Marschall S. Runge, MD, PhD

• Charles Addison and Elizabeth Ann Sanders Distinguished
• Professor of Medicine
• Professor and Chair, Department of Medicine
• Division of Cardiology
• University of North Carolina School of Medicine
• Chapel Hill, North Carolina

This is known as muscle tone gastritis diet nih buy diarex 30caps amex, and occurs because spinal reflexes activate one group of motor units followed by another group gastritis caused by diet buy cheap diarex line. In most cases gastritis upper left abdominal pain 30caps diarex, eccentric contractions put the body in position for concentric contractions gastritis diet x program generic diarex 30 caps online. Examples of activities that used combined eccentric and concentric contractions include throwing and jumping gastritis burning pain in back generic diarex 30 caps with mastercard. Examples include attempting to move a load that is greater than the tension that the muscle can handle gastritis diet plans effective diarex 30 caps. Isometric contractions occur when we maintain our upright posture or when the joints are held stationary while other joints are moving. In isometric contractions, the cross-bridges generate force, but the thin filaments do not move. Tension Isotonic and Isometric Contractions the two primary types of muscle contractions are termed isotonic and isometric. When enough tension has developed for the needed movement, tension stays nearly constant through the remainder of the contractile period. In concentric contractions, when the elbow is flexed to move a weight toward the shoulder, the biceps muscle contracts concentrically. These contractions are about 50% more forceful than concentric contractions when the same load is moved. However, eccentric contractions cause delayed onset soreness of the muscle more often. An example of an eccentric contraction is when the calf muscles are used to climb a hill. Muscle damage causes creatine kinase to leak across plasma membranes into the bloodstream. High blood levels of creatine 232 Chapter 9 Muscle Tissue kinase usually mean that serious muscle damage has occurred. Oxygen Use and Debt Oxygen is required for the breakdown of glucose in the mitochondria. The pigment myoglobin is synthesized in the muscles to give skeletal muscles their reddish-brown color. Myoglobin can also combine with oxygen and temporarily store it to reduce muscular requirements for continuous blood supply during contraction. When skeletal muscles are used for a minute or more, anaerobic respiration is required for energy. In one type of anaerobic respiration, glucose is broken down via glycolysis to yield pyruvic acid, which reacts by producing lactic acid. Lactic acid can accumulate in muscles but diffuses in the bloodstream, reaching the liver, where it is synthesized into glucose. This acid is a three-carbon molecule, which dissociates into one hydrogen ion and one negatively charged lactate ion. The movement of lactate to the liver and glucose back to muscle cells is called the Cori cycle. As lactic acid increases, an oxygen debt develops, also referred to as excess postexercise oxygen consumption. Endurance is defined as the amount of time during which a particular muscular activity can be performed without fatigue. Aerobic endurance is the amount of time muscle contraction can continue while being supported by the activities of the mitochondria. Muscles may experience a change in their metabolic activity as exercise levels change. Muscle Fatigue Prolonged exercise may cause a muscle to become unable to contract. When a muscle becomes fatigued and cramps, it experiences a sustained, involuntary contraction. Although not fully understood, muscle cramps appear to be caused by changes in the extracellular fluid surrounding muscle fibers and motor neurons. After moderate activity, muscle fibers may need several hours to completely recover. Muscle tissue generates a lot of heat because muscles form much of the total body mass. Body temperature is partially maintained by the blood transporting heat generated by the muscle to other body tissues. Heat energy produced from muscle contraction is released through the integumentary system. Fibromyalgia is diagnosed by tests such as erythrocyte sedimentation rate, C-reactive protein, creatine kinase, and sometimes tests for hypothyroidism and hepatitis C because these diseases can cause general myalgia and fatigue. Fibromyalgia cannot be cured, but symptoms may be lessened by exercise, local heat, stress management, drugs that improve sleep, and analgesics. Smooth Muscle Smooth muscle lacks coarse connective tissue sheaths such as are found in the skeletal muscle. Most smooth muscle is made up of sheets of fibers that are closely apposed, such as in the walls of all except the smallest blood vessels and in the walls of hollow organs of various systems. Usually, there are two sheets of smooth muscle, with their fibers situated at right angles to each other. Examples of such smooth muscle action include the rectum, urinary bladder, uterus, lungs, and stomach. In smooth muscle sarcoplasm, calcium ions interact with calmodulin, which is a calcium-binding protein that activates the enzyme myosin kinase. Stretched smooth muscles adapt to their new lengths and remain able to contract on demand, a condition known as plasticity. In the digestive tract, pacesetter cells spontaneously trigger contraction of entire sheets of muscle. The rate and intensity of smooth muscle contraction can, however, be modified by both neural and chemical stimuli. In smooth muscles, innervating nerve fibers exist, which are part of the autonomic (involuntary) nervous system. They have many bulb-like swellings called varicosities, which release neurotransmitters into a wide synaptic cleft near smooth muscle cells. The sarcolemma of smooth muscles has many caveolae, which are pouch-like infoldings. The caveolae contain some extracellular fluid with a high concentration of calcium ions near the membrane. Most of these ions enter through