1.

Inflammation & Repair

INTRODUCTION
Q. I.I. What is inflammation ? Describe the salient features of inflammation and its main types. A property of living organism is self-defence. Aiming at selfdefence the human body (as any other living creature) reacts sharply to any stimulus received by it. The reactions of the body to the normal or noninjurious stimuli constitute, with other activities of the body, the physiologic process. The reaction of the body to injurious stimuli (trauma) is of the following types : 1. Vascular reaction termed inflammation. 2. Phagocytosis. 3. Entrapment by specialised cells (haemocytes) and subsequent ingestion. 4. Neutralization by cellular hypertrophy. Of these inflammation occurs only in vertebrates; in lower animals without vascular system, the reaction to trauma is of later three types. Thus inflammation may be defined as response of the vascular tissue to trauma. Inflammation is not a disease which enters from outside; it is rather a mechanism developed by body itself-a tool to fight an outside attack.

Cardinal signs of Inflammation

The cardinal signs of inflammation described by Cornelius Celsus in the first century A.D. are : 1. Rubor i.e. redness. 2. Tumor i.e. swelling. 3. Calor i.e. heat. 4. Dolor i.e pain. (In so many centuries only one sign has been added i.e.) 5. Loss of function.

Advantages of Inflammation and Repair

1. Limitation of infection 2. Healing of wounds 3. Normalisation of injured tissue.

Disadvantages of Inflammation and Repair

1. Development of crippling diseases e.g. rheumatoid arthritis. 2. Life-threating sensitivity reactions. 3. Fatal glomerular disease. 4. Disfiguring scars. 5. Joint stiffness. 6. Scar tissue hampers vital functions.

Causes of Inflammation
Inanimate Mechanical Foreign body Injury Necrosed tissue Physical Heat or cold Electric burn Radiation Chemical Acids Alkalis Other irritants Animate Bacteria Parasites Protozoa Helminths Fungi

Types of Inflammation and Repair

The response of the tissue to trauma depends upon the nature and amount of trauma. The response may be immediate and brief when trauma is extremely mild. The inflammation caused subsides before it becomes noticeable (latent

inflammation). To certain types of trauma the tissue may react sharply by undergoing severe changes. Such form of response is acute inflammation. The tissue changes occuring in acute inflammation may subside partly or completely after trauma is overcome. Often the type of trauma is such that is continues to elicit the response over prolonged period in subsidised form. The resultant inflammation is called the chronic inflammation. A' chronic inflammation may be the aftermath of acute inflammation ; in that case exacerbations may render the inflammation acute periodically. Alternatively chronic inflammation may originate as an independent entity without being preceded by acute form. The salient features of acute inflammation and chronic inflammation are enumerated below :

Acute Inflammation
I. Stereotypical response to all forms of injury irrespective of the type of causative agent. Causes of Inflammation Inanimate Animate Mechanical Physical Chemical Bacteria Parasites Fungi Foreign Injury Necrosed Acids Alkalis other Protozoa Helminths Body tissue irritants Heat or cold Electric burn Radiation 2. Relatively short duration, ranging from a few minutes to 1-2 days. 3. Exudation of fluid and plasma protein (oedema). 4. Emigration of leucocytes, mainly polymorphs.

Chronic Inflammation
1. Less uniform 2. Generally of longer duration 3. Presence of lymphocytes and macrophages. 4. Proliferation of small blood vessels and fibroblasts.

ACUTE INFLAMMATION
Q,. 1.2. What are the varieties of acute inflammation ? Describe vascular phenomena in acute inflammation.

Varieties of Acute Inflammation

1. Catarrhal inflammation (i) Affects mucous membranes, acini and ducts of glands, mainly of upper respiratory tract, large intestine, and urinary tract. (ii) Mucus secretion is abundant. (iii) Desquamation of surface epithelium. (iv) Discharge initially mucoid, later mucopurulent. Examples : Bronchitis, gastritis, colitis. 2. Serous inflammation (i) Affects mostly serous cavities viz. pleura, peritoneum, pericardium ; may occur anywhere. (ii) Exudate is fluid and composed mainly or serum. Example : Bristles of burnt skin.

3. Croupous or fibrinous inflammation (i) Affects serous membranes e.g. pleura, pericardium, peritoneum, joints, meninges. (ii) May occur in epithelial surfaces e.g. alimentary canal, urinary tract, gall bladder, lungs. (iii) Exudate more concentrated with excess of plasma, protein, mainly fibrinogen. Examples : Dysentery, lobar pneumonia (early stage). 4. Haemorrhagic Inflammation (i) Caused by increased fragility of blood vessels and capillaries as in leukaemia, anaemia, various forms of purpuras. (ii) Inflammation attended with extravasation of red blood cells. Examples : "Black" small pox, measles, diphtheria. 5. Purulent inflammation (i) Digestive softening of the tissues with formation of pus. (ii) Pus is semifluid, yellow or greenish-yellow material, opaque creamy and granular. (iii) Odour may be offensive if gas forming organisms e.g. Esch. coli are associated. Example: Abscesses. 6. Necrotic inflammation. Inflammation accompanied by necrosis e.g. oriental sore. 7. Pseudomembranous inflammation Formation of a false membrance composed of necrosed epithelium and fibrin. Examples: Diphtheria, dysentery.

Vascular phenomena
Vascular phenomena constitute the local manifestations of acute inflammation. These have three main components: 1. Dilatation of blood vessels. 2. Emigration of leucocytes. 3. Escape of blood plasma.

1. Dilatation of blood vessels

(i) Often preceded by a brief vasoconstriction. (ii) Most marked in arteries, less in veins, and least in capillaries. (iii) Transitory acceleration of blood stream followed by slowing. (iv) Increased vascularity results in redness and heat. (v) There may be complete stasis of local circulation, the condition being termed as sludging of the red blood corpuscles. This results in death of the part. (vi) Pavementing of the leucocytes. The leucocytes, which normally flow intermingled with the red cells, occupy the outer, plasma tic zone. Thus the inner wall of the vein becomes paved by an unbroken line of leucocytes. (vii) The lining cells of the vascular endothelium be come enlarged and

proliferate. They assume a rounded form, project into the lumen and exhibit arnoeboid movement.

Fig. 1.1. Vascular Phenomena

2. Emigration of leucocytes
(i) The ground substance of the swollen endothelium becomes loosened ; the individual elements of the vessel wall lose their sharpness. (ii) Through such vessel wall, the leucocytes flow out. (iii) A number of erythrocytes also flow out ; when these are numerous, the inflamation is said to be haemorrhagic.

3. Escape of blood plasma

(i) Blood plasma accompanies the leucocytes through the damaged vessel wall. (ii) This results in swelling of the tissue (inflammatory oedema). (iii) The fluid contained in inflammatory oedema is termed inflammatory exudate. (see Q. 1.3).

Mechanism of Vascular Phenomena

1. Nervous impulses. The vascular changes, both dilatation and exudation are influenced by nervous impulses. When nerve to a part is divided, the normal constrictor impulses are cut off and inflammation develops much more rapidly. In such a part, the capillaries permit a greater emigration of leucocytes and a greater transudation of lymph through their walls. 2. Chemotaxis. The emigration of leucocytes is controlled by the phenomenon of

chemotaxis. Both positive and negative chemotaxis are recognised. (i) Some substances such as quinine, alcohol, and lactic acid repel the leucocytes but dilute solutions of the same chemicals attract the leucocytes. (Negative chemotaxis changed to positive one). (ii) Extremely virulent bacteria cease to have any chemotactic power ; they just paralyse the leucocytes. (iii) Leucocytes show differential response to chemotaxis. Polymorphs are most active; lymphocytes are much less active presumably because of smaller quantity of cytoplasm. The products of parasites attract mainly the eosinophils. 3. Globulin factor. A soluble globulin factor has a powerful effect on the vessel wall. Two factors exist in the globulins of normal serum-one enhances the capillary permeability whereas the other inhibits this process. Permeability globulin precursor is activated by liberation of serotonin (5-Ht) and histamine in damaged tissue cells. There is degranulation of mast cells which are thought to be a source of heparin, histamine and a permeability factor.

Chemical mediators
The tissue response to injury is believed to be mediated through chemical substances of varied nature originating from plasnia, from cells, or from damaged tissue. The evidences of chemical mediation are: 1. Inflammatory reaction to different types of injurious stimuli has a fairly uniform pattern. 2. Inflammation develops in tissues devoid of nerve supply. The chemical mediators may be divided into the following groups. I. Vasoactive amines (i) Histamine. (ii) Serotonin. 2. Plasma proteases (a) Kinin system (i) Bradykinin. (ii) Kallikrein. (b) Complement system (i) C3 fragment. (ii) C5 fragment. (c) Coagulation-fibrinolytic system (i) Fibrinopeptides. (ii) Fibrin degradation products. 3. Prostaglandins. 4. Neutrophil products (i) Cationic proteins. (ii) Acid proteases. (iii) Neutral proteases. 5. Lymphocyte factors.

6. Other mediators. (i) Show reacting substance (SRS-A). (ii) Endogenous pyrogen. (iii) Substance P.

INFLAMMATORY EXUDATE
Q. 1.3. Define inflammatory exudate and name its various components. Discuss the role it plays in limiting infections. Q. 1.4. Discuss the role played by the cellular exudate in the process of inflammation. Q. 1.5. Describe the formation of inflammatory exn-date and discuss its significance. Q. 1.6. Describe in detail the cellular elements of the inflammatory exudate.

Cellular elements of Exudate

1. Neutropbils. 2. Eosinophils 3. Basophils and mast cells. 4. Monocytes and macrophages. 5. Lymphocytes and plasma cells. 6. Giant cells.

Neutrophils
1. Active agents in acute inflammation particulaly when the causative organisms are pyogenic bacteria. 2. Chief constituent of pus. 3. In section of inflammed tissue, the vessels may he packed with these leucocytes. 4. Collect in great number around the dilated vessel. 5. Pass through the tissue spaces by the their remarkable amoeboid movement but cannot swin through a fluid. 6. Form first line of defence of the body against the pyogenic bacteria ; having devoured such bacteria, they digest them by means of an enzyme which dissolves the bacterial bodies. 7. Large number of neutrophils are killed by bacterial toxins ; on disintegration, they release a proteolytic enzyme which dissolves the dead tissue and thus hastens the process of recovery. 8. In a fresh exudate the cell outline is sharp and the nucleus distinct ; as degeneration proceeds, the cytoplasm becomes granular the outline indistinct and the nucleus eventually disappears. 9. Many of the cells which survive reenter the circulation.

Eosinophils
1. Appear early in the inflammatory exudate and may disappear.

2. A marked eosinophlia is characteristic of many parasitic infestations. 3. In bronchial asthma, the bronchial mucosa is often crowded with eosinophils. 4. Eosinophilia may be a reaction against a foreign protein in both the above instances. 5. -A marked eosinophilia is sometimes seen in : (i) Subacute or chronic appendicitis. (ii) Lymph nodes in Hodgkin's disease. 6. Eosinophilia in allergic reaction may be produced by antibodies rather than antigen as it rises in convalescence with rise in antibody titre. 7. Eosinophils on breaking down release histamine with resulting increase in capillary permeability and outpouring of more antibodies with neutralisation of antigen. Fig. 2. Cellular elements of exudate.

Fig. 1.2. Cellular elentents of the inflammatory exudate.

Basophils and Mast Cells

1. Basophils are of haematogenous and mast cells of tissue origin. 2. The two types of cells have similar function in hypersensitivity reactions mediated by immunoglobulin lgE.

3. They release heparin, histamine. and serotonin, in response to antigenantibody complexes, drugs and trauma. 4. Immunoglobulin IgE binds selectively to the surface of these cells. 5. Degranulation of basophils and mast cells, triggered by : interaction of immunoglobulin (antibody) with specific; antigen, results in release of histamine and other mediators.

Monocytes and Macrophages

1. Monocytesandmacro-phages belong to mononudear phagocyte system (MPS). also called reticuloendothelial system (RES). 2. These are found in the bone marrow, peripheral blood, and tissues with function of intracellular digestion ; in connective tissue these are termed histiocytes. 3. Macrophages involved in inflammation are derived from monocytes and have the following properties : (i) Phagocytosis and digestion of invading organisms or foreign particles. (ii) Release of potent enzymes which degrade connective tissue. (iii) Release of chemotactic and permeability factors which may prolong inflammation. (iv) Release of substances causing leucocytosis and fever (viz prostaglandins, endogenous pyrogen). (v) Release of factors which aid in healing. (vi) Secretion of antibacterial, antiviral substances and such other proteins.

