VINNITSA NATIONAL MEDICAL UNIVERSITY BY N.I.PIROGOV

GENERAL HISTOLOGY

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VINNITSA NATIONAL MEDICAL UNIVERSITY NAMED BY N.I.PIROGOV

DEPARTMENT OF HISTOLOGY,CYTOLOGY, EMBRYOLOGY

GENERAL HISTOLOGY

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VINNITSA 2008

Authors:

Maevsky Alexander Yevgenyevich, the candidate of medical sciences

Cherepakha Elena Leonidovna, assistant

Edited by Pushkar Michail Stepanovich, the doctor of medical sciences, professor

Material of the general histology are written according to the curriculum оn histology, cy-

tology and embryology for medical higher schools. The lectures contains materials of cell

and tissues morphofunction characteristics, embryology. Material can be used for prepara-

tion both for practical classes and for exams.

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SUBJECT OF HISTOLOGY IN SYSTEM OF MEDICAL EDUCATION. METHODS OF RESEARCH

Histology is a science about development, basic features and abilities of vegetative and animal or-ganisms living tissues, organs and system of organs. The modern histology studies structures of the hu-man and animal organisms and has a direct relationship with processes occuring in them. The subject of histology opens a correlation between function and structure, studies interrelation of a metabolism and structural parts of organism, and also microscopic structures architectonics.

Histology divides into three basic units:1. Cytology - the doctrine about a cell.2. The general histology - the doctrine about tissues.3. Special histology (microscopic anatomy) - the doctrine about a microscopic structure of organs, their cellular and tissues structure.

Histology has a direct relationship to other biological and medical disciplines and is essential for their understanding - comparative anatomy, biochemistry, pathological anatomy, pathological physiology, hematology. The general embryology and special embryology is included in the program of course of his-tology in medical higher schools.

The histology is closely connected with embryology, studying process of individual development of organisms - ontogenesis. During the certain periods of embryogenesis develops tissues. Occurrence of tissues - process during which embrional germ turn to tissue structures, therefore studying of embrional developments basic stages should precede studying of tissues.

Histophysiology study interrelation of cells, tissues and organs structures with their function. Study of a living organism cells and tissues histophysiology is of great importance for the decision of many medical questions.

Cytochemistry and histochemistry study localization of various chemical substances in cells and tissues structures, find out dynamic of exchange processes in cells and tissues, interrelation between a me-tabolism and structural elements. It is an example of fruitful development of scientific researches on the verge of adjacent sciences - histology and biochemistry. It is necessary to note, that modern discoveries are carried out at cooperation of two-three, and sometimes a lot of independent branches of knowledge more often. Scientific research of the modern day histologist is closely connected by image to successes of physics, chemistry, mathematics.

Thus close interaction of various branches of knowledge promotes the profound penetration of sci-entists into secrets of the nature. The histology is closely connected to biological and medical sciences, lakes the important place in system of medical education, being alongside with others general biological disciplines the base on which many theoretical and clinical disciplines are under construction.

Development of histology is closely connected with a microscope which is the basic instrument of the researcher. Each new improvement of a design of a microscope results in expansion and a deepening of our knowledge in the field of cytology, histology, histochemistry, immunocytochemistry.

Now the majority of researchers think, that the first microscope has been created by A. Levenguk. Before to speak about research of Levenguk and general principles of a design of a microscope it is nec-essary to stop on features of our sight. The person can distinguish a subject in the size of 0,07-0,08 mm on a distance of 25 sm from examined object if is not requiring for glasses. The distance between retina photosensitive cells does not allow to see a subject under a corner of less than 1 conditional minute.

By Abbe's theoretical calculation resolution of a microscope is equaled 1/3 ray wave rate. In prac-tice it corresponds 1/2 ray wave rate. Therefore the usual light microscope refuses to work at resolution less than 2000 A. Angstrem (A) - unit of length equal 0,1 microns or 108 sm. In angstrems the submicro-scopic structures of cells opened with the help of an electronic microscope are measured.

Our eye is most sensitive to rays with rate of a wave about 5000 A. Hence a limit of the sanction of a usual microscope 2000-2500 A. The conclusion from the given situation arises itself. It is possible to take instead of seen light ultra-violet (length of a wave about 2000 A). The ultraviolet is absorbed by

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usual glass, but absorption can be avoided if to make lenses of quartz or to construct a microscope on concave mirrors. The image in an ultraviolet (UV) is projected on the luminous screen or a photographic plate.

UV rays applied for microscopic researches have formed a basis for wide development of spectro-scopic researches in cytology and histology. On this basis very perspective direction - cytospectrometria has developed.

The ultra-violet microscope has been created approximately 90 years ago. Now it applied in many areas of natural sciences. He gives resolution up to 1200 A.

Last years unit of measure Angstrem (A) widely used earlier is applied seldom. The modern units of measurements used at histological researches:1 millimeter (1 mm) = 10-3 m = 103 microns = 106 nanometers = 107 A1 micrometer(1 micron) = 10-6 m= 10-3 mm = 103 nanometers= 104 A1 nanometer (1nм) = 10-9 m= 10-6 mm = 10-3 microns = 10 A1 angstrem (1 A) = 10-10 m = 10-7 mm = 10-4 microns = 10-1 nanometers

Luminescent microscope. It has been noticed, that if to illuminate a preparation with ultra-violet or violet rays sideways many structures of alive cells start to shine red, green or yellow colour. Due to this effect "the luminescent microscopy" widely used in modern biological researches subsequently was born. For these researches special luminescent microscopes and prefixes are used.

Histochemistry. Specific chemical constituents of tissues and cells can be localized by the method of histochemistry and cytochemistry. These methods capitalize on the enzyme activity, chemical reactiv-ity, оr other physicochemical phenomena associated with the constituent оf interest.

Immunocytochemistry. Uses fluorescinated antibodies and antibodies to provide more precise in-tracellular and extracellular localization of macromolecules than is possible with histochemistry. In the direct method the antibody against the macromolecule is labeled with a fluorescent dye. In the indirect method a fluorescent-labeled antibody is prepared against the primary antibody specific for the macro-molecule of interest.

The phase contrast microscope. The idea being simple and very fruitful is put in a basis of a de-sign of phase contrast microscope. The eye of the person and a photographic plate do not register changes of a phase of a ray wave, but well distinguish change of its amplitude. In phase contrast microscope there is a special device which will transform shift of waves on a phase (such shift occurs at passage of rays through a preparation) in shift on amplitude well felt by an eye. Due to this transformation the image gets contrast.

Roentgenostructural analysis studies a spatial structure of microscopic structures with the help of X-rays. On the basis of this method Watson and Cric created in 1953 the model of DNA molecule. Value of this spatial model that it well explains physical, chemical and biological properties of DNA and, espe-cially, the mechanism of reproduction. The researches carried out recently bring an attention to the ques-tion on the agenda, whether serves DNA as the unique structure carrying the genetic information, or stor-age and transfer of the information is carried out in cells as well at other levels. Obviously now unique system of a stream of the information which essence we start to comprehend is a system which starting point is DNA. Opening of this system of a stream of the information is a triumph of modern biology.

Now it is found out, that DNA is no absolute beginning of a biochemical stream of the information since the signals from other sites of a cell can influence it.

The radioautography enables to study a metabolism in various structures. The method requires in-corporation of radioactive isotope -most commonly tritium - into the compound being studied. Radioac-tive substances in histological sections come to light with the help of a photoemulsion, which render on preparations and then show. This method allows to determine speed of exchange processes in cells and tissues. For example, autoradiography has been used to follow the time course of incorporation of tritiated proline into the basement membrane underlying endodermal cells of the thyroid gland. In this manner, the sequence of events occurring in the synthesis of type IV collagen - the main protein in the lamina densa of the basal lamina - was visually demonstrated.

Culture of tissues outside of an organism. Selected of an organism of the man or animals cells, small samples of tissues of various organs, are located in special glasses which contain a nutrient

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medium: plasma of blood, embryonal extract and growth factors of cells. The constant temperature close to a body temperature is supported. In these conditions cells save for a long time the basic parameters of life: ability to growth, duplication, differentiation, movement. The method of tissues culture has the spe-cial importance at carrying out of experimental researches on human cells and tissues.

The vitale (lifetime) and the supravitale colouring. At vitale staining color is entered in an organ-ism of animals. It selectively stains the certain cells or tissues. For example tripane dark blue selectively stains macrophage. The supravitale staining is called staining the alive cells selected from an organism.

Electron microscope. The modern physics considers light waves not only as electromagnetic waves of the certain length and frequency. It is a stream of the particles called in quantums or photons. On the other hand electrons not only corpuscles with the certain weight. Flying electron it is possible to consider as a wave which length is deduced from the equation of de Broylya. The faster less length of its wave goes electron. To disperse electron in emptiness it is possible an accelerating voltage. If it makes 50 watt, the length of a wave of electron near 0,05A - a hundred times is less than length of a wave of green light. The electrons are possible to reject magnetic lenses, simply electromagnets.

On the basis of the stated positions the electronic microscope which on appearance essentially dif-fers from microscope of Levenguk has been created, but the principle of work of both devices is identical.

Let's consider some moments of a design of an electron microscope in comparison with optical. The optical microscope begins with the gaffer - an energy source. Levenguk used for this purpose the sun or smoking an oil lamp. For three hundred years the gaffer has done a fair way, having turned in the best designs of a microscope in monochromator, giving light of strictly certain length of a wave that eliminates a chromatic aberration.

In an electron microscope as the gaffer is the electron gun. Optical systems of an electron micro-scope are submitted by electromagnets or constant magnets which carry out a role of the condenser, lens and ocular. The received image is projected on the screen similar to the screen of the TV. The record sanction of a modern electron microscope is less 1,5A.Theoretically resolution of an electron microscope about 0,025A. Electron microscopes of the first class increase in 250 thousand times. This break in secrets of a microcosm does not concede on the value to what 300 years ago has made A. Levenguk. Compare 1,5 A and 700 thousand А (0,07мм) the sizes of the way gone by mankind in this field of knowledge from Levenguk up to now for 300 years are those.

Transmission electron microscopy uses much thinner section compared with light microscopy and required heavy metal precipitation techniques rather than water-soluble stains to stain tissues.

Scanning electron microscopy provides a three-dimensional image of the specimen. This method is used to view the surface of a solid specimen.

Histology technicHistology technic is required to prepare in the handy position for microscope research. Varied

methods are used in such invastigation. The most important are fixing and dyeing the slides:1. Finding out the necessary matherials.2. Fixing it.3. Washing it.4. Depriving it of water and dencing.5. Placing the matherial in paraphine or celloidin.6. Depositing celloidin or paraphine blocks.7. Displaying the slides on the mycrothome.8. Dyeing the slides.9. Replacing dyed slides into the balsam.

I. The matherial should be taken in small parts in size (1-2cm3) in order to be quickly fixed, and souked with fixing mixture.

II. The fixing mixture should be capable to fast into tissue, turn sour albumen and not to damage the cell structure. Fixing liquids could be ordinary and complex.

Ordinary: 6

a) phormalin 10-12%b) ether alcohol absolute 100%Complex:a) mixture of Nikiforov. Consists of two equal shares of alcohol and ether.b) mixture of Zenker, Maximov, Flemming and other.c) mixture of Karnua (alcohol, vinegar, chlorophorm).All these mixtures are used in different methods of histologycal research in proportions 1: 30-40,

sometimes even 1: 100 times more according to fixing matherials. III. Washing. It is done in running water (1-24 hours). This quarantees even dyeing.IV. Draining and dencing.The purpose is to prepare the tissues for absorbing of paraphine or celloidin. The matherial for that

take through the battery of alcohols of rising concentration (60o, 70o, 80o, 90o, 96o, 100o). V. Placing in paraphine.

Paraphine dissolved in chlorophorm, xylol, ether.1. the pieces are put into alcohol-xylol for 1,5-2 hours.2. repeat xylol for 1,5-2 hours.3. mixture of paraphine and xylol under temperature 37o in thermostate for 1,5-2 hours.4. paraphine under the temperature 54-56o in thermostate for 1,5-2 hours.5. wrapping (placing) in paraphine with very fast cool.

Celloidin – the clearest sort of nytrocelloidin dissolved in the mixture Nikiforov. We more often use films or R-films dissolved in this mixture.

1. the piece is placed in mixture of Nikiforov for 24 hours.2. in 2% celloidin for 7-10 days.3. in 4% celloidin for 7-10 days.4. in 8% celloidin for 7-10 days.

VI. The pieces are stuck to wooden planks, ready to be cut handy on mycrothome. Celloidin`s blocks are kept in 70o alcohol. Paraphin`s blocks may be kept in the open air.

VII. Histologycal slides are prepared with the help of sledge-rotation or freezing mycrothom. This gives the slides of 5-15 mcm thick.

VIII. Dyeing slides of histologycal colours:Nucleus colours:

1. hematoxylin – dyes the nucleus of cells in violet.2. carmin – into red.3. saphranin – into purple.

Cytoplasmic colours:1. eosin – dyes cytoplasm into pink.2. fuxin – into red.3. pycrin acid – into yellow.

Specific colours:Dye only definite structures of a cell.

1. orsein – ellastic fibers into brown.2. resorcin-fuxin – into violet.3. sudan III – dyes fat of a cell into orange.4. sudan black – dyes fat of a cell into black.5. osmy acid – dyes the fat into black.

When studying the nerve system the method of impregnation is used. The tissues are put into nytro-silver solving, chlorid gold, chlorid platinum and in definite period of time they become metals.

IX. Replacing into balsam.

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CYTOLOGY. GENERAL PLAN OF A CELL CONSTRUCTION Cytology is the science about a cell. The term cytology occurs from two Greek words: a cytos-cell

and logos-science. In this section we consider the general organization of a cell. Structural features of each cell will be investigated in process of studying tissues and organs in rates of the general and special histology. Cell is the basic smallest morphofunctional unit of living complex plants and animals organ-ism.

The cell is the alive system limited to an active cell membrane consisting of cytoplasm and a nu-cleus and being a basis of a structure, development and ability to live of vegetative and animal organisms. From positions of the system approach a cell is open, automatically adjusting and self reproductive sys-tem.

Studying of cytology is of great importance for the future doctor as practically all diseases are in-fringements of a cell structure and function.

Cells in tissues undergoing growth or repair use more of their resources preparing for, and carry-ing out, cell division. Fully differentiated cells typically concentrate on more specialized functions, such as secretion and contraction. Maintaining a constant internal environment(homeostasis), even in apparently quiescent cells, requires the expenditure of significant amounts of en-ergy and other resources.

Cellular Differentiation. Refinements in cell structure and function accompany embryonic and fe-tal development, as well as maturation and aging. This cellular differentiation generally results in a cell's dividing less often and having fewer, but more efficient, capabilities than an embryonic cell. The func-tions of a differentiated cell can be roughly gauged by the organelles it contains. For example, cells spe-cialized for protein secretion contain abundant RER and a well-developed Golgi complex. Although dif-ferentiation can result in dramatic changes, it does not occur suddenly. It occurs in a series of steps, often separated by one or more passes through the cell cycle, and involves interactions among the cell's envi-ronment, the metabolic machinery in its cytoplasm, and the information in its DNA. Among the more ob-vious changes taking place during differentiation are the often dramatic changes in the genes being ex-pressed.

Intercellular Communication. Tissues, organs, and organ systems are collections of cells and cell products that act in concert to carry out their complex functions. The embryonic cells that ultimately form a tissue develop communication strategies early in embryogenesis. Many types of intercellular communi-cation occur—some direct and som indirect.

Direct communication. During cell-to-cell recognition or contact inhibition of cell division, signal transmission may require temporary physical contact. In some tissues, especially in epithelia, cells have more permanent direct contact with their neighbors over large areas of their surface membranes. These ar-eas of contact are often marked by specialized plasma membrane structures called junctional complexes.

Indirect communication. Signals also can be transmitted from one cell to another even when the cells are not in contact. In proximal communication, the signal traverses a short distance (hormones, growth factors, or other signal molecules may be produced by one cell type and have effects on another cell type in the same tissue). In distal communication, the signal travels farther (when hormone-producing cells in one tissue elicit responses from targets in different tissue).

Cellular Adhesion. Many cell functions, especially those involving cell shape and tissue integrity, depend directly or indirectly on cell adhesion. Cell-to-cell adhesion, especially in epithelia, requires link-ages between the cytoskeletons of neighboring cells. Intercellular binding is mediated by transmembrane proteins called cadherins. The intracellular domains of cadherins are linked to the cytoskeleton by special adaptor proteins, which may form plaques on the cytoplasmic surface of the membrane. Cell-substrate ad-hesion involves linkages between the cytoskeleton and collagen fibers of the extracellular matrix. The transmembrane proteins in these attachments are called integrins. In these junctions, intracellular adaptor proteins attach integrins to the cytoskeleton and extracellular adaptor proteins (laminin and fibronectin) attach integrins to the collagen fibers.

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Cells of an animal and human organism are various on size, shape and an internal structures. The shape of a cell is determined by its function. Most often there are following shapes of cells: rounded, oval (for example blood cells), flat, cubic, cylindrical or columnar (for example cells of epithelium), star-like (cell of a nervous tissue, a bone tissue), polygonal (cells of a liver), fusiform (cells of a muscular tissue).

The sizes of cells in human and mammals organism change over a wide range - from 4-5 micron (a cell of a granular layer of a cerebellum) up to 110-130 microns (female sexual cell and brain cortex cells). In development and differentiation the cell can change the shape and the sizes: nervous cells get long processes, red blood cells -erythrocytes become denuclearized, etc. Each cell consists of three basic parts - the cell membrane - plasmolemma or plasma membrane, cytoplasm and nucleus.

Cytoplasm is complex colloidal system. The bulk of the cytoplasm is water, in which various inor-ganic and organic (proteins, lipids, carbohydrates) chemicals are dissolved or suspended. This fluid sus-pension is called the cytosol. The cytosol contains organelles, metabolically active structures that perform distinctive functions. Staining of cytoplasm depends on its chemical compound. If cytoplasm of a cell has ulkaline reaction it is stained by acid color, i.e. oxyphilia or acidophilia. Most often as acid color is ap-plied eosin, therefore structures stainted acid color are called eosinophilic. Properties of oxyphilia shows extracellular structures (collagen fibres of a connective tissue, srtiated muscle fibres), and cells of epitelium, connective and nervous tissues, a granule in cytoplasm of some leukocytes. Leukocytes with granules stained by acid colors have received the name eosinophilic leukocytes. If cytoplasm of a cell has acidic reaction it is stainted by alkaline or basic color, i.e. shows properties of basophilia. As a rule, alka-line color applies hematoxylin which stains cytoplasm in blue-violet color. The basic color stains cyto-plasm of all active synthesize protein cells and also nucleus of all cells as they contain nucleonic acids. Structures which are simultaneously stained both acid and basic colors are called neutrophilous or poly-chromatophilous. An example can be neutrophilic leukocytes granules. Some histologic structures are ca-pable to change color of the basic color. This ability is called metachromasia. Metachromatic basic sub-stance of a connective tissue, cartilagic tissue, granules of basophils is stained.

Cytoplasm of a cell consists of organelles, inclusions and hyaloplasm. Hyaloplasm, or cytoplasm matrix, is the internal environment of a cell, free from organelles and inclusions. The structure q hyalo-plasm includes water, proteins, nucleinic acids (RNA), varioj polysaccharides, a plenty of enzymes. The colloid system of hyaloplasm can be in a liquid status (a status of sole) or gets gel consistence ( a status of

a gel). In an electronic microscope hyaloplasm looks as electron transpar-ent granular structure.

Cell membrane - is an universal system, which form many structures of a cell. Each cell is bounded by a cell membrane (als known as the plasma membrane or plasmalemma). The nucleus is separated from the cy-toplasm by a nuclear membrane - karyolemma or nuclear envelope. Many of organelles are made up of membranes. The various membranes within the cell have a common basic structure. We shall consider it on an

example of plasmolemma. The structure of each membrane includes proteins, lipids and carbohydrates. Proteins make 50-60 % of its weight, lipids - 30-40 %, and carbohydrates - 5-10 %. Cell membrane is about 7,5 nm thick and appears as a trilaminar structure of two thin, dense lines with an intervening light area. It is known that this trilaminar structure is produced by the arrangement of phospholipid molecules that constitute the basic framework of the membrane. The inner (cytoplasmic) dense line is inner leaflet, the outer dense line is its outer leaflet. Each leaflet is composed of a single layer of phospholipids. Each phospholipid molecule consists of an enlarge head composed of glycerol and of a thin tail. The head end

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is also called the polar end while the tail end is the non-polar end. The head end is soluble in water and is referred to as hydrophilic. The tail end is insoluble and is referred to as hydrophobic. The dark staining part of the membrane are formed by the heads of the molecules, while the light staining intermediate zone is occupied by the tails, thus giving the membrane its trilaminar appearance. The nonpolar fatty acyl tails of the two layers face each other within the membrane form weak noncovalent bonds with each other, holding the bilayer together. Because the phospholipid molecule is composed of a hydrophilic head and a hydrophobic tail, the molecule is said to be amphipathic. Other amphipathic molecules, such as glycol-ipids and cholesterol, are also present in the cell membrane. In addition to these molecules of phospho-lipids the cell membrane contains several proteins. They either span the entire lipid bilayer as integral proteins (transmembrane proteins) or are attached to the cytoplasmic aspects of the lipid bilayer as periph-eral proteins. The proteins are present in the form of irregular rounded masses and have the ability to float like icebergs in the sea of phospholipids. This model is referred to as the fluid mosaic model of membrane structure (model of Singer-Nikolson).

The proteins of the membrane are of great significance as follows.1. They may form an essential part of the structure of the membrane i.e., they may be structural proteins.2. Some proteins (carrier proteins) play a vital role in transport across the membrane and act as pumps. Ions get attached to the protein on one surface and move with the protein to the other surface.3. Some proteins (channel proteins) are so shaped that they form passive channels through the mem-brane.4. Other proteins act as receptors (receptor proteins) for specific hormones or neurotransmitters.5. Some proteins act as enzymes (enzyme proteins).

Membranes permeability depends on cholesterol: the more cholesterol in structure of a membrane, the macromolecular proteins complexes in a bilipid layer easier move. Molecules of proteins also have the polar and non-polar part. The polar part of proteins is inverted to polar head of lipids, and non-polar part to non-polar tail of lipids.

Carbohydrates are present at the surface of the plasma membrane. They are attached either to the transmembrane proteins (forming glycoproteins) or to the lipids (forming glycolipids). The carbohydrate layer is specially well developed on the external surface of the plasma membrane forming the cell bound-ary. This layer is referred to as the cell coat or glycocalyx. The most important function of the glycocalyx is protection of the cell from interaction with inappropriate proteins, from chemical injury, and from physical injury. Other cell coat function includes cell-cell recognition and adhesion, as occurs between endothelial cells and neutrophils. Oligosaccharidic chains of glycocalix are individual for each cell, by means of which cell distinguish each other and the microenviroranent.

Under the cell membrane lies a cortical layer of cytoplasm. This part of cytoplasm has higher den-sity or viscosity as contains a plenty of microfilaments and microtubules. They carry out function of a cy-toskeleton, participate in exocytosis and in moving integrated proteis of plasmalemma.

The plasmalemma and other membranes of a cell carry out some the important functions:1. Barrier. The plasmalemma separates a cell from an environment and other cells, the nucleus is

separated from cytoplasm, a membranes organelles - from gyaloplasm.2. Receptor on a surface of plasmolemma. There are special structures - receptors due to which the

cell finds out various chemical substances, physical factors, other cells, hormones, antigenes. A roll of re-ceptors play glycoproteins and glycolipids of the cytoplasms located on a surface of a membrane more of-ten. Stimulation of such receptors can profound effects on the activity of the cell.

Enzymes present within the membrane may be similarly activated. One important enzyme associ-ated with the plasma membrane is adenylate cyclasa. Activation of this enzyme leads to changes in con-centration of cyclic adenosine monophosphate (AMN) within the cell. This profoundly influences impor-tant functions like DNA synthesis and protein synthesis.

3. Transport - through a membrane of a cell freely pass water, salts and substances with low molecular weight. Such transport is called passive. But the alive membrane differs from lifeless, that can carry out active transport of substances against a gradient of concentration, i.e. to transport molecules from the environment with low concentration of substance to environment with higher concentration. As an example sodium pump can serve a potassium.

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Such transport occurs to an expense of energy at disintegration ATP. So molecules, amino acids and other connections are transferred through the passive channels of plasmolemma. An example of ac-tive transport is work of kidneys. Large molecules enter the cell by invaginating part of the cell mem-brane, which first surrounds the molecule and then separates (from the rest of the cell membrane) to form a pinocytotic or endocytic vesicle. This vesicle can move through the cytoplasm to other parts of the cell. The endocytosis is divided into phagocytosis and pinocytosis. The phagocytosis is absorption and diges-tion by a cell of hard substances, bacteria, fragments of other cells. The pinocytosis is absorption by a cell of liquid products. The form of transport is also exocytosis. Molecules produced within the cytoplasm (e.g., secretions) may be enclosed in membranes to form vesicles that approach the cell membrane and fuse with its internal surface. The vesicles then rupture releasing the molecule to the exterior.

During evolutionary development of multicellular organisms intercellular connections or contacts between adjoining cells were formed. Through intercellular contacts an information exchange between cells, a metabolism, passes contractions or nervous pulses takes place. Lateral membrane specialization reveal the presence of junctional complex. 1. Simple contact - membranes of two cells are on distance of 10-12nm in such manner that the glycocalix one cell adjoins with glycocalix of another cell. The basic function is metabolism and information interchange between cells. 2. Zonulae occludentes – also known as tight junctions. Zonula occludens are located between adjacent plasma membranes most typically near the apices of epithelial cells. They form a "belt-like" junction that encircles the entire circumference of the cell. In electron micrographs, the adjoining cell membranes approximate each other; their outer leaflets fuse, then diverge, then fuse again several times within a distance of 0.1 to 0.3 microns. At the fu-sion sites, claudrins and occludins, transmembrane junctional proteins lies. Claudrin have more active role because these are the proteins that are probably responsible for the obliteration of the intercellular space by forming the tight junction strands. Claudins are calcium-independent, they do not form strong cell adhesions. As a result, their contact must be reinforced by proteins cadherins. These junctions act as a barriers that prevent the movement of molecules into the intercellular spaces. Apart from epithelial cells, zonulae occludens are also present between endothelial cells. 3. Zonular adherentes are belt-like junctions that assist adjoining cells to adhere to one another. It locate just basal to the zonulae occludentes and also encircle the cell. The intercellular space of 15 to 20 nm between the outer leaflets of the two adjacent сell membrane is occupied by the extracellular moieties of cadherins - transmembrane linker proteins. This junction not only joins the cell membranes to each other but also links the cytoskeleton of the cells via the transmembrane linker proteins. The actin filaments are attached to each other and to the cell membrane by vinculin and -actinin. Apart from epithelial cells zonular adherents are also seen between smooth muscle cells, and between myocytes of cardiac muscle in the region of intercalated discs. 4. Desmosomes (Macu-lae adherens). This is the most common type of tight junction between adjoining cells. A desmosome is a small circumscribed area of attachment - attachment plaques. At the side of a desmosome the plasma membrane (of each cell) is thickened because of the presence of dense layer of protein on its inner sur-face. The thickened areas of the two sides are separated by a gap of 20 nm or more. The region of the gap is rich in a glycoprotein called desmoglein. The thickened areas of two membranes are held together by intermediate filaments of cytokeratin that appear to pass from one membrane to the other across the gap. Closer examination shows, that the filaments do not pass from one cell to the other.

The cytoplasmic aspects of the thickened areas of the cell membrane also gives attachment to nu-merous fibrils that pass into the cytoplasm. Desmosomes are present where strong anchorage between cells is needed. Single sided or hemidesmosomes may be seen at some sites. They are serve to attach the basal cell membrane to the basal lamina. The cytoplasmic aspects of transmembrane linker proteins are attached to the plaque, whereas their extracellular moieties bind to laminin and type IV collagen of the basal lamina. The transmembrane linker proteins of hemidesmosomes are integrins, a family of extracel-lular matrix receptors, whereas those of desmosomes belong to the cadgerin family of cell-to-cell adhe-sion proteins. 5. Gap junctions, also called nexus or communicating junctions, are regions of intercellular communication.

They are widespread in epithelial tissues, in cardiac muscle cells, smooth muscle cells and neu-rons. Gap junctions are built by six closely packed transmembrane proteins connexins that assemble to from structures called connexons, aqueous pores through the plasma membrane extending into the inter-

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cellular space. The two connexons fuse, forming the functional intercellular communication channel. The hydrophilic channel permits the passage of ions, amino acids, cyclic adenosine monophosphate (cAMP) small molecules and hormones. 6. Plasma membrane enfoldings of the basal plasma membrane increase the surface area available for transport. The basal surface of some epithelia, especially those involved in ion transport, possesses multiple enfoldings of the basal plasma membrane. These enfoldings partition the basal cytoplasm and many mitochondria into the finger-like enfoldings. This is the origin of the term stri-ated for kidney tubules and ducts for certain ducts of the pancreas and salivary glands. 7. Synapse - type of contact between two nervous cells or between a nervous cell and a muscle. Through synapses pass ner-vous impulses. In more detail synapses will be investigated in partition "the Nervous tissue".

Except for cells, multicellular organisms contain noncellular structures, which always are derivates of cells or products of their secretion. The sincytium, symplastos and extracellular substance concern to postcellular structures. The symplastos is a large formation with the big mass of cytoplasm and a plenty of nucleus (more ten). An example of symplastos are striated muscle fibers and external layer of placenta trophoblast. The sincytium is a formation, where connection between cells as cytoplasmic pro-cesses stay after cell divisions. Distinguish true sincytium and false. A true sincytium is one of stages in formation of man's sex cells when spermatogones remain connected by bridges from cytoplasm.

False sincytium are, for example, the mesenchyma and a reticular tissue in which cells are bridged in a uniform net by means of the processes. In a light microscope border of cells are not visible. In elecr-ton microgramms it is clear visible, that the plasmolemma of one cell is separated from a plasmolemma another by intercellular contacts. Intercellular substance will consist of fibers and the basic substance and is a product of a secretion of cells. Especially well it is advanced in all kinds of a connecting tissue; inter-cellular substance is the blood plasma and a fluid part of a lymph.

Cell theoryOriginal positions of the modern cellular theory have been incorporated in 1839-1858 years by

works of Shleyden, Shvann and Virhov. They say:1. A cell is the smallest structurally functional, biological and genetical alive unit. All animal and

plants will consist of cells. Outside of a cell there is no life. Even the life cycle of a virus is connected only to a living cell.

2. Animal and plant cells are homologous (similar) on a construction and carried out functions.3. Appearance of new cells descends only by division of an nitial mother cell ("each cell from a

cell" on Vyrkhov).4. Bunches of the cells similar on a constitution and functions combine in a tissue of which organs

consist. The organism is an integrated system, in which tissues and organs are aggregated by nervous and humoral connections.

Cell death may result from accidental cell injury with mechanisms that cause cells to self-destruct. The two different mechanisms of cell death are:

Necrosis, or accidental cell death. Necrosis is a pathologic process. It occurs when cells are ex-posed to an unfavorable physical or chemical environment (e.g., hypothermia, hypoxia, radiation, low pH, cell trauma) that causes acute cellular injury and damage to the plasma membrane. Under physiologic conditions, damage to the plasma membrane may also be initiated by viruses, substances such as comple-ment, or proteins called performs. Rapid cell swelling and lysis are two characteristic features of this process.

Apoptosis. During embryogenesis, many cells, such as those that would give rise to a tail in the human embryo, are driven into the genetically determined process of dying, that is, an active means of programmed cell death (apoptosis). Apoptosis occurs in postnatal as well as in adult stages of life; specifi-cally, older cells (especially mature blood cells) are driven into apoptosis, as are cells that have suc-cumbed to attack by pathogens, such as viruses. Because apoptosis has formidable consequences for the cell involved as well as for the organism, it must be carefully regulated, controlled, and monitored.

The process of apoptosis is regulated by a number of highly conserved genes that code for a fam-ily of enzymes known as caspases, which degrade regulatory and structural proteins in the nucleus and in the cytoplasm. Activation of caspases is induced when certain cytokines, such as tumor necrosis factor (TNF), released by signaling cells, binds to the TNF receptor of the target cell. These TNF receptors are

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transmembrane proteins whose cytoplasmic aspect binds to adapter molecules to which caspases are bound. Once TNF binds to the extracellular moiety of its receptor, the signal is transduced and caspase becomes activated.

The activated caspase is released and, in turn, triggers a cascade of caspases that results in the degradation of chromosomes, nuclear lamins, and cytoskeletal proteins. Finally, the entire cell becomes fragmented.

The cell fragments are then phagocytosed by macrophages. These macrophages do not release cy-tokines that would initiate an inflammatory response.

Organelles and inclusions of the cellIn the cytoplasm of all cells of an organism various constant structures - organelles, and also

changeable formations - inclusions are observed.Organelles constantly present in a cell. These are obligatory microstructures of all cells, carrying

out vital functions.According to the principle of organization organelles are divided into membranous organelles and

non-membranous organelles. Membranous organelles are mitochondrias, a cytoplasmic reticulum, Golgi apparatus, lysosomes and peroxisomes. Non-membranous organellas are ribosomes and polysomes, cen-trioles, a microtubules, microfilaments and intermediate filaments.

In some specialized cells organelles share in formation of the special structures playing the impor-tant role in life activity of a cell. Therefore organelles are sectioned into general purpose organelles, which are in each cell, and organelles of special purpose, which are only in the specialized cells. All set above membranous and non-membranous organelles concern to general purpose organelles. Organelles of special purpose are neurofibrils in nervous cells, myofibrils in muscle cells, cilias and microvilli in an ep-ithelium, etc.

Membranous organellesMembranous organelles are the most part of organelles of a cell.Endoplasmic Reticulum. This complex organelle is involved in the synthesizing, packaging, and

processing of various cell substances. It is a freely anastomosing network (reticulum) of membranes that form vesicles, or cisternae; these may be elongated, flattened, rounded, or tubular. Transfer vesicles bud from the endoplasmic reticulum and cross the intervening cytoplasm, delivering their contents to the Golgi complex for further processing or packaging. In mature cells, endoplasmic reticulum occurs in two forms: rough and smooth.

Rough endoplasmic reticulum also called granular endoplasmic reticulum, is studded with ribo-somes in polysomal clusters. Rough endoplasmic reticulum cisternae are typically parallel, flattened, and elongated, especially in cells specialized for protein secretion (pancreatic acinar cells, plasma cells), in which the rough endoplasmic reticulum is particularly abundant. Proteins unique to rough endoplasmic reticulum membranes include docking protein and ribophorins.

The rough endoplasmic reticulum synthesizes proteins for sequestration from the cytoplasm, in-cluding secretory proteins such as collagen, proteins for insertion into cell membranes (integral proteins) and lysosomal enzymes.

The rough endoplasmic reticulum is suspended in the cytoplasm and shows continuity with the nuclear envelope's outer membrane.The RER in protein-secreting epithelial cells often lies in the basal cytoplasm, between the plasma membrane and the nucleus.

Smooth endoplasmic reticulum lacks ribosomes and thus appears smooth in electron micrographs. Smooth endoplasmic reticulum cisternae пае are more tubular or vesicular than those of the rough endo-plasmic reticulum. Smooth endoplasmic reticulum stains poorly, if at all; thus, with the light microscope, it is indistinguishable from the rest of the cytoplasm.

Because it lacks ribosomes, smooth endoplasmic reticulum cannot synthesize proteins. It has many enzymes that are important in lipid metabolism, steroid hormone synthesis, glycogen breakdown (glucose-6-phosphatase), and detoxification. The last occurs by means of enzymatic conjugation, oxida-tion, and methylation of potentially toxic substances.

The smooth endoplasmic reticulum is suspended in the cytoplasm of many cells and is especially abundant in cells synthesizing steroid hormones (in the adrenal cortex and gonads). It is also abundant in

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liver cells (hepatocytes), where it is involved in glycogen metabolism and drug detoxification. Specialized smooth endoplasmic reticulum termed sarcoplasmic reticulum is found in striated muscle cells, where it regulates muscle contraction by sequestering and releasing calcium ions.

Golgi apparatus. The Golgi apparatus for the first time have been described in 1898 by the Italian scientist Kamillo Golgi. Having applied a method of an impregnation (interlinking of salts of heavy met-als - for example osmium or silver with membranes of cells), he has found in cytoplasm around of a nu-cleus of nervous cells formation as a reticulum consisting of dark strands and beads. Later similar frames have been described in all animal cells. The Golgi apparatus participates in many activities, particularly those associated with secretion. It is a focal point of membrane flow and vesicle traffic among organelles.

This membranous organelle comprises three major compart-ments: (1) a stack of 3 to 10 discrete, slightly curved, flattened cistemae; (2) numerous small vesicles peripheral to the stack; and (3) a few large condensing vacuoles at the concave surface of the stack. The cis face (convex face, forming face) of the stack is usually closest to adjacent dilated endoplasmic reticulum cis-temae and is surrounded by transfermembranous organelle comprises three major compartments: (1) a stack of 3 to 10 discrete, slightly curved, flattened cistemae; (2) numerous small vesicles peripheral to the stack; and (3) a few large condensing vacuoles at the concave surface of the stack. The cis face (convex face, forming face) of the stack is usually closest to adjacent dilated endoplasmic reticulum cistemae and is

surrounded by transfer vesicles. Its cistemae stain darkly with osmium. The trans face (concave face ma-turing face) often harbors several condensing vacuoles and generally faces away from the nucleus. It is connected to a system of tubules and vesicles called the trans Golgi network, from which secretory and transfer vesicles exit.

Main functions are:1. Polysaccharide synthesis. The Golgi complex contains glycosyl-transferases that initiate, lengthen, or shorten polysaccharide or oligosaccharide chains one sugar at a time.2. Modification of secretory products. The cis Golgi contains enzymes that glycosylate proteins and lipids and sulfate glycosaminogly-cans. It is thus important in synthesizing secretory glycoproteins, proteoglycans, glycolipids, and sulfated glycosaminoglycans.3. Sorting of secretory products. Products synthesized by the rough endoplasmic reticulum and modified in the cis Golgi are sorted in the trans Golgi network. For example, lysosomal enzymes marked with mannose-6-phosphate and secretory proteins destined for constitutive versus regulated exocytosis are segregated into different vesicles.4. Packaging of secretory products. The trans Golgi network packages the segregated products into vesicles. These secretory vesicles, or se-cretory granules, are transported to the plasma membrane for exocytosis.5. Concentration and storage of secretory products. The Golgi complexes of some cells concentrate and store secretory products prior to secretion. Concentration is a major function of the condensing vacuoles of the trans Golgi network, which also often serve as precursors to secretory granules.

Golgi complex typically is near the nucleus (juxtanuclear) and is often found near centrioles (which have a role in directing vesicle traffic). Golgi complexes are best developed in neurons and glan-dular cells, which are specialized for secretion. Secretory materials have long been thought to follow a one-way route (cis to trans) through the Golgi complex. This view currently seems to be an oversimplification. Golgi-associated vesicles differ in their source, destination, function, contents, and surface composition. Certain nonclathrin, vesicle-coating

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proteins are associated with specific Golgi complex regions, suggesting that various vesicle types fuse with, and bud from, the cis, trans, or intermediate Golgi membranes.

Lysosomes are spherical, membrane-limited vesicles that may contain more than 50 enzymes each and function as the cellular digestive system. Their enzyme activities distinguish them from other cellular granules. The enzyme most widely used to identify them is acid phosphatase because it occurs almost ex-clusively in lysosomes. Other common enzymes in lysosomes include ribonucleases, deoxyribonu-cleases, cathepsins, sulfatases, beta-glucuronidase, phospholipases, various proteases, glucosidases, and lipases. An inherited deficiency or lack of a particular lysosomal enzyme can result in life-threatening ac-cumulations of its substrate in the cytoplasm. Lysosomal enzymes usually occur as glycoproteins and are most active at acidic pH. Lysosomes occur in various sizes and electron densities depending on their ac-tivity.

Primary lysosomes are small (5-8 nm in diameter), with electron-dense contents; they appear as solid black circles in electron microscope. Enzymes in this storage form of lysosomes are mostly inactive. Lysosomal enzymes synthesized and core glycosylated in the rough endoplasmic reticulum are trans-ferred to the Golgi complex for further glycosylation and packaging in vesicles. Primary lysosomes, dis-perse through the cytoplasm. They occur in most cells but are abundant in phagocytic cells (macrophages, neutrophils).

Secondary lysosomes are larger, less electron-dense. They form by the fusion of one or more pri-mary lysosomes with a phagosome. Their primary function is digesting products of heterophagy and au-tophagy. Lysosomal enzymes that mix with phagosome contens become active. Digestion produces me-tabolites for cell maintenance and growth (small molecules diffuse into the surrounding cytoplasm) and aids in organelle turnover. Lysosomal enzymes also catabolize some cell synthesis products, thus regulat-ing the quality and quantity of secretory material. Secondary lysosomes occur throughout the cytoplasm in many cells, in numbers that reflect the cell's lysosomal and phagocytic activity.

Residual bodies are membrane-limited inclusions of various sizes and electron densities associated with the terminal phases of lysosome function. They contain indigestible materials, such as pigments, crystals, and certain lipids. Some cells (macrophages) expel residual bodies as waste, but long-lived cells (nerve, muscle) accumulate them. In the latter, waste-containing residual bodies reflect cellular aging and are termed lipofuscin granules. These granules appear yellow-brown in light microscopy and as electron-dense particles in electron microscope.

Peroxisomes are membrane-limited, enzyme-containing vesicles slightly larger than primary lyso-somes. In rats, they differ from lysosomes because of their electron-dense, granular urate oxidase nu-cleoid. Peroxisomes function in hydrogen peroxide metabolism. They contain urate oxidase, hydroxyacid oxidase, and D-amino acid oxidase, which produce hydrogen peroxide capable of killing bacteria; they also contain catalase, which oxidizes various substrates and uses the hydrogen removed in the process to convert toxic hydrogen peroxide to water. Peroxisomes also participate in gluconeogenesis by assisting in fatty acid oxidation. They occur dispersed in the cytoplasm or in association with smooth endoplasmic reticulum.