calcium channels directly from the extracellular space. Myoblasts are the embryonic mesoderm cells from which most muscle tissue develops. Development occurs quickly, with the embryo experiencing skeletal muscle fiber contraction by week 7. The nerve endings release another chemical to eliminate receptor sites that have not been innervated or stabilized by the released agrin. Certain smooth muscles are stimulated by these neurotransmitters, whereas others are inhibited. The whole muscular sheet responds to a stimulus in unison because there is electrical coupling of smooth muscle cells by gap junctions. This differs from skeletal muscle, in which the fibers are electrically isolated from each other. Skeletal muscle fibers are stimulated to contract by their own neuromuscular junctions. The gap junctions of smooth muscle allow the transmission of action potentials from fiber to fiber. A summary of smooth muscle contraction is the sliding filament mechanism occurs for the interaction of actin and myosin. A rise in the intracellular calcium ion level is the final trigger for contraction. Different autonomic nerves serve visceral smooth muscle, releasing different neurotransmitters. Hormonal regulation: Hormones are chemicals that have the ability to affect smooth muscle contraction. The hormone gastrin, for example, simulates the stomach to contract so that its churning actions of food are more efficient. Local chemical regulation: Smooth muscles that lack a nerve supply depolarize spontaneously or in response to chemicals that bind to G protein-linked receptors. Direct responses to chemical stimuli affects smooth muscle activity based on local tissue needs. Chemical factors can cause contraction or relaxation without action potentials by altering calcium ion entry into the sarcoplasm. It is important to understand that chemical factors may include some hormones as well as histamine, lack of oxygen, low pH, and excess carbon dioxide. Smooth muscle takes approximately 30 times longer than skeletal muscle to contract and relax. It can maintain the same amount of contractile tension for long periods, with less than 1% of the energy expended. In small arterioles and other visceral organs, the smooth muscle regularly maintains a small amount of contraction (smooth muscle tone) with fatigue. Most adjacent smooth muscles have slow, synchronized contractions, in which the whole muscular sheet responds in unison to stimuli. As discussed earlier, this is related to gap junctions, which allow action potentials to be transmitted from fiber to fiber. The contraction of smooth muscle is regulated by neural, hormonal, and local chemical factors. Unique factors of smooth muscle contraction include response to stretching and changes in length and tension. Stretching of smooth muscle causes contraction, resulting in the automatic movement of substances along internal tracts. The increased tension is only brief and the smooth muscle quickly adapts to stretching, and then relaxes. Therefore, the stress relaxation response is important for organs such as the intestines and stomach, which must store their contents for enough time so that digestion and nutrient absorption can occur. The urinary bladder also must store urine, which is continuously made, until it can be voided. Types of Smooth Muscle Smooth muscles vary in fiber arrangement, fiber organization, innervation, and how they respond to stimuli. There are two major types of smooth muscle: Neural regulation: Neurotransmitter binding generates an action potential. Some types of smooth muscle only respond to neural Visceral smooth muscle: Also known as unitary smooth muscle, it exists in the walls of all hollow organs except for the heart. The cells often Effects of Aging on Muscle Tissue 235 show rhythmic spontaneous action potentials. Recruitment is not utilized in unitary smooth muscle and it is able to respond to various chemical stimuli. Visceral smooth muscle fibers can stimulate each other and adjacent fibers experience excitability. They display a pattern of repeated contractions known as rhythmicity, which is caused by self-exciting fibers. The wave-like motion of many tubular organs, known as peristalsis, is caused by these features of visceral smooth muscle. Peristalsis helps to move the contents of organs such as the intestines from the stomach to the outside of the body. Multiunit smooth muscle: this type exists in the large lung airways, large arteries, arrector pili muscles of the hair follicles, and the internal eye muscles that adjust the pupils and allow the eyes to focus. Multiunit smooth muscle has fibers that are structurally independent of each other. It has many nerve endings, with each forming a motor unit having a number of muscle fibers. Multiunit smooth muscle, has only one nucleus, responds to neural stimulation and has graded contractions involving recruitment. Effects of Aging on Muscle Tissue Nearly all types of muscle tissue develop from the embryonic mesoderm cells known as myoblasts, which fuse to form the myotubes of skeletal muscle fibers. Skeletal muscle fibers begin contracting at approximately the 7th week of embryonic development. The somatic nervous system begins to control muscle fibers and the amount of fast and slow contractile fibers is determined. Very early in the development, the myoblasts that produce cardiac and smooth muscle cells develop gap junctions instead of fusing. They allow limited regeneration of dead skeletal muscles, but this ability lessens with age. Smooth muscles regenerate well, with their cells dividing continually throughout life. Muscular development occurs in a pattern, from head to toe and from proximal to distal directions. By the middle of adolescence, humans reach total neural control of their muscles, which can be improved by athletic activities. Strenuous exercise increases muscle enlargement in males more than females, again because of testosterone. Skeletal muscle is highly resistant to infection because of its rich blood supply.

