process : but certain forms appear to have distinct functions therein: these are the finely granular oxyphile (neutrophile), the coarsely granular oxyphile (eosinophile), and the hyaline cells. » A word should here be said concerning the cells of later development, appearing as a result of inflammation — giant-cells, Ranvier's cells, and Gluge's corpuscles. Of these the last are evidently leucocytes of the hyaline type which have taken up the fatty products of tissue degeL ora- tion; the second — colossal cells breaking down with great ease — ar*i of doubtful origin. Giant-cells would seem to be of more than one variety : some appear to be due to aberrant cell growth, wherein the nuclei undergo division without the protoplasm of the cell body following suit. The characteristic giant-cells of tuberculosis and chronic inflammation may now be said with fair certainty to be plasmodia, in all respects com- parable to the masses of fused cells seen to form in the lower animals around foreign bodies, and by Kanthack and Hardy around masses of bacteria in the lymph of frogs outside the body. The recent observations of Borel and of Duenschmann strongly support this opinion. Phagocytosis. — In the case of a very large number of pathogenic micro- organisms (so large a number that merely to enumerate them, with the names of the observers and of the animals upon which the observations have been conducted, makes a list so long that in the bibliographical table at the end of this article I give only the more important references, and not nearly the complete list), after inoculation into the organism, a very considerable proportion are to be discovered, sooner or later, within wandering cells which have collected in the region of inocula- tion. I have already mentioned more than one case of this nature in discussing the comparative pathology of inflammation. Evidently under certain conditions one of the functions of certain of the leucocytes is to attack and incorporate bacteria. The leucocytes having these properties are more especially the finely granular oxyphile (where the injection has VOL. I G 82 SYSTEM OF MEDICINE been into a neighbourhood richly supplied with vessels), the hyaline cells chiefly where the microbes have found an entry into the body cavity. It is, for instance, the finely granular oxyphile cell which is found in overwhelming numbers in an extending subcutaneous abscess, and these are seen to contain great numbers of the micrococci. The conditions leading to this phagocytosis have been very fully worked out by Metschnikoff. He has amply demonstrated that the microbes can be taken up in a living condition. Thus, if the Vibrio Metschnikovi (a form closely allied to the cholera spirillum) be inocu- lated into the anterior chamber of the eye of an immunised animal, within a very few hours phagocytes are discovered filled with the small, slightly curved vibriones. If now one such cell be isolated, placed in a drop of a^' -a Vio. 1. — Resolution of acute infectious disease (relapsinf? fever), spleen pulp of monkey (Macaous erytlir.), showing (") mioropbogc, inultinuclear, witli inceptod spirochaetes ; (b) solitary, and (o) forininf? dense tangle, (d d) nuclei of splenic tissue (Zeiss, ■fg ocular 4 ; x 1515 diam.)- — [Motsch- nlkutr (61). ] broth upon a coverslip, made into a hanging drop preparation and exam- ined under the microscope, it is seen that the broth causes the death of the leucocyte; while with time, and favourable temperature, the microbes proliferate rapidly, and completely fill the corpuscle until it disinte- grates; whereupon they proceed to multiply in the surrounding fluid. This seizing and incorporation of microbes does not then necessarily lead to their death. In certain cases of acute disease there may be abundant phagocytosis, and the disease progress nevertheless; the phagocytes being destroyed by the products of the incorporated organ- isms. This is the case in mouse septicaemia, in swine erysipelas, and (as has been shown quite recently by Gabritchewski) in diphtheria. As M. Koux remarks : " lis ont fait de leur mieux en englobant les microbes, mais ceux-ci se sont adaptes au milieu iiiterieur des cellules, et ils out triomphes." * ^Uuux. — Trans. Internal. Oongreaa of Hygiene, Loudon, 1891, ii. p. 120. INFLAMMA TION 83 In other less acute diseases, such as gonorrhoea; and in chronic maladies of a tubercular nature — in tuberculosis, leprosy, and glanders — the bacilli may in certain stages be found within the cells and rarely free in the lymph spaces, they appear to be almost parasitic, after the manner of the microsphaera previously referred to as infesting the amoeba. Fio. 2,— Two giant-cells, seen nnder high magnification (x 161B dlam.) from a rodent, the spermophllo, . Inocnlated with tuberculosis, to show stages In the destruction of the bacilli, a, unaltered bacillus ; h, bacillus staining badly, and with greatly thickened capsule ; c, bacillus granular and breaking up ; <2 e, " shadows." — [Metschnlkoff (51).] In these cases it would seem as though the toxic properties of the microbes and the antagonising powers of the cells were nearly balanced. In tuberculosis, for instance, it is not unusual to find in the giant-cells some bacilli which evidently are undergoing degenerative changes, stain- ing poorly and irregularly, or but faintly traceable as unstained, translu- cent shadows, while elsewhere they are apparently proliferating despite their intracellular position.^ . 1 It is, however, unsafe to declare in all cases that because a micro-organism con- tinues to stain well therefore it was living at the moment the preparation was taken and SYSTEM OF MEDICINE And this equality, or almost equality of the resisting powers of cells and microbes, may explain the chronic nature of the diseases above men- tioned. Nevertheless, in general, it may be stated that there is some rela- tionship to be recognised between tlie amount of phagocytosis and the viru- lence of the microbe ; the more virulent the microbes the less the proportion of them taken up by the cells ; and, as Kanthack and Hardy have pointed out, the longer the time before the phago- cytes come into action. As is the case in the unicellular organisms, so in the wandering cells of higher animals the process of destruction of the included microbes can, under suitable condi- tions, be seen to be digestive. Sev- eral observers have seen the anthrax bacillus, in frogs and other animals, wholly or in part surrounded by a vacuole developed within the leucocyte ; and, as an evident result, the Vw. 8. — Phogocytos, mocrophof^e and mlcro- Jilm^o, to shuw HtitKus of di^eBttoii and testriiction of bncllH, from splcun and evo respectively of wldto rat wltli anthrax. In i, part of the bauillim is uiiatfcvtod, Iiiit a viicnolo lias forii> *d around the otlier part, wliicli ftirthor lias now lost the power of talcing tho stain. In S, various stages tro seen, tho bacilli passing through the granu- lar badly staining, to tho vacuolated un- stained, until flnully but tcAwt " shadows " ore observable (Zeiss A, oo. 8). — [Metsch- nlkotl(51).] Fio. 4. —Anthrax of pigeon (an animal but slightly misceptiblo to tho diseaso) to show stogoB of destruction of bacilli by phagocytes. 1 and 2, macrophages : 1, from exudation from eye of re- froctory bird ; 2, ft-om muscle of region of inoculation of bird that buccuuiImmI ; 3, A, 5, micro- nhages —all from eye twenty-seven hours after in(H!ulation ; a a, unaltered bacilli; &• //' b*, bacilli becoming more and more degenerated and indistinct: o c, d6brls of bacilli (Zeiss A, ooulur 3).— [Met8chnlkoir(51).] portion so surrounded has been seen to become swollen and fainter when stained, until it has undergone a veritable digestion and dissolution. As with the lower organisms, so with the wandering cells of fixed by heat. Tims in pneumonia after tlie crisis a fair number of diplococci may bo found Avithin the leucocytes of tho expectorated contents of the alveoli, and these may stain perfectly well ; yet it may bo impossible to gain a single growth of tho diplocovcus from tho same material. INFLAMMA TION 8S the higher, there is an evident attraction, or chemiotaxis, whereby these cells pass towards the microbes and their products; and this chemiotaxis would also seem in general to be in the inverse ratio of the virulence of tlie microbes. I say in general,- for with chemiotaxis as with phagocytosis there appear to be exceptions to any uniform law; and cases can be brought forward — of diphtheria, for example — in which the leucocytes, instead of being repelled, are attracted in great numbers to the region of inoculation of a most virulent bacillus. The chemiotactic properties of the wandering cells have been especially studied by Pekelharing, Leber, Massart and Bordet, and by Gabritchewski. Of the results obtained by these observers the most important are that leucocytes are variously attracted towards various substances. Thus Leber found that the introduction into the system of finely-powdered copper and various compounds of mercury caused an abundant collection of the wandering cells around the particles, while powdered gold, silver and iron exerted no such attraction. Gabritchewski and A. Schmidt showed that the products of bacterial growth in general possessed chemio- tactic properties yet more powerful than simple chemical compounds. While the degrco of positive chemiotaxis is found to vary within wide limits, the examples brought forward of negative chemiotaxis exerted by bacterial products have so far been very few — so few as to support the contention of Dr. Kanthack, that it is very doubtful whether any microbes by their products actually repel the leucocytes, though they are capable of causing the rapid destruction of the attracted leucocytes, and so of rendering the area around the microbes relatively free from wandering cells. A very good study of the action of bacteria of different degrees of virulence can be made by repeating an experiment of Metschnikoff. The rabbit is an animal susceptible to the growth within its tissues of the bacillus of anthrax. As is well known, there are various means whereby the virulence of this microbe can be diminished ; so that if cultures of the "attenuated" bacillus be inoculated into susceptible animals, these, instead of causing a fatal disease, induce but a transient local inflam- matory disturbance, accompanied by fever, and followed by complete recovery. If now a small quantity of a virulent culture of the bacillus be inoculated into the one ear of a rabbit, and an equal quantity of an attenuated culture into the other, the results are very instructive. Within twenty-four hours it can bo noticed that an acute inflammation has been induced in both ears ; in both the vessels round the seat of inoculation are greatly congested, but whereas at the seat of inoculation of the virulent organism there is a serous inflammation so intense that the skin is raised and separated from the subjacent tissues by a clear, transparent, reddish fluid which also infiltrates the decj)er tissues, in the other ear there is not nearly the same amount of swelling and serous exudation; the region of inoculation is more opafjue and solid. Upon mure minute examiuutiuu the serous fluid iu the first uui- is fouud to 85 86 SYSTEM OF MEDICINE contain relatively very few leucocytes ; the firmer mass in the second is composed of a huge aggregation of leucocytes [yid. art. " Anthrax "]. Evidently, therefore, the relative number of leucocytes migrating, and the quantity of serum exuded, depend very largely upon the inten- sity of the irritant; and by the intensity of the irritant, and the behaviour of the leucocytes, the forms of the inflammatory process may be classified. But to the subject of classification I shall refer later. In the meantime it is well to sum up the theory of phagocytosis as upheld by Metsch- nikoff and those who see in this phenomenon the all-important factor in inflammation and the repair of injury (as also in the production of immunity), in order that, having put clearly forward the tenets of those upholding the theory, I may the more readily state wherein lies the strength and wherein the weakness of the doctrine. The theory of phagocytosis as set forth in MetschnikofiE's later writings may be summed up in the following theses : — 1. That certain of the leucocytes present in the blood and lymph, notably the finer granular oxyphile or neutrophile, and the large hyaline, are capable under certain conditions of taking up bacteria which have gained entry into the system. 2. That in addition to these the splenic corpuscles, the cells form- ing the endothelium of capillaries, and sundry other fixed cells of meso- blastic origin, possess the same property, although they exert it to a less extent. 3. That these phagocytes seize upon and destroy living and active microbes under certain conditions. 4. That the more virulent the microbe the less the tendency for the leucocytes above mentioned, and for the other fixed cells, to take up the bacteria. The less virulent the microbe the more extensive the phago- cytosis. 5. That in addition to this power on the part of certain cells (the phagocytes) to take up and destroy certain bacteria, another factor has to be called in to explain why the wandering cells of the body migrate towards the focus or foci where the micro-organisms have gained an entry into the body. This factor is the "cliemiotaxis" exerted by the products of bacterial growth, and by some other substances, Hiicli, for example, as the productsof dcatli of tissue and of wanderingcolls ; and experimentally also certain chemical irritants as, for example, turpen- tine and mercury. In the case of the virulent microl)es the leucocytes are not attracted to the focus of infection. There is a "negative" chomiotaxis, and thus, in the absence of j)hagocytosi8, the i)roliforation of the microl)es takes ))la('.e without hindrance; whereas the loss virulent microbes and their ])roduct8 attract the leucocytes, they exert a positive cliemiotaxis, so that there is a migration of leucocytes through tlie capillary and venous walls to the fotuis of infection, and the leucocytes taking up the microbes tend to arrest the infective process. (5. That the leucocytes may become acciustomed and eventually w n n \ INFLAMMA TION 87 attracted to substances from which at first they were repelled, and thus a negative may be transformed into a positive chemiotaxis. 7. That the cells, having once acquired positive chemiotactic pro- perties in relation to the products of any specific microbe, retain and transmit these properties through a series of cell generations, the length of which varies according to the microbe, the extent of the primary reaction, and the idiosyncrasies of the individual. 8. That, consequently, the cure of zymotic or mycotic disease, whether localised or general, and immunity also, are mainly brought about by the activity of special cells (the phagocytes), and are prima- rily dependent upon the attraction existing between these cells and the products of bacterial metabolism. 9. The process of inflammation is essentially the endeavour on the part of the organism to promote the migration of leucocytes, and to aid the inclusion and destruction of the irritant. "The essential and primordial element of a typical inflammation is a reaction of phagocytes against the irritant (agent nuisible)." (14) Or, more fully, " inflamma- tion is to be regarded, on the whole, as a phagocytic reaction of the organism against irritants, — a reaction which at times is accomplished by the wandering cells alone, at times with the aid of the vascular (fixed) phagocytes, or with that of the nervous system." 10. That in rare cases bacteria may be affected if not destroyed by extracellular action, by substances derived from the leucocytes and dissolved in the surrounding lymph. In the terms of this theory, then, phagocytosis is the all-important factor in the inflammatory i)rocess, the vascular, exudative, nervous and other phenomena being auxiliary means whereby the phagocytic pro- perties of the wandering and fixed mesodermal cells may be brought more fully into action: the determination of leucocytes that I have described is almost entirely to be attributed to an endeavour on the part of these cells to take up and destroy the irritant. It is necessary now to ask to what extent this doctrine is to bo accepted. Certainly phagocytosis is a factor in the inflammatory pro- cess — no antagonist of this doctrine nowadays is prepared to deny this — but does it occupy the all-imitortant position arrogated to ifc by Metschnikoff ? Metschnikoff himself admits tliat there are certain wandering cells — the coarsely granular oxyphiles — which never act as phagocytes. When powers so great are found to belong to one set of leucocytes, is it likely that another sot, which is also C8i)0cially attracted to the inflammntory focnis, is absolutely devoir of either ba(!tericidal or antitoxic function? Or, to approach the matter from another stand- point, let us take a case su|)plied recently by (labritchowski from Metschnikoff 8 laboratory. If a guineorpig Iw rendered refractory to the bacillus of diphtheria, and if the vulva be cauterised aiul infected by a virulent culture of tliis bfieillus, there vosiilts a necrosis of tlio surface layers. On the free surface of the necrosed region lie the j)rolifcrating microl)os; apposed to the uiulcr surftwie of the necrosed area is a hirgo 88 SYSTEAf OF MEDICINE collection of migrated leucocytes. In about three days the necrosed tissue sloughs off, and recovery and repair ensue. But in this process little phagocytosis is observable. The phagocytosis is evidently not commensurate with the extent of the inflammation ; and if, as Metschni- kotf urges, the leucocytes are the all-important factor, their powers of defence must here include something beyond the incorporation of the micro-organisms. The same additional something would seem to be wanted to explain the healing of abscesses. A crucial test of the importance of phagocytosis has been devised by Baumgarteu, and repeated, with like results, by Sanarelli. If microbes be placed in an animal which has normally the power of withstanding the growth of such microbes; and if, further, they be so placed (in bags of filter paper, celloidin, or pith) that the leucocytes cannot attack them, although the body fluids can easily bathe them, then, if Metschni- koff bo right, the microbes ought to flourish unatt'ected. liaumgarten and Sanarelli found that this is not so, that the microbes are destroyed despite the absence of phagocytes ; but Metschnikoff, repeating these experiments, obtained diametrically opposite results, lioth Baumgarten and Sanarelli are capable observers jtlthough it is true that the former by the very violence of his attack upon Metschnikoff has materially weakened his position. It is, however, ditticult to explain away their positive results, or to arrive at a conclusion other than that under certain conditions the microbes may bo destroyed without being ingested. Tlie Humoral Theory. — The conception that there is some agency besides phagocytosis pure and simple has led bacteriologists, in the study of phenomena of inflammation and immunity, to engage in a very remarkable series of experiments. Altlumgh some of them have failed to establish a satisf.octory theory of immunity, they have led to results of such high importance as the discovery of the serum treatment of diphtheria and tetanus. The majority of tl' "e researches, indeed, bear especially upon the production of immunity, and only secondarily upon the inflammatory process. It is unnecessary for me, therefore, to describe them in detail ; it will suffice if I indicate the direction taken by the more important among them. First in order of time may bo mentioned Nuttall's observations. In an attempt to repeat Metschnikoff's researches upon the destruc- tion of the anthrax bacillus, this observer noticed that if ho placed a fine canula containing a fresh culture of attenuated anthrax bacilli in the tissue of a rabbit's oar, there resulted in sixteen hours a rich cellular exudation; but phagocytosis appeared not to reach its maximum for twenty-two hourfl, and even then half of the bacilli lay free and not taken up by cells; and ho found, further, that tho free bacilli showed involu- tion and degeneration to the same extent as aid the ingested. Tliis led hiui to stiuly the (effect of blood serum, deflbrinated ])lood and lym])h upon the bacilli, and he discovered that those fluids had a remarkably rajiid action, destroying great numbers within a vc^ry few hours. Moritz, Tratibe, Von Kodor and others, had previously recognised this rapid i! IN FLAM MA TION 89 destruction of microorganisms in the living blood, but Nuttall's very full research appeai-ed to show conclusively that the bacteria-destroying power resided largely in the serum, and that in inflammation the exuded fluid rather than the leucocytes brought about the destruction of the microbes. These observations were confirmed and extended by Nissen, Behring, and Buchner, and a most valuable series of contributions (see article on the "General Pathology of Infection") have been made by Hankin, Buchner, Vaughan, Tizzoni and Cattani, Behring, and others, upon the nature and properties of the substances to be derived from the blood serum of animals either naturally immime to certain diseases, or rendered immune by one or other procedure. What is more, it has been rec- ognised that two orders of substances are recognisable: one capable of destroying pathogenetic microbes, the other not destroying them, but rendering their products inert. It would thus at first sight appear that in these discoveries there is a direct contradiction to the theory of phagocytosis. Yet upon further study this is found not to be the case. As was shown by Nuttall, at the commencement of these studies, the blood serum removed from the body acts far more rapidly and energeti- cally than do the blood plasma and lymph within the bddy. The dis- parity of action between the two is remarkable. Thus Lubarsch has shown that in order to kill a rabbit by anthrax, by injection into the circulating blood, at least 10,000 virulent bacilli of the disease must be introduced: a smaller number produces only a transient disturbance. That is to say, the whole circulating blood can only destroy less than 1C,000 bacilli at a time. On the other hand, one cubic centimeter (15 minims) of rabbit's blood serum can in a few minutes kill an equal or even greater number. 