Mitochondria generate the cell's energy. Mitochondria are comparable to bacteria in size (typically 2-6 nm in length and 0.2 nm in diameter), and have various shapes (spherical, ovoid, fila-mentous). Each mitochondrion is bounded by two unit mem-branes.

Outer mitochondrial membrane has a smooth contour and forms a continuous but porous covering. It is permeable to small molecules (<5 kDa) owing to large channel-forming proteins called porins.

Inner mitochondrial membrane is less porous (semiperme-able) and has many infoldings, or cristae. The cristae of most mi-tochondria are shelflike, but in steroid-secreting cells are tubular. The inner surface is covered by inner membrane subunits, also called Fl subunits (or lollipops, because of their shape); these are

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sites of mitochondrial ATP synthase activity. Intercalated within the inner membrane are components of the electron transport system, including enzymes and cofactors that have important roles in mitochondrial function (cytochromes, proton pumps, dehydrogenases, flavoproteins). Mitochondrial ribosomes also as-sociate with the inner surface.

The mitochondrial membranes create two membrane-limited spaces. The intermembrane space is located between the inner and outer membranes and is continuous with the intracristal space, which ex-tends into the cristae. The intercristal space, or matrix space is enclosed by the inner membrane and con-tains the mitochondrial matrix.

Mitochondrial matrix contains water, solutes, and large matrix granules, which play a role in mito-chondrial calcium ion concentration. It also contains circular DNA and mitochondrial ribosomes similar to those of bacteria. The matrix contains numerous soluble enzymes involved in such specialized mito-chondrial functions as the citric acid (Krebs, tricarboxylic acid) cycle, lipid oxidation, and mitochondrial protein and DNA synthesis.

Mitochondria provide energy for chemical and mechanical work by storing energy generated from cellular metabolites in the high-energy bonds of ATP. Energy is generated by oxidative phosphorylation. ATP leaves the mitochondria and releases its stored energy at a variety of intracellular sites. Mitochon-dria synthesize their own DNA and some proteins. They grow and reproduce by fission or budding and can undergo rapid movement and shape changes.

Mitochondria occur in nearly all eukaryotic cells, and in most are dispersed throughout the cyto-plasm. They accumulate in cell types and intracellular regions with high energy requirements. Cardiac muscle cells are notable for abundant mitochondria. Epithelial cells lining kidney tubules have abundant mitochondria interdigitated between basal plasma membrane infoldings, where active ion and water trans-port occcurs.

Non-membranous organellesRibosomes. These protein-synthesizing organelles has two unequal ribosomal subunits, named for

their ultracentrifugal sedimentation (but often called simply "large" and "small"). Cytoplasmic ribosomes are composed of ribosomal RNA (rRNA) synthesized in the nucleolus and many proteins synthesized in the cytoplasm. They are intensely basophilic. Light microscopy reveals cytoplasmic accumulations of ri-bosomes as basophilic patches, formerly termed ergastoplasm in glandular cells and Nissi bodies in neu-rons. In electron microscope ribosomes appear as small, electron-dense cytoplasmic granules.

Cytoplasmic ribosomes occur in two forms. Free ribosomes are dispersed in cytoplasm. Polyribo-somes, or polysomes, are ribosomes attached to a single strand of messenger RNA (mRNA), permitting synthesis of multiple copies of a protein from the same message. Ribosomes read (translate) the mRNA code and thus play a critical role in assembling amino acids into specific proteins. Polysomes occur free in the cytoplasm (free polysomes) and attached to membranes of the rough endoplasmic reticulum; free polysomes synthesize structural proteins and enzymes for intracellular use. Polysomes of rough endoplas-mic reticulum synthesize proteins to be secreted or sequestered. Various signal sequences are encoded in the 5` end of mRNAs, helping to direct the proteins that contain them to different organelles. The signal sequences directing secretory proteins to the rough endoplasmic reticulum. Other signal sequences direct proteins to, and help them enter, the nucleus, mitochondria, and peroxisomes.

Centriole is a cylinder of microtubules, 150 nm in overall diameter and 350- to 500-nm long, containing nine microtubule triplets in a pinwheel array. Each micro-tubule in a triplet shares a portion of its neighbor's wall. An interphase (nondividing) cell has a pair of adjacent centrioles with perpendicular long axes, each surrounded by several electron-dense satellites, or pericentriolar bodies containing y-tubulin. Cyto-plasmic microtubules radiate from the pericentriolar bodies into the cytoplasm.

Centrioles are the cell's structural organizers. Centriole duplication is required for cell division. During mitosis, the centrioles organize the mitotic spindle. Even in vitro, isolated centrioles control microtubule polymerization; in the cell, centrioles transmit physical organizing forces by means of the microtubules radiating from the pericentriolar bodies. Through their effects on microtubules, centrioles control organelle, vesicle, and granule traffic within the cell. Centrioles also give rise to basal bodies. However, centrioles are not nucle-

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ation sites for cytoplasmic microtubules; the y-tubulin rings in the pericentriolar bodies serve this func-tion.

Between cell divisions, centrioles lie near the nucleus, often surrounded by Golgi complexes. The centrioles and associated Golgi apparatus constitute the centrosome (cell center), which appears as a clear juxtanuclear zone. During the S phase of interphase, each centriole duplicates, forming a procentriole per-pendicular to the original. During mitosis, new centriole pairs migrate to opposite cell poles to organize the spindle.

Mitotic Spindle Apparatus: In preparation for mitosis cytoplasmic microtubules depolymerize and repolymerize as the mitotic spindle apparatus. This spindle-shaped microtubule array occurs between two centriole pairs at opposite poles of mitotic cells. Some spindle microtubules (continuous fibers) extend from centriole to centriole. Others (chromosomal fibers) extend from one centritile to the centromere of a chromosome at the equatorial plate. The spindle apparatus is crucial for chromosome separation during mitosis.

Cytoskeleton is a mesh of filamentous elements called microtubules, microfilaments, and interme-diate filaments, provides structural stability for the maintenance of cell shape. It is also important in cell movement and in the rearrangement of cytoplasmic components.

Microtubules are the thickest (24-nm diameter) cytoskele components. In electron microscope these fine tubular structures vary in length and have dense walls (5-nm thick) and a clear internal space (14 nm across). The walls consist of subunits called tubulin heterodimers, each of which comprises one a-tubulin and one - tubulin protein molecule. The tubulin heterodimers are arranged in threadlike polymers called protofilaments, 13 of which align parallel to one another to form the wall of each microtubule. Each microtubule is polarized, with a plus (+) and minus (-) end. In vivo, they exist in a state of dynamic instability, undergoing abrupt changes in length through changes in the balance between polymerization and depolymerization.

Microtubules form a remarkable network of roadways in the cell, deploy cytoplasmic organelles (including the endoplasmic reticulum and Golgi apparatus), shuttle vesicles from one part of the cell to anoth and move chromosomes during mitosis. Their instability is critical to faction. The drug known as Taxol interrupts their function by permanently stabilizing them and leads to cell death. Most microtubules anchor by their minus ends in y-tubulin rings that act as nucleation sites in the cytocenter, a juxtanuclear region containing the centrioles. Stabilized microtubules acquire ATPase-containing molecular motors (kinesin and dynein) capable of binding cellular structures and “walking” them along the microtubules, provide an intracellular transport system. Kinesin carries its cargoes mainly toward the plus end, and dynein toward the minus end, of stabilized microtubules. Different motors appear to exist for each type of organelle or vesicle. Thus microtubule struts that spread the endoplasmic reticulum through the cytoplasm withthe aid of kinesin, when exposed to colchicine (a drug causing net microtubule depolymerization), col-lapse, allowing the endoplasmic reticulum to collapse around the nucleus. Conversely, dynein-assisted ag-gregation of the Golgi complex toward the nucleus fails, causing Golgi dispersion, in the presence of the same drug.

Microtubules originate repeatedly from the cytocenter, growing outward through the cytoplasm and retracting if they fail to connect. Microtubules supports organelle deployment and vesicle traffic throughout the cell. Stabilized microtubule arrays occur in cilia, flagella, basal bodies, centrioles, and the mitotic spindle apparatus.

Microfilaments are the thinnest cytoskeletal elements (5- to 7 nm wide) and are more flexible than microtubules. They are filamentous polymers of one of several types of globular actin protein monomers. In striated muscle cells, actin filaments form a stable paracrystalline array association with myosin fila-ments. Actin filaments in other cells are less stable and can dissociate and reassemble. These changes are regulated in part by calcium ions, cyclic adenosine monophosphate (AMP), and by a host of actin-binding proteins in the cytoplasm. In addition to their effects on polymerization and depolymerization, actin-bind-ing proteins arrange microfilaments into the networks and bundles that carry out many of their important functions.

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Microfilaments are contractile, but to contract they must interact with myosin. In muscle cells, myosin forms thick filaments. In nonmuscle cells, it exists in soluble form and binds to microfilaments by its globular head, leaving its tail (free end) to attach to the plasma membrane or other cellular components to move them. Treatment with cytochalasins disrupts microfilament organization and interferes with the following functions: endocytosis; exocytosis; formation and contraction of microvilli; cell movement; movement of organelles, vesicles, and granules cytoplasmic streaming; maintenance of cell shape; and equatorial constriction of dividing cells.

In nonmuscle cells, microfilaments are distributed as an irregular mesh throughout the cytoplasm. Local accumulations occur as parallel strands in cores of microvilli; in the cytoplasm at the leading edge of pseudopods; in association with the plasma membrane, organelles or other cytoplasmic components; or as a belt ("purse string") aroundl equator of dividing cells.

Intermediate filaments are ropelike and composed of shorter threadlike protein subunits assembled and twisted around one another to form filaments of intermediate thickness (10-12 nm) between micro-tubules and microfilaments. Their protein subunits are globular at their amino and carboxy terminals, with an elongated, linear central domain. The individual proteins differ depending on the cell type.Examples: cytokeratins in epithelial cells, vimentin in mesenchymally derived cells (fibroblasts, chondrocytes), desmin in muscle cells, glial fibrillary acidic protein in glial cells, and neurofilaments (intermediate fila-ment bundles) in neurons. The stability and longevity of these proteins, together with their cell-type speci-ficity, make them particularly useful in determining the origin of neoplastic cells.

Intermediate filaments are notable for their tensile strength and durability. Their abundance in cells subjected to mechanical stress (cells of skin, connective tissue, and muscle) indicates that they play a role in stabilizing cell structure and in the many functions that depend on maintaining cell shape.

In most cells, intermediate filaments form a network surrounding the nucleus and extend through-out the cytoplasm. Their ordered arrangement in certain cells (neurons and keratinocytes of the skin) re-flects their special role in maintaining cell shape. Cytokeratin-containing tonofilaments of desmosomes are a good example of such arrangement.

Cilia: Cilia is hair-like projections from the free surfaces of some epithelial cells. In the living cili-ated cell typically has hundreds of cilia, which are motile, 5- to 10-nm long, 0,25 nm wide, cell-surface evaginations covered by plasma membrane. The free part of each cilium is called the shaft. The region of attachment of the shaft to the cell surface is called the base (also called the basal body, basal granule, or kinetosome). The free end of the shaft tapers to a tip. In structure the cilium consists of (I) an outer cover-ing which is formed by an extension of the cell membrane; and (II) an inner core or axoneme, composed of nine peripheral microtubule doublets surrounding a pair of unjoined microtubules (the "9 + 2" arrange-ment). The peripheral doublets consist of a full A microtubule and a partial A microtubule. Attached to each A microtubule are two dynein arms, which interact with the A microtubule in the adjacent doublet and drive the sliding of the doublets past one another. Other proteins that crosslink the doublets prevent simple sliding and convert the motion into bending. Ciliary movement occurs in two phases: a forward power stroke, in which the distal part of the cilium remains straight and rigid, and a return or recovery stroke, in which the cilium is more flexible and bent.

Tne cilia lining an epithelial surface move in coordination with one another the total effect being that like a wave. Asa result fluid, mucous, or small solid objects lying on the epithelium can be caused to move in a specific direction. Movements of cilia lining the respiratory epithelium help to move secretions in the trachea and bronchi towards the pharynx. Ciliary action helps in the movement of ova through the uterine tube, and оf spermatozoa through the male genital tract.

In some situations there are cilia-like structures that perform a sensorу function. They may be non-motile, but can be bent by external influences. Such “cilia” present on the cells in the olfactory mu-cosa of the nose are called olfactory cilia: they are receptors for smell. Similar structures called kinocilia are present in some parts of the internal ear. In some regions there are hair-like projections called stere-ocilia these are not cilia at all, but are large microvilli.

Flagella is similar to a cilium but it is longer and typically оnly one or two are present in a cell. The movements of flagella are different from those of cilia. In a flagellum movement starts at its base. The segment nearest the base bends in one direction. This is followed by bending of succeeding segments

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in opposite directions so that a wave like motion passes down the flagellum. In mammals, flagella occur in the tails of spermatozoa, which typically are 50-to 55m long and 0.2- to 0.5m thick along most of their length. The axoneme of a flagellum is identical to that of a cilium but is separated from the surrounding plasma membrane by large protein masses. Flagellar movement resembles a turning corkscrew more than the whiplike action of the cilia.

Basal Bodies. In cells bearing cilia or flagella, centrioles migrate to the apical plasma membrane and give rise to basal bodies as in centriole self-duplication. Basal bodies are structurally similar to centri-oles, with nine microtubule triplets. They are located in the cytoplasm—one at the base of each cilium or flagellum—and serve as the anchoring points and microtubule organizers for these structures.

Microvilii are finger-like projections from the cell surface that can be seen only with the electron microscope. Each microvillus consists of an outer covering of plasma membrane and a cytoplasmic core in which there are numerous microfilaments. Numerous enzymes have been located in microvilii.

With the light microscope the free borders of epithelial cells lining the small intestine appear to be thickened: the thickening has striations perpendicular to the surface. In some cells the microvilii are not arranged so regularly. With the light microscope the microvilii of such cells give the appearance of a brush border. Microvilii greatly increase the surface area of the cell and are, therefore, seen most typically at sites of active absorption e.g., the intestine, and the proximal and distal convoluted tubules of the kid-neys. Modified microvilii called stereocilia are seen on receptor cells in the internal ear, and on the ep-ithelium of the epididymis.

InclusionsInclusions are changeable ingredients of cytoplasm. They divides into: .1 trophic, 2. pigmen, 3. se-

cretory, 4. excretory inclusions. Trophic or nutrient inclusions can be introduced to lipids, carbohydrates, proteins or their com-

plexes. An example of trophic incorporations can be inclusions in adipose cells as separate shallow drops or one drop of lipid. At nutrient lack of an organism these drops solve. In a liver cells, in muscles trophic inclusions are introduced by carbohydrates - glycogen, which can turn to the glucose necessary for a feed-ing. Glycogen granules are PAS-positive in light microscopy and appear in electron microscope as rosettes of electron-dense particles. In female sex cells in composition of the trophic inclusions, necessary for development of an embryos, protein vitellin in a complex with lipids.

Pigmen inclusions are divided on exogenous - acting in an organism from an external environ-ment, and endogenic - developed inside an organism. From endogenic pigments the most wide-spread is melanin. It is brown or black colour pigment often found in electron-dense, membrane-limited granules termed melanosomes, which is synthesized in cells melanocytes and imbues a skin, brows, a hair eye-lashes, an iris of the eye of an eye of the person. The pigment of red colour contains in erythrocytes of a blood - a haemoglobin and in muscles - myoglobin. Pigments of yellow colour are in agin cells a lipofus -cin (a pigment of aging), in a liver, in bile - abilirubin, in an ovary - lutein.|

Secretory inclusions it is products of life activity of the cells, necessary for an organism. Secrets are, for example, the gastric juice, a spit, coliform juice, bile, etc. In relation to hormones which also are necessary for an organism, the term not a secret, and an incretion as they are secreted in an internal envi -ronment of an organism, for ехample, a blood and a lymph is sometimes applied.

Excretory inclusions are products of life activity of a cell, which should be removed from a cell for its normal metabolism (for example nitrogen compounds which are toxic for an organism).

Nucleus of a cellNucleus of a cell is obligatory structure of of all eucaryotic cells in which DNA is detached from

cytoplasm. The nucleus constitutes the central, more dense part of the cell. It is usually rounded or ellip-soid. Occasionally it may be elongated, indented or lobed. It is usually 4-10 nm in diameter. The nucleus contains inherited information, which is necessary for directing the activities of the cell. Nuclei vary in appearance from tissue to tissue, from cell to cell, and during different phases of the cell cycle. Although some mature cell types (erythrocytes) lack nuclei, at least one nucleus is present during at least one stage in all yotic cells. The microscopic appearance of the nucleus is important in identifying and classifying both normal and diseased cells and tissues. Nuclei display wide variations in:

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1. Nuclear size. The size of the nucleus varies, both in absolute terms end relative to the amount of cy-toplasm in the cell (nucleocytoplasmic ratio).2. Number per cell. Cells may be enucleate, mononucleate, binucleate, or multinucleate.3. Chromatin pattern. The amount and distribution of heterochromatin varies according to cell type and cellular activity.4. Nuclear location. The relative position of a nucleus within a cell varies according to cell type and may be basal, central, or eccentric.

The nucleus contains in its chromatin a linear code (DNA) for the synthesis of cell components and products, which confers on the cell a range of adaptability to changing environmental con-ditions and to extrinsic signals such as hormones. It is also indis-pensable for cellular reproduction, which occurs through a succes-sion of nuclear and cytoplasmic changes comprising the cell-divi-sion cycle (or cell cycle). This cycle ends with mitosis (cell divi-sion), which produces two identical daughter cells from a single parent. Continuous cycling occurs only with the presence and ac-tivity of regulatory molecules that allow progress beyond particular checkpoints. Each nucleus has a nuclear envelope chromatin, one to several nucleoli, and avariable amount of nucleoplasm.

The nuclear contents are set apart from the cytoplasm by a double membrane called the nuclear envelope and a narrow (40 to 70 nm) intermembrane space called the perinuclear cisterna, or

perinuclear space. The nuclear envelope's outer surface (external surface) often is peppered with ribo-somes and shows occasional continuities with the rough endoplasmic reticulum.

The inside of the inner membrane (internal surface) is lined with a fibrous lamina, which consists of proteins called lamins. Cells contain as many as five distinct lamin proteins of two types, A or B, which are structurally related to the cytoplasmic intermediate filament proteins (vimentin and desmin). Lamins form networks that organize the nuclear envelope as well as interactions between the envelope and the chromatin; thus lamins may regulate the size, shape, and chromatin pattern of the nucleus and may affect transcription. Associations between lamins and other nuclear components are regulated by en-zymatic phosphocleosomes contains an additional 48 base pairs. Another histone (usually HI) binds to the nucleosome surface and to the linker. The HI histone appears to help the beaded strand coil into a 30-nm thick superhelix with six nucleosomes per turn (a selenoid). Further coiling of the selenoid is required to form the condensed form of chromatin (heterochromatin).

At several points the inner and outer layers of the nuclear membrane fuse leaving gaps called nu-clear pores. Each pore is surrounded by dense protein: the region of dense protein and the pore toghether form the pore complex. Nuclear pores represent sites at which substances can pass from the nucleus to the cytoplasm and vice versa. The nuclear pore is about 80 nm across. It is partly covered by a diaphragm, which allows passage only to particles less than 9 nm in diameter. A typical nucleus has 3000 to 4000 pores.

Nuclei containing following chromatin types: heterochromatin stain darkly with basic dyes. Be-cause the DNA of chromatin must uncoil to be transcribed, dark-staining (heterochromatic) nuclei reflect less DNA transcription activity and the use of less of their total genome. Uncoiled chromatin, termed eu-chromatin, stains poorly and is difficult to distinguish even by electron microscopy.

Large, pale-staining (euchromatic) nuclei usually indicate more transcriptional activity and contin-uous cell division. Nuclei which are large and in which relatively large areas of euchromatin can be seen are referred to as open-faced nuclei. Nuclei which are made up mainly of heterochromatin are referred to as closed-face nuclei.

The amount and distribution of nuclear chromatin are often used to identify cell types, especially in cells with no characteristic cytoplasmic staining properties. Even in mostly euchromatic nuclei, a rim of heterochromatin is often found on the inner surface of the nuclear envelope associated with the fibrous

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lamina. This envelope-associated heterochromatin allows the nuclear boundary to be seen with the light microscope.

Chromosomes are the most condensed form of chromatin and are visible during mitosis. To form chromosomes, solenoids coil further and wind on a central nonhistone protein scaffold. Of the 46 chromo-somes present in human cells, 44 (the somatic chromosomes) occur in 22 structurally similar (homolo-gous) pairs. The other pair (sex chromosomes) consists of dissimilar chromosomes (XY) in males and similar chromosomes (XX) in females. In females, only one X chromosome (either of the two) is used by each cell; the inactive X is often visible as a clump of heterochromatin, termed sex chromatin, or the Barr body. In most cells, the Barr body attaches to the nuclear envelope's inner surface. In a neutrophilic leukocyte, it may appear as a drumstick-shaped appendage of the lobulated nucleus.

Each chromosome consists of two parallel rodlike elements that are called chromatids The two chromatids are joined to each other at a narrow area, which is light staining and is called the centromere (or kinetochorej Typically the centromere is not midway between the two ends of the chromatids, but somewhat towards one end. As a result each chromatid can be said to have a long arm and a short arm. Such chromosomes are described as being submetacentric (when the two arms are only slightly different in length); or as acrocentric (when the difference is marked). In some chromosomes the two arms are of equal length: such chromosomes are described as metacentric. Finally, in some chromosomes the cen-tromere may lie at one end: such a chromosome is described as telocentric.

Differences in the total length of chromosomes, and in the position of the centromere are impor-tant factors in distinguishing individual chromosomes from each other. Additional help in identification is obtained by the presence in some chromosomes of secondary constrictions. Such constrictions lie near one end of the chromatid. The part of the chromatid “distal” to the constriction may appear to be a rounded body almost separate from the rest of the chromatid: such regions are called satellite bodies. (Secondary constrictions are concerned with the formation of nucleoli and are, therefore, called nucleolar organizing centres).

Cell's karyotype is its chromosome inventory or an image of its chromosomes arranged by type. Preparing such an image is called karyotyping. Cells in culture are stimulated to enter mitosis with phyto-hemagglutinin (a plant-derived mitogen).

The dividing cells are treated with colchicine to arrest them in metaphase, when the chromosomes are highly coiled and visible. Lysing the cells with a hypotonic solution causes the chromosomes to spread on the slide with little or no overlapping. The chromosome spread is images, and chromosome im-ages are selected, paired, and arranged in a specific sequence. Karyotyping allows chromosome cata-loging to detect structural abnormalities and deleted or excess chromosomes.

Nucleolus. During interphase (between mitoses), each nucleus typically contains a basophilic body called a nucleolus. Nucleoli synthesize most ribosomal RNA (rRNA).

They are usually distinguishable from heterochromatin In ordinary preparations nucleoli can be distinguished from heterochromatin by their rounded shape. (In contrast masses of heterochromatin are very irregular). Nucleolus are larger and more numerous in embryonic cells, in cells actively synthesizing proteins, and in rapidly growing malignant tumor cells. Some heterochromatin attaches to the nucleolus; the significance of this nucleolus-associated chromatin is unknown.

The nucleolus disappears in preparation for mitosis and reappears after mitosis is completed. Dis-tinct nucleolar components can be seen with the electron microscope:

1. Pars amorpha: This pale-staining nucleolar region contains the nucleolar organizer DNA, which carries the code for rRNA. In humans, five chromosome pairs have nucleolar organizer regions; thus 10 nucleoli per cell are possible, but fusion of the organizers into fewer, larger nucleoli is more common. Newly synthesized rRNA first appears in this region.

2. Nucleolonema: This light microscopy term refers to a threadlike basophilic substructure of the nucleolus. It contains two rRNA- rich components distinguishable by electron microscope:

a. The pars fibrosa consists of densely packed ribonucleoprotein fibers that are 5 to 10 nm in di-ameter. These fibers consist of the newly synthesized primary transcripts of the rRNA genes and associ-ated proteins imported from the cytoplasm. Newly synthesized rRNA makes its second appearance in this region.

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b. The pars granulosa contains dense granules, 15 to 20 nm in diameter, that represent maturing ri-bosomal submits undergoing assembly for export to the cytoplasm. Newly synthesized rRNA makes its third appearance in this region.

Parts of the chromosomes located within nucleoli constitute the pars chromosoma of nucleoli. Nu-cleoli are sites where ribosomal RNA is synthesized. The templates for this synthesis are located on the related chromosomes. Ribosomal RNA is at first in the form of long fibres that constitute the fibrous zone of nucleoli. It is then broken up into smaller pieces that constitute the granular zone. Finally, this RNA leaves the nucleolus, passes through a nuclear pore, and enters the cytoplasm where it takes part in protein synthesis.

The nucleoplasm is the matrix in which other intranuclear components are embedded. It consists of enzymatic and nonenzymatic proteins, metabolites, ions, and water. It includes the nuclear matrix, a fibrillar "nucleoskeletal" structure that appears to bind some hormone receptors, and newly synthesized DNA.

Nuclear function:Cellular Reproduction: The reproductive cycle of a cell is termed the cell cycle. Each complete

cycle ends with cell division (mitosis) and yields two daughter cells.Cell cycle includes mitosis and interphase. Early views of if cellular reproduction focused on eas-

ily detected structural changes that occur during mitosis. The apparently inactive phase between succes-sive mitoses seemed a resting period and was dubbed the interphase. Yet, even in rapidly dividing cells, the duration of mitosis is brief compared with the length of interphase. Currently we know that cells carry out important activities during interphase, including those needed to recover from the previous mitosis and to prepare for the next. Both mitosis and interphase currently are viewed as complex and important cell-cycle components and each has been divided into steps to facilitate our understanding.

Steps in cell division (mitosis). Mitosis is a brief, continuous process. Structural changes observed during this complex process have been used to divide it into four successive phases: prophase, metaphase, anaphase, and telophase.

During prophase, chromatin coils to form chromosomes. As the nucleolar organizer DNA coils into its respective chromosomes, the nucleoli disintegrate. The nuclear membrane remains intact. The two centriole pairs migrate to opposite poles of the cell, cytoplasmic microtubules depolymerize, and the mi-totic spindle apparatus begins to assemble between the centriole pairs.

During metaphase, lamin phosphorylation promotes nuclear envelope disintegration. Chromo-somes line up at the cell equator between the centriole pairs, and each chromosome splits lengthwise to form a pair of sister chromatids. Each chromosome has a centromere (late-replicating DNA, or kineto-chore) to which microtubules of the spindle apparatus attach.

During anaphase, replication of kinetochore DNA allows the sister chromatids to separate and move to opposite poles of the now-elliptical cell along the mitotic spindle. The centromere leads, with the chromatin dragging behind, often in a V shape.

During telophase, the chromosomes begin to uncoil. Nucleoli and nuclear envelopes reappear as components of two separate nuclei at opposite ends of the cell. Nuclear envelope reassembly involves the dephosphorylation of nuclear lamins, A purse-string constriction, formed by bands of microfilaments be-neath the plasma membrane, appears at the equator. Tightening of the constriction eventually divides the cytoplasm and organelles between the daughter cells, a process termed cytokinesis, which signals the end of mitosis. After cytokinesis is completed, the spindle apparatus depolymerizes and repolymerizes as the interphase microtubule network. This allows vesicles derived from the Golgi apparatus and endoplasmic reticulum to be reassembledas functional organelles in the daughter cells.

Interphase divides into three phases: G1 S, G2:1. G1 Phase (Presynthesis, gap 1) of interphase follows the telophase of mitosis. RNA and protein

syntheses do occur during the gap phases, and each daughter cell grows to the parent's size. G 1 typically the longest phase of the cycle, is also the most variable in length among different types. In rapidly divid-ing (embryonic and neoplastic) cells, G1 is shot and the transition to subsequent phases is continuous. Cells that are more differentiated may withdraw from the cycle in G1 (and enter a phase called Go, in

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which preparations for mitosis are suspended in favor of specialized functions. G0 cells unable to reenter the cycle (muscle, nerve) are said to be terminally differentiated. Other cells in G0 (hepatocytes, fibrob-lasts) can reenter the cell cycle in response to growth factors encountered during or after an injury.

2. During the S (synthesis) phase, DNA synthesis and replication occur. The centrioles often self-duplicate during this stage.

3. During G2 Phase (Postsynthesis, gap 2), the final preparations for cell division occur; these in-clude repair of damaged DNA, synthesis of tubulin for the spindle apparatus, and ATP accumulation for the energy-expensive mitosis. Very little synthesis occurs during mitosis.

4. Proteins controlling cell-cycle progression. Transitions between cell-cycle phases required for continuous cycling occur only under specific conditions involving the actions of permissive or inhibitory proteins, many of which are highly conserved evolutionarily. Hence, some mammalian cell-cycle-regulat-ing proteins are quite capable of regulating cell-cycle progression in more primitive cells, such as yeast. Cyclin-dependent kinases (Cdks) are enzymes that phosphorylate serine and threonine residues on other proteins, initiating or blocking activities crucial to cell-cycle progression. Cdks are active only when bound to certain cyclins (A, B, C, D, and E) to form Cdk-cyclin complexes. During continuous cycling, intracellular Cdk concentrations tend to be constant, whereas cyclins are so named because their concen-trations rise and fall as the cell progresses through the cycle. Growth factors in a cell's environment can induce cyclin and Cdk synthesis and thus reentry from G0 into active cycling. Cydin-dependent kinase in-hibitors are protein families (Kip/Cip and INK4) whose members are capable of binding to Cdk-cyclin complexes and inhibiting their activity.

5. Cell-cycle checkpoints. Certain "checkpoints" in the cycle are susceptible to control by Cdk-cy-clin complexes. To progress past these points, enough Cdk-cyclin complexes must be present to over-come inhibition; otherwise, progression may be halted either briefly or for extended periods. Not surpris-ingly, some aspects of cell-cycle control involve feedback from specific steps in the cycle itself. In this way, progression occurs only when conditions indicate that the previous phase has been successfully completed. If mitosis is entered before DNA replication is completed, the daughter cells are subject to de-struction or serious genetic damage. Other aspects of cell-cycle control involve signals from the cell's en-vironment. Excessive growth, even when sufficient nutrients and oxygen are present, may compromise tissue function and be detrimental to the entire organism. Hence, there are two main checkpoints in the mammalian cell cycle: one in G1 controlling the onset of DNA synthesis (S phase), and one in G2 control-ling the onset of mitosis (M phase). Each checkpoint requires the presence of a different class of cyclin (cyclins or mitotic cyclins).

Endoproduction it is a type of specific cell division without increasing of their quantity, at which appear cells with enlarged DNA content. Types of it are: endomitosis, polythenia, amitosis. The endomi-tosis is a result of the uncompleted mitosises, at which after DNA reduplication in the synthetic phase of an interphase there is no mitosis. The result of an endomitosis is appearance of polyploidal cells. The polyploidy is an increasing of DNA quantity, aliquot to a haploid number of chromosomes. It meets in norm in liver cells. Polytenia is appearance of huge (polytene) chromosomes. Thus there is a multiple reduplication of strands (chromonemes) of which chromosomes consist. It is observed in cells of salivary glands of double coveredic hexapods (mosquitos). Amitotic division is direct division of a cell by a stran-gulation without a DNA reduplication or with DNA reduplication without formation achromatic spindles. Amitotic division is accompanied division of a cell into two filial by transversal strangulation, or a nu-clear fission without separation of cytoplasm that results in appearance of multinucleate cells. So cells of urinary bladder and cells doomed for destruction, for example cells of embryonic membranes can be di-vided in norm. Amitotic division is not considered a high-grade method of cell division. Fission does not descend precise and a uniform distribution of chromosomes between daughter cells.

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Basic of embryology The embryology is a science, which studies laws of formation of an embryos and process of his

development.Development of living organisms section on historical or evolutionary development - phylogene-

sis and individual development - an ontogenesis. In individual development are two basic stages:1. A prenatal ontogenesis is development till birth.2. Postnatal ontogenesis is development from birth up to death of an individual.

Thus, the embryogenesis (development of an embryos and fetus) is a part of an ontogenesis. Process of human embryonic development grows out the long-lived evolution and in a fixed measure re-flects features of development of other forms of fauna. Some early stages of human development are sim-ilar to analogous stages of an embryogenesis of more lower organized animals. In this connection the study of a human embryogenesis is preceded with an account of bases of a comparative embryology.

In development of embryos some stages characterized by certain quantitative and qualitative changes are observed: 1. fertilization; 2. cleavage and formation of a blastula; 3. gastrulation - formation on germinal (embryonic) layers; 4. development of tissues - a histogenesis; 5. development of organs - organogenesis аnd development of systems - systemogenesis.

In the modern embryology the concept of a progenesis (the pregerminal period) or gametogenesis as the stage preceding naturally to embryonic development is injected. It is the period of maturation and functional formation of sex cells.

Common difference of mature sex cells - gametes from somatic is presence of a haploid number of chromosomes and other nuclear - cytoplasmatic attitude. Two types of sex cells are distinguished:

1. male cell is spermatozoon or sperm cell;2. female cell is ovum or ovocyte.The spermatozoon (spermatozoid) is

a man's gamete which produced in testis. The spermatozoon is an extremely elongated cell (about 65 nm long) consisting of three main components, the head, neck and tail. The tail is subdivided into three segments, the middle piece, principal piece and end piece. The head is the most variable structure between different mammalian species. In humans, the head is about 7 nm long and has a flattened pear shape.

The nucleus, which occupies most of the head, is composed of very condensed chromatin; in humans, this contains a vari-able number of areas of dispersed chromatin called nuclear vacuoles. Surrounding the an-terior two-thirds of the nucleus is the acroso-mal cap, a flattened membrane-bound vesi-cle. It is product of Golgi apparatus.

Acrosome contains a range of glyco-proteins and a variety of hydrolytic enzymes, principally acrosyn (neural proteinase), mu-colytic enzyme hyaluronidase and tripsin, neuraminase, acid phosphotase and other. The enzymes disaggregate the cells of the corona radiata and dissolve the zonapellucida during fertilisa-tion. Cytolemma of the head in the front part contains enzyme glycosyltransferrase, which interacts with ovum reseptors, enabling spermatozoid to recognize female sex cells.

The neck is a very short segment connecting the head with the tail. It contains vestiges of the cen-trioles, one of which gives rise to the axoneme.

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The axoneme has the standard "nine plus two" arrangement of microtubule doublets seen in cilia. The protein of microtubules-tubulin - noncontractive protein, and protein of "arms" - dynein has ATP ac-tivity. Slight displacement of dublicates of microtubules causes the change of the whole fibrillar system and leads to wavy movement of fragellum.

One of the form sterility may be caused by genetic absence of dynein, which result in immobility of spermatozoids.

The axoneme of the neck is surrounded by several condensed fibrous rings. In human spermato-zoa, a significant amount of cytoplasm remains in the neck region.

The middle part, the first part of the tail, is about the same length as the head and consists of the flagellar axoneme surrounded by nine coarse (outer dense) fibres arranged longitudinally. External to this core, elongated mitochondria are arranged in a tightly packed helix providing the energy required for flagellar movement. A fibrous thickening beneath the plasma membrane, called the annulus, prevents the mitochondria from slipping into the principal part. The principal part, which constitutes most of the tail length, consists of a central core, comprising the axoneme and the nine coarse fibres continuing from the middle part. Surrounding this core are numerous fibrous ribs arranged in a circular manner. Two of the longitudinal fibrils of the core are fused with the surrounding ribs so as to form dorsal and ventral col -umns extending throughout the length of the principal part. This arrangement divides the principal part longitudinally into two functional compartments, one containing three coarse fibrils and the other contain-ing four. Little is known of the mechanism of flagellar motion but this asymmetry may account for the more powerful stroke of the tail in one direction, the so-called "power stroke"; this can easily be observed in fresh, live preparations of spermatozoa viewed with the light microscope. The end part is merely a short tapering portion of the tail containing the axoneme only.

Conserving a general plan of a construction, animal spermatozoons differ from each other an in-terrelation of the basic parts and, especially, the form of the head. The mammalian spermatozoons are fac-ultative anaerobes. They can awakely move both at presence, and at lack of oxygenium. Locomotion in oxygen-free (anaerobic) medium descends due to glycolysis of the fructose keeping in testis fluid. Sper-matozoons are capable to acquire and other monosaccharides: glucose, monose which are found in con-tents of a sexual tract of a female organism. In aerobic conditions the spermatozoons can keep the neces-sary energy at oxidation of endocellular phosphotides.

Ovums or ovocytes are formed in female sex glands - ovaries during an ovogenesis. As a rule they have a round form, larger than spermatozoons volume of cytoplasm and nucleous, and do not have the ability move actively.

The ovum is characterized by the presence of protein-lypid inclusion of yolk in cytoplasm. Yolk (ledthos - fat) - is a nutrient material which influences the character of embryogenesis. Yolk is like granu-las, spheres or plates and it forms in the endoplasmatic reticulum and in Golgi apparatus. Such granule or plate consists of more compact (dense) central zone and less dens peripheral zone and is covered by oxyphile membrane.

The compact zone is formed by molecules of phosphovitin (complex of proteins and phosphates) and has the appearance of crystal grate. Peripheral zone consists of lypoviteline (complex of proteins and lypids). The composition of ovum is characterised by polarity, which is connected with amount of yolk granules cytoplasm. The part of cytoplasm where there is a majority of organelles and a nucleus and little yolk compounds animal pole. The part, where yolk is accumulated, forms vegetative pole.

A singularity of cytoplasm of ovocytes is the great many of ribosomes, information and acceptor RNA which amount in hundreds and thousand times exceeds their content in somatic cells. The nucleus of ovocytes light, similar to a bubble, contains a haploid number of chromosomes.

The ootid is coated by cytolemme, ovolemme or an initial envelope. Many ootids are enclosed by the secondary envelope consisting of proteins and carbohydrates, and the some ovums have also a tertiary envelope (for example, shellic and undershellic).

The amount of a yolk in cytoplasm depends on duration of an embryogenesis and from require-ments of development animal. During evolution at more difficult organized animal collected more and more yolk. So olygolecithal ovums is observed at primitive Chordata, mesolecithal ovums is observed at amphibians, and polylecithal ovums - at auks. At mammalian the embryos developes inside uterine and

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feeds due to a maternal organism, therefore the major nutrient reserve is not necessary for him. Therefore olygolecithal cells divide on the primary (at primitive Chordata) and the secondary (at mammalian animal and the man).

Other classification of ootids is based on allocation of a yolk in cytoplasm. To this indication dis-tinguish isolylecithal ovums in which the yolk distributed evenly on cytoplasm, telolecithal ovums, in which the yolk distributed nonuniformly and centrolecithal ovums, in which the yolk is at the center. Telolecithal ootids are sectioned on moderately telolecithal in which there is no sharp shift of a nucleus and organelles to animal pole, and sharply telolecithal, in which nucleus and organelles are sharply dis-placed to animal pole.

In evolution in series chord animal the following phylums of ovums were formed. At primitive Chordata Amphioxus is primary isolecithal ovum. The dimensions of an ovum is some tens micron. A nu-cleus and organelles are at the center, are not enough yolk. Its small granules distributed evenly. At am-phibians is mesolecithal, moderately telolecithal ovum. Its dimensions is some millimeters, a nucleus and organelles are displaced to animal pole. A yolk lies in the center, it looks like larger granules and full-spheres. At birds is polylecithal, sharply telolecithal ovum. The dimensions of an ovum achieve several centimeters and even tens in sm (for example, an ovum of an ostrich). A nucleus and organelles are on a surface of a yolk as a small stain magnitude about the pin head. It is animal pole. All remaining yolk eggs compounds a vegetative pole. The yolk looks like large full-spheres and plates.

At mammalian is the secondary olygolecithal, isolecithal ovums. Their dimensions on the average is 105 -110 microns, a nucleus is almost in the center, yolk granules shallow distributed practically evenly. In cytoplasm the apparatus of protein synthesis (a yolk nucleus) around of which mitochondrions and Golgi apparatus focused is well advanced. On a rim derivates of Golgi complex - cortical granules range. The cell center misses. The mammalian ovum, except of ovolemma, is coated with two more en-velopes: jelly-like zona pellucida and a radiate crown corona radiata. The zona pellucida is formed in a growth period of an ovocyte in a follicle of an ovary as a result of synthetic activity of the ovum and fol-licular epithelial cells. Composition of zona pellucida enter glykozamynoglykans and glykoproteins. In a light microscope the zona pellucida has homogeneous frame, and at a submicroscopy in its periphery dis-tinguish strands in length about 2-3 microns and depth up to 7 nanometers. In zona pellucida glycopro-teins is discharged fractions Zp - 1, Zp - 2 and Zp - 3. Fraction Zp-1 bridges among themselves circum-scribed glycoprotein fibrils formed by fractions Zp - 2 and Zp – 3. Besides fraction Zp - 3 contains recep -tors for the spermatozoons representing saccharum N - acetylglycosamin. Follicular cells are posed radi-ally, have drop-shaped form, large nucleus and processes. Processus inpour through zona pellucida to ov-olemma, ensuring not only protective but also trophic function. Ovolemma forms microvillis towards to processes of follicular cells.

The fertilization represents penetration of a spermatozoon into an ovum as a result of which it is restored number of chromosomes and the single-celled embryos - a zygote is formed. The fertilization de-scends in three phases: 1. distant interaction and coming together of gametes. 2. contact of gametes. 3. in-filtration of sperm cell in an ovum and a gametic syngamy - a syngamy. In first distant phase the sperma-tozoon awakely goes towards to an ovum due to flagella cutting, to a rheotaxis and chemotaxis. The rheo-taxis is a spermatozoons locomotion against a current of fluid which is formed as a result of a secretion of an epithelium of female sex organs. Chemotaxis is ability of spermatozoon to move in a direction of the chemicals secreted by an ovum. The important role in chemotaxis play homons. Distinguish ginohomons are produced by ovum and androhomons are made with a spermatozoon. Ginohomons (fertilizins and an-tifertilizins) can activate spermatozoons locomotion or bond spermatozoons, to prevent a polyspermia- in-filtration into an ovum of many sperm cells. Androhomons can depress motility of spermatozoons or par-ticipate in their coagglutination, interacting with ginohomons.

In this phase in spermatozoons occurs capacitation - activation of spermatozoons. From its surface the proteins of seed fluid leave. Then the glycoproteins of a plasma membrane changes. Capacitation at mammal occurs under action of secrets of a uterus and uterine tubes, a hormone of corpus luteum - pro-gesterone, and also enzymes -glycolidaze which produced by the follicular cells. Capacitation lasts for mice sperm cells 1 hour, for the rabbit 6 hours, for the man 7 hours. Movement of ovum towards sperma-tozoons occurs passively thanking smooth muscles contraction of uterine tubes which is prostaglandin ad-

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justed, to promotion of a secret of a uterine tubes and cilia fluctua-tions of simple columnar epithelium in a direction of a uterus. In-fringement of a cilia structure and function can result in tubal pregnancy. A lot of spermatozoons surrounds ovum and the sec-ond phase of fertilization -contact of gametes begins. The impor-tant role in this process is played by acrosome reaction. External acrosome membrane in the certain points merges with a plas-matic membrane of sperm cells. Through formed pores from acro-some enzymes are allocated. At mammal these enzymes split gly-cosaminoglycans, destroying communications between follicular cells of corona radiata. This process is called denudation. At mammal at fertilisation only one sperm cell penetrate in ovum, it is monospermia. At invertebrates ani-mals and also fishes, amphibians, birds it is possible polyspermia. It is penetration of several spermato-zoons in ovum. In this case with ovocyte nucleus the nucleus only one spermatozoon merges. At compat-ibility of ovum and spermatozoons proteins one spermatozoon breaks integrity of zona pellucida and is carried out penetration in ovum. Plasmatic membranes of both cells fuse and occurs association of cyto-plasm of both gametes. In the field of merge of membranes appears small tuberculum - a cone of fertilisa-tion. As a result of retraction of a cone the spermatozoon head moves inside eggs and it appears included in ovoplasma. The touch of spermatozoon to an ovum surface causes reciprocal changes in a boundary layer of ovoplasma. It is cortical reaction of ovoplasma or a impulse of activation. The third phase of fer-tilisation begins. Cortical reaction starts with inflow of ions of sodium through a site in which the sperma-tozoon membrane is built in a ovum membrane. Cortical granules move to a surface of a plasmatic mem-brane and their contents secrites in the space environmental ovum. Glycoproteins from cortical granules connect water and break off communications between a transparent environment and plasmalemma. The factor promoting hardening of a zona pellucida and formation from it of fertilisation membrane (zoned re-action) which blocks polyspermia. At zoned reaction molecule Zp-3 change in such a manner that lose abilities to be receptors for spermatozoons. In ovoplasm the spermatozoon head turns on l80 degrees, ap-proximated and turns in male pronucleus. Spermatozoon brings in the ovocyte centrioles which are neces-sary for cell division. The ovum nucleus also turns in female pronucleus. Male pronucleus comes nearer to female one, occurs DNA reduplication in everyone pronucleus and there is a stage of pronucleus fusion or synkaryon. The general metaphase plate is formed and restored characteristic for the given organism diploid number of chromosomes. The fertilised ovum (zygote) gets the genes inherited from both parents.

The zygote enters the following stage of embryonic development which is termed as cleavage. Cleavage is some mitotic divisions of a zygote and an early embryos as a result of which cells - blas-tomeres appears. Cleavage differs from a routine mitotic division that in an interphase G 1 (growth period) is not expressed, therefore generatored cells decrease in the dimensions after each division. Such cells have termed as blastomeres (from blastos - a germ).

Cleavage is finished, when the dimensions of blastomeres reach the dimensions of somatic cells. On early stages of cleavage all blastomeres are totipotent, i.e. they conserve a developmental potency of each blastomere in a self-contained organism (in it the cause of development of monozygotic twins). Sul-cuses of cleavage pass in strictly fixed sequence. If first division passes simultaneously through animal and vegetative poles of a zygote and splits the zygote into two equel cells cleavage is termed as the meridional. If the cleavage collaterally surfaces of a zygote it is tangential cleavage. The type of cleavage depends on quantity and allocation of a yolk in an ovum, i.e. from type of an ovum. Distinguish the com-plete or holoblastic (from holos- whole, all) and incomplete or meroblastic (meros - a part) cleavage. The complete cleavage terms cleavage at which all stuff of a zygote is divided. Incomplete cleavage at which the vegetative pole crowded with a yolk, is not divided. The yolk is a stuff which cleavage inhibits, there-fore cleavage can be also equual if the yolk is distributed in a cell evenly, and unequal at unequal alloca-tion of a yolk in cytoplasm. At equal cleavage blastomeres have identical magnitude, and their quantity even (2, 4, 8,16, 32, etc.). At unequal cleavage cells of animal pole are divided faster since on animal pole there is no yolk and shallow cells -microblastomeres are formed. Cells of a vegetative pole in which there is more yolk, are divided more slowly, larger cells -macroblastomeres therefore are formed. If cleavage

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on a vegetative pole is a little detained, such cleavage is termed asynchronous. At asynchronous cleavage it is formed both even and odd quantity of blastomeres (2, 3, 4, 8, etc.).

In series of chordata animals the following types of cleavage are observed: at simple chordata Amphioxus is the complete (holoblastic) equal synchronous; at amphibians the complete (holoblastic) un-equal; at birds- incomplete (meroblastic) unequal since it is divided only animal pole which looks like a small disk; at mammalian - the complete (holoblastic) unequal asynchronous.

As a result of cleavage a morula is formed. Blastomeres produce or inhaust fluid, which collects between them. Thus the morula turns to an embryos with a cavity - a blastula. The wall of a blastula wears the name of a blastoderm, a cavity - blastocele. In ablastoderm distinguish a roof of a blastula, which results from cleavage of animal pole, a bottom of a blastula - a stuff of a vegetative pole and fringe region between them.

Series of chordata animals the following types of cleavage are observed: at simple chordata Am-phioxus is the complete (holoblastic) equal synchronous; at amphibians the complete (holoblastic) un-equal; at birds - incomplete (meroblastic) unequal since it is divided only animal pole which looks like a small disk; at mammalian - the complete (holoblastic) unequal asynchronous.

As a result of cleavage it is formed - a morula. Blastomeres produce or inhaust fluid, which col-lects between them and the morula, turns to an embryos with a cavity - a blastula. The wall of a blastula wears the name of a blastoderm, a cavity - blastocele. In a blastoderm distinguish a roof of a blastula, which results from cleavage of animal pole, a bottom of a blastula - a stuff of a vegetative pole and fringe region which is between them. The type of a blastula is determined by type of an ovum and cleavage. For simple chordata Amphioxus the single-layer coeloblastula, in which the blastoderm consist of one layer of identical blastomeres and blastocele is in the center, is characteristic. Amphibians has the multilayer am-phiblastula. Roof of amphiblastula consists of microblastomeres, the bottom consists of macroblas-tomeres. The blastocele is displaced to animal pole. The multilayer discoblastula of auks represents the germinal disk posed on a surface of not split yolk. Blastocele is sharply displaced to animal pole and is between a disk and a yolk. At mammalian the stage similar to a blastula, wears the name a blastocyste. She differs from a blastula because embryo body is not formed of a blastocyste wall. From a blastocyste wall develops extraembryonal membranes. Blastomeres of a blastocyste wall form a trophoblast and blas-tomeres, accumbent as a nodule to a trophoblast, wear the name embryoblast. The cavity filled-by fluid, is termed as a cavity of a blastocyste.

The gastrulation is a stage of an embryogenesis in which are formed three germ layers: outside layer - an ectoderm, intrinsic layer – an endoderm and middle layer - a mesoderm. The gastrulation repre-sents complex process during which reproduction, growth, directional travel and a differentiation of cells take place. As a rule, during gastrulation the cells arrange themselves into two distinct germ layer- the ec-toderm and endoderm. Later the mesoderm is formed and the embryo acquires a trilaminar constitution called a gastrula.

There are four basic methods of gastrula formation in various animals depend on type of an ovum. Invagination is observed, for example at simple chordata Amphioxus. At an invagination the bottom of a blastula invaginate in its cavity also turns to an entoderm, and the roof of a blastula which is taking place outside, becomes an ectoderm of a embryos. Epiboly is characteristic for amphibians: at epiboly fast di-vided blastomeres of animal pole accrue on a surface of sluggishly divided blastomeres of a vegetative pole. The ectoderm is formed of cells of animal pole and the entoderm is formed of a vegetative pole or a bottom of a blastula. At auks it is observed serially two types of a gastrulation - at firsl delamination, then - immigration. Delamination or flaking it is scission on two plates. There is a flaking of a germinal disk on an outside plate - an initial ectoderm or epiblast and an intrinsic plate - an endoderm or a hypoblast, which face to a cavity of a blastocyste. Epiblast contains a cellular stuff of an ectoderm, and also the fu-ture nerve plate, a chorda and a mesoderm. The hypoblast includes a stuff only endoderms. Immigration is a travel of cells which are installed between ecto - and endoderm and form a mesoderm. By delamina-tion and immigration descends a gastrulation at mammalian. In a blastocyste descends delamination of embryoblast on epiblast and a hypoblast. Epiblast adjoins to trophoblast and the hypoblast is inverted in a cavity of a blastocyste. Then on a epiblast surface as a result of migration of a germinal stuff the initial strip and a primitive knot is formed.

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The important role in an embryogenesis plays cell division resulting in increasing of mass of an embryo and a fetus. In embryonic tissues the mitotic index is higher, than in tissues of an adult organism. Growth of tissue germs is determined by rate of cell division. In embryonic development the essential role plays so-called growth factors. They represent biochemical active agents influencing cells and tissues, frameing necessary conditions for specific body part growth. The promote effect has epidermal growth factor, nerve growth factor, growth factor of fibroblasts, substances which control a hemopoiesis - ery-thropoietins, lymphopoietin, tropbopoietin and other. Body growth is monitored by activity of some hor-mones, in particular somatotropic hormone of a pituitary body, thyroid and sex hormones. Except for ac-celerators of body height there are its inhibitors which have received the name chalones. They represent the complicated molecules of polysaccharides retarding rate of cell division in those tissues where they are contained. Therefore in different fields of a fetus body the growth rate is unequal.

Increase of fetus mass can descend by a hypertrophy. A hypertrophy is augmentation of volume and weight of a tissue or it part, accompanying with augmentation of volume of cellular elements at the expense of endocellular neogenesis of organellas. The hypertrophy is routinely accompanied by augmen-tation of the dimension of nucleus. In a basis of a hypertrophy intensification of synthesis of proteins, in-tensifying of activity of enzymes of an oxidation-reduction cycle lays. A hyperplasia is augmentation of number of building blocks of tissues by their exuberant neoplasm. The hypertrophy accompanies, for ex-ample, with processes of a differentiation of skeletal muscles and muscles of heart.

The differentiation is a process at which in a nucleus and cytoplasm of cells arise quality and the quantitative changes allowing cells to execute specialized functions. As a result of reprisal and depression of various genes transferring from undifferentiated cells to more differentiated is made. At early stages of an embryogenesis in undifferentiated cells there are no special organellas and consequently they execute only general functions of a feeding, respiration, a breeding. During a differentiation comes up more and more differences between cells. In their cytoplasm processes of synthesis and disintegration variate, ap-pear specific organelles and specific incorporations, cells acquire ability to synthesize extracellular sub-stance, secretory granules and other products and tissue become differentiated, i.e. functionly special-ized. Developing embryonal tissues and organs can transfer the information of possible pathes of develop-ment to environing tissues and organs having express receptors for perception of this information. A clas-sical example of embryonic induction are G.Shpemana's experience on transplantation chordomesodermal germ from dorsal surfaces of an embryo on ventral. Influence of a grafted field of a mesoderm has given in development of a blastemal with two bookmarks chordomesoderm and a neurotubule. G.Shpeman also had been developed methods of the experimental fetology, allowing to study embryonic induction which had so major value for a fetology and developmental biology as a whole, that the author of this discover-ing in 1935 has been awarded with the Nobel Prize. In a basis of an induction the surface interactions of membranes of cells and chemical transfer of inducing activity, apparently, lay at a diffusion of materials – inducers from one tissue in other. The chemical nature of inducers can be various: proteins, nucleopro-teins, fatty acids, steroids, some inorganic matters for example, chloride or lithium.

At sperm examination in clinical practice carry out calculation of various forms of spermatozoons in stained smears, counting up their percentage (spermiogramm). According to the World organization of public health services (CART), normal characteristics of sperm of the person has the following parame-ters:

1. Concentration of 20-200 million/ml, the maintenence more than 60% of normal forms. Along-side with normal forms in sperm of the person always present abnormal ones: with two flagelles, with the defective sizes of the head (macro-, microforms), with the amorphous head, with two heads, unmature forms (with the rests of cytoplasm in the area of a nack and a tail), with flagella defects.

2. In ejaculate of healthy men prevail typical spermatozoons. The quantity of various kinds of atypical spermatozoons should not exceed 30%. Besides there are unmature forms of sexual cells sper-matides, spermatocytes (up to 2 %), and also somatic cells -epitheliocytes, leukocytes.

3. Among spermatozoons in ejaculate should contain alive cells of 75% and more, and actively mobile is 50 % and more. The established normative parameters are necessary for an estimation of devia-tions from norm at various forms of man's sterility and other pathologies.

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In acidic environment spermatozoons quickly lose ability to movement end fertilisation. Ability to fertilisation depends also on spermatozoons concentration in a seed liquid, duration of their stay in ejacu-late, etc. Immobility spermatozoons stick together.

Fertilization, the process by which the male and female gametes fuse, occurs in the ampullary re-gion of the uterine tube. This is the widest part of the tube and is located close to the ovary. While sper-matozoon can stay alive in the female reproductive tract for about 24 hours, the secondary oocyte is thought to die 12 to 24 hours after ovulation, if not fertilized.

The spermatozoons pass rapidly from the vagina into the uterus and subsequently into the uterine tubes. This ascent is probably caused by contractions of the musculature of the uterus and the tube. It must be kept in mind that spermatozoa, upon arrival in the female genital tract, are not capable of fertiliz-ing the oocyte. They must undergo capacitation and the acrosome reaction.

Capacitation is a period of conditioning in the female reproductive tract which, in the human, lasts approximately seven hours. During this time a glycoprotein coat and seminal plasma proteins are re-moved from the plasma membrane that overlies the acrosomal region of the spermatozoa. Completion of capacitation permits the acrosome reaction to occur.

The acrosome reaction occurs in the immediate vicinity of the oocyte under influence of sub-stances emanating from the corona radiata cells and the oocyte. Morphologically multiple point fusions between the plasma membrane and the outer acrosomal membrane take place, permitting the release of the acrosomal contents needed to penetrate the corona radiata and zona pellucida. During the acrosome reaction the following substances are released: (I) hyaluronidase needed to penetrate the corona radiata barrier; (2) trypsin-like substances needed for digestion of the zona pellucida; and (3) zona lysin, attached to the inner surface of the acrosomal membrane, also needed to help the spermatozoon cross the zona pel-lucida.

Sperm binding occurs through interaction of sperm glycotyltransferate and ZP3 receptors located on the zona pellucida.

PHASE 1: PENETRATION OF THE CORONA RADIATA. Of the 200 to 300 million spermato-zoa deposited in the female genital tract only 300 to 500 reach the site of fertilization. Only one of those is needed for fertilization and it is thought that the others aid the fertilizing sperm in penetrating the first barrier protecting the female gamete, the corona radiata. Initially the enzyme hyaluronidase was assumed to be the important enzyme in the dispersal of the corona cells. Presently it is thought that the corona cells are dispersed by the combined action of sperm and tubal mucosa enzymes.

PHASE 2: PENETRATION OF ZONA PELLUCIDA. This second barrier protecting the female gamete is penetrated by the sperm with the aid of enzymes released from the inner acrosomal membrane. Once the spermatozoon touches the zona pellucida, it becomes firmly attached and penetrates rapidly. The permeability of the zona pellucida changes when the head of the sperm comas in contact with the oocyte surface. This results in the release of substances that cause an alteration in the properties of the zona pellucida, the zona reaction, and inactivate species specific receptor sites of spermatozoa. Indeed, other spermatozoa have been found embedded in the zona pellucida, but only one seems to be able to pen-etrate into the oocyte proper.

PHASE 3: FUSION OF OOCYTE AND SPERM CELL MEMBRANES. As soon as the sperma-tozoon comes in touch with the oocyte cell membrane, the two plasma membranes fuse. Since the plasma membrane covering the acrosomal cap has disappeared during the acrosome reaction, actual fusion is ac-complished between the oocyte membrane and the membrane that covers the posterior region of the head. In the human both the head and the tail of the spermatozoon enter the cytoplasm of the oocyte, but the plasma membrane is left behind on the oocyte surface. As soon as the spermatozoon has entered the oocyte the egg responds in three different ways:

Cortical and zona reactions. As a result of the release of cortical oocyte granules the (a) oocyte membrane becomes impenetrable to other spermatozoa and (b) the zona pellucida alters its structure and composition, possibly through removal of specific receptor sites for spermatozoa. In this manner polyspermy is prevented.

Resumption of the second meiotic division. The oocyte finishes its second meiotic division imme-diately after entry of the spermatozoon. One of the daughter cells receives hardly any cytoplasm and is

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known as the second polar body, the other daughter cell is the definite oocyte. Its chromosomes (22 + X) become arranged in a vesicular nucleus known as the female pronucleus.

Metabolic activation of the egg. The activating factor is probably carried by the spermatozoon. The postfusion activation may be considered to encompass the initial cellular and molecular events asso-ciated with early embryogenesis. The spermatozoon meanwhile moves forward until it lies in close prox-imity to the female pronucleus. Its nucleus becomes swollen and forms the male pronucleus. The tail is detached and degenerates. Morphologically the male and female pronuclei are indistinguishable. During the growth of the male and female pronuclei (both haploid and containing only in DNA) each pronucleus must duplicate its DNA. If not, each cell of the two-cell stage zygote would have cells with half the nor-mal amount of DNA. Immediately after DNA synthesis the chromosomes become organized on the spin-dle in preparation for a normal mitotic division. The 23 maternal and 23 paternal (double) chromosomes split longitudinally at the centromere and the sister chromatids move to the opposite poles, thus providing each cell of the zygote with the normal number of chromosomes and the normal amount of DNA. While the sister chromatids move to the opposite poles, a deep furrow appears on the surface of the cell, gradu-ally dividing the cytoplasm into two pans.

The main results of fenilization are: (I) restoration of the diploid number of chromosomes, half from the father and half from the mother. Hence, the zygote contains a new combination of chromosomes, different from both parents.

(2) Determination of the sex of the new individual. An X-carrying sperm will produce a female (XX) embryo, and a Y-carrying sperm a male (XY) embryo. Hence, the chromosomal sex of the embryo is determined at fenilization.

(3) Initiation of cleavage. Without fenilization the oocyte usually degenerates 24 hours after ovu-lation.

Infertility is a problem for 15% to 30% of couples. Male infertility may be a result of insufficient numbers of sperm and/or poor motility. Normally, the ejaculate has a volume of 3 to 4 ml, with approxi-mately 100 million sperm per ml. Males with 20 million sperm per ml or 50 million sperm per total ejacu-late are usually fertile. Infertility in a woman may be due to a number of causes, including occluded oviducts (most commonly caused by pelvic inflammatory disease), hostile cervical mucus, immunity to spermatozoa, absence of ovulation, and others.

In vitro fertilization (IVF) of human ova and embryo transfer is a frequent practice conducted by laboratories throughout the world. Follicle growth in the ovary is stimulated by administration of go-nadotropins. Oocytes are recovered by laparoscopy from ovarian follicles with an aspirator just before ovulation when the oocyte is in the late stages of the first meiotic division. The egg is placed in a simple culture medium and sperm are added immediately. Fertilized eggs are monitored to the eight-cell stage and then placed in the uterus to develop to term. Fortunately, because preimplantation-stage embryos are resistant to teratogenic insult, the risk of producing malformed offspring by in vitro procedures is low.

A disadvantage of IVF is its low success rate; only 20 % of fertilized ova implant and develop to term. Therefore, to increase chances of a successful pregnancy, four or five ova are collected, fertilized, and placed in the uterus. This approach sometimes leads to multiple births.

Another technique, gamete intrafallopian transfer (GIFT), introduces oocytes and sperm into the ampulla of the fallopian (uterine) tube, where fertilization takes place. Development then proceeds in a normal fashion. In a similar approach, zygote intrafallopian transfer (ZIFT), fertilized oocytes are placed in the ampullary region. Both of these methods require patent uterine tubes.

Cleavage. Once the zygote has reached the two-cell stage, it undergoes a series of mitotic divi-sions, resulting in a rapid increase in mber of cells. These cells, which become smaller with each cleavage division, are known as blastomeres. Type of cleavage is holoblastic - complete equal asynchronous. Ap-pear small dark blastomeres (embryoblast) and big light blastomeres (trophoblast). Blastomeres are con-sidered totlpotent (capable of forming a complete embryo) up to the 4- to 8-cell stage (important when considering monozygotic twinning).

After three to four divisions of the zygote, develops similar in appearance to a mulberry, is known as the morula. This stage is reached about three days after fertilization and the embryo is about to enter the uterus. At this time (12 to 16-cell stage) the morula consists of a group of centrally located cells, the

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inner cell mass, and a surrounding layer the outer cell mass. The inner cell mass will give rise to the tis-sues of the embryo proper (embryoblast), while the outer cell mass forms the trophoblast, which later contributes to the placenta.

Blastocyst Formation. At about the time that the morula enters the uterine cavity, fluid begins to penetrate through the zona pellucida into the intercellular spaces of the inner cell mass. Gradually the in-tercellular spaces become confluent and finally a single cavity, the blastocele, is formed. At this time the embryo is known as the blastocyst. The cells of the inner cell mass, now referred to as the embryoblast are located at one pole, while those of the outer cell mass, or trophoblast, flatten and form the epithelial wall of the blastocyst. The zona pellucida has now disappeared, allowing implantation to begin. First step of implantation is adhesia.

In the human the trophoblastic cells over the embryoblast pole begin to penetrate between the ep-ithelial cells of the uterine mucosa (second step is invasion) at about the sixth day. It is probable that the penetration and subsequent erosion of the epithelial cells of the mucosa result from proteolytic enzymes produced by the trophoblast. The uterine mucosa, however, promotes the proteolytic action of the blasto-cyst, so that implantation is the result of mutual trophoblastic and endometrial action.

Uterus at Time of Implantation. The wall of the uterus consists of three layers: (1) the cn-dometriuin or mucosa lining the inside wall; (2) the myometrium, a thick layer of smooth muscle; and (3) the perimetrium the peritoneal covering lining the outside wall. At the time of implantation the mucosa of the uterus is in the secretory or progestational phase. If the oocyte is fertilized, the glands in the en-dometrium show increasing secretory activity and the arteries become tortuous and form a dense capillary bed just beneath the surface. As a result the endometrium becomes highly edematous. Normally the hu-man blastocyst implants in the endometrium along the posterior or anterior wall of the body of the uterus.

Not infrequently implantation sites are found outside the uterus, resulting in extra-uterine or ec-topic pregnancy. This may occur at any place in the abdominal cavity, ovary, or uterine tube. Ectopic pregnancy usually leads to death of the embryo and severe hemorrhaging by the mother during the second month of pregnancy. In the abdominal cavity the blastocyst most frequently attaches itself to the peri -toneal lining of the recto-uterine cavity (Douglas' pouch). The blastocyst also may attach itself to the peri-toneal covering of the intestinal tract or to the omentum. Rarely does an extra-uterine embryo come to full term.

Sometimes the blastocyst develops in the ovary proper, causing a primary ovarian pregnancy. More commonly an ectopic pregnancy is lodged in the uterine tube (tubal pregnancy). In the latter case, the tube ruptures at about the second month of pregnancy, resulting in severe internal hemorrhaging by the mother.

Bilaminar Germ Disc (Second Week of Development). At the eighth day of development the blas-tocyst is partially embedded in the endometrial stroma. Implantation in which the embryo becomes com-pletely embedded in the endometrium is termed interstitial implantation. In the area over the embryoblast, the trophoblast has differentiated into two layers: (1) an inner layer of mononucleated cells, the cytotro-phoblast, and (2) an outer, multinucleated zone without distinct cell boundaries, the syncytiotrophoblast or syncytium. Mitotic figures are usually found in the cytotrophoblast but never in the syncytium, yet the thickness of the latter increases considerably. This suggests that the trophoblast cells divide in the cytotro-

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phoblast and then migrate into the syncytiotrophoblast, where they fuse and lose their individual сell membranes.

Cells of the inner cell mass or embryoblast also differentiate into two layers (first step of gastrula-tion is delamination): (a) a layer of small cuboidal cells adjacent to the blastocyst cavity, known as the hy-poblast layer, and (b) a layer of high columnar cells adjacent to the amniotic cavity, the epiblast layer. To-gether, the layers form a flat, disc, which is known as the bilaminar germ disc. At the same time, a small cavity appears within the epiblast. This cavity enlarges to become the amniotic cavity. Epiblast cells adja-cent to the cytotrophoblast are called amnioblasts; together with the rest of the epiblast, they line the am-niotic cavity. The endometrial stroma adjacent to the implantation site is edematous and highly vascular. The large, tortuous glands secrete abundant glycogen and mucus.

Ninth Day of Development. The blastocyst is more deeply embedded in the endometrium, and the penetration defect in the surface epithelium is closed by a fibrin coagulum. The trophoblast shows consid-erable progress in development, particularly at the embryonic pole,where vacuoles appear in the syn-cytium. When these vacuoles fuse they form large lacunae, and this phase of the trophoblast development is therefore known as the lacunar stage.

At the abembryonic pole, meanwhile, flattened cells probably originating from the endoderm form a thin membrane, known as the exocoelomic (Heuser's) membrane, which lines the inner surface of the cytotrophoblast. This membrane, together with the endoderm, forms the lining of the exocoelomic cavity (primitive yolk sac).

Elevent to Twelfth Days of Development. By the 11th to 12th day of development the blastocyst is completely embedded in the endometrial stroma, and the surface epithelium covers almost entirely the original defect in the uterine wall.

The trophoblast is characterized by lacunar spaces in the syncytium which form an intercommuni-cating network. Concurrently the syncytial cells penetrate deeper into the stroma and erode the endothe-lial lining of the maternal capillaries. They are congested and dilated and are known as sinusoids. The syncytial lacunae then become continuous with the sinusoids and maternal blood enters the lacunar sys-tem. As the trophoblast continues to erode more and more sinusoids maternal blood begins to flow through the trophoblastic system, thus establishing the uteroplacental circulation.

In the meantime, a new population of cells appears between the inner surface of the cytotro-phoblast and the outer surface of the exocoelomic. These cells form a fine, loose connective tissue, the extra-embryonic mesoderm, which eventually fills all of the space between the trophoblast externally and the amnion and exocoelomic membrane internally. Soon, large cavities develop in the extra-embryonic mesoderm and when these become confluent, a new space, known as the extra- embryonic coelom, is formed. This space surrounds the primitive yolk sac and amniotic cavity except where the germ disc is connected to the trophoblast by the connecting stalk. The extra-embryonic mesoderm lining the cytotro-phoblast and amnion is called the extra-embryonic somatopleuric mesoderm; that covering the yolk sac is know as the extra-embryonic splanchnopleuric mesoderm.

Thirteenth Day of Development. The trophoblast is characterized by the first appearance of villous structures. The сells of the cytotrophoblast proliferate locally and penetrate into the syncytium, thus form-ing cellular, columns surrounded by syncytium. The cellular columns with the syncytial covering become known as the primary stem villi. In the meantime the endodermal germ layer produces additional cells that migrate along the inside of the exocoelomic membrane. These cells proliferate and gradually form a new cavity within the exocoelomic cavity. This new cavity is known as the secondary or definitive yolk sac. This yolk sac is much smaller than the original exocoelomic cavity or primitive yolk sac. During its formation large portions of the exocoelomic cavity are pinched off. These portions are represented by the so-called exocoelomic сysts, which are often found in the extra-embryonic coelom or chorionic cavity.

In the meantime the extra-embryonic coelom expands and forms a large cavity known as the chorionic cavity. The extraembryonic mesoderm lining the inside of the cytotrophoblast is then known as the chorionic plate. The only place where extraembryonic mesoderm traverses the chorionic cavity is in the connecting stalk. With the development of blood vessels the stalk will become the umbilical сord.

Formation of Mesoderm Germ Layer. The most characteristic event occurring during the third week is the formation of the primitive streak on the surface of the ectoderm.

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Initially the streak is vaguely defined, but in a 15- to 16-day embryo it is clearly visible as a nar-row groove with slightly bulging regions on either side. The cephalic end of the streak, known as primi-tive node, consists of a slightly elevated area surrounding a small pit. In a transverse section through the region of the primitive groove it is seen that the cells are flask-shaped and that a new cell layer develops between the ectodermal and endodermal layers. It is now generally believed that cells of the ectodermal layer migrate in the direction of the primitive streak (second step of gastrulation - immigration). Once the cells have arrived between the ectodermal and endodermal layers they form an intermediate cell layer, known as intraembryonic mesoderm. This is the mesodermal or third germ layer.

As more and more cells move in between the ectodermal and endodermal layers, they begin to spread in lateral and cephalic directions. Gradually they migrate beyond the margin of the disc and estab-lish contact with the extra-embryonic mesoderm covering the yolk sac and amnion. In cephalic direction they pass on each side of the prochordal plate to meet each other in front of this area, where they form the cardiogenic or heart forming plate.

Formation of Notochord. The cells invaginating in the primitive pit move straight forward in cephalic direction until they reach the prochordal plate. In this manner they form a tube-like process, known as the notochordal or head process. The small, central canal is considered as the forward extension of the primitive pit.

By the 17th day of development the mesoderm layer and the notochordal process separate the en-doderm and ectoderm layers entirely with the exception of the prochordal plate in the cephalic region and the cloacal plate in the region caudal to the primitive streak.

The latter plate also consists of the tightly adhering endodermal and ectodermal layers. By the 18th day of development the floor of the notochordal process fuses with the underlying endoderm and in the merged areas the two layers disintegrate. With further development the notochordal cells proliferate and form a solid cord, known as the definitive notochord. The notochord forms now a midline axis, which will serve as the basis of the axial skeleton. It extends from the prochordal plate (the future buccopharyngeal mem-brane). A small canal, the neurenteric canal, temporar-ily connects the yolk sac and the amniotic cavity.Concomitantly with the formation of the cloacal mem-

brane, the posterior wall of the yolk sac forms a small diverticulum which extends into the connecting stalk. This diverticulum, the allantoenteric diverticulum, or allantois, appears at about the 16th day of develop-ment. Although in some lower vertebrates the allantois serves as a reservoir for the excretion products of the renal system, in man it remains rudimentary and plays no role in the development.Further Development of Trophoblast. By the begin-

ning of the third week the trophoblast is characterized by primary stem villi which consist of a cytotro-phoblastic core covered by a syncytial layer. During further development mesodermal cells penetrate the core of the primary villi and grow in the direction of the decidua. The newly formed structure is known as the secondary stem villus. By the end of the third week

the mesodermal cells in the core of the villus begin to differentiate into blood cells and small blood ves-sels, thus forming the villous capillary system. The villus is now known as the tertiary stem villus. The capillaries in the tertiary villi make contact with capillaries developing in the mesoderm of the chorionic plate and in the connecting stalk. These vessels in turn establish contact with the intra-embryonic circula -

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tory system, thus connecting the placenta and the embryo. Minwhile, the cytotrophoblastic cells in the villi penetrate progressively into the overlying syncytium until they reach the maternal endometrium. Here they establish contact with similar extensions of neighboring villous stems, thus forming a thin outer cytotrophoblast shell. This shell gradually surrounds the trophoblast entirely and attaches the chorionic sac firmly to the maternal endometrial tissue.

Embryonic Period (Fourth to Eighth Week). During the fourth to eighth week of development, a period known as the embryonic period, each of the three germ layers gives rise to a number of specific tissues and organs. By the end of the embryonic period the main organ systems have been established. As a result of the organ formation, the shape of the embryo changes greatly and the major features of the ex-ternal body form are recognizable by the end of the second month.

Derivatives of Ectodermal Germ Layer. At the beginning of the third week of development, the ectodermal germ layer has the shape of a flat disc which, in the cephalic region, is somewhat broader than caudally. Simultaneously with the formation of the notochord, and in all probability under its inductive influence, the ectoderm overlying the notochord gives rise to the central nervous system.

Initially the nervous system appears as a thickening of the ectoderm, rather narrow in the cervical region and somewhat wider in the cephalic region of the embryo. This elongated, slipper-shaped plate, the neural plate, gradually expands towards the primitive streak. By the end of the third week the lateral edges of the neural plate become more elevated to form the neural folds, while the depressed midregion forms a groove, the neural groove. Gradually the neural folds approach each other in the midline, where they fuse. This fusion begins in the region of the future neck (fourth somite) and proceeds in cephalic and caudal directions. As a result the neural tube is formed. At the cephalic and caudal ends of the embryo the tube remains temporarily in open connection with the amniotic cavity by way of the anterior and posterior neuropores, respectively. Closure of the anterior neuropore occurs approximately at day 25 (18- to 20-somite stage), whereas the posterior neuropore closes at day 27 (25-somite stage). The central nervous system then forms a closed tubular structure with a narrow caudal portion, the spinal cord, and a much broader cephalic portion characterized by a number of dilatations, the brain vesicles.

By the time the neural tube is closed, two other ectodermal thickenings, the otic placode and the lens placode become visible in the cephalic region of the embryo. At approximately the same time, the lens placode appears. This placode also invaginates and during the fifth week forms the lens.

In general terms it may be stated that the ectodermal germ layer gives rise to those organs and structures that maintain contact with the outside world:(1) the central nervous system; (2) the peripheral nervous system; (3) the sensory epithelium of ear, nose, and eye; and (4) the epidermis including hair and nails. In addition it gives rise to: the subcutaneous glands; the mammary gland; the pituitary gland; and the enamel of the teeth.

Derivatives of Mesodermal Germ Layer. Initially the cells of the mesodermal germ layer form a thin sheet of loosely woven tissue on each side of the midline. By about the 17th day, however, the cells close to the midline proliferate and form a thickened plate of tissue, known as the paraxial mesoderm. More laterally, the mesoderm layer remains thin and is known as the lateral plate. With the appearance and coalescence of intercellular cavities in the lateral plate, this tissue is divided into two layers: (1) a layer continuous with the mesoderm covering the amnion, known as the somatic or parietal mesoderm layer; and (2) a layer continuous with the mesoderm covering the yolk sac, known as the splanchnic or visceral mesoderm layer. Together, these layers line a newly formed cavity, the intra-embryonic coelomic cavity, which, on each side of the embryo, is continuous with the extraembryonic coelom. The tissue con-necting the paraxial mesoderm and the lateral plate is known as the intermediate mesoderm.

By the end of the third week the paraxial mesoderm breaks up into segmented blocks of epithe-lioid cells, the somites. These are 4 occipital, 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 8 to 10 coc-cygeal pairs. The first occipital and the last 5 to 7 coccygeal somites later disappear.

Differentiation of the somite. By the beginning of the fourth week the epithelioid cells forming the ventral and medial walls of the somite lose their epithelial shape, become polymorphous, and migrate to-ward the notochord. These cells, collectively known as the sclerotome, form a loosely woven tissue known as mesenchyme or young connective tissue. They will surround the spinal cord and notochord to form the vertebral column.

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The remaining dorsal somite wall, now referred to as the dermatome, gives rise to a new layer of cells, characterized by pale nuclei and darkly stained nucleoli. The tissue so composed is known as the myotome. Each myotome provides the musculature for its own segment. After the cells of the dermatome have formed the myotome, they lose their epithelial characteristics and spread out under the overlying ec-toderm. Here they form the dermis and subcutaneous tissue of the skin. Hence, each somite forms its own sclerotome (the cartilage and bone component), its own myotome (providing the segmental muscle com-ponent), and its own dermatome, the segmental skin component.

The mesoderm also gives rise to the vascular system, that is, the heart, arteries, veins, lymph ves-sels, and all blood and lymph cells. Furthermore, it gives rise to the urogenital system— kidneys, gonads, and their ducts (but not the bladder). Finally, the spleen and suprarenal glands are mesodermal deriva-tives.

In development of an embryo the mesenchyma appear very early. It consist of cells with processus which forms syncitium. It occurs at early stages, immediately after formation of germ layers, filling in in-terspaces between them. The mesenchyma represents origin of many tissues and organs: all types of con-nective tissues, smooth muscle cells. A main source of a mesenchyma is mesoderm (from range of spinal segments, from walls of a splanchnotome). Other germ layers share in formation of a mesenchyma also. Ectomesenchyma develops from ectoderm. Neuromesenchyma develops from medullary plate. It shares in formation of meninxes.

Derivatives of endodermal germ layer. The endodermal germ layer provides the epithelial lining of the gastrointestinal tract, respiratory tract, and urinary bladder. It further forms the parenchyma of the tonsil, thyroid, parathyroids, thymus, liver, and pancreas. Finally, the epithelial lining of the tympanic cavity and Eustachian tube are lined by epithelium of endodermal origin.

Initially the endodermal germ layer has the shape of a flat disc, forming the roof of the yolk sac and closely apposed to the ectoderm. With the development and the growth of the brain vesicles, how-ever, the embryonic disc begins to bulge into the amniotic cavity and to fold in cephalo-caudal direction.

This folding is most pronounced in the regions of the head and tail, where the so-called head fold and tail fold are formed. As a result of the cephalo-caudal folding, a continuously larger portion of the en-doderm lined is cavity is incorporated into the body of the embryo proper. In the anterior part the endo-derm forms the foregut; in the tail region the hindgut. The part between the foregut and hindgut is known as the midgut. The midgut remains temporarily in open connection with the yolk sac by way of a broad stalk, the omphalornesenteric or vitelline duct. This duct is initially wide, but with further growth of the embryo it becomes narrow and much longer.

At its cephalic end the foregut is temporarily bounded by the prochordal plate, an ectodermal-en-dodermal membrane, which is now called the buc-copharyngeal membrane. At the end of the third week the buccopharyngeal membrane ruptures, thus establishing an open connection between the amniotic cavity and the primitive gut. The hindgut also terminates temporarily at a membrane known as the cloa-cal membrane.

While the foregut and hindgut are established mainly as a result of the formation of the head fold and tail fold, respectively, the midgut remains in communication with the yolk sac. Initially, this connec-tion is wide, but as a result of the lateral folding it gradually becomes long and narrow, the vitelline duct. Only much later, when the vitelline duct is obliterated, does the midgut lose its connection with the origi-nal endoderm lined cavity and obtain its free position in the abdominal cavity.

Another important result of the cephalo-caudal and lateral folding is the partial incorporation of the allantois into the body of the embryo, where it forms the cloaca. The distal portion of the allantois re-mains in the connecting stalk. By the end of the fourth week the yolk sac stalk and connecting stalk fuse to form together the umbilical cord.

In man, the yolk sac is vestigial and in all probability has a nutritive role only in the early stages of development. Its diameter is never more than 5 mm. In the second month of development it is found in the chorionic cavity.

Placenta is a temporary organ whose formation begins during implantation. It has both embryonic (chorion frondosum or pars fetalis) and maternal (decidua basalis or pars materna) components. Pars fe-talis consist of villous chorion covered by amniotic membrane. Pars maternal it is modified endometrium

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of uterus, which reject during delivery. The placenta transfers maternal nutrients and oxygen to the em-bryo, cleanses the fetal blood and secretes hormones.

Human placenta is hemochorioidal discoidal villous. Continued erosion of the highly vascular en-dometrium by the syncytiotrophoblasts also erodes the maternal blood vessels. The blood from these ves-sels empties into the lacunae. Thus, the maternal blood provides nourishment for the developing embryo. With further growth and development, the placenta begins to be formed with the resultant separation be-tween the blood of the developing embryo and that of the mother (maternal blood). From the remainder of the trophoblast cells, the chorion develops and evolves into the chorionic plate, which gives rise to the chorionic villi.

The developing trophoblasts induce changes in the endometrium in their vicinity, altering it to be-gin the formation of the maternal portion of the placenta. This altered maternal tissue, called the decidua, is subdivided into three regions:

1. The decidua capsularis is interposed between the uterine lumen and the developing embryo.2. The decidua basalis is interposed between the developing embryo and the myometrium. It

forms a compact layer, known as the basal plate.3. The decidua parietalis composes the balance of the decidua. Initially, the entire embryo is sur-

rounded by decidua in order to nourish it. The region of the chorion in contact with the decidua capsularis forms short, insubstantial villi, thus remaining smooth surfaced; that region of the chorion is known as the chorion laeve. The region of the decidua capsularis, however, becomes highly vascularized by maternal blood vessels; it is in this region that the placenta develops. The region of the chorionic plate in contact with the decidua basalis forms extensive chorionic villi, primary villi; thus, this region of the chorion is known as the chorion frondosum or villous chorion.

The primary villi are composed of both syncytiotrophoblasts and cytotrophoblasts. With further development, extraembryonic mesenchymal cells enter the core of the primary villi, converting them into secondary villi. The connective tissue of the secondary villi becomes vascularized by extensive capillary beds, which are linked to the developing vascular supply of the embryo. So appear tertiary villi.