The pigment cells have critical biochemical interactions with the light receptors of the retina found in the neural part gastritis symptoms vs. heart attack purchase diarex 30caps on line. The neural part also contains supporting cells and neurons that handle preliminary processing and integration of visual information gastritis diet ������ order diarex paypal. The two retinal layers are normally close together gastritis ibuprofen generic diarex 30 caps on-line, but not interconnected very tightly gastritis define generic 30 caps diarex with amex. The neural part extends anteriorly up to the ora serrata and forms a cup-like structure that creates the posterior and lateral boundaries of the posterior cavity gastritis symptoms uk order diarex master card. These permanent abnormalities remain in the same part of the visual field and are caused by optic nerve compression gastritis diet ���� buy cheapest diarex and diarex, photoreceptor damage, or damage to the center part of the visual pathway. Floaters or small spots that drift across the visual field are usually temporary and caused by cellular debris or blood cells in the vitreous body. They tire because of the need for nearly continuous accommodation, papillary constriction, and convergence. Special Senses 381 Retina A Direction of light Fibers of the optic nerve Ganglion cell Amacrine cell Bipolar neuron Horizontal cell Retina focused on the optic disc cannot be seen. Rods are hundreds of times more sensitive to light than cones, providing vision in dim light without color. Cones provide sharper images, whereas rods provide more general outlines of objects. In the fovea centralis, the ratio of ganglion cells and cones is approximately 1:1. They provide information about color, fine detail, and edges of objects in bright light. Up to 1000 rods may conduct information via bipolar cells to just one ganglion cell. The larger ganglion cells that monitor information from the rods are called M cells. In dim light, M cells function to provide information about object shapes as well as motion and shadows. Certain ganglion cells, known as on-center neurons, are inhibited by light striking the edges of their receptive field but are excited by light that arrives in the center of their sensory field. Together, on-center and off-center neurons help to improve detection of the edges of objects in the visual field. If you have 20/30 vision, this means you must be 20 feet away from an object to see it clearly that a person with normal vision could see clearly at 30 feet. Once visual acuity falls below 20/200, even if contact lenses or glasses are used, the person is considered to be legally blind. The term blindness actually means a total absence of vision because of eye or optic pathway damage. Conditions that may lead to blindness include diabetes mellitus, cataracts, corneal scarring, glaucoma, retinal detachment, and even hereditary factors. The retina also contains other neurons that process light responses and glial cells (glia). The retina has a complex structure of distinct layers, with a central depression (the fovea centralis) in the portion of the retina that produces the sharpest vision and a yellowish spot (the macula lutea). The optic disc is the point where nerve fibers leave the retina and join the optic nerve in the posterior wall (fundus). Because the optic disc area lacks receptor cells, it is referred to as the blind spot. By comparing the relative positions of objects within the images seen by each eye, depth perception is achieved. Depth perception is 382 Chapter 15 Special Senses defined as the interpretation of three-dimensional relationships among viewed objects. Lateral to the blind spot of each eye is an oval region known as the macula lutea (yellow spot). Both rods and cones are located in the deep portion of the retina near a layer of pigmented epithelium. The epithelial pigment helps to keep light from reflecting off surfaces inside the eye. The rods and cones synapse with approximately six million neurons that are known as bipolar cells. These cells then synapse inside layers of ganglion cells near the posterior cavity of the eye. A horizontal cell network continues across the outer retina between photoreceptors and bipolar cells. Rhodopsin is a light-sensitive biochemical in rods that is also known as visual purple. In the presence of light, rhodopsin breaks down into a clear protein called opsin and a yellowish pigment called retinal or retinine made from vitamin A. When rods exposed to intense light need time to generate rhodopsin, this is called the phenomenon of dark adaptation. The lightsensitive proteins in cones are made of retinal and three different opsin proteins. The three types of cones each contain one of three visual pigments: erythrolabe (sensitive mostly to red light waves), chlorolabe (sensitive mostly to green light waves), or cyanolabe (sensitive mostly to blue light waves). Therefore, the three types of cones are referred to as red cones, green cones, and blue cones. It is caused by a congenital lack of one or several cone pigments and is an inherited X-linked condition. Most often, red-green color blindness occurs, in which these colors are seen as being the same. The process of photoreception involves photons striking the retinal portions of rhodopsin molecules in the membranes of photoreceptor discs. This activates phosphodiesterase, an enzyme that breaks down cyclic guanosine monophosphate. Each adjacent bipolar cell then senses that the photoreceptor has absorbed a photon. Visual nerve pathways begin as axons of the retinal neurons and leave the eyes to form optic nerves. The fibers from the nasal half of the left eye and temporal half of the right eye form the right optic tract, and fibers from the nasal half of the right eye and temporal half of the left eye form the left optic tract. Most fibers enter the thalamus and synapse in its lateral geniculate body, where visual impulses enter nerve pathways called optic radiations leading to the visual cortex of the occipital lobe. After you spend 30 minutes or more in the dark, nearly all visual pigments become fully receptive to stimulation, which is known as the dark-adapted state. The visual system is very sensitive at this time, with a single road hyperpolarizing in response to a single photon of light. Turning the room lights on at first seems excessively bright, but over a few minutes, sensitivity to light decreases as bleaching occurs. This is soon balanced by the speed at which the visual pigments reform, which is called the light-adapted state. In the brain stem, visual processing is integrated with movements of the head and neck. The pineal gland along with the suprachiasmatic nucleus use visual information to establish the circadian rhythm. This provides a shorter focal length, so an object close to the retina can be seen more clearly. The lens is actually enclosed by a thin, elastic capsule and is avascular, like the cornea. There are normally two steps involved in focusing as light passes through the cornea, and then passes through the lens. It occurs when light waves pass at oblique angles from one optical density medium to a different one. The lens differs from the cornea in that its high elasticity allows it to change shape and bend light actively instead of on a constant basis allowing fine focusing to occur. Most refraction occurs when light reaches the corneal tissues, which have a density similar to that of water, but additional refraction occurs when the light passes from the aqueous humor into the lens. This additional refraction is required to focus light rays from an object toward a focal point, which is a certain point of intersection on the retina. Focused light waves Air Lens Many suspensory ligaments hold the transparent, biconvex lens in position behind the iris and pupil. The suspensory ligaments pull to adjust the lens and help it to focus, controlled by the ciliary muscles. Focal distance is determined by the distance of the object from the lens and the shape of the lens. Causes of cataracts include natural aging, in which they are called senile cataracts, as well as reactions to drugs, injuries, and radiation. The lens turns a yellow color and becomes cloudy, causing larger amounts of light to be necessary for reading. Visual clarity is reduced and the person may become functionally blind if the lens becomes totally opaque. Cataracts can be shattered by high-frequency sound waves, removed, and replaced by artificial lenses. Internal Chambers and Fluids the iris divides the anterior cavity into an anterior chamber and a posterior chamber. The posterior chamber can be better understood as being "between the iris and the lens. The entire anterior segment is filled with aqueous humor, which is similar to blood plasma in composition. When aqueous humor leaves the anterior chamber, it filters through connective tissue fibers near the base of the iris to enter the scleral venous sinus or canal of Schlemm. This is a passageway that extends around the eye at the level of the corneal limbus. In general, this movement is at the same pace as the rate of generation at the ciliary processes. The intraocular pressure of the eye can be measured in the anterior chamber, because the fluid pushes against the inner corneal surface. This is usually done by applanation tonometry, which involves a small, flattened disk being placed on the anesthetized cornea. The posterior cavity is filled with a clear, jelly-like fluid called vitreous humor, which along with collagenous fibers makes up the vitreous body of the eye, giving it support and shape. The vitreous humor contains large amounts of water, contributes to intraocular pressure by helping to counteract the forces of the extrinsic eye muscles, supports the posterior lens surface, holds the neural retinal layer against the pigmented layer, and transmits light. Unlike the aqueous humor, the vitreous humor does not form or drain continually and is not always in motion. When a nearby object is viewed, the eyes actually turn inward to converge, which focuses the image on each fovea. Convergence occurs so much during our daily lives that it can cause straining of the extrinsic eye muscles. Minor astigmatism is very common, and many people are not even aware they have the condition. As it becomes more serious, light passing through the cornea and lens is refracted improperly, causing distortion of visual images. Treatments include glasses, contact lenses, corneal modification procedures, and laser surgery. The cornea differs from the lens in that it cannot be adjusted to focus on objects that are up close. The flexibility of the Special Senses Retina 385 Focal point Light from distant source Divergent light rays from near source would come into focus behind the retina if lens could not increase its refractive power. Focal point Focal point Light from near source is focused on retina as lens thickens. Also known as nyctalopia, it may be very dangerous to drive a car at night because of the oncoming lights of other vehicles. Night blindness may be caused by nearsightedness, glaucoma, cataracts, diabetes, retinitis pigmentosa, or vitamin A deficiency. Retinitis pigmentosa is actually a group of inherited retinopathies that are the most common inherited visual abnormalities. In these retinopathies, visual receptors deteriorate over time, leading to blindness. The eyes begin to lose the ability to see clearly up close or to focus when not in bright light. The ear canals become thinner, earwax production changes, and the ability to perceive certain ranges of frequencies becomes difficult or even impossible. Causes of hair cell loss include nerve damage, trauma, loud noises, and certain medications. Aging also affects our balance and coordination and the perception of smells and tastes. Summary the special senses have receptors within large, complex sensory organs of the head. The five basic types of taste sensations are sweetness, sourness, saltiness, bitterness, and umami (deliciousness). The outer, middle, and inner ear work together to receive vibrations perceived as sounds. The outer ear consists of the auricle (pinna), external acoustic meatus (external auditory canal), and eardrum (tympanic membrane). The middle ear (tympanic cavity) contains the auditory ossicles (malleus, incus, and stapes) and is connected to the throat via the auditory (Eustachian) tube.

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Leukocytes: White blood cells; they protect the body against disease and develop from hemocytoblasts in red bone marrow gastritis symptoms how long do they last diarex 30 caps visa. Leukocytosis: A condition of white blood cells exceeding 10 mild gastritis diet quality 30caps diarex,000 per cubic millimeter chronic gastritis lasts best purchase for diarex, indicating an acute infection gastritis diet ��� discount 30 caps diarex mastercard. Leukotrienes: A class of biologically active compounds that occur naturally in leukocytes and produce allergic and inflammatory reactions similar to those of histamine gastritis symptoms treatment mayo clinic order diarex toronto. Lever: Any rigid structure that moves on a fulcrum when force is applied; in the body gastritis upper right quadrant pain buy diarex 30caps lowest price, the bones act as levers. Leydig cells: the cells of the interstitial tissue of the testes; they secrete testosterone. Ligamentum teres: the ligament of the femur heat, a flattened intracapsular band connecting the femur head to the lower edge of the acetabulum. Glossary Lower limbs: the femurs, tibias, fibulas, patellae, tarsals, metatarsals, and