27te Cellulo-Humoral Tfieorif. — If the serum and if the blood plasma contain bactericidal substances, these must in all likelihood be developed by certain cells, and thus at b ttom tlio humoral theory must be cellular; and the very fact of the great increase in the bactericidal properties of the blood immediately on its withdrawal from the body, must suggest that in the changes which occur in the extravascular blood there is a liberation and solution of bactericidal substances. Now the first and foremost of these changes is the breaking down of the leucocytes as the blood begins to clot. It may therefore be that this breaking down of the leucocytes, with liberation of tlieir conteuts, is capable of explaining the increased bactericidal action of defibrinated blood and blood serum. That the leucocytes contain bactericidal substances was first demon- strated by Dr. Hankin, who obtained from the lymy'^mtic glands and spleens of animals immune to antlirax (flogs and cats), a proteid of tlio nature of a globulin identical with Dr. Halliburton's cell globulin /8, and having a bacteria-killing power similar to that iiosseasod by blood serum. In later observations upon the rat he showed that there was a relationship 89 90 SYSTEM OF MEDICINE between the amount and activity of these " defensive proteids " and the power of resistance of the animal to the disease. Thus Hankin showed that in animals possessing the power of destroying bacilli, the organs containing the largest collections of leucocytes yielded notable quantities of a bacteriardestroying substance. For the last few years I have steadily urged this view, and observa- tion after observation is proving it to be correct. Recently Buchner has shown that if sterilised emulsions of the gluten of wheat be injected into the pleural cavity of a dog and rabbit, its presence leads to the pouring out of an aseptic exudation peculiarly rich in leucocytes, and this exudor tion is more bactericidal than is the blood and serum of the animal. Further, Victor C. Vaughan is led to the conclusion that the bactericidal action is associated with the leucocytes by his discovery that from blood serum a nuclein (or nucleinic acid) can be separated — a body, that is, which so far has been found exclusively in connection with nucleated cells. This nuclein is either itself bactericidal, or has a bactericidal substance in intimate association with it ; and Vaughan's observations and conclusions have been substantiated by the later and independent researches of Kossel upon nucleinic acid. Further confirmation of the correctness of these views — that the bactericidal action of the blood serum is due to the breaking down of the leucocytes — has been supplied from the laboratory of Denys at Louvain. Denys and Havel have shown that the blood and exudations of the dog, freed from leucocytes either by filtration or by centrifugal action, lose their bactericidal action, regaining it when the leucocytes are reintro- duced. Van der Velde induced an exudation rich in leucocytes by injecting into the pleural cavities of rabbits sterilised cultures of the pyococci, and killing the animals at various periods. Centrifugalising the pleural fluid, he found that the older the exudation, and the richer it had boon in wandering cells, the more powerful its bactericidal action, — this being out of all proportion to the bactericidal action of the blood serum removed at the same time and similarly centrifugalised. liut more convincing proof has been gained by a study of the leuco- cytes in action. Even in 1887 Ribbert, in his studies upon the fate of spores of various species of aspergillus and mucor inoculated into the anterior chamber of the rabbit's eye, had found that two stages of reaction were recognisable : at first the spores and developing hyphal filaments became surrounded by dense clusters of leucocytes, which renuiinod in apposition to, but did not ingest the micro-organisms. Nevertheless they appeared to bring about a weakening and lowering of vitality on the part of the spores and filaments, so that after a time other cells could manifest their phagocytic activity and take them up. llibliert, it is true, attributed the lowering of vitality to the walling in ('* Wallbil- dung") by the leucocytes, and consecpicnt lack of nutrition ; but the fact remains that he demonstrated a preparatory extracellular action upon the micro-organisms by the leucocytes. Altogether the fullest and most imi)ortant studios upon this extra- i|ll£ INFLAMMA TION 91 ,■'1 \\'i cellular action have been those of Kanthack and Hardy. In their first communication to the Royal Society these observers showed (and their experiment can be repeated without diinculty) that if a drop of frog's lymph be placed upon a coverslip, with the addition of a few anthrax bacilli, and this preparation be suspended in a moist chamber, an ex- amination extending over four or five hours reveals the following suc- cession of changes : — 1. The coarsely granular oxyphile cells are strongly attracted to the bacilli : they move towards them, and apply themselves to their surface ; their protoplasm, ordinarily sluggish, exhibits quick streaming move- ments. Next the eosinophile granules are discharged, and the bacilli begin to show signs of degeneration. During this stage the hyaline cells, the phagocytes proper, remain quiescent, and are not even at- tracted towards the bacilli. 2. The hyaline cells proliferate and eventually approach the masses of oxyphile cells surrounding the bacilli; they fuse with these — forming a Plasmodium around the chains — and for the next hour or two nothing can be clearly made out as to the action of individual cells. 3. The first stage in the dissolution of the mass is the separation and wandering away of the oxyphile cells ; next, the hyadiue phagocytes containing remnants of the bacilli within vacuoles slowly break apart. 4. A third set of cells, with basophile granules, is observed to approach during this last period; as to their functions Kanthack and Hardy are a little doubtful. Here, then, we have clear evidence of division of labour among the wandering cells of the frog : the coarsely granular oxyphile cells act as unicellular glands discharging or excreting their granules, and these granules dissolving appear to exert a deleterious action upon the bacilli, in consequence of which the hyaline cells are now capable of ingesting them. I may add that occasionally the coarsely granular cells may bo seen to act when not in immediate apposition to the microbes ; the num- ber of granules in a cell may diminish, and at th o same time neighbour- ing bacilli manifest signs of partial dissolution.^ Continuing their research Kanthack and Hardy have demonstrated these distinctions in the function of the different forms of leucocytes throughout the vertebrata up to man. They have shown that in general the hyaline cells act as the phagocytes of the lymphatic and cffilomic system ; the finely granular oxyphile (neutrophile and amphophile) as the phagocytes of the haemal system; while the coarsely granular oxypliilo (eosinophile) when present possess excretory functions. if capillary chambers filled with bacilli or their products, or some irritant such as nitrate of silver or turpentine, were placed under the skin, or in the peritoneal cavity, and allowed to remain there for periods 1 Mesnil, in a long and often suRKostive work, which apponrod wliilo thiH article waa in tlio proHH, contradictH those obsorvatinnH of Kanthaclc and Iliirdy. Appiintiitly lin novor once attempted to repeat their prncodiiro, never onco attempted tlie Hlmple metliods I ocossary to contirui their results. His oritiuiRni must titorofore bo relatively valueless. 91 92 SYSTEM OF MEDICINE up to twenty-four hours, they were found to contain a multitude of cells, chiefly of the coelomic type. ] f the irritant were situated in such a position as to appeal to the bloo 1-vessels of a vascular membrane rather than to the cells of the connectiv e tissue spaces, then the cells were those of the haemal system. In both cases in the earliest stages there was usually found a preponderance of the coarsely granular oxyphile cells. Even in cutaneous blisters induced upon themselves, while the main mass of cells present in the serous exudation were the finely granular oxyphile of haemal origin, the coarsely granular were always more abundant rela- tively to the others than in the blood. The rate of accumulation was found to vary according to the irritant. Thus, comparing the action of the virulent B. anthracis and the harmless B. ramosus upon rabbits and guinea-pigs, it was seen that if cultures of these two forms were placed within capillary tubes and introduced into the peritoneal cavity, with the former only the coarsely granular oxyphile found its way into the tubes (even after seven hours) ; whereas with the latter enormous numbers of the hyaline phagocytes had invaded the chambers within two and a half hours. In the former case also the total number of invading cells of all kinds was very much less than in the latter case ; and there was clear evidence of the abundant disintegration and dissolution of many of the cells. This destruction of a certain number of cells occurred, whatever the nature of the microbe introduced into the system ; and, as these observers point out, it must profoundly alter the chemical constitution of the plasma, and may therefore play an important part in the struggle with the bacilli. They obsei ved phenomena of the same nature as those of the frog's lymph, when they placed anthrax bacilli in han":ing drops of human blister fluid and examined the preparations upon the warm stage, noticing here also the rapid diminution of the granules of the eosinophilo cells. Finally, it must be added that MetschnikofE (while misunderstanding wholly the drift of these last-mentioned researches) has recently admitted that the wandering cells are capable of exerting an extracellular activity upon the bacteria. Certain observations of R. Pfeiffer had revealed that, under certain conditions, when guinea-pigs have been rendered highly refractory to the spirillum of cholera, these microbes when injected into the peritoneal cavity are rapidly modified, becoming swollen and spheri- cal before any phagocytosis has time to come into play ; and this alteration was explained by Pfeiffer as due to the fluid secreted by the peritoneal cells following upon the inoculation. Without detailing MetschnikofE's criticism of the value of these observations, it will suffice to say that, carefully repeating them, he discovered that five minutes after such injection the leucocytes in the peritoneal fluid — " polynucloar," mononu- clear, and cosinopliilous — were surrounded by a layer of spirilla, while the lymphocytes and red corpuscles were entirely free from any such surrounding. Here in the immediate neighbourhood of the wandering cells, the short, curved bacillary forms could be seen to have undergone the transformation into globules. Motschnikoff further recognised a clear INFLAMMA TION 93 zone, evidently of exuded liquid, between the leucocytes and the spirilla. Whether this be a true secretion, or an accompaniment of the death of the cells, he is not at present prepared to say. In this way Metschnikoif admits that, besides phagocytosis, an extra- cellular action of the wandering cells does occur ; so that now the only point of paramount importance to be agreed upon is the extent to which the extracellular activity is manifested intra vitam. Metschnikoff at present holds that h plays a very secondary part compared with phago- cytosis ; others, like Buchner in Germany, Denys in Belgium, Kanthack and Hardy in England, hold that its part is of high importance. Person- ally, while holding that phagocytosis has been conclusively proved to be of singularlv bigh importance, I cannot but see in this extracellular action of acti\ e and of disintegrating leucocytes an adjuvant to the former factor, and one which under certain conditions is even of greater value to the organism in its attempt to neutralise microbic and other irritants. Whether the fixed tissue cells of the body have similar " extracellular " action upon living irritants, or not, is a matter that has not yet been ascertained. There are indications that this may be so. Summary. — Thus, to sum up the facts gathered together in this chapter, the chief results of recent researches into the functions of the wandering cells, as they affect our knowledge of thd inflammatory process, would seem to be the following : — 1. That in the higher animals there are several forms of leucocytes. 2. That a distinction can be made out in the distribution of the various forms, some being characteristic of the blood, others of the con- nective tissue spaces and of the coelom and coelomic fluid in general. 3. That the forms of cells accumulating during the inflammatory process consequently vary according to the region of injury. 4. That a variation is to be made out also in the rate of accumula- tion of the different forms of cellb: the coarsely granular oxyphile (eosinophilous), which in the main are pre-existent in the connective tissue spaces, being attracted sooner than the finely granular oxyphile (neutrophile haemal) and the hyaline (coelomic) respectively. 5. That a further distinction is to be made out in the mode of action of these cells : the coarsely granular oxyphile never act as phagocytes, but possess excretory properties ; the hyaline and finely granular oxy- phile are characteristically phagocytic. 6. That the accumulation of leucocytes is due in part to migration, in part to proliferation in situ. 7. That under certain conditions (what these are and what their relative importance have yet to be more fully worked out) the phago- cytes are capable of directly incorporating pathogenetic bacteria. The main conditions would seem to be the possession by the bacteria of relatively weak irritant or pathogenetic properties, and by the organism of relatively strong powers of resistance. 8. That under other conditions (where, for example, the microbes are endowed with fuller irritant properties, or the constitutional resistance is 94 SYSTEM OF MEDICINE lower) phagocytosis may be preceded by an excretory process on tlie part of certain cells, notably the coarsely granular oxyphile, whereby apparently the vitality and irritant pr' ^ rties of the microbes undergo a diminution. Here again we are as yet ignorant of the exact value of all the factors leading to active intervention of these excretory cells. 9. That the bactericidal and antitoxic action of the blood serum and body fluids outside the body is due to the liberation into these fluids of bactericidal and antitoxic substances step by step with the disintegration of the leucocytes. 10. That clearly this liberation of bactericidal and antitoxic sub- stances by excretion from living cells, and by disintegration, does not obtain to the same extent in the fluids within the living body ; never- theless it does occur, more especially as the result of irritation, and its occurrence is fitted to explain those cases in which the amount of phagocytosis observable is not co-extensive with the disappearance of the microbic irritants. 11. That where the bacteria jare endowed with great virulence, there the wandering cells migrating to the region are both fewer in numbers, and, being killed, undergo dissolution to a very considerable extent. This dissolution may in itself, by the liberation of bactericidal substances into the inflammatory exudation, hinder the proliferation of the microbes to a greater or less extent. If, however, the dissolution be unaccom- panied by a massing of active leucocytes peripherally around the region of irritation, then the microbic irritants may be carried away from the inflammatory focus, and induce generalised disease. To complete this summary I will here add other conclusions deduced from a study of the later stages of inflammation and discussed in a later chapter (" Upon the pai't played by the fixed Cells in the Inflammatory Process "), viz. : — 12. In the later stages of inflammation the growing fibroblasts may often be seen to contain leucocytes in process of digestion. Presumably, therefore, a certain number subserve nutrition. 13. Others are, in certain cases, recognisable in the lymph-spaces outside the inflammatory focus, containing the debris of dead tissue. Emigration can therefore occur as well as immigration. 