Lymphocytes and Plasma Cells

I. Appear late during the chronic phase of inflammation and are particularly prominent in tuberculosis, syphilis, other granulomous diseases, viral and rickettsial infections. 2. Plasma cells develop from lymphocytes by synthesizing an increased amount of RNA and gamma-globulin in their cytoplasm. 3. Lymphocytes and plasma cells are a prominent source of globulin antibodies.

Giant Cells
When the individual macrophages are unable to deal with particles to be removed, they fuse together and form multinucleated giant cells. The giant cells are of three types : (i) Tumour giant cells. (ii) Foreign body giant cells. (iii) Miscellaneous. Tumour giant cells are seen in: (a) Osteogenic sarcoma, (b) Glioblastoma multiforme, (c) Rhabdomyosarcoma and (d) Primary carcinoma of liver. They are large cells and have one or several nuclei but these are never

numerous. Their nuclei are always hyperchromatic and may vary considerably in size and shape. The tumour giant cells are formed by division of the nucleus while cytoplasm of the cell fails to divide. These giant cells are not derived from the macrophages but from tumour cells, whether connective tissue or epithelial in nature. Tumour giant cells are found in neoplasms only and are absent in inflammation. The foreign body giant cell is larger than an ordinary cell and may be of enormous size. It contains numerous nuclei, sometimes as many as 50-100. The nuclei, are regular in size, seldom large and are scattered through the cytoplasm. However, in certain conditions e.g. tuberculosis the nuclei may be arranged around the periphery (Langerhan's giant cells). Foreign body giant cells are seen in; (a) Tuberculosis, (b) Syphilis, (c) Leprosy and (d) Actinomycosis, etc. The third group 'miscellaneous' include the giant cells of mesodermal origin e.g. Aschoff cells of rheumatic nodule. Another member is the Reed-Strenberg cell of Hodgkin's disease.

Formation of Inflammatory Exudate

I. Increased permeability or porosity of the capillary endo-thelium caused by damage results in increased flow as well as increased protein content of the lymph. 2. Initial increase in permeability results from local release of histamine. 3. The presence of abundant leucocytes in the tissues may lead to local production of lactic acid by anaerobic glycolysis and this in turn further increases capillary permeability. 4. With the mechanical escape of red corpuscles, plasma also escapes and adds to protein content of exudate. 5. The extreme result of damage is necrosis of capillary walls and thrombosis within, the intermediate stages are the phenomenon of stagnation, exudation and diapedesis of red corpuscles. The exudation is thus a result of damage to the capillary endothelium.

Role of Exudate
1. Dilutes the irritant. 2. Lowers the concentration of toxins e.g. leucocidin. 3. Bactericidal effect on some species. 4. May inhibit growth of some bacteria. 5. Makes bacteria susceptible to phagocytosis by leucocytes.

RESOLUTION

Q. 1.7. What is resolution of Inflammation ? Discuss the process of resolution in an acutely inflammed tissue. Resolution is the process of retrogression of various phenomena occuring in inflammation. In resolution there is tendency to restoration of normal blood flow and absorption of exudate. 1. As the irritant is removed from the tissue or its effect otherwise encountered, the stagnation passes off and blood flow is restored though a certain amount of vasodilation often persists for some time. 2. The exudate, if fluid, is absorbed chiefly by lymphatics and fibrin is digested by leucocytes and thereafter absorbed. 3. If fibrin is abundant or dense, its absorption is effected only after ingrowth of fibroblasts and capillaries i.e. by a process of organisation. This is the common result in the case of a fibrinous exudate on serous membrane. 4. Connective tissue cells which have become swollen and separated in an inflammed part become attached again to fibres or form new fibres. 5. The defects in the endothelial lining may be completely restored by the surviving cells. 6. Healthy leucocytes may pass back through the endothelium of the venules to the blood stream, but those damaged and also extravasated red cells are either taken up by phagocytes or are carried by lymph to the lymph nodes where they are similarly dealt with. 7. The phagocytes are macrophages developing from both monocytes and cells of tissue origin (histiocytes), within a macro-phage, sometimes several polymorphonuclear leucocytes are seen. The phagocytosed leucocytes are gradually digested and disappear. Damaged red corpuscles are also taken up by these phagocytes and destroyed.

Fig. 1.3. Resolution of Inflammation

. 8. As a sequel to phagocytosis by nongranular cells, there is marked diminution of inflammatory cells, ultimately' those left are almost exclusively of nongranular type, lymphocytes become relatively increased in number. Fig. 3. Resolution of Inflammation. The most striking example is met with in acute lobar pneumonia where all the phenomena described above are well observed. After destruction of the organisms, a gradual softening and digestion of fibrin in the air vesicles follows and in this the leucocytes are chiefly concerned. The degenerated leucocytes and red cells are taken up by lymphatics to the bronchial lymph nodes, where they undergo intracellular digestion. With the absorption of the fluid content of the air vesicles, these again become air containing and part returns

practically to normal. Some of the liquefied exudate is expectorated but the amount may not be large and in every case major part of the exudate is absorbed. -

CHRONIC INFLAMMATION
Q. 1.8. What are the causes of chronic inflammation ? Discuss its histological characters and effects. Chronic inflammation is the response of body tissues to the persistent traumatic stimuli.

Causes
1. Infective organisms (i) Mycobacterium tuberculosis. (ii) Treponema pallidum. 2. Mild poison in solution - Lead. 3. Particulate irritants (i) Silica dust. (ii) Vegetable cells (iii) Lime salts. (iv) Pigments.

Pathogenesis
Chronic inflammation in various organs may occur in three ways: 1. It may follow an episode of acute inflammation where the inciting stimulus persists in the body. 2. There may be repeated attacks of acute inflammation with healing phase in between as in cholecystitis and pyelonephritis. 3. Chronic inflammation may develop as a primary entity without a preceding attack of acute inflammation, as in rheumatoid arthritis, tuberculosis, chronic bronchitis.

Pathology
The characteristic features of chronic inflammation are : 1. Infiltration of mononuclear cells. 2. Proliferation of fibroblasts. . 3. Proliferation of blood vessels. Emigration of mononuclear cells is an important component of chronic inflammation. The monocyte, on reaching the extracellular tissue, gets changed into a much larger cell, the macrophage. Macrophages accumulate in large numbers in three ways.

1. Continuous inflow of monocytes from circulation maintained by chemotactic factors. 2. Local proliferation of macrophages by mitotic division. 3. Prolonged survival and immobilization of macrophages within the site of inflammation. The other cells encountered in chronic inflammation are plasma cells, lymphocytes, and occasionally eosinophilis and poly-morphonclear leucocytes. When the irritant is of particulate nature or a substance difficult for absorption, foreign body giant cells are often a predominant feature. When degenetrative changes are going on in the neighbourhood, the macrophages may contain droplets of fat and other lipid material. Cells filled with globules of myelin fat (foamy cells) are common being especially abundant in the granulomatous lesions of actinomycosis. Another characteristic of chronic inflammation is the overgrowth of interstitial connective tissue which in earlier stages may be comparatively cellular, the cells being spindle shaped and connective tissue fibres delicate and scanty e.g. in congenital syphilitic cirrhosis of the liver. The vascularity of the new tissue also varies greatly. There is sometimes a considerable formation of new blood vessels and the interstitial tissue may appear reddish as is often seen in cirrhosis of liver and kidney. In the later stages or where the process has been of very slow nature throughtout, the chief change is a thickening of collagenous fibres whilst cells and vascularity are relatively scanty. The various types of chronic inflammatory lesions have some relatively distinguishing features in the structure, however, they are not always specific. The tubercle follice is characteristic of lesion due to Mycobacterium tuberculosis, but this organism may at times produce a quite different and much more acute exudative lesions in the meninges or pleura. Also the Treponema pallidum commonly induces a diffuse chronic inflammatory response, but at times in older lesions, a markedly follicular character may be seen and an erroneous diagnosis of tuberculosis may then be made. Tubercle follicles are also very chharacteristic of sarcoidosis and are frequently induced in the tissue by foreign bodies.

Effects of Chronic Inflammation

1. Contraction of newly formed tissue leads to narrowing of orifices and tubes e.g. (i) Stenosis of mitral valve and chronic endocarditis. (ii) Stenosis of small intestine in regional ileitis. 2. Uneven affection of interstitial tissue results in coarse granularity of the surface e.g. in chronic pyelonephritis. 3. Loss of parenchymal cells of the organ. 4. Replacement of specialised connective tissue by more resistant connective tissue cells e.g. in liver cirrhosis.

ABSCESS
An abscess is a localised collection of pus caused by suppuration burried in a tissue, organ, or confined space.

Formation of Abscess
Abscesses are usually produced by the deep seeding of pyogenic bacteria into a tissue. Two chief changes occur inside the tissues viz. 1. A progressive emigration of polymorphs which come to pack the tissue. 2. Gradual destruction and disappearance of the tissue elements. The special cells of the part become necrosed, break down into granular material and melt away, while the supporting connective tissue fibrils, capillaries, etc, are digested and disappear. The accumulation of leucocytes still goes on and the tissue gradually becomes replaced by pus, in which remains of the dead tissue are present. There is thus, an actual destruction of tissue and a return to normal is no longer possible. The progressive emigration of leucocytes is due to a continued supply of chemotactic substances from the bacteria. Although the pyococci are most frequently concerned, suppuration may be produced by a great variety of organisms, the essential point being that they should be able to persist in the tissue and produce their effects. Digestion and liquefaction of the tissue is chiefly due to proteolytic enzymes produced by leucocytes. Certain pyogenic organisms have a digestive action on proteins but others e.g. strepto-cocci and pneumococci have no such property. Digestive softening Fig. 4. Liver abscess. of the tissue by leucocytes follows damage or actual necrosis due to bacterial toxin, as there is no evidence that leucocytes, however numerous, will attack normal tissues. Digestive action by the leucocytes is seen also when suppuration is preceded by much exudation of fibrin e.g. in pleurisy. The fibrin is to a large extent digested and disappears and this is closely analogous to the action of leucocytes in removing fibrin in the process of resolution of inflammation as seen in pneumonia. In dense tissues, complete suppurative softening may fail owing to the density of the tissue. A portion of dead tissue or solugh then forms and may persist for considerable times.

Fig. 1.4. Liver abscess

Subsequent fate

When suppuration ceases to spread, at the periphery of an art abscess, a reactive proliferation of the connective tissue cells with new formation of blood vessels forms a zone of granulation tissue around it. The outer part of it becomes denser and a definite wall to the abscess is formed (pyogenic membrane). If the abscess is of small size, the pus may be absorbed and a smaller scar results. The pus may, however, be too abundant for this to occur. Then it. becomes thickened and changed into granular debris. In this debris, lime salts may be deposited. When an abscess forms near a free surface as in subcutaneous tissue, the tension of the contents causes the suppuration to extend in the direction of surface so that the overylying skin is involved. The abscess is then said to "point". It may ultimately discharge its contents spontaneously.

HEALING AND REPAIR

Q. 1.9. Describe the process of healing in a clean incised wound. Mention the factors that may modify the course of healing.

Healing
Factors affectin wound healing .

A. General factors
1. Age. Healing is quickest in children. As the age advances, the process is impaired due to comparatively less blood supply. 2. Nutrition. The nutritional state of the patient, particularly the protein intake is of utmost importance. Serious protein deficiency with hypoproteinaemia and oedema predisposes to prolonged and complicated wound healing. 3. Vitamin C. It is necessary for the formation of intercellular substance and maturation of collagen of connective tissue. 4. Vitamin K. Vitamin K. deficiency with hypoprothrombi-naemia and a bleeding tendency may interfere with normal wound healing by the formation of haematomas and serum collection. These in turn predispose to wound separation and wound infections.

Table 1.1 - Healing in a Clean Incised Wound 5. Vitamin A, D and B-complex. Their deficiency lowers the rate of phagocytosis and bacterial digestion, thus predisposing to local wound infection. 6. Fluid and electrolyte balance. It is necessary for optimum wound healing. Dehydration may be associated with delayed wound healing. Wounds also heal poorly in presence of a water-salt overload and oedema.

B. Local factors:
I. Bacterial infection, either invasive or uninvasive, interferes with the healing process. 2. Devitalised tissue from mechanical or chemical trauma predisposes to bacterial infection thus delaying the process' of healing. 3. Haematomas and serum collections. 4. Ischaemia. 5. Foreign bodies. 6. Desiccation of the tissues.

7. Improper examination.

Healing in a clean incised wound

In a simple incised wound such as is made in aseptic surgery, the process of healing is simple and rapid. Such a wound is said to heal by primary union. When bleeding has been arrested and the margins have been fixed in apposition, the adjacent surfaces are glued together with a thin layer of coagulum. There is a slight degree of congestion of the superficial vessels with some liberation of plasma which coagulates, but ordinarily this is scanty and only a few leucocytes emigrate from the vessels into the clot. Within a short time the connective tissue cells become swollen and divide by mitosis. These cells in the form of fibroblasts, migrate into the thin layer of coagulum, which undergoes absorption by the action of these cells and of leucocytes. Capillary bands accompany the fibroblasts, but often little vascularisation is necessary. The fibroblasts from adjacent sides become intermingled ; they arrange themselves at right angles to the line of wound and produce the collagen fibrils which bring about the permanent union. At the same time the epithelial cells grow over the line of incision from the two sides and restore the continuity of epithelial covering. At the end of 5-6 days the process is practically completed and only a narrow band of young connective tissue remains to mark the line of incision. If the wound surface has been irritated or if the wound has been a large one, serious discharge from the vessels may be considerable. In such a case the emigration of leucocytes contirnues for a longer time and formation of fibroblasts and new capillaries is likewise of longer duration and more abundant resulting in a more distinct line of fibrous tissue than in the case of simple aseptic healing. The process of healing is summarised on page 19. Q. 1.10. Describe the process of healing in an infected wound. Healing process in an infected wound is by granulation tissue and is termed secondary union. It consists of two parts : 1. Removal of inflammatory material and necrotic debris which may be much or little. 2. Replacement or reconstruction of the original tissue, as far as possible. It involves the invasion and replacement of dying and dead tissue by immature mesenchyme .called granulation tissue. The process commences at the base and works to the surface, so that the youngest tissue is always at the surface. Such a surface is highly vascular and bleeds very readily. In addition to the fixed cells of the part (fibroblasts and vas cular endothelium), wandering cells also form an important element of granulation tissue. In the early stages, these are mainly poly-morphonuclear leucocytes which migrate from the new capillaries in response to irritation. They serve to keep the surface free from

infection. In the later stages and in deeper layers, the wandering cells are mainly macrophages and lymphocytes. Till the leucocytes have overcome the infection, the epithelium begins to cover the surface and true healing is said to have commenced. On account of its cellularity a granulating surface has a remarkable power of resisting bacterial infection. It presents so powerful a barrier that septicaemia cannot occur once an intact wall of granulation tissue has been formed. The granulation tissue grows in maturity from below upwards. In the superficial layers the fibroblasts run at right angle to the surface and therefore parallel to the vessels, whereas in deeper parts of the wound where the process is older they are arranged parallel with the surface; eventually all the fibroblasts and the fibres which they produce run in this direction. The direction depends largely upon the pull which is exerted on them. When the surface is covered by epithelium the process of de-vascularisation begins. The new vessels gradually disappear and the scar which is first red becomes white and bloodless. Q. 1.11. What is repair ? Describe in detail the process of repair in a fractured bone. Enumerate the causes of delayed union. The term repair refers to the process of restoration to a normal stage after injury. The process of repair may result in regeneration of normal tissue e.g. in liver and kidney parenchyma, or in filling the gap by connective tissue when the original tissue has no power of regeneration.

Repair of Fracture
When a bone undergoes a simple fracture, there is necessarily tearing of blood vessels and of soft tissues and a varying amount of haemorrhage occurs between the broken ends. The periosteum is usually torn through and separated from the bone to a varying extent in the neighbourhood of the breach. Bleeding soon ceases and coagulation of the effused blood occurs. Soon there follows reaction on the part of the vessels. There is exudation from them which leads to a swelling of the tissues at the site. The process of repair begins by proliferation of cells and , formation of new blood vessels. The proliferation takes place in cells of the endosteum and of the deep or cambium layers of the periosteum as well as in cells derived from the bone especially from the Haversion canals. All these cells possess osteogenic function i.e. are osteoblasts. The new blood vessels accompanied by the cells grow out from the pre-existing blood vessels and make their way into the clot which gradually becomes replaced by a cellular and vascular tissue. In this newly formed tissue the young bone cells, the osteoblasts have branching processes from which delicate fibrils pass in all directions. In the process of bone formation, the young bone cells and the fibrils are seen to become enclosed in a

somewhat homogeneous matrix forming trabeculae of osteoid tissue which become osseous (bony) tissue by deposit of lime salts. The newly formed bone has a somewhat spongy character, and it coroes to enclose and unite the ends of the fractured bone. It is then known as provisional callus. The callus is sometimes artificially divided into an internal callus in the medullary cavity, an intermediate callus between the ends of the bone, and an external callus outside. The amount of callus varies very much in different cases and is least abundant in case of simple fractures. While the newly formed tissue is mainly a vascular osteoid and osseous tissue, islets of young cartilage may also develop especially when there has been much movement. Pro-visional callus is formed rapidly and serves to bring about early union. The next stage is one of strengthening the union and adapting the configuration of the bone to the functional requirements. Parts of the callus are penetrated and resorbed by the new blood vessels surrounded by osteoblasts and these cells then lay down bone by lamellar apposition in the form of Haversian systems. This process goes on till a more compact type of bone is produced, which forms the permanent union ; this is known as the definitive callus. The external callus is to a great extent absorbed so that if there has been a proper apposition, the configuration of the bone is largely restored. When abone has been united in a wrong position, the newly formed bone is not only more abundant but is arranged and moulded in a striking way, according to the muscular requirements. The repair of the compound fracture proceeds in a similar way but entry of organisms may cause suppuration and may interfere with formation of callus sometimes leading to resorption of callus already formed. When there is exit for pus the healing takes place very much as in a granulating fracture would. There is an advancing line of ordinary granulation tissue behind which granulation goes on and ultimately any space occupied by pus may be obliterated and the process of bone formation may be completed. Just as in soft tissues, where long continued suppuration produces much overgrowth of fibrous tissue, so in the case of compound fracture there may be considerable and irregular formation of new bone. When a sequestrum is present, it becomes a nidus for organismal growth, pus forms around it ; suppuration may in this way, be kept up for an indefinite period of time, the pus being discharged from the sinus which leads down to the dead bone.

Causes of delayed union

1. Ischaemia. 2. Poor reduction. 3. Improper immobilisation. 4. Interposition of soft tissue. 5. Destruction of fragments. 6. Loss of fracture haematoma. 7. Infection.

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2.Nutritional Disturbances
DEGENERATIONS
Q.2.1 Describe briefly the various types of degene-rations occuring in the tissues. Types ofdegenerations 1. Cloudy swelling. 2. Hydropic degeneration. 3. Fatty change (degeneration and infiltration). 4. Lipoidal degeneration. 5. Glycogen infilteration. 6. Mucoid degeneration. 7. Hyaline degeneration.

1. Cloudy swelling
It is the commonest form of degeneration caused by : (i) Acute fevers. (ii) Bacterial infections. (iii) Chemical poisons, e.g.. As, Hg. (iv) Malnutrition.

Fig. 2.1. Kidney - Cloudy swelling

Cloudy swelling results from disturbance in protein and water metabolism resulting in increased intracellular colloidal osmotic pres-sure. Mitochondria are damaged. Water is ab-sorbed into the cells which become swollen. Commonly affected organs are kidney, liver adrenals and heart. The organ is slightly enlar-ged and looks pale. The cut surface is hazy. The cells are swollen. Cyto plasm shows albuminous granules soluble in Fig- 9. Kidney-Cloudy swelling. acetic acid.

2. Hydropic degeneration
Very large amount of water is retained by the cells resulting in marked swelling. Granules are absent in the cytoplasm. Cytoplasm is vacuolated or reticulated. Hydropic degeneration of liver is caused by poisoning due to chloroform, diethylene glycol and carbon tetrachloride.

3. Fatty degeneration and infiltration (Fat,ty change)

Fatty degeneration is caused by poisons which may be bacterial or chemical. It also occurs due to anoxia in chronic venous congestion. The common organs are liver, kidney and heart. The organ becomes greasy and yellowish. Microscopic examination reveals small vacuoles representing fat globules dissolved away during staining process. Fatty infiltration is caused by overload of fat and lack of lipotropic factors. It is commonly found in liver. The nucleus is pushed to the periphery and becomes elongated and narrow. There may be individual cells or fat cysts.

4. Lipoidal degeneration
In the cells undergoing autolysis, cholesterol becomes visible as needle shaped crystals. Tissue with such cells is said to have developed lipoidal degeneration. Cholesterol crystals may be present in caseous tissue, infaras, old haemorhages, atheroma, degenerating goitres, dermoid cyst, bydro-cele fluid etc.

5. Macoid degencration
Mucus is a loose combination of protein with mucopolysaccharides of high molecular weight. Mucous granules appear to be produced by mitochondria, then moving to the Golgi apparatus, where they are changed into mucin granu-es. When this process is exaggerated with excessive secretion of mucus associated with degeneration of the cells, it is called muCoid degeneration. Thus it is degeneration of mucous membranes.

6. Hyaline degeneration
It is a non-specific degeneration affecting mainly the collagenous connective tissue and fibrous tissue-in the walls of the blood vessels (connective tissue hyaline.). The other form is cellular hyaline. Connective tissue hyaline appears as a homogeneous swelling of collagen and the walls of the vessels in arteriosclerosis. It is present in (i) Vascular hypertension ; (ii) Chronic nephritis ; (iii) Stroma of tumor ; (iv) Reticulum of lymph nodes (in chronic inflammation). The cellular hyaline is seen in :

(i) Renal tubules (in amyloidosis). (ii) Pancreas (in amyloidosis). (iii) Prostate. (iv) Old infarcts of lungs.

FATTY DEGENERATION
Q.2.2. What arc the causes of fatty degeneration? How does it differ from fatty Infiltration ? Discuss the change occuring in any organ during fatty degeneration. Accumulation of fat in degenerated or damaged cells is termed fatty degeneration. It is differentiated from the term fatty infiltration in which fat accumulates in obviously normal cells. However, the differentiation is an obsolete one and now it is believed that fat seen in fatty degeneration is in fact also the infilterated fat. Thus the two conditions are collectively termed fatty change. In stead, pathological adiposity, synonymous with fatty infilteration, is the term used for an increase in fat in the' tissues which normally store fat.

Causes of fatty degeneration

1. Diminished oxidation (i) Severe anaemia (a) Pernicious anaemia (b) Post-haemorrhage anaemia (ii) Arteriosclerosis (iii) Imperfect nourishment. (a) Tumours. (b) Collections of desquamated cells as in chronic nephritis. 2. Poisons. (i) Chemical : (a) Phosphorus. (b) Arsenic. (c) Carbon tetrachloride. (ii) Bacterial toxins : (a) Typhoid. (b) Smallpox. (c) Yellow fever. (d) Diphtheria. 3. Neurogenic. Wallerian degeneration. Fatty Liver. Macroscopic appearance : (i) Enlarged. (ii) Yellowish in colour. (iii) Greasy to touch. (iv) Soft. Microscopic appearance: (i) Liver cells represented by large fat globules. (ii) Nucleus pushed to the periphery. AMYLOIDOSIS Q. 2.3. What do you understand by Amyloidosis ? Describe the methods of demonstrating it in the laboratory.

Q. 2.4. Describe the various types of amyloidosis. What are its effects ? Q. 2.5. Name the various cellular degencrations. Describe the lesions in primary generalised amyloidosis. Amyloidosis a type of cellular degeneration in which there is a deposition of amyloid in the tissue. Amyloid is a glyepprotein, the carbohydate part being a sulphated polysaccharide and the protein part being globulin. Methods of demonstration. Amyloid is demonstrated by its staining reactions. The following methods are employed : 1. Iodine solution produces a dark brown colour when poured over the cut surface of an organ. 2. Methyl violet and cresyl violet give a metachromatic reaction, the amyloid material staining rose red whilst the surroun-didg tissue is coloured blue-the most reliable reaction. 3. Congo-red produces a brilliant pink colour. 4. Periodic acid-Schiff gives an intense positive red reaction 5. Van-Gieson's stain gives khaki colour. 6. With ultraviolet light, amyloid gives a specific bright yellow fluorescence. Types of Amyloidosis 1. Generalised: (i) Secondary; (ii) Primary. 2. Localised. Generalised Secondary Amyloidosis Most frequently, amyloidosis is secondary to other disease, particularly chronic suppuration. Vsually this is the result of chronic tuberculosis of lungs, bones and joints, but chronic suppura-tive osteomyelitis is often a cause. It may also be secondary to nonsuppurative tuberculosis, syphilis, leprosy, tumour,' chronic nephritis, hepatic cirrhosis and rheumatoid arthritis. Secondary amyloidosis affects principally the parenchymatous organs viz. spleen, kidneys, liver and adrenals but may also be present in other organs. In the spleen, the amyloid is found first in the media of the central arteriole of the follicles. Subsequently it appears in the follicles as a network made up of very coarse fibres which finally collect to form a solid mass of amyloid. Still later it extends out through the pulp of the spleen, usually along the walls of the splenic sinuses. Grossly the organ is large, elastic and firm. A cut surface looks waxy and transluscent. In the kidneys, the change is seen first in the capillary loops of the glomerular tufts. It is also likely to be found in the walls of the arteriae rectae of the pyramids and, to lesser extent, in the interlobular arterioles of the cortex. In advanced cases, amyloid may be found lying under the epithelial cells of tubule,- involving the basement membrane. Grossly the kidneys are enlarged but may be shrunken in the chronic cases owing to the associated fibrosis. In the liver, amyloid in most cases affects primarily small arteries and veins of Glisson's capsule. It is likely to be most. extensive, however, in the sinusoids of the lobules. Here it appears immediately outside the endothelium of sinusoids, particularly in the middle parts of the lobule. As it becomes more extensive, the central and peripheral parts of the lobule also are affected. As the condition advances the pressure atrophy of the liver cells

becomes more and more marked and amyloid from adjacent sinusoids may fuse to form a solid mass of considerable size. Grossly, the liver is enlarged, heavy and firm. A slice looks waxy and transluscent. Generalised Primary Amyloidosis This idiopathic type of amyloidosis is rare and is characterised by the amyloid deposition, often massive, in mesodermal tissues viz. I. Heart : Amyloid is found in the subendothelial connective ' tissue of the endocardium of the right atrium. It may occasionally be found in the capillaries or the myocardium of the ventricular walls. 2. G.I.T. : The tongue is enlarged and voluminous (macro-glossia). The amyloid is deposited between the muscle fibres. The intestines are affected particularly in the muscular coat, but occasionally amyloid may be found sharply defined in the capillary loops of the villi. 3. Skeletal muscles. 4. Respiratory tract : Larynx and lungs. ' 5. Urinary system : Ureters and bladder. 6. Endocrine glands : Pituitary, thyroid, adrenals. 7. Skin. Localised Amyloidosis Localised amyloid deposits are observed in the Vicinity of abscesses and the lymph nodes draining them, probably as a direct effect of suppuration on adjacent tissue elements. However, it is the rarest form. Small connective tissue growths in the larynx, bronchi and nasal septum are sometime composed mainly of amyloid. Effect of Amyloidosis The amyloid deposit may cause injury to cells because it accumulates in amount sufficient to produce pressure upon surrounding cells leading to atrophy of these cells. The amount of amyloid may be so great as to substantially limit the internal callibre of the affected vessels, thereby leading to cloudy swelling, fatty degeneration and atrophy or necrosis, because of limitation of nutrition. Cellular atrophy is best seen in the liver, whereas the nutritional changes are best seen in the kidneys. Amyloid disease of the intestine is often attended by watery diarrhoea, probably due to increased permeability though this is not certain. Not withstanding the presence of a considerable amount of amyloid, the disease may not lead to any detectable effect on the function of an organ. Amyloid Spleen. Macroscopic appearance : 1. Enlarged. 2. Elastic. 3. Firm. 4. A cut surface looks waxy transluscent. Microscopic appearance. Amyloid deposited in : (i) Walls of the arteries in Malpighian bodies. (ii) Connective tissue of the venous sinuses. (iii) Reticulum of the pulp. NECROSIS Q.2.6. Define necrosis. Mention inbrief, causes and types of necrosis. By necrosis is meant death of a cell or group of cells, when they still form part of the living body. It may or may not be preceded by degenerative changes. When it is preceded

by degenerative changes, the term 'necrobiosis' is applied. Causes. (1) Loss of blood supply. This isseeninaninfarct caused by blockage of a vessel by a blood clot which produces immediate local anoxia. Even if the loss of blood supply is incomplete the cells may be killed. (2) Bacterial toxins. If the toxin is weak, inflammation is produced ; if it is strong, the result is necrosis. (3) Physical irritants. Excessive heat, excessive cold, radiation, trauma. (4) Chemical irritants. Caustics, strong acids. Types of necrosis. (1) Coagulation Necrosis. It is the commonest form and is seen in the infarcts of the spleen and kidney. The part becomes dry, homogeneous opaque. There is COagulation of the cytoplasm by intracellular enzymes. Perhaps some of the surrounding lymph may be absorbed and coagulated in the same way. All the cellular detail is lost. The coagulated material may remain unchanged for long periods of time, but at the margin of the infarcted area there is a gradual process of absorption owing to the action of the proteolytic enzymes in the leucocytes brought about by the circulating blood. In the course of time calcification may occur. (2) Liquefaction Necrosis. It occurs in the central nervous system. The necrosed areas becomes softened and liquefied, and the fluid material is absorbed leaving a cyst like space. The change probably.. in some way, depends upon the high lipid content of the nervous tissue. (3) Cassation Necrosis. In this type, all the details of structure are wiped out, with the production of a dry, cheesy granular material which is completely amorphous. Both the cells and the stroma are involved. Caseation is the characteristic necrotic change of tuberculosis and syphilis. Caseous material has a high fat content. It frequent gets calcified. (4) Fat Necrosis. Fat necrosis occurs in acute pancreatitis. Lipase acts upon the surface of the omentum and the pancreas with the production of small opaque white areas of fat necrosis. It may also result from trauma. GANGRENE Q. 2.7. What is gangrene ? Describe its causes and types in detail. What is gangrene ? Gangrene is death of a part accompanied by putrefaction of the tissue by saprophytic bacteria. It occurs in the organs exposed to atmosphere directly or indirectly e.g. skin, mouth, bowel, lung, cervix etc. Causes of gangrene? The part may be killed by putrefactive bacteria (primary gangrene) or death of part may be produced by some other cause e.g. ischaemia and followed by putrefaction. Primary gangrene is produced by Clostridium welchii and fusiform bacillus. The causes of secondary gangrene are as follows* : 1. Raynaud's disease due to spasmodic narrowing of the arterioles 2. Ergot poisoning 3. Old age (Senile)-due to narrowing of arteries by arteriosclerosis. *lnitials remembered by the word 'RESTED' 4. Thromboangitis obliterans (Buerger's disease). 5. Embolism-Due to blockage of arteries. 6. Diabetes-Due to narrowing of arteries.

Types of gangrene I.. Primary gangrene : 1. Gas gangrene.; 2. Noma. II. Secondary gangrene: 1. Dry gangrene ; 2. Moist gangrene. Gas gangrene The affection is common in the wounds inflicted in wars or in street accidents. The infecting organisms are anaerobic clostridia of which Clostridium welchii is the most common and important member. The infection is predisposed by damaged muscle and by foreign bodies in the wound as the necessary anaerobic conditions are then more easily established. The affected muscles become swollen and pinkish and are crepitant owing to the formation of gas bubbles by the fermentive action of the Clostridium welchii on the muscle sugar. The organism has practically no power of breaking down proteins. There is, thus, a rapidly spreading oedema followed by necrosis which, owing to the spread of the organisms within the sarcolemmal sheath, affects a muscle throughout its length; the neighbouring muscles remaining unaffected. In the early stages there is no pus formation and very little emigration of leucocytes. Later the tissues, having been killed by the Clostridium welchii are invaded by putrefactive organisms and true gangrene results. Noma It is gangrenous condition which occassionally occurs in poorly nourished children especially after some debilitating infection. It begins on gum margin and spreads to the cheek where an inflammatory patch of dusky red appearance forms and then becomes darker in colour and ultimately gangrenous. The original necrosis is caused by a characteristic fusiform bacillus, the dead tissue then undergos putrefaction. Deficient intake of vitamin B-complex especially of nicotinic acid, predisposes to the condition. Dry gangrene Dry gangrene occurs where there is little fluid in the tissues owing to vaporisation or a good venous drainage. It is, therefore, confined to the extremities and is caused by the gradual narrowing of the lumen of an artery by arteriosclerosis so that the tissues have a time to dry out. The part is cold, pulseless and there is no collateral circulation. It begins in one of the toes, with or without a slight injury. The part contains so little blood that invading bacteria grow with difficulty in the dead tissue and spread of the gangrene is slow. The part becomes dry, shrivelled and dark. The gangrene extends slowly upwards until it reached a point where the circulation is sufficient to keep the part alive. At this level, a line of separation is formed between the living and dead tissue and finally brings about complete separation The microscopic picture is one of complete necrosis, but in addition there is usually a blurring and sludging of outline, a disintegration and breaking up of tissue beyond what is seen in simple necrosis. Moist gangrene In this type, there is abundant fluid in the part due to venous obstruction, lack of vaporisation, etc., a condition which favours the growth of putrefying bacteria. Moist gangrene develops also when there is sudden obstruction of an artery as the part has no

time to become dried up. It occurs in the internal organs (bowel, lung) or in the extremities, when veins as Well as arteries are occluded. The classical example in the bowel is the gangrene of the strangulated hernia. It may also develop in naturally moist external organs e.g. vulva. The tissue becomes rotten and putrid. Owing to the abundant moisture, there is rapid growth of putrefactive bacteria. The part becomes foul smelling. There is liquefaction of the tissues and sometimes gas formation, so that blebs of fluid form under the skin and bubbles of gas give an emphysematous crackling when the part is palpated. The local spread is rapid and there is no attempt at forming the line of demarcation. The absorption of toxic products causes profound toxaemia and finally death. ATROPHY Q. 2.8. What is 'atrophy'? Give an account of the causes. The term 'atrophy' refers to the acquired wasting or diminution in size of a cell or of the essential tissue of an organ. Causes of Atrophy (i) Defective nutrition. (ii) Diminished functionl activity. (iii) Interference with nerve supply. (iv) Continuous pressure. Defective Nutrition This may be produced locally by arterial disease interfering with blood supply to a part, when the reduction is not so severe as to cause fiecrosis. The functional parenchymatous elements of the tissue then undergo atrophy and sometimes there is also a concomitant overgrowth of the connective tissue, the condition being called fibroid atrophy. This is often well seen in the heart wall and in the kidneys where small atrophic depressions result from narrowing of the lumina of the small arteries. When the muscle cells of arterial wall are atrophied, the overgrowth of connective tissue becomes very marked. This is probably compensatory since it gives support and minimises dilatation. General, atrophy is seen is cases of starvation, emaciation depends chiefly upon utilisation of fat of the adipose tissue but there is also a great wasting of the tissues. The various organs may thus diminish in weight, the liver and spleen are markedly affected, the kidneys and heart to lesser degree whilst the central nervous system is only slightly affected In the great majority of cases of wasting disease, however, such as malignant growth of the alimentary tract, chronic tuberculosis or suppuration, etc., a toxic element is concerned in production of the wasting. Various degenerations may thus come to be associated with atrophy and secondary anaemia is present, the latter condition being absent or little marked in case of pure starvation. The term cachexia is often applied to a condition of wasting, anaemia and weakness. . Diminished Functional Activity Diminution in the ketabolic process leads to anabolism below the normal and thus to diminution in size of the cells. When a part is under-functioning, the blood supply diminishes, and it might be supposed that this is the cause of atrophy. Accordingly it is likely that atrophy depends on diminished metabolism. This disuse atrophy is seen when a gland e.g. pancreas has its duct obstructed, its functional activity is stopped and it undergoes atrophy. Similarly tubules of the kidney undergo atrophy when their glomeruli are thrown out of action. The muscles around a joint which has been fixed for some time

undergo marked atrophy and the bones may also be affected. Interference.with the Nerve Supply This form of atrophy is seen where there is any destructive lesion of the lower motor neurones or their axons, the motor nerves. This type is often called neuropathic atrophy. There is not only a simple wasting but also more active degenerative changes in the nerve fibres and muscles. In the former, Wallerian degeneration takes place, in which the myelin breaks down into fatty globules ; whilst in the latter, fatty degeneration also occurs followed by absorption of the sarcous substance and increase of the interstitial connective tissue. Sometimes marked atrophy occurs also in the bones from the same cause e.g., in cases of infantile paralysis. This bones of the limb may become thin and light. Deficiency of the Endocrine Glands The effects of endocrine deficiency are seen mainly when it occurs at an early period of life, so that the full development of the body is interfered with and thus hypoplasia results. This is especially seen in the deficiency of thyroid and of the anterior lobe of the pituitary. A striking example of true atrophy in the adult, however, is seen in myxoedema due to thyroid deficiency. There occurs marked atrophy of the structures of skin, i.e. hair follicles, sweat glands, and sebaceous glands. Continuous Pressure The continuous pressure acts mainly by interfering with the blood supply and also the functions of a tissue. Thus the pressure atrophy may be produced by simple tumours, cysts, etc, Even bone may undergo atrophy from pressure but in this instance, there is active absorption of tissue by cellular activity, osteoclasts being concerned in the process. PIGMENTATION Q..2.9. What are the types of pigmentation occuring in the tissue ? Describe each type with suitable examples. Types of Pigmentation 1. Endogenous pigmentation 1. Melanin pigmentation: (i) Addison's disease (ii) Chloasma (iii) Vitiligo (iv) Irregular pigmentation of skin : (a) Chronic arsenical poisoning I (b) Bronzed diabetes (c) Familial multiple polyposis (v) Melanosis coli (vi) Ochronosis. 2. Haeroatogenous pigmentation : (i) Malarial pigmentation : (ii) Haemochromatosis (iii) Biliary pigmentation. 3. Atrophic pigmentation: (i) Brown atrophy (ii) Fuscous degeneration. II. Exogenous pigmentation 1. By inhalation:

(i) Anthracosis (ii) Silicosis. 2. By ingestion : (i) Argyria (ii) Chronic lead poisoning. Endogenoas Pigmentation 1. Melanin Pignientation. The melanins are iron-free sulphur containing pigment varying in colour from pale yellow to deep brown. They are formed intracellularly from colourless precursors, melanogens, by the metabolic activities of the cells and are very stable substances resistant to acids and many other reagents, but soluble in strong alkalis. They are related to the aromatic compounds, tyrosine, phenylalanine and tryptophan and may be formed from such substances by oxidation. On treating sections of the skin with dihydroxyphenylalanine (dopa) certain cells in the epidermis oxidize this subsiance by means of an enzyme like tyrosinase and become blackened in consequence. These cells are 'dopa-positive'. The only cells in the skin which are dopa-positive in vivo are the dendritic cells which lie extended between the basal cells of the epidermis. These cells are the only true melanoblasts and after elaborating the pigment in the form of fine granules they transfer it by means of their processes into the basal epidermal cells and also into certain phagocytic cells in the dermis which may thus become heavily pigmented with coarse pigment granules. Melanin pigmentation occurs in the following conditions. (i) Addison's disease. Following destruction of the adrenal cortex there occurs a general increase in pigmentation, especially in the parts exposed to light and in those normally pigmented. There may also be pigmentary deposit on the inner surface of the checks on a line corresponding to the junction of the teeth, and on the sides of the tongue, the position of the deposit being apparently determined by irritation. (ii) Chloasma. It is a condition sometimes due to ovarian disorder and sometimes related to pregnancy, pigmented patches occur on the skin of the face, and pigmented parts, e.g., the nipples, may become of deeper tint under the influence of oestrogenic and melanocyte stimulating hormone. (iii) Leucoderma (vitiligo) may be attended by increase in pigment in the intervening parts. In the affected areas the dendri-tic cells are of abnormal structure and have lost their capacity to oxidize 'dopa' to form pigments. (iv) Chronic arsenic poisoning. (v) Neurofibromatosis. (vi) Bronzed diabetes. (vii) Peutz syndrome. 2. Hacmatogenoas pigmentation. Normally the breakdown of haemoglobin begins with opening of the porphyin ring system. Iron is carried away attached to the plasma *bglobulin transferrin (siderophyllin) for preferential reutilization in blood-formation. The residual biliverdin pigment is then reduced to bilirubin which is absorbed and carried by the plasma *a-globulin to the liver where it is dissociated and the pigment, conjugated with glucuronic acid is excreted in the bile. In pathological states, haemoglobin is broken down in similar manner and many cells have the power to effect the change. The resulting pigments may be deposited in the tissues around some local destruction, e.g., that following a haemorrhage, or in certain organs where there has been a process of

general blood destruction. When haemorrhage occurs into the tissues the red cells become haemolysed and their haemoglobin is broken down by tissue enzymes and by the action of phagocytes. The pigments usually deposited are haematoidin (iron-free) and haemosiderin (iron-containing). Haematoidin is formed mainly from large accumlations of blood ; thus the rhombic crystals are often met with in the sites of old cerebral haemorrhages, in thrombi, haemorrhagic infarct, etc. It is found both in the free condition and within cells. Accumulation of haemosiderin in organs, or visceral siderosis occurs in malignant malaria and where there has been much haemorrhage into the tissues, e.g., in purpuric diseases. Malarial pigmentation. The malarial parasites within the red corpuscles produce from the haemoglobin a dark-brown pigment, haematin, in the form of very minute granules, which accumulates within the intracorpuscular parasites. It become free when the corpuscles are broken down, and is taken up by phagocytes and deposited in the organs, especially the spleen and liver, where it remains practically unchanged for many years. Haemochromatosis. This term is applied to a condition in .which there is an extensive deposit of haemosiderin in the organs and tissues, without anaemia or other evidence of increased blood destruction. It appears to be an inherited abnormality of iron metabolism leading to excessive absorption. The largest amount is present in the liver, but the haemosiderin may occur in even greater concentration in the lymph nodes in upper part of the abdomen. It occurs in the skin especially around the sweat glands, also in the pancreas, gastric glands, heart muscles, thyroid etc. In the liver it is always accompanied by a somewhat fine cirrhosis, usually with enlargement. Biliary pigmentation. This occurs especially in jaundice, the coloration of skin and other tissues is usually due to reabsorption of bile pigments from the liver after conjugation with glucuronic acid. The bile pigment retained in the liver cells is deposited in the form of small greenish brown granules, most prominently in the central parts of the lobules. The reabsorbed bile pigment is excreted by the kidneys, and a finely granular deposit occurs in the cells of the convoluted tubules. Portions of the pigmented cells are broken off and form granular collections In the tubules, and these on passing downwards become condensed, 'so that in the lower parts hyaline cylinders of brownish-green colour may be present. 3. Atrophic Pigmentation. In the later years of life a fine brownish-yellow pigment tends to appear in the heart muscle, nonstriped muscle, etc. ; and in wasting diseases this accumulation of pigment is more marked. In the heart muscle the pigment accumulates in the central parts of the cells at the poles of the nucleus, and when this is associated with wasting of the muscle, the term, brown atrophy is applied. Similar pigments may occur in the liver cells; especially in the central parts of the lobules, in the cells of the testis and the nerve cells of the brain cortex. In the last situation a considerable amount of pigment is met with in senile insanity and allied conditions, the change being known as fuscous degeneration. Exogenous Pigmentation 1. By inhalation. A certain amount of coal-dust and stone dust enters and accumulates in the lungs of all individuals living in urban co'nditions, but the accumulation becomes excessive in those whose occupation exposes them to an atmosphere rich in dust. The lungs may be infiltrated in this way by foreign particles of various kinds-coal, stone, iron, cinnabar and various organic substances- and pathological results may follow. The degree

of irritation resulting depends on the nature of the particles. Large collections of carbon particles may provoke little or no overgrowth of connective tissue, anthracosis, whereas this is very marked in the case of certain kinds of stone-dust, the condition ofsilicosis resulting. 2. By ingestion. The common example is argyria, which results from the ingestion of silver preparations for long periods. Silver forms an albuminate which is carried in the plasma to various tissues and when it undergoes reduction, many minute brownish-grey nodules are formed. These are present especially in the wall of the intestine, in the skin, liver and kidneys. In chronic lead poisoning an albuminate is produced in a similar way and the action of H,S on it around the teeth produces the characteristic blue line on the gums. 3. Tattooing. In tattooing, fine particles such as India ink, ultramarine, cinnabar, etc., introduced through the epidermis, are taken up by histioeytes and lodge in small spaces or clefts in the connective tissue of the cutis. Some particles are carried also by the lymph stream to the regional lymph nodes and then are conveyed by phagocytes into the lymphoid tissues. Pathological Calcification Pathological calcification may occur in normal tissue as a result of blood being flooded with calcium or it may represent the deposition of calcium in tissue which is injured, degenerating or dead. In the former case, it is known as melastatic calcification and in the latter, dystrophic calcification. Metastatic calcification may be induced by repeated injections of parathyroid hormone or it may occur in decalcifying diseases of bone such as osteoporosis of forced immobility (poliomyelitis, etc.), osteomalacia, general carcinomato-sis of bone and multiple myeloma. The calcium is either removed from the bones or not laid down there, but deposited in other tissues, more particularly the kidneys. Dystrophic calcification, in which calcium is laid down in dying or dead tissue irrespective of blood calcium level, is much more common. Both phosphate and carbonate are deposited in practically the same proportion as is found in the bone. There is a tendency for any dying or dead tissue, accessible to the body fluids to become calcified. Necrosis and hyaline changes are the two chief antecedents of calcification. Several examples of pathological calcification are often seen, the more important being : (i) Caseous tuberculous areas free from viable tubercle bacilli. (iii) Arteriosclerosis-Monckeberg's sclerosis. (iv) Healed endocarditis and pericarditis. (v) Phleboliths. (vi) Degenerating uterine fibroids. (vii) Lithopedion (calcified foetus from a tubal pregnancy). (viii) Renal convoluted tubules in mercuric chloride poisoning. Metaplasia Metaplasia is the transformation of one type of tissue into another type. This process has define limits. An epiblastic tissue can only produce another epiblastic tissue, mesoblast can only produce mesoblast. Metaplasia is best seen in the closely related connective tissues as when cartilage is converted into bone. Thus depending upon the type of tissue involved, metaplasia may be epithelial metaplasia, connective tissue metaplasia and endothelial metaplasia.

True epithelial metaplasia occurs in response to call for altered unction or at least the result of altered environment. If the prolapsed uterus becomes everted, the columnar epithelium is changed into a stratified squamous form better suited to withstand friction. As a result of continued irritation, e.g., from gall stones, the colu-mar epithelium of the gall bladder may also become squamous. The more highly specialised glandular epithelia (liver, kidney, etc.), appear to be incapable of true metaplasia. Connective tissue metaplasia is of common occurence. Fibrous tissue, myxomatous tissue, cartilage and bone are all closely related and one may become changed into another. The commonest change is that of cartilage into a bone. In old age, ossification of the laryn-geal and tracheal cartilages is .common. This is certainly not due to altered function but may be connected with the altered environment. Bone may be formed in the walls of degenerated arteries or in an eye which is destroyed and functionless. It may be encountered in the edges of a wound in the abdominal wall. In myositis ossificans, bone is formed in the voluntary muscles and may replace them to a large extent. The cells of an osteogenic sarcoma of bone may form fibrous tissue, cartilage or bone. Endothelial metaplasia is observed when serosal endothelium as that lining the pleura or peritoneum is irritated. In place of being flattened it may become cubical, columnar or even stratified. The cubical and columnar cells may surround spaces so as to give glandular appearance. ---------------------------------------------------------------------------------------------------------------------------------

3.Circulatory Disturbances
OEDEMA Q. 3.1. Define the term 'Oedema'. Discuss in detail the various factors involved in the formation of oedema, giving examples. Q. 3.2. Discuss the factors concerned in the development of oedema in the following conditions : (a) Acute nephritis. (b) Nephrotic syndrome. The term "Oedema" may be defined as an abnormal accumula- tion of fluid in the tissue spaces and serous cavities. This accumula-tion may be local or general. When water collects in the tissues, if may be in free or combined form. When combined, it is united with the protoplasm of the tissue elements. When free, it lies between these elements and can be moved from one place to another. Common forms of Oedema I. Anasarca. Severe and generalised oedema causing diffuse swelling of all tissues and organs in the body) particularly noticeable in the subcutaneous tissues. 2. Ascites. Collection of oedema fluid in the peritoneal cavity. 3. Hydrothorax. Collection of oedema fluid in the pleural cavity. 4. Pericardial effusion (hydropericardium). Collection of oedema fluid in the pericardial sac. Transudate is protein-poor noninflammatory oedema fluid as occurs in heart failure and kidney disease. Exudate is the protein-rich inflammatory oedema fluid.