phalanges. Lumbar plexus: A nervous plexus in the lumbar region of the body that forms part of the lumbosacral plexus. Lumbar puncture: Also called a spinal tap, this is a procedure in which cerebrospinal fluid is removed for analysis via a needle inserted into the subarachnoid space inside the meningeal sac inferior to the lumbar region of the spine. Lumbosacral plexuses: Made up of the last thoracic nerve and the lumbar, sacral, and coccygeal nerves and extend into the pelvic cavity; they are associated with the skin and muscles of the lower abdominal wall, buttocks, external genitalia, thighs, legs, and feet. Lumbosacral trunk: the entire anterior division of the fifth, and part of the fourth lumbar nerves. Lyme disease: An infection caused by a spirochete transmitted by the bite of infected ticks; joint inflammation, pain, and arthritis develop in half of cases as long as two years after transmission. Lymph nodes: Specialized, bean-shaped organs that act as filters or traps for foreign particles. Lymph sinuses: Spaces inside lymph nodes that comprise complex channels through which lymph moves. Lymphatic capillaries: Microscopic vessels extending into interstitial spaces in complex networks. Lymphatic pathways: Tiny tubes formed from lymphatic capillaries that merge to form larger vessels. Lymphatic trunks: Structures that drain lymph from lymphatic vessels and join either the thoracic duct or the right lymphatic duct. Lymphatic vessels: Those that conduct lymph; they are similar to veins, but with thinner walls, and have valves to prevent backflow. Lymphoid tissue: the cells and organs that make up the lymphatic system, including the leukocytes, bone marrow, thymus, spleen, and lymph nodes. Lysosomes: Tiny sac-like organelles that dispose of cell wastes and worn-out cell parts. M M line: A fine dark band in the center of the H zone in the myofibrils of striated muscle fibers. Macromolecules: Large, complex molecules with as few as 100 to over 10,000 amino acids; most proteins are macromolecules. Macrophages: Large, actively phagocytic cells of various types; fixed macrophages or histiocytes are found in certain tissues and organs, such as the microglia of the nervous system and Kupffer cells of the liver sinusoids; free macrophages travel throughout the body, such as alveolar macrophages, which monitor exchange surfaces of the lungs. Macula densa: A group of modified epithelial cells in the distal convoluted tubule that control renin release by relaying information about sodium concentration to the juxtaglomerular cells. Maculae: Equilibrium receptor regions of the saccule and utricle, which are the two membranous sacs suspended in the perilymph of the vestibule of the inner ear; the maculae respond to gravity and transmit impulses concerning changes in head position. Macular degeneration: An eye condition that may cause blurred vision or no vision in the center of the visual field; it is most common in older people and occurs from damage to the macula of the retina. Main pancreatic duct: the primary excretory duct of the pancreas, usually united with the common bile duct, before entering the duodenum at the major duodenal papilla. Major histocompatibility complex: A surface antigen that is important to the recognition of foreign antigens; it plays a role in coordination and activation of the immune response. Male secondary sex characteristics: Increased body hair, decreased hair growth on the scalp (sometimes), enlargement of the larynx, thickening of the vocal folds, thickening of the skin, increased muscular growth, broadening of the shoulders, narrowing of the waist, thickening and strengthening of the bones. Maltose: A disaccharide formed in the hydrolysis of starch, composed of two glucose residues, the fundamental structural unit of glycogen and starch. Mechanically gated channels: They respond to physical distortions of membrane surfaces by opening or closing; important in sensory receptors involving pressure, touch, or vibration. Mechanoreceptors: Receptors that sense mechanical stimulation such as changes in pressure or tension. Medial canthus: the part of the eyelid that is the location of the lacrimal caruncle, which produces rheum or "sleep," the gritty substance often present when awakening. Medial condyles: Processes that, along with the lateral condyles, are flanked superiorly by the lateral and medial epicondyles; the points of articulation between the femur and tibia. Medial epicondyles: the sites of muscle attachment; along with the lateral epicondyles, they superiorly flank the lateral and medial condyles. Medial longitudinal arch: the arch of the foot that curves significantly because of the position of the talus. Median antebrachial vein: A superficial vein of the upper limb, draining the venous plexus on the palmar surface of the hand. Median nerve: the nerve that supplies most muscles in the anterior forearm; commonly injured through compression in carpal tunnel syndrome. Median sacral crest: the structure formed by the fused spinous processes of the sacral vertebrae in the spine. Mediastinum: the medial cavity of the thorax, which contains the heart, its large vessels, the trachea, esophagus, thymus, lymph nodes, and other structures and tissues. Medulla oblongata: the most inferior part of the brain stem; it blends into the spinal cord and contains the cardiovascular center, respiratory centers, and various other brain centers. Medullary cavity: the central cavity in a long bone, surrounded by a thick collar of compact bone; the cavity is called the yellow marrow cavity in adults because it contains fatty yellow marrow. Medullary cords: Structures of lymphatic tissue in the medulla of a lymph node; they include plasma cells, macrophages, and B-cells. Medullary respiratory center: the dorsal and ventral respiratory groups as well as the respiratory group of the pons. Medullary sinuses: Also called sinusoids; vessel-like spaces separating the medullary cords of a lymph node. Mammillary bodies: Two paired, small round masses in the fossa of the midbrain, forming part of the hypothalamus. Mandibular foramen: the opening where the mandibular canal begins, allowing blood vessels and nerves to pass that service the lower teeth. Maple syrup urine disease: An inherited disorder in which certain amino acids cannot be processed; characterized by sweet-smelling urine, poor feeding, vomiting, lethargy, and developmental delays. Mast cells: Cells to which antibodies, formed in response to allergens, attach, bursting the cells and releasing allergy mediators, which cause symptoms. Mastication: Chewing, tearing, or grinding of food with the teeth while it becomes mixed with saliva. Mastoid antrum: A cavity continuous with mastoid cells; it is separated from the middle cranial fossa above by the tegmen tympani. Mastoid process: One of two projections below each external acoustic meatus; it provides a point of attachment, and is attached to certain neck muscles. Matrix: A combination of connective tissue, blood vessels, and minerals that compose bone. Matter: Liquids, gases, and solids both inside and outside of the human body; it takes up space and has weight. Maxillary artery: One of the two larger terminal branches of the external carotid arteries arising from the neck of the mandible, dividing into six branches, and supplying the deep facial structures. Mechanical advantage: A power lever; when the load is closer to the fulcrum (or joint) and effort is applied far away; a small effort exerted over a relatively large distance can move a large load over a small distance. Mechanical barriers: Innate defenses that include the skin, mucous membranes, hair, sweat, and mucus. Glossary Melanocytes: Skin cells that produce melanin; they are found in the stratum germinativum layer of the epidermis, just above the dermis. Melanosomes: Granules within melanocytes that contain tyrosinase and synthesize melanin; they are transferred from the melanocytes to keratinocytes. Melatonin: A catecholamine hormone synthesized and released by the pineal gland; it is involved in regulation of sleep, mood, puberty, and ovarian cycles. Membranous labyrinth: the labyrinth of the ear that is lodged within the bony labyrinth and has the same general form; it is much smaller, however, and separated from the bony walls by the fluid known as the perilymph. Membranous urethra: the part of the male urethra situated between the layers of the urogenital diaphragm; it connects parts of the urethra passing through the prostate gland and penis. Memory cells: Cells that develop from any clone cells that do not become plasma cells; if they encounter the same antigen later, they can cause an almost immediate humoral response. Memory consolidation: A category of processes that stabilize a memory trace after its initial acquisition; it utilizes synaptic and systems consolidation, along with the process of reconsolidation of memories. Memory: the ability to recall information or sensations; it can be divided into short-term and long-term memory. Meningeal branch: A division of each spinal nerve that is very small, reentering the vertebral canal, innervating meninges and blood vessels lying inside. Menstrual cycle: Also called the uterine cycle, it is coordinated with the ovarian cycle, and includes a menstrual phase, proliferative or preovulatory phase, and a secretory, postovulatory phase. Mental foramina: the openings that allow nerves to pass through the mandible, allowing sensory information from the lips and chin to reach the brain. Mesenchymal cells: Stem cells in connective tissues that respond to local infection or injury; they divide, producing daughter cells that differentiate into various connective tissue cells, including fibroblasts and macrophages. Mesentery: A double-layered fold of peritoneal membrane that suspends the jejunum and ileum from the posterior abdominal wall. Mesosalpinx: A short mesentery that supports the peritoneum that externally covers the uterine tubes; it is part of the broad ligament. Mesothelium: the epithelium inside serous membranes, which line the ventral body cavity and cover its organs. Mesovarium: the fold of peritoneum that suspends each ovary in between the uterus and pelvic wall; it is part of the broad ligament. Metabolism: the cellular chemical reactions that break down and build up substances inside living cells. Metarterioles: Small peripheral blood vessels between arterioles and true capillaries that contain scattered groups of smooth muscle fibers in their walls. Micelles: Droplets with hydrophilic portions on the outside; consisting of bile salts, monoglycerides, and fatty acids, in the lumen of the intestinal tract. Microcirculation: the passage of blood in the arterioles, capillaries, and venules. Microfilaments: the smallest of the cytoskeletal elements, they provide cell movement. Microglial cells: Neuroglia found throughout the central nervous system that have phagocytic actions. Microphages: Phagocytic white blood cells that include neutrophils and eosinophils; that are attracted to sites of infection or injury by chemicals released by macrophages and mast cells. Microscopic anatomy: the study of small body structures, requiring the use of a microscope. Microtubules: Thin, tubular structures in the cytoplasmic ground substance of most cells, involved in maintaining cell shape and movements of organelles; they form the spindle fibers of mitosis. Microvilli: Tiny, hair-like folds in the plasma membrane extending from the surface of many absorptive or secretory cells. Middle cardiac vein: the vein beginning at the heart apex, ascending in the posterior interventricular sulcus to the coronary sinus. Middle cerebral arteries: Two large terminal branches of the internal carotid artery. Motor (efferent) nerves: Peripheral nerves that carry impulses only away from the central nervous system; they are relatively rare in the human body. Motor areas: the parts of the cerebrum, mostly in the frontal lobes, that control skeletal muscle functions. Motor end plate: the flattened end of a motor neuron that transmits neural impulses to a muscle. Motor endings: the elements of the peripheral nervous system that activate effectors by releasing neurotransmitters. Motor output: Responses by the nervous system that activate the effector organs (muscles and glands). Mucosa (mucous membrane): the surface epithelium, connective tissue, and smooth muscle of the alimentary canal. Mucosal barrier: A barrier of tissue created by epithelium, such as the linings of the mouth, esophagus, stomach, intestine, and anal canal. Mucous cells: Also called goblet cells; mucus producing unicellular glands in certain epithelia of the digestive and respiratory tracts. They are called mucous cells when they are found in the stomach mucosa, respiratory mucosa, and salivary glands. Mucous membranes: Membranes that line cavities and tubes that open to the outside of the body. Mucus: Related to digestion, it is a thick liquid that binds food particles and lubricates them during swallowing. Multiaxial movement: Motion of, pertaining to , or occurring in more than two axes. Multipennate: the term describing a muscle in which the fiber bundles converge to several tendons. Multiple-allele inheritance: When a human inherits only two out of more than two possible alleles. Multiunit smooth muscle: Found in the irises of the eyes and walls of blood vessels, it has separated muscle fibers and contracts only when stimulated by nerve impulses or certain hormones. Middle suprarenal arteries: Two small vessels arising from either side of the abdominal aorta opposite the superior mesenteric artery.