14. The process of development of wandering into fixed cells has been observed ; but this is the exception, not the rule. 15. The contrary process of development of wandering cells from degenerating tissue (muscle fibres) has also been recorded by more than one observer. Chapter 2. — The Inflammatory Exudation Whenever injury to the tissues leads to vascular dilation there is an increased effusioii of plasma from the blood. The extent of this effusion varies greatly; it varies with the tissue affected, the state of the organism, and the quality and nature of the irritant. Dense f I 'i INFLAMMA TION 95 tissue permits of little exudation, while loose vascular tissue, under the action of an irritant of no great intensity, may undergo great exudative swelling. There is, for instance, a peculiar liability in serous and cutaneous surfaces (or more truly in subserous and dermal layers), when inflamed, to manifest abundant exudation. Their vascularity and the slight external resistance would appear to explain this liability. There is not the same tendency to abundant exudation from mucous surfaces save where, as in the alveoli of the lungs, the epithelium is reduced to a single layer of delicate flattened cells ; on the other hand there is a marked tendency towards serous infiltration and swelling of the sub- mucosa. That some general state of the organism is a factor concerned is seen when virulent anthrax bacilli are inoculated subcutaneously into an ordinary rabbit and into one that has been rendered immune : in the former the exudation is of a serous nature, in the latter little fluid is exuded from the vessels. The effect of the quality of the irritant is observable upon comparison of the results of inoculation of various microbes. Some cause little exudation of fluid. Theso are in general of low pathogenic quality, but not always ; certain virulent microbes (such as those of tetanus) lead, when inoculated, to relatively little effusion of fluid from the vessels. On the other hand, it may be stated definitely that where in a moderately dense tissue the injection of a pure culture of a micro-organism leads to well-marked exudation, the micro- organism is of high virulence. Can any meaning be ascribed to this effusion? Is it an attempt at increased nutrition in the injured region? It has been sug- gested, in accordance with Virchow's theory of inflammation, that the injury, stimulating the surrounding fixed cells, leads to increased local metabolism ; and that the exudation is a means of bringing to the region the increased nourishment demanded by the increased cellular activity. But inasmuch as exudation is most marked in those cases where there is most profound and rapid cell destruction, and again at the early stage of the inflammatory reaction, when evidences of growth and proliferation of the fixed cells of the region may be, and most often are, wholly wanting, this view can scarcely be upheld. Yet at a later period of the process, and again in chronic inflammation, the overgrowth of the connective tissue cells would appear to stand in close relationship to the over-nutrition caused by the continued dilation of the vessels and the pouring out of excessive lymph into the tissues. There is, appar- ently, a close relationship between the increased exudation and inflam- matory hyperplasia. That the exudation exerts a " flushing out " action is very evident in many cases. Thus the inflammation induced by plunging an animal's leg into hot water is accompanied by great increase in the amount of lymph obtainable from the efferent lymphatics of the part. It is shown also by the presence of streptococci in the lymph channels outside the area of acute inflammation in erysipelas, by the frequent implication of the nearest lymph glands in suppurative disturbances, and by the appearance 95 of lesions, duo to the direct action of bacterial products, in organs far removed from the focus of bacterial proliferation in such diseases as diphtheria and tetanus, wherein, as a rule, the bacteria remain strictly localised. It is clear that the exudation into an inflamed area can accom- plish a removal of irritant matters. It is clear also, from more than one of the examples given above, that a process which may be beneficial to the region of injury may be harmful to the system as a whole. It is interesting to note that this effect of flushing, in part beneficial, in part harmful, has, if I may so express it, gained a certain amount of recognition on the part of the organism. Where the irritant can be con- veyed to the exterior an abundant exudative inflammation generally occurs — an abundant flushing ; where it can be conveyed into one of the body cavities the same holds good ; but here a mechanism is often called into action whereby the exudate with its contained irritants is held within the serous cavity for days and weeks after all signs of active inflammation have subsided. The organisin, that is to say, would seem to restrain its drainage to the general lymphatic system. Where the irritant is merely the product of tissue change the profuse exudate is rapidly conveyed away; where, on the other hand, the injury is of bacterial origin, the passage of lymph from the focus of inflammation, is, generally speaking, not nearly so free ; it is of thicker consistency and drains away si awly. In short, as I have already indicated, where the microbe is not too virulent a cellular rather than a serous inflamma- tion is produced ; and in place of abundant flushing an increased anti- bacterial and antitoxic action of the exuded lymph conies into play. But besides this " flushing out " effect the exudation subserves another purpose, namely, dilution of the irritant and reduction of its injurious properties, so that it acts with lessened force upon the tissues, and permits the wandering cells to be attracted to the region where they may exert their functions. Where a comparatively mild physical irritant leads to abundant exudation the flushing out action appears to be in the ascendant, where microbic irritants cause great local inflammatory oedema, judging from the less extensive lymph flow from the region, the diluent action must be regarded as the more important. I have already pointed out that a relation may be traced between the intensity of bacterial irritation and the extent of the exudation. In short, there may be great exudation under two apparently opposed conditions : in the presence of comparatively mild physical irritants, and in that of severe bacterial irritants. In the former case it more especially sub- serves removal, in the latter dilution of the poison. The fundamental distinction between the inflammatory exudation and ordinary lymph is its richness in proteids. Whether we regard lymph as a filtrate pure and simple from the blood, or, with the majority of modern physiologists, follow Heidenhain in regarding it as the result of a selective filtration, it is eminently probable that in inflammation the exudate approaches in its composition more nearly to the blood plasma than does ordinary lymph. The dilatation of the cauillaries, the couse- I) ii INFLAMMA TION 97 ill quent thinning of the endothelial layer with, it may be, the opening of some lacunae between the individual cells, and the direct action of the irritant upon these cells, may all be expected to aid the transuda- tion. In this way the amount of proteid matter in the lymph may be increased. But equally important must be the addition of proteids due to the breaking down of leucocytes and tissue cells. I have already discussed this destruction of the cells, and need not here give the evi- dence of its occurrence. In addition to the proteids the inflammatory lymph may contain other substances worthy of more than passing note. Of these the more important are ferments, the results of proteolysis (notably fibrin and its precursors, and peptones), and in many cases mucin, together with bactericidal substances, and, where bacteria are present, the products of their growth. The presence and amount of these substances depend largely upon the intensity and character of the inflammation. Thus the total quantity of proteids, and the proportion of fibrin, albumin, and globulin present, vary within wide limits. The following table ' of observations made by Dr. Halliburton shows well this variation in proteids, and the difference existing between inflammatory exudations and dropsical effusions : — rl I' Pleural Fluid from 8p. Or. Percontago Quantity of Total Proteid. Fibrin. Serum- globulin. Serum- albumin. Acute pleurisy, Case 1 „ „ Case 2 Case 3 Hydrothorax . . \ Average of three cases j 1023 1020 1020 1014 5123 3-4371 5-2018 1-7748 0-016 0-0171 0-1088 0-0086 3-002 1-2406 1-76 0-6137 2-114 1-1895 3-330 1-1557 Between the amount of fibrin present in exudations and the amount of peptones there is an inverse ratio. Peptones are especially devel- oped in connection with suppurative inflammation; and the more an inflammation tends to be suppurative the greater is the breaking down of the fibrin, as also of fixed and wandering cells, and the more evident the production of peptones, until in chronic abscess-formation of fair extent the peptones pass into the general circulation, and are excreted and recognisable in the urine. Into the discussion of the mode of formation of fibrin I need not en- ter here, intimately connected as the subject is with the inflammatory process. The greater text-books of Physiology enter exhaustively into the matter. Suflice it to say that, as in the blood, a direct relationship 1 Theso fij^ures aro thoroughly ia accord with those of other analyses by Beuss, Hofiuaun, Muhu, and Letulle. VOL. I B 97 98 SYSTEM OF MEDICINE B0US8, is made out between the breaking down of leucocytes and the develop- ment of this substance in inflammatory exudations. It is in connection with inflammation affecting serous and epithelial surfaces ^ that fibrin is most clearly recognisable, forming, it may be, thick coatings of the badly-named " inflammatory lymph " over the in- flamed surfaces. This deposit is in all respects comparable to the forma- tion of thrombi in the blood-vessels. Here, as there, the deposit occurs only when the endothelium has undergone destruction and the roughened sub-endothelial tissues are exposed. And here also the fibrin may be deposited either in filamentous or homogeneous and hyaline form accord- ing to circumstances. Leaving out of account coagulation-necrosis as not occurring in direct connection with exudates, it may be said that similar fibrin for- mation is frequently recognisable in connection with primary inflamma- tion of parenchymatous tissues." The beneficial effects of fibrin formation in serous cavities have been rendered abundantly manifest by the increase in abdominal surgery. No one who has followed any considerable number of operations for appendici- tis can have failed to remark how, in case after case, despite the intricacy of the abdominal coils and their mobility, the strongly irritant matter pro- duced by gangrene of the appendix, or oozing through perforations in it, is restricted within a relatively small space by the surrounding fibrinous adhesions which form rapidly between the intestinal loops. ]?y this mean^ alone the peritonitis is restricted and " regional," instead of being general- ised from the onset. Even when inflammation (as in pericarditis) affects tlie whole extent of a serous cavity, the layer of fibrin acts as a protective coat closing the lymphatic stomata, hindering the free absorption of the morbid material by the lymph and blood-vessels, and filtering bacteria out of such fluid as does find its way through to the tissues beneath. It is not a little remarkable to call to mind how case after case of purulent pericarditis or purulent pleurisy may be examined in which, despite the intense suppurative disturbance in the serous cavity, the tissues at the other side of the deposit of fibrin — the myocardium or the lung tissue — show little or no tendency to abscess formation. Let there be primary abscess formation or gangrene in the lung, and perforation of the pleura and hydrothorax may supervene; pleurisy, however intense, does not lead to this unless complicated by other disease. Let there be primary or metastatic abscess in the myocardium, then there maybe aneurysm and rupture of the heart; yet such rupture produced by extension inwards of a purulent pericarditis is of the utmost rarity. Let there be inflammation originating in the submucosa of the intestines, as in enteric fever, and 1 Of epithelial surfaces, more especially those covered by a single cell layer, as notably the pulmonary alveoli. 2 Where there are abundant and distensible lymph channels there extensive clotting may be seen in the lymph. This is peculiarly well marked in the contagious pneumonia of cattle (contagious pleuro-pneumonia). In acute intlammation of various organs, by appropriate methods of staining, similar formations of threads uf fibrin, often starting from colls as centres, may be observ d in the tissue spaces. I S« /" INFLAMMA TION 99 perforation may result ; general peritonitis, while often due to perfora- tion, never — so far as I can call to mind — directly induces that event. In all these cases the natural protective layer of the serous surface is removed or gravely injured at a very early stage ; and the layer of fibrin, replacing the serous endothelium, forms an effective barrier. I may add that the mucin, extruded so as to form a layer over inflamed mucous surfaces, presents a similar protective action. Passing now to the ferments and ferment-like bodies present in the exudate, I may briefly state that these are not only generated and excreted by the pathogenetic bacteria present, but are liberated by the breaking down of the wandering cells. Abundant evidence of the exist- ence of bacterial ferments capable of acting upon proteids, gelatine, sugars, etc., is supplied by the study of the growth of these microbes outside the body. That ferments also originate from the wandering cells has been demonstrated by Leber, who, placing pieces of copper in the anterior chamber of the eye, thereby produced a purulent collection devoid of microbes, and showed that the exudate was capabl >. of digest- ing proteid matter. It would seem, therefore, that, more especially in pyogenetic inflam- mation, the removal of dead tissue cells and dead leucocytes may, to a large extent, be due to the action of the inflammatory exudations, apart from any phagocytic action on the part of living active cells ; although this also comes often into play. Of the bactericidal substances present in the inflammatory exudate I have already treated. Here I need only repeat that the researches of Kanthack and Hardy, of Denys, and lastly of Pfeiffer and Metschnikoff, fully prove that substances capable either of destroying microbes or of hindering their growth are present therein. Summary. — To sum up what is known concerning the inflammatory exudate, it may be said — 1. That the exudate varies in amount and in character with (a) the nature and intensity of the irritant, (6) the condition of the organism, (c) the region of irritation. 2. That while it undoubtedly augments the nutrition of the affected region, increased nutrition at the early stage of an acute inflammatory process would not seem to be of benefit or to play any important part. At a later stage and in chronic inflammation the increased nutrition in all probability aids the hyperplasia. 3. That in many cases the exudate exerts a beneficial action by flushing out the injured area. 4. That the exudate plays an important part in diluting the irri- tant. 6. That the development of fibrin in certain inflammatory exudates is associated with the breaking down of the wandering cells, and is of manifest benefit in so far as it cinnimscribes the inflamed area, and prevents the ])aBsago of morbid material outwards. 0. That the uxudute may possess digestive functions, causing the pro- 99 loo SYSTEM OF MEDICINE duction of peptones ; the ferments being developed from the cells alone when the exudate is aseptic, from these and the microbes together where pathogenetic microbes are present. 7. That the exudate may further contain substances; generated by the cells, capable of hindering bacterial growth, and of destroying pathogenetic microbes. Chapter 3. — The Part played by Blood- Vessels The study of the action and function of the leucocytes in inflamma- tion has profoundly modified our conception of the inflammatory process. When the leucocytes were regarded as purely passive agents, and their diapedesis as purely secondary to moditied conditions of the blood cur- rent and of the vascular walls, the theory of Cohnheim was that most generally accepted. And this theory regarded the changes in the vessels as of the first importance. Thus it was that for several years our atten- tion was mainly concentrated upon the determination of the various chaages of the vessel walls, and of the mechanism whereby these chiinges were brought about. Nowadays less attention is directed to this side of the inflammatory process, and it may be said that during the last ten years little advance has been made in determining the mechanism of the dilatation that accompanies inflammation. The subject, indeed, is beset with difliculties. It is most difficult to observe the changes that occur in the cells forming the endothelium of the congested vessels ; we are still, for instance, far from being sure whether the opinion of Arnold is correct, namely, that the leucocytes, and, it may be, a large portion of the exuded plasma, find their way out through the dilated stomata between the endothelial cells ; or whether the leucocytes pass directly through these cells as one soap bubble may be passed through another. And when we come to discuss whether the inflammatory exudation be a filtration, or whether, on the other hand, it be more of the nature of an excretion, or what may be termed a selective filtration — certain components of the blood plasma being permitted to pass through, while others are withheld — we are met with the ditticulty that, of the extravasated leucocytes, a varying pro})ortion undergo rapid destruction and dissolution. Thus, in analysing the inflammatory serum, we are not dealing simply with the extravasated fluid, but with a fluid which in addition contains ])n)teid and other constituents derived largely from broken-down white (•or])U8cles, and in part, it may be, from the modified cells of the inflamed area. Though Arnold's observations upon the altered condition of the vascular endothelium in inflannnation ap))ear at first very convincing, upon further study tliey seem at most to indii-ato tluit with dilation of the vessels ther(> is an increase in the size of tiie sjKices between the endothelial cells. They do not, however, prove that these are other than virtual spaces filled with intercellular substance; and indeed Arnold himself came eventually to the conclusion that some sucli substance was IN FLAM MA TION lOI present filling them. The fact that viscid, gelatinous substances injected into the circulation may be detected passing through these stigmata is not a proof that the spaces are actual ; all it proves is that the walls are weaker in these regions: it must be remembered that increased force and increased intravascular pressure are necessary to promote the passage of the injected mass along the vessels. The passage of the mass through the walls may therefore be an " artefact." There is this further difficulty in the assumption that these are actual spaces — that in acute inflammation the exuded fluid in general contains a smaller quantity of proteids than does the blood plasma. It is true, no doubt, that the stigmata are so small they may possibly act like the pores of a filter, and consequently may not permit the free passage of certain constituents of blood plasma. Yet, granting all this, if the same principles be in action as those governing the ordinary (non-inflamma- tory) transudation, we must, with Heidenhain, be inclined to regard the endothelium as playing not a i)assive, but an active role. To enter into the large subject of the nature of lymph would be to pass too far afield ; recent researches, on the whole, favour the view that the inflammatory exudation is not a mere filtrate, but is the result of a selective activity on the part of the endothelial cells. We have not a little evidence that these cells play an important part in the vascular phenomena of inflammation. To their power of taking up microbes and acting as phagocytes I have already referred ; into their connection with the slowing of the blood stream I shall enter later. Here I would point out that microscopically these cells can be seen to alter during the inflammatory process; they become enlarged and project into the lumen of the smaller vessels, and in my experience this enlargement affects not only the cell bodies, but also the nuclei, which at the same time would seem to contain more chromatin and to stain more intensely. In cases of chronic inflammation the enlargement is followed by proliferation, notably in the arterioles and capillaries, — a process which may lead to the ultimate occlusion of these small vessels. And in acute inflammation, according to numerous observers, mitosis is to be seen occurring in these endothelial cells at an earlier period than in the surrounding tissues. A further and very important process intimately connected with the proliferation of the endothelium of the cajjillaries is the formation of new v(!S8els as tlio result of continued inflammation. It is true that llindflciscih and others have described this as being brought alnjut by vaso-formative cells situated externally to the vessels ; and that others have advanced so far as to suggest that there are cells in the newly- forming granulation tissue which become hollowed out and gain attach- ment to the pre-existing capillaries in a manner wholly similar to that observable in the vascular zoni! of the chicken embryo. I hav(i sought for such intracellular deV(!lo|>nient, but never have I seen the slightest indication thereof; nor again have 1 been able to discover cells arranging themselves after the method described by Kindfleisch iu I03 SYSTEM OF MEDICINE \ columns or parallel rows preparatory to the passage of blood between them ancJ to the formation of a capillary. The ser.rch for the earliest signs of new capillaries is a matter of peculiar difficulty. I will not peremptorily state that Eindileisch mis- took an arrangement of cells not unf requently seen in granulation tissue for stages in the development of new vessels. I will only say that my own observations coincide with those of Arnold, and of the majority of those who have more recently studied the question, and lead me to regard the formation of new capillaries as originating from the endothelium of the vascular loops already in existence. The first step in the process is often recognisable, in cases of pleurisy and pericarditis, in the projection of loops of pre-existing capillaries beyond the line which indicates where the serous endothelium used to be, and into the fibrinous clot now adherent to the sub-endothelial layer. Such loops are markedly distended, and " point," as it were, at riglit angles to the denuded surface. A similar pointing or giving way of the wall along the convex margin of the loop is also to be made out not unfrequently ir newly-developed capillaries. In these there is not, as might be exnt ' \ a thinning of the endothelium along this outer mar- gin, but certa le cells on the contrary appear large and active. At times a small .. ^...^ protrnt"ion of the vessel wall can be detected in the region of pointing. This isj best seen in the capillaries that are them- selves but newly formed, and composed of nothing but a layer of endo- thelial cells. In this layer the protrusion can bo made out to be in direct continuity with the endothelial cells of the region. At first it is solid, but in the later stages it can be seen to be nucleated, and to be growing by proliferation of the endothelial cells which thus jut out- wards. Even before any further change is noticeable in this projecition from the capillary wall it may be seen to be united with a similar pro- cess originating from a neighbouring vascular loop. Finally, it would appear that the joined processes become hollowed out, and thus are developed into fully-formed capillary loops. It seems impossible to make precise observations on tlie phenomena of now vascular formation in its successive stages. I can b>it state that these appear to be the steps of the process. By what means the new vascular projections join together to form loops we are ignorant. Metschnikoff suggests that there must be an attraction between tlie neighbouring projections — a chemiotaxis — leading them to come into apposition; this, however, is no more than a suggestion. That they do join is very clear to those who have stmlied granulation tissue, or have observed the vascular network connecting the previously separated surfaces of a wound. A further function of the vt^ssol walla is to be seen in the slowing of the blood current. It is difficult, and in fact impossible, to explain this slovring l)y altered diameter of the arteries and veins. The alterations observed in the diameters of the vessels of the inflamed area are sucli as, acting alone, would led to incnMised rate of flow. Nor again is the a}>parent amount of exudation, and of lymph flow from the att'ected 11 2J\rFLA MM A TION 103 11 part, sufficient to make it probable that (as Wharton Jones first suggested) the sloAving is in the main due to the concentration of the blood, relative drying of the corpuscles, and consequent increase of friction : while this may be an adjuvant we must, I think, tind some more potent factor. What this factor is was pointed out long ago by Lister, who, in 1858, noticed that coincident wrih the slowing of the blood stream, the cor- puscles move sluggishly along the vessel wall as though attracted by it. Lister essayed to pro\e this by ai: experiment performed previously by Weber. He ligaturod a frog's leg, then irritated a portion of the web by a little mustard, r.ud fourid that, although the blood current had ceased, there was never'^heless an accumulation of corpuscles in the vessels of the irritated area, the corpuscles gliding into the affected region and becom- ing adherer.c there. Other observers have shown that this accumulation is not due to increased adhesiveness of the red corpuscles, inasmuch as similar skwint noted by Binz, has been confirmed by several observers, among whom Disselhorst made out also that, if these same leucocytes be re- moved from the vessels, they exhibit their usual amoeboid movements. The quinine has not paralysed them, as Binz supposed ; but, as Metsch- nikoff pointed out, it has neutralised the previous positive attraction, a negative or repulsive chemiotaxis being brought into play. It is diffi- cult to see how the above facts can be otherwise explained. The view that diapedesis is an active process gains further support from, and at the same time explains certain interesting observations made by, Bouchard, Roger, and Ruffer. These observers have independ- ently shown that in sundry instances the results of local injection of viru- lent cultures are greatly modified if, shortly before or coincidently, the microbes and their products are introduced into the circulation. Thus, as Ruffer points out, a drop of the culture of the bacillus pyocyaneus in- oculated into the anterior chamber of the rabbit's eye leads ordinarily to a great migration of leucocytes — to an acute purulent inflammation. If, however, the toxins produced by this microbe have previously been injected into the circulating blood, no accumulation of leucocytes follows inoculation into the eye. Dr. Ruffer has also extended most suggestively certain observations of Roger. Subcutaneous or intramiisoular inocula- tion of the rabbit with the bacillus of s^miptomatic anthrax leads to the production of a local abscess with extbiisive accumulation of leucocytes. After simultaneous injections of fluid containing vir\ilont bacilli and their products into the vein of the ear and the muscles of the hind leg, INFLAMMA TION 107 li Ruffer found the rabbit dead, within fifteon hours, with a huge tumour in the inoculated limb. Here, upon examination, the muscle fibres were found widely separated by exudation fluid, in which there had been great multiplication of the bacilli ; but leucocytes were entirely absent. In both of these cases we have therefore diapedesis and determination of leucocytes following the purely local action of the toxin; want of diapedesis and absence of leucocytes when the toxin at the same time circulates in the blood stream. If any large proportion of the leucocytes which find their way to a focus of irritation emerge from the blood stream, these divergent results are only to be explained by some theory which is capable of reconciling the difference in the action of the leucocytes when they are circulating in normal and toxin-containing blood respectively. Now, the resvdts in these two cases are entirely consonant with what we know concerning the sensitiveness and reaction to stimuli not only of unicellular organisms, but also of the higher animals. Organisms, whether lowly or of most complex development, only perceive and react to alteration in their environment when the alteration exceeds a definite ratio. Thus, as PfefEer has pointed out, a motile bacterium (the " B. termo ") is attracted towards solutions of peptone : if it be already in a peptone solution, in order for it to be attracted towards and move into a more concentrated solution, this last must be five times as strong as is the former. The only possible explanation that I can see of the above observations of Euffer and Roger is that the passage and want of passage of the leucocytes out of the vessels depends upon the ratio of diffusible bacterial products present in the blood stream and in the tissues respec- tively. Where the products are localised at one focus in the tissues, the leucocytes are attracted out of the unaltered blood, and there is active diapedesis ; where there was already a solution of the bacterial products in the blood, the ratio of difference between the percentage amount of toxin in blood and tissue may be insufficient to stimulate the leucocytes ; no diapedesis then ensues. As is well shown in the experiment with symptomatic anthrax, the presence of the bacillus and its products in the circulating blood did not prevent inflammation at the region of local injection ; inflammation and exudation were abundantly manifest — there was, in fact, a more extensive exudation than ever. The irritant — that is to say, the toxic products of the bacilli — at the point of injection was in no wise hindered from exerting effects upon the fixed cells of the vessel walls, and promoting all the changes in calibre and condition of the walls and in the blood ^ream characteristic of inflammation. But with vascular changes, if ny thing more prominent than in the case where local inoculation alone had been practised, the leucocytes stayed within the vessels : now the only cause to which we can attribute this abstention of the cells from emigration, is lack of attraction — certainly not lack of vascular change or lack of blood pressure. Sunxmanj. — I am thus led to the following conclusions regarding o; ur es en at. io8 SYSTEM OF MEDICINE the passage of cells out of the blood stream into an inflamed area : — 1. The diapedesis of the leucocytes is, as the name implies, an active and not a passive process ; it is due to active amoBboid movements on the part of the cells. 2. The stimulus leading to diapedesis is that of positive chemiotaxis. It is the attraction exerted upon the leucocytes by the diffusible sub- stances associated with the irritant. 3. Irritants, if themselves diffusible, or the diffusive substances developed while the irritants are within the tissues, are capable of two separate actions : one direct upon the vessel walls, leading to vascular changes ; the other through the walls upon the leucocytes, whereby emigration may be induced. 4. These two actions need not (and frequently do not) manifest them- selves pari passu. 6. In relation to diapedesis, the dilation of the vessels, the altered rate of blood stream, the altered disposal of the corpuscles in the stream, and the modified endothelium, may all be regarded as adjuvants. 6. The passage of red blood corpuscles from the blood-vessels into the inflamed area is passive, due to the blood pressure and to lack of con- tinuity of the vessel walls. Such lack of continuity is afforded in many instances by the migration of the leucocytes through the walls. Chapter 5. — On the Part played by the Nervous System If the vascular changes in inflammation were due to reflex influcmces proceeding from the central nervous system, and were in fact controlled by the centres in the brain and spinal cord (as has been held by the supporters of neuro-humoral theories) then, in the first place, there should be a rapid and almost immediate response on the part of the vessels of any region on the introduction of an irritant. But this is not by any means constantly to be observed. Thus, as Cohnheim pointed out, if croton oil be rubbed upon a rabbit's ear more than an hour may elapse before the first beginnings of hyperaemia can be detected ; yet the inflammation eventually set up may be very intense. In the second place, section of all the nerves passing to any region of the body should have this effect, that injury in the region in question should be unaccompanied by the ordinary vascular reaction. But this is not the case. Divide all the nerves which supply a rabbit's ear for example, and then injure that ear, either by heat, cold, or inoculation of pathogenetic micro-organisms, and inflammation manifests itself with all the stages recognisable in an ear with intact nerve-supply. The vascular changes which accompany inflammation can occur then independently of any central nervous influences. We can proceed farther, and state that regions deprived of their nerve-supply are peculiarly prone to inflammatory changes. But this liability to inflammatory disturbances in such regions is not directly dun ^i TNFLAMMA TION 109 to the destruction of vaso-motor tracts and the cutting off of central influences from the vessels of the part, but is, it would seem, immediately connected with the loss of sensation. Divide the ocular branch of the fifth nerve of a rabbit, and, if the eye be not protected, ulceration and necrosis of the cornea manifest themselves in the course of a few days. Protect the eye, either by bringing the lids together or by placing a shade over it in such a way that dust and foreign particles are prevented from settling upon the surface, and no such ulcerative disturbance mani- fests itself. From this it is clear that the primary cause of the inflam- mation is not any trophic change in the region, but is the lack of sensa- tion, whereby irritant substances are permitted to gain a lodgment upon the outer surface without any attempt being made to remove them. That, in addition, there is a lowered vitality in parts deprived of their nerve-supply, and that this renders those parts a more favourable seat for inflammatory disturbances is more than probable; nevertheless, this would not seem to be the primary cause of the increased liability to inflammation. [Fide art. on "Nutritional Eetrogressive Changes."] This, then, in the first place, is clearly recognisable — that the vascular changes accompanying inflammation can occur independently of central nervous influences. Hence it follows that there must be a peripheral nervous mechanism controlling the vessels. It remains, therefore, to determine the nature of this peripheral mechanism : is it wholly under the guidance of peripheral nerve cells situated in the vessel walls, or is it, in part at least, idiopathic ? In the present state of our knowledge the answer to this question must be guarded. The more carefully the innervation of the various regions is studied, the more clearly is it demonstrated that throughout all the tissues of the body there exists a wonderfully fine and complicated network of nerve filaments with occasional isolated ganglion cells. Yet proof is wanting that this system in connection with the vessels is sensorimotor. Indeed, so far as regards the heart and ventricular muscle (which may be looked upon as the region of the vascular system wherein the motile portion of the walls has become specially developed), the researches of Romberg and His lead rather to the conclusion that the peripheral nervous system subserves sensation alone. Dr. H. J. Berkley's careful series of researches recently brought together in a Johns Hopkins Hospital Report (Neurology II., 1894) throws much light upon the termination of the nerves in various organs, and upon the relation of these nerves to the vessel walls. Berkley finds in connection with the ventricular muscles a dense network of nerve filaments, with small bulbous terminations upon the individual fibres. These observations, it must be admitted, tend to weaken the belief in the idiomuscular, or, more truly, idioneural action of the heart muscle. At the same time, the more the activity of the various tissues is studied, the more fully it is seen that many cells retain what may be termed reminiscences of an earlier and more embryonic condition in which their functions were varied and less specialised. There is an 1 109 no SYSTEM OF MEDICINE inherent probability that the endothelial cells can react directly to stim- uli, and that they are capable of idiopathic contraction and expansion on appropriate stimuli. We have seen that these cells are capable of taking up microbes, and thus seem to exhibit an independent activity similar to that observed in the amoeba or the wandering phagocyte. If these cells, then, are capable of throwing out pseudopodia, and thus of enclosing non-motile bacteria, are they not capable of contracting and expanding, as a whole, according to the stimulus of altered environ- ment ? As a matter of fact, such contractility of the endothelial walls of the capillaries has been demonstrated by Klebs and Severini. I can- not but conclude, then, that the endothelium of the capillaries is to some extent self -regulative or neuro-muscular. It is quite possible — but "non-proven" — that the muscular coats of the smaller arteries are likewise capable of self-regulation, and respond directly to stimuli. This view — that the vascular phenomena of inflammation can occui' independently of the central nervous system and of the peripheral nerves — does not imply that the nervous system, central and peripheral, is without its influence upon the process ; far from it. We have evidence, in the first place, that the state of the vascular walls is modified after destruction or severance of the nerves. I do not here refer only to the consequent alterations in calibre of the vessels, but also to the changes in other properties. Thus Gergens, and to a less extent lltltimeyer, noticed that after destruction of the spinal cord the blood-vessels of the frog permit a larger quantity of fluid, and even particles of granular colouring matter, to permeate them. In the second place, we have evidence that the central nervous system exercises some direct influence upon the inflammatory process. From Cohnheim onwards it has been a matter of common observation that when all the nerves of a part have been severed, the stages of the process succeed each other with greater rapidity. It may be that the modified state of the capillary walls, noted in the preceding paragraph, is capable of accounting for this fact, and that, in the absence of central influences, dilation of the vessels and exudation of fluid lead to the cardinal symptoms of redness and swelling, with associated changes in the tissue, at an earlier period. Of the part played by the different sets of nerves the external ear of the rabbit again furnishes an excellent study. This part has a double nerve-supply through the auriculars (major and minor) passing from the cervical plexus and the sympathetic branches proceeding from the superior cervical ganglion: stimulation of the former leads to dilation of the ear vessels, of the latter to contraction of the same. If, as shown by Samuel, the sympathetics be divided on the one side, and the auricular branches upon the other, the ear vessels of the former side become widely dilated, and those of the latter markedly constricted. Under these conditions, if both ears be subjected to the action of water warmed to 54° C, there is a characteristic difference in their reaction. In the organ deprived of sympathetic influence the INFLAMMA TION III congestion and hyperemia become yet more pronounced: an acute inflammation sets in which proceeds rapidly to recovery. In the opposite ear, with its constricted vessels, no hyperaemia is set up; but there is stasis, and gangrene may supervene. These results have been confirmed by Eoger, who, taking a rabbit and dividing the sympathetic on one side and then inoculating both ears with like quantities of a culture of the streptococcus of erysipelas, found that the erysipelatous process manifested itself much more promptly upon the paralysed side, and came to an end at an earlier date. The reverse was the case when the auriculars of the one side had been divided : here the process was of slower development than on the intact side, and of slower course, resulting in mutilation of the organ.* The inference to be drawn from these observations is that section of all the nerves passing to the rabbit's ear permits the inflammatory process to run a more rapid course ; section of the sympathetics (vaso-constrictors) alone has the same effect ; while the uncontrolled action of the sym- pathetics after section of the auriculars (vaso-dilators) hinders or prevents the manifestation of the ordinary processes of inflammation, and by preventing the destruction or removal of irritant matter favours necrosis of the tissues. We have yet to learn whether these results are capable of a general application, and to discover how far they are borne out by clinicAl observations on diverse cases of localised paralysis. So far as they go they afford direct evidence of the power of the central nervous system to modify the course of the inflammatory process, while they demonstrate admirably how potent an auxiliary is the dilation of the vessels in the inflammatory process. Other evidence that the state of the nerve^supply of a region influences the manifestation of inflammation is afforded in sundry neuropathies. In all of these, in the present state of our knowledge, it is difficult to trace out the nervous factors associated with the lesions to which I refer. Our knowledge of the respective influences of trophic and vaso-motor nerves is far too limited to permit us to say more than that a relation exists between the condition of the nerve-supply of the affected area and the inflammatory lesions there observable; that in a certain number of cases inflammation affecting the area sup- plied by one branch of a nerve may have associated with it definite inflammatory disturbances in the areas supplied by other branches of the same nerve, and that, similarly, when inflammation affects a viscus, inflammatory phenomena may be sympathetically developed in regions innervated from the same area in the brain or spinal cord. I have already given examples in support of the first statement : the familiar redness, swelling, heat and pain of the side of the face which may accompany toothache is an example in support of the second, while the condition of labial herpes in pneumonia is an evidence of the results of 1 Although these results have been criticised by Samuel aud other observers, upon re- viewing carefully the whole literature of the subject, I cannot but think that the above paragraph represents the general trend of more recent work. Ill cute the the ike the the was the iwer iia SYSTEM OF MEDICINE the third. Another example is to be found in the acute nephritis, which at times rapidly follows the passage of a catheter, or the impaction of a stone in the urethra. It is not unlikely that many of these sympathetic inflammations are not direct, but secondary. Thus, the first noticeable symptom of catheter fever is suppression of the urine. Such suppression might be brought about either by reflex contraction of the renal arteries, or, contrariwise, by reflex great dilatation and congestion of the vessels of the kidneys. If it be caused by the former then the nephritis can only be regarded as secondary, and as due to the injury done to the organ by the stoppage of its blood-supply for some little time. From the multitude of the factors involved, these examples, taken separately, afford at most only a great probability that the nervous system can directly originate inflammatory changes. There i' , however, the clearest proof that the nervous system does possess this power, and this is afforded by the results of certain observations upon hypnotic effects. There are persons susceptible to hypnotic suggestion, in whom the suggestion that a red-hot substance has been placed apon the hand will, in the course of a few minutes, lead to great reddening of the part supposed to have been burned, and this reddening may be followed by great local exudation and swelling — in fact, by all the sympto'^is of acute inflammation. Here then actual inflammatory reaction folh \:ih supposed injury. It is unnecessary to do more than point out the light that this intervention of the central nervous system throws upon the subject of counter-irritation, and upon the modifications of the course of inflamma- tions brought about by idiosyncracy of the individual. From what has been said in the preceding paragraphs, it foll\.)Ws that : — 1. Acute inflammation in all its stages may proceed regularly in the absence of all centrifugal nervous influences. 2. The vessels of an injured area are capable of reacting apart from central influences ; it may be either directly, or under the control of a peripheral system of nerve cells. 3. The central nervous system is capable of modiiyi g the process of inflammation. It would appear that when the vaso-dilators alone are called into action the successive stages of the process are accelerated. When the vaso-constrictors alone are acting the process is retarded. 4. Centrifugal impulses alone, apart from any local injury, may originate a succession of phenomena of inflammation in a part. 5. Hence, in all probability a nervous and central origin must be ascribed to some, at least, of the sympathetic inflammations seen to occur in areas supplied by the other branches of a nerve supplying a part primarily inflamed ; and again in areas supplied from the same region of the brain or cord as the inflamed organ. INFLAMMA TION "3 Chapter 6. — On the Pakt flayed by the Cells of the Tissues As a consequence of irritation two opposed processes may be mani- fested in the cells of the affected area, — changes leading to impairment and death, and changes leading to overgrowth and proliferation ; de- generation and regeneration. Either of these two processes may, it is true, be wholly wanting. In very acute suppurative disturbances, destruction of the tissue cells and the steps leading to destruction may be the only recognisable changes. Again, in the first stage of most injuries, whether of me- chanical, chemical or bacterial nature, degenerative changes are wont to take the lead. On the other hand, there are irritants so mild that little or no cell destruction results from their action; an extreme example of this category of inflammations is seen in those epithelial overgrowths commonly known as "corns," due, as Sir James Paget pointed out in his lectures, to intermittent pressure and irritation of moderate intensity.^ Other examples are to be found in the " catarrhal " inflammations, in which there is marked initial overgrowth and prolif- eration of the cells of mucous membrane ; and in tuberculosis, again, in which characteristically the earliest effects upon the pre-existing cells, produced by the presence and growth of the tubercle bacilli, are those of enlargement and multiplication — necrotic changes, as a rule, only appearing at a much later stage. Once more, in the later healing stages of injuries, cell proliferation may be in the field alone. Nevertheless, in a very great number, if not in the majority of inflammations, the two processes may be found occurring together — destruction and degeneration being in evidence at the focus of irritation, and growth and proliferation towards the boundary zone, where the irritant is acting in a less concentrated form. Although the two processes are thus so frequently associated, it vHll be well, for the orderly review of our subject, to consider them separately. Degeneration of the Tissue Cells. — Death of the ])re-existing cells as an iiumediate conse([ucnce of injury cannot be regarded as one of the phenomena ot the inflammatory process. Immediate death of the cells may be a result of injury, and the disintegration of the dead cells may in itself lead the way to all the symptoms of inflammation. But cessation * It may very well bo that tlilH Ih not an cxtretno oxnmplo. Neoplasms as a clasH, wliotliur iiiaiiKiiaiit or iMMii^n, not iiiiproliiilily tltwelop hh a c<)ii8i'<|iieiu'u of suinc iiriliitioii liaviiiK III) intensity jUNt MiiOleiuiit to indiico cell proliforation, aiii;etablo pathology favouring this rela- tionship between intlainniiition .'ind neoplastic growth- Thn objection may be raised, with considerable force, that substances which lead to rell-pniliferalion ant stimuli and not irritants, and that a line should be drawn between intliinimation proper and overgrowth the result of irritation. I, for otie, would w illingly make this difference, but while it is easy to draw the liiu( in certain well-nuirked ex- amples, in others, as I shall procoid to show, cellular proliferation is so essential a purt uf the whole inllummutory prucuss that the divisiuii bucuuies impussiblu. Vob I t »*3 p THE Tissues !s may be mani- to impairment oliferation; de- ivholly wanting, the tissue cells ly recognisable whether of me- anges are wont ts so mild that n; an extreme those epithelial I- James Paget nd irritation of :he " catarrhal " wth and prolif- ulosis, again, in e-exi sting cells, lacilli, are those as a rule, only r healing stages Nevertheless, lammations, the lestruction and on, and growth the irritant is eiated,itwilll)e lem separately, e-existing cells Ml as one of the ath of the cells dead cells may But cessation >pla8mH ns n rlnss, of HoiiK' iiriliitioii tinned for n limo tnf mpidniiiltiiilU voiirihK tbiH rulii- u'«'H wliicli load to )o ilriiwii l)olwt*(>n u, would willihKly ;> woll-nmrkcd cx- «> esNunliul II pitrt lu. 114 SYSTEM OF MEDICINE of action is not reaction, nor is failure response, and throughout this article inflamiaation has been considered as the reaction following injury, and tho response to it. Thus immediate death of tissue cells is resultant and not reactive, and may be eliminated from the category of the essential phenomena of inflammation. The same is to some extent true of cell degeneration, but not entirely. While it is impossible nowadays to accept Virchow's old view, that inflammation, is essentially a process characterised by increased nutritive changes in the cells of the tissues, it remains most probable that in very many cases irritation induces increased, even if perverted, activity of certain orders of cells. The proliferation, swelling, and more or less rapid dej feneration of these cells cannot be wholly ascribed to the toxic influence of the irritant, but must in part be regarded as a result of over-stimulation and overwork. This is most noticeable in connection with catarrhal and parenchymatous inflam- mations. In parenchymatous nephritis, for example, such as that set up by cantharidin or septic infection, the cells especially aifected are those whose functions are especially excretory ; and their degenera- tion would appear to be intimately related to the performance of their functions. Such degeneration, preceded or accompanied, as it so fre- quently is, by excessive proliferation, may truly be regarded as reactive, and not as wholly and primarily destructive. Of the degenerations which atfect the tissue cells in inflammation (and often at the same time the leucocytes) there are many varieties ; in fact, according to the nature of the irritant, one, or other, or all the degenerations affecting the tissues in different pathological conditions may manifest themselves, save, perhaps, simple atrophy and j)igmental degeneration (as apart from pigmental infiltration). Most commonly recognised are cloudy and fatty changes, but nnicoid and hydropic chau"es are far more frequent than is generally noted. Even so special- ised :> change as amyloid degeneration has been observed occurring locally in chronic inflammations — as, for example, in gummata; while in these same chronic lesions hyaline degeneration in the vessel walls is very often to be encountered. There is also to be seen in inflammatory disturbances of moderately acute type a further form of degeneration, which receives a passing mention in the text-books, it is true, but so far has not to my knowledge been duly treated as an entity ; nor has its significance been fully grasjied. This is what may be termed " reversionary" degeneration. It is to bo seen affecting tissues, in which the individual comjMments in the fully- formed state are not single cells, but cell complexes or compounds. Such compoimds are the voluntary muscle aiul meduUatcd n(>rve fibres, and, as (irawitz has ]>ointed out, the fat cells of connective tisstie.' These are formed by the fusion and united growth of several cells ; 1 1 horo, and tliroiiKhoiit this nrtiide, loavo wholly out of account (Irawit/.'s " Rlum- b«^rinf; ctdl " Micory —a tluMiry incapnblo of actual proof, and at varlnnuu with thu cull tbuury upuu wbiub is buiiud Ihu uutiro uuponttruuturu uf luudoru biulu({y. INFLAMMA TION "5 I and in inflammation, as under other pathological conditions, the de- generation of the cell-compound as a whole manifests itself by a certain amount of proliferation of the nuclei (of the muscle fibre, sheaths of Schwann, and periphery of the fat cells respectively), protoplasm can be observed to accumulate around these active nuclei, and with the assump- tion by the component cells of an independent existence the degeneration may be said to be complete — that is to say, beyond this point only the shell and debris of the original compound are left to be considered. All these degenerations are inevitably associated with disturbance of the functions of the affected cells, and lead to their death if the irritation which has induced them be continued. But death is not the final stage to be considered. The ultimate fate of the necrosed cells varies according to the situation of the inflamed area, the intensity of the irritation, and the specific character of the irritant. From a free surface the dead material may be freely cast off. In acute suppurative inflammations, whether superficial or deep, and, in general, wherever there is an abundant determination of leucocytes, there obtains a diges- tion and solution of the necrosed cells ; and, as I have already pointed out, this is associated with the development of peptones and albumoses, and is brought about largely through the extracellular action of the leucocytes. When there is a lai'ge area of cell destruction, with well- developed encystment and limitation of necrosis by granulation tissue, there the solution of the dead material and subsequent absorption may be incomplete, and a fatty debris left behind, which may eventually become infiltrated with lime salts (the calcareous degeneration falsely so-called). In tuberculosis, despite the presence of many leucocytes in the immediate vicinity, the dead material of the centre of the tubercle undergoes very little absorption, but remains as an inspissated, cheesy mass. In syphilis, on the other hand, in large gummata, wliile tliero is similar death of the central cells and absence of removal, fatty metamorphosis does not occur nearly to the same extent. Lastly, although very little is known about the subject, attention must be drawn to the fact tliat filong with the tissue cells the inter- cellular matrix undergoes modifications r degenerative changes dur- ing inflammation. Among these, in all probability, is to bo clnssed an increase in the amount of intercelhihir mucin, a mucoid degeneration. The inflam^natory exudate is in many cases rich in mucin, and althougli our knowledge of the changes in the matrix is scanty, the fai't that the tissue cells in general show little evidence of storage of mticoid or mucinogenous material, renders it probable that what mucin is formed is either excreted or elaborated between the cells. Connective tissue fibrils, which may be regarded as i)art of the matrix, undergo dissocijir tion and swelling, and eventually, in acute inflamination, disapyiear. In chronic disturbaru^es they am espc^cially prone to hyaline change. Ittycverdtinn of the Ti'hhuc (Mh ; Orcrifroivth and l*ri>Jifvmtinn. — In the lower animals, as we lrocess. r-i rt INFLAMMA TION 1x7 As Baumgarten showed in his studies upon the development of tubercles, in the irritation set up by the growth of the B. tuberculosis in the tissue, a like overgrowth with proliferation of the fixed cells occurs in the immediate neighbourhood of the bacilli witbo' t any primary evi- dence of cell degeneration. It is true that of late the researches of Borel have thrown doubt upon Baumgarteu's observati(. as lut they confirm the earlier researches so far as regards the mitosi of pre-existing cells, and the absence of degeneration of these in the earlier stages of the tubercular growth. Borel would regard all the large epithelioid cells of the tubercle as modifi^id leucocytes. For myself I cannot admit that he has proved this, careful as his researcihes seem to be ; and until the leucocytic nature of these cells be firmly established I am inclined, with the majority ox histologists, to regard many of them as similar in nature and origin co the modified cells just described in connection with simple inflammation. The diffic'iity of determining the origin of the growing cells in inflammation has formed the greatest trial of the pathologist throughout an entire generation, and yet longer ; nor can we now assert without chance of dispute what cells are niainly concerned in the formation of new tissue. When we examine newly -formed granulation tissue we can distin- guish cells of more than one type — (1) small round cells with poly lobu- lar and fragmented nuclei, (2) other cells containing oxyphil granules, (3) larger cells with a single nucleus and a relatively large quantity of proto- plasm, and again (4) cells of varying but generally large size, varying in shape, but on the whole having the appearance of spindle colls with single oval nucleus and abundant protoplasm. These can be made out easily. The first two forms of cells are clearly leucocytes. Further study of their fate shows that they disappear ; they play no further part in the organisation of the tissue save that, as is well shown by Scheltema and Nikiforotf, many of them are absorbed by the growing connective tissue cells, and thus would seem to aid in their nutrition. The last form likewise presents, as such, no difficulties. These are fibroblasts — cells in the process of growth into connective tissue. But what is their rela- tionship to the previous form, — to the round mononucleated cells with fairly abundant protoplasm, — what are these last, and what in short is the origin of the fibroblasts, — is it from leucocytes or from pre- existing connective tissue cells? Upon this most difficult question more ingenuity and more rest^arch have been expended than upon any other part of this well-worked field of inflammation. There can be no doubt nowadays that a large proportion of the fibro- blasts in g "anulation tissue are developed from pre-existing connective tissue cells. The genei\il consensus of recent researches leads de- cidedly in this diriH'tion ; and it is from the laboratory of Ziegler, who by lus classical observations hul pathologist;: for some years to hold the contrary view, that th(! studies have emanated which '>iosi. conclusively sh jw the part played by the connective tissue ; the researches of KrafTt, Ii8 SYSTEM OF MEDICINE Podwyssozki, Coen, Fischer, and Nikiforoff, confirmed and strengthened by the researches of Arnold, Marchand, lieinke, and Sherringtou, all bring forward evidence in one direction. It is the clearly recognisable pre-existing cells of the tissue — connective, endothelial and epithelial — which show most constantly the signs of nuclear division: every stage of enlargement, mitosis and cell division, can be made out in them. Even if we did not possess the information afforded by nuclear changes, the fact that new tissue is always developed in the immediate neighbourhood of pre-existing tissue would in itself point strongly to this same conclusion. We may rest assured of this much. But can we advance farther, and state that all newly-formed connective tissue cells originate from the pre-existing cells of the tissue, and that none of them are derived from wandering cells ? In tlie present state of our knowledge the answer to this (question must be an unhesitating " Ko." If we base our observations upon the morphology of the cells in granulation tissue, we find that with our present methods the large, round, mononuclear cells seen therein are undistinguishable on the one hand from large hyaline leucocytes, on the other from one stage in the development of fibroblasts. If we examine into their properties we find that they act as pliagocytes incorporating the multinuclcar leucocytes. The fibro- blasts, according to Nikiforoff's careful studies, have an identical action ; so also, according to Metsv^hnikoff, Kuffer, ]*>orel, and others, have the large mononuclear hyaline leucocytes. If Ave study their mode of divi- sion they, like the connective tissue cells, exhibit indirect or nuclear division. It may be (as has been more than once suggested) that the large mononuclear hyaline leucoiiytes differ from the other forms in being of endothelial origin. Were this so a path would be found oiit of our present difficulty. Certainly the most that can now be said is that it is quite ]wssible that among the higher animals this one form of wan- dering cell may be contributory to new fibrous tissue formation, quite possible that the connective tissue cells which develop as a result of in- fiammation are not all derived from the pre-existing cells of the region.* It must be borne in mind that leucocytes, endf»thelial, and connective tissue cells are very simple forms of tissue, that they are all of like mesoblastic origin, and < iius being homogeneous, may be more variously modified, without imjiairment of activity, than more highly specialised cells. I must hcie add that in lower forms — in the tadpole's tail, for examj^le — Metschnikoft" has followed day by day the transition from leucocyte into typical (»inu'ctivo tifauo cell, and that, largely in conse- quence of these oljsorvations, Fren'.;h pathologists hold the view that the leucocytes enter fai more actively into new tissue formation than I hero recognise. The German school, with the exception of Arnold (whoso 1 In this connection may be mentioned fho observntions of IVfptschnikofT, confirmed l)y Barfurth, and more recently l»y Dr. .Joseph (IrldlthH, which show that in the dcnenor- alion and disintegration of miisclo flhrcs (of the tadpole's tail) the proliferated nnclei of the fibres become the nuclei of individual wandering colls — leucocytes. ri'i ki \m\: INFLAMMA TION 119 views correspond on the whole with my own), has with Ziegler passed over to the opposite camp of connective tissue only from connective tissue. For myself I have carefully sifted the evidence adduced by either side. What is said above gives, I believe, thfi estimate of the matter for the time being; while what follows gives in brief the state of our knowledge of the part played in intlamiuation by the tissue cells in general. (1) Two series of changes may occur in the cells of an inflamed tissue, which may be included under the terms degeneration and regeneration respectively. (2) The extent to which one or other of these series of changes pre- dominates varies with the nature and intensity of the irritart. (3) Degeneration and death of the tissue cells may be a direct and immediate result of the pieseuco of the irritant, and then can scarcely be regarded as essential phenomena ot inflammation. Or they may be of more gradual onset, associated with evidexHC; of ovoi -stimulation and increased activity of the cells. (4) Fatty, cloudy, hydropic and mucoid cire the most frequent forms of degeneration affecting the tissue cells iu acute inflammation; hyaline in chronic; other forms are rare. (5) The ultimate fate of the necrosed cells varies as the situation, intensity of irritant, and specific character of irritant. (6) Cell-proliferation is so constant an accompaniment of certain forms of inflammiit ion that it is impossible to regard this as an adjunct and not as an essential part of the process. (7) The tissues wiiieh show the greatest potentiality for reproduc- tion in consequence of inflammation are those which are least highly organised. (8) The origin of fibroblasts and new connective tissue cells cannot be regarded as entirely determined, but this much would seem to bo clearly demonstrate 1 : (a) That a large proportion of the fibroblasts are derived from pre-existing connective tissue cells. {&) That in lower forms — as, for example, the tadpole — leucocytes can be seen to develop into connective tissue cells, (y) It is quite possible, indeed probable, that in the higher animals one form of wandering cell, the large hyaline mononuclear, contributes to the formation of new fibrous tissue. Chapter 7. — On Fibrous Hyperplasia and its Relationship to Inflammation The succession of change* from embryonic cells to fully-formed tis- sue can best be studied in cases where there has been a relatively largo area of destruction — as, for example, after severe burns, or excision of organs or large portions of organs ; or again, where inflammation has been of a chronic character. If healthy granulation tissue be examined, the process of growtli is seen to originate iu the immediate neighbourhood of if not in direct I20 SYSTEM OF MEDICINE connection with the dilated new capillaries. It is around these vessels, formed of little more than a single layer of cells, that the fusiform fibro- blasts are in greatest abundance. At a later stage, in regions more remote from the advancing margin of the granulations, the fibroblasts have a more j^'eueral distribution in the intercapillary spaces, and are more elongated ; {iiound them may be seen the earliest wavy fibres of white connective t ;-3ue. These are essentially of cellular origin — as much so as is the substance of striated muscle fibres. The elongated fibroblasts not only break or extend at their poles into fine processes, but also along their sides the protoplasm undergoes modification into fine parallel fibrillse. With the continuance of this change the cells become smaller and smaller until little is left but the attenuated nuclei, often so flattened and narrow as to be scarcely recognisable. It is generally accepted that the fibrillar substance contracts with increasing age ; certainly the newly-formed cicatricial tissue diminishes greatly in volume, and with this diminution the previous great vascularity of the part disappears ; the capillaries shrink until the majority become completely occluded. Thus in place of the abundant, soft and succulent granulation tissue, rich in cells, blood-vessels and exuded fluid, there is eventually a firm, shrunken, anaemic mass of fibrous tissue, with rare flattened nuclei, rich only in closely-pressed bundles of white, semi-transparent fibrils. Fibrous hyperplasia is to be encountered in almost every tissue of the body as a sequence of very diverse morbid conditions. To speak of it in any case as " fibroid degeneration " is a misnomer. The overgrowth of any tissue, however lowly, is not a degeneration. Fibn is tissue may and often does become the seat of degenerative processes, . ttably the hyaline; but that is another matter. To regard every condition of generalised or localised fibroid change of the organs of the body as a chronic " — itis " is equally erroneous, until we have proof absolute that connective tissue only undergoes excessive growth directly or indirectly under the stimulus of injury. It is interesting to note the opposed tendencies of the two branches of our profession on this subject; the surgeons strive to restrict the idea of inflammation to acute pyogenic disturbance, the physicians to extend the idea so as to include all cases of chronic progressive " fibrosis." I will not say that the latter is as untenable a position as the former, for it is a matter of peculiar difficulty and delicacy to state what is and what is not an inflamma- tory fibrosis; after all, there is more danger of being tossed about helplessly in the Charybdis of including too little, than there is oi striking upon the Scylla of including too much in our idea of inflam- mation. Here I wish to point out how divergent are the conditions which lead to fibroid hyperplasia, and to draw attention to the fact that there is reasonable ground for not classing all forms under the one common heading, even thougli the resulting appearances maj?^ be undistinguish- able ancl the effects the same. Cicatricial fibrosis presents little difficulty ; it is plainly the result of i INFLAMMA TION 121 inflammation ; so too is the fibrous overgrowth upon chronically inflamed serous surfaces. Capsular fibrosis is clearly of the same nature ; it is to be seen around foreign bodies, around chronic abscesses, in the walls of tubercular cavities, and encapsulating tubercles, gummata, and other neoplasms inflammatory and non-inflammatory. Allied to these is the fibroid replacement in old infarcts (including that following upon " myomalacia " cordis). Here, studying a series of cases, it can be made out that the necrosed material becomes surrounded by a zone of inflammation, and that, with the passage of leucocytes into the dead area and absorption of the effete material, there is soon manifest a new connective tissue overgrowth advancing inwards from the pe:i- phery. Among the generalised scleroses there is one form frequently encoun- tered which may, without hesitation, be regarded as the accompaniment of inflammation. This is seen well in the general interstitial nephritis accompanying subacute and chronic parenchymatous inflammation of the kidney. Of similar nature are some forms at least of hepatic cirrhosis, diffuse syphilitic cirrhosis, the diffuse tubercular cirrhosis to which at- tention has more especially been drawn by French pathologists, and an extensive pericellular cirrhosis in cattle, which I have of late been engaged in studying, due, it would seem, to the abundant multiplication of a diplobacillus in the bile capillaries and liver substance. Whatever be the immediate cause of other forms of cirrhosis, overgrowths of fibrous tissue would appear in these to precede atrophy of the liver cells, and to be associated with the presence of an irritant. But there are other varieties of fibroid growth concerning which it is less easy to arrive at a just conclusion. First may be mentioned the replacement or compensatory fibroses. An excellent example of this is to be seen in the sclerosis of well-defined tracts of the spinal cord follow- ing destruction of the ganglion cells governing those tracts, or sections of the fibres, at a point proximal to their trophic cells. The fibrosis in these cases is not secondary to a progressive inflam- mation, but to a simple atrophy of the nerve fibres. These shrink, and their place is taken by fibrous tissue. Another equally instructive example is to be found in the dystrophic sclerosis of the cardiac muscle fibres to which attention has been called, more especiaU y by Drs. Martin and Huchard. This occurs in certain cases of arterio- sclerosis, and is best seen in the papillary muscles, the fibroid change occurring, not around the thickened arterioles, but at the periphery of the area supplied by each. The muscle fib''"s around the arterioles are healthy ; but farther away, through lack ot nutrition, they have atro- phied, and their place is taken by a zone of fibrous tissue which fre- quently manifests hyaline degeneration. In this instance the morbid condition of the arteries is in itself a hindrance to active dilatation of the vessels, and the exhibition of the ordinary accompaniments of in- flammation. Indeed this peripheral zone is singularly free from leu- cocytes, yet well-marked sclerosis appears nevertheless. 122 SYSTEM OF MEDICINE Id IS je Id pe fg pe 3t A Can these be regarded as cases of inflammatory fibrous hyperplasia? According to our definition they may : the fibrosis ensues as a reaction to injury. It is legitimate to conceive that the dying and atrophic tissue elements here, as in the grosser condition of infarct, act as irritants. But, on the other hand, the only recognisable evidence of inflamma- tion is this very extension of cicatricial tissue ; and even this is strictly limited in amount, being just sufficient to replace the dead tissue, and nothing more. Active hyperaemia is not a prominent characteristic of any stage in the first instance cited above, and is throughout absent in the second. Still, as I showed in an earlier portion of this article when treating of injuries to non-vascular areas, active hyperaemia is not absolutely indispensable. Active hyperaemia is entirely wanting in yet another form of fibrosis — that resulting from passive congestion, whether of the blood (as in clubbed fingers, in that variety of cirrhosis of the liver which may result from obstructive lung or heart disease, and in the spleen of portal obstruction), or of the lymph (as in chronic oedema, sclerema, elephantiasis and macroglossia). Is this to be regarded as an inflam- matory fibrosis ? Everything points to the conclusion that connective tissue cells and their progenitors, like the Chinaman and the Polish Jew, can thrive and multiply upon a pabulum which is starvation to those of a higher standard. Iq passive congestion, as in obstruction to the onward flow of lymph, there results undoubtedly a bathing of the tissues with increased lymph. Can this alone account for the hyperplasia, or must we invoke the aid of the irritation or stimulus of retained effete matters contained in the lymph? This question is one that is most difficult to answer. Underlying it are the further ques- tions whether one broad explanation can be found to apply to all cases of tissue hyperplasia ; and whether cell growth in general, under physio- logical as under pathological conditions, is due to increased nutrition, or to stimulation of the cells, to increased physiological activity of the same, or to removal of pressure and other conditions preventing growth, or to a combination of all, or nearly all of these. This last question at present remains unanswered. In the examples before us of hyperplasia following passive congestion, one possible factor, that of removal of pressure from the cells, is absent ; and we are narrowed down, I think, to two of the possible factors named above — relatively increased nu- trition, and stimulation by effete matters. If it were shown that there are states in which stimulation or irritation by effete matters plays no part in the overgrowth of new connective tissue, then we could, I think, safely declare that forms of fibrous hyperplasia exist which cannot como under the heading of inflammatory fibrosis, and that the fibrosis ol passive congestion may be included among them. Now such conditions do exist. That increased nutrition alone can lead to hypertrophy of the tissues was established long ago by Hunter's classi- cal experiment of transplanting the cock's spur on to the cock's comb, — > INFLAMMA TION 13} moving it from a slightly vascular to a richly vascular region. In the ensuing overgrowth there can here be no question of irritation by any- thing beyond the normal blood.^ And passing from the general to the particular, we have evidence that there is such a condition as fibrous hyperplasia due, as it would seem, to increased nutrition unassociated with the presence of toxins or other cellular irritants. In his wonder- fully painstaking series of observations upon arterial changes, Thomas has adduced two cases which he describes, no doubt, as examples of endarteritis, but in which the inflammation is not apparent, nor indeed any factor other than altered tension of the arterial walls leading to altered conditions of nutrition. He shows that immediately after birth there is developed a thickening of the intima — a connective tissue proliferation immediately below the endothelium — of that portion of the aorta lying between the ductus Botalli and the passing off of the umbilical arteries. During later foetal life the umbilical arteries are the largest branches of the aorta ; and, when the circvdation through them is arrested, the aorta above is too large for the amount of blood requisite for the abdominal viscera and the lower extremities. The arterial current becomes therefore relatively sh-wed, and presumably, judging by the analogy of what occurs in the adult when large branches of the aorta are ligatured, the aortic blood pressure is for a time raised. With this slowing and increased pressure there appears a compensatory overgrowth of the intima leading to contrac- tion of the vessel and its lumen. Generally speaking, when the area of distribution of an artery is diminished, as, for example, when a limb is amputated, the artery shows a similar proliferation of the intima. In both cases the blood remains healthy, and the intima has undergone no injury; the only recognisable change has been a slowing of the blood stream, and probably increased blood pressure; and as the intima is nourished, not through the vasa vasorum, but directly from the main arterial fluid, it would appear that with the slowing an increased nutrition is brought into action. I can see no satis- factory reason for calling either of these cases an endarteritis. It is quite possible that other cases of thickening of the intima are due not to irrita- tion, but to increased nutrition brought about by heightened arterial tension. The difficulty urged by Councilman that high arterial pressure does not invariably lead to overgrowth of the intima is not, in my opinion, insuperable. It must suffice if here I point out that it is more than probable that certain cases of endarteritis are in no sense of inflam- matory origin, or secondary to degenerative changes ; but are primarily associated with nutritional changes. In this connection it was shown by Prof. Roy and myself that when the aorta of the dog is suddenly and greatly contricted, and as a consequence the pressure in the (* 1 1 here leave out of account a factor which may bo important, but about which wo know practically nothing — namely, the effect of altered innervation. I am forced to assume, perhaps wrongfully, that, as this factor plays a like part in all the cases und:..- consideration, it may for present purposes bo disregarded. 124 SYSTEM OF MEDICINE proximal portion of the vessel greatly increased, the plasma of the blood is forced into the cusps of the aortic valves, and vesicles of lymph make their appearance on the under surface in that region where fibroid thickening is most frequent in cases of chronic high arterial pressure. Thus, to express briefly the distinction that I would draw between inflammatory and non-inflammatory fibrous hyperplasia, I would say that where local injury leads to increased nutrition of the connective tissue, with increased functional activity of the cells, the ensuing fibrous hyper- plasia is to be regarded as of inflammatory origin ; where, on the other hand, local injury is not recognisable as the primary cause of the cell growth, the hyperplasia must be held to be non-inflammatory. In pas- sive congestion, obstructed lymph-flow, and increased nutrition conse- quent upon arterial change, as in the cases cited above, we can so far see no cause for the fibrous hyperplasia beyond altered conditions of nutrition ; there has been no primary lesion in the affected regions induc- ing the reaction. Such cases must be considered as non-inflammatory. But while I lay down this distinction, I must impress upon the reader that the last word has by no means been said upon this matter, and that further research may cause a radical reconstruction of our opinions. Forms of Fibrous Hyperplasia A. Of Inflammatory Origin. 