Mechanism of Oedema Five factors are involved in formation and promotion of oedema. 1. Increased capillary premeability. 2. Diminished colloid osmotic pressure of the plasma proteins. 3. Increased hydrostatic pressure of the blood. 4. Lymphatic obstruction. 5. Salt retention. Increased Capillary Permeability. Although the capillary endothelium is completely permeable to water and crystalloids, the outward passage of colloids is closely related to the condition of the vessel wall. Under normal conditions, protein is almost completely prevented from passing out from the blood into the tissues. But when the vessels are damaged e.g. by toxins, anoxia, etc., they become readily permeable to proteins as seen in inflammatory oedema. The escape of proteins is of the greatest importance in the production of oedema, for it lowers the colloid osmotic pressure of the" blood and raises that of the tissues. As a result, water readily passes out through the capillary wall. Decreased Colloid Osmotic Pressure of the Plasma Proteins. Under normal conditions, the colloid osmotic pressure of the plasma proteins hold the water inside the blood vessels and prevents it from passing into the tissues. When the level of plasma proteins become low resulting in decreased osmotic pressure, water passes out from the vessels into the tissues and hence oedema develops. A fall of plasma proteins below five percent will cause oedema. Thus long continued anaemia is apt to be associated with oedema. Marked ascites, when the fluid is rich in protein content, as in malignant disease of the peritoneum may lead to generalised oedema (anasarca) owing to severe blood protein loss. The osmotic pressure of albumin is about four times that of globulin. Thus when there is reversal of albumin-globulin ratio (3: 1) as in subacute glomerulonephritis and nephrotic syndrome, oedema sets in. The colloid osmotic pressure, therefore depends partly on the total amount of plasma proteins and-partly on their relative proportion. Increased Hydrostatic Pressure of the blood. The pressure in the capillaries is the force which overcomes the colloid osmotic pressure of plasma and enables the normal passages of nutritive material into the tissues. If it is increased, oedema will result. The pressure in the capillaries depends upon the venous blood pressure and not upon the arterial pressure. In cardiac failure, the venous pressure rises markedly, and the increased capillary pressure leads to oedema. The stretching and dilatation of the capillaries also renders them more permeable. The oedema which follows thrombosis of the main vein of a limb is largely due an increase in the capillary blood pressure. Lymphatic Obstruction. This is an important factor in the production of local but not general oedema. Much of the intercellular fluid in the tissues escapes by way of the lymphatics, so that obstruction to outflow through these channels will cause local oedema. The obstruction may be due to inflammation, to the presence of tumour cells within the lumen or filariasis. Pressure from outside may be due to a tumour or to collection of fluid. As the fluid increases, the lymphatic obstruction becomes more marked, so t.hat a vicious cycle is formed. Examples of lymphatic oedema are swelling of the arm in breast cancer, swelling of the legs, scrotum, .etc. in elephantiasis, chylous ascites and chylothorax in thoracic duct obstruction. Milroy's disease or hereditory oedema is also probably lymphatic in origin.

Chloride Retention. It is a secondary factor as it does not cause the production of oedema but it aggravates and continues the already existing oedema. Once oedema is established and the chlorides pass into the tissues with water, more water is retained by the tissues because of increased osmotic pressure. In renal oedema the withdrawal of salt from food is often followed by rapid disappearance of the oedema and a corresponding increase in the flow of urine. Generalised Oedema in Clinical States Congestive Heart Failure. In congestive heart failure, oedema results primarily from increased hydrostatic pressure due to venous stasis. The consequent diminished cardiac output induces : 1. Hyperaldosteronism. 2. Increased adrenergic stimuli. 3. Deranged renal baemodynamics. All these factors promote salt and water retention, and hypo-volaemia, further contributing to increased hydrostatic pressure. Acute Nephritis. The oedema in acute nephritis cannot' be due to protein loss in the urine since the plasma proteins are normal and the oedema fluid is rich in protein. The factors involved include. oliguria due to glomerular damage, and increased reabsorp-tion of sodium and water from the renal tubules. It is probable that the cutaneous capillaries are simultaneously damaged with those of the kidneys. A further factor is congestive heart failure with riss in capillary blood pressure. Nephrotic Syndrome. The following factors are probably concerned with the production of oedema : 1. Hypoproteinaemia. The colloid osmotic pressure is lowered by loss of protein in the urine, and hence fluid passes from the blood into the tissue spaces. The normal colloid osmotic pressure is 40-50 cm, of water ; in nephrotic syndrome it is 5-20 cm. of water. The protein lost from the plasma is albumin rather than globulin, owing to the smaller size of its molecule. The protein content of the plasma in nephrotic syndrome does not usually fall below 4 G percent. A further fall in the albumin figure is compensated by a rise in globulin, content. A second factor which may be partially responsible for the fall of the albumin content of the plasma is failure to synthesize new protein from the aminoacids. The capillary permeability does not appear to be increased in nephrotic syndrome as the oedema fluid and the ascites fluid content is low. 2. Sodium Retention. This is of great importance. It has been shown experimentally that if there is no sodium in the diet, the plasma proteins may be low without the production of oedema. In nephrotic syndrome, however it is not the chief cause. 3. Reduction in Plasma Volume. Hypoalbuminaemia cannot be the only cause of oedema, because diuresis may occur in nephrotic syndrome without any rise in the albumin content of the plasma. This diuresis may be due to an increase in plasma volume. Liver Cirrhosis. Liver cirrhosis often produces generalized oedema, particularly excessive accumulation of oedema fluid in the peritoneal cavity (ascites). The factors predisposing to oedema are: 1. Increased hydrostatic pressure due to development of arteriovenous shunts in the scarred liver tissue (portal hypertension). 2. Sodium retention due to increase of vascular bed.

3. Loss of plasma osmotic pressure due to lack of synthesis of senim albumin resulting from hepatocellular damage. Causes of Oedema A. Arteriolar dilatation 1. Inflammation 2. Heat 3. Toxins 4. Neurohumoral excess or deficit. B. Diminished effective osmotic pressure (a) Hypoproteinaemia 1. Malnutrition 2. Cirrhosis 3. Nephrotic syndrome 4. Protein losing gastroenteropathy. (b) Leaky vascular endothelium 1. Inflammation 2. Burns 3. Trauma 4. Allergic or immunologic reaction (c) Lymphatic obstruction. C. Increased venous pressure 1. Congestive heart failure 2. Thrombophlebitis 3. Liver cirrhosis. D. Sodium retention (a) Excessive salt intake. (b) Increased tubular sodium reabsorption 1. Diminished renal perfusion 2. Increased renin-angiotension-aldosterone secretion Localized Oedema in Clinical States Impaired Venous Drainage. It elevates the capillary hydrostatic pressure thus causing localized oedema. 1. Thrombosis e.g. in deep veins of legs. 2. Incompetent venous valves e.g. in varicose veins. 3. Compression of wins eg. by tumours, enlarged organs, tight garments, surgical dressings or plaster casts. 4. Prolonged periods of sitting in normal persons. Increased Vascular Permeability. It occurs in inflammatory allergic conditions e.g. 1. Anaphylaxis 2. Urticaria 3. Hay fever 4. Angioneurotic oedema. The increased permeability in allergic conditions is due to release of histamine from mast cells induced by antigen-antibody reaction. Lymphatic Obstruction. In occurs in : 1. Injury

(i) Traumatic (ii) Surgical (iii) Inflammatory (iv) Radiation. 2. Parasitic infestations e.g. filariasis. 3. Congenital malformation or absence of lymphatics (Mil roy's disease). THROMBOSIS Q. 3.3. What is thrombosis? Describe its effects and sequelae. Q. 3.4. Describe the mechanism of formation of intra-vascular thrombus. Describe the different varieties and their ultimate fate. What is thrombosis? Clotting of the blood inside a vessel during life is termed thrombosis. Thrombosis is essentially a platelet deposition. Types of thrombosis ? Thrombosis is classified according to its site : 1. Veins. The veins are the commonest site of thrombosis. The thrombosis may be divided into two groups : (i) Venous thrombosis : associated with (a) General circulatory failure. (b) Interference with respiration. (c) Trauma Common site is the deep veins of calf muscles. (ii) Thrombophlebitis. It may be septic or simple. (a) Septic thrombophlebitis is secondary to infection and inflammation of the vein wall (phlebitis). It occurs in cavernous sinus infections of the face and in pelvic veins in puerperal sepsis. (b) Simple thrombophlebitis-associated with inflammatory reaction in the vein wall without any evident bacterial infection. There may be painful swelling of an entire limb developing after delivery. 2. Arteries. Common in the (a) Coronary arteries. (b) Cerebral artery. (c) Aorta. (d) Femoral arteries. 3. Heart. Found in (a) Valves. (b) Left ventricle. (c) Left auricle. 4. Capillaries. Occurs in (a) Sickle-cell anaemia. (b) Malaria. Causes of thrombosis There are three factors described as Virchow's triad. I. Slowing of the blood stream More common in veins due to slow blood flow commonly seen as post-operative complication in patients with an ageing heart muscle Common in congetive heart failure

especially when combined with confinement to bed. Normally platelets flow in the central portion of the stream. As the stream becomes slow, they flow in the peripheral portion. 2. Changes in the vessel wait Injury to the intima may occur in the arteries, the veins or the heart. In the arteries, the smooth intima may be roughened by atheroma which also narrows the lumen and retards the stream. It may become necrotic as a result of malignant hypertension, periarteritis nodosa or disseminated lupus. The veins are liable to injury by trauma, by pressure and by infection. In the heart, the valves are injured by inflammation so that thrombi are deposited on the surface. 3. Changes in the blood (i) Increased stickiness of platelets. (ii) Rapid production of platelets-after operation. -after childbirth. -after injury. (iii) Increased viscosity of the blood-In polycythaemia. Mechanism of thrombosis. In the process of thrombosis generally, the first occurence is deposition of platelets which become agglutinated and fused together. The subsequent structure of the thrombus depends mainly on the rate of blood flow. If this is rapid, as in an artery or over heart valve, the thrombus is mainly formed by the progressive deposition of platelets. If it is less rapid, as in a vein the deposition of platelets leads to the formation of trabeculae or laminae which grow out from the vessel wall and to the surface of which the leucocytes adhere. Around the platelet masses thromboplastin diffuses and leads to coagulation in the interspaces. Finally when the Formation of a thrombus. is formed with relative rapidity and is mainly the result of ordinary coagulation. If a vessel wall is merely damaged, thrombosis may not occur, but if at the same time the damaged part is projected inwards, the platclets are brought into contact with its surface to which they adhere, heaping themselves up and in this way starting a thrombus. Effects of thrombosis. When a pure thrombosis is completely successful in its function, it is clinically silent. When complicated by clotting it may or may not become clinically manifest. The following effects pay be produced depending on the site of the thrombus, the type of vessel involved and the degree of occlusion : 1. Oedema of a limb. Occurs when venous thrombosis is complicated by perivenous lymphangitis. 2. Post-thrombotic ulceration. Occurs in the lower extremities due to local venous hypertension following canalization, of the deep venous system. 3. Gangrene of a limb. Caused by thrombosis of a main artery or occulsion by embolism from a thrombus in the heart or aorta. 4. Gangrene of the bowel. Due to thrombosis of the mesenteric artery or vein or to arterial embolism. 5. Infarction of the myocardium, retina, etc.. due to arterial thrombosis. 6. Embolism. Ultimate Fate (Sequelae) of Thrombosis 1. Fibrinolysis. Restoration of the vascular channel after thrombotic occlusion may occur

by a combination of fibrinolysis and shrinkage of the thrombus. The fibrinolytic mechanism depends on the activation of plasminogen in the plasma and this may become very active when there has been large scale intravascular coagulation. 2. Organisation. The thrombus becomes permeated by young connective tissue cells and capillaries, the latter growing in from the vasa vasorum and from the initial endothelium. Its substance becomes gradually absorbed and ultimately replaced by connective tissue. In some instances, the young vessels that grow in from the vascular endothelium covering the thrombus anastomose and then enlarge to form new cannels by which the thrombus is said to be canalised. 3. Infection. Venous thrombi may become infected with pyogenic organisms and may then undergo suppurative softening so that portions are carried away by the blood stream and give rise to abscesses in other parts of the body producing pyaemia. Q. 3.5. What is thrombosis ? How does it differ from coagulation of blood ? What is thrombosis? (See Q. 3.3). Differ dices from Coagnlation Thrombosis Coagulation 1. Intravascular. 1. Extravascular. 2. Essentially a platelet deposition. 2. Essentially a conversion of fibrinogen into fibrin. 3. Thromboplastin not essential 3. Thromboplastin-an essential factor. 4. Occurs in streaming blood. 4. Occurs in stagnant blood. 5. Firmly attached to vessel wall. 5. Weakly attached to vessel wall. 6. Fibrin threads and cellular components produce laminar lines ofZahn. 6. Homogeneous, non-laminated. 7. Friable. 7. Rubbery. 8. Embolism common. 8. Embolism rare. EMBOLISM Q. 3.6. What is embolism ? What are the various types of emboli ? Describe the mode of their formation. What is embolism ? Partial or complete obstruction of some part of the cardi'o-vascular system by a foreign body transported by the blood stream if termed embolism. Types of Emboli 1. Depending on the physical state, the emboli may be :(1) Solid: (i) Detached thrombus. (ii) A mass of tumoni cells. (iii) Parasites. (2) Liquid: (i) Fat gloubles. (ii) AmniotiC fluid. (3) Gas : Air. 2. Depending on the site, the emboli may be : (1) Arterial. (2) Venous. (3) Lymphatic. (4) Paradoxical: An embolus arising in the vein but obstructing an artery. It occurs in

congenital heart disease e.g. patent foramen ovale and septal defects. Mode of formation 1. Solid emboh. (i) An arterial thrombus may arise from left side of the heart or aorta. (ii) A venous thrombus commonly arises from pelvic veins. (i) Tumour cell embolism may be formed in two ways. (a) The tumour cells may gain entrance in the blood stream and form an embolus in some distant capillaries. (b) There may be growth of a tumour into a large vein and a portion of it may get detached, carried by the blood and impacted in a vessel. 2. Liquid embolism, (i) Fat embolism occurs as a result of laceration of a vein surrounded by adipose tissue and its commonest cause is fracture of a long bone with laceration of the fatty marrow, laceration of a fatty liver and Caisson's disease. (ii) Amniotic . fluid embolism may occur during or immediately after labour. Fluid may enter through tears or during rupture of membranes through venous sinuses of the uterus. 3. Air embolism. Occurs in (i) Operation on neck. (ii) Blood transfusions. (iii) Vaginal dousching. ISCHAEMIA Q,. 3.7. What is ischaemia ? Enumerate its causes aad effects. Ischaemia or local anaemia is the local diminution of blood supply due to obstruction of inflow of arterial blood. Causes of ischaemia A. Intravascular. 1. Thrombosis. 2. Embolism. B. Vascular. 1. Endarteritis. 2. Raynaud's disease. 3. Ergot poisoning. C. Extravascular. 1. Tumours of surrounding structures 2. Ligatures and contractures. Effects of ischaemia When the process of ischaemia is slow, there is sufficient time for collateral circulation to develop. In that case, the tissue changes are degenerative and atrophic with replacement fibre sis. Brain tissue is softened. If the cessation of blood supply is sudden and complete, the result is infarction, necrosis or gangrene. INFARCT Q,. 3.8. What is an infarct ? Describe the pathology of infarction in kidney, heart, lung and spleen. What is an infarct ? t ' An infarct is an area of coagulation necrosis due to complete sudden loss of blood supply of an organ. Collateral circulation is usually inadequate. Infaret is termed 'pale' when collateral circulation is minimal (e.g. in kidney, heart and brain). When collateral circulation is marked, .yet inadequate, the infaret is called 'red' haemorrhagic (e.g. in lung, bowel and spleen), Infarct of kidney. The infaret is observed as an irregular area on the surface, often slightly depressed ; surrounded by a pink zone of hyperaemia. F'E 7. Kidney Infaret A cut surface shows wedge shaped area involving whole width of the cortex and some of the medulla, pale in colour and surrounded by a pink border. Microscopic examination reveals an area of coagulation necrosis surrounded by a zone of congestion.

A thin rim of uninvolved tissue separates the infaret from the capsule The emboli causing infaret of kidney may come from :- I (i) Left atrial appendage in mitral stenosis. I (ii) Mural thrombi from the left ventricle in myocardial in-farction. (iii) Vegetations of bacterial endocarditis. (iv) Aortic aneurysm. (v) Thrombosis of renal arteries and veins. I Infaret of Heart. (See Q. 7.5). , Infaret of Lung. (See Q. 9.12). Infaret of Spleen. In- farct of spleen is red haemorr- hagic. Old infarcts, however, are always pale for the haemoglobin is gradually removed, the red cells disappear and decololisation takes place. The infaret reaches the surface which is also involved, (cf. Kidney infaret). Fig. 8. Spleen Infaret. SHOCK Q,. 3.9. Define shock. Disenss its pathogenesis and poct-mortem appearance. Definition. Shock is the clinical manifestation of an inadequate volume of circulating blood accompained by physiological adjustment of the body to the progressive discrepancy between the capacity of the vascular system and the volume of blood to fill it. Pathogenesis. The shock may result from : I. Reduction of blood volume. (i) Whole blood loss-Haemorrhage. (ii) Fluid loss-Burns, crushing injuries to a limb, vomiting, diarrhoea. 2. Increase in vasular bed. Brought about by : (i) Neurogenic stimuli-Painful stimuli. -Anxiety states. (ii) TOXins-Toxic metabolic products, bacterial toxins. (iii) Anoxia. 3. Acute circulatory failure : (i) Myocardial infarction. (ii) Paroxysmal tachycardia. (iii) Cardiac temponade. They sequence of events in shock is believed to be : (i) Redaction in blood volume. (ii) Decreased venous return. (iii) Decreased cardiac output. (iv) Reduced arterial pressure. (v) Ischaemia and anoxia of the organs. (vi) Reflex vasoconstriction. At first the blood pressure may be sustained (hypertensivereaction) or occasionally even raised, possibly due to the diversion of blood flow from the kidneys with consequent liberation of pressor substances but later the blood pressure falls, owing to loss of tone in the capillaries throughout the body, with result that blood accumulates in them and their permeability is increased so that plasma is lost into the tissues and the blood volume is further reduced, a vicious circle is thus established. The pressor substances causing initial hypertensive reaction are termed vaso-excitor material (VEM). This material is produced by cortex of the kidney while the kidney loses the power to destroy it. The loss of capillary tone and increased capillary permeability have been attributed to the effects of anoxaemia leading to the liberation of vasodepressor material (VDM) from the liver and muscles. The vasodepressor material is believed to be ferritin. The vaso-excitor material and vasodepressor material are collectively termed humoral vasotropic factors. Post-mortena appearances. The lesions are those of anoxia and increased capillary permeability. 1. Lungs ;. (i) Dark and filled with blood and fluid. (ii) The capillaries are widely dilated. (ill') Alveoli show marked oedema.

2. Heart muscle :-Fatty degeneration. 3. Liver : (i) Fatty degeneration commencing in the cen-ral zone and extending to the capillaries. (ii) Sinusoids dilated and engorged. 4. Adrenals: (i) Cortex widened and bright yellow in colour. (ii) Foci of local necrosis in the cortex. 5. Kidneys : (i) Severe tubular degeneration (Shock kidney). (ii) Pigment in the tubules. CHRONIC VENOUS CONGESTION Q.3.10. Describe the causes of chronic general venous congestion. Describe the pathology of the liver and long in this condition. Causes. 1. Cardiac. -(i) Mitral stenosis. (ii) Mitral incompetence. (iii) Aortic valvular disease. (iv) Chronic myocardial failure. 2. Pulmonary-(i) Emphysema. (ii) Fibrosis. Changes in the liver Macroscopic. The liver becomes enlarged and tender. The cut surface shows a mottled appearance of dark brown and light yellow areas (Nutmeg liver). Microscopic. The sinusoids at the centre of the lobule are distended with blood. The liver cells are degenerated and atrophic probably as a result of anoxia, whilst at the periphery the cells are normal or merely show fatty degeneration. In very chronic cases there may be collapse of the lobules and fibrous thickening of the walls of the central veins with extension of fibrous tissue into surrounding lobules. This condition has been called cardiac cirrhosis or cardiac sclerosis. Changes in the lung Two forms are recognised, namely, the brown induration, a chronic process and hypostatic congestion, usually a terminal one. Brown induration is always associated with hypertension in the pulmonary circuit. The lungs are voluminous, brown in colour, tough and indurated, Microscopi- colly, the lung is filled with blood. the alveolar vessels being widely distended and alveoli containing many red blood cells filled with yellow pigment. These cells are known as heart failure cells, However, it is a misnomer as the condition is not always associated with cardiac lesion. The pigment is haemosiderin, derived from the red blood cells Fig. 9. Lung-C.V.C. In hypostatic congestion, the dependent part of the lung appears to be consolidated. The air in the alveoli is replaced by plasma .and red blood cells, but a pneumonic process may be added aa a result of terminal infection. --------------------------------------------------------------------------------------

4.Granulomata
INTRODUCTION

Q, .4.1. What is a granaloma and how docs it differ from a tumor ? Describe the various types of granniomata giving the histology of one of them. A granuloma is a variety of chronic inflammation characterised by lesions which tend to be strictly circumscribed and by cells of histiocytic rather than of haematogenous type. A granuloma is essentially a highly specific reaction of the reticuloendothelial system. Thus the granuloma must be regarded as special example of inflammation a nd not as a tumour since the latter should have no co-relationship with the reaction to injury of limitation of infection. The lesion in granuloma is a small 1-2 mm collection of inflammatory cells, principally modified macrophages, usually surrounded by a rim of lympbocytes. The characteristic cell is a modified macrophage (epithelioid cell) with abundant, pale-pink cytoplasm. Epithelioid cells, like all macrophages, are derived from blood monocytes. These are rich in endoplasmic reticulum. Golgi apparatus, vesicles and vacuoles. However, the epithelioid cells do not have marked phagocytic activity. These are better adapted for extracellular secretion rather than phagocytosis. A number of epithelioid cells coalesce and fuse to form giant cells. The giant cells may be 40-50 n in diameter and may contain upto 50 nuclei. In addition a granuloma may have fibroblasts, plasma cells and neutrophils. Types of granulomata 1. Infective granulomata: 1. Bacterial (i) Tuberculosis. (ii) Leprosy. (iii) Tularemia. 2. Spirochaetal. (i) Syphilis. (ii) Yaws. 3. Fungal (i) Actinomycosis. (ii) Machiromycosis. (iii) Blastomycosis. (iv) Coccidiomycosis. (v) Aspergillosis. 4. Viral, (i) Gramiloma inguinale. (ii) Lymphopathia venerium. 5. Idiopathic. (i) Sarcoidosis. II. Foreign body granulomata: (i) Lint granuloma. (ii) Berrylium granuloma. (iii) Lipogranuloma. TUBERCULOSIS Q. 4.2. Discuss the etiology and spread of tuberculosis. Give the differences between lesions in childhood tuberculo* sis and adult tuberculosis. Etiology of Tuberculosis Tuberculosis is caused by the acid fast organism, Mycobac-terium tuberculosis. Two types, human and bovine, are known to cause infection in human beings. Both types are equally pathogenic for man. The bovine type bacillus is primarily a parasite of cattle. In man it is mainly responsible for tuberculosis of lymph nodes and bones in children. Infection with the human type is air-borne from patients "with pulmonary tuberclosis (i.e., with viable bacilli in the sputum). Infection is commonest under five years of age when it is likely to be rapidly progressive and fatal. Then it declines until late adolescene, reaching its maximum in women between 20-25 and 'n men , between 40-50 years of age. In the adult the discase in much more I chronic. Infection may occur through the alimentary tract by ingestion of infected milk especially in the rural population where proper boiling is not practised. Congenital infection through the placenta is rare. Spread The tubercle bacillus re non-motile but it can be transported in the bodies of phagocytes.

The spread may occur by: (i) direct extension, (ii) lymphatics, (iii) blood stream, (iv) natural passages. by direct extension occurs from the primary site of lesion. The extension is effected by amoeboid movement of the phagocytes harbouring the bacilli. Thus the bacilli are carried into the lymph spaces of the surrounding tis'sue. Spread by lymphatics results in transportation of the bacilli from the infected lymph spaces to the regional lymph nodes whence they disseminate widely in the lymphatic system. Ultimately the bacilli are poured into the venous blood stream through the thoracic duct. The venous blood carries the bacilli to the lungs and sometimes to systemic circulation. Spread by blood stream may occur either via the lymphatic-venous route or by ulceration of a caseous focus into a vein. In the '. former case, a simple bacillaemia results leading to isolated lesions in almost any organ of the body. While ulceration of a caseous focus into a vein results in general miliary tuberculosis and the circulation is flooded with bacilli, tiny miliary tubercles, macroscopic or microscopic, are present in every organ of the body. Spread along the natural passages may occur through the bronchi, ureters and vas deferens. In these cases, however, it is difficult to be certain that the bacilli have not been carried along the lymphatics in the submucosa. Differences between Childhood and Adnit Tuberculofis Childhood Tuberculosis Adult Tuberculosis (i) Usually results from primary infection. Results from reaction or super infection. (H) Healing takes place by calcification or by complete removal of tuberculous tissue. Healing takes place by fibrosis and scarring. (i(r)) Glandular involvement usually predominates. Glandular involvement not common. (iv) Parenchymal lesions usually perihilar. Parenchymal lesions usually apical. (v) Cavities, when present, usually acute and necro-tic. Cavities usually chronic and walled up. (vi) Haematogenous infection is common. Haematogenous infection less common. Histology of Tuberculosis. (Described in Q. 4.3). Q. 4.3. Describe the gross and microscopic appearance of tuberculous inflammation-with special reference to fibro-caseous pulmonary tuberculosis. Gross appearance The gross appearance varies in primary infection and secondary infection. The primary or Ghon lesion is a small caseous focus, seldom more than one cm in diameter, usually single. The caseous centre becomes surrounded with a fibrous capsule. Calcification and sometimes ossification occur and the healed lesion is represented by a small scar or calcified nodule. Foci in the regional lymph nodes also become encapsulated and calcified but may harbour tubercle bacilli for many years. Spread occurs along the lymphatics so that regional lymph nodes are enlarged and caseous. A chain of tubercles can be traced from the primary lesion to the infected lymph nodes. One

of the caseous nodes may open into a blood vessel and cause general miliary tuberculosis. The appearance in the secondary infection depends on the dose of bacilli and the degree of resistance. If the dose is small and resistance high there will be complete healing or a quiet fibro-caesous lesion. If the resistance is not so good there may be rapid excavation. Microscopic appearance When a few tubercle bacilli gain a foothold in a tissue, they are rapidly ingested by phagocytes and a focus of reaction occurs resulting in the formation of what is known as atubercle follicle. At a very early stage, the centre of focus consists of a collection of swollen macrophages whilst around them there is a \ zone of round cells chiefly lymphocytes. Soon macrophages be come oval, spindle shaped or irregular in form, with fairly' abundant protoplasm and a faintly staining nucleus, they are then called epithelioid or endothe-lioid cells. Very soon, however the central cells become swollen Fig. 10. Primary tubercle. and lose their outline, their nuclei cease to stain and ultimately they become fused into a homogeneous or slightly granulan, structureless, material. Sometimes certain amount of fibrinous exudate is added to the necrotic material; the ultimate result is a necrotic centre surrounded by epithelioid cells and these again by small round cells. In the outer zone of the follicle, reticulum fibres are numerous. Amongst the epithelioid cells of the tubercle are the giant cells, with somewhat irregular outline and numerous oval or rounded nuclei resembling those of the epithelioid cells. The nuclei are often arranged at the periphery or in clumps while the central part of the cell may show signs of degeneration being granular or hyaline in appearance. These are known as Langerhan's giant cells. The typical follicle may appear to contain a central giant cell surrounded by a zone of a epithelioid cells and those again by a zone of round cells. The endothelioid cells are derived mainly from the tissue histio-cytes and also from nongranular leucocytes which emigrate from the blood to become incorporated in the follicle. The giant cells are formed from endotbelioid cells, some by amitotic division of the nuclei while the cytoplasm does not divide but si'mply increases in amount while others are formed by fusion of endothelioid cells. Whilst the initial reaction conforms generally to the description given above, the ultimate fate varies greatly and thus the tuberculous lesions come to present very different characters. Some examples are as follows : (i) Acute miliary tuberculosis. When the tubercle bacilli gain entrance into the blood vessel through lymphatics or through ulcer-tion of a tubercular focus into a blood vessel, miliary tuberculosis. results. The tubercle nodules in various organs present several partially fused tubercle follicles. These nodules may be nearly of the fame character and therefore of the same age due to extensive dissemination of the bacilli about the same time. (ii) Caseous lesions. Large areas of caseation result by the fusion of individual tubercles with caseation in the centre. The periphery is thus composed at first of the remains of the outermost ring of tubercles and around these connective tissue may form. encapsulating the lesion. Large caseous masses are specially common in the lymph nodes and often occur in the kidneys. epididymus, suprarenals, etc. (iii) Tuberculous granulation tissue. (vi) Fibrotic lesions. Fibrocaseous Pulmonary Tuberculosis. (Described if' Q. 9.11).

SYPHILIS Q. .4.4. Describe the types of lesions enconntered in ' syphilis with a reference to congenital syphilis. The lesions encountered in syphilis are described in three stages viz. primary, secondary and tertiary. 1. Primary lesion. The primary lesion appears at the site of inoculation". This is usually on the genitalia but it may be extragenital e.g. on lips and fingers. The common genitalia sites are the peais in the male and the cervix in the female. The cervical chancre is highly infective on account of the moist character of its surroundings and it is easily overlooked owing to its bidden nature and freedom from pain and discharge. The primary lesion is generally single but may be multiple. If usually develops in form three to four weeks after infection but this latent period may be two to six \veeks. It first takes the form of a hard nodule but the surface tends to become ulcerated and a 'hard sore' or chancere is formed from the surface of which enormous number of spirochacies are discharged. The chancre is the earliest clinical manifestation but from the pathological standpoint the chancre is really a late affair. The hardness is due to dense cellular infiltration but does not appear during the first few days. Later it is caused by a marked degree of fibroplasia. In the course of a few weeks, healing occur? which may or may not leave a scar. Microscopically, there is dense accumulation of lymphocytes and plasma cells especially around the sm^ll vessels and fibroblasts multiply and lay down collagen fibrils. Destruction of the tissue is seldom marked but the surface epithelium is usually lo^t. The regional lymph nodes are enlarged, hard and shotty but not painful ' or tender. 2. Secondary lesion. After the appearance of primary lesion, there is a latent period. In two or three months after infection, secondary lesions appear in the skin, mucous membranes and the central nervous system. These persist for a period of months and then disappear There is no destruction of the tissue at this stage so that no scars are left. Secondary lymphadenitis is one of the earliest changes. The nodes all over the body are enlarged. Swelling of the epitrochlear or posterior cervical nodes are specially characteristic. The lesions of the skin are of great variety, but they 'are symmetrical in distribution. They are polymorphous in type, i.e., present several varieties of the lesions at the same time. The lesions may be macular, papular or pustular. 3. Tertiary lesions. The subsidence of the secondary lesions is followed by another latent interval during which all is quiet. In a year or not for many years a third set of lesions appears. These are not symmetrical. They affect deep as well as superficial structures and show a tendency to necrosis and destruction. These are not infective. Two main types of tertiary lesions may occur. The one is gross and localised (the gumma), the other is microscopic and diffuse. The gumma is a necrotic, localised, yellowish, homogeneous mass of rubbery consistence composed of usual mononuclear cells. In the- centre of the lesion necrosis and caseation occcur with the formation of peculiar gummy material, but three is not the same complete wiping out of structure as in tuberculous caseation. A few giant cells may be seen at the margin. Gummata of skin, mouth, tongue and nose may lead to extensive ulceration The liver may show one or several masses which heal with fibrosis so that deep scars are formed producing a peculiar lobed appearance known as 'Hepar lobatum. In the testicle, gumma forms a hard mass which may be confused with tumour. Gumma in the bone, the

brain and other places may be confused with tumours of these, organs. In the difiuse lesions, the spirochaetes are widely distributed and set up a diffuse chronic inflammatory reaction which lymphocy-tes and plasma cells, tissue destruction but no caseation. The principal sites are the thoracic aorta and. the testicle. In the thoracic aorta a frequent result is the development of an aneurysm of that vessel. The most ^rious of all the late lesions are those of the central nerous system which may appear many years after the original infection. These may affect chiefly the meninges, the braita and the spinal cord. Congenital Syphilis Syphilis may be transmitted from the father or mother but in all cases mother is infected though the infection may not be manifest. There are three possibilities : 1. Ths child may be born dead showing well marked evidence of syphilis. 2. The child may be born alive with external evidence of syphilis. 3. The child may appear healthy but lesion? develop after. When the child is born dead, the appearance is usually chara-teristic. There is no primary lesion, as infection takes place through the placenta. The child is usually premature and undersized. The skin may be macerated. The spleen and often the liver are enlarged. Syphilitic epiphysitis is the most diagnostic feature. The chief microscopic dhange is an interstitial round cell (infiltration of many of the internal organs combined with a varying degree of fibrosis. In the liver this produces a fine form of intercellular cirrhosis. If the child is born alive the skin may show varied lesions described in the acquired form. Common sites of lesion are the buttocks, anus, angles of the mouth, palms of the hands and the soles of 'the feet. Enlargement of spleen is very constant. The liver and the other organs show the changes already described. In the late type, lesions develop over a period of years. The permanent teeth show the appearance known as "Hutchinson teeth". These are small, widely spaced, peg-shaped and central incisors are notched : molars are pitted and honey-combed. An interstitial keratitis develops at the time of puberty producing a ground-glass opacity in the cornea. Nerve deafness is common. There may be involvement of the central nervous system similar to that seen in the acquired form. LEPROSY Q,.4.5. Describe the local and systemic changes in a case of leprosy. There are four types of lesions in leprosy : I - Lepromatous. 2. Tuberculoid. 3. Indeterminate. 4. Borderline or Dimorphic. Lepromatons Leprosy This form is manifested especially in the skin by diffuse involvement in which the skin becomes erythematous, swollen and often smooth and glistening. It is firm and usually painless. Projecting nodules may develop, either discrete or fusing to form large conglomerate masses. When the latter involve forehead and face together with loss of eye brows and eye lashes, the face is described as leonine. Involvement of conjunctivae leads to blindness ; hearing, smell and taste sensations are sometimes lost. The nodules vary in size form microscopic to 2 cm. diameter. The large nodules, often in the skin, ace well defined, have a tense overlying epiderm, are firm somewhat elastic and

cut with resistance. They show a slight buidging ; pale yellow or light grey in crosf section. Situated in the cori-urn, they may extend deeply Microscopically, the nodule is made up principally of large, mononuclear cells, with an irregular intermingling of lymphocytes, plasma cells and multinucleate giant cells of Langerhan's type. The large mononuclears and giant cell are often foamy and contain the acid fast bacilli. These foam cells may also contain fat. The bacteria may also be found in vascular endothelium, in polymor-phonocicar leucocytes and even in epithelium. They ar? present as small clusters of organisms termed 'Cigar pack' and as large masses. Extracellular organisms are also found but these are originally intracellular. Occasionally, lepromas are made up largely of large mononuclear cells without foamy cytoplasm. Sometimes there is an ingrowth of connective tissue and the lesion becomes cicaterized. Tnbercnioid Leprosy Tuberculoid lesions are tiny granulomas, often near blood vessels, made up of lymphocytes, large mononuclears, and occasional giant cells. When in the s^in they are in the upper corium, and the overlying epidermis is often atrophic. The lesions are smaller than the usual leproma and also differ in that they contain few demonstrable bacteria. Sometimes tuberculoid lesions, especially in the lymph nodes and bones, closely resemble the granulomas of sarcoidosis. In rare instances, tuberculoid lesions undergo extensive necrosis with the formation of painless ulcers, called lazarine leprosy. Indeterminate Leprosy The lesions are not distinctive histologically. Hyperaemia is prominent in the erythematous macules. Infiltration of lymphocytes may be noteworthy, especially around blood vessels. Dimorphic Leprosy The histology is not characteristic. As change" occur, the lepromatous or tuberculoid features may be prominent. -----------------------------------------------------------------------------------------------