X monosomy might promote autoimmunity by preventing tol erance to autoantigens encoded by both X chromosomes gastritis diet suggestions generic 30 caps diarex free shipping. Vitamin D and Sunlight Exposure correlation between the incidence of autoim mune disease and increasing latitude gastritis diet king cheap 30caps diarex mastercard. Dietary vitamin D and vitamin D synthesized in response to ultravioletB radiation in sunlight determine serum vitamin D levels erythematous gastritis definition purchase diarex 30 caps without prescription. Loss of Immune Tolerance to Autoantigens and Perpetuation of Autoimmune Diseases Overview In addition to its roles in bone mineralization and calcium homeostasis gastritis poop 30 caps diarex sale, vitamin D modu lates immune reactions and risk for autoim munity [19] gastritis diet 1200 30caps diarex with mastercard. Reduction in sunlight exposure and synthesis of 1 gastritis x estres diarex 30caps on-line,25dihydroxyvitaminD3 (D3) might explain, in part, the strong Autoimmune diseases are uncommon, despite the high frequency of genetic suscep tibility and environmental exposure to microbial pathogens and xenobiotics, including drugs. Evidence that low levels of autoimmune reactions are common in healthy people highlights the fact that Chapter 2 Concepts of Autoimmunity Relevant to Autoimmune Liver Diseases 35 these initial steps are common but only dele terious when not immunoregulated. Multiple factors and mechanisms to break tolerance to selfantigens have been identified. The increasing incidence of autoimmunity and inflammatory diseases observed world wide is correlated with changes in environ mental factors, including a more modern lifestyle, improved hygiene, a Western diet, use of antibiotics, and elimination of childhood parasitic infections. Although the proposed causal link between the gut microbiome and autoimmunity has not been proved, available data indicate that interplay between the gut microbiota and the innate and adaptive immune systems of the intestine and liver plays key roles in both normal and dysfunc tional systemic immunity. Thus, the gut microbiome and intestinal immune responses appear to influence systemic immunity, and risk for autoimmunity, through the innate and adaptive immune responses of the liver. Whether dysbiosis is the cause or the effect of autoimmunity remains a key unresolved issue. Female sex hormones can also alter the gut microbiome, which may contribute to the female predilection in autoimmunity. If an altered gut microbiota or increased gut permeability were causally related to autoim mune diseases, then restoration of a normal microbiota and mucosal integrity could be therapeutic. Gut microbiota are composed of commensal bacteria, fungi and viruses, as well as poten tially pathogenic bacteria and fungi. In addition, the microbiota process food, xenobiotic pollutants and drugs to generate micronutrients and metabolites. Bacterial, fungal or viral infections can insti gate innate and adaptive immune responses that result in autoimmunity [21]. This proinflammatory environment could 36 Section I Scientific Basis of Clinical Autoimmune Liver Diseases promote adaptive immune responses to autoantigens in dead or dying cells. Molecular Mimicry of Autoantigens Molecular mimicry is a key mechanism leading to loss of tolerance to autoantigens [21]. It is defined as the crossreactivity of immune responses to antigenic epitopes of microbial peptides with autoantigenic epi topes of host peptides. Molecular mimicry has been observed between human autoanti gens and peptide antigens of several viral, bacterial and fungal pathogens. Yet molec ular mimicry is an insufficient explanation for a sustained loss of tolerance, which also requires failure to control the autoimmune response. Thus, molecular mimicry repre sents an environmental trigger capable of progressing to autoimmunity. Molecular mimicry to adjuvants (substances that enhance immune responses to an antigen) involves nucleosomes or ribonucleoproteins released after cell death. These molecules mimic viruses by stimulating an antiviral like, innate immune response with produc tion of type 1 interferon. Biochemical modifications of self antigens can also increase the immunoge nicity of autoantigens. The best example is citrullination, produced by posttranslational conversion of arginine to citrulline. Failure of Apoptosis to Conceal Autoantigens and Eliminate Autoreactive Cells Neoantigens, also called cryptic antigens, can elicit autoimmune responses against autoan tigenic epitopes that are not immunogenic until modified by either somatic hypermuta tions or binding of haptens [22]. Haptens are small molecules, most often metabolites of drugs or environmental xenobiotics, that are incapable of eliciting an immune response unless bound to host carrier proteins. Defective apoptosis might also contribute to the persistence of autoreactive T and B cells in autoimmune diseases. Immune Deviation of Activated T Cells Tcell Receptor Revision in the Periphery Immune deviation refers to the evolution of dominant populations of effector T cells, which alter local immune responses and com promise tolerance [1]. Th1 predominance pro duces greater immunopathology associated with autoimmune diseases that cause tissue damage. The signature cytokines of Th1 and Th2 cells inhibit the proliferation and secre tion of the cytokines of each other, resulting in a dynamic balance. Skewing of this balance contributes to either the maintenance or the loss of tolerance. Thus, polarization of immune responses toward Th1 and Tfh cells greatly increases the consequences of autore active T and B cell activation. Perpetuation of Autoimmune Diseases the primary factor in perpetuation of autoim mune diseases is failure to immunoregulate and terminate the initial activation of B and T cells to autoantigens or their mimics [1]. While the mech anisms already discussed focus on factors leading to autoantigen recognition, it is now clear that epigenetics dictates the subsequent obligatory failure to regulate and terminate 38 Section I Scientific Basis of Clinical Autoimmune Liver Diseases autoimmune reactions. In addition, epigenetics controls suppression of autophagy, which dysregulates immune modulation in effector cells and pro motes persistence of cytokineactivated target cells/tissues in autoimmune diseases. The hypothesis that apoptosis is involved in epitope spreading is attractive because apoptotic blebs do not contain random samples of intracellular constitu ents, but instead contain high concentrations of known autoantigens. By extending the autoreactive Tcell and B cell repertoire mediating autoimmune dis ease, epitope spreading greatly reduces the prospect that host immunoregulatory mech anisms can resume control. Theses cytokines are expressed by both immune and Chapter 2 Concepts of Autoimmunity Relevant to Autoimmune Liver Diseases 39 epithelial cells and result in bilateral stimula tion. These cytokines have a dual potential to immunoregulate innate and adaptive immune responses or to promote immuno pathogenesis. These cytokines are most often pathogenic in autoimmune diseases, perpet uating chronic tissue inflammation. Epithelial Cellinduced Transformation of iTreg to Th17 Cells ation of autoimmunity provide conceptual as well as realistic targets for interventions to prevent and treat autoimmune diseases [1]. However, it may become possible to identify children at risk of autoimmunity and develop strategies to reduce their risk of autoimmune diseases. The development of new immunosuppressive medications, inhibi tion of cytokine production and function, and epigenetic inhibitors increase the probability of controlling a variety of autoimmune dis eases in the near future. Strategies to Prevent Autoimmunity Vitamin D deficiency is epidemiologically associated with risk of autoimmunity [19]. Achieving and maintaining high normal serum levels of vitamin D3 is a realistic and achievable goal, which could reduce the incidence and severity of autoimmune diseases. Prevention of Autoimmunity and Therapeutic Control of Autoimmune Diseases Overview It remains unclear if changes in the fecal microbiota associated with specific autoim mune diseases represent causes or effects [20]. Were causal relationships identified for either initiation or perpetuation of autoim munity, several strategies theoretically could decrease the risk of autoimmunity, espe cially if used during pregnancy and infancy. These include probiotics to shape the evolu tion of the gut microbiota and sustain the mucosal barrier, fecal microbiota transplan tation to create a preventive gut microbi ome, and either deliberate infection with nonpathogenic helminths or ingestion of specific parasite peptides to promote a systemic immunosuppressive Th2 environ ment [28]. Oral Tolerance Our current understanding of the mecha nisms involved in the generation and perpetu Ingestion of antigens leads to absorption and interaction with the reticuloendothelial system of the liver. Repeated ingestion can 40 Section I Scientific Basis of Clinical Autoimmune Liver Diseases result in oral tolerance, defined as the inability to respond to the ingested antigen when given parenterally [29]. The second strategy involves generating antigenspecific iTregs from peripheral blood mononuclear cells ex vivo for infusion. Epigenetic Enhancer Regulation At the time of diagnosis, the initiating events of most autoimmune diseases likely occurred months to years earlier and mechanisms of perpetuation are well established. This poses challenges for clinical management and focuses attention on therapeutic strategies to control inflammation, modify symptoms and signs, and retard progression. Progress in understanding the pathogenesis of autoim mune diseases provides rationales for addi tional conventional and novel therapies (Table 2. Inducible T Regulatory T Cells Studies of two strategies to produce iTregs specific for autoantigens are in progress (Table 2. The theoret ical fear that targeting epigenetic regulatory proteins might cause severe toxicity has not been observed with firstgeneration inhibitors. Intracellular B lymphocyte signalling and the regulation of humoral immunity and autoimmunity. Tolerogenic dendritic cells and Tregulatory cells at the clinical trials crossroad for the treatment of autoimmune disease: emphasis on type 1 diabetes therapy. Approaches and advances in the genetic causes of autoimmune disease and their implications. Chapter 2 Concepts of Autoimmunity Relevant to Autoimmune Liver Diseases 45 19 Dankers, W. Evolving models of the immunopathogenesis of T cellmediated drug allergy: the role of host, pathogens, and drug response. Overlooked mechanisms in type 1 diabetes etiology: 25 26 27 28 29 how unique costimulatory molecules contribute to diabetogenesis. Therapeutic potential of helminths in autoimmune diseases: helminthderived immuneregulators and immune balance. Only a relatively small proportion of overall genetic risk of developing autoimmune liver diseases is explained by the new loci determined so far. In addition, it is generally recommended that genomewide significant associations identified in a "discovery panel" be confirmed by replicating the association in an independent "validation panel" (albeit at a less stringent level of significance). The iChip is an Illumina Infinium array containing 196 524 rare to common variants across 186 known autoimmunity risk loci. Such dense coverage enables fine mapping of risk loci to refine the association signal and pinpoint candidate genes. Highthroughput genetic studies of these conditions undertaken to date are listed in Tables 3. These studies have undoubtedly been successful, identifying numerous risk loci for these disorders that were hitherto unknown, providing fresh insight into the genetic basis of autoimmune liver disease. Discovery panel Study Design Ancestry Cases Controls Validation panel Cases Controls Hirschfield et al. Discovery Study Design Ancestry Cases Controls Validation Cases Controls Karlsen et al. Discovery Study Design Ancestry Cases Controls Cases Validation Controls de Boer et al. Causal variants and genes may be prioritized through functional annotation of risk loci but laboratory experiments linking genotype and molecular phenotype are required to confirm (and explain) the contribution of the variant and gene to disease pathogenesis [50]. The reader is reminded that the potential role of these genes in the pathogenesis of autoimmune liver disease is obvious but also speculative. The mechanism by which causal variants lead to disease is unknown and may be different for each risk locus. It has been observed, however, that many candidate causal variants for complex disorders are regulatory variants, meaning that they overlap regulatory elements. Association is detected with the index variant owing to correlation with the causal variant. The index variant is correlated to numerous other variants, however, making it difficult to know which one is causal. Bioinformatics approaches are helpful for prioritizing candidate genes but functional studies are ultimately required to confirm causality and elucidate mechanism. This suggests that many variants contribute to disease by influencing the regulation of gene expression. They identified 244 independent multidisease signals and showed that comorbidities among the five disorders were best explained by 56 Section I Scientific Basis of Clinical Autoimmune Liver Diseases Box 3. It degrades a broad variety of small peptides, especially those containing neutral bulky aliphatic or aromatic amino acid residues. It is a key negative regulator of cytokine signaling and plays a critical role in hematopoiesis. It plays an essential role in regulation of Bcell differentiation, proliferation and maturation to an effector state. It induces apoptosis and anoikis, and may function as an essential initiator of apoptosis in thymocytenegative selection. However, it also promotes the differentiation of activated T cells into effector T cells and memory T cells, which is critical for immunity. Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression, and developmental events. Pervasive sharing of risk variants of genes across a variety of autoimmune diseases is relevant because crossphenotype analyses might therefore be helpful in identifying molecular targets for therapies with widespread applications (although this cannot be assumed). Paradoxically, genetic studies of autoimmune liver disease highlight the likely importance of environmental factors in shaping disease. It is conceivable that common causal variants for complex disorders have escaped neutral processes. Interpretation of genetic findings may therefore require better knowledge of the environmental factors involved in disease, justifying ongoing efforts to identify these factors.