WEEK+2+Alterations+in+cellular+tissue+integument

__//**1. Review cellular/tissue/integumentary content from Nursing 138 (Nursing Care I).

2. Review the anatomy and physiology of cells/tissues/systems and the integumentary system.

3. Review the techniques for physical assessment of the integumentary system.

4. Describe the structure and function of cellular components.**//__ (Huether 2-7) The **nucleus,** which is surrounded by the cytoplasm and generally is located in the center of the cell, is the largest membrane-bound organelle. The nucleus contains the **nucleolus, and** most of the cellular DNA. The DNA “chain” in eukaryotic cells is so long that it is easily broken. Therefore the histones that bind to DNA cause DNA to fold into chromosomes ([|Figure] [|1-2] ), which decreases the risk of breakage and is essential for cell division in eukaryotes. The primary functions of the nucleus are cell division and control of genetic information. Other functions include the replication and repair of DNA and the transcription of the information stored in DNA. Cytoplasm is an aqueous solution (cytosol) that fills the **cytoplasmic matrix**—the space between the nuclear envelope and the plasma membrane. The cytosol represents about half the volume of a eukaryotic cell. It contains thousands of enzymes involved in intermediate metabolism and is crowded with ribosomes making proteins. Functions include synthesis of proteins and hormones and their transport out of the cell, isolation and elimination of waste products from the cell, metabolic processes, breakdown and disposal of cellular debris and foreign proteins (antigens), and maintenance of cellular structure and motility. The cytosol is a storage unit for fat, carbohydrates, and secretory vesicles. [|Table] [|1-1] lists the principal cytoplasmic organelles. They control the composition of the space they enclose. They control the movement of substances from one compartment to another. The plasma membrane also has an important role in cell-to-cell recognition. Other functions of the plasma membrane include cellular mobility and the maintenance of cellular shape ([|Table] [|1-2]). __//Membrane composition//__ The outer surface is dimpled with cavelike indentations known as **caveolae** (“tiny caves”). Caveolae serve as a storage site for many receptors and provide a route for transport into the cell. The major chemical components of all membranes are lipids and protein. Carbohydrates are associated mainly with plasma membranes, where they combine chemically with lipids, forming glycolipids, and with proteins, forming glycoproteins. __//Lipids//__ The basic component of the plasma membrane is a bilayer of lipid molecules. responsible for the structural integrity of the membrane. Each lipid molecule is said to be polar, or **amphipathic,** which means that one part is hydrophobic (uncharged, or “water hating”) and another part is hydrophilic (charged, or “water loving”) ([|Figure] [|1-3]). The bilayer serves as a barrier to the diffusion of water and hydrophilic substances, while allowing lipid-soluble molecules, such as oxygen (O2) and carbon dioxide (CO2), to diffuse through it readily. __//Proteins//__ Integral membrane proteins are embedded in the lipid bilayer The integral proteins can be removed from the membrane only by detergents that solubilize (dissolve) the lipid. **Peripheral membrane proteins** are not embedded in the bilayer but reside at one surface or the other, bound to an integral protein. Proteins act as (1) recognition and binding units (receptors) for substances moving into and out of the cell; (2) pores or transport channels (3) specific enzymes that drive active pumps (4) cell surface markers, such as **glycoproteins** (5) **cell adhesion molecules** (CAMs)**,** or proteins that allow cells to hook together and form attachments of the cytoskeleton for maintaining cellular shape; and (6) catalysts of chemical reactions, for example, conversion of lactose to glucose ([|Figure] [|1-4]). __//Carbohydrates//__ The carbohydrate contained within the plasma membrane is generally in the form of glycoprotein. Intercellular recognition, required for tissue formation, is an important function of membrane glycoproteins. protein molecules on the plasma membrane, in the cytoplasm, or in the nucleus that can recognize and bind with specific smaller molecules called **ligands.** Hormones, for example, are ligands. Recognition and binding depend on the chemical configuration of the receptor and its smaller ligand, which must fit together somewhat like pieces of a jigsaw puzzle. **Plasma membrane receptors** protrude from or are exposed at the external surface of the membrane and often are attached to integral proteins ([|Figure] [|1-6]). Receptors are classified based on their location and function.
 * **Nucleus**
 * **Cytoplasmic Organelles**
 * **Plasma Membranes**
 * **Cellular receptors**