As development continues, the cytotrophoblast population decreases because these cells join the syncytium and contribute to its growth. The decidua basalis forms large vascular spaces, lacunae, that are compartmentalized into smaller regions by placental septa, extensions of the decidua. The fetal part of the placenta is divided by the placental (decidual) septa into 15 to 25 areas called cotyledons. Wedge-like placental septa form the boundaries of the cotyledons, and because they do not fuse with the chorionic plate, maternal blood can circulate easily between them. Cotyledons are visible as the bulging areas on the maternal side of the basal plate.

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Fetal blood enters the placenta through a pair of umbilical arteries. As they pass into the placenta, these arteries branch into several radially disposed vessels that give numerous branches in the chorionic plate. Branches from these vessels pass into the villi, forming extensive capillary networks in close asso-ciation with the intervillous spaces. Gases and metabolic products are exchanged across the thin fetal lay-ers that separate the two bloodstreams at this level. Antibodies can also cross this layer and enter the fetal circulation to provide passive immunity against a variety of infectious agents, e.g., those of diphtheria, smallpox, and measles. Fetal blood returns through a system of veins that parallel the arteries except that they converge on a single umbilical vein.

Secondary villi project into these vascular spaces and are surrounded by maternal blood that is de-livered to and drained from the lacunae by maternal blood vessels of the decidua basalis. Most of the villi arе not anchored to the decidua basalis but are suspended in maternal blood of the lacunae like roots of vegetables grown in hydroponic environments; these are known as free villi. The villi anchored to the de-cidua basalis are called anchoring villi. Capillaries of free and anchoring villi are near the surface of the villi and are separated from the maternal blood by a slight amount of connective tissue and the syncy-tiotrophoblasts covering the secondary villus. Thus, maternal blood and fetal blood do not intermix; in-stead, nutrients and oxygen from the maternal blood diffuse through the syncytiotrophoblasts, connective tissue, and endothelial cells of the capillaries of the villi to reach the fetal blood. The maternal-fetal boundary is further marked by fibrinoid, a layer of the products of necrosis that may form a nonantigenic barrier and may explain maternal tolerance of fetal antigens. Certain sub-stances, such as water, oxygen, carbon dioxide, small molecules, some proteins, lipids, hormones, drugs, and some antibodies (especially immunoglobulin G) can penetrate the placental barrier, whereas most macromolecules cannot. In addition to being the site where nutritious substances, waste, and gases are ex-changed between maternal and fetal blood, the placenta, specifically the syncytiotrophoblast, serves as an endocrine organ, secreting chorionic gonadotropin, chorionic thyrotropin, progesterone, chorionic corti-cotropin, estrogen, chorionic somatomammotropin В (a growth-promoting and lactogenic hormone) and placet lactogen. Also, stromal connective tissue cells of the deciduas form the decidual cells, which en-large and synthesize prolactin and prostaglandins.

At the end of pregnancy a number of changes occur in the placenta, which may be an indication of a reduced exchange between the two circulations. These changes include: (1) an increase of the fibrous tissue in the core of the villus; (2) an increase in the thickness of the basement membrane of the fetal cap-illaries; (3) obliterative changes in the small capillaries of the villi; and (4) the deposition of fibrinoid (fib-rinoid of Langhance) on the surface of the villi in the junctional zone and in the chorionic plate. Excessive fibrinoid formation frequently causes infarction of an intervillous lake or sometimes of an entire cotyle-don. The cotyledon then obtains a whitish appearance.

The line of reflexion between the amnion and the ectoderm, the amnio-ectodermal junction, is oval-shaped, and known as the primitive umbilical ring. At the fifth week of development the following structures pass through the ring: (1) the connecting stalk containing the allantois and the umbilical vessels consisting of two arteries and one vein; (2) the yolk sac stalk (vitelline duct) accompanied by the vitelline vessels; and (3) the canal, connecting the intra- and extra-embryonic coelomic cavities. The yolk sac proper occupies a space in the chorionic cavity, that is the space between the amnion and chorionic plate.

During further development the amniotic cavity enlarges rapidly at the expense of the chorionic cavity, and the amnion begins to envelop the connecting and yolk sac stalks thereby crowding them to-gether and causing the formation of the primitive umbilical cord. Distally the cord contains then the yolk sac stalk and the umbilical vessels. More proximally it contains some intestinal loops and the remnant of the allantois.The yolk sac is found in the chorionic cavity and is connected to the umbilical cord by its stalk. At the end of the third month the amnion has expanded to such an extent that it comes in contact with the chorion, thereby obliterating the chorionic cavity. The yolk sac then usually shrinks and is gradu-ally obliterated.

The abdominal cavity is temporarily too small for the rapidly developing inlestinal loops and some of them are pushed into the extra-embryonic coelomic space in the umbilical cord. These extruding intestinal loops from the so-called physiological umbilical hernia. At about the end of the third month, the loops are withdrawn into the body of the embryo and the coelomic cavity in the cord is obliterated. When,

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in addition, the allantois, the vitelline duct, and vessels are obliterated, all that remains in the cord are the umbilical vessels (two arteries and vein) surrounded by the jelly of Wharton. This tissue is rich in mu-copolysaccharides and functions as a protective layer for the blood vessels.

The walls of the arteries are muscular and contain many elastic fibers, which contribute to a rapid constriction and contraction of the umbilical vessels after the cord is tied off. At birth the umbilical cord is approximately 2 cm in diameter and 50 tо 60 cm long. It is tortuous, causing the so-called false knots. An extremely long cord may encircle the neck of the fetus, whereas a short one may cause difficulties during delivery by pulling the placenta from its attachment in the uterus.

The epithelium of an amnion at early stages is simple squamous. It consists of large polygonal, in-timately accumbent to each other cells in which stationaryly there is a mitotic division. On 3-rd month of an embryogenesis the epithelium is transformed in simple columnar epithelium. On a surface of an ep-ithelium there are microvillis. Cytoplasm always contains small droplets of lipids, granules of glycogen and glycosaminoglycans. In apical parts of cells locate vacuoles, which contents are excreted in an am-nion cavity. The epithelium of an amnion in a region of a placental disk is simple columnar and some-times is pseudostratified columnar. It has preferentially secretory function. The basic function of epithe-lium of an extraplacental amnion is resorption of amniotic fluid.

In a stroma of amniotic membrane distinguish a basal mem-brane, a layer of the dense fibrillar connective tissue and a spongy layer of loose fibrillar connective tissue linking amnion with a chorion. In a layer of the dense connective tissue it is possible to dis-charge an ancellular part laying under a basal membrane and a cellula part. Cellula part consists of several layers of fibroblasts between which there is a heavy-bodied net of the collagen and reticular fibers. The spongy layer is formed by a mucous connective tissue with infre-quent fascicles of the collagenf ibers being. prolongation of collagen fibers of the dense connective tissue, binding an amnion with a chorion. This connection is very unfast and consequently both mem-branes are easy for separating from each other. In the ground substance of a connective tissue it is a lot of glycosaminoglycans.

Amniotic fluid. The amniotic cavity is filled with a clear, watery fluid produced by the amniotic cells and derived from maternal blood. During the early months of pregnancy, the embryo is suspended by its umbilical cord in this fluid, which serves as a protective cushion. The fluid (1) absorbs jolts, (2) prevents the adherence of the embryo to the amnion, and (3) allows for fetal movements. The water in the amniotic fluid changes every three hours indicating the enormous exchange between the amniotic cavity and the maternal circulation. Probably from the beginning of the fifth month, the fetus swallows its own amniotic fluid, and it is estimated that it drinks about 400 ml a day, which is about half of the total amount. Fetuses unable to swallow, either because of esophageal atresia or through lack of nervous con-trol of the swallowing mechanism, as in anencephaly, are usually surrounded by large amounts of amni-otic fluid (hydramnios). Under normal conditions the amniotic fluid is absorbed through the gut of the fe-tus into the blood stream and passes into the maternal blood by way of the placenta. At the end of preg-nancy, urine is daily added to the amniotic fluid. This urine is mostly water, since the placenta is function-ing as the kidney. During childbirth, the amnion and chorion combined form a hydrostatic wedge that helps to dilate the cervical canal.

On the ninth day of development at the embryonic pole, meanwhile, flattened cells probably origi-nating from the endoderm form a thin membrane, known as the exocoelomic (Heuser's) membrane, which lines the inner surface of the cytotrophoblast. This membrane, together with the endoderm, forms the lin-ing of the exocoelomic сavity (primitive yolk sac).

On the thirteenth day of development the endodermal germ layer produces additional cells that migrate along the inside of the exocoelomic membrane. These cells proliferate and gradually form a new cavity within the exocoelomic cavity. This new cavity is known as the secondary or definitive yolk sac. This yolk sac is much smaller the original exocoelomic cavity or primitive yolk sac. During its fomation

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large portions of the exocoelomic cavity are pinched off. These portion are represented by the so-called exocoelomic cysts.

In the meantime, a new population of cells appears between the inner surface of the cytotro-phoblast and the outer surface of the exocoelomic. These cells form a fine, loose connective tissue, the extraembryonic mesoderm, which eventually fills all of the space bet the trophoblast externally and the amnion and exocoelomic membrane internally. Soon, large cavities develop in the extra-embryonic meso-derm and when these become confluent, a new space, known as the extra-embryonic coelom, is formed. This space surrounds the primitive yolk sac and amniotic cavity except where the germ disc is connected to the trophoblast by the connecting stalk. The extra-embryonic mesoderm lining the cytotrophoblast and amnion is called the extra-embryonic somatopleuric mesoderm; that covering the yolk sac is known as the extra-embryonic splanchnopleuric mesoderm.

Yolk sac does not contain any yolk and has no nutritive function in main. Function of yolk sac:

1. The first blood islands appear in mesoderm surrounding the wall of the yolk sac at 3 weeks of development and slightly later in lateral plate meso-derm and other regions. These islands arise from mesoderm cells that are induced | by fibroblast growth factor 2 (FGF-2) to form, hemangioblasts, a common precursor for vessel and blood cell forma-tion.

2. Yolk sac endoderm is origin for primordial germ cells, which then migrate to the primitive sex cords.

3. Roof of the yolk sac give rise for the primitive gut.Alantois. Concomitantly with the formation of the cloacal membrane, the posterior wall of the

yolk sac forms a small diverticulum which extends into the connecting stalk. This diverticulum, the allan-toenteric diverticulum, or allantois, appears at about the 16th day of development. Although in some lower vertebrates the allantois serves as a reservoir for the excretion products of the renal system, in man it remains rudimentary and plays no role in the development. It may be involved in abnormalities of blad-der development. The proximal part of the allantois enters in the formation of the urinary bladder while its distal part (the urachus) is obliterated forming the median umbilical ligament which extends from the apex of the urinary bladder to the umbilicus. The allantoic vessels form the umbilical vessels.

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GENERAL PRINCIPLES OF THE TISSUES ORGANIZATION. EPITHELIUMA tissue is a complex assemblage of cells and cell products that have a common construction, ori -

gin and functionStructural and functional elements of tissues are: 1. Cells are a main element of all tissues, defin-

ing their basic properties and originative to series of derivates given below.2. All tissues are composed of an extracellular matrix, a cumulative product of activity of the cells.

Extracellular matrix is a complex of nonliving macromolecules manufactured by the cells and exported by them into the extracellular space. Some tissues, such as epithelium, form sheets of cells with only a scant amount of extracellular matrix. At the opposite extreme is connective tissue, composed mostly of extracellular matrix with a limited number of cells scattered throughout the matrix. Cells maintain their associations with the extracellular matrix by forming specialized junctions that hold them to the surround-ing macromolecules.

3. Postcellular structures are derivates of cells, which have lost of nucleus, a part of organelles and the major cell features during a differentiation. They have gained series of the properties necessary for specialized function performance. To postcellular structures of the person refer erythrocytes and thrombo-cytes (uniform elements of a blood), horny cells of skin epidermis, a hair and nails.

4. The symplastos is a large formation with the big mass of cytoplasm and a plenty of nucleuses (more ten). Symplastos is formed as a result of cell fusion with loss of their borders and shaping of uni-form cytoplasm mass in which there are nucleuses. On the mechanism of formation symplastos differ from the similar to them multinucleate cells incipient as a result of repetitive cell fission without cyto-plasm division. To symplastos refer osteoclasts, external layer of placenta trophoblast (symplastotro-phoblast), a fiber of a sceletal muscle tissue.

5. The sincytium is a formation, where connection between cells as cytoplasmic processes stay af-ter cell divisions. Earlier the sincytium assigned to series of various tissues of the person (reticular tissue, mesenchyme, to the epithelium of a thymus gland and a pulp of an enamel organ). In a light microscope border of cells are not visible. In electron microgramms it is clear visible, that the plasmolemma of one cell is separated from a plasmolemma another by intercellular contacts. Later such structures have re-ceived a title of "false" sincytium. A "true" sincytium is one of stages in formation of man's sex cells in testis when spermatogones remain connected by bridges from cytoplasm.

The systemic principle of the organization of tissues shows that each tissue represents system of cells and their derivates, therefore it is characterized by series of properties which miss at separate cells. Cells is the basic functional unit of the body, it is really the tissues, through the collaborative efforts of their individual cells, that are responsible for maintaining body functions. Cells within tissues communi-cate through specialized intercellulare junctions, thus facilitating this collaborative effort and allowing the cells to operate as a functional unit. Other mechanism that permit the cells of a given tissue to function in a unified manner include specific membrane receptors and anchoring junctions between cells. At the same time, tissues enter as systems of more higher level - organs. Between histic and organic levels in some cases is a level of morphofunctional units - the smallest replicating part of an organ fulfilling its function (for example, a nephron, a follicle of a thyroid gland or hepatic lobule). Laws of evolutionary development of tissues are extended in the theory of divergent development of tissues (N.G.Hlopin) and the theory of collateral series, or parallel development of tissues (A.A.Zavarzin). The theory of divergent development of tissues in phylogenesis and an ontogenesis surveys evolu-tionary transormations of tissues (as well as the whole organisms) as divergent process (from a Latin word diverge I wedge, I go away) during which everyone embryonic germ gives rise to the tissues gradu-ally gaining more and more expressed differences of the structural and function performances. This the-ory uncovers the basic directions of evolution of tissues.

The theory of parallel development of tissues is based on resemblance of a construction of the tis-sues fulfilling identical functions, at bunches far from each other in the phylogenetic attitude animal. It shows a continuity of the structural and function organization of tissues and specifies an independent ("parallell") course of evolution of functionly of the same type tissues in different branches of the fauna,

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given to development of resemblance of their structural organization. This theory emphasizes adaptable properties of tissues and uncovers the reasons of their evolution.

Theories of divergent development of tissues and parallelism are aggregated in the uniform evolu-tionary concept of development of tissues (A.A.Braun and V.P. Michaylov) according to which similar structures in various branches of a phylogenetic tree arose parallel during divergent development.

Development of each tissue type (histogenesis) is stimulated by processes of a determination and a differentiation of their сells. Determination of tissues descends during their development from embryonic origin and is the process of "programming" the direction of their development. At a molecular-biological level this process is carried out by blocking of those or other genes.

Differentiation is a process during which cells of the given tissue implement potencies anchored by a determination. Thus they pass series of stages of development, gradually gaining structural and func-tional properties of mature elements. The differentiation of cells descends both in developing, and in ma-ture tissues and is characterized by an expression of a part of a genome, fixed process of their determina-tion. The tissue usually contains cells with a different differentiation level.

Differon is a plurality of all cells amounting the given line of a differentiation - from the least dif-ferentiated (stem cells) up to the most mature differentiated. Many tissues contain various differons, which interact with one another. Each bunch of tissues can include series of subgroups. Inside a separate tissue may be various cell populations. The last can be parted further on individual subpopulations.

The many body tissues are grouped according to their cells and cell products into four basic types: epithelial, connective, muscular, and nervous.

Epithelium (epithelial tissue), which covers body surfaces, lines body cavities, and forms glands.Connective tissue, which underlies or supports the other three basic tissues, both structurally and

functionally. Muscle tissue, which is made up of contractile cells and is responsible for movement.Nerve tissue, which receives, transmits, and integrates information from outside and inside the

body to control the activities of the body.Each of these basic tissues is defined by a set of general morphologic characteristics or functional

properties. Each type may be further subdivided according to specific characteristics of their various cell populations and any special extracellular substances that may be present.

In classifying the basic tissues, two different definitional parameters are used. The basis for defini-tion of epithelium and connective tissue is primarily morphologic, whereas for muscle and nerve tissue, it is primarily functional. Moreover, the same parameters exist in designating the tissue subclasses. For ex-ample, while muscle tissue itself is defined by its function, it is subclassified into smooth and striated cat-egories, a purely morphologic distinction, not a functional one. Another kind of contractile tissue, myoep-ithelium, functions as muscle tissue but is typically designated epithelium because of its location.

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EPITHELIAL TISSUEEpithelial tissues is a plurality of differons of the polarly differentiated cells close as a layer on a

basal membrane on border with an external or an internal environment, and also forming a majority of body glands.

Epithelial tissue is present in two forms: (1) as sheets of contiguous cells (epithelium) that cover the body on its external surface and line the body on its internal surface and (2) as glands, which originate from invaginated epithelial cells.

Epithelial tissues often are structurally minor but functionally important components of an organ. Epithelial tissue has some general features. 1. Epithelium is the sheets of contiguous cells, which are tightly bound together by junctional complexes. 2. Epithelia display little intercellular space and little ex-tracellular matrix. 3. Because epithelium is avascular, the adjacent supporting connective tissue through its capillary beds supplies nourishment and oxygen via diffusion through the basal lamina. 4. Epithelia rest on an extracellular basal lamina (or basement membrane) that separates them from an underlying connective tissue layer called the lamina propria. 5. Epithelia are continuously renewed and replaced. Cells closest to the basal lamina undergo continuous mitosis, and their progeny replace the surface cells. 6. Polarity (structural and functional asymmetry) is characteristic of most epithelial cells. It is most clearly seen in simple epithelia, where each cell has three types of surfaces: an apical (free) surface, lat-eral surfaces that abut neighboring cells, and a basal surface attached to the basal lamina. 7. When ex-posed to сhronic environmental changes, epithelia undergo metaplasia (ie, they change from one type to another).

Cytochemical marker of epithelial cells is protein cytokeratin, forming intermediate filaments. In various types of epithelium it has various molecular forms. It is known more than 21 forms of this pro-tein.

A basal lamina or basement membrane underlies all true epithelial tissues. The basal lamina is a sheetlike structure, typically composed of type-IV collagen, proteoglycan (usually heparan sulfate), laminin (a glycoprotein that helps bind cells to the basal lamina), and entactin (a glycoprotein associated with laminin). The basal lamina exhibits electron-lucent and electron-dense layers termed the lamina lu-cida (lamina rara) and the lamina densa, respectively. The lamina densa is a 20- to 100-nm thick fibrillar network; the amount of lamina lucida is variable. Basal lamina components are contributed by the epithe-lial cells, the underlying connective tissue cells, and (in some locations) muscle, adipose, and Schwann cells. In some sites, a layer of type-III collagen fibers (reticular fibers), produced by the connective tissue cells and termed the reticular lamina, underlies the basal lamina. м 11 пае accompanied by reticular lami-nae are often thick enough to be seen with the light microscope as PAS-positive layers and are sometimes termed basement membranes. The basal lamina forms a barrier between the epithelium and connective tissue. It aids in tissue organization and helps maintain cell shape through cellular adhesion. Attachment between epithelial cells and their basal lamina is mediated by integral membrane proteins called integrins. Specifically, the cytoplasmic domains of integrins are linked to microfilaments by specific actin-binding proteins. Their extracellular domains bind laminin subsequently, laminin binds tightly to type-IV colla-gen, establishing a strong physical attachment between the cytoskeleton and the basal lamina.

Polarity and specialization of epithelial cells.Intracellular Polarity. The nucleus and organelles are often found in characteristic regions of ep-

ithelial cells, a feature particularly important to glandular cells. For example, in protein-secreting cells, the rouph endoplasmic reticulum is preferentially located in the basal cytoplasm, the nucleus in the basal-to-middle region just above the rouph endoplasmic reticulum, and the Golgi complex just above the nu-cleus. Mature secretory vesicles collect in the apical cytoplasm. The polarized deployment of organelles is regulated by microtubules and attached motor proteins.

Specializations of the apical surface: The cell's apical surface is on the organ's external or internal (lumen) surface. It is specialized to carry out functions that occur at these interfaces, including secretion, absorption, and movement of luminal contents:

1. Cilia membrane-covered, cell-surface extensions typically occur in tufts or cover the entire api-cal surface. They beat in waves, often moving a surface coat of mucus and trapped materials. Ciliated ep-

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ithelia include ciliated pseudostratified columnar (respiratory) epithelium and the ciliated simple colum-nar epithelium of the oviducts.

2. Flagella are also concerned with movement. Spermatozoa, derived from seminiferous epithelia, are the best examples of flagellated human cells.

3. Microvilli are plasma membrane-covered cell-surface extensions. An absorptive cell's apical surface is usually covered with microvilli, which greatly increase the surface area when extended. Mi-crovillus-covered, epithelia, which exhibit a striated border, or brush border, include the absorptive sim-ple columnar epithelium lining the small intestines and the absorptive simple cuboidal epithelium lining the kidney`s proximal tubules.

4. Stereocilia are not cilia but are very long microvilli. They are found in the male reproductive tract (epididymis, ductus deferens), where they have an absorptive function, and in the internal ear (hair cells of the maculae and organ of Corti), where they have a sensory function.

Specializations of the Lateral Surfaces: Epithelial cells attach tightly to one another by specialized intercellular junctions. Junctions occur in three major forms: zonulae are bandlike and completely encir-cle the cell; maculae are disklike and attach two cells at a single spot; and gap junctions are macular in shape but differ in composition and function. A junctional complex is a combination of extracellular junc-tions, typically lying near the cell apex.

Specializations of the basal surface. The basal surface contacts the basal lamina. Because it is the surface closest to the underlying blood supply, it often contains receptors for blood-borne factors such as hormones.

Hemidesmosomes are located on the inner surface of basal plasma membranes and are in contact with the basal lamina in epithelia exposed to extreme stress (stratified squamous). In these strong attach-ments, integrins mediate a connection between the basal lamina and intermediate filaments of epithelial cells. In these junctions, the adaptor proteins connecting the integrins and the intermediate filaments form a plaque on the cytoplasmic surface of the basal plasma membrane.

Sodium-potassium ATPase is a plasma membrane-bound enzyme localized preferentially in the basal and basolateral regions of epithelial cells. It transports sodium out of and potassium into the cell.

An epithelium may serve one or more functions, depending on the activity of the cell types that are present:

Secretion, as in the columnar epithelium of the stomach and the gastric glands;Absorption, as in the columnar epithelium of the intestines and proximal convoluted tubules in the

kidney;Transport, as in transport of materials or cells along the surface of a epithelium by motile cilia or

in transport of materials across an epithelium to and from the connective tissue; Protection, as in the stratified squamous epithelium of the skin (epidermis) and the transitional ep-

ithelium of the urinary bladder. Separate self from nonself;Receptor function, to receive and transduce external stimuli, as in the taste buds of the tongue, ol-

factory epithelium of the nasal mucosa, and the retina of the eye;Divide the body into functional compartments; Barriers. Form barriers that monitor, control, and modify substances that traverse them.

Classifications of epithelium1. Distinguish the surface (integumentary and covering) and glandula epithelium.

The surface epithelium is the boundary tissue locating on a body surface (integumentary), mu-cosas of internal organs (a stomach, an intestine, urinary bladder, etc.). They abjoint an organism and its organs of external environment and participate in a metabolism between them, realizing functions of ab-sorption of materials and abjections of products of an exchange. Except for these functions, the integu-mentary epithelium fulfills the important protective function, protecting liable tissues of an organism from various external actions – chemical, mechanical, infective, etc. For example, the epidermal epithe-lium is a potent barrier for microorganisms and many poisons. At last, the epithelium covering serous cavity, frames requirements for their motility, for example for heart contraction, lung excursion, etc.

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The glandula epithelium form glands, realizes secretory function, i.e. synthesizes and excretes specific products - secrets. For example, the secret of a pancreas participates in a digestion, secrets of en-docrine glands is hormones, which control many processes (body height, a metabolism, etc.).

2. Cell arrangement and morphology are the bases of morphological classification of epithelium. Epithelial membranes are classified according to the number of cell layers between the basal lamina and the free surface and by the morphology of the epithelial cells. If the membrane is composed of a single layer of cells, it is called simple epithelium; if it is composed of more than one cell layer, it is called strat -ified epithelium

Simple squamous epithelium is a single layer of flat, platelike cells that functions as a semiperme-able barrier between compartments. It lines blood vessels (endothelium) and body cavities (mesothelium) and forms the parietal layer of renal corpuscles. Mesothelium - the fields of a cell keeping a nucleus, and de-nuclearized fields have identical depth (an epithelium of serous shells). An endothelium - the fields of cells keeping a nucleus, have major depth, than denuclearized fields (an epithelium lining blood and lymph vessels).

Simple cuboidal epithelium is a single layer of blocklike cells that forms the walls of secretory and excretory ducts and regulates ion and water concentration in some of these. It acts as a protective barrier in some locations. Specific examples include kidney tubules and the smaller (intercalary and intralobular) ducts of many glands. It also covers the ovary`s free surface and the lens capsule's inner surface.

Simple columnar epithelium is a single layer of roughly cylin-dric cells whose apical (free) surfaces may be covered with cilia or mi-crovilli. It functions in secretion and absorption, and, when ciliated, in the propulsion of mucus. It often acts as a protective barrier. It lines the stomach, intestines, rectum, uterus, and oviducts, as well as the larger ducts of some glands and the papillary ducts of the kidneys.

Pseudostratified columnar epithelium is a single layer of cells of variable shape and height, with nuclei at two or more levels. Distinguish four basic types of cells: ciliated, mucous or goblet, basal and small granule cells. Cells that reach the surface often are ciliated. It forms a protective barrier and, when ciliated, moves surface mucus and trapped debris. Ciliated pseudostratified columnar epithelium, or respiratory ep-ithelium, lines the larger diameter respiratory passageways. Pseudostratified columnar epithelium also lines parts of the male reproductive tract, where its apical surfaces often are covered with nonmotile stereocilia.

Stratified squamous epithelium occurs in two forms:The keratinized (comified) type is a multilayered sheet of cells.

The surface cells are squamous, dead, enucleated, and filled with the scleroprotein keratin (stratum corneum). Deeper layert (stratum spinosum, stratum granulosum, stratum lucidum) have polygonal cells in progressive stages of keratinization. The deepest layer is stratum basale (germinativum) has cuboidal to columnar cells and lies on the basal lam-ina. Keratinized stratified squamous epithelium is found in the skin and forms a specialized barrier against friction, abrasion, infection, and water loss.

The nonkeratinized (noncomified) type is similar but is thinner. Its surface cells are flat, nucleated, and nonkeratinized. As a protective barrier, nonkeratinized stratified squamous epithelium, also called mucous membrane, is less resistant to water loss than the keratinized type. It lines wet cavities subject to abrasion (mouth, esophagus, vagina, anal canal, and vocal folds).

Stratified cuboidal epithelium typically has two to three layers of cuboidal cells. It is relatively rare and lines the ducts of some glands (eg, salivary, sweat).

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Transitional epithelium received its name because it was erroneously believed to be in transition between stratified columnar and stratified squamous epithelia. This epithelium is now known to be a dis-tinct type located exclusively in the urinary system, where it lines the urinary tract from the renal calyces to the urethra. Transitional epithelium is composed of many layers of cells; those located basally are ei-ther low columnar or cuboidal cells. Polyhedral cells compose several layers above the basal cells. The most superficial cells of the empty bladder are large, are occasionally binucleated, and exhibit rounded dome tops that bulge into the lumen. These dome-shaped cells become flattened and the epithelium be-comes thinner when the bladder is distended.

Epithelium are derived from all three embryonic germ layers, although most of the epithelia are derived from ectoderm and endoderm. The ectoderm gives rise to the oral and nasal mucosae, cornea, the epidermis of skin, and the glands of the skin and the mammary glands. The liver, pancreas, and lining of the respiratory and gastrointestinal tract are derived from the endoderm. The uriniferous tubules of the kidney, the lining of the male and female reproductive systems, the endothelial lining of the circulatory system, and the mesothelium of the body cavities develop from the mesodermal germ layer.

3. Alongside with morphological classification is used ontophylogenetics classification built by Russian histologist N.G. Hlopin. On this classification it is excreted five basic types of the epithelium, de-veloping in an embryogenesis from various germ layers.

The epidermal type of an epithelium is formed of an ectoderm. It has a multilayer construction and accomodate to performance first of all protective function (for example, a stratified squamous keratinized epithelium of a skin).

The endodermal type of an epithelium develops from an endoderm. It is a simple epithelium, real-izes processes of an adsorption (for example, a simple columnar epithelium of an intestine) and secretion (for exnmple, a simple columnar epithelium of a stomach and gastric glands).

Celonephrodermal type of an epithelium develops from a mesoderm. It is a simple squatnous ep-ithelium, realizes a barrier or excretory function (for example, a simple squamous epithelium of serous membranes: mesothelium, endothelium, simple columnar or cuboidal epithelium of urinary tubes of kid-ney).

Ependymoglial type of an epithelium develops from the neurotubule. It expresses by epithelium covering, for example, sinuses of a brain and canalis centralis of the spinal cord.

To angiodermal type of an epithelium refer a simple squamous epithelium endothelium, which line the blood vessels. It develops from mesenchyme.

GlandsGlands originate from glandular epithelial cells that leave the surface where they developed and

penetrate into the underlying connective tissue, manufacturing a basal lamina around themselves. The se-cretory units, along with their ducts, are the parenchyma of the gland, whereas the stroma of the gland represents the elements of the connective tissue that invade and support the parenchyma.

1. Simple coiled tubular2. Simple branched tubular3. Simple acinar4. Simple branched acinar

5. Compound tubular6. Compound acinar7. Compound tubuloacinar

Glandular epithelium manufacture their product intracellularly by synthesis of macromolecules that are usually packaged and stored in vesicles called secretory granules. The secretory product may be a polypeptide hormone (e.g., from the pituitary gland); a waxy substance (from the ceruminous glands of the ear canal); a mucinogen (from the goblet cells); or milk, a combination of protein, lipid, and carbohy-drates (from the mammary glands). Other glands (such as sweat glands) secrete little besides the exudate

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they receive from the bloodstream. In addition, striated ducts (those of the major salivary glands) act as ion pumps that modify the substances produced by their secretory units.

Glands are classified into two major groups on the basis of the method of distribution of their se-cretory products:

Exocrine glands secrete their products via ducts onto the external or internal epithelial surface from which they originated.

Endocrine glands are ductless, having lost their connections to the originating epithelium, and thus secrete their products into the blood or lymphatic vessels for distribution. Endocrine cells specialized to secrete steroid hormones are polygonal or rounded, with a central nucleus and pale-staining, acidophilic cytoplasm containing lipid droplets. Their abundant smooth endoplasmic reticulum contains enzymes for cholesterol synthesis and for converting steroid hormone precursors (pregnenolone) into specific hor-mones (androgens, estrogens, and progesterone). Their mitochondria have tubular rather than shelflike cristae and contain enzymes that convert cholesterol to pregnenolone. Steroid hormones include testos-terone, produced by the testes' interstitial cells; estrogen, from ovarian follicle cells; progesterone, from granulosa lutein cells of the corpus luteum; and cortisone and aldosterone, from cells of the adrenal cor-tex.

Exocrine glands are classified according to the nature of their secretion, their mode of secretion, and the number of cells (unicellular or multicellular).

Classification according nature of secretion:Mucous glands secrete mucinogens, large glycosylated proteins that, upon hydration, swell to be-

come a thick, viscous, gel-like protective lubricant known as mucin, a major component of mucus. Histo-logic characteristics of mucous cells include a light-staining, foamy appearance, owing to the large mu-cus-containing vesicles concentrated near the cell apex; PAS-positive staining from abundant oligosac-charide residues. Nuclei are in the cell's base. Examples of mucous glands include goblet cells and the mi-nor salivary glands of the tongue and palate.

Serous glands, such as the pancreas, secrete an enzyme-rich watery fluid. Serous cells are protein-secreting cells that usually are smaller, darker-staining, and more basophilic than mucus-secreting cells. They include pancreatic acinar cells and secretory cells of parotid salivary glands.

Mixed glands contain acini (secretory units) that produce mucous secretions as well as acini that produce serous secretions; in addition, some of their mucous acini possess serous demilunes, a group of cells that secrete a serous fluid. The sublingual and submandibular glands are examples of mixed glands.

Cells of exocrine glands exhibit three different mechanisms for releasing their secretory products: (1) merocrine, (2) apocrine, and (3) holocrine.

The release of the secretory product of merocrine glands (parotid gland) occurs via exocytosis; as a result, neither cell membrane nor cytoplasm becomes a part of the secretion. Although many investiga-tors question the existence of the apocrine mode of secretion, historically it was believed that in apocrine glands (lactating mammary gland), a small portion of the apical cytoplasm is released along with the se-cretory product. In holocrine glands (sebaceous gland), as a secretory cell matures, it dies and becomes the secretory product.

Classification according the number of cells.Unicellular exocrine glands, represented by isolated secretory cells in an epithelium, are the sim-

plest form of exocrine gland. The primary example is goblet cells, which are dispersed individually in the epithelia lining the digestive tract and portions of the respiratory tract. The secretions released by these mucous glands protect the linings of these tracts. Goblet cells derive their name from their shape, that of a goblet. Their thin basal region sits on the basal lamina, whereas their expanded apical portion, the theca, faces the lumen of the digestive tube or respiratory tract. The theca is filled with membrane-bound secre-tory droplets, which displace the cytoplasm to the cell's periphery and the nucleus toward its base. The process of mucinogen release is regulated and stimulated by chemical irritation and parasympathetic in-nervation, resulting in exocytosis of the entire secretory contents of the cell.

Multicellular exocrine glands consist of clusters of secretory cells arranged in varying degrees of organization. Multicellular glands are classified as simple if their ducts do not branch and compound if

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their ducts branch. They are further categorized according to the morphology of their secretory units as tubular, acinar (also referred to as alveolar, resembling a grape), or tubuloalveolar.

Larger multicellular glands are surrounded by a collagenous connective tissue capsule, which sends septa—strands of connective tissue—into the gland, subdividing it into smaller compartments known as lobes and lobules. Vascular elements, nerves, and ducts utilize the connective tissue septa to enter and exit the gland. In addition, the connective tissue elements provide structural support for the gland.

Acini of many multicellular exocrine glands such as sweat glands and major salivary glands pos-sess myoepithelial cells that share the basal lamina of the acinar cells. Although myoepithelial cells are of epithelial origin, they have some characteristics of smooth muscle cells, particularly contractility. These cells exhibit small nuclei and sparse fibrillar cytoplasm radiating out from the cell body, wrapping around the acini and some of the small ducts. Their contractions assist in expressing secretions from the acini and from some small ducts.

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BLOOD. LYMPH. RETICULAR TISSUEStuffs of the present lecture are devoted to one of types of tissues of a body internal environment -

to a blood. The blood, a lymph and all types of a connective tissue concern to tissues of an internal envi-ronment of an organism. From stuffs of the previous lectures it is known, that the called tissues consider-ably differ from each other (for example a loose connective tissue and a bone tissue). They combine to-gether by homogeny, a constitution and functions.

The generality of a constitution of these tissues will consist available extracellular substance, which by an amount always dominates above cell-like elements.

Blood is composed of a fluid component (plasma) and formed elements, consisting of the various types of blood cells as well as platelets.

Light microscopic examination of circulating blood cells is performed by evenly smearing a drop of blood on a glass slide, airdrying the preparation, and staining it with mixtures of dyes specifically de-signed to demonstrate distinctive characteristics of the cells. The current methods are derived from the technique developed in the late 19th century by Romanovskv, who used a mixture of methylene blue and eosin. Most laboratories now use either the Wright or Giemsa modifications of the original procedure, and identification of blood cells is based on the colors produced by these stains. Methylene blue stains acidic cellular components blue, and eosin stains alkaline components pink. Still other components are colored a reddish blue by binding to azures, substances formed when methylene blue is oxidized.

Functions of a blood:а) Protective function of a blood consists in security of humoral and cell-like immunodefence.b) Respiratory - transmission of oxygenium and carbonei dioxydum.c) Trophy - transmission of nutrients.d) Excretory function is connected with deduction from an organism of the various waste products

generator during his life activity.e) Humoral function - a carrier of hormones and others biologically active agents.f) Homeostatic function - maintaince constances of an internal environment of an organism.Blood is a unique fluid tissue. It supplies an organism with oxygenium, delivers nutrients, serves

as an original carrier for processing matters and regulators - hormones and protective proteins – antibod-ies. Besides the blood realizes monitoring behind serviceability of blood vessels - trunks, on which flows.

At the adult person the blood compounds 7-8 % from body weight. Hence in an organism of the person in weight of 70 kg 5-6 litres of a blood circulate. At neonatal the blood compounds 15 % of weight, at children of one year and elder compounds 10-11 of weight.

There are two basic blood cell types: the erythrocytes, or red blood cells, and the leukocytes, or white blood cells.

Erythrocytes also called red blood cells are the most abun-dant formed elements in blood (female 3,7-4,9 x 1012/L; male 4,5-5,5 x 1012/ L). Their presence in most tissues and organs makes them useful in estimating the size of other structures (through esti-mates of multiples or fractions of red blood cells diameter). Ery-throcytes are structurally and functionally specialized to transport oxygen from the lungs to other tissues. Their cytoplasm contains the oxygen-binding protein hemoglobin. Their small diameter (7-8 nm) and biconcave shape (in humans) help to maximize their sur-face-to-volume ratio, facilitating oxygen exchange. Because of the opposing concavities at the center of a normal red blood cells, the staining intensity appears to be reduced in this region, creating a central pallor.

An increase in the size of this pale-staining region indicates an abnormally low amount of hemoglobin in the cytoplasm. Mature red blood cells lack nu-clei and organelles, which they lose during differentiation. Their lack of mi-tochondria necessitates the use of anaerobic glycolysis for the energy needed, to maintain hemoglobin function. Without ribosomes, glycolytic en-

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zymes and other proteins cannot be renewed. Mature erythrocytes therefore have a limited life span (120 days) in the circulation before their removal by spleen and bone marrow macrophages.

At all backboned, since auks and finishing fishes, erythrocytes have nucleus and the form of a convexo-convex plate. Erythrocytes of all mammalian, except for a camel and the lama, denuclearized cells. Separate erythrocytes of a camel and the llama contain nucleus.

Anisocytosis refers to a high percentage of red blood cells with size variations. Macrocytes are larger than 9 microns in diameter. Microcytes are smaller than 6 microns. In some disease states, nuclear fragments, or Howell-Jolly bodies (Cabot rings when they form circles), remain in otherwise mature red blood cells. Some red blood cells recently released from the bone marrow contain a small amount of residual rouph endoplasmic reticulum and ribosomes that can be precipitated into blue, netlike structures with the vital dye brilliant cresyl blue. When these reticulocytes constitute more than approximately 10% of the circulating red blood cells, they indicate an increased demand for oxygen-carrying capacity (from a loss of red blood cells caused by hemorrhage, anemia, or recent ascent to a high altitude).

At locomotion of erythrocytes on capillars it is possible to observe a modification of their form. They can be drawn out in length, at 5-10 time exceeding the normal diameter, but then come in a refer-ence state. It speaks about their major elastance. Erythrocytes are imbued by acidic stains. It descends due to presence in them of a haemoglobin. The young erythrocytes in process of development, are imbued less intensively, than mature and frequently replicate the basic stains. Colouring depends on an amount of a haemoglobin in cytoplasm. About 0,2% in norm of mature erythrocytes are capable to be stained both acidic, and the basic stains - a polychromatophilia.

Each hemoglobin molecule consists of four polypeptide subunits, each of which includes an iron-containing heme group. Hemoglobin can bind reversibly to oxygen, forming oxyhemoglobin, and to car-bon dioxide, forming carbaminohemoglobin. Hemoglobin binds irreversibly to carbon monoxide, how-ever, forming carboxyhemoglobin, which reduces the blood's oxygen-carrying capacity. Hemoglobin (Hb) exists in different forms, distinguishable by their amino acid sequence. In humans, only three forms are normal during postnatal life: НbAj constitutes 97%, HbA2 2%, and HbF 1% of the hemoglobin of healthy adults. HbF makes up 80% of a newborn's hemoglobin; however, this proportion gradually de-creases until normal adult levels are reached at approximately 8 months of age. HbS is an abnormal form of HbA that is found in patients with sickle cell anemia; it differs by a single amino acid substitution in the beta chain (valine in HbS, glutamine in HbA). Unlike HbA, HbS becomes insoluble at low oxygen tensions and crystallizes into inflexible rods that deform the erythrocytes, giving them the characteristic sickle shape, When the rigid sickled cells pass through narrow capillaries, they cannot bend as normal red blood cells do. They may become trapped, obstructing blood flow, or rupture, decreasing the number of erythrocytes available for oxygen transport (anemia).

In a blood of an organism of the person are 25 billion erythrooytes. Erythrocytes are formed in a bone marrow, whence enter a blood with a velocity about 2,5x 106 /s. In a blood they work during all life (100-120 day), making with a blood-groove a path more than 1000 kms and passing through a system of a circulation more than 100 thousand times. They are blasted by macrophages of a spleen and to a lesser de-gree a liver and bone marrow. Reticular macrophages englobe iron, which goes on build-up of new ery-throcytes.

Total amount of erythrocytes at the person of 2 litres. Amount of erythrocytes at norm in 1 liter: at women of 3,7-4,9x 1012 /L, men of 4,5-5,5x 1012 /L, at neonatal 6-7x 1012 /L, by 8 years is of 5x 1012 /L. After 60 years is of 6x 1012 /L, but in them it is less than haemoglobin, than in young age. The amount of erythrocytes varies in dependence on a physiological state of an organism.

Depressing of number of erythrocytes - an erythropenia. A raise of number of erythrocytes - a polycytbemia. Erythrocytes of the person and mammalian have the form of concave disks. At some dis-eases in a blood there are erythrocytes of the various form: echinocytes (erythrocytes with spins), stoma-tocytes, spherocytes. It is a poikilocytosis (poikilos - manifold).

When placed in a hypotonic solution, erythrocytes swell and release their hemoglobin into the sur-rounding solution, a process termed hemolysis; they ieave behind an empty shell, or red cell ghost, com-posed of the plasmalemma and the stroma. The stroma consists of proteins such as spectrin that are asso-ciated with the plasmalemma's inner surface; it maintains the red blood cells biconcave shape. The plas-

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malemma's outer surface is covered by a carbohydrate-rich glycocalyx, which contains genetically deter-mined antigens that allow blood types (including А, В and О groups) to be distinguished. The major RBC integral membrane glycoprotein is glycophorin.

Leukocytes, or white blood cells, are nucleated and are larger and less numerous (4-9x109/L) than erythrocytes. Leukocytes can be divided into two main groups, granulocytes and agranulocytes, accord-ing to their granule content. Each group can be further divided based on size, nuclear morphology, ratio of nuclear to cytoplasmic volume, and staining properties. Two classes of cytoplasmic granules occur in leukocytes: specific and azurophilic granules. Specific granules occur only in granulocytes; their staining properties (neutrophilic, eosinophilic, or basophilic) distinguish the three granulocyte types. Azurophilic granules occur in both agranulocytes and granulocytes; their lytic enzymes suggest that they function as lysosomes. Unlike the erythrocytes all leukocytes can exit the capillaries by squeezing between endothe-lial cells thanking of contractive activity of their cytockeleton elements and to their numerous revertive adhesive actions to cells of various tissues (a process termed diapedesis) and enter the surrounding con-nective tissue in response to infection or inflammation. Extravascular leukocyte activity is cell-type spe-cific.

The bunch of granular leucocytes is characterized by presence in cytoplasm of specific granules and segmented nucleus. At colouring a blood by an admixture acidic (eosine) and basic (azur) stains on method Romanovsky-Giemsa in one leucocytes discovers affinity to acidic stains, and such leucocytes are termed eosinophil or acidophil, in othe - to the basic stains - basophil leucocytes; stippling of the third discovers affinity to acidic and basic stains, such leucocytes are termed neutrophil or heterophil.

The bunch of agranulocytes differs lack of specific granules in cytoplasm and unsegmented nu-cleus. They are sectioned into lymphocytes and the monocytes having different morphological and func-tion parameters.

Basic problems of leucocytes - a guard of an organism from an infection contamination. There are some aspects of cells of fixed type, each of which "is on guard" of an organism. Lifetime of leucocytes are rather various - from several hours (neutrophils) to about several decades (lymphocytes). Platelets ex-ist 3-5 days.

Granulocytes have segmented nuclei and are described as polymorphonuclear leukocytes. De-pending on the cell type, the mature nucleus may have two to seven lobes connected by thin strands of nucleoplasm. Granulocyte types are distinguished by their size and staining properties and by the EM ap-pearance of the abundant specific granules in their cytoplasm. These granules are membrane-limited and bud off of their small Golgi complex. Each granulocyte also contains a few mitochondria, free ribosomes, and sparse RER.

Neutrophils are the most abundant circulating leuko-cytes. They constitute 47 to 75% of the white blood cells, and are characterized by a limited range of normal variation (50 to 75%). They are also found outside the bloodstream, especially in loose connective tissue. Neutrophils are the first line of cellular defense against bacterial invasion. After they leave the bloodstream, they spread out, develop ame-boid motility, and become active phagocytes. Unlike lym-phocytes, neutrophils are terminally differentiated and hence incapable of mitosis.

Neutrophils are cells of the spherical form. Size of neutrophils approximately 12 mcm in circulation; as large as 20 mcm in tissues. Contains condensed chromatin and is multilobed (usually three lobes, more than five (hypersegmented) in aging cells). Small heterochromatic drum stick may extend from one lobe. Repre-sents female Barr body (inactive X chromosome). Abundant small (0.3-0.8 mcm), salmon pink, specific (neutrophilic) granules; fewer reddish-purple azurophilic granules. Specific granules contain alkaline phosphatase and bactericidal cationic protein called phagocytins. Granules of neutrophils represent the typical lysosomes keeping alkaline phosphatase and other hydrolases. Taping histochemical activity of al-kaline phosphatase it is possible to trace originating and the further destiny of granules of neutrophils.

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Thes beads arise in side parts of tanks of a plate complex. Then they are abjointed from them and disperse on cytoplasm. As soon as the neutrophil traps a bacterium, acidic phosphatase will sharply be activated, contents of lysosomes are poured out in digestive vacuole. In 30 minutes after seizure bacteria the cell loses the beads and is blasted. Abundant glycogen also is present.

Neutrophils phagocytose and destroy bacteria by using the contents of their various granules. Neu-trophils interact with chemotactic agents to igrate to sites invaded by microorganisms. They accomplish this by entering postcapillary venules in the region of inflammation and adhering to the various selectin molecules of endothelial cells of these vessels by use of their selectin receptors. The interaction between the neutrophil's selectin receptors and the selectins of the endothelial cells causes the neutrophils to roll slowly along the vessel's endothelial lining. As the neutrophils are slowing their migrations, interleukra-1 (IL-1) and tumor necrosis factor (TNF) induce the endothelial cells to express intercellular adhesion mol-ecule type 1, to which the integrin molecules of neutrophils avidly bind.

When binding occurs, the neutrophils stop migrating in preparation for their passage through the endothelium of the postcapillary venule to enter the connective tissue compartment. Once there, they de-stroy the microorganisms by phagocytosis and by the release of hydrolytic enzymes (and respiratory burst). In addition, by manufacturing and releasing leukotrienes, neutrophils assist in the initiation of the inflammatory process. Because of their phagocytic functions, neutrophils are also known as microphages to distinguish them from the larger phagocytic cells, the macrophages. Bacteria are killed not only by the action of enzymes but also by the formation of reactive oxygen compounds within the phagosomes of neutrophils.

Young neutrophils (metamyelocytes) are the most young neutrophil cells meeting in a blood in norm. They have fabiform nucleus. They are discovered in a blood in small amounts (up to 1% from total number of leucocytes).

Band neutrophils are rather sparse young cells amounting 1-6% of total number pf leucocytes. Their nucleus contains in the form of a rod, a horseshoe only planned intakes. Abundance of relating to stab neutrophile cells is a parameter of a velocity of inflow of neutrophils in a blood-groove. It routinely increases at a neutrophilia (a raise of a content of neutrophils in a blood), being combined in the ex-pressed events with increase of number of juvenile neutrophils. This fact estimates as “left-shift” on a haemogram.

Eosinophils are 9 mcm in circulation; as large as 14 mcm in tissues. Contains condensed chromatin and typically two lobes, often partly obscured by abundant specific granules. Abundant large (0.5- 1.5 mcm), brightly eosinophilic, specific granules that are specialized lysosomes carrying peroxidase, acid phosphatase, cathepsin, ribonuclease, major basic protein, eosinophilic antipara-sitic agent and fewer, reddish- purple azurophilic granules. In EMs, specific granules are ovoi: with a dense internum sur-rounded by an electron-lucent externum.

Eosinophils constitute only 1 to 5% of the circulating leukocytes in healthy adults. They may exit the bloodstream by di-apedesis, spread out, and move about in the connective tissues. They are capable of limited phagocytosis, with a preference for antigen-anti body complexes. Circulating eosinophil numbers in-crease (eosinophilias) during allergic reactions and parasitic infec-tions and rapidly decrease during corticosteroid treatment.

Eosinophils are associated with the following functions:1. The binding of histamine, leukotrienes, and eosinophil chemotactic factor released by mast

cells, basophils, and neutrophils) to eosinophil plasmalemma receptors results in the migration of eosinophils to the site of allergic reaction, inflammatory reaction, or parasitic worm invasion.

2. Eosinophils degranulate their major basic protein or eosinophil cationic protein on the surface of the parasitic worms, killing them by forming pores in their pellicles, thus facilitating access of agents such as superoxides and hydrogen peroxide to the parasite; or they release substances that inactivate the

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pharmacological initiators of the inflammatory response, such as histamine and leukotriene C; or they en-gulf antigen-antibody complexes.

3. Internalized antigen-antibody complexes pass into the endosomal compartment for eventual degradation.

The content of eosinophils in a blood within day changes. The maximum falls at night hours, a minimum - morning. It is determined by a level of a secretion of a glucocorticoid - hidrocortizonum in an organism. Eosinophils are in a blood vessels from 3 till 8 o'clock then they migrate in a connective tissue where function.

Basophils are the least numerous circulating leukocytes, consituting 0.5 to 1 % in healthy adults. Basophils are 10—12 mcm, smaller than neutrophils. They are round cells in suspen-sion but may be pleomorphic during migration through connec-tive tissue. In electron micrographs, the small Golgi apparatus, few mitochondria, extensive RER, and occasional glycogen de-posits are clearly evident. Contains condensed chromatin and typically three lobes, often in an S shape, partially or completely obscured by abundant. Heterochromatin is chiefly in a peripheral location, and euchromatin is chiefly centrally located; typical cy-toplasmic organelles are sparse. The basophil plasma membrane possesses numerous Fc receptors for im-munoglobulin E (IgE) antibodies. In addition, a specific 39-kDa protein called CD40L is pressed on the basophil's surface. CD40L interacts with a com-plementary receptor (CD40) on В lymphocytes, which results in increased synthesis of IgE.

The basophil cytoplasm contains two types of granules variablesized (0.3-1.5 mcm): specific gran-ules that are larger than the specific granules of the neutrophil and nonspecific azurophilicgranules. These granules contain a variety of substances, namely, heparin, histamine, eosinophil chemotactic factor, neu-trophil chemotactic factor, peroxidase and SRS-A. Histamine and the SRS-A are vasoactive agents that, among other actions, cause dilation of small blood vessels. Heparan sulfate is a sulfated glycosaminogly-can that is closely related to the heparin found in the granules of tissue mast cells. The amount of sulfate in this molecule accounts for the intense basophilia of the specific granules of the basophil. No role for heparan sulfate in inflammation has yet been elucidated.

Azurophilic granules are the lysosomes of basophils and contain a variety of the usual lysosomal acid hydrolases similar to those in other leukocytes. Basophils may exit the circulation but are capable of only limited ameboid move ment and phagocytosis. Extravascular basophils are seen at sites of inflamma-tion and are important cells at sites of cutaneous basophil hypersensitivity. Despite similarities to mast cells, basophils differ ultrastructurally.

In response to the presence of some antigens in certain individuals, plasma cells manufacture and release a particular class of immunoglobulin, IgE. The Fc portions of the IgE molecules become attached to the FceRI receptors of basophils and mast cells without any apparent effect. Binding of antigens to the IgE molecules on the surface of a basophil causes the cell to release the contents of its specific granules into the extracellular space. The release of histamine causes vasodilation, smooth muscle contraction (in the bronchial tree), and leakiness of blood vessels.

Leukotrienes have similar effects, but these actions are slower and more persistent than those as-sociated with histamine. In addition, leukotrienes activate leukocytes, causing them to migrate to the site of antigenic challenge. Basophils function as initiators of the inflammatory process.

Agranulocytes have unsegmented nuclei. These mononuclear leukocytes lack specific granules but contain azurophilic granules (0.05- 0.25 mcm in diameter). Lymphocytes constitute a diverse class of cells; they have similar morphologic characteristics but a variety of highly specific functions. They nor-mally account for 17 to 37% of adult white blood cells. Lymphocytes may be:

Small: 6-8 mcm (chief circulating form). Is spheric, often flattened on one side, densely hete-rochromatic, purplish blue to black. Thin rim locate around nucleus. Cytoplasm pale basophilic, has many

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ribosomes, sparse endoplasmic reticulum, few mitochondria, small Golgi apparatus, few azurophilic gran-ules, no specific granules.

Medium and large: 8-18 mcm (often antigen-activated cells). Is large, less heterochromatic, reddish purple. More abundant, pale basophilia, many ribosomes, sparse endoplas-mic reticulum, few mitochondria small Golgi apparatus, few azurophilic granules, no specific granules. Lymphocytes are also found outside blood vessels, grouped in lymphatic organs or dispersed in connective tissues. They respond to invasion of the body by foreign substances and organisms and assist in their inactivation. Unlike other leukocytes, lymphocytes never become phagocytic and may recirculate after leaving the blood-stream. The two major functional classes of lymphocytes are T cells and В cells.

Memory cells and effector cells. When stimulated by an antigen, lymphocytes undergo blast transformation, a process of enlargement, and clonal expansion, a series of mitotic divi-sions. Some of the daughter cells, called memory cells, return to an inactive state but can respond more quickly to the next encounter with the same antigen. Other daughter cells, called effector cells, become activated to carry out an immune response to the antigen. Ef-fector cells may derive from either В cells or T cells. Although circulating В and T cells are morphologi-cally indistinguishable, they carry different cell-surface components (antigens recognized by other species) and can be identified by special procedures.

1. В lymphocytes differentiate into plasma cells, which secrete antigen-binding molecules (anti-bodies or immunoglobulins) that circulate in the blood and lymph and serve as a major component of hu-moral immunity. B cells have variable life spans and are involved in the production of circulating anti-bodies. Mature В cells in blood express IgM and IgD on their surface as well as MHC II molecules. Their specific markers are CD9, CD 19, CD20, and CD24.

2. T-lymphocyte derivatives serve as the major cells of the cellular immune reponse. T cells have a long life span and are involved in cell-mediated immunity. They express CD2, CDS, and CD7 marker proteins on their surface; however, they are sub-classified on the basis of the presence or absence of CD4 and CDS proteins. CD4 T lymphocytes possess the CD4 marker and recognize antigens bound to major histocompatability complex II (MHC II) molecules. CD8+T lymphocytes possess the CDS marker and recognize antigen bound to MHC I molecules. They produce a variety of cytokines (interferon) that influ-ence the activities of macrophages and of other leukocytes involved in an immune response. There are several types:

Cytotoxic (killer) cells secrete substances that kill other cells and in some cases kill by direct con-tact; they play the principal role in graft rejection.

Helper T cells enhance the activity of some В cells and other T cells.Suppressor T cells inhibit the activity of some В cells and other T cells.3. NK cells are programmed during their development to kill certain virus-infected cells and some

types of tumor cells. NK cells are larger than В and T cells (15 mcm in diameter) and have a kidney-shaped nucleus. Because NK cells have several large cytoplasmic granules easily seen by light mi-croscopy, they are also called large granular lymphocytes (LGLs). Their specific markers include CD 16, CD56, and CD94.

4. Null cells are circulating cells that morphologically resemble lymphocytes but exhibit neither B-cell nor T-cell surface antigens. They may represent circulating stem cells of lymphocytes or other blood cell types.

The primary (central) lymphoid organs include the thymus, where lymphocyte precursors are pro-grammed to become T cells, and in birds, the bursa of Fabricius. where lymphocyte precursors are pro-grammed to become В cells. Humans have no bursa; our В cells are programmed in the bone marrow.

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Monocytes are often confused with large lym-phocytes. They are large and constitute only 3 to 11% of the white blood cells in healthy adults. They are 12-15 mcm in circulation; as large as 20 mcm in tissues. Usually nucleus is kidney- or horseshoe-shaped, eccen-tric. Chromatin is less-dense, with smudgy reddish-pur-ple appearance and 2-3 nucleoli. Cytoplasm abundant, faint blue— gray, has many small azurophilic granules, no specific granule; many small mitochonria, well-de-veloped Golgi apparatus, sparse rough endoplasmic reticulum and polyribosomes.

Monocytes occur only in the blood, but remain in circulation for less than a week before migrating through capillary walls to enter other tissues or to become incorporated in the lining of sinuses. Outside the bloodstream, they become phagocytic and do not recirculate. They phagocytose and destroy dead and defunct cells (such as senescent erythrocytes) as well as antigens and foreign particulate matter (such as bacteria). The destruction occurs within the phagosomes through both enzymatic digestion and the forma-tion of superoxide, hydrogen peroxide, and hypochlorous acid.

Macrophages produce cytoldnes that activate the inflammatory response as well as the prolifera-tion and maturation of other cells. Certain macrophages, known as antigen-presenting cells, phagocytose antigens and present their most antigenic portions, the epitopes, in conjunction with the integral proteins, class II human leukocyte antigen (class II HLA; also known as major histocompatibility complex antigens [MHCII]), to immunocompetent cells. In response to large foreign particulate matter, macrophages fuse with one another, forming foreign-body giant cells that are large enough to phagocytose the foreign parti-cle.

The mononuclear phagocyte system consists of monocyte-derived phagocytic cells throughout the body. Examples include the liver's Kupffer cells and some connective tissue macrophages.

Platelets or thrombocytes, the smallest formed elements, are disklike cell fragments that vary in diam-eter from 2 to 5 mcm. In humans they lack nuclei. They range in number from 180-320xl09/L of blood and have a life span of approximately 8-10 days. In blood smears they appear in clumps. Platelets are de-rived from large polyploid cells (cells whose nuclei contain multiple sets of chromosomes) in the bone marrow, called megakaryocytes. In platelet formation, small bits of cytoplasm are separated from the periph-eral regions of the megakaryocyte by extensive platelet demarcation channels. The membrane that lines these channels arises by invagination of the plasma membrane; therefore, the channels are in conti-nuity with the extracellular space. The continued development and fusion of the platelet demarcation membranes results in the complete partitioning of cytoplasmic fragments to form individual platelets.

Each platelet has a peripheral hyalomere that stains a faint blue and a dense central granulomere containing a few mitochondria, glycogen granules, and various purple granules. Delta granules are 250 to 300 nm in diameter and contain calcium ions, pyrophosphate, ADP, and ATP; they take up and store serotonin. Alpha granules are 300 to 500 nm in diameter and contain fibrinogen, platelet-derived growth factor, and other platelet-specific proteins. Lambda granules (lysosomes) are 175 to 200 nm in diameter and contain only lysosomal enzymes. The hyalomere contains a marginal bundle of microtubules that maintains the platelet's discoid shape. The glycocalyx is unusually rich in glycosaminoglycans and is as-sociated with adhesion, the major function of platelets. Platelets plug wounds and contribute to the cas-cade of molecular interactions among the various clotting factors dissolved in the plasma.

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If the endothelial lining of a blood vessel is disrupted and platelets come in contact with the subendothelial collagen, they become activated, release the contents of their granules, adhere to the dam-aged region of the vessel wall (platelet adhesion), and adhere to each other (platelet aggregation). Interac-tions of tissue factors, plasma-borne factors, and platelet-derived factors form a blood clot.

Features of platelet aggregation are as follows:1. Normally the intact endothelium produces prostacyclins and NO, which inhibit platelet aggre-

gation. It also blocks coagulation by the presence of thrombomodulin and heparin-like molecule on its lu-minal plasmalemma. These two membrane-associated molecules inactivate specific coagulation factors.

2. Injured endothelial cells release von Willebrand factor and tissue thromboplastin and cease the production and expression of the inhibitors of coagulation and platelet aggregation. They also release en-dothelin, a powerful vasoconstrictor that reduces the loss of blood.

3. Platelets avidly adhere to subendothelial collagen, especially in the presence of von Willebrand factor, release the contents оf their granules, and adhere to one another. These three events are collec-tively called platelet activation.

4. The release of some of their granular contents, especially adenosine diphospbate (ADP) and thrombospondin, makes platelets "sticky," causing circulating platelets to adhere to the collagen -bound platelets and to degranulate.

5. The aggregated platelets act as a plug, blocking hemorrhage. In addition, they express platelet factor 3 on their plasmalemma, providing the necessary phospholipid surface for the proper assembly of the coagulation factors (especially of thrombin).

6. As part of the complex cascade of reactions in volving the various coagulation factors, tissue thromboplastin and platelet thromboplastin both act on circulating prothrombin, converting it into tbrom-bin. Thrombin is an enzyme that facilitates platelet aggregation. In the presence of calcium (Ca2+), it also converts fibrinogen to fibrin. The fibrin monomers thus produced polymerized and form a reticulum of clot, entangling additional platelets, erythrocytes, and leukocytes into a stable, gelatinous blood сlot (thrombus). The erythrocytes facilitate platelet activation, whereas neutrophils and endothelial cells limit both platelet activation and thrombus size.

7. Approximately 1 hour after clot formation, actin and myosin monomers form thin and thick fil-aments, which interact by utilizing ATP as their energy source. As a result, the clot contracts to about half its previous size, pulling the edges of the vessel closer together and minimizing blood loss. An inherited abnormality in factor VIII results in the clotting disorder known as hemophilia.

When the vessel is repaired, the endothelial cells release plasminogen activators, which convert circulating plasminogen to plasmin, the enzyme that initiates lysis of the thrombus. The hydrolytic en-zymes of A-granules assist in this process.

Hematocrit: When anticoagulants (heparin, citrate) are added, blood samples can be separated in a centrifuge into three major fractions. Erythrocytes are the densest of these and end up at the bottom. The hematocrit is the percentage of packed erythrocytes per unit volume of blood. In adults, normal hemat-ocrit values vary from 45-55 and are sex-dependent. Leukocytes are less dense, less numerous (approxi-mately 1% of blood volume), and form a thin white or grayish layer over the erythrocytes, called the buffy coat.

Over the buffy coat is a thin layer of platelets. The least dense fraction is the clear layer of plasma, which constitutes 42 to 47% of lood volume and overlies the buffy coat.

PlasmaPlasma is a yellowish fluid in which cells, platelets, organic compounds, and electrolytes are sus-

pended or dissolved. Plasma contains 90% water and by 10% solutes by volume. These solutes include plasma proteins, other organic compounds, and inorganic salts.

Plasma proteins. Plasma contains many soluble proteins (7% by volume). Albumin is the most abundant plasma protein (3.5-5.0 g/L of blood) and is mainly responsible for main taining blood's osmotic pressure. Water-insoluble substances (lipids) are carried in plasma associated with albumin. Alpha, beta, and gamma globulins are globular proteins dissolved in the plasma. Gamma globulins include antibodies,

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or immunoglobulins. Fibrinogen is converted by blood-borne enzymes into fibrin during clot formation. Fibrinogen is synthesized and secreted by the liver. Other organic compounds.

Other organic molecules in plasma (2.1% by volume) include nutrients such as amino acids and glucose, vitamins, and a variety of regulatory peptides, steroid hormones, and lipids. Inorganic salts in plasma (0.9% by volume) include blood electrolytes such as sodium, potassium, and calcium salts. Dur-ing coagulation, some of the organic and inorganic components leave the plasma to become integrated into the clot. The remaining fluid, which differs from plasma, is straw-colored and is called serum.

The fluid component of blood leaves the capillaries and small venules to enter the connective tis-sue spaces as extracellular fluid, which thus has a composition of electrolytes and small molecules simi-lar: that in plasma. The concentration of proteins in extracellular fluid is much lower than that in play however, because it is difficult even for small proteins, such as albumin, to traverse the endothelium lin-ing of a capillary. In fact, albumin is chiefly responsible for the establishment of blood's colloid osmotic pressure, the force that maintains nomis, blood and interstitial fluid volumes.

The extracellular surface of the red blood cell plasmalemma has specific inherited carbohydrate chains that act as antigens and determine the blood group of an individual for the purposes of blood insfu-sion. The most notable of these are the A and В antigens, which determine the four primary blood groups, A, B, AB, and O. People who lack either the A or В antigen, or both, have antibodies against the missing antigen in their blood; if they undergo transfusion with blood containing the missing antigen, the donor erythrocytes are attacked by the recipient's serum antibodies and are eventually lysed.

Another important blood group, the Rh group, is so named because it was first identified in rhesus monkeys. This complex group comprises more than two dozen antigens, although many are relatively rare. Three of the Rh antigens (C, D, and E) are so common in the human population that the erythrocytes of 85% of Americans have one of these antigens on their surface, and these individuals bus said to be Rh+.

Reticular Connective TissueReticular fibers (type-Ш collagen) form a delicate network on which cells (the predominant ele-

ment) are suspended. Reticular cells attach to and cover the fibers with their long, thin processes. Other cells (lymphocytes) are suspended in the network's spaces. There is little ground substance. Reticular fibers are stained by silver salts in black - brown colour, therefore reticular fibers are frequently termed argyrophil. Separate fields of a reticular sincytium can stand apart in reticular cells, capable (in opinion of some explorers) to turn to monocytes. Except for that for a reticular tissue the well-marked phagocytosis is characteristic.

Reticular fibers are still rather primitive, therefore a reticular tissue count undeveloped because it can turn to other types of a conective tissue.

There are two types of reticular cells:1. Unmature, their cytoplasm stain slightly basophilic, does not contain incorporations. Around a

nucleus the cell-1-center, the endoplasmic reticulum and mitochondria lies. A nucleus is oval-shaped with a well-marked nucleoluses. These cells are not phagocytes and do not trap electronegative colloidal stains. They have ability at a boring to turn to other types of cells - hemocytoblusts, fibroblasts, etc.

2. The second type of reticular cells - more differentiated cells generatored from first. They are characterized by more pigmented nucleus, the turgent cytoplasm. In spite of the fact that they are linked by processes with each other, have ability to a phagocytosis and accumulation of particles of a stain in cy-toplasm. At a boring they are rounded off, lose touch with environing cells and turn to free macrophages.

Reticular connective tissue supports motile cells and filters body fluids. It occurs mainly in hematopoietic tissues, such as bone marrow, spleen, and lymph nodes.

LymphThe lymph represents fluid, which circulates on capillars and vessels. The volume of a lymph in

an organism of the person compounds, on the average, 1 - 2 litres. It consist from lymphoplasma and uni-form elements. Lymphoplasma chemical composition comes nearer to composition of a blood plasma, but it contains less protein. Plasma of a lymph has alkali reaction pH 8,4 - 9,2. Lymph proteins are moustly albumines. Lymphoplasma contains also neutral lipids, saccharum, mineral substances. Uniform elements of a lymph are mainly lymphocytes (95-98 %) and other types of leucocytes. Concentration of uniform el-

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ements varies in limens 2-20x10 9/L and can vary essentially within day or as a result of various actions. Composition of a lymph in various parts of a body unequal. For example the lymph flowing off from an intestine contains a lot of lipids. A lymph past through lymph nodes rich in lymphocytes. Distinguish a peripheric lymph (up to lymph nodes), the intermediate (after transit of lymph nodes) and central (a lymph of thoracal and dextral lymphatic ducts).

Functions of a lymph:1. homeostatic is maintenance of a constance of a cell microenvironment by a regulation of vol-

ume and composition of interstitial fluid.2. metabolic is participation in a regulation of a metabolism by a carrier of metabolites, proteins,

enzymes, water, mineral substances and biologic active molecules.3. trophic - a carrier of nutrients (preferentially lipids) from an intestin to a blood.4. protective is participation in immune responses (a carrier of antigens, antibodies, lymphocytes,

macrophages).The mechanism of a lymph formation is connected with a filtration of plasma from blood capillar-

ies in interstitial space, therefore interstitial (histic) fluid is formed. At the person in weight in 70 kg in in-terstitial space contains up to 10,5 L fluids. Fluid partly reabsorpe again in a blood, partly passes in lym-phatic capillaries and forms a lymph. Process of a lymph formation is promoted by boosted hydrostatic pressure in interstitial space, and also differences in oncotic pressure between blood vessels and intersti-tial fluid. 100-200 g of protein daily entering from a blood in an intercellular fluid. These proteins through lymphatic system are completely reverted in a blood.

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CONNECTIVE TISSUESConnective tissues is a complex of mesenchyme derivatives, consisting of cells diferons and big

quantity of extracellular matrix (fibers and ground substance), participating in supporting gomeostase of body enternal environment and differing from other tissues by lesser need in aerobic oxidation processes.

Connective tissue comprises more than 50% of human body mass. It participates in formation of organs, layers between other tissues, derm of a skin, skeleton. Blood is also specialized connective tissue.

1. All varieties of connective tissue develops from one source- mesenchyme.2. All varieties of connective tissue consists of cells and extracellular matrix, and extracellular ma-

trix prevails in quantity over cells.3. Functional properties of various types of connective tissue are defined by physical and chemical

characteristics of extracellular matrix. It may be liquid, jelly, dense and this defines functions of varieties of connective tissue.

4. Connective tissue has high abilities for regeneration and adaptation to changing existence con-ditions.

In the process of differentiation of mesoderm from dermotoms and sclerotoms appears embryonic origin of connective tissue - mesenchyme. It develops from mesoderm, but some portion of mesenchyme give rise from ectoderm. Craniofacial mesenchyme derives from the neural crest (mesectoderm) and en-doderm of anterior part of hingut. The mesenchymye occurs very early, right after appearance of germ layers. It fills in interspaces between germ layers. Cells of a mesenchyme have the tapered or star-like shape. Proccesses of cells form a reticular stroma. By treating under a light microscope processes of one cell transfer in another and the sincytium is formed. Between cells intercellular substance (fluid or semi-liquid gelatinous mass is posed. From the moment of abjection of a mesenchyme differentiation, resulting in to formation of a blood, a lymph, connective tissues proper, a cartilage, a bone, smooth muscle cells begins.

Main functions of connective tissue are:1. Support. Structural support is the major function of connective tissue, which forms the frame-

work on which all other body tissues are assembled. Its physical properties allow it to bind, to fill spaces, and to separate functional units of other tissues and organs. It thus maintains functional units in their proper three-dimensional relationships, allowing the maintenance and coordination of all body functions.

2. Defense.a. Physical. The viscosity of the extracellular matrix, which is due largely to the presence of

hyaluronan, slows the spread of many bacteria and foreign particles. Sheets of tightly packed, often inter-woven, collagen fibers, as in organ capsules, help to confine local infections. However, some bacteria se-crete enzymes that hydrolyze matrix components (staphylococci, clostridia, streptococci, and pneumo-cocci) secrete hyaluronidase, and Clostridium perfringens secretes collagenase).

b. Immunologic. Foreign bodies that penetrate epithelia are intercepted by immunoresponsive cells inhabiting the underlying connective tissue. These cells activate local immune responses (inflamma-tion) and mobilize the immune system to supply additional cells by means of the bloodstream. Recruited cells migrate through capillary and venule walls into the connective tissue, a process callol diapedesis.

3. Repair. Rapidly closing breaches in the body's protective barriers is an important connective tissue function. Injury stimulates invasion of the site by immunocompetent cells and also stimulates the proliferation of fibroblasts. Macrophages remove clotted blood, damaged tissue, and foreign material while fibroblasts secrete matrix materials to fill the breach. Rapidly formed collagenous matrices that close wounds are often less well-organized than original tissues and form scars.

4. Storage. Reserves of water and electrolytes, especially sodium, are stored in extracellular ma-trix, owing to the high polyanionic charge density of glycosaminoglycans. Energy reserves in the form of lipids are stored in adipocytes.

5. Except in the central nervous system, most blood and lymphatic vessels and peripheral nerves are surrounded by loose connective tissue, which is thus a crossroads for transporting substances to and from other tissues.

Connective tissue types differ in appearance, but all consist of cells and extracellular matrix (fibers and ground substance). Connective tissue types and subtypes are classified according to the

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amounts, types, and arrangement of these components. The abundant matrix of connective tissues largely determines their mechanical properties. The two fiber types are collagen and elastic. The ground sub-stance, in which the fibers and cells are embedded, is composed mainly of glycosaminoglycans (GAGs) dissolved in tissue fluid. Matrix viscosity and rigidity are determined by the amount and types of cross links among the matrix components. Fiber and ground substance components are synthesized and se-creted by connective tissue cells (mainly fibroblasts), and the fibers are assembled in the extracellular space.

Connective Tissue Proper. Connective tissue proper, found in most organs, is characterized by a predominance of fibers (mainly type-1 collagen). Its varied functions chiefly relate to binding cells and tissues into organs and organ systems. Its subclasses are based on the type, density, and orientation of its fibers.

Dense connective tissue. Collagen fibers (nearly all type I) predominate in dense connective tis-sue. The cells are mainly mature fibroblasts (fibrocytes). There are two types: regular, with a ropelike ar-rangement of fiber bundles, and irregular, with a fabriclike arrangement.

Dense regular connective tissue. The fibers in this tissue are tightly packed into parallel bundles, between which are a few attenuated fibroblasts. The condensed, flattened fibroblast nuclei occur in rows between the fibers; the cytoplasm is virtually indistinguishable with the light microscope. There is little room for ground substance, which nevertheless permeates the tissue. The collagen fibers' tensile strength makes them ideal for transmitting mechanical force over long distances with a minimal use of material and space. This tissue transmits the force of muscle contraction, attaches bones, and protects other tissues and organs. It is found in tendons, ligaments, periosteum, perichondrium, deep fascia, and organ capsules.

Dense irregular connective tissue. The components of this tissue are identical to those in dense regular connective tissue. Dense irregular connective tissue seems poorly organized, but the complex wo-ven pattern of its collagen bundles resists tensile stress from any direction. It covers fragile tissues and or-gans, protecting them from multidirectional mechanical stresses. It occurs in the reticular layer of the der-mis and in most organ capsules.

Elastic Connective Tissue. Fibers predominate and most are elastic. Elastic fibers are collected in thick, wavy, parallel bundles. The bundles are separated by loose collagenous tissue and fibroblasts with attenuated cytoplasm and condensed, oblong nuclei. Other connective tissue cells may be present in small numbers. The ground substance is sparse and similar to that of other dense connective tissues. Elastic connective tissue provides flexible support and predominates in the vertebral column's ligamenta flava and the suspensory ligament of the penis.

Mucous Connective Tissue. This tissue has few cells and fibers distributed randomly in the abun-dant ground substance, which has a syrupy to jellylike consistency and is composed chiefly of hyaluro-nan. Mucous tissue jields readily to pressure but returns to its original shape. This tissue is useful for pro -tecting underlying structures from excess pressure. It is the predominant components (Wharton's jelly) of the umbilical cord, of the intervertebral disks' nucleus pulposis, and of the pulp of young teeth.

Adipose tissue, or fat, is a connective tissue that is specialized to store fuel. If we were unable to store fuel, all of our time would be spent obtaining food. There are two basic types of adipose tissue: white adipose tissue, or white fat, and brown adipose tissue, or brown fat. Clusters of adipocytes are di -vided into lobes and lobules by collageous connective tissue septa of variable density. Individual cells are surrounded by a reticular fiber network. Ground substance is sparse.

Subcutaneous fat (hypodermis) is the layer of white adipose tissue that is present under the skin, except in the eyelids, penis, scrotum, and most of the external ear (there is some fat in the earlobe). Other prominent fat accumulations occur within the eye orbits, around major joints (knees), and in pads in the palms and soles. In infants, it forms a thermal insulating layer of uniform thickness that covers the entire body and is known as the panniculus adiposus.

Brown fat is less abundant than white fat at all ages. Young and middle-aged adults have little or none, but fetuses, newborns, and the elderly have accumulations in the axilla, near the carotid artery and the thyroid gland, and around the renal hilus. Its metabolic activity is more intense and can generate heat.

Loose connective tissue (areolar tissue) appears disorganized. It consists of a loose network of different fiber types, on which many fixed and wandering cells are suspended. The abundant ground

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substance is only moderately viscous. This flexible yet deliceate tissue surrounds and suspends vessels and nerves, underlies and supports most epithelia, and fills spaces between other tissues. It also supports the serous membranes of the pleura, pericardium, and peritoneum. Always well-vascularized, areolar tis-sue conveys oxygen and nutrients to avascular epithelia. Its cells function in immune surveillance for for-eign substances entering the body through the blood or epithelia.

CellsConnective tissue cells can be grouped into two classes: fixed and wandering.1. Fixed (permanent resident) cells are native to the tissue in which they are found.Mesenchymal cells are the precursors of connective tissue cells. Embryonic mesenchyme com-

prises a loose network of stellate cells and abundant intercellular fluid. Some mesenchymal cells remain undifferentiated in adult connective tissue and constitute a reserve population of stem cells called adventi-tial (pericytes) cells, which are difficult to distinguish from fibroblasts.

Fibroblasts are the predominant cells in connective tissue proper. They synthesize, secrete, and maintain all major extracellular matrix components. In the life cycle fibroblasts pass series of transient stages from undifferentiated elements (stem cells) up to mature cell, lost ability to the further differentia-tion, which has obtained a title - a fibrocyte. This population of cells is called fibroblast differon.

Fibroblast differon include stem cell, unmature fibroblast, mature (active) fibroblast, myofibrob-last, fibroclast and fibrocyte. Unmature fibroblast is mitotically active cell with short processus and round or oval-shaped nucleus. Its cytoplasm is stained slightly basophilic and rich in RNA molecules. Size of the cell is 20-25 mcm. Rouph endoplasmic reticulum and Golgi complexes are undeveloped. Production of collagen and other matrix components very poor. Mature fibroblast is stellate, with long cytoplasmic processes and a large, ovoid, pale-staining nucleus with 1-2 big nucleolus. Size of the cell is 40-50 mcm. The cells are mitotically active, with abundant rouph endoplasmic reticulum and Golgi complexes. This cell type is important in producing collagen and other matrix components and are capable of some move-ment by collagen fibers.

Myofibroblasts are modified fibroblasts that demonstrate characteristics similar to those of both fi-broblasts and smooth muscle cells. Myofibroblasts have bundles of actin filaments and dense bodies simi-lar to those of smooth muscle cells. Additionally, the surface profile of the nucleus resembles that of a smooth muscle cell. Myofibroblasts differ from smooth muscle cells in that an external lamina (basal lam-ina) is absent. Myofibroblasts are abundant in areas undergoing wound healing; they also are found in the periodontal ligament, where they probably assist in tooth eruption.

Fibroclast is cell with high phagocytotic and hydrolytic activity, share in resorption of extracellu-lar matrix in an involution of organs (for example, a uterus after the end of pregnancy). It combine fea-tures of mature fibroblast (well developed rouph cytoplasmic reticulum, Golgi apparatus and rather large, but scarle mitochondrias), and lysosomes with hydrolases. Excreted enzymes disjoins cementing sub-stance of collagenic fibers. Then there is an phagocytosis and lysis of a collagen fibers by acidic proteases of lysosomes. Fibrocytes are less active because they are more mature. Fibrocytes are smaller and spin-dle-shaped, with a dark, elongated nucleus and fewer organelles. They may revert to the fibroblast state and participate in tissue repair.

Macrophages are large, stellate cells derived from monocytes that infiltrate connective tissue and develop into phagocytes. Resident macrophages can proliferate and form additional macrophages. Dye particles injected into the body are engulfed by these cells and accumulate in cytoplasmic granules. Oth-erwise, these cells are difficult to detecl in hematoxilin and eosin-stained sections. Macrophages contain many lysosomes, which aid in digesting phagocytosed materials, and a well -developed Golgi complex. They help maintain connective tissue integrity by removing foreign substances and cell debris, and they participate in the immune response by presenting phagocytosed antigens to lymphocytes. To remove large foreign objects, such as splinters, macrophages may fuse to form multinuclear giant cells.

Monocyte-derived phagocytes, which together constitute the mononuclear phagocyte system, in-clude the macrophages (lymphoid organs, lungs, serous cavities, and connective tissue), as well as Kupf-fer cells (liver), osteoclasts (bone), and microglial cells (central nervous system).

Mast cells are large (20 to 30 mcm) cells derive from bone marrow precursors and have abundant basophilic cytoplasmic granules that are electron-dense in electron microscope. Mast cells also have

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many small plasma membrane folds and a well-developed Golgi complex. The granules, which often ob-scure the small central nucleus, contain heparin, histamine, and eosinophilic chemotactic factor of ana-phylaxis (ECF- A). Mast cells have surface receptors for the IgE antibodies that trigger degranulation, the exocytosis of the granule contents that initiates the local inflammation of allergic reactions. In addition to heparin, mast cell granules also contain neutral proteases (tryptase, chymase, and carboxypeptidases), aryl sulfatase (as well as other enzymes, such as glucuronidase, kininogenase, peroxidase, and superoxide dis-mutase) and neutrophil chemotactic factor (NCF). These pharmacological agents present in the granules are referred to as the primary mediators (also known as preformed mediators). Besides the substances found in the granules, mast cells synthesize a number of mediators from membrane arachidonic acid pre-cursors. These newly synthesized mediators include leukotrienes (LTD4, LTE4 and LTC4), thrombox-anes (TXA2 and TXB2), and prostaglandins (PGDg). A number of other cytokines are also released that are not arachidonic acid precursors, such as platelet-activating factor (PAF), bra-dykinins, interleukins (IL-4, IL-5, IL-6), and tumor necrosis factor-alpha (tnf). All of these newly synthesized mediators are formed at the time of their release and are collectively referred to as secondary (or newly synthesized) mediators.

Adipose cells or adipocytes are mesenchymal derivatives specialized for lipid storage. There are two basic types of adipose tissue: white adipose tissue, or white fat, and brown adipose tissue, or brown fat. A white adipocyte contains a single large lipid droplet; a brown adipocyte contains many small droplets. Unilocular adipocytes derive from mesenchymal precursors resembling fibroblasts. The appear-ance of numerous small cytoplasmic lipid droplets signals their transformation into lipoblasts. As lipid ac-cumulation continues, small droplets fuse until a single lipid droplet forms.

In mature white adipose cells the droplet is so large that it displaces the nucleus and remaining cy-toplasm to the cell periphery. Cell diameter varies from 50 to 150 nm. Adipocytes in histologic sections have a signet-ring appearance because the lipid is washed away during prepation, leaving only a flattened nucleus and a thin rim of cytoplasm. The cytoplasm near the nucleus contains a Golgi com-plex, mitochondria, a small amount of rouph endoplasmic reticulum, and free ribosomes. The cytoplasm in the thin rim contains smooth endoplasmic reticu-lum and pinocytotic vesicles. This tissue is sometimes termed yellow adipose tissue or yellow fat; dietary carotenoids accumulate in the lipid droplets, caus-ing the tissue to appear yellow.

In mature brown adipose cells small lipid droplets locate in cytoplasm. Brown adipocytes are smaller than white adipocytes and have a spherical, cen-tral nucleus. They contain many mitochondria; mitochondrial cytochromes are chiefly responsible for the tan to red-brown tissue color. Loose connective tis-sue septa give brown adipose tissue a lobular appearance resembling a gland in histologic section.