1. Cicatricial. 2. Perivisceral. Localised ■! 3- Capsular. 4. Replacement — Gross (of infarcts, etc.). Fine (dystrophic; scle.'osis, etc.). 5. Cirrhotic, associated vy;*^^> parenchymatous Generalised { intlammation, interstitial and lymphan- gitic. B. Of Non-Inflammatory Origin. 1. Hyperplasia of increased (arterial) nutrition. 2. " of venous conjjestion. 8, " of lymphatic obstruction. C. Neoplastic. 1. Fibromata. ( f Upon the Increased Temperature of Inflamed Areas Very little has of late been added to our knowledge in this division of our subject : what is to be said appears now to be so well established that I need do little more than state the main conclusions. The long controversy that raged before these conclusions were fully accepted, and 1 IN FLAM MA TION kiH^ John Hunter's original views shown to be in the main correct, scarcely comes within the scope of this article. 1. The temperature of superficial regions is raised, it may be several degrees above the normal, by the onset of inflammatory hypersemia. 2. The temperature of internal organs when inflamed may be raised above the normal, but undergoes no material increase beyond that of other unaffected internal organs tested at the same time. 3. The rise above the normal, which is often present, is an indication of the febrile state accompanying the inflammation, and not of locally increased heat production. 4. The increased temperature of superficial areas when inflamed is due, not to the production of heat in the part, but to the increased quantity of blood passing through it. When the congestion is so great that stasis ensues there may be actual decrease in the temperature of the part. 5. The maintenance of high external temperature may exert a favourable effect upon the duration and progress of specific inflammation. Thus Filehne has recently shown that the course of experimental erysip- elas in rabbits is more rapid and more benign when they are kept at a high temperature than at a low. We possess no clear evidence that this is due to the unfavourable effect of the heightened temperature on the growth of the microbes. Pasteur's well-known experiments upon the production of anthrax in fowls (ordinarily insusceptible to this disease) by lowering their temperature can be explained on other grounds. We have abundant evidence that heightened temperature promotes vascular dilation: the experiment of Filehne may therefore supply a further demonstration of the favourable effects of dilation of the vessels and hyperaemia in the inflammatory process. 6. Low external temperature, or the application of cold to the surface, contracts the vessels : hence, upon the lines of what has already been said, it would appear that (a) It is calculated to diminish the amount of exudation. (6) It is calculated in consequence to diminish the pain associated with inflammation. (c) It has no directly good effect upon inflammation due to tho presence and growth of pathogenetic micro-organisms, but may have the reverse effect of preventing the fullest reaction on the part of the organism. Where the irritant does not itself grow and multiply, or present cumulative action, there the application of cold may not only be of no harm, but of positive advantage, by lessening the in- flammatory reaction and preventing this, where extensive, from being itself a cause of further injury to surrounding tissues. The increase of systemic heat will be considered in the article on Fever. (d) I ised It of tion lally |d is ised Ireat the 126 SYSTEM OF MEDICINE ( ' PART III. — On the Vakious Forms of Inflammation Chapter 1. — Classification The minute changes which characterise the process as it affects one or other organ, and the various specitic forms of inflammation, will be fully described in special articles. I have only to indicate more general causes and main varieties. To give a complete classiiication is impossi- ble unless each separate tissue be taken 'n order, for each tissue presents peculiarities either in liability to inflamm-*"ion, or in the course assumed by the process. Even to attempt a classification in broad outline is beset with difficulties, for the inflammatory manifestation varies, not according to one or two series of causes, but according to four at least ; the permutations are thus so numerous, and the appearances so varied, that to give an adequate scheme of classification would require a diagram in four dimensions. These four causes of variation are — A. Nature of tissue affected. B. Position of tissue affected. C. In- tensity of irritation, or more correctly ratio between resistant powers of the organism and intensity of the irritant. D. Nature of irritant. A. Nature of Tissue affected. — As I have already shown in the first portion of this article, there is in the earlier stages of the process a difference in the reaction of vascvdar and non-vascular tissues, the one series exhibiting marked congestion and vascular disturbance, the other not. At a later stage, or in more chronic irritation, as new vessels invade the non-vascular areas, the changes in the two series do no doubt approxi- mate ; but in the earlier stages we may distinguish between an ordinary inflammation and " inflammatio sine inflammatione." The relative denseness and compactness of the tissues also introduce characteristic alterations : a dense tissue, such as bone, does not show the signs of reaction to injury to nearly the same extent as does a loose tissue — such as the omentum, for example — thus, in the former there may be a process almost as atypical as in non-vascular areas. The rigid framework of a tissue like bone prevents great vascular dilatation and exudation, but at the same time may be the seat of great pain due to pressure of the confined exudate upon the nerve endings. The loose connective tissue of a structure like the omentum, on the other hand, permits great exudation with little or no pain. The influence of structure is well seen in comparing the course of in- flammation affecting cutaneous, mucous and serous surfaces respectively. Where we have to deal with cutaneous surfaces, or surfaces formed of squamous epithelium, there the increased exudation, and the resistance offered by the layers of flattened cells to the free exit of the exuded fluid, lead towards the formation of vesicles or blisters. In the case of serous surfaces, which form the walls of a moist cavity, the irritant, affecting primarily but one portion of the surface, is very likely to bo borne into the cavity with the exudate and to set up an inflammation rt:i INFLAMMA TION 127 extending over a very large portion of the surface. Mucous and cuta- neous surfaces, which are not thus the boundaries of cavities, exhibit a more marked disposition to the production of localised inflammation and of ulcers ; the superficial layers indeed of a well-formed epithelium or mucous membrane, by the protective powers of their cells, form a defence against irritation from without: thus the superficial exudate from a region of local inflammation cannot easily produce a superficial exten- sion of the process. Not only the nature of the tissues, but their function also, profoundly affect the character of the inflammatory manifestation. Thus, excretory organs, by the very nature of their function, during the attempt to remove noxious substances from the system, are especially liable to generalised parenchymatous inflammations, — the irritation not being local, but affecting at the same time all the cells whose part it is to take up and excrete the irritant bodies. B. The Position of Tissues. — It is difficult to consider the position and relationship of tissues as they affect the inflammatory manifesta- tions, without continually touching upon their structure. iN'^evertheless, the two, though very closely connected, do not go hand in hand. A familiar instance of modification in form brought about ))y position is to be seen in the result of suppurative inflammation — in the develop- ment of ulcerous conditions when the process affects free surfaces, of abscesses when it attacks deeper tissues. The process in the two cases is virtually the same : there is the same abundant determination of louco- cytes, tlie same degeneration of them into pus. Yet apart from the gross difference in form, there are minor differences between the two. There is, for instance, relatively much more serous exiulatiou from the free surface of an ulcer than there is into and around an abscess. As a general rule, inflamed tissues near a free surface are the seat of more abundant exudation. Of this liability for free surfaces to be the seat of serous inflammation I have already spoken. The skin, with its thick dermal layer, affords a good example : when the full suppurative stage is not reached, inflammation affecting the outermost layers of the derma is most often of a vesicular or (edematous character ; when it affects the deeper layers of the derma the serous infiltration is less evident. Yet another example of the influence of position in modifying form is seen in enteric fever. In this malady, the lymphoid tissue forming the Peyer's ])atehes becomes the seat of excessive (H?llular infiltration and proliferation, undergoes necrosis, and is cast off, leaving the well- known ulcers. The lymphoid tissue of the neighbouring mesenteric gland likewise undergoes great infiltration and enlargement, but necrosis rarely implicates the whole of a gland : notwithstanding the previous extensive inflammation, the glands commonly recover their normal ai)pearance and size. Jieyond this there are few broad i)rincii)le8 to l)0 laid down concern- ing the relationship l)etwecn forms of inHaninuiiion and ]iosition that do not essentially depend upon the structure and functions of the tissues. 127 d cuta- chibit a on and lium or lefence from a exten- 128 SYSTEM OF MEDICINE Much can be sai'l concerning the intimate connection between position and liability to inflammation ; but this and the allied and most impor- tant subject of the protective mechanisms of sundry tissues against injury are away from our present point. C. The Relative Intensity of the Irritant is a more frequent and potent cause of variation. I have already in several places referred to tlie ratio between the resistant powers of cells and the intensity or virulence of the irritant as it affects the inflammatory process, and have shown how much that was previously vague has been made clear by bacteriological research ; while, at the same time, it has brour^ht home the truth that the various forms of inflammation merge insensibly one into the other. Broadly speaking, it may be stated, as a result of these studies, that, cfMeris paribus, increased virulence of any given microbe or diminished power of resistance on the part of the organism or of the tissues, leads to corresponding alterations in the phenomena of inflam- mation at the region of inoculation ; and vice versa. Thus, if a pathogenetic microbe, such as that of anthrax or erysipelas, be greatly attenuated, the effects of inoculation into the subcutaneous tissues may be scarcely recognisable. If the attenuation be not so extreme some hyperoemia, a determination of leucocytes, and, relatively, very little exudation, will be seen ; and in the course of a day or two all traces of inflammation may have disappeared. Witli sliglitly more virulent microbes the migration of leucocyt«?s may be followed by their breaking down and couse(pient abscess formation ; with further increase of intensity of action the migration of leucocytes may be wanting, while the exudation extends and the inflammation rai)idly spreads and leads to a septictcmia. A like ;ieries of changes is observable if the strength of virns be constant and animah more and more susceptible (or less and less refractory) be inoculated. The variation in tubercular lesions, from isolated dense fibroid masses to loosely formed cell accumulations and diffuse tubercular in- flammatioji, is evidently explicable on this law. Tlie law holds good also, not merely for bacterial produ(!ts, but for other irritants also. The eft'ectof croton oil varies with the strength of the solution ajjplied; and, as shown by Samuel, according to the condition of the animal. The same is true of abrin p.nd other vegetable extracits. Turning to physic, il irritants, while here the intensity of the irritant alone or almost alone is called into play, numerous exami)les can be given of the effects of V!':i;il.i()n in thit one respect upon the intlamnia- tory manifestation — effects of cold, for instance, varying from chilblain through inflammatory (I'denui to gans^rene; of h(>at varying from hypenemia through vcsicrular inflammation to (uunph'to dcstriu'tion of tissue; and, again, effects of caustic substances. In this era of aseptic surgery wo may forget what was well known to the last gcmiratiun of surgeons, that caustic substanct's may be eniploytul either to originate a benign and reparative inflammation (as in the case of indolent idcois) ; Iltii INFLAMMA TION 129 or, in larger quantities or greater intensity, to bring about a state in which the death of the tissue elements is far in excess of the subsequent repair. Thus then, according to the above-mentioned ratio, inflamma- tion in a tissue may vary by insensible gradations from a mere hyperuimia up to a spreading suppurative or gangrenous process ; and from a purely local manifestation to the development of what may be termed an in- flammation of the whole organism. D. The Nature of the Irritant. — It is clear, then, that it is impos- sible to base a classification upon the nature of the irritant : the attempt to mark off sharply the inflammations caused by mechanical and chemical noxai from those produced by bacteria and tlieir ])roducts must be given up. Huter's proposition that suppuration can only be induced by microbes has been repeatedly shown to be erroneous. Thanks more especially to the researches of Councilman, Leber, Grawitz and de IJary and Straus (many more names might be mentioned in tliis connection), we now know that many chemical substances are (iapable of causing pus formation.' Among these may be menti(med turpen- tine, croton oil, mercury, cojijier aiul silver nitrate. On the other hand, although this pyogenetic j)ropei-ty is not conflned to microbes and their products, yet among microbes it is not the common property of all. Some, like the bacillus of tetanus, never in themselves induce jius forma- tion: others, like the bacillus of tuberculosis, lead characteristically to tissue growth and the formation of inflammatory neo{)lasnis rather tliau to pus formation. Even aiuong those which, like the micrococci, are highly pyogenetic, the formation of abscesses only occurs when there is a deflnito relationship between the virulence of the microbe and the resistance of the organism. The reverse is equally true, that numerous laicrobes, not specially pyogenetic, produce pus under peculiar condi- tions. Thus, the bacillus of enteric fever, when it multii)lies in the middle ear, induces a suppurative otitis, and, as Dr. ('. F. Martin has shown, it is further capable of originating a sui)])urative arthritis. Im fact, uiuler varying conditions the same microbe can induce very various forms of inflammation. Thus, Charrin has shown that the M. pyocyaneus and its products are cajjable of inducing in out! organ — \\w. kidni^y — ])atli()logical conditions so diverse as acute, chronic, ]»arenchy- inatous, interstitial and thrombotic ne])hritis, with, in addition, cyst iormatitju and iiiuyloid degeneration.^ This same microbe can induce acuti! suppuration in the anterior cliamber of the; eye ; and wlien inocu- lated into tlu^ blood cause a luemorrhagi(! inflammation of the s(^rous surfaces. Hence we can ])rocecd further and state that no strict classi- flcati(m of inflammation can be made according to the nature of the > VVIillfl thiN iH HO, it inuflt bo b()rno in mind Mint under ordinary conditions tlioHo HuliHtiincuH viry riindy net upon tlio orKutilHiu in n Hiato of HiifHcittnt concent riition to lin ])yo(;(d area. It would seem that local inflamma- tion in some way brings about an over-stimulation of lymjjh glands, whereby an increased number of leucocytes are j)()ured into the blood ; or it may initiate increased proliferation of the leucocytes alnvidy in the cinndation; but how one or other of these effects is ])ro(luce(l is at present unknown. (Certainly tlie direct introduction of the products of i)a(!terial growth into the ciicuiating blood may lead to a more or less pronounced and rapid dimitnition of tlie number of leucocytc^s in the blood, and this diminution, as shown by Ii()witz, may be preliminary to a subsequent increase. The further important gem^al disturbance associated with local injury, more esp*Miidly when of bacterial origin, uainely, tlte occurrence of fever, will be desc; ibed in another artichi. IJacteriological studies INFLAMMA TION nz lead to the conclusion that traumatic fever, at any rate, is largely due to the diffusion in the blood stream of soluble bacterial products, and of the products of tissue destruction derived from the inflammatory focus. , Chapter 3. — Conclusion In studying thus the reactions of the organism to injury, we are impressed by the multifariousness of natural processes; the end may be attained not in one way only but in many. "It is not by cells of one order alonf» -by phagocytes — or by leucocytes in general and only leucocytes, ui icerely by the reaction on the part of the fixed cells of the tissue, or Uy vascular changes alone, or by altered tempera- ture, or solely by the A nical and mechanical action of the exudate that repair is effecte- \ . Aii /neaus are employed to antagonise the irritant and to effect healin.' '^' c Us of the body, fixed and free, play their part ; the nervous sysi Luds the process ; the bodily humours render efficient help; modificctUons ' '.r vessel walls and blood stream are valuable auxiliaries. Divers* , co-Mjsses are employed, now one more particularly, now another, according to the needs of the moment, but none exclusively." The time has come when, example after example having clearly indi- cated the meaning and the tendency of that response, we may securely acknowledge the t( ndency, and see in inflammation not merely the re- sponse to injury, b it the attempt to repair injury. To object that a definition containing this statement is teleological is absurd in the face of fact after fact that can be interpreted on this assumption only. What is the development of cicatricial tissue nut an attr^mpt at repair? What other meaning can be ascribed to the increased bactericidal power of the inflammatory exudate as compared with that of ordinary lymph and blood serum ? Why do leucocytes accumulate in a region of injury ? Why do some of them incorporate bacteria and irritant parti< les, and others bring about the destruction of these without necessarily ingest- ing them? All these are meaiiH wherel)y irritiints are antagonised or removed, and reparation and return to the f»«^)rmal sought after. It must be kept in mind that attempt to • oair luav be far from repair. Indeed, we frequently find that the reaction to injury is (Mspnv portionate to the strength of the irritant, being . ither insuflicieii or ex- cessive. The exudation may p()ss«!ss but sliglit bactericidal powers, (»r may be poured out in such (juantities that the microbic ii -itant, instead of being retained in the region of injury, is conveyed outside that reginti ; the wandering cells instead of destroying, may undergo destruction ; they may incorporate bacteria, but not be abh^ to annihilate tht>m ; the fixed cells may either form an incomplete cicatrix, or continue to ]iroliferate in excess. The means of defence on the part of the organism are not so much a preparation in advance as an inheritance or an arquirement — either a transmission from those forms which, being possessed of the most highly developed means of defence, have survived wluh^ forms with f«'.wer resources have been destroyed; or, on the other liand, an accession derived 134 SYSTEM OF MEDICINE k : from previous successful resistance : not being a preparation in advance, the reaction to injury is not exactly proportionate to any and every irritant. But the mere statement that inflammation is an attempt to repair injury, or that it is the response thereto, is insufficient as a detini- tion, for thereby the general disturbances which may accompany the changes occurring at the seat of lesion are included ; these, kowever, may be excluded without seriously affecting our conception of the process, in fact with positive advantage to a clear comprehension of the distinction between inflammation and fever. And, further, if what I have urged in the chapter upon the part played by the nervous system be correct, account must be taken of the fact that the leading phenomena associated with the inflammatory process may occasionally present themselves solely under the direction of perverted nerve action, and apart from actual local injury. Hence I am inclined to consider that we can now pass beyond the conception of the process with which I began this article, and cannot merely regard it as a succession of changes in a part constituting the re- action to injury, but can with propriety acknowledge the purpose of that succession. From these considerations I am led to define infla^imation as the series of changes constituting the local manifestation of the attempt at repair of actual or referred injur n to apart, or, briefly, as the local attempt at repair of actual or referred injury. So diverse are the opinions of pathologists upon many branches of this sidiject of inflammation, and so great is the amount of recent research that I can neither hope that all the conclusions here set down will gain acceptance, nor that in these pages, inevitably condensed as they are, I have succeeded in recognising and duly acknowledging all work of primary importance. It is possible also that, having been unavoidably prevented of iate from seeing and discussing with others the results they have ob- tained, I may in some cases have viewed facts in a wrong persiicctive. In the rapid progress of our science, much, it may be, that is here set forth will be modified. Nevertheless I hold that the ('onco])tion of the inflammatory process indicated in this arti(!lc is that wliich embraces the largest number of like phenomena, and exc^ludcs most satisfactorily those which if associated are unessential ; and that it is by the study of ci'llular pathology in its strictest sense that the surest advance has been and is to be made in our knowledge of this the dominating process in disease. JouN Geouoe Auami. SELECT BIBLIOGi: \PHY I. Of Inflammation in Oeneraij 1. Rknnrt. 0» Tnjfammafinii. E/«'«/. 1 Sill. No. L'O. — 4. HuitDDN-aANDKRSdV. Unlinrx'n Sf/Kfcm of Suri/iTi/, i. (jiivi'spxtciisivoseltict biblioii- riipliy). — f). HitRn<)N-SANi>KiiS(i\. Crooniuii liecdircH, 1K!)'_'. (/(/" I.nnrrt, ii. ISii'J, pp. 1027, I08.'t„ 114(», ami 1207. -- fi. Coiinhkim. VorloKtmiirti, sccon.i clition. I^tipzi^. 1H82. TriuiHlateil by Hr. A. H. M'K«e, New Sytlenhiim Socioty, IMK) - INFLAMMA TION m 7. CoRNiL ET Rantibr. MoTivel d'Histolof/ie pathologique, i. — 8. Councilman. Dennis's System of Surgery, i. 1895. — 9. Hamilton. Text-book of Pathology, i. 1889 (gives extensive bibliography). — 10. HUtbr. Grundriss der Chb-urgie, i. 1883. — 11. Kocu. Wunditifectionskrankheiten. Leipzig, 1878. — 12. Leber. Die Entstehung der ErUzdndung, Leipzig, Engelmann, 1891. — 13. Lbtulle. L' Inflam- mation. Paris, 1893. — 14. Mbtschnikoff. Pathologic compare de I' Inflammation. Paris, Masson, 1892. Eng. transl., London, 1894. — 15. Neumann. " Uber dem Entziinduiigsbegriff," Ziegler's Beitr. v. 1889, p. 347. — 10. Recklinghausen. Handhh. d. allyein. Path. 1883. — 17. Roser. Entziindtmg vnd Heilung. Leipzig, 188C. — 18. Samuel. Virch. Arch. Iv. 1872, p. iJSO. — 19. Samuel. Die Entzdnd- ungsprocess, 1873. — 20. Thoma. "Ueber Entziindung," Berlin klin. Wochenschr., 188(5 (on tlie suppression of tlie term " Inliammation "). — 21. Virchow. CellvUtr Pathology. Eng. transl. from second edition by Chance. London, 1860. — 22. Wagnkii. Hdbuch. der alluem. Path. Eng. translation. New York, W. Wood, 1879 (gives older literature very fully). — 23. Weigert. " Entziindung," Eulenburg'a Realenryclopadie, 1880, iv. p. 044. — 24. Ziegler. Lehrbuch der allgemeinen pathologische Anatomie, 8th German edition, 1894. — 25. Ziegler. Rede gehalten am 25 April 1892 zur akademi- tchen Feier, Freiburg, Lehmaun, 1892. II. The Comparative Pathology of Inflammation 20. Greenwood, Miss M. — J. of Physiol, vii. 1880, p. 254; viii. 1887, p. 263; xi. 1890, p. 570; xvi. 18S)4, p. 441. — 27. Proc. Roy. Soc. liv. 1893, p. 400, "Inter- cellular Digestion." — 28. Hardy. J. of Physiol, xiii. 1892, p. 105, "Blood Corpuscles of Crustacea." — 29. Krukknbbrg. Unters. a. d. physiol. Inst, in Heidelberg, ii. 1H78, p. 273, " Intercellular Digestion." — 30. Le Dantec. Ann. de I'Inst. Pasteur, iv. 18it0, p. 770, and v. 1891, p. 103. — 31. Loeu. Biol. Lectures, Marine Biol. Lap., Wood's Hole, 1893. Boston, Ginn and Co., 18!»4, p. 43. — 32. Metschnikoff. A. de I'Inst. P. iii. 1889, and No. 14, gives main literature. — 33. Pfkffer. Unters. a. d. botan. Inst, in Tiibingen, vols. i. and ii. — 34. Reinke. Unters. a. d. bot. Inst, in Gottingen, 1881.-35. Stahl. Botan. Zeitung, 1884, Nos. 10-12. III. The Steps of the Inflammatory Process in the Higher Animals In addition to Noa. 0, 7, 8, 12, 19 and 23, consult — 30. Flemming. Virch. Arch. Ivi. 1872, p. 140, on "Development of Fibrin in Inflamed Tissues." — 37. Hess. Virch. Arih. cix. 1887. p. ;«>.'>. — 38. Hohnfeldt. Ziegler's Beitr. iii. 1888, p. 343. — 39. Jacobs. Britr. z. Histol. d. acut. Entziindung d. Cornea, Inaug. Diss. Bonn, 1887.-40. Ranvier. t'tes. rend. d. I'Acad. d. s'c. 1891, April 20th, p. 846. — 41. Sknftleben. Virch. Arrh. Ixxii. p. .542. — A satisfactory bibliography of thi.s sub- ject is given by Biirdon-Sandermon. Nos. 4 and 5. For full references to recent work upon mycotic inflammation consult Baumgarteu's Jahrcsbericht. IV. On the Forms and Varieties of Leucocytes 42. Ehrlich. " Farbenanalytischo Unters. z. Histol. u. Klinik dcs Blutes," Oesnmni. Mitthl. Berlin, Hirschwald, 1891.-43. Everard, Drmoor, and Massart. A. dp I' I. P. vi:. 1893.-44. Gi.uge. Observnt. nonn. microscop. in Ivflnmm. W.Vt. — 4.5. (IVLLAND. Lab. Rep, R. C. P. Kdin. iii. 1891, p. 100.— 40. Gulland.' J. of J'athii/. ii. 1804, p. 447.-47. Wharton Jones. Phil. Trans. 1840, p. 04.-48. Kanthack. Med. Chron. Now scries, i. 18it4, pp. 240, 332.-49. Kanthack and Hardy. J. of Pathol, xvii. 1894, p. 81; and Phil. Trans. 1804. — .HO. Mf.snil. A. de I'l. P. ix. 1895, May.— 51. Metschnikoff. B. M. J. 31st Jan. 1891, and No. 14.-52. Ranvier. "Dps Clasmatocytes," (Jtes. rend. d. I' Acad, dcs Sc. ex. 1«89, p. 105. —53. Rifder. licitr. z. Kenntniss d. Leucocytose, Leipzig, 1892; and itlas (I. klin. Microscopip rfr.s lilutps. Leipzig. 1892.-54. UiNDFLEiscir. Pathol. Histohx/ip, 1801; und Ezptelle. Studicn ii. d. HiMohgie dcs Blutes. Leipzig. 180.3.— 55. Max Hchultze. Arrh. f. vukr. Anat. i. 1803, p. 1.-50. SHEKRiNOTOTif. Proc. Roy. Soc. Iv. 1893. p. 101. — 57. SiAwciLLo. A. de I'l. P. ix. May 1895. — For fuller bibliography consult Nos. 40, 48, and 53. 136 SYSTEM OF MEDICINE V. On tbb Nature of Giant Cells 58. BuBREL. A. de I'Inst. Pasteur, vii. 1893, p. 593.-59. Dubnschmamn. J. of Pathol, iii. 1894, p. 118. —60. Fabbb, Knud. J. of Pathol, i. 1893, p; 349. -61. Koch. Mittheil. a. d. kaiserl. Gesundheitsamt, ii. 18M. — (J2. Lanouans. Virch. Arch. xlii. 18U8, p. 382, and xlix. 1870, p. G6.— (J3. Marchand, P. Virch. Arch. xciii. 1883. — 64. Johannes Mulleu. Ueber den feineren Jtau und die Formen der Krankhaften-Geschwiilste. Berlin, 1838. — (55. Kibbbrt. Der unteryang. pathogen. Schimmelpilze im Korner. Bonn, 1887.-66. Buffer. A. de I'Inst. P. v. 1891. — 67. SouDAKEWiTCH. Virch. Arch. cxv. 1889.-68. Stchastny. A. de I'Inst. P. V. 1891, p. 225.-69. Vikchow. Virch. Arch. xiv. 1858, p. 47. —70. Weiuert. D. med. Wochcnschr. 1885, and Virch. Arch, cxiii. 1889. — 71. Zieolbr. Expt. Unter- auch. a. d. IIe7-kunft d. Tuhi'.rkelclemente. Wurzburg, 1875. — Earlier literature given by Mabcuand (Nu. 63), later by Faber (No. 60). VI. On Chbmiotaxis 72. Councilman. Virch. Arch. xcii. 1883.-73. Gabbitchewski. A. de VI. P. iv. 1890, p. 34(i.— 74. Kanthack. See No. 48, and B. M. ./., June 18th, 1892. — 75. Leber. See No. 12.-76. Massart, J. A. de I'l. P. vi. 1892, p. 321.— 77. Massakt and BoRDET. J. d. I. Sue. Boy. d. Sc. Med. et Nat. de Jiruxelles, 1890. — 78. Massart and BoRDET. A. de I'l. P. v. 1891, p. 417. —79. rBKBLHARiNQ. La Scmaine med. 1HH9, No. 22, p. 184.-80. Pfeiffeb. See No. 33. — 81. Stahl. See No. 35.— For fuller bibliography consult Massart and Bordet, No. 77. VII. On Phaqocytosis — General Abticlbs 82. Adami. Med. Chron. Nov. and Dec. 1891.— 83. Baumgarten. Ctbl. f. klin. Med. 1888, No. 26; Zeigler's Beitr. vii. 1889; Berl. klin. Woch. 1884, Nos. 50 and 51. — 84. Bitter. Zeitachr. f. Hygiene, iv. 1888, p. 405.-85. Discussion on Immunity (Roux, Metsclinikoff, Hankin, Behring, Buchner, etc.). Trans. Internal, Vongr. of Hygiene, London, 1891, vol. ii. — 86. Discussion on Immunity. Internal. Vongr. of Hygiene Buda-Pesth, 1894 (Metschnikoff, Roux, Buchner, Denys, etc.), Ctbl. f. Baku 1894. — 87. Discussion on Immunity. Path. ISoc. London, 1892 (Woodhead, Klein, Hankin, Martin, etc.) ; Path. Trans. 1892, v. ; also B. M. J. of Feb. 20 and 27, 1892.-88. LuBARSCH. Fortschr. d. Med. viii. 1890, No. 17. — 89. Lubarsch. Zeitschr. f. klin. Med. xviii. 1891, p. 421.— 90. Methchnikoff. See Nos. 14 and 51.-91. NiEczAjEFF. Verhandl. das X. Internal. Med. Congress, Berlin, 18itO, ii, pt. 3, p. 54. — 5)2. Sanarelli. Ctbl. f. Bakt. x. 1891, p. .'514.-93. Sternberg. Am. J. of Med. Sc. April 1881. — For the abundant literature on this subject consult Bitter (No. 84) and Lubarsch (No. 88), as also the full bibliography (up to 1893) given by Sternberg in his Manual of Bacteriology. New York, 1892, and (to 1895) in his Iinmur nity, Protective Inoculation, etc. New York, 1895. VIII. Phagocytosis in Connection with Pathogenic Microbes of Vabious Diseases (for Shortness Names of Diseases alone given) Actinomycosis: — 94. Marchand. Eulcnburg's liealencyclopudie, article "Actino- mycosis." — 95. BosTKiiM. Zeigler's Beitr. ix. 1890. — 9(i. Pawluwsky and Maksukoff. a. de I'Imt. Pasteur, vii. 1893, p. 544. Anthrax :— i)7. Hess. Virrh. Arch. cix. p. .•565.-98. Koch. Cohn'a Beitr. z. Biol, der Pflanzen, ii. 1876. — 9i). Lubarsch. Fortschr. d. Med. 1888, p. 4. — 100. Metschnikoff. Virch. Arch, xcvii. p. 502. and A. de I'Inst. Pasteur, i. 1H87, p. 7.-101. Nutall. Zeitschr. f. Hygiene, iv. l>-;88. — 102. Petruschky. Zeigler's Beitr. iii. 1888, p. 357, and Fortschr. d. Med. viii. 1«90, No. 15. Cholera : — 103. Metschnikoff. A. de VI. P. viii. 185)4, p. 529. — 104. Pfeiffer and Wasserman. Zeitschr. f. Hygiene, xiv. 1893, p. 55). — 105. Cantacuzene. Rtichcrrhrs .inr le mode de destruction du Vibrinn Cholerique. Paris, 1HS)4. Diphtheria : — KKJ. GABRirrHEWSKi. A. de VI. P. viii. 185H. — 107. Massart. See No. 76. Erysipelas : — 108. Metschnikoff. Virvh. Arch. evil. 1887, p. 209, and numerous other observers. Gonorrhoea : — 109. Neissbr and all subse- i!' S-! IN FLA MM A TION 137 qnent observers (for bibliography see Sternberg). Hog Cholera : — 110. Metschnikoff. A. de VI. P. vi. 1802, p. '28'J. Leprosy : — 111. Metschnikoff aud Soudakewitch. Virdi. Arch. cvii. 1887, p. 228 (and all recent observers). Malaria: — 112. Gulgi. Guz. degli Ospitali, 1886, No. 53 (parasites in leucocytes, as distinguished from red corpuscles). Mouse Septicsemia : — 113. Metschnikoff. A. de I'Inst. P. v. 1891. Pathogenetic Toruls in Daphnia : — 114. Metschnikoitf. Virch. Arch. xcvi. Patho- genic Moulds (Aspergillus, etc.) : — 115. Ribbkrt. See No. G6. Pneumonia (Diplo- coccus) : — Ufi. Gamaleia. A. de VI. P. ii. 1888, p. 445. — 117. Isaeff. Ihid. vii. 18!)3, p. 260. — 118. Tchistovitch. Ibid. iii. 1889, p. 337. Relapsing Fever: — 11!>. Metschnikoff. Ihid. i. 1887, p. 329. — 120. Soudakewitch. Ihid. v. 1891, p. 545. Suppuration (Staphylococcus pyogenes) : — 121. Fleck. Die acute Entziindunn der Lunge. Dissort., Bonn, 1886. — 122. Hess. See No. 37. — 123. Hohn- FELDT. See No. 38. — 124. Lahr. Ueher d. Untergang d. Staph, in der Lunge. Dissert., Bonn, 1887 (and numerous other observers). Swine Erysipelas ("Rouget" or " Rothlauf ") : — 125. Metschnikoff. A. de VL P. iii. 1889, p. 289. — 126. Schiitz. Arh. a. d. Kaiserl. Qenundheitsumt, i. 1885, p. 61. — 127. Tchistovitch. See No. 118. Symptomatic Anthrax (Quarter-evil) : — 128. Rcffeb. li. M. J. May 24th, 1890. — 129. RuFFER. A. de VI. P. v. 1891, p. 673. Tuberculosis : — 130. Bokrbl. See No. 58. — 131. Mktschnikoff. See No. 51. — 132. Stschastny. Virch. Arch. cxv. 1889, and No. 68. Vibrio Gamaleia vel Metschnikovi : — 133. Metschnikoff. A. de VI. Pasteur, v. 1891, p. 465. — 134. Sanarelli. /6td. vii. p. 225. IX. On the Bactbricidal Action of the Bodily Humours 135. Behrino and Nissen. Zeitsehr.f. Hygiene, viii. 1890, p. 424. — 136. Buchner. Arch./. Hygiene, x. 1890, pts. 1 and 2 ; Centrlhl.f. Bakt. v. 1889, p. 817, and vi. p. 1. — 137. Emmerich and di Mattel Fortschr. de Med. vi. p. 729. — 138. Von Fodor. D. Med. Woch. 1887, p. 745; and Cthl.f. Bakt. vii. 18SK), p. 753. — 139. Hankin. See No. 150.— 140. LuBARscH. Cthl.f. Bakt. vi. 1889, p. ^Ul. —141. Nissen. Zeitsehr.f. Hygiene, vi. 1889, p. 487. — 142. Nuttai l. Ibid. iv. 18HR, p. ;*o,'<. — 143. Pekelharinq. La Sem. mid. 1892, p. 503. — 14t. Tkaube and ijdCH l,eidb?:. Jahresbr. d. Schlesischen Gesell. Iii. 1874, p. 179.-145. Weigert. Fortschr. t. 2, p. 52?> (on "Now Formation of Vessels"). — Fuller references given iu Ziegler (No. 24) and Hamilton (No. 9). 137 m SYSTEM OF MEDICINE XII. On the Diapedesis of Leucocytes 165. Addison. Exptl. and Pract. Researches upon Infl. London, 1843. — IGfi. Arnold. Virch. Arch. Ivili. 1872, Ixvi. 1874, and Ixviii. 1875. —I(i7. Binz. Virch. Arch, lix., Ixziii., and Ixxxix. ; Arch./, expt. Path. vii. and xiii. — 1(W. Cohnhkim. See No. 6. — 1()9. Dissklhorst. Virch. Arch, cxiii. 1888, p. 108. — 170. Herino. Wivn. Acad. Bericht. Ivii. 18()8, p. 170 (on the "Adhesion of Corpuscles"). — 171. Kalten- brunner. Exp. circa stat. sanguinis et tKisoruin in infl. 182(>. — 172. KErtNKR. Pfliigcr's Archiv, vii. — 173. Lavdowsky. Virch. Arch, xevii. — 174. Mkthchnikoff. See No. 14. —17.5. Pekklharing. F/rc/i. ^?t^. ci. 1886. — 170. Re(ki,in(;ti \u8BN. Strieker's Hanilh. Article, "Das Lymphfjefiisssysteni." — 177. Schki.ai Pfli'iger's Arch. i. 18()8, pp. ()03 and (»7. — 178. Thoma. lierl. klin. IFoc/t. 18> u. Waller. Phil. Mag. xxix. 184G, pp. 217, 2!)8, 3«7. (a) On THE Effect of Intra and Extra- Vascular "T( un ui- in Diapedesis 180. Bouchard. Esxni d'une thiorie de V infection. Verhandl. d. X. Internat. Med. Congr. Berlin, 18!K). — 181. Chakrin. Ibid. ii. pt. ;<, p. 29. — 182. Roger. Cnntrib. a V4tude de I'ininiuii. acquire, p. 1. — 18;i. Ruffku. A. de I'l. P. v. IHid, p. 673. — The earlier literature of diapedesis is fjiven in detail by WA(iNER (No. 22) and Hamilton (No. 9). The last (German) edition of Ziegler (No. 24) is also very full. Xin. On thk Part played by the Nervous System in Inflammation 184. Berkley. Anat. Anz. viii. 1893. Nos. 23 and 24, and ix. 1893, Nos. 1 and 2; Joum. of Cotnp. Neurol, iii. 1893, p. 107; Pathol. Studies, Johns Hopkins Univ., Neurology, ii. 1894 ("Upon Nerve Entlings in Vessel Walls, etc."). — 18."). Charcot. Le(;ons .curies maladies du syvt. nerveux. Paris, 1873, p. lOiJ. — 18(1. Cohnhkim. See No. 6.-187. Dache and Malvoz. A. de VI. P. vi. 1892, p. 5;!8 (on "Influence of Nervous System in Mycotic InHammations"). — 188. De I'volis. IVifonna Medica, 1889, No. 200. — 189. Frenkel. Arch. d. med. expt. iv. 1892, p. ()38. — 190. (JEiuiENS. Pfliiger's Arch. xiii. p. 591. — 191. Kt.kbs. Allg. Pathol, ii. 1889, p. 384. — 192. Len- HossEK. Arch. f. mikr. Anat. xxxix. 1892 (on " Nerve Endings"). — 193. Mitchell, S. Weir. Injuries of Nerves. I'hila. 1872, p. 108. — 19+. Ochotine. Arch, de ni^d. expt. iv. 1892, p. 245. — 19."). Retzius. Biol. Untersuchungen, Neue Foljje, iii. 1891, p. 49, and iv. — 19(!. Roger. Comptes Bend. Soc. de Biol. 3rd May 1890, and 22nd Nov. 1890.-197. Rijti,mb:yer. Arch. f. e.rpt. Pathol, xiv. p. 3.V4. — 198. Samuel. Virch. Arch. cxxi. — 199. Saviotti. Virch. Arch. 1. 1870, p. .592 (on "Dilation and Contraction of Arteries accordinji to Nature of Irritant"). — 2(X). Severini. La con- trattilita dei capillari, 1881. — 201. Wagner, A. Arch. f. kiln. Chirurg. xi. 1869, p. 1. XIV. On the Part played by the Connective Tissue Cells in Inflammation 202. Arnold. Arch. f. Mikr. Anat. xxx. 1887. — 203. Baumoarten. Virch. Arch. Ixxviii. 1879; Ueber Tuherkel und Tuberkulose, i. Die Ilistogenese des Taber- kulosenprocesses. Berlin, 1885. — 204. Bourel. See No. .58. — 205. Cokn. Ziegler's Beitr. ii. 1887.— 206. Cornil and Ranvier. See No. 7.-207. Discussion at the Tenth Internat. Med. Cong. Berlin, 1890. (Ziegler, Marchand, Grawit/.) Verhmnll. ii. pt. 3, p. 1. — 208. Fischer. Untersuch. ii. die 11 dung von Schnittvunden dcr Ilant. Inaug. Diss. Tubingen, 1888.— 209. Flemming. Virch. Arch. Ivi. 1872, p. IKi. — 210. Grawitz. D. Med. Wochenschr. 1889. No. 2.3, on " Slumbering Cell8." — 211. Grawitz. Virch. Arch, cxviii. 1889.-212. (Jriffith, J. ,/. of Pathol, ii. 18!t4 (on "Development of Wandering from Fixed Cells"). — 213. Gull and Sutton. Med.- Chir. Trans. Iv. 1872, p. 273. —214. Huchakd. Traits des maladies du cteur. Paris, 1889 (on "Dystrophic Sclerosis").- 21.5. Krafkt. Zi^gl. Beitr. 1. 1884.-216. JLiRCHAND, Ibid. iv. 1888.-217. Metschnikoff. Hini. Cenfrbl. 1883, p. 5lil : A. de VI. P. vi. 1892, p. 1 (im " nevclopmeiit of Wandering from Fi.xed Cells ").— 218. NiKiFOROFF. Ziegl. Beitr. viii. 1890, p. 419.-219. Podwyssozki. Ibid. i. 1884, THE DOCTRINE OF FEVER •39 and ii. 188C. — 220. Ranvieh. Comptcs rend, de I' Acad. d. Kc. 1891, p. 843. —221. Rkinkk. Zie(/l. Beitr. v. 1,S8'.>. — 222. Roy and Apami. B. M. J. 15th Dec. 1888. — 22;{. ScHKLTKMA. D. Med. Woch. 1887, p. 4t}3. — 224. Shekrinoton and Ballance. J. of Physiol. 188i), p. 85f). — 22;'). Soudakewitch. A. de I'l. P. vi. 18!»2, p. 13. — 220. Stkicker. atudirn a. d. Inst./, exp. Pathol. Vienna, i. 1870. — 227. TourET. Des modifications cellul. dans I'inft. simple du pcritoine. Thesis, Paris, 1887. — 228. ZiBOLKR. Ej-p. Untersuch. ii. die Herkutift der Tuberkelelement. Wiirzburg, 1875. — 229. ZiEGLKR. Untersuch. ii. pathol. Bindgewebs- und Ge/iissnenbildung. Wnrz- burg, 187(). — 230. Grawitz, No. 211, gives a very full bibliography up to 1889 of the part played by the connective tissue cells. Consult also Virchow (No. 21), Cohnheim (()), Metschnikoff (14), and Zieglkr (24). The later German editions of Zir(/l/'r's Handbook contain a very judicial discussion of the relationship of librous hyperplasia to iutlammation. XV. On the TEMPERATtTRE CHANGES IN INFLAMED ArEAS 231. Billroth and Hufschmipt. Arch. f. klin. Chirurg. vi. 1804, p. 373.-232. Hunter, John. On the Blood, Inflammation, and Gunshot Wounds. London, 1793. — 233. HuppKRT. Arch. d. Ildlkuiide, xiv. 1873, p. 73. — 2.'54. Jacobson and Bkrn- H.\RDT. M. Laupien. Ibid. 18G9, No. 19. — 2;«i. Schneider. Ibid. 1870, No. 34.-237. Simon. Ilolmrs's System of Surgery, 1860, article " Iiiflammatiou." — 238. Weber, O. IJeutsch. Klin. 1864, Nos. 43 and 44. J. G. A. Us L I ••7 M WH: '''*ifl V^cjiA iii,i