__//**5. Examine cellular metabolism.**//__ (Huether-12-14) Heavy topic, should read this section in book!!! All of the chemical tasks of maintaining essential cellular functions are referred to as **cellular metabolism.** The energy-using process of metabolism is called **anabolism** (build up), and the energy-releasing process is known as **catabolism** (break down). Metabolism provides the cell with the energy it needs to produce cellular structures **.** A key feature of cellular metabolism is the directing of biochemical reactions by protein catalysts or enzymes. Role of Adenosine Triphosphate When 1 mole of glucose metabolically breaks down in the presence of oxygen into carbon dioxide and water, 686 kilocalories (kcal) of chemical energy are released. The energy stored in ATP can be used in various energy-requiring reactions and in the process is generally converted to adenosine diphosphate (ADP) and inorganic phosphate (Pi). The energy available as a result of this reaction is about 7 kcal/mol of ATP. The cell uses ATP for muscle contraction and active transport of molecules across cellular membranes. Food and Production of Cellular Energy Catabolism of the proteins, lipids, and polysaccharides found in food can be divided into the following three phases ([|Figure] [|1-12]):
 * **Digestion.** Large molecules are broken down into smaller subunits
 * **Glycolysis** and **oxidation.** The most important part of phase 2 is glycolysis, the splitting of glucose.
 * **Citric acid cycle (Krebs cycle).** Most of the ATP is generated during this final phase. It begins with the citric acid cycle and ends with oxidative phosphorylation.


 * Oxidative phosphorylation** occurs in the mitochondria and is the mechanism by which the energy produced from carbohydrates, fats, and proteins is transferred to ATP. If oxygen is not available to the electron-transport chain, ATP will not be formed by the mitochondria. Instead, an anaerobic metabolic pathway synthesizes ATP. This process is called **substrate phosphorylation** or **anaerobic glycolysis and** is linked to the breakdown (glycolysis) of carbohydrate.

__//**6. Explain the principles of membrane transport:(Huether) a. Passive transport (pg,15)**//__ -In **passive transport,** water and small, electrically uncharged molecules move easily through pores in the plasma membrane's lipid bilayer. This process occurs naturally through any semipermeable barrier. It is driven by osmosis, hydrostatic pressure, and diffusion, all of which depend on the laws of physics and do not require life. The process does not require any energy expenditure by the cell.
 * **Diffusion** is the movement of a solute molecule from an area of greater solute concentration to an area of lesser solute concentration. Thisdifference in concentration is known as a **concentration gradient.** The higher the concentration on one side, the greater the diffusionrate.Usually, the smaller the molecule and the more soluble it is in oil, the more hydrophobic or nonpolar it is and the more rapidly it will diffuseacross the bilayer. Oxygen, carbon dioxide, and steroid hormones are all nonpolar molecules. Water-soluble substances, such as sugars andinorganic ions, diffuse very slowly, whereas uncharged lipophilic (“lipid-loving”) molecules, such as fatty acids and steroids, diffuse rapidly.
 * **Filtration** is the movement of water and solutes through a membrane because of a greater pushing pressure (force) on one side of the membrane than on the other side. **Hydrostatic pressure** is the mechanical force of water pushing against cellular membranes. In the vascular system, hydrostatic pressure is the blood pressure
 * **Osmosis** is the movement of water “down” a concentration gradient—that is, across a semipermeable membrane from a region of higher water concentration to one of lower concentration. For osmosis to occur, (1) the membrane must be more permeable to water than to solutes and (2) the concentration of solutes must be greater so that water moves more easily. Osmosis is directly related to both hydrostatic pressure and solute concentration but //not// to particle size or weight.
 * //__b. Mediated & Active transport (pg,17)__//**- involves proteins with receptors that are highly specific for the substance being transported. This is much faster than simple diffusion. Channel proteins are examples which forms a water filled pore across the bilayer which specific ions can pass. The active transport system for Na+ and K+ is the antiport(Na+ moving out, K+ moving in) pump.

__//**c. Transport by vesicle formation (pg,19)**//__ Endocytosis and exocytosis The active transport mechanisms by which the cells move large proteins (macromolecules) across the plasma membrane are:
 * **endocytosis,** a section of the plasma membrane enfolds substances from outside the cell, invaginates (folds inward), and separates from the plasma membrane, forming a vesicle that moves into the cell ([|Figure] [|1-20,] [|//A//]). Two types of endocytosis are designated based on the size of the vesicle formed. **Pinocytosis** (cell drinking) involves the ingestion of fluids and solute molecules through formation of small vesicles, and **phagocytosis** (cell eating) involves the ingestion of large particles, such as bacteria, through formation of large vesicles (vacuoles).
 * **Exocytosis** has two main functions: (1) replacement of portions of the plasma membrane that have been removed by endocytosis and (2) release of molecules synthesized by the cells into the extracellular matrix.