Pericytes, derived from undifferentiated mesenchymal cells, partly surround the endothelial cells of capillaries and small venules. Technically, these perivascular cells are outside the connective tissue compartment because they are surrounded by their own basal lamina, which may be fused with that of the endothelial cells. Pericytes possess characteristics of smooth muscle cells and en-dothelial cells, suggesting that, under certain conditions, they may differentiate into other cells.

Wandering (transient) cells are immigrant cells, usually from blood or bone marrow. Some retain their original characteristics and may eventually leave the connective tissue; most differentiate and be-come permanent residents.

Plasma cells differentiate from antigen-stimulated В lymphocytes. As the primary producers of circulating antibodies, they are the main effectors of the humoral immune response. They are sparsely dis-tributed throughout the body but are abundant in areas susceptible to penetration by bacteria. Plasma cells are large and ovoid, with an eccentric nucleus and abundant rouph endoplasmic reticulum. The character-istic "clock face" nucleus results from a large, central nucleolus and large heterochromatin clumps regu-larly spaced around the nuclear envelope's inner surface envelope. These cells often exhibit a clear jux-tanuclear area (cytocenter) containing a well-developed Golgi complex and centrioles.

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Other blood-derived connective tissue cells. Many wandering cell types originate in the bone mar-row and are carried to connective tissue by the blood and lymph. Blood-derived cells found in connective tissues include the leukocytes (white blood cells, including lym-phocytes, monocytes, neutrophils, eosinophils, and basophils), which have roles in the immune response.

Components of extracellular matrixCollagen is the body's most abundant protein. There are many types, some of

which form fibers. Collagen fibers often form bundles, ranging from 0.5 to 15 nm in diameter. Synthesis and assembly:

Intracellular steps. Free polysomes reading collagen mRNA attach to the rouph endoplasmic reticulum, and protocollagen polypeptides are deposited in the cistemae. Each protocollagen, or alpha chain, has a mass of approximately 28 kDa and contains approximately 250 amino acids; every third amino acid is glycine. Pro-line and lysine residues in the chains are hydroxylated by proline and lysine hydroxylases (possibly in the smooth endoplasmic reticulum) to form hydroxyproline and hydroxylysine, rare amino acids present in large amounts in collagen. Core sugars (galactose and glucose) attach to the hydroxylysine residues in the endoplasmic reticulum. With the aid of registration peptides at the ends of the alpha chains, three chains coil around one another to form a triple-helical molecule called procollagen. Further glycosylation may occur in the Golgi complex, where procollagen is packaged. Golgi vesicles release procollagen into the extracellular space by exocytosis.

Extracellular steps. In the extracellular space, the enzyme procollagen peptidase cleaves the regis-tration peptides from procollagen, converting it to tropocollagen. Nearby cells align tropocollagen mole-cules in a staggered fashion to form collagen fibrils, and also arrange fibrils into fibers. Cell attachments to the fibers are mediated by plasma membrane integrins that bind to the matrix glycoprotein fibronectin, which in turn binds to the collagen. The extracellular enzyme lysyi oxidase stabilizes the nascent fibers by cross-linking lysine and hydroxylysine residues in adjacent tropocollagens.

Collagen types. Of the 20 known collagen types, seven are of particular importance. Their struc-tures differ in the amino acid sequences of their alpha chains. Type I, the most abundant and widespread, forms large fibers and fiber bundles. It occurs in tendons, ligaments, bone, dermis, organ capsules, and loose connective tissue. Type 11 occurs in adults only in the cartilage matrix (some occurs in embryonic notochord) and forms only thin fibrils. Type Ш resembles type I, but is more heavily glycosylated and stains with silver. Often occurring with type I, type III forms networks of thin fibrils (reticular fibers) that surround and support soft flexible tissues (adipocytes, smooth muscle cells, nerve fibers). It is the major fiber of hematopoietic tissues (bone marrow, spleen) and of reticular laminae of epithelial basement membranes. Type IV is the major collagen type in basal laminae. It does not form fibers or flbrils. Type V occurs in placental basement membranes and blood vessels. Type X is found in the matrix surrounding hypertrophic chondrocytes of growth plate cartilage in sites of future bone formation. Types IX and XI occur in association with type II in cartilage.

Collagen occurring in large or small bundles of fibrils or as individual fibrils stains pink in H & E-stained sections. All collagen fibrils and fibers have stripes at 64-nm intervals along their length. This pe-riodicity reflects the staggering of tropocollagen molecules.

The most important mechanical property of collagen fibers is tensile strength, which is, weight for weight, greater than that of steel.

Collagen fibers occur in all connective tissues and in reticular laminae of basement membranes. In bone, their lacunar regions (spaces between overlapping tropocollagen) act as nucleation sites for hydrox-yapatite crystals.

Reticular fibers resemble collagen fibers but are thinner (0,1- 1.5 nm), are more highly glycosylated, and form delicate silver-stain-ing networks instead of bundles. The supportive fiber networks allow motile cells to move about in loosely arranged (hematopoietic) tissues. Reticular fibers consist mainly of type-Ill collagen and glycoproteins.

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Elastic fibers range in diameter from 0.1 to 10 nm. They con-sist of the amorphous protein elastin, in which are embedded mаnу protein microfibrils.

Synthesis and assembly:Intracellular steps. Microfibrillar proteins and proelastin are

synthesized on rouph endoplasmic reticulum and secreted sepa-rately. Proelastin contains large amounts of three hydrophobic amino acicids- glycine, proline, and valine—which accounts for elastin's insolubiliti. Microfibrillar protein contains mostly hy-drophilic amino acids.

Extracellular steps. Proelastin molecules polymerize extracellularly to form elastin chains. Lysyi oxidases subsequently catalyze the conversion of some elastin lysine residues to aldehydes, three of which condense with a fourth, unaltered lysine to form desmosine and isodesmosine. These amino acids, rare except in elastin, cross-link individual elastin chains. Elastin subsequently associates with many mi-crofibrils to form a branching and anastomosing network of elastic fibers. Owing to elastin's unusual composition, its turnover requires the specialized enzyme elastase.

Because it has few charged amino acids, elastin stains poorly standard with ionic dyes. Special stains, such as Verhoeffs stain or Weigert`s resorcin-fuchsin stain, are used in light microscopic prepara-tions. In electron microscope preparations, both the elastin and microfibrils can be visualized.

Elastic fibers can stretch to 150% of their length without breaking and return to their original length. Elastic fibers occur where their mechanical properties are needed to allow tissues to stretch or ex-pand and return to their original shape (in arterial walls, the lungs' inter-alveolar septa, bronchi and bron-chioles, vocal ligaments and cartilages, and ligamenta flava of the vertebral column).

Ground substance primarily consists of two glycoconjugate classes: proteoglycans and glycopro-teins. Tissue fluids and salts also are present. Proteoglycans consist of a core protein to which gly-cosaminoglycans (GAGs) are attached. GAGs of proteoglycans are straight-chain polymers of repeating amino sugar heterodimers made up of a hexosamine (glucosamine or galactosamine) and a uronic acid (glucuronic or iduronic acid). Five major classes of GAGs, differing in their sugars, exist in connective tissues: hyaluronic acid (which does not form proteoglycans), phondroitin sulfate, dermatan sulfate, ker-atan sulfate, and heparan sulfate.

Glycoproteins are proteins to which shorter, branched oligosaccharide chains are cova-lently bound. Glycoproteins of ground substance are much smaller than proteoglycans. Examples: fibronectin, which mediates cell adhesion to the extracellular matrix, and laminin, a basal lamina component that me-diates epithelial cell adhesion. For both of these adaptor proteins, linkages between the matrix and the cy-toskeleton are mediated by integrins.

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IMMUNE SYSTEMThe immune system of an organism consist of two basic ingredients: organs of a hemopoiesis and

lymphoid organs (a red bone marrow, a thymus gland, a spleen, a lymph nodes) and immune cells, or im-munocytes.

Main function of immunocytes is to provide organism responses on a specific discernment and de-struction (elimination) of an antigen.

Typical immunocytes are T-and B-lymphocytes, macrophages and plasmocytes. The leading part in responses of artificial immunity belongs to lymphocytes as only they can specificly recognize a con-crete antigen.

All lymphoid tissues and organs produce lymphocytes. In peripheral lymphoid organs (lymph nodes, spleen, tonsils) and unencapsulated lymphatic aggregates, lymphocyte production is antigen-de-pendent and provides committed immunocompetent cells that respond to specific antigens. In central lym-phoid organs (thymus, bone marrow, bursa of Fabricius [in birds]), lymphocyte production is antigen-in-dependent and supplies uncommitted T-lymphocyte (thymus) or B-lymphocyte (bone marrow, bursa) precursors that subsequently move to peripheral organs and tissues. Mounting effective immune re-sponses to new antigens requires ongoing production of uncommitted lymphocytes by the central lym-phoid organs.

Cellular (cell-mediated) immunity. Activated T -lymphocytes differentiate into specialized cell types, some of which (CD8+) contact and kill intruding cells, and some of which (CD4+) release cy-tokines, substances that enhance various aspects of the immune response. Cytokines are interleukins (IL): IL 1, IL 4, IL 5, IL 6, interferons, the factor of a necrosis of tumour.

Humoral immunity. Activated В lymphocytes differentiate into plasma cells that secrete antigen-binding immunoglobulins (antibodies), which circulate in the blood and lymph.

Immunologic memory. Lymphoid function in response to initial exposure to a particular infection protects an organism during subsequent exposure to the same infective agent.

Specificity. An ability to respond to one type of infection (chicken pox) does not imply resistance to another (tuberculosis).

Tolerance. Antigen-disposal mechanisms directed toward the body's own cells (as occurs occa-sionally in autoimmunity) can be disastrous, even fatal. Thus, a key aspect of immune function is the abil-ity to distinguish "self from "nonself' antigens, and to tolerate the self.

Lymphocyte programming and activation: This multistep process is outlined below.1. Cells of mesodermal origin are programmed in the bone marrow or thymus as B- or T-lympho-

cyte precursors, respectively.2. These cells subsequently move to peripheral organs, where each encounters a specific antigen

to which it becomes programmed (committed) to respond. The concentration of antigens on the surfaces of antigen-presenting cells, or the delivery of processed antigens to lymphocytes by macrophages, im-proves the efficiency of this step over that available from random lymphocyte-antigen collisions.

3. Not all lymphocytes can respond to all antigens. Our ability to respond to a variety of antigens rests in the diversity of antigen-binding capabilities of virgin (preactivated) lymphocytes. It is estimated that lymphocytes able to bind more than a billion different antigens are present prior to any antigenic challenge. When such a challenge occurs, a lymphocyte able to bind the antigen is selectively stimulated to divide (activated). Activated cells enlarge and form lymphoblasts (blast transformation) and subse-quently undergo a series of divisions (clonal expansion), forming a clone of cells competent to recognize that antigen. This process is termed clonal selection. Many immunocompetent lymphocyte clones may be generated in response to different parts of a single antigen.

4. The products of this initial clonal expansion undergo differentiation into two basic cell types; effector cells, which immediately begin antigen disposal (primary immune response), and memory cells, which are held in reserve for subsequent encounters with the antigen (secondary immune response). T-lymphocyte derivatives form three main effector cell types, which enter the circulation and search the body for their antigens, providing cellular immunity. B-lymphocyte derivatives form only one effector cell type: plasma cells. These usually remain in the tissue or organ, where they differentiate and secrete into body fluids the Igs that provide humoral immunity.

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5. When the same antigen is again encountered, memory cells generated during the initial clonal selection and expansion (either T or B) undergo the same process—blast transformation, clonal expansion and differentiation—that occurs during the primary response, but more rapidly (with a shorter lag time between exposure and response) and more effectively (owing to the increased number of responsive cells, and the greater affinity of the antibodies) than before.

AntigensThese are foreign (nonself) substances that are able to elicit an immune response (cellular, hu-

moral, or both). They can be entire cells (bacteria, tumor cells) or large molecules (proteins, polysaccha-rides, nucleoproteins). Their antigenicity is determined by several factors: larger and more complex (branched or folded) molecules are more potent antigens than smaller, simpler ones; proteins are more antigenic than carbohydrates; and lipids are nonantigenic unless complexed with a more potent antigen. Particularly potent antigens are said to be immunodominant. The site of entry of an antigen into the body also can affect its antigenicity. The specific part of an antigen that elicits the immune response (and to which the antibodies bind) is called an antigenic determinant, or epitope; it can consist of a monosaccha-ride or as few as four to six amino acids. Thus a bacterium can have many antigenic determinants and elicit many cellular and humoral responses.

Immunoglobulins (Ig)These antibodies are proteins secreted by plasma cells into body fluids (blood, lymph, tissue fluid,

saliva, tears, milk, mucus) in response to antigenic stimulation. They bind with high affinity to the anti-genic determinants that elicited their production and make up most of the blood's gamma-globulins.

Immunoglobulins (antibodies) are immune protective proteins. Everyone Ig has rigorous speci-ficity to concrete antigen. Exist in two forms: a) as membranous receptors of a B-lymphocytes; b) as the antibodies loosely circulating in a blood plasma and a lymph. Function value of immunoglobulins con-sists in: 1) a specific discernment and the subsequent interlinking of antigens; 2) interaction Ig with other immunocytes having receptors to Ig. Ig, circulating in a blood and a lymph, participate in the initial stage of the immune answer. At infiltration of antigens in a blood, molecula Ig with the help of a Fab-frag-ment contacts it. Thus cell-bound immune complex, or a complex "an antigen - an antibody" is formed. Molecula Ig incorporates two major fields: 1) A Fab-fragment (fragment antigen binding) is a field for in-terlinking an antigen and 2) a Fc-fragment, in charge of bracing Ig on a plasmolemma of lymphocytes and antigen-presenting cells. On a plasmolemma of immunocytes (macrophages) there are Fc-receptors for a discernment of a Fc-fragment. After formation of a cell-bound immune complex antigen-presenting cells (macrophage) with the help of a Fc-receptor attaches it and, then, phagocyte. Thus, Ig facilitate and accel-erate an englobement of an antigen. Such relief of an englobement is termed opsonization.

Immunoglobulin structure: Familiarity with the Y-shaped structure of Igs and the positions of their components facilitates understanding of the lymphoid system.

Heavy and light chains. Each IgG has two heavy chains (50 kDa each) and two light chains (23 kDa each). The heavy chains form the stem and part of each arm of the Y. The light chains lie in the arms, parallel to the heavy chains.

Constant and variable domains. Each chain (heavy or light) includes a region that is constant from one IgG to another and a region of variable structure that determines the antibody's binding specifity. The veriable domains occupy the distal ends of the arms, and the constant regions ale in the stem and proximal parts of the arms.

Fc and Fab regions. The proteolytic enzyme papain cleaves each Ig into three fragments at the branch point of the Y (hinge region). The single cryslallizable fragment (Fc region) includes part of the constant domain occupying the stem. It is crystallizable because only a pure preparation of a single pro-tein crystallized and because even in a mixture of antibodies with different binding affinities, the stem structure is constant. There are two antigen-binding fragments (Fab regions), which include the entire light chain and variable and constant portion of the heavy chain. Because they vary from one antibody to another, Fab fragments from a mixture of IgGs are not crystallizable.

4. Antigen-binding and cell-binding regions. The amino-terminal region of the variable portions of each arm of the Y is the antigen-binding site. Thus, each Ig has two antigen-binding sites. The cell-bind-

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ing region is the carboxyl terminus at the base of each heavy chain. Thus, the Fc fragment harbors the cell-binding region and differs among the immunoglobulin types.

Igs comprise five major groups based on the nature of their Fc regions.IgG. The most abundant type in blood (75% of serum Ig), IgG occurs mainly as a monomer.

When it binds to its antigen, its Fc region extends away from the antigen and is accessible to Fc receptors on cells (neutrophils, macrophages), making IgG very effective at promoting antigen disposal by phago-cytosis. IgG appears later than IgM after an initial antigenic challenge and is a bit less effective in com-plement activation, but it shows greater antigen-binding specificity. It constitutes most of the secondary humoral immune response and can remain active in blood for many weeks (six times as long as IgM). IgG can cross the placenta to confer passive immunity on the fetus; it is also found in human milk.

IgA. This secretory antibody is the main Ig in body secretions (saliva, tears, mucus, colostrum, nulk, semen, vaginal fluid), but makes up only 0.2% of serum Ig. Exists in 2 forms: serum and secretory. Secretory IgA includes two IgA monomers linked through their Fc regions by protein J to form dimers. This renders IgA more soluble and less likely to be sequestered by binding to Fc receptors on cells. An-other protein, the secretory, or transport, component is produced by mucosal epithelial cells. This protein is carried on mucosal cell surfaces and allows these cells to pick up IgA-protein J complexes from plasma cells in the connective tissue underlying epithelia and transport them from the cells' basal surface to the lumen where they are released into the secretions.

IgM. Although it constitutes only 10% of serum Ig, IgM is the major Ig in the primary immune re-sponse. Secreted soon after a new antigenic challenge, it is larger and less antigen-specific than IgG. It occurs as a monomer, along with IgD, on the surface of virgin B lymphocytes. When antigen binds to these surface antibodies, В cells are activated. They begin differentiating into plasma cells and secreting a soluble IgM. Secreted IgM forms pentamers, with its Fc regions joined at the core of the macromolecule and its antigen-binding regions directed outward. IgM is highly effective in complement activation. The half-life is peer to 5 days. Circulate in a blood. Besides fulfill function of antigen receptors of B-lympho-cytes. In a regulation of their synthesis T lymphocytes of participation do not accept.

IgE. Normally, IgE occurs as a monomer in very small amounts in the serum. Its Fc portion binds avidly to cell-surface Fc receptors on mast cells and basophils, leaving its antigen-binding site's extending away from the cell surface. Antigens binding to IgE cross-link the receptors and stimulate the release of histamine, heparin and leukotrienes from the cytoplasmic granules. Antigens that bind to IgE or stimulate its production are termed allergens, and IgE plays a major role in allergic reactions and parasitic infec-tions.

IgD. The least understood immunoglobulin, IgD may function as an embryonic or fetal Ig. It is rarely secreted, and its plasma concentration is low (1% of serum Ig). It occurs chiefly as an antigen re-ceptor on the surface of В lymphocytes along with IgM. A half-life 3 days. Does not pass through a pla-centa. Plays the important role in a differentiation of B-lymphocytes under influence of an antigen chal-lenge.

A major histocompatibility complex (MHC).The special protein molecules present on a plasmolemma of all cells and defining genetical

uniqueness of a concrete organism, are termed molecules of major histocompatibility complex (MHC) or human leukocyte antigen (HLA). The MHC are responsible: 1) an expressiveness of transplantant re-sponses of a casting-off reaction, 2) immune response to the taken antigen. Proteins of MHC are divided into 3 classes: the MHC of 1-st class (MHC 1), MHC of 2-nd class (MHC 2), the MHC of 3-rd class (MHC 3). MHC 1 is present on a plasmolemma of all cells of an organism. The MHC 2 is present on a plasmolemma only immunocytes (T-and B-lymphocytes, antigen-presenting cells). MHC 1 contact with endogenic cell-like peptides and are represented to T lymphocytes killers/supressors (CD 8+to cells) for a discernment "own"-"another's " and the subsequent activation of these cells.

Antigen presenting cells. A processing of an antigen. Role of the MHC 2.Classical antigen presenting cells (APC) are macrophages (MP) and series of other cells (B-lym-

phocytes, dendritic cells ofthe epidermis and oral mucosa, epithelial reticular cells of thymus). For devel-opment of the immune response it is necessary, that there was an activation of T0 lymphocytes helpers with phenotype CD 4+0. Such T0 lymphocytes helpers are formed in a thymus gland and, then, in periph-

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eric hemopoietic it-organs become active after contact with APC (macrophages). Beforehand macrophage process an antigen. Thus macrophage phagocytose, catabolize and process an antigen. As a result of a processing the big molecule of a protein antigen (bacteria) is disjoined on small peptides from several amino acids. These small peptides are termed epitopes. Macrophage attach their epitopes to MHC II mol-ecules on the plasmalemma and present this complex to T cells. T cell with the help of CD4+ receptor finds out MHC II molecules with an epitope.

Macrophage produce interleukin 1. After that contact T0 lymphocytes helpers is labilized and dif-ferentiated into 2 active subclasses: 1) T helper 1-st type and 2) T helpers 2-nd type. In this differentia -tion paticipate blood basophil producing interleukin 4. T helper 1 -st type secrete interleukin 2 and gamma-interferon and this substances activate cytotoxic T lymphocytes (syn: T-killer, CD 8 + cells), i.e. the cellular immune answer. T helpers 2-nd type produce the interleukin 4, the interleukin 5, the inter-leukin 6 also activate by them В lymphocytes. В lymphocytes differentiates in a plasma cells and the B-memory cell. Thus, T helpers 2-nd type induces the humoral immune answer. The plasma cells begins Ig production.

Macrophages typically are monocyte derivatives (components of the mononuclear phagocyte sys-tem). Others may differentiate in situ from mesenchymal precursors. They are large, often migratory phagocytic cells. In both cellular and humoral immunity, they phagocytose complex antigens and enhance their antigenicity by breaking them into myriad antigenic determinants and by complexing them with MHC molecules on their surface for presentation to lymphocytes. They also phagocytose antigen-anti-body complexes. Macrophages interact with T lymphocytes chiefly through direct cell contact, presenting the MHC-complexed antigens on their surface. Macrophages line vascular sinuses, are distributed among the lymphocytes of lymphoid organs and tissues, and are dispersed in loose connective tissues.

Clusters of a differentiationOn a plasmolemma of lymphocytes and other immune cells is special glycoprotein moleculas

which are termed clusters of a differentiation (CD-molecules, abbr. from " Clusters of differentiation "). At each cluster the order number. Scientists define presence of clusters on a plasmolemma of lympho-cytes with the help immunohistochemistry methods. As even in an electron microscope it is impossible to distinguish from each other various subpopulations of lymphocytes (the T-killer from a T-lymphocyte helper), scientists differentiate them on presence of those or other clusters. Clusters compound phenotype of lymphocytes. Lymphocytes with phenotype of CD 4 + fall into to T-lymphocytes helper, and with phe-notype of CD 8+ concern simultaneously to T-killers and T-lymphocytes supressors. Lymphocytes with phenotype of CD 19+, 20+, 21+, 22 + are B- lymphocytes. The molecule of CD 4 at T-helper fulfills re-ceptor function of a recognition of a molecule of the MHC 2 on a surface of antigen- presenting cells. The molecula of CD 8 at T-cytotoxic lymphocyte fulfills receptor function for a discernment of molecules of the MHC 1 on a plasmolemma of all cells of an organism.

LymphocytesThese are the principal cells of the lymphoid system. Their ability to recognize and respond to for-

eign cells and substances is the basis for initiating an immune response, but lymphocytes are not phago-cytic. Bone marrow-derived precursors enter the circulation and populate central lymphoid organs. Those in the thymus become T-lymphocyte precursors. B-lymphocyte programming apparently occurs in spe-cific bone marrow microenvironments.

Lymphocytes are basic immunocompetent cells. Compound in a blood plasma of the adult person 19 %-37 % from all leucocytes. Are agranulocytes. Indications of lymphocytes is presence of a large un-segmented nucleus, frequently with a cutting, and a fine-bored fillet of cytoplasm. Specific granules miss. On a plasmolemma microvillis can be observed. The major features all lymphocytes:

1. Constantly leave from hemopoietic organs for a blood and a lymph, circulate in a blood, and, then, leave from vessels through a unimpaired endothelium for tissues in searches of an antigen for secu-rity of function of immune supervision. After patroling tissues and eliminations of an antigen are re-verted back in a blood. Such ability of lymphocytes is termed recirculation.

2. After contact to an antigen the mature lymphocyte is labilized and is capable to be differentiated in the opposite direction, i.e. in a young lymphoblast. It is termed lymphocytes blast transformation. The lymphoblast is actively divided by a mitosis (proliferation), yielding hundred thousand and more than the

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filial lymphocytes absolutely similar on a panel of cell-like receptors on the lymphocyte - precursor. Such ability of lymphocytes is termed a clonal expansion (cloning).

3. Contain on a plasmolemma cellular receptors for a specific discernment and connection an anti-gen.

T lymphocytesT cells are primarily responsible for cell-mediated immunity. They compound a long-lived and

sluggishly recirculating population of cells. Term of life is till 15-20 years. Their quantity in a periphery blood compounds 55-75 % from total number of lymphocytes. They carry antibody-like antigen receptors (but not Igs) on their surfaces. When antigens bind to these receptors, T lymphocytes undergo blast trans-formation and proliferation and produce both effector and memory cells. They require the aid of macrophages or other types of antigen- presenting cells for an optimal response. This reflects the need for an antigen to be complexed with major histocompatibility complex (MHC) molecules for T-cell activa-tion. Two major T-lymphocyte effector cell types are distinguishable based on characteristic cell-surface molecules (CD4 and CD8) and their different roles in immunity:

Helper T cells carry the CD4 marker on their surface and are thus said to be CD4-positive or CD4+ T cells. Exist in the zero (naive) and activated form. Labilize function of T-cytotoxic lymphocytes (T helpers of 1 -st type, by means of a secretion the interleukin 2). Collaterally labilize blast transforma-tion and a proliferation of В lymphocytes (T helpers of 2-nd type, by means of a secretion the interleukin 4, 5,6, 10 and interferon). They are activated by antigen complexed with MHC class II molecules on the surface of antigen-presenting cells. Because proteins in the coat of the human immunodeficiency virus (HIV) bind selectively to the CD4 protein, CD4+ cells are important targets of HIV infection. Moreover, the disposal of HIV-infected CD4+ cells by the immune system is a major factor in the immunodeficiency characterizing acquired immunodeficiency syndrome (AIDS).

Cytotoxic T cells carry the CD8 marker on their surface and are thus CD8+ T cells. They recog-nize, adhere to, and kill - by cell lysis—invading bacteria, virus-infected cells, transplanted cells, and tu-mor cells. Are effectors of cellular immunodefence. These cells play a principal role in graft rejection. Their killing activity requires activation hi by their specific antigen.

Natural killer (NK) cells are circulating lymphocytes that cannot be classed as either T or В cells (they lack both T and В surface antigens). Marker clusters for them is CD 16 and CD 56. Compound 10 % from all lymphocytes. Like cytotoxic T cells, they attack and lyse invading cells (tumor cells and virus-infected cells) through direct cell-cell contact. However, NK cell-mediated killing appears to be indepen-dent of antigenic activation (it is natural or innate). The mechanism whereby these cells target nonself cells for destruction is not entirely clear, but may involve IgG. They also enhance immune responses by secreting the cytokine interferon.

Supressor T cells appears to be a third type of T effector (also CD8+), based on evidence that some interactions between T and В cells actually inhibit B-cell activity. Prevent development of autoim-mune responses. Whether this is true inhibition or redirection of the immune response is not yet clear.

Memory cells. Remember the first meeting with an antigen. Accelerate the secondary immune an-swer.

T-hypersensitivity of time-lagged type (T-HTT). Participate in development of allergic responses.T-cellular receptors

Except of molecules of the MHC and CD, on a plasmolemma of T lymphocytes are T-cellular re-ceptors (TCR) with which help they recognize an antigen. Receptors on a surface of T lymphocyte are strictly specific to one type of an antigen. After contact to an antigen and the received help from T-helper of 1-st type as the interleukin 2 T-killers undergo blast transformation and proliferation. Appear a clone of dauter cytotoxic lymphocytes with precisely same TCR.

The mechanism of cytolytic activity of the T-killer (T-cytotoxic lymphocyte) on a cell - target

T-cytotoxic lymphocyte is effector of cellular immunodefence. Cytotoxic (cytolytic) responses is effector immune mechanisms direct on elimination of cells which are too large for a phagocytosis by rou-tine phagocytes (neutrophils). The cell of an antigen (a bacterium, a cancer cell, cell with virusis) is a cell - target for the T-killer. The cell with virus contains a complex consisting of the MHC 1 and virus pep-

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tides on the plasmolemma. The T-killer with help of TCR recognize an antigenic peptide, and with the help of receptor CD8 finds out a molecula of the MHC 1. Thus the T-killer forms with a cell - target strong communication. Then the T-killer secrite from the granules proteins perforin and granzims. Per-form invokes pores and ion channels in a plasmolemma of a target cell. Through pores inside of a cell - target water starts to come uncontrolledly and it bursts. Besides through pores go to cytoplasm granzims (major of them granzim B). They include in a nucleus of a cell - target the mechanism of apoptosis (ge-netical programmed destruction of a cell). As a result of an apoptosis activation the cell - target blasts it-self. After a secretion of perform and granzim T-cytotoxic lymphocyte is disconnected from a target and searches for a new antigen to manufacture new cytolysis.

В lymphocytes and plasmocytes are effectors of humoral immunodefence. В lymphocytes com-pound in a periphery blood 30 % from total number of lymphocytes. Duration of their life is insignificant and is calculated by days or weeks. В lymphocytes fulfill double function: 1) can be differentiated in plas-mocytes, which produce antibodies, 2) to appear in a role antigen presenting cells.

В lymphocytes (B cells) are primarily responsible for humoral immunity and carry IgM and IgD on their membranes as antigen receptors. When antigens bind to these Igs, В lymphocytes undergo blast transformation and clonal expansion. Most of the resulting daughter cells differentiate into plasma cells; others become memory cells that react to the same antigen in subsequent encounters. В cells require assis-tance from helper (CD4+) T cells to respond to antigens incapable of cross-linking B-cell surface antigen receptors; these antigens are called T-dependent (thymus-dependent) antigens.

Plasma Cells (plasmocytes) are differentiated B-lymphocyte effector cells secrete the Igs primarily responsible for humoral immunity. Their morphology includes a "clock face" nucleus, basophilic cyto-plasm and abundant rouph endoplasmic reticulum typical of protein-secreting cells. Plasma cells, found in all lymphoid tissues and loose connective tissue, occur in high concentration in the medullary cords of lymph nodes, the red pulp cords in the spleen, and the lamina propria under mucosal and glandular epithe-lia. They are rare in the thymus, occurring only in the medulla. Each plasma cell secretes only one class of Ig that binds only one antigen. Summing up, it is possible to note the basic stages of the immune an-swer of an organism (by the example of introduction of exogenic antigen):

1) Introduction of an antigen in a blood, connection it to Ig with formation of a cell-bound im-mune complex and, thus, opsonization of phagocytosis.

2) A phagocytosis of a cell-bound immune complex by antigen-presenting cell (macrophage), a processing of an antigen up to peptides (epitopes).

3) Presentation of an epitope together with the MHC 2 to "zero" T-helper. Its differentiation on T-helper of 1-st and 2-nd type.

4) T-helper of 1-st type stimulate cellular immune answer, i.e. help (by means of a secretion the interleukin 2 the T-killer. A discernment the T-killer of an antigen and an activation of this effector. Blast transformation and cloning of T-killers. Cytolysis of a cell-target with the help of performs and gramzins.

5) Stimulation by T-helper of 2-st type humoral immune answers, i.e. the help to а В lymphocyte (by means of a secretion the interleukin 4, the interleukin 5, the interleukin 6, the interleukin 10). A dis-cernment by a B lymphocyte of an antigen and an activation of this effector. Blast transformation and cloning. Formation of plasma cells and В cells of immunological memory. A secretion of all 5 classes of immunoglobulins by a clone of plasma cells.

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CARTILAGEThe characteristic indications distinguishing dense connective tissue from other types of a connec-

tive tissue are:1. Prevailing development of extracellular substance (especially fibers) and concerning a small

amount of cells. The cells are mainly mature fibroblasts (fibrocytes).2. A regulated locating of histological elements.3. Presence of interlayers of loose connective tissue. Distinguish a fibrous and elastic dense connective tissue. There are two types: regular, with a ro-

pelike arrangement of fiber bundles, and irregular, with a fabriclike arrangement.Dense irregular connective tissue contains mostly collagen fibers. Cells are the fibroblast. This tis-

sue also contains relatively little ground substance. Because of its high proportion of collagen fibers, dense irregular connective tissue provides significant strength. Typically, the fibers are arranged in bun-dles oriented in various directions thus the term "irregular"), which can withstand stresses on organs or structures. Hollow organs (e.g., the intestinal tract) possess a distinct layer of dense irregular connective tissue called the submucosa, in which the fiber bundles course in varying planes. This arrangement allows the organ to resist excessive stretching and distension. Similarly, skin contains a relatively thick layer of dense irregular connective tissue in the dermis, called the reticular layer of the dermis. Dense irregular connective tissue in most organ capsules. It provides resistance to tearing as a consequence of stretching forces from different directions.

Dense regular connective tissue is characterized by ordered and densely packed arrays of fibers and cells. It is the main functional component of tendons, ligaments and aponeuroses. As in dense irregu-lar connective tissue, the fibers of dense regular connective tissue are the prominent feature, and there is little ground substance. However in dense regular connective tissue, the fibers are arranged in parallel ar-ray and are densely packed to provide maximum strength. The cells that produce and maintain the fibers are packed and aligned between fiber bundles.

Tendons are cord-like structures that attach muscle to bone. They consist of parallel bundles of collagen fibers.

Situated between these bundles are rows of fibroblasts called tendinocytes. In most hematoxiline and eosin stained longitudinal sections tendinocytes appear only as rows of typically flattened basophilic nuclei. The cytoplasmic sheets that extend from the body of the tendinocytes are not usually evident be-cause they blend in with the coollagen fibers. The substance of the tendon is surrounded by a thin connec-tive tissue capsule, the epitendineum, in which the collagen fibers are not nearly as orderly. Typically, the tendon is subdivided into the first-order fascicles by endotendineum, a connective tissue extension of the epitendineum. Some first-order fascicles form the fascicle of the second order enclosed by a more heavy extension of a loose connective tissue peritendineum. Some second-order fascicles form the fascicle of the third order enclosed by a thin connective tissue capsule, the epitendineum. It contains the small blood vessels and nerves of the tendon.

Ligaments, like tendons, consist of fibers and fibroblasts аrranged in parallel. The fibers of liga-ments, however, are less regularly arranged than those of tendons. Ligaments join bone to bone, which in some locations, such as in the spinal column, requires some elasticity. Although collagen is the major ex-tracellular fiber of most ligaments, some of the ligaments associated with the spinal column (e.g., liea-menta flava) contain many elastic fibers and fewer collagen fibers. These ligaments are called elastic liga-ments.

Aponeuroses resemble broad, flattened tendons. Instead of fibers lying in parallel arrays, the fibers of aponeuroses are arranged in multiple layers. The bundles of collagen fibers in one layer tend to be ar-ranged at a 90° angle to those in the neighboring layers. The fibers within each of the layers are arranged in regular arrays; thus it is a dense regular connective tissue. This orthogonal array is also found in the cornea of the eye.

Cartilage is a skeletal connective tissue characterized by firmness and resiliency. It forms the fetal skeleton and persists where its mechanical properties are needed. Most fetal cartilage is replaced by bone.

Like all connective tissues, cartilage consists of cells, fibers, and ground substance. The extracel-lular matrix predominates and determines its mechanical properties. Collagen is a characteristic cartilage

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matrix component. The abundant ground substance is firm and gel-like. Cartilage possesses cells called chondrocytes, which occupy small cavities called lacunae within the extracellular matrix they secreted. The substance of cartilage is neither vascularized nor supplied with nerves or lymphatic vessels; however, the cells receive their nourishment from blood vessels of surrounding connective tissues by diffusion through the matrix. Owing to their meager oxygen supply, chondrocytes produce much of their energy by anaerobic glycolysis. The extracellular matrix is composed of glycosaminogly-cans and proteoglycans, which are intimately associated with the collagen and elastic fibers embedded in the matrix. The flexibil-ity and resistance of cartilage to compression permit it to function as a shock absorber, and its smooth sur-face permits almost friction-free movement of the joints of the body as it covers the articulating surfaces of the bones.

Three types of cells are associated with cartilage: chondrogenic cells, chondroblasts, and chondro-cytes.

Chondrogenic cells are spindle-shaped, narrow cells that are derived from mesenchymal cells. They possess an ovoid nucleus with one or two nucleoli. Their cytoplasm is sparse, and electron micro-graphs of chondrogenic cells display a small Golgi apparatus, a few mitochondria, some profiles of rough endoplasmic reticulum, and an abundance of free ribosomes. These cells can differentiate into both chon-droblasts and osteoprogenitor cells.

Chondroblasts are derived from two sources: mesenchymal cells within the center of chondrifica-tion and chondrogenic cells of the inner cellular layer of the perichondrium (as in appositional growth). Chondroblasts are plump, basophilic cells that display the organelles required for protein synthesis. Elec-tron micrographs of these cells demonstrate a rich network of rough endoplasmic reticulum, a well- de-veloped Golgi complex, numerous mitochondria, and an abundance of secretory vesicles.

Chondrocytes are chondroblasts that are surrounded by matrix. Those near the periphery are ovoid, whereas those deeper in the cartilage are more rounded, with a diameter of 10 to 30 nm. Histologi-cal processing creates artifactual shrinkage and distortion of the cells. Chondrocytes display a large nu-cleus with a prominent nucleolus and the usual organelles of protein-secreting cells. Young chondrocytes have a pale-staining cytoplasm with many mitochondria, an elaborate rough endoplasmic reticulum, a well-developed Golgi apparatus, and glycogen. Older chondrocytes, which are relatively quiescent, dis-play a greatly reduced complement of organelles, with an abundance of free ribosomes. Thus, these cells can resume active protein synthesis if they revert to chondroblasts.

There are three types of cartilage according to the fibers present in the matrix. No distinction is made among the cells in different cartilage types.

Hyaline cartilage contains type II collagen in its matrix; it is the most abundant cartilage in the body and serves many functions.

Elastic cartilage contains type II collagen and abundant elastic fibers scattered throughout its ma-trix, giving it more pliability.

Fibrocartilage possesses dense, coarse type I collagen fibers in its matrix, allowing it to withstand strong tensile forces.

The perichondrium is a connective tissue sheath covering that lies over most cartilage. It has an outer fibrous layer and inner cellular layer whose cells secrete cartilage matrix. The perichondrium is vas-cular, and its vessels supply nutrients to the cells of cartilage. In areas where the cartilage has no peri-chondrium (e.g., the articular surfaces of the bones forming a joint), the cartilage cells receive their nour-ishment from the synovial fluid that bathes the joint surfaces.

Histogenesis and Growth of Cartilage. Cells responsible for hyaline cartilage formation differenti-ate from mesenchymal cells.

In the region where cartilage is to form, individual mesenchymal cells retract their processes, round up, and congregate in dense masses called chondrification centers. These cells differentiate into chondroblasts and commence secreting a matrix around themselves. As this process continues, the chon-droblasts become entrapped in their own matrix in small individual compartments called lacunae.

Chondroblasts surrounded by matrix are referred to as chondrocytes. These cells are still capable of cell division, forming a cluster of two to four or more cells in a lacuna. These groups are known as isogenous groups. As the cells of an isogenous group manufacture matrix, they are pushed away from

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each other, forming separate lacunae and thus enlarging the cartilage from within. This type of growth is called interstitial growth.

Mesenchymal cells at the periphery of the developing cartilage differentiate to form fibroblasts. These cells manufacture a dense irregular collagenous connective tissue, the perichondrium, responsible for the growth and maintenance of the cartilage. The perichondrium has two layers, an outer fibrous layer composed of type I collagen, fibroblasts, and blood vessels and an inner cellular layer соmposed mostly of chondrogenic cells. The chondrogenic cells undergo division and differentiate into chondroblasts, which begin to elaborate matrix. In this way cartilage also grows by adding to its periphery, a process called appositional growth. Interstitial growth occurs only in the early phase of hyaline cartilage forma-tion.

Articular cartilage, however, which lacks a perichondrium, grows only by interstitial growth. This type also occurs in the epiphyseal plates of long bones, where the lacunae are arranged in a longitudinal orientation parallel to the long axis of the bone: therefore, interstitial growth serves to lengthen the bone. The cartilage in the remainder of the body grows mostly by apposition, a controlled process that may con-tinue during the life of the cartilage.

Thus development of a cartilaginous tissue is passed through the following stages: 1) precartilagi-nous tissue which basic role is determined by intensity of a tissue; 2) the initial cartilaginous tissue de-scribed by appearance of extracellular substance; alongside with a turgor internal stress of a tissue is frameed by interstitial body height; 3) unmature cartilage; in intercellular substance occur chondromucoid and chondroitin acid; alongside with young oxyphilic fields arise basophilous; 4) mature cartilage; the most aged fields of it are stained oxyphilic; arise chondric balls and sharply intensity of tissues increases; 5) the asbestk dystrophia of a central part of the intercellular substance, resulting in to an atrophy of this part and an intussusception in the struck fields of blood vessels. Appearance of vessels improves a feed-ing the stayed cartilage, and in some cases stipulates replacement of a cartilage by an osteal tissue.

Hyaline CartilageHyaline cartilage, the most common type in both fetus and adult,

is white and translucent when fresh, with a firm, gel-like consistency. The costal (rib) cartilages, most of the laryngeal cartilages, the cartilagi-nous rings supporting the trachea, and the irregular cartilage plates in the walls of the bronchi are hyaline cartilage. As fetal cartilage is replaced by bone, hyaline cartilage remains in the epiphyseal plates at the ends of long bones, allowing these bones to lengthen from birth to adulthood. At all ages, hyaline cartilage without a perichondrium covers the articular surfaces of bone, where its resistance to compression and its smooth tex-ture provide cushion and a low-friction surface.

Because the refractive index of the collagen fibrils and that of the ground substance are nearly the same, the matrix of hyaline cartilage ap-pears to be an amorphous, homogeneous mass with the light microscope.

The matrix of hyaline cartilage contains primarily type II colla-gen, but types IX, X, and XI and other minor collagens are also present in small quantities. Type-11 collagen contains more hydroxylysine than does type I. Type II collagen does not form large bundles, although the bundle thickness increases with distance from the lacunae. Fiber orientation appears to be related to the stresses placed on the cartilage. The chondrocytes are embedded in the matrix either singly or in isogenous groups of two to eight cells derived from one parent cell. The matrix is subdivided into two regions: the territorial (capsular) matrix, around each lacuna, and the interterritorial (intercapsular) matrix. The territorial matrix is poor in colla-gen and rich in chondroitin sulfate, which contributes to its basophilic and intense staining with periodic acid-Schiff (PAS) reagent. The bulk of the matrix is interterritorial matrix, which is richer in type II colla-gen and poorer in proteoglycans than the territorial matrix.

A small region of the matrix, 1 to 3 /nm thick, immediately surrounding the lacuna is known as the pericellular capsule. It displays a fine meshwork of collagen fibers embedded in a basal lamina-like

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substance. These fibers may represent some of the other minor collagens present in hyaline cartilage; it has been suggested that the pericellular capsule may protect chondrocytes from mechanical stresses.

Ground substance the predominant tissue component, com-prises the following:

(1) Glycosaminoglycans (GAGs), which are mostly chon-droitin sulfates and hyaluronan but also include small amounts of keratan sulfate and heparan sulfate.

(2) Proteoglycans, which are core proteins with covalently bound GAG side chains.

(3) Proteoglycan aggregates (aggrecans), which аre proteo-glycans noncovalently linked to long chains of hyaluronan by link protein.

(4) Glycoproteins, including link protein, tenascin fi-bronectin, and chondroneetin, which attach various matrix compo-nents to one another and cells to the matrix. These small regulatory and structural proteins influence interactions between the chondro-

cytes and the matrix and have clinical value as markers of cartilage turnover degeneration.(5) Tissue fluid, an ultrafiltrate of blood plasma.Except for articular (joint) cartilage, hyaline cartilage is surrounded and nourished by perichon-

drium. Articular cartilage is nourished by the synovial fluid in the joint cavity.Elastic Cartilage

Elastic cartilage is yellow when fresh and is more flexible than hyaline. In humans, elastic carti-lage occurs in the external ear, the external auditory canals and auditory tubes, the epiglottis, and the comiculate and cuneiform cartilages of the larynx. Elas-tic cartilage provides flexible support. It occurs alone and with hyaline carti-lage; the two may gradually blend into each other at the border between them to form one cartilage mass.

Elastic cartilage resembles hyaline but contains, in addition to type II collagen fibers, a dense network of branching elastic fibers. This network is densest at the core of the cartilage mass and, when stained with an elastic stain (Verhoeff or Weigert), may obscure tissue organization. The matrix is not as ample as in hyaline cartilage, and the elastic fiber bundles of the territo-rial matrix are larger and coarser than those of the interterritorial matrix. The chondrocytes characteristically occur in isogenous groups. A perichondrium is present. The outer fibrous layer of the perichondrium is rich in elastic fibers.

Elastic cartilage develops from a primitive connective tissue containing wavy fibril bundles that differ from both elastin and collagen in protein composition. Fibroblasts subsequently secrete elastin, and the fiber bundles are transformed into branching elastic fibers by an unknown nchanism. Chondrocyte de-velopment, the production of other matrix materials, and further growth resemble that of hyaline cartilage.

FibrocartilageFibrocartilage, unlike hyaline and elastic cartilage, does not possess a perichondrium and its ma-

trix possesses type I collagen.Fibrocartilage is present in intervertebral disks, in the pubic symphysis, in articular disks, and at-

tached to bone. Fibrocartilage is always associated with dense connective tissue, and the border between the two is indistinct. Its combination of cartilaginous ground substance and dense collagen bundles al-lows fibrocartilage to resist deformation under great stress, a quality that is important in attaching bone to bone and providing restricted mobility.

Unlike the other two types of cartilage, fibrocartilage does not posses a perichondrium, displays a scant amount of matrix (rich in chondroitin sulfate and dermatan sulfate), and exhibits bundles of type 1 collagen, which stain acidophilic. The capsular matrix resembles that of hyaline cartilage and contains

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some type-П collagen. The chondrocytes are distributed in columnar isogenous groups between the densely packed type-I collagen bundles.

Where strong mechanical stresses occur, fibrocartilage develops from dense regular connective tissue through the transformation of fibroblasts or fibroblast-like precursors into chondrocytes. Fibrocarti-lage growth has not been closely examined.

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BONEBone tissue is the special form of a connective tissue with calcified interstitial matrix. In particular

the bone tissue accomodates for support and protection and plays the important role in mineral metabolism of an organism. Bone is the main constituent of the adult sceletal system. It supports and pro-tects fragile tissues and organs, harbors hematopoietic tissue and forms levers and pulleys that multiply and focus the contractile forces of muscle. The constant turnover of bone tissue results from a balance between the activities of the bone-forming osteoblasts and the bone-resorbing osteoclasts and allows bone matrix to function as an important storage site for calcium and other essential minerals.

The term "bone" refers to both a tissue and an organ. Individ-ually named elements of the adult skeleton, bones are organs com-posed largely of bone tissue that also contain other connective tis-sues, bone marrow, blood vessels, and nerves.

Bone is a connective tissue composed of cells, fibers, and ground substance.

Bone matrix, which contains abundant mineral salts, is the chief tissue component. Bone's hardness makes it difficult to section. Obtaining thin sections involves grinding bone slices until translu-cent, or demineralizing fixed bone by immersion in dilute acid or calcium-chelating agents. Demineralized bone can be sectioned and stained by standard methods.

Bone cells are:Osteoprogenitor cells are stem cells found in endosteum and periosteum. These spindle-shaped

cells have ovoid to elongate nuclei and unremarkable cytoplasm. Two types are distinguishable in elec-tron microscope; one forms osteoblasts and the other forms osteoclasts. Osteoblast precursors derive from mesenchyme and have sparse rouph endoplasmic reticulum and Golgi apparatus. Osteoclast precursors derive from blood monocytes and have abundant free ribo-somes and mitochondria.

Osteoblasts, the major bone-forming cells, are cuboidal; each possesses a large, round nucleus and a basophilic cytoplasm. These cells form one-cell-thick sheets resembling simple cuboidal epithelium on surfaces where new bone is deposited. Osteoblasts exhibit high alkaline-phosphatase activity and have the well-developed rouph endoplasmic reticulum and Golgi complex typical of protein-secreting cells. Os-teoblasts excrete an alkaline phosphatase, which disjoins glycerophosphates keeping in a peripheric blood on carbohydrate bonds and a phosphoric acid. Last reacts with salts of calcium and in a result crystals of hydroxyapatite are formed. During a calcareous infiltration of osteoid the important role play lysosomes "matrix granules". They have high activity of an alkaline phosphatase and pyrophosphatase, contain lipids, accumulate calcium on the intrinsic surface of coating them membrane. The important value dur-ing a calcareous infiltration plays glycoprotein osteonectin, selectively linking calcium salt and phospho-rus salt with a collagen.

Osteoblasts synthesize and secrete all the organic components of bone matrix and participate in bone mineralization. After they are surrounded by matrix, osteoblasts are mature and are called osteo-cytes.

Osteocytes are terminally differentiated bone cells found in cavities in the bone matrix called lacu-nae. Their long, thin cytoplasmic processes, called filopodia, radiate from the cell body in fine extensions of the lacunar cavity called canaliculi. Osteocytes are isolated from one another by the impermeable bone matrix and contact one another at the tips of their filopodia through gap junctions. This arrangement pro-vides limited cytoplasmic continuity between the cells and explains how osteocytes obtain nutrients and oxygen and dispose of wastes at considerable distances from blood vessels. Although they are incapable of mitosis, osteocytes retain synthetic and resorptive capacity, by means of which they turn over and maintain nearby bone matrix. Osteocyte death results in bone breakdown, or resorption. Osteocytes re-

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cently derived from osteoblasts lie near bone surfaces in rounded lacunae; older cells lie farther from the surface in flattened lacunae.

Electron microscopy has revealed osteocytes in various functional states. Indeed, there is evidence that the osteocyte can modify the surrounding bone matrix through synthetic andreabsorptive activities. Three functional states, each with a characteristic morphology, have been described:

Quiescent osteocytes exhibit a paucity of rouph endoplasmic reticulum and a markedly diminished Golgi apparatus. An osmiophilic lamina representing mature calcified matrix is seen in close apposition to the cell membrane.

Formative osteocytes show evidence of matrix deposition and exhibit certain characteristics simi-lar to those of osteoblasts. Thus, the rouph endoplasmic reticulum and Golgi apparatus are more abun-dant, and there is evidence of osteoid in the pericellular space within the lacuna.

Resorptive osteocytes, like formative osteocytes, contain numerous profiles of endoplasmic reticu-lum and a well-developed Golgi apparatus. Moreover, secondary lysosomes are conspicuous. That the re-sorptive osteocyte removes matrix is supported by the observation that the pericellular space is devoid of collagen fibrils and may contain a flocculent material suggestive of a breakdown product. The more pe-ripheral, nonresorbed matrix is bounded by an osmiophilic lamina, which presumably represents the boundary of the intact mature calcified matrix. Resorption of bone by this mechanism, called osteocytic osteolysis, with the concomitant release of calcium ions, allows increases in blood calcium to maintain appropriate levels. The stimulus for the resorption of bone is increased secretion of parathyroid hormone.

Osteoclasts are bone-resorbing cells lying on bony surfaces in shallow depressions termed How-ship's lacunae. They are large and multinucleated (2-50 per cell), with an acidophilic cytoplasm that con-tains many lysosomes and mitochondria and a well-developed Golgi apparatus. The cell surface facing the depression exhibits a ruffled border of plasma-membrane infoldings, forming many compartments between the cell and the bone surface. The cells release acid, collagenase, and other lytic enzymes into the compartments; these break down bone matrix and release minerals, a process called bone resorption. Osteoclasts respond to parathyroid hormone by enlarging their ruffled borders and increasing their activity; together, these re-sponses result in increased blood calcium levels. Parathyroid hormone effect is mediated by a signal from the osteoblasts. Calcitonin which decreases blood calcium, reduces surface ruf-fling and osteoclast activity. Although their immediate precur-sors lie in the endosteum and periosteum, osteoclasts ulti-mately form by fusion of blood monocyte derivatives and are considered components of the mononuclear phagocyte system.

Bone matrix. Bone matrix contains organic compo-nents, or osteoid, and inorganic components, or bone mineral.

Organic components or osteoid (fibers and unmineral-ized ground substance) constitutes approximately 50% of bone volume and 25% of bone weight. It consist of:

(1) Fibers. Osteoid is 90 to 95% type-l collagen. The overlapping pattern of staggered tropocolla-gen results in periodic gaps (lacunar regions), which contain as much as 50% of the hydroxyapatite crys-tals (mineral).

(2) Ground substance. Hydroxyapatite crystals and collagen fibers are embedded in the acidic ground substance of proteins, carbohydrates, and some proteoglycans and lipids. The proteins include glycoproteins, phosphoproteins, sialoproteins (osteopontin), and those containing g-carboxyglutamic acid. The carbohydrates glycosaminoglycans include chondroitin and keratan sulfates. Some ground sub-stance components are hydroxyapatite crystal nucleation sites.

Inorganic components. Bone mineral accounts for approximately 50% of bone volume and 75% of bone weight. It consists chiefly of calcium and phosphate, with some bicarbonate, citrate, magnesium, and potassium and trace amounts of other metals. Calcium and phosphate form needlelike crystals of hy-

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droxyapatite. Hydrated ions at the crystal surface form an enveloping hyd ration shell, through which ions are exchanged between the crystal and surrounding body fluids.

The adult skeleton comprises more than 200 bones, which, together with cartilage and ligaments, form the body's supportive framework.

Bones are classified by their shape (long bones, flat bones) and the process by which they form (endochondral bones, membrane bones). Most exhibit protuberances that serve as attachment sites for muscles, tendons, and ligaments.

The outer surfaces of bones are covered by a double-layered connective tissue coat known as the periosteum. The periosteum's outer, or fibrous, layer is dense connective tissue; its inner, or osteogenic, layer is looser tissue containing bone cell precursors. Sharpey's fibers are periosteal collagen fibers that penetrate bone matrix to anchor periosteum to bone. The internal surfaces of bones are covered by a thin-ner, condensed reticular connective tissue called endosteum, which contains bone and blood cell precur-sors. The endosteum lines marrow cavities and extends into haversian canals.

Most bones (femur) are categorized as long bones; knowledge of their parts is important in the study of regional bone histology. The diaphysis is the long bone's shaft, and the epiphyses are its bulbous ends. The diaphysis is cylindrical, with walls of compact bone and a central marrow cavity lined with en-dosteum. Each epiphysis contains mostly spongy bone. Where bones contact other bones to form movable joints, their surfaces are covered by articular cartilage.

Bone tissue is classified by its architecture as spongy or compact and by its fine structure as pri -mary (woven) or secondary (lamellar). All bone tissue begins as primary bone, but nearly all is eventually replaced by secondary bone. The distinction between intramembranous and endochondral bone is based on histogenesis but is not microscopically detectable in mature bone.

The two basic organizational classes of adult bone, spongy and compact, are similar in composi-tion and microscopic appearance but differ in overall architecture.

Spongy bone, also called cancellous bone, forms a fine three-dimensional lattice with many open spaces. The branching and anastomosing slips of bone between the spaces, termed trabeculae, or spicules, align along the lines of stress to which the bones are subjected, maximizing their weight-bearing capacity. Spongy bone fills the epiphyses of mature long bones and short bones (phalanges) and lies between the thick plates, or tables, of the skull's flat bones, where it is called diploe. It may be either primary or sec -ondary bone.

Compact bone, also called dense bone, or cortical bone, lacks the large spaces and trabeculae of spongy bone. It forms the thick diaphyseal cylinder of long bones, a thin covering around the epiphyses, and the tables of the skull's flat bones. Compact bone is always secondary bone.

Histogenesis1. Primary bone. The first bone tissue to appear during new bone formation, or during fracture re-

pair, is termed primary bone, or woven bone. This immature bone, always spongy, is subsequently re-placed by secondary bone, except near the skull sutures and in alveolar bone of the mandible and maxilla. Its collagen fibers do not form concentric rings but exhibit an irregular "woven" appearance. It is less mineralized than secondary bone, making it more radiolucent (penetrable by x-rays), and it has a higher osteocyte-to-matrix ratio. Primary bone can develop by means of intramembranous or endochondral bone formation.

Intramembranous bone formation occurs within membranelike masenchymal condensations. The cells in such connective tissue membranes differentiate into osteoblasts and begin to synthesize and se-crete osteoid, which later becomes mineralized. This initial site of bone formation is the primary ossifica-tion center. Osteoblasts surround themselves with bone matrix, forming spicules that eventually fuse into a spongy lattice of primary bone. Mesenchyme between the spicules participates in bone marrow develop-ment. Only a few human bones form entirely in this way; most are flat and called membrane bones. Mem-brane bones of the skull are the frontal and parietal bones, the mandible, and the maxilla. The term "mem-brane bone" also refers to the tissue type formed by this mechanism. Membrane bone forms parts of some bones, such as the temporal and occipital bones of the skull and the periosteal bone collar of endochon-dral bones.

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Endochondral bone formation involves replacing cartilage with bone and occurs in all except membrane bones; thus, it is easiest to remember which bones are membrane bones and that the remainder are endochondral bones (or "cartilage bones").

Basic steps in the formation of an endochondral bone.1. Cartilage model. In the embryo, a hyaline cartilage model resembling the bone to be formed

develops first.2. The periosteal bone collar. Capillaries penetrate the perichondrium, and mesenchymal cells on

its inner surface become osteoprogenitor cells. Some differentiate into osteoblasts and secrete bone ma-trix, creating primary bone spicules just inside the perichondrium (now the periosteum). The spicules eventually fuse to form a thin periosteal bone collar of membrane bone around the cartilage model. Thus, ironically, the first bone tissue in an endochondral bone forms by intramembranous ossification.

3. Proliferation. While the periosteal bone collar forms, structural and functional changes begin in the cartilage model. Chondrocytes near the collar proliferate rapidly, forming stacks (isogenous groups) of flattened cells parallel to the bone's long axis.

4. Hypertrophy. The chondrocytes hypertrophy rapidly into large, rounded cells that are not sepa-rated by matrix. The result is tubelike superlacunae filled with columns of hypertrophic chondrocytes, which secrete type-X collagen.

5. Calcification. As hypertrophy progresses, the strips of cartilage matrix between the tubular su-perlacunae begin to calcify. Thus oxygen, nutrients, and cellular wastes can no longer diffuse through the matrix, and the hypertrophic chondrocytes die.

6. Formation of the primary marrow cavity. Dead cells and part of the calcified cartilage matrix are removed by chondroclasts (large, multinucleated cells resembling osteoclasts). Tunnels at the center of the developing bone, created by chondrocyte proliferation and hypertrophy and enlarged by chondro-clasts, become the bone's primary marrow cavity.

7. The periosteal bud is a small cluster of blood vessels and perivascular tissue from the perios -teum that penetrates the primary marrow cavity. This bud and its branches invade the tunnels left by the dead chondrocytes. Osteoprogenitor cells and bone marrow stem cells, delivered by the invading blood vessels, are deposited on the calcified cartilage matrix surface.

8. Ossification. Term requires attention to context. In its broadest sense, ossification is synony-mous with bone formation. Here, in a more restricted connotation, it refers to the final steps (osteoid de-position followed by mineralization). Osteoprogenitor cells divide and differentiate into osteoblasts, which deposit primary bone on the calcified cartilage matrix strips. The primary bone and the residual calcified cartilage are subsequently resorbed and replaced by secondary bone.

Ossification centers. The previous steps may occur more than once during the formation of a bone. In long bones, the process осcurs first in middiaphysis, forming the primary ossification center. Sec-ondary ossification centers form later, by the same process, in the epiphyses. The region between primary and secondary ossification centers is the metaphysis. Ossification centers enlarge until all that separates them is a thin plate with resting cartilage at its center—the epiphyseal plate. The primary and secondary ossification centers of a bone should not be confused with primary and secondary bone. In some bones, tertiary ossification centers subsequently form the bony tubercles and ridges to which large muscle groups or ligaments attach. In humans, the first bone to ossify is the clavicle.

9. Histologic appearance of developing endochondral bone. The microscopic structure of the metaphyses of developing endochondral bones has five overlapping zones. The zone of resting cartilage is typical hyaline cartilage and is farthest from the primary marrow cavity. The zone of proliferation con-tains stacks (isogenous groups) of flattened chondrocytes. In the zone of hypertrophy, chondrocytes in the stacks are enlarged and rounded. The zone of calcification is characterized by a more basophilic matrix. Overlap often results in a single zone of hypertrophy and calcification. The zone of ossification borders on the primary marrow cavity. It is characterized by intensely acidophilic osteoid, osteocytes within the bone matrix, and a mono-layer of basophilic osteoblasts on the newly formed primary bone's surface.

2. Secondary bone. In adults, both dense and spongy bone are secondary bone, or lamellar bone.Secondary bone formation (remodeling). Osteoclasts erode the primary bone matrix; blood ves-

sels, nerves, and lymphatics invade the cavity formed by the erosion; and osteogenic cells in the perivas-79

cular connective tissue are deposited on the cavity's walls. Osteoblasts descended from these cells, along with osteocytes released from their lacunae during resorption, deposit secondary bone in concentric lay-ers, or lamellae, the oldest of which are farthest from the vessels. The collagen fibers are laid down paral -lel to one another in any given lamella but in different directions in adjacent lamellae. Owing to its greater organization, secondary bone is more efficient than the primary bone it replaces. Remodeling helps re-shape growing bones to adapt to changing stresses and loads; it occurs continuously, even in adults, as secondary bone is eroded and replaced by new secondary bone.

Compact secondary bone is composed of wafer-like thin layers of bone, lamellae, that are ar-ranged in lamellar systems that are especially evident in the diaphyses of long bones. These lamellar sys-tems are the outer circumferential lamellae, inner circumferential lamellae, osteons (haversian canal sys-tems), and interstitial lamellae.

The outer circumferential lamellae are just deep to the periosteum, forming the outermost region of the diaphysis, and contain Sharpey's fibers anchoring the periosteum to the bone.

The inner circumferential lamellae, analogous to but not as extensive as outer circumferential lamellae, completely encircle the marrow cavity. Trabeculae of spongy bone extend from the inner cir-cumferential lamellae into the marrow cavity, interrupting the endosteal lining of the inner circumferen-tial lamellae.

The bulk of compact bone is composed of an abundance of haversian canal systems (osteons); each system is composed of cylinders of lamellae, concentrically arranged around a vascular space known as the haversian canal. Frequently, osteons bifurcate along their considerable length. Each osteon is bounded by a thin cementing line, composed mostly of calcined ground substance with a scant amount of collagen fibers.

Collagen fiber bundles are parallel to each other within a lamella but are oriented almost perpen-dicular to those of adjacent lamellae. This arrangement is possible because the collagen fibers follow a helical arrangement around the haversian canal within each lamella but are pitched differently in adjacent lamellae. Each haversian canal, lined by a layer of osteoblasts and osteoprogenitor cells, houses a vascu-lar bundle with its associated connective tissue. Haversian canals of adjacent osteons are connected to each other by Volkmann's canals. The blood supply of a bone is carried out by blood vessels which in-pour from a periosteum through transversal perforating (Volkmann's) canals. Further these vessels inpour in haversian canals. In some places blood vessels of adjoining osteons are bridged by anastomoses. On them the collateral blood supply is carried out at breaking blood supply of any osteon. These vascular spaces are oriented oblique to or perpendicular to haversian canals. The diameter of haversian canals varies from ap proximately 20 to about 100 /nm. During the formation of osteons, the lamella closest to the cementing line is the first one to be formed. As additional lamellae are added to the system, the diam-eter of die haversian canal is reduced, and the thickness of the osteon wall increases. Because nutrients from blood vessels of the haversian canal must traverse canaliculi to reach osteocytes, an inefficient process, most osteons possess only 4 to 20 lamellae.

Formation of a new osteon in compact bone involves initially the creation of a tunnel-like space, the resorption cavity, by osteoclast activity. This resorption cavity will have the dimensions of the new osteon. When osteoclasts have produced an appropriately sized cylindrical tunnel by resorption of com-pact bone, blood vessels and their surrounding connective tissue occupy the tunnel. As the tunnel is occu-pied, new bone deposition on its wall begins almost immediately.

These two aspects of cellular activity, namely, osteoclast resorption and osteoblast synthesis, con-stitute a bone-remodeling unit. A bone -remodeling unit consists of two distinct parts: an advancing cut-ting cone (also called a resorption canal) and a closing cone. The cutting cone consists of active osteo-clasts followed by an advancing capillary loop and pericytes. It also contains numerous dividing cells that give rise to osteoblasts, additional pericytes, and endothelial cells. The osteoclasts cut a canal about 200 nm in diameter. This canal establishes the diameter of the future osteonal (Haversian) system. The cutting cone constitutes only a small fraction of the length of the bone-remodeling unit; thus, it is seen much less frequently than the closing cone.

After the diameter of the future Haversian system is established, osteoblasts begin to deposit the organic matrix (osteoid) of bone on the walls of the canal in successive lamellae. With time, the bone ma-

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trix in each of the lamellae becomes mineralized. As the successive lamellae of bone are deposited, from the periphery inward, the canal ultimately attains the relatively narrow diameter of the adult osteonal canal.

Bone growthBones grow from birth to early adulthood. During growth, bone tissue is continuously remodeled.

Growth occurs in two directions. Growth in the length of long bones occurs primarily by means of chon-drocyte division in the epiphyseal zone of proliferation, under the influence of growth hormone. Child-hood growth hormone levels cause cartilage to be produced in the epiphyseal plates as fast as it can be re -placed by endochondral bone formation. At puberty, growth hormone levels decline and endochondral bone gradually overtakes and replaces the remaining cartilage, a process termed epiphyseal closure. Growth in girth occurs by proliferation and differentiation of osteoprogenitor cells in the periosteum's in-ner layer and bone deposition on the bone's outer surface.

Bone repairBone fractures tear vessels in the periosteum, endosteum, and haversian and Volkmann's canals,

causing local hemorrhage and clot formation between the bone's broken ends. The periosteum and endos-teum provide macrophages and fibroblasts; the macrophages remove the clot, and the fibroblasts fill the breach with fibrous connective tissue. Some connective tissue cells differentiate into chondrocytes; this tissue eventually becomes a callus, containing islands of fibrocartilage and hyaline cartilage that serve as a model for bone formation. The presence of cartilage in the callus is typical of endochondral bones (long bones), whereas flat membrane bones (the mandible) often heal without cartilage formation. Beginning in the subperiosteal region (as soon as 2 days after an injury in young people), the callus is replaced by pri-mary bone, which is subsequently remodeled and replaced by secondary bone. The time required for com-plete healing depends on the site and extent of the injury and is longer in older people.

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MUSCLE TISSUEMuscle cells are structurally and functionally specialized for contraction. The length of muscle

cells, which sometimes reaches 4cm, is greater than their width. Muscle cells are therefore often called muscle fibers, or myofibers. Muscle cells requires two types of special protein filaments called myofila-ments; these include thin filaments containing actin and thick filaments containing myosin.

Classification of muscle tissues is based on their features:(а) Constructions and function (morphofunctional classification) and(b) Sources of development (histogenetic classification).Morphofunctional classification of muscle tissues: Two principal types of muscle are recognized:Striated muscle, in which the cells exhibit cross-striations at the light microscope level. It in-

cludes both skeletal and cardiac muscle.Smooth muscle, in which the cells do not exhibit cross-striations.Smooth muscle occurs mainly in the walls of hollow organs (intestines and blood vessels); its con-

traction is slow (often occurring in waves) and involuntary. Skeletal muscle occurs mainly in association with bones, which act as pulleys and levers to multiply the force of its quick, strong, voluntary contrac -tions. Cardiac muscle occurs exclusively in the heart; its contractions are quick, strong, rhythmic, and in-voluntary.

Histogenetic classification of muscle tissues:Histogenetic classification divides muscle tissues on three basic types - somatic, coelo-mic and

mesenchymal.1) The muscle tissue of somatic type developes from myotomes of somites; forms a striated

skeletal muscle.2) The muscle tissue of coelomic type developes from a myoepicardial plate of a visceral layer

of a splanchnotome (coelomic lining in a cervical part of an embryo); forms a striated cardiac muscle my-ocardium).

3) The muscle tissue of mesenchymal type developes from a mesenchyma, forms a smooth muscles of an internal organs.

4) Myoepithelial and myoneural cells sometimes describes as separate types of muscle tissues. First represent the modified epithelial cells of some glands developing from an ectoderm and a prechordal plate, second have neural origin and form muscles of an iris of an eye. Both types of muscle cells fall into smooth muscle tissue.

Nearly all muscle arises from mesoderm. Mesenchymal cells differentiate into muscle cells through a process involving an accumulation of myofilaments in the cytoplasm and the development of special membranous channels and compartments. Smooth muscles of the iris arise from ectoderm.

Muscle tissues are groups of muscle cells organized by connective tissue. This arrangement allows the groups to act together or separately, generating mechanical forces of varying strength. The muscles of the body (biceps brachii) are organs made up of highly organized muscle tissue.

Smooth muscleMost smooth muscle cells differentiate from mesenchyme in the walls of developing hollow or-

gans of cardiovascular, digestive, urinary, and reproductive systems. During differentiation, the cells elongate and accumulate myofilaments. Smooth muscles of the iris arise from neural tube.

Mature smooth muscle fibers are spindle-shaped cells with a single central ovoid nucleus. The smallest morphofunctional unit of smooth muscle tissue is smooth muscle cell. The sarcoplasm at the nu-clear poles contains many mitochondria, some rouph endoplasmic reticulum, and a large Golgi complex. Each cell produces its own basal (external) lamina, which consists of proteoglycan-rich material and type-III collagen (reticular) fibers.

Myofilaments in smooth muscle cells are:Thin filaments. Smooth muscle actin filaments are similar to those of skeletal and cardiac mus-

cle. They are stable and are anchored by F-actinin to dense bodies associated with the plasma membrane. Actin is associated with tropomyosin but with the notable absence of troponin.

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Thick filaments. Smooth muscle myosin filaments are less stable than those in striated muscle; they form in response to contractile stimuli. Unlike the thick filaments in striated muscle cells, those in smooth muscle have heads along most of their length and bare areas at the ends of the filaments.

The thick and thin filaments run mostly parallel to the cell's long axis, but they overlap much more than those of striated muscle, accounting for the absence of cross-striations. The greater overlap results from the unique organization of the thick filaments and permits greater contraction. The ratio of thin to thick filaments in smooth muscle is approximately 12:1, and the arrangement of the filaments is less regu-lar and crystalline than in striated muscle.

Sarcoplasmic reticulum. Smooth muscle cells contain a poorly organized sarcoplasmic reticulum that participates in Ca2+ sequestration and release but does not divide the myofilaments into myofibrillar bundles. Abundant surface-associated membrane-limited vesicles, caveolae, aid in Ca2+ uptake and re-lease. The small size and slow contraction of these fibers make an elaborate stimulus-conducting system unnecessary; these fibers have no T tubules, dyads, or triads.

Although the smooth muscle cells are similar in morphology, these cells can be classified accord-ing to developmental, biochemical, and functional differences.

Visceral smooth muscle derives from splanchnopleural mesenchyme and occurs in the walls of respiratory, digestive, urinary, and reproductive organs. In addition to thick myosin and thin actin fila-ments, its sarcolemma-associated dense bodies are linked by desmin-containing intermediate filaments. Owing to their poor nerve supply, the cells transmit contractile stimuli to one another through abundant gap junctions, acting as a functional syncytium.

Vascular smooth muscle differentiates in situ from mesenchyme around developing blood ves-sels. Its intermediate filaments contain vimentin, as well as desmin.

Smooth muscle of the iris. The sphincter and dilator pupillae muscles are unique.Unlike striated muscle fibers, which abut end to end, smooth muscle fibers overlap and attach by

fusing their endomysial sheaths. The sheaths are interrupted by gap junctions, which transmit the ionic currents that initiate contraction. Smooth muscle fibers form fascicles smaller than those in striated mus-cle. The fascicles, each surrounded by a meager perimysium, are often organized in layers separated by the thicker epimysial connective tissue. Fibers in adjacent layers may lie perpendicular to one another.

Smooth muscle contraction involves a modified sliding-filament mechanism. First, the myosin fil-aments appear and the actin filaments are pulled toward and between them. Continued contraction in-volves the formation of more myosin filaments and further sliding of the actin filaments. The sliding actin filaments pull the attached dense bodies closer together, shortening the cell. Unlike striated muscle fibers, individual smooth muscle fibers may undergo partial peristaltic, or wavelike, contractions. During relax-ation, the myosin filaments disintegrate.

Initiation of Smooth Muscle Contraction: Like cardiac muscle fibers, smooth muscle fibers are ca-pable of spontaneous contraction that may be modified by autonomic innervation. Motor end-plates are absent. Neurotransmitters diffuse from terminal expansions of the nerve endings between smooth muscle cells to the sarcolemma. Sympathetic (adrenergic) and parasympathetic (cholinergic) endings are presents and exert antagonistic (reciprocal) effects. In some organs, contractile activity is enhanced by cholinergic nerves; and decreased by adrenergic nervri; in others, the opposite occurs.

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Control of Smooth Muscle Contraction. Although the regulation of contraction in smooth muscle depends on Ca2+ the control mechanism differs from that encountered in striated muscle because smooth muscle thin filaments are devoid of troponin.

Contraction of smooth muscle fibers proceeds as follows: 1. Calcium ions, released from caveolae, bind to calmodulin (a regulatory protein ubiquitous in

living organisms), thereby altering its conformation. The Ca2+ -calmodulin complex then activates myosin light chain kinase.

2. Myosin light chain kinase phosphorylates one of the myosin light chains, known as the regula-tory chain, permitting the unfolding of the light meromyosin moiety to form the typical, "golf club"-shaped myosin molecule.

3. The phosphorylated light chain unmasks the myosin's actin binding site, permitting the interac-tion between actin and the S1 subfragment of myosin that results in contraction.

Because both phosphorylation and the attachment-detachment of the myosin cross-bridges occur slowly, the process of smooth muscle contraction takes longer than skeletal or cardiac muscle contraction. It is interesting that ATP hydrolysis also occurs much more slowly and the myosin heads remain attached to the thin filaments for a longer time in smooth muscle than in striated muscles. Thus, smooth muscle contraction not only is prolonged but also requires less energy.

Decrease in the sarcoplasmic calcium level results in the dissociation of the calmodulin-calcium complex, causing inactivation of myosin light chain kinase. The subsequent dephosphorylation of myosin light chain, catalyzed by the enzyme myosin phosphatase, brings about masking of the myosin's actin binding site and the subsequent relaxation of the muscle.

Regeneration of Smooth Muscle. Smooth muscle contains a population of relatively undifferen-tiated mononucleate smooth muscle precursors that proliferate and differentiate into new smooth muscle fibers in response to injury. The same mechanism appears to be involved in adding new muscle to the my-ometrium as the uterus enlarges during pregnancy to accommodate the growing fetus.

Skeletal muscleSkeletal muscle arises from mesenchyme of mesodermal

origin. The mesenchymal cells retract their cytoplasmic pro-cesses and assume a shortened spindle shape to become my-oblasts; these fuse to form multinucleated myotubes. Myotubes elongate by incorporating additional myoblasts while myofila-ments accumulate in their cytoplasm. Eventually, the accumu-lated myofilaments organize into myofibrils and displace the nu-clei and other cytoplasmic components peripherally. Mature skeletal muscle fibers are elongated, unbranched, cylindrical, multinucleated cells. The flattened, peripheral nuclei lie just un-der the sarcolemma (muscle cell plasma membrane); most of the organelles and sarcoplasm (muscle cell cytoplasm) are near the poles of the nuclei. The sarcoplasm contains many mitochon-dria, glycogen granules, and an oxygen-binding protein called myoglobin, and it accumulates lipofuscin pigment with age. Ma-ture skeletal muscle fibers cannot divide. Each cell is sur-rounded by endomysium, whose fine reticular fibers intermingle with those of neighboring muscle cells. Small satellite cells, which have a single nucleus and act as regenerative cells, are lo-cated in shallow depressions on the muscle cell's surface, shar-ing the muscle fiber's external lamina. The chromatin network of the satellite cell nucleus is denser and coarser than that of the muscle fiber. Myofilaments in skeletal muscle fibers are of two major types.

1. Thin (actin) filaments have several components.84

Filamentous actin (F-actin) is a polymeric chain of globular actin (G-actin) monomers. Each thin filament contains two F-actin strands wound in a double helix.

Tropomyosin is a long, thin, double-helical polypeptide that wraps around the actin double helix, lies in the grooves on its surface, and spans seven G-actin monomers.

Troponin is a complex of three globular proteins. TnT (troponin T) attaches each complex to a specific site on each tropomyosin molecule, TnC (troponin C) binds calcium ions, and Tnl (troponin I) in-hibits interaction between thin and thick filaments.

2. Thick (myosin) filaments. A myosin molecule is a long, golf club-shaped polypeptide. A thick (myosin) filament is a bundle of myosin molecules whose shafts point toward and overlap in the bundle's middle and whose heads project from the bundle's ends. This arrangement leaves a headless region in the center of each filament corresponding to the H band. Papain (a proteolytic enzyme) cleaves myosin into two pieces, at a point near the head. The piece containing most of the thin shaft is termed light meromyosin; the head and associated section of the shaft make up heavy meromyosin. The head portion of heavy meromyosin has an ATP-binding site and an actin-binding site, both of which are necessary for contraction. Heavy and light meromyosins, which are enzyme-generated fragments, should not be con-fused with heavy and light myosins, which are distinct gene products (proteins) that combine to form a thick myosin filament.

Skeletal muscle banding reflects the grouping of its thick and thin myofilaments into parallel bun-dles called myofibrils. Each muscle fiber may contain several myofibrils, depending on its size.

Myofibrils in cross-section containing both filament types have six thin filaments in hexagonal ar-ray around each thick filament. Еach thick filament shares two of its surrounding thin filaments with each adjacent thick filament to form a repeating crystalline pattern.

Myofibrils in longitudinal section. At both light and electron microscopic levels, each myofibril exhibits repeating, linearly arranged, functional subunits called sarcomeres, whose bands (striations) run perpendicular to the myofibril's long axis. The sarcomere is separated from its neighbors at each end by a dense Z line, or Z disk. A major Z- disk protein, a-actinin, anchors one end of the thin filaments and helps maintain spatial distribution. The thin filaments extend toward the middle of the sarcomere. Thin fila-ments are held in register by the rod-shaped protein a-actinin, a component of the Z disk that can bind thin filaments in parallel arrays. In addition, two molecules of nebulin, a long, nonelastic protein, are wrapped around the entire length of each thin filament, further anchoring it in the Z disk and ensuring the maintenance of the specific array. Thick filaments are positioned precisely within the sarcomere with the assistance of titin, a large, linear, elastic protein. Two titin molecules extend from each half of a thick fila-ment to the adjacent Z disk; thus, four titin molecules anchor a thick filament between the two Z disks of each sarcomere. The center of each sarcomere is marked by the M line, which holds the thick filaments in place. Vimentin, dystrophin, desmin-containing intermediate filaments are found in both M lines and Z disks. The thick filament bundles lie at the center of each sarcomere, are bisected by the M line, and over-lap the thin filaments' free ends. The overlap between thick and thin filaments produces the banding pat-tern and differs depending on the myofibrils' state of contraction.

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Under the light microscope, skeletal muscle fibers ex-hibit alternating light- and dark-staining bands that run per-pendicular to the cells' long axes. The light-staining bands contain only thin filaments and are known as I bands (iso-tropic) because they do not rotate polarizedlight. Each I band is bisected by a Z line. Thus, each sarcom-ere has two half I bands, one at each end. One dark-staining band lies in the middle of each sarcomere and shows the po-sition of the thick filament bundles; this is known as an A band (anisotropic) because it is birefringent (rotates polar-ized light). At the electron microscopy level, each A band has a lighter central region, or H band, which is bisected by an M line. The H band lies between the thin filaments' free ends and contains only the shafts of myosin molecules. The darker peripheral parts of the A bands are regions of overlap between the thick and thin filaments and contain the myosin heads. Interaction between the myosin heads of the thick fil-aments and the thin filaments' free ends causes muscle con-traction.

Sarcoplasmic reticulum is the smooth endoplasmic reticulum of striated muscle cells and is specialized to sequester calcium ions. In skeletal muscle, this anastomosing complex of membrane-limited tubules and cistemae ensheathes each myofibril. At each I band junction, a tubular invagination of the sarcolemma, termed a transverse tubule (or T tubule), pene-trates the muscle fiber and overlies the surface of the myofibrils. On each side of the T tubule lies an ex-pansion of the sarcoplasmic reticulum termed a terminal cisterna. Two terminal cistemae and an interven-ing T tubule comprise a triad. Triads are important in initiating muscle contraction.

Deep to the sarcolemma and interspersed between and among myofibrils are numerous elongated mitochondria with many highly interdigitating cristae. The mitochondria may lay parallel the longitudinal axis of the myofibril or wrap around the myofibril.

Mechanism of Contraction: According to the sliding-filament hypothesis, skeletal muscle contrac-tion involves a multistep cascade whereby the completion of each step initiates the succeeding step. Dur-ing contraction, individual thick and thin filaments do not shorten; instead, the two Z disks are brought closer together as the thin filaments slide past the thick filaments (Huxley's sliding-filament theory). Thus, when contraction occurs, the motion of the thin filaments toward the center of the sarcomere cre-ates a greater overlap between the two groups of filaments, effectively reducing the widths of the I and H bands without influencing the width of the A band. The many steps occur nearly instantaneously. Because each step depends on the one that precedes it, a disease process that interferes with even a single step can interrupt the entire cascade and result in paralysis.

When neural stimulation ends, all of the membranes repolarize, allowing the sarcoplasmic reticu-lum to sequester Ca2+ from the sarcoplasm by active transport. This removes Ca2+ from the TnC and re-turns the Tnl to a position in which it inhibits binding of the myosin head to the actin filament.

The process of contraction, usually triggered by neural impulses, obeys the all-or-none law, in that a single muscle fiber either contracts or does not as a result of stimulation.

The following sequence of events leads to contraction in skeletal muscle:1. An impulse, generated along the sarcolemma, is transmitted into the interior of the fiber via the

T tubules, where it is conveyed to the terminal cis-ternae of the sarcoplasmic reticulum.2. Calcium ions leave the terminal cistemae through voltage-gated calcium release channels, enter

the cytosol, and bind to the TnC subunit of troponin, altering its conformation.3. Conformational change in troponin shifts the position of tropomyosin deeper into the groove,

unmasking the active site (myosin binding site) on the actin molecule.4. ATP present on the S1 subfragment of myosin is hydrolyzed, but both adenosine diphosphate

(ADP) and inorganic phosphate remain attached to the S1 subfragment, and the complex binds to the ac-86

tive site on actin.5. Inorganic phosphate is released, resulting not only in a greater bond strength between the actin

and myosin but also in a conformational alteration of the S1 subfragment.6. ADP is also released, and the thin filament is dragged toward the center of the sarcomere

("power stroke").7. A new ATP molecule binds to the S1 subfragment, causing the release of the bond between

actin and myosin.Each motor neuron has a single axon that may terminate on a single muscle fiber or undergo ter-

minal branching (arborization) and terminate on multiple muscle fibers. A motor neuron and all the mus-cle fibers it innervates (1 to >100) comprise a motor unit. Muscles responsible for delicate movements (extraocular muscles) are composed of many small motor units; those responsible for coarser movements (gluteus maximus) are composed of fewer large motor units. A motor end-plate, or myoneural junction, is a collection of specialized synapses of a motor neuron's terminal boutons with a skeletal muscle fiber's sarcolemma. It transmits nerve impulses to muscle cells, initiating contraction. Each myoneural junction has three major components:

1. The presynaptic (neural) component is the terminal bouton. Although extensions of Schwann cell cytoplasm cover the bouton, the myelin sheath ends before reaching it. The bouton contains mito-chondria and acetylcholine-filled synaptic vesicles. The part of the bouton's plasma membrane directly facing the muscle fiber is the presynaptic membrane.

2. The synaptic cleft lies between the presynaptic membrane and the opposing postsynaptic mem-brane and contains a continuation of the muscle fiber's basal lamina. It also contains acetylcholinesterase, which degrades the neurotransmitter so that when neural stimulation ends, contraction ends. The primary synaptic cleft lies directly beneath the presynaptic membrane and communicates directly with a series of secondary synaptic clefts created by infoldings of the postsynaptic membrane.

3. The postsynaptic (muscular) component includes the sarcolemma (postsynaptic membrane) and the sarcoplasm directly under the synapse. The postsynaptic membrane contains acetylcholine receptors and is thrown into numerous junctional folds. The sarcoplasm beneath the folds contains nuclei, mito-chondria, ribosomes, and glycogen, but lacks synaptic vesicles.

Muscles use glucose (from stored glycogen and from the blood) and fatty acids (from the blood) to form the ATP and phosphocreatine that provide chemical energy for contraction. When ATP is not available, actin-myosin binding becomes stabilized, accounting for rigor mortis, the muscular rigidity that occurs shortly after death.

The three basic skeletal muscle fiber types differ in myoglobin content, number of mitochondria, and speed of contraction. In humans, most skeletal muscles are mixtures of these fiber types. Initially, muscle fiber types were distinguished by enzyme histochemistry targeting the fiber-type-specific myosin ATPase activity. Currently, immunohistochemistry targeting fiber-type-specific expression of four main myosin heavy chain (MHC) isotypes (I, IIA, IIB, and IIХ) provides more reliable information. a. Red fibers contain more myoglobin and mitochondria. Their contraction in response to nervous stimulation is slow and steady, which has resulted in their designation as slow fibers. They predominate in postural muscles and occur in large numbers in certain limb muscles. Slow fibers are characterized by a predomi-nance of MHC type I. b. White fibers contain less myoglobin and fewer mitochondria. They react quickly, with brief, forceful contractions but cannot sustain contraction for long periods; thus, they are termed fast fibers. These fibers predominate in the extraocular muscles. Fast fibers are characterized by a predominance of one or more MHC type-II isoforms. с Intermediate fibers have structural and func-tional characteristics between those of red and white fibers but are a subclass of the latter. They are dis -persed among the red and white fibers in muscles where either type predominates. As a subclass of fast fibers, intermediate fibers contain mostly MHC type-II isoforms.

Each skeletal muscle (biceps brachii) is a bundle of muscle fascicles surrounded by a sheath of dense connective tissue termed the epimysium. Each fascicle is a bundle of muscle fibers surrounded by a dense connective tissue sheath called the perimysium, comprising septumlike inward extensions of epimysium. Each muscle fiber is a bundle of myofibrils surrounded by the sarcolemma, which is in turn surrounded by a delicate connective tissue sheath termed the endomysium, which consists of a basal lam-

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ina and a loose mesh of reticular fibers. Each myofibril is a bundle of myofilaments surrounded by an in-vestment of sarcoplasmic reticulum, with a triad at both A-l junctions of each sarcomere. The connective tissue investments are continuous with one another.

Muscle-Tendon Junctions. The attachment of muscle to tendon must be secure to prevent the mus-cle from tearing away during contraction. The tendon's collagen fibers blend with the epimysium and pen-etrate the muscle along with the perimysium. Near the junction with the tendon, the ends of the muscle cells taper and exhibit many infoldings of their sarcolemmas. Collagen and reticular fibers enter the in-foldings, penetrate the basal lamina, and attach directly to the outer surface of the sarcolemma. The attachment of actin filaments to the inner surface of the sarcolemma helps stabilize the associ-ation between the collagen fibers and the muscle cell.

The response of muscle to injury depends on the muscle type. The wound closure mechanism al-ways involves the proliferation of perimysial and epimysial fibroblasts and the synthesis of connective tissue matrix. Small, mononucleate satellite cells are scattered in adult skeletal muscles within the basal lamina (endomysium) of mature fibers. Mature skeletal muscle fibers are incapable of mitosis, but the normally quiescent satellite cells can divide after muscle injury, differentiate into myoblasts, and fuse to form new skeletal muscle fibers.

Muscle spindles and Golgi tendon organs are sensory receptors that monitor muscle contraction. Muscle spindles, which provide feedback about the changes in muscle length as well as the rate of alter-ation in muscle length. Golgi tendon organs, which monitor the tension as well as the rate at which the tension is being produced during movement.

Information from these two sensory structures is generally processed at unconscious levels, within the spinal cord. The information also reaches the cerebellum and even the cerebral cortex, however, so a person may sense muscle position.

Muscle spindles continuously monitor the length and the changes in length of the muscle. When muscle is stretched, it normally undergoes reflex contraction, or stretch reflex. This proprioceptive re-sponse is initiated by the muscle spindle, an encapsulated sensory receptor located among, and in parallel with, the muscle cells. Each muscle spindle is composed of 8 to 10 elongated, narrow, very small, modi-fied muscle cells called intrafusal fibers, surrounded by the fluid-containing periaxial space, which in turn is enclosed by the capsule. The connective tissue elements of the capsule are continuous with the collagen fibers of the perimysium and endomysium. The skeletal muscle fibers surrounding the muscle spindle are unremarkable and are called extrafusal fibers.

Intrafusal fibers are of two types: nuclear bag fibers and the more numerous, thinner nuclear chain fibers. Furthermore, there are two categories of nuclear bag fibers: static and dynamic. The nuclei of both types of fibers occupy the centers of the cells; their myofibrils are located on either side of the nuclear re-gion, limiting contraction to the polar regions of these spindle-shaped cells. The central regions of the in-trafusal fibers do not contract. The nuclei are aggregated in the nuclear bag fibers, whereas they are aligned in a single row in nuclear chain fibers.

Within a specific muscle spindle, a single, myelinated, large, sensory nerve fiber (group la) wraps spirally around the nuclear regions of each of the three types of intrarusal fibers, forming the primary sen-sory endings (also known as dynamic and la sensory endings). Additionally, secondary sensory nerve endings (also known as static and II sensory nerve endings) are formed by group II nerve fibers, which wrap around every nuclear chain fiber as well as around the static nuclear bag fibers.

Cardiac muscleCardiac muscle arises as parallel chains of elongated splanchnic mesenchymal cells in the walls of

the embryonic heart tube. Cells in each chain develop specialized junctions between them and often branch and bind to cells in nearby chains. As development continues, the cells accumulate myofilaments in their sarcoplasm. The branched network of myoblasts forms interwoven bundles of muscle fibers, but cardiac myoblasts do not fuse.

Cardiac muscle fibers are long, branched cells with one or two ovoid central nuclei. The sar-coplasm near the nuclear poles contains many mitochondria and glycogen granules and some lipofuscin

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pigment. Mitochondria lie in rows between the myofilaments, whose arrangement yields striations as in skeletal muscle. Cardiac muscle cells adjoint to one another by intercalated disks. These unique histologic features of cardiac muscle appear as dark transverse lines between the muscle fibers and represent spe-cialized junctional complexes. In electron microscope, intercalated disks exhibit three major components arranged in a stepwise fashion. a. The fascia adherens, similar to a zonula adherehs, is found in the verti-cal (transverse) portion of the step. Its F-actinin anchors the thin filaments of the terminal sarcomeres. b. The macula adherens (desmosome) is the second component of the junction's transverse portion. It pre-vents detachment of the cardiac muscle fibers from one another during contraction. с The gap junctions of intercalated disks form the horizontal (lateral) portion of the step. They provide electrotonic coupling between adjacent cardiac muscle fibers and pass the stimulus for contraction from cell to cell.

The sarcoplasmic reticulum of cardiac muscle fibers is less organized than that of skeletal muscle and does not subdivide myofilaments into discrete myofibrillar bundles. Cardiac T tubules occur at Z lines instead of A-l junctions. In most cells, cardiac T tubules associate with a single expanded cistema of the sarcoplasmic reticulum; thus, cardiac muscle contains dyads instead of triads.

Types of cardiac muscle fibersa. Atrial cardiac muscle fibers are small and have fewer T tubules than ventricular cells. They

comprise many small membrane-limited granules that contain a precursor of atrial natriuretic factor, a hormone secreted in response to increased blood volume that opposes the action of aldosterone. It acts on the kidneys to cause sodium and water loss, reducing blood volume and blood pressure.

b. Ventricular cardiac muscle fibers are larger cells with more T tubules and no granules.Owing to the abundant capillaries in the endomysium, cardiac muscle fibers appear more loosely

arranged than those of skeletal muscle. The whorled arrangement of cardiac muscle fibers in the heart wall accounts for the myocardium's ability to "wring out" blood in the heart chambers.

Although the arrangement of the sarcoplasmic reticulum and T-tubule complex of cardiac muscle fibers differs from that of skeletal muscle, the composition and arrangement of myofilaments are almost identical. Thus, at the cellular level, skeletal and cardiac muscle contractions are essentially the same.

Unlike skeletal muscle fibers, which rarely contract without direct motor innervation, cardiac muscle fibers contract spontaneously with an intrinsic rhythm. The intrinsic spontaneous contraction or beat of cardiac muscle is evident in embryonic cardiac muscle cells as well as in cardiac muscle cells in tissue culture. The heart receives autonomic innervation through axons that terminate near, but never form synapses with, cardiac muscle cells. The autonomic stimulus cannot initiate contraction but can speed up or slow down the intrinsic beat. The initiating stimulus for contraction is normally provided by a collection of specialized cardiac muscle cells called the sinoatrial node; it is delivered by specialized cells called Purkinje fibers to the other cardiac muscle cells. The stimulus is passed between adjacent cells through the gap junctions of the intercalated disks. The gap junctions establish ionic continuity among cardiac muscle fibers, allowing them to work together as a functional syncytium. Sympathetic stimulation accelerates the heartbeat by increasing the frequency of impulses to the cardiac conducting cells. Parasympathetic stimulation slows down the heartbeat by decreasing the frequency of the impulses. The impulses carried by these nerves do not initiate contraction but only modify the rate of intrinsic car-diac muscle contraction by their effect at the nodes. Cardiac muscle has little regenerative ability after early childhood. Lesions of the adult heart are repaired by replacement with connective tissue scars.

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NERVE TISSUEThe nervous system enables the body to respond to continuous changes in its external and internal

environment. It controls and integrates the functional activities of the organs and organ systems. The ner-vous tissue compound a basis of the nervous systems which regulate all processes in an organism and ex-ercising interrelation with an external environment.

The basic property of a nervous tissue - an excitability and conduction. The nervous tissue takes the special place in an organism of higher animals. Through sensitive nerve endings the organism obtains information about an external world.

Nerve tissue consists of neurons that transmit electrochemical impulses and the supporting cells that surround them. It contains little extracellular material.

NeuronsNeurons are specialized to receive, integrate, and transmit electrochemical messages. Each has a

cell body, also called the soma ("body") or perikaryon ("around the nucleus"), comprising the nucleus and the surrounding cytoplasm and plasma membrane. Each neuron has a variable number of dendrites (cyto-plasmic processes that collect incoming messages and carry them toward the soma) and a single axon (a cytoplasmic process that transmits messages to the target cell). Axons of most neurons have a myelin sheath formed by supporting cells and interrupted by gaps called nodes of Ranvier. Myelinated axon seg-ments between the gaps are called internodes.

The cell body (soma, perikaryon) is the neuron's synthetic and trophic center. It can receive sig-nals from axons of other neurons through synaptic contacts on its plasma membrane and subsequently re-lay them to its axon. The nucleus typically is large, central, and euchromatic. It has a prominent nucleolus and heterochromatin around the nuclear envelope's inner surface. The cytoplasm of the soma contains many organelles, including mitochondria, lysosomes, and centrioles. The abundant free and rouph endo-plasmic reticulum-associated polyribosomes appear as clumps of basophilic material collectively called Nissl bodies. The Golgi complex, which is well developed, packages (and glycosylates) neurotransmitters in neurosecretory, or synaptic, vesicles. Once packaged, the vesicles are transported by molecular motor proteins down the axon to the terminal bouton.

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Dark brown to black melanin granules are found in neurons in certain regions of the central ner-vous system and in the sympathetic ganglia of the peripheral nervous system. The function of these gran-ules in these various locations is unknown. However, dihydroxyphenylalanine, or methyldopa (DOPA), the precursor of this pigment, is also the precursor of the neurotransmitters dopamine and noradrenaline. It has been suggested, therefore, that melanin may accumulate as a by-product of the synthesis of these neurotransmitters.

Lipofuscin, an irregularly shaped, yellowish brown pigment granule, is more prevalent in the neu-ronal cytoplasm of older adults and is thought to be the remnant of lysosomal enzymatic activity. Lipofus-cin granules increase with advancing age and may even crowd the organelles and nucleus to one side in the cell, possibly affecting cellular function.

Lipid droplets sometimes are observed in the neuronal cytoplasm and may be either the result of faulty metabolism or energy reserves. Neurotubules (microtubules) and bundles of neurofilaments (inter-mediate filaments) are found throughout the perikaryon and extend into the axon and dendrites.

Dendrites are extensions of the soma increasing the surface available for incoming signals. The farther they are from the soma, the thinner they are, owing to successive branching. Much of their surface often is covered with synap-tic contacts, and some have sharp projections, termed den-dritic spines, or gemmules, that act as synaptic sites. Dendrites lack Golgi complexes but contain small amounts of other or-ganelles found in perikarya.

Axon is one in each neuron. It is a complex cell process that carries impulses away from the soma. An axon is divisible into several regions. The axon hillock, the part of the soma leading into the axon, differs from the rest of the perikaryon in that it lacks Nissl bodies. An entire axon is usu-ally not visible in sectioned material, but its origin is distin-guishable from that of dendrites by the absence of Nissl-re-lated basophilia. The initial segment is the part of a myeli-nated axon between the axon hillock's apex and the beginning of the myelin sheath. It is characterized by a thin layer of elec-tron-dense material, or dense undercoating, beneath the plasma membrane and it contains neurotubule and neurofilament bundles originating in the axon hillock. The axon proper is the axon's main trunk. Unlike those of dendrites, axons' diameters tend to be constant along their entire length. The larger an axon's diameter, the more likely it is to be myelinated and the higher its rate of impulse conduction. Some axons have branches, termed collaterals, which may contact other neurons or even return to the soma of origin to modulate their own subsequent depolarization. The axoplasm (cytoplasm) contains few organelles other than some mitochondria and parallel bundles of neu-rotubules and neurofilaments. It has limited metabolic activity, but it conveys metabolic products to and from the axon terminals. Signal transmission relies heavily on the asymmetric ion distribution (potential differences) on either side of the axolemma, the axonal plasma membrane. Many axons undergo branch-ing (arborization) near their terminations. The degree of terminal arborization depends on axon size and the function of the axon. Each terminal branch ends in an enlargement called a terminal end-bulb or ter -minal bouton. Swellings in an axon's wall before its termination are termed boutons enpassage. Each bou-ton contains many mitochondria and neurosecretory vesicles. A specialized region of its plasma mem-brane, the presynaptic membrane, forms part of a synapse.

Most neurons have abundant smooth endoplasmic reticulum throughout the cell body; this reticu-lum extends into the dendrites and the axon, forming hyolemmal cisternae directly beneath the plas-malemma. These cisternae are continuous with the rouph endoplasmic reticulum in the cell body and weave between the Nissl bodies on their way into the dendrites and axon. Although it is unclear how they function, it is known that hypolemmal cisternae sequester calcium and contain protein. These cisternae

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may serve as a conduit for the distribution of protein throughout the cell. Some authors theorize that transport and synaptic vesicles bud from these cisternae, but much of this tissue is still unclear.

Mature neurons are incapable of mitosis and are often used as examples of terminally differenti-ated cells. The inability of neurons to divide makes repair of nerve tissue more difficult than repair of most other tissues. Neuron cell bodies lost through injury or surgery cannot be replaced, but if an axon is severed or crushed and the cell body remains intact, axonal regeneration is possible. Axoplasmic (axonal) Transport. Movement of metabolic products through the axoplasm, which can be fast (400 mm/day) or slow (1 mm/day), involves neurotubules and neurofilaments. Anterograde or orthograde axoplasmic transport moves newly synthesized products and synaptic vesicles toward the axon's terminal arborization and can be fast or slow. Retro grade axoplasmic transport, the return of worn materials to the perikaryon for degradation or reutilization, is usually fast. Neurons are classified morphologically into three major types according to their shape and the arrangement of their processes.

Bipolar neurons possess two processes emanating from the soma, a single dendrite and a single axon. Bipolar neurons are located in the vestibular and cochlear ganglia and in the olfactory epithelium of the nasal cavity.

Unipolar neurons (formerly called pseudounipolar neurons) possess only one process emanating from the cell body, but this process branches later into a peripheral branch and a central branch. Each of the branches is morphologically axonal and can propagate nerve impulses, although the very distal aspect of the peripheral branch arborizes and displays small dendritic ends, indicating its receptor function.

Pseudounipolar neurons develop from embryonic bipolar neurons whose processes migrate around the cell body during development and eventually fuse into a single process. During impulse trans-mission, the impulse passes from the dendritic (receiving) end of the peripheral process to the central process without involving the cell body. Unipolar neurons are present in the dorsal root ganglia and in some of the cranial nerve ganglia.

Unipolar neurons present only in fetuses. Multipolar neurons, the most common type, possess various arrangements of multiple dendrites

emanating from the soma and a single axon. They are present throughout the nervous system, and most of them are motor neurons. Some multipolar neurons are named according to their morphology (pyramidal cells) or after the scientist who first described them (Purkinje cells).

Neurons also are classified into three general groups according to their function:Sensory (afferent) neurons receive sensory input at their dendritic terminals and conduct im-

pulses to the central nervous system for processing.Motor (efferent) neurons originate in the central nervous system and conduct their impulses to

muscles, glands, and other neurons.Interneurons, located completely in the central nervous system, function as interconnectors or in-

tegrators that establish networks of neuronal circuits between sensory and motor neurons and other inte-meurons. With evolution, the number of neurons in the human nervous system has grown enormously, but the greatest increase has involved the intemeurom. which are responsible for the complex functioning of the body.

Supporting cells are called neuroglia ("nerve glue") or glial cells. Their functions include structural and nutritional sup-port of neurons, electrical insulation, and enhancement of im-pulse conduction velocity. By providing neurons with structural and functional support, these cells play a passive role in neural activity. Positioned between the blood and the neurons, they de-fine compartments and monitor materials passing between them. It is difficult to maintain neurons in tissue culture without adding supporting cells.

Supporting cells of central nervous system. There are ap-proximately 10 neuroglial cells per neuron in the central nervous system. Glial cells are generally smaller than neurons. Their

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processes, although abundant and extensive, are indistinguishable without special stains. Identification is based on nuclear morphology. The supporting cells in the central nervous system are the macroglia (astro-cytes and oligodendrocytes), the microglia, and ependymal cells.

Astrocytes are the largest glial cells. Their nuclei, also the largest, are irregular, spherical, and pale-staining, with a prominent nucleolus. Their branching cytoplasmic processes are tipped by vascular end-feet; these surround capillaries of the pia mater and are important components of the blood-brain bar-rier. Protoplasmic astrocytes (mossy cells) are more common in gray matter. They have ample granular cytoplasm and short, thick, highly branched processes. Fibrous astrocytes are more common in white matter. Silver stains reveal fibrous material in their cytoplasm. Their long, thin processes are less branched than those of protoplasmic astrocytes.

Oligodendroglia, or oligodendrocytes, the most numerous glial cells, occur in both gray and

white matter. Their spherical nuclei range between those of astrocytes and those of microglia in size and staining intensity. Like the Schwann cells of the peripheral nervous system, oligodendrocytes form myelin and occur in rows to myelinate entire axons. Unlike a Schwann cell, each may provide myelin for segments of several axons.

Ependymal cells derive from ciliated neuroepithelial cells lining the neural tube. In adults, they retain their epithelial nature and some cilia, and they line the neural tube derivatives (the brain's ventricles and aqueducts and the spinal cord's central canal). The lining resembles a simple columnar epithelium, but ependymal cells have basal cell processes extending deep into the gray matter. The ependymal lining is continuous with the cuboidal epithelium of the choroid plexus.

Where the neural tissue is thin, ependymal cells form an internal limiting membrane lining the ventricle and an external limiting membrane beneath the pia, both formed by thin fused pedicels. Modifi-cations of some of the ependymal cells in the ventricles of the brain participate in the formation of the choroid plexus, which is responsible for secreting and maintaining the chemical composition of the canalis centralis fluid.

Tanycytes, specialized ependymal cells, extend processes into the hypothalamus, where they ter-minate near blood vessels and neurosecretory cells. It is believed that tanycytes transport CSF to these neurosecretory cells.

Microglia, the smallest and rarest of the glia, occur in both gray and white matter. Their nuclei are small and often bean-shaped, and their chromatin is so condensed that they often appear black in H & E-stained sections. Their processes are shorter than those of astrocytes and are covered with thorny branches. Microglial cells may derive from mesenchyme, or they may be glioblasts (immature oligoden-drocytes) of neuroepithelial origin. Some microglia are components of the mononuclear phagocyte system and have phagocytic capabilities.

Supporting cells of the peripheral nervous system:Schwann cells are the supporting cells of peripheral nerve fibers. One Schwann cell may envelop

segments of several unmyelinated axons or provide a segment of a single myelinated axon with its myelin sheath. Myelinated axons (nerve fiber) are surrounded by a lipid-rich layer called the myelin sheath. Ex-ternal to, and contiguous with, the myelin sheath is a thin layer of Schwann cell cytoplasm called the

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sheath of Schwann, or the neurilemma. This layer contains the nucleus and most of the organelles of the Schwann cell. Surrounding the Schwann cell is a basal or external lamina.

Functionally, the myelin sheath with its external lamina and the neurilemma isolates the axon from the surrounding extracellular compartment. The axon hillock and the terminal arborizations where the axon synapses with its target cells do not have a myelin sheath.

The myelin sheath is composed of multiple layers of Schwann cell membrane wrapped concentri-cally around the axon. To produce the myelin sheath, each Schwann cell wraps in a spiral around a short (0.08 to 0.1 mm) segment of the axon. During the wrapping of the axon, cytoplasm is squeezed out from between the membrane of the concentric layers of the Schwann cell. The inner leaflets of the plasma membrane then fuse. With the electron microscope, these fused inner leaflets are electron opaque, appear-ing as the major dense lines of the myelin. These concentric dense lamellae alternate with the slightly less dense intraperiod lines that are formed by fusion of the outer membrane leaflets.

The myelin sheath is segmented because it is formed by numerous Schwann cells arrayed sequen-tially along the axon. The junction where two adjacent Schwann cells meet is devoid of myelin. This site is called the node of Ranvier. Therefore, the myelin between two sequential nodes of Ranvier is called an internodal segment.

During formation of the myelin sheath, the axon initially lies in a groove on the surface of the Schwann cell. Fusion of the edges of the groove to en close the axon produces the inner mesaxon, the nar-row intercellular space of the innermost rings. The first few lamellae are not compactly arranged; i.e., some cytoplasm is left in the first few concentric layers. Similarly, the outermost layer contains some cy-toplasm as well as the Schwann cell nucleus. The apposition of the plasma membrane of the last layer to itself as it closes the ring produces the outer mesaxon, the narrow intercellular space adjacent to the exter-ernal lamina. Myelin is rich in lipid because as the Schwann cell winds around the axon, its cytoplasm, as noted, is extruded from between the opposing layers of the plasma membranes. Electron micrographs, however, typically show small pimounts of cytoplasm in several locations: the inner collar of Schwann cell cytoplasm, between the axon and the myelin; the Schmidt- Lanterman clefts, small islands within successive lamellae of the myelin; perinodal cytoplasm, at the node of Ranvier; and the outer collar of perinuclear cytoplasm, around the myelin. These areas of cytoplasm are what light microscopists identi-fied as the Schwann sheath. Cytoplasm of the clefts contains lysosomes, occasional mitochondria and mi-crotubules, as well as cytoplasmic inclusions, or dense bodies. The number of Schmidt-Lanterman clefts correlates with the diameter of the axon; larger axons have more clefts.

The Schwann cells in the unmyelinated nerve fibers are elongated in parallel to the long axis of the axons, and the axons fit into grooves in the surface of the cell. The lips of the groove may be open, ex-posing a portion of the axolemma (axon plasma membrane), the cell membrane of the axon, to the adja-cent external lamina of the Schwann cell, or the lips may be closed, forming a mesaxon. A single axon or a group of axons may be enclosed in a single imagination of the Schwann cell surface. Large Schwann cells in the peripheral nervous system may have 20 or more grooves, each containing one or more axons.

Satellite cells are specialized Schwann cells in craniospinal and autonomic ganglia, where they form a one-cell-thick covering over the cell bodies of the neurons (ganglion cells). Their nuclei are spher-ical, with mottled chromatin. In sections, the nuclei typically appear as a "string of pearls" surrounding the much larger ganglion cell bodies. Supporting cells, unlike neurons, can divide if stimulated by injury.

Impulse ConductionSignals (impulses) are generated in the spike trigger zone of the neuron and propagated as a wave

of depolarization along the plasma membrane of the dendrites, soma, and axon. Depolarization involves channels (ionophores) in the membrane, which allow ions (Na+, K+) to enter or exit the cell. In unmyeli-nated axons, depolarization occurs in waves over the entire surface. In myelinated axons, depolarization occurs only at nodes of Ranvier, jumping from node to node (saltatory conduction). Impulse conduction is therefore faster in myelinated axons.

Neurons and other cells are electrically polarized with a resting potential of about —90 mV (the inside is less positive than the outside) across the plasma membrane. This potential arises because of the difference between ion concentrations inside and outside the cell. In mammalian cells, the concentration

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of K is much higher inside the cell than outside the cell, whereas the concentration of sodium ions (Na+ and chloride ions Cl- is much higher outside the cells than inside.

Although maintenance of the resting potential depends primarily on K+ leak channels, Na+ - K+ pumps in the plasma membrane assist by actively pumping Na+ out of the cell and K+ into the cell. For ev-ery three sodium ions pumped out, two potassium ions enter the cell, also making a minor contribution to the potential difference between the two sides of the membrane.

In most cells, the potential across the plasma membrane is generally constant. In neurons and mus-cle cells, however, the membrane potential can undergo controlled changes, making these cells capable of conducting an electrical signal, as follows:

1. Stimulation of a neuron causes opening of voltage-gated Na+ channels in a small region of the membrane, leading to an influx of Na+ into the cell at that site. Eventually, the overabundance of Na+ in-side the cell causes a reversal of the resting potential (the cytoplasmic aspect of the plasma membrane be-comes positive relative to its extracytoplasmic aspect), and the membrane is said to be depolarized.

2. As a result, the Na+ channels become inactivated for 1 to 2 msec, a condition known as the re-fractory period. This is a time during which the Na+ channels are inactive; that is, they cannot open or close and Na+ cannot traverse them. The presence of the refractory period is due to the specialized con-struction of the voltage-gated Na+ channels.

3. During the refractory period, voltage-gated K+ channels open, permitting an efflux of К+ into the extracellular fluid that eventually stores the resting membrane potential; however, there may be a brief period of hyperpolarization.

4. Once the resting potential is restored, the voltage-gated K+ channels close, and the refractory period is ended with the closing of the activation gate and the opening of the inactivation gate of the volt-age- gated Na+ channel.

The cycle of membrane depolarization, hyperpolarization, and return to the resting membrane po-tential is called the action potential, an all-or- none response that can occur at rates of 1000 times/second. The membrane depolarization that occurs with the opening of voltage-gated Na+ channels at one point on an axon spreads passively for a short distance and triggers the opening of adjacent channels, resulting in the generation of another action potential. In this manner, the wave of depolarization, or impulse, is con-ducted along the axon. In vivo, an impulse is conducted in only one direction, from the site of initial de-polarization to the axon terminal. The inactivation of the Na+ channels during the refractory periods pre-vents retrograde propagation of the depolarization wave.

Cold, heat, and pressure on a nerve can block impulse conduction. Local anesthetics allow more complete and reversible impulse blocking by disturbing the resting potential. Some poisons block ion channels and prevent propagation of the action potential.

Transmission of impulses from the terminals of one neuron to another neuron, a muscle cell, or a gland occurs at synapses.

Synapses are specialized junctions by means of which stimuli are transmitted from a neuron to its target cell. Artificially stimulated axons can propagate a wave of depolarization in either direction, but the signal can travel in only one direction across a synapse, which functions as a unidirectional signal valve. Synapses are named according to the structures they connect (axodendritic, axosomatic, axoaxonic, and dendrodendritic). The three major structural components of each synapse are the presynaptic and postsy-naptic membranes and the synaptic cleft between them.

Schematic diagram of different types of synapses; a. Axodendritic or axosomatic; b. Axodendritic, in which an axonal terminal synapses with a dendritic spine; c. Axoaxonic

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Presynaptic membrane is the part of the terminal bouton membrane closest to the target cell. It includes an electron-dense thickening into which many short intermediate filaments insert, as in a hemidesmosome. In response to stim-ulation, neurosecretory vesicles in the bouton fuse with the presynaptic membrane and exocytose their neurotransmitters into the synaptic cleft. Neurosecretory vesicles occur only in the presynaptic component of the junction. Vesicle mem-brane added to the presynaptic membrane is recycled by en-docytosis of the membrane lateral to the synaptic cleft. Intact vesicles do not cross the cleft.

Synaptic cleft (Synaptic gap) is a fluid-filled space, generally 20-nm wide, between the presynaptic and postsy-naptic membranes. It is shielded from the rest of the extracellular space by supporting cell processes and basal lamina material that binds the presynaptic and postsynaptic membranes together. Some clefts are traversed by dense filaments that link the membranes and perhaps guide neurotransmitters across the gap.

Postsynaptic membrane is thickening of the plasma membrane of the target cell (neuron or mus-cle) resembles the presynaptic membrane but also contains receptors for neurotransmitters. When enough receptors are occupied, hydrophilic channels open, depolarizing the postsynaptic membrane. Neurotrans-mitter (acetylcholine) remaining in the cleft after stimulating the postsynaptic neuron (or other target cell) is degraded by enzyme (acetylcholinesterase) in the cleft. Degradation products undergo endocytosis by coated pits in the bouton membrane, lateral to the presynaptic thickening. Removal of excess transmitter allows the postsynaptic membrane to reestablish its resting potential and prevents continuous activation of the target cell in response to a single stimulus.

Neurotransmitters are signaling molecules that are released at the presynaptic membranes and ac-tivate receptors on postsynaptic membranes.

Cells of the nervous system communicate mostly by the release of signaling molecules. Signaling molecules that act as "first messenger systems" (act on receptors directly associated with ion channels) are now referred to as neurotransmitters. Signaling molecules that invoke the "second messenger system" are referred to as neuromodulators or neurohormones. Because neurotransmitters act directly, the entire process is fast, lasting usually less than 1 msec. Events utilizing neuromodulators are much slower and may last as long as a few minutes. There are perhaps 100 known neurotransmitters (and neuromodula-tors), represented by the following three groups: small-molecule transmitters; neuropeptides and gases.

Small-molecule transmitters are of three major types:Acerylcholene (the only one in this group that is not an amino acid derivative).The amino acids glutamate, aspartate, glycine, and GABA.The biogenic amines (monoamines) serotonin and the three catecholamines dopamine, norepi-

nephrine (noradrenaline), and epinephrine (adrenaline).Neuropeptides, many of which are neuromodulators, form a large group. They include the follow-

ing:The opioid peptides: enkephalins and endorphins.Gastrointestinal peptides, which are produced by cells of the diffuse neuroendocrine system: sub-

stance P, neurotensin, and vasoactive intestinal peptide (VIP).Hypothalamic-releasing hormones, such as thyrotropin- releasing hormone and somatostatin.Hormones stored in and released from the neurohypophysis (antidiuretic hormone and oxytocin).Certain gases act as neuromodulators. They are nitric oxide (NO) and carbon monoxide (CO).Embryonic development of nerve tissueAll neurons and supporting cells derive from ectoderm. Cells of the early embryo's midline dorsal

ectoderm are induced by the underlying notochord to form a thickened neural plate. The plate's lateral border thickens and the center invaginates, forming a troughlike neural groove. As the groove deepens, the lateral borders contact each other to close the groove and form the neural tube. Cells lining the tube

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elongate to form a mitotically active pseudostratified columnar epithelium (neuroepithelium), and they eventually form the layers that generate the entire central nervous system. As the neural groove closes, cells at its lateral borders proliferate to form two columnar masses that eventually lie dorsal to the neural tube and form the neural crest. Neural crest cells migrate away from the neural tube and form the periph-eral nervous system, including the sensory neurons of the craniospinal ganglia, the postganglionic neu-rons of the autonomic nervous system, the Schwann cells of peripheral nerves, and the satellite cells of ganglia. Neural crest cells also form the meninges and the craniofacial mesenchyme. Neural crest deriva-tives include the odontoblasts of developing teeth, the skin's melanocytes, and the adrenal medulla's chro-maffin and ganglion cells.

On a cross section of developing neurotubule three layers of which the nervous tissue is formed are visible:

Ependymal layer (intrinsic) with a mitotic division of cells. Mantle layer consists of mitotic divid-ing cells, which may travel from inner ependymal layer.

The marginal layer is formed by processes of cells of ependymal and mantle layers. Cells of in-trinsic (ependymal) layer turn to cells of the cylindrical form and cover the central canal of a spinal cord. From a mantle layer the neuroblasts gradually turning into mature nervous cells.

Spongioblasts give rise to astrocytes and oligodendrocytes. In a light microscope the first indica-tion of a differentiation of nervous cells is appearance of thin fibrils in their cytoplasm. The body of a cell gains the piriform shape and from its point end the process - an axon educes. Such cells are termed neu-roblasts. They further turn to neurones. Division of neuroblasts descends by a mitosis.

Peripheral nervesPeripheral nerves contain myelinated and unmyelinated axons, Schwann cells, and fibroblasts, but

lack neuron cell bodies. Nuclei seen in peripheral nerve cross-sections belong to Schwann cells (large, pale-staining) or to fibrocytes (mature fi-broblasts; small, dark-staining). Each peripheral nerve is surrounded by a dense connective tissue sheath, or epineurium, branches of which penetrate the nerve, dividing the nerve fibers into bundles, or fascicles. The sheath surrounding each fascicle is called the perineurium. Fine slips of reticular con-nective tissue from the perineurium penetrate the fascicles to surround each nerve fiber, forming the endoneurium. Branches of blood vessels in the epineurium penetrate the nerve along with the con-nective tissue.

Nervous endingsPeripheral nerve terminals are of two structural types: (l) terminals of axons, which transmit im-

pulses from the central nervous system to skeletal and smooth muscles (motor endings) or to glands (se-cretory endings), and (2) terminals of dendrites, called sensory endings or receptors, which perceive vari-ous stimuli and transmit this sensory input to the central nervous system. These sensory receptors are classified into three types, depending on the source of the stimulus, and are components of the general or special somatic and visceral afferent pathways: Exteroceptors, located near the body surface, are special-ized to perceive stimuli from the external environment. These receptors, sensitive to temperature, touch, pressure, and pain, are components of the general somatic afferent pathways.

Proprioceptors are specialized receptors located in joint capsules, tendons, and intrafusal fibers within muscles. These general somatic afferent receptors transmit sensory input to the central nervous system, which is translated into information that relates to an awareness of the body in space and in movement.

Interoceptors are specialized receptors that perceive sensory information from within organs of the body; therefore, the modality serving this function is general visceral afferent.

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The dendritic endings of certain sensory receptors, specialized to receive particular stimuli, in-clude mechanoreceptors, thermoreceptors, and nociceptors.

Mechanoreceptors respond to mechanical stimuli that may deform the receptor or the tissues sur-rounding the receptor. Stimuli that trigger the mechanoreceptors are touch, stretch, vibrations, and pres-sure.

Peritricial nerve endings, the simplest form of mechanoreceptors, are unmyelinated, lack Schwann cells, and are not covered by a connective tissue capsule. Such nerve endings are located in the epidermis of skin, especially in regions of great sensitivity, such as the face and the cornea of the eye, where they respond to stimuli related to touch and pressure. Additionally, peritricial nerve endings are wrapped around the base and shaft of hair follicles and function in touch perception related to the defor-mation of the hairs. Moreover, some naked nerve endings function as nociceptors or as thermoreceptors.

Merkel's disks are slightly more complex mechanoreceptors. Specialized for perceiving discrimi-natory touch, these receptors are composed of an expanded unmyelinated nerve terminal associated with Merkel cells, specialized epithelial cells interspersed with keratinocytes in the stratum basale of the skin. These receptors are located mostly in nonhairy skin and regions of the body more sensitive to touch.

Meissner's corpuscles are encapsulated mechanoreceptors specialized for tactile discrimination. These receptors are located in the dermal papillae of the glabrous (nonhairy) portion of the fingers and palms of the hands, where they account for about half of the tactile receptors. They also are located in the eyelids, lips, tongue, nipples, skin of the foot, and forearm. Meissner's corpuscles are located in the der-mal papillae with their long axes oriented perpendicular to the skin surface. Each Meissner's corpuscle is formed by three or four nerve terminals and their associated Schwann cells, all of which are encapsulated by connective tissue. Contained within the capsule are stacks of epithelioid cells, possibly modified Schwann cells or fibroblasts, that serve to separate the branching nerve terminals.

Pacinian corpuscles, another example of the encapsulated mechanoreceptors, are located in the dermis and hypodermis in the digits of the hands and in the breasts as well as in connective tissue of the joints and the mesentery. These mechanoreceptors are specialized to perceive pressure, touch, and vibra-tion. Pacinian corpuscles are large, ovoid receptors 1 to 2 mm long by 0.1 to 0.7 mm in diameter. Each re-ceptor is composed of a single unmyelinated fiber that courses the entire length of the corpuscle. The core of the corpuscle contains the nonmyelinated nerve terminal and its Schwann cells, surrounded by ap-proximately 60 layers of modified fibroblasts, each layer separated from the next by a small fluid-filled space. An additional group of 30 less dense modified fibroblasts surround the core and are, in turn, en-veloped by connective tissue, forming the capsule around the core. The arrangement of the cells in the lamellae makes the histological section of a pacinian corpuscle resemble a sliced onion.

Ruffini's endings (corpuscles) are encapsulated endings located in the dermis of the skin, nail beds, and joint capsules. These large receptors, 1 mm long by 0.2mm in diameter, are composed of branched nonmyelinated terminals interspersed with collagen fibers and surrounded by four to five layers of modified fibroblasts. The connective tissue capsule surrounding each of these receptors is anchored at each end, increasing their sensibility to stretching and pressure in the skin and in the joint capsules.

Krause's end bulbs are spherical, encapsulated nerve endings located in the papillary region of the dermis. Originally, they were thought to be receptors sensitive to cold, but present evidence does not sup-port this concept. Their function is unknown.

Both muscle spindles and Golgi tendon organs are encapsulated mechanoreceptors involved in proprioception. Muscle spindles provide feedback concerning the changes in muscle length as well as the rate of alteration in the length of the muscle, and Golgi tendon organs monitor the tension as well as the rate at which the tension is being produced during movement.

Thermoreceptors, which respond to temperature differences of about 2°C, are of three types: warmth receptors, cold receptors, and temperature-sensitive nociceptors.

Although specific receptors have not been identified for warmth, it is assumed that these receptors are naked endings of small nonmyelinated nerve fibers that respond to temperature increases. Cold recep-tors are derived from naked nerve endings of myelinated fibers that branch and penetrate the epidermis. Because thermoreceptors are not activated by physical stimulation, they are believed to respond to differ-ing rates of temperature-dependent biochemical reactions.

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Nociceptors are receptors sensitive to pain caused by mechanical stress, extremes of temperature, and cytokines, such as bradykinin, serotonin, and histamine. These receptors are naked endings of myeli-nated nerve fibers that branch freely in the dermis before entering the epidermis.

Response of nerve tissue to injuryBecause mature neurons cannot divide, dead neurons cannot be replaced. Regeneration can occur

in axons injured or severed far enough from the soma to spare the cell. Partial degeneration, and subse-quent regeneration, follow.

Degeneration. A crushed or severed axon degenerates both distal and proximal to the injury. Dis-tal to the injury, both the axon and myelin sheath degenerate completely because the connection with the soma has been lost. During this wallerian, descending, or secondary degeneration, which takes approxi-mately 2 to 3 days, nearby Schwann cells proliferate, phagocytose degenerated tissue, and invade the re-maining endoneurial channel. Proximal to the injury, degeneration of the axon und myelin sheath is simi-lar but incomplete. This retrograde, ascending, or primary degeneration proceeds for approximately two internodes before the injured axon is sealed. The cell body also changes in response to injury. The perikaryon enlarges; chromatolysis, or dispersion of Nissl substance, occurs; and the nucleus moves to an eccentric position. Proximal degeneration and cell body changes take approximately 2 weeks. Regenera-tion begins during the third week after injury. As the perikaryon gears up for increased protein synthesis, the Nissl bodies reappear. The axon's proximal stump gives off a profusion of smaller processes called neurites; one of these grows into the endoneurial channel while the others degenerate. In the channel, the neurite grows 3-4 mm/day, guided and subsequently myelinated by the Schwann cells. Growth is main-tained by orthograde axoplasmic transport of material synthesized in the soma.

When the neurite tip reaches its termination, it connects with its end-organ or another neuron in the chain. If a severed nerve's cut ends are matched by fascicle size and arrangement and sutured together by their epineurial sheaths within 3 to 4 weeks, innervation often can be restored. If the gap between the cut ends is too wide, the neurites may fail to find endoneurial sheaths and may grow out in a potentially painful disorganized swelling called a neuroma.

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3. Histology and atlas. Michael H. Ross at al. – 1995. – C. 823.

4. Histology for the first year medical students by Dr.Adel Zohdy. – 2000. – C. 286.

5. Basic Histology. Nai Sarak at al. – 2003. – C. 470.

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