__//**d. Movement of electrical impulses (pg,21)**//__ ACTION POTENTIALS read on own, complicated!!! The difference in electrical charge, or voltage, is known as the **resting membrane potential**. When a nerve or muscle cell receives a stimulus that exceeds the membrane threshold value, a rapid change occurs in the resting membrane potential, known as the **action potential.** cell membranes become more permeable to sodium and the membrane potential decreases. This decrease is known as **depolarization.** The depolarized cell is more positively charged, and its polarity is neutralized. To generate an action potential, the **threshold potential** must be reached. The sodium gates open, and sodium rushes into the cell, causing the membrane potential to reduce to zero and then become positive (depolarization). The rapid reversal in polarity results in the action potential. During **repolarization,** the negative polarity of the resting membrane potential is reestablished. As the voltage-gated sodium channels begin to close, voltage-gated potassium channels open, so potassium ions leave the cell. The sodium gates close, and with the loss of potassium, the membrane potential becomes more negative. The Na+, K+ pump then returns the membrane to the resting potential by pumping potassium back into the cell and sodium out of the cell. __//**7. Examine the various growth factors and their physiologic actions(Huether,24).**//__
 * Growth factors,** also called **cytokines,** are peptides (protein fractions) that transmit signals within and between cells. They have a major role in the regulation of tissue growth and development . Having nutrients is not enough for a cell to proliferate; it must also receive stimulatory chemical signals (growth factors) from other cells, called **stroma** . These signals act to overcome intracellular braking mechanisms that tend to restrain cell growth and block progress through the cell cycle.
 * ~ Growth Factor ||~ Physiologic Actions ||
 * Platelet-derived growth factor (PDGF) || Stimulates proliferation of connective tissue cells and neuroglial cells ||
 * Epidermal growth factor (EGF) || Stimulates proliferation of epidermal cells and other cell types ||
 * Insulin-like growth factor I (IGF-I) || Collaborates with PDGF and EGF; stimulates proliferation of fat cells and connective tissue cells ||
 * Vascular endothelial growth factor || Mediates functions of endothelial cells; proliferation, migration, invasion, survival, and permeability ||
 * Insulin-like growth factor II (IGF-II) || Collaborates with PDGF and EGF; stimulates or inhibits response of most cells to other growth factors; regulates differentiation of some cell types (e.g., cartilage) ||
 * Transforming growth factor β (TGBβ; multiple subtypes) || Stimulates or inhibits response of most cells to other growth factors; regulates differentiation of some cell types (e.g., cartilage) ||
 * Fibroblast growth factor (FGF; multiple subtypes) || Stimulates proliferation of fibroblasts, endothelial cells, myoblasts, and other multiple subtypes ||
 * Interleukin-2 (IL-2) || Stimulates proliferation of T lymphocytes ||
 * Nerve growth factor (NGF) || Promotes axon growth and survival of sympathetic and some sensory and central nervous system (CNS) neurons ||
 * Hemopoietic cell growth factors (IL-3, GM-CSF, G-CSF, erythropoietin) || Promote proliferation of blood cells ||

__//**8. Describe the three ways that cells adhere to each other to form tissues and organs.(**//__Huether 8-10) (**1)-** **cell adhesion molecules (CAMs),** or proteins that allow cells to hook together and form attachments of the cytoskeleton for maintaining cellular shape;

The **extracellular matrix** is an intricate meshwork of fibrous proteins embedded in a watery, gel-like substance composed of complex carbohydrates ([|Figure] [|1-7]). The matrix is like glue; however, it provides a pathway for diffusion of nutrients, wastes, and other water-soluble traffic between the blood and tissue cells. Interwoven within the matrix are three groups of **macromolecules**:
 * (2)-Extracellular Matrix**
 * **Collagen** forms cable-like fibers or sheets that provide tensile strength or resistance to longitudinal stress.
 * **Elastin** is a rubber-like protein fiber most abundant in tissues that must be capable of stretching and recoiling
 * **Fibronectin** promotes cell adhesion and cell anchorage.
 * The matrix and the cells within it are known collectively as **connective tissue,** They can be hard and dense, like bone; flexible, like tendons or the dermis of the skin; resilient and shock absorbing, like cartilage; or soft and transparent, like the jelly that fills the eye.

Cells in direct physical contact are often linked together at specialized plasma membrane regions called **cell junctions.** Cell junctions have two main functions: (1) to hold cells together and (2) to permit small molecules to pass from cell to cell, allowing coordination of the activities of cells that form tissues. The three main types of cell junctions are
 * (3)-Specialized cell junctions-**
 * **Desmosomes** hold cells together by forming either continuous bands or belts of epithelial sheets or button-like points of contact. Desmosomes also act as a system of braces to maintain structural stability.
 * **Tight junctions** are barriers to diffusion, prevent the movement of substances through transport proteins in the plasma membrane, and prevent the leakage of small molecules between the plasma membranes of adjacent cells.
 * **Gap junctions** are clusters of communicating tunnels or connexons that allow small ions and molecules to pass directly from the inside of one cell to the inside of another. Cells connected by gap junctions are considered ionically (electrically) and metabolically coupled. They are important, for example, for synchronizing contractions of heart muscle cells.

The four basic types of tissues are
 * //__9. Review the four basic tissue types.(Huether,25-31)__//** Look at box's 1-1,1-2,1-3
 * nerve-Neural tissue is composed of highly specialized cells called //neurons//, which receive and transmit electrical impulses rapidly across junctions called //synapses//
 * Epithelial-**simple/stratified squamous, cuboidal, columnar,** Many types look at pg 26-27
 * connective- **Loose, dense, elastic, adipose, cartilage, bone, plasma**. Attaches skin to inderlying tissue, holds organ in place, supports blood vessels, protective barrier, forms strong tendons of mucles, ligaments, strength and elasticity to walls of arteries
 * muscle. **Skeletal, cardiac, smooth**

atrophy, hypertrophy, hyperplasia, dysplasia, and metaplasia____. __ __  Huether 63-65, module 2   __//** __// **Atrophy:** //__ decrease or shrinkage in cellular size. Cell does not die. If occurs in significant # of organ's cells, entire organ shrinks Normally cells receive hormonal & neural stimulation from environment. They also receive nourishment; O2, glucose, a. acids, ect. If they receive less stimulation or resources, they will atrophy. Can affect any organ but most common in skeletal musc., heart, brain, & 2ndary sex organs. Atrophy can be physiologic (normal like w/ aging. eg; breast tissue shrinks w/out estrogen after menopause) or pathologic  ( eg;decrease in workload, pressure,use, blood supply, nutrition, ect). W/ shrinkage cells contain less (eg; endoplasmic reticulum, mitochondria and do less. One of the most important processes in atrophy is the catabolism (breakdown) of proteins which occurs via the ubiquitin-proteasome pathway. This helps control protein turnover. It is deregulation of this pathway that leads to the profound wasting called cachexia that is seen in many individuals with advanced cancer.     Atrophy may include the formation of more than usual autophagic vacuoles, usually w/ chronic malnutrition. These vesicles inside of cells contain damaged cell contents and hydrolytic enzymes to digest them.      hypertrophy; An increase in size of cells, leading to increase of organ. Heart and kidneys most prone. Can be physiologic or pathologic and can be caused by hormonal stimulation or increased functional demand ( workload ). The increase in size is due to increase of internal components to meet demands NOT increase in cellular fluid. Workload examples ; biceps from lifting weights, Remaining kidney after removal of other. Hormonal ex ; uterus hypertrophy w/ pregnancy. Pathologic ex ; hypertrophy of heart with hypertension or faulty valves. **Hyperplasia ; ** an increase in number of cells resulting from increased rate of cellular division. Only occurs in cells able to divide NOT in nerve, skel. muscle, myocardial or lens cells of eye. Hypertrophy and hyperplasia usually occur together. 3 ways; ** __Compensatory hyperplasia__ **   **;** adaptive mechanism allowing certain organs to regenerate. eg; w/ partial liver removal, cells will regenerate or a callus results on skin when excessive friction occurs. **__ Hormonal hyperplasia; ____ occurs in  __** estrogen-dependent organs eg; estrogen stimulates endometrium to thicken (hyperplasia) in preparation of fertilized egg. If fertilized, hyperplasia (& hypertrophy occurs in uterus. __ **Pathologic hyperplasia** __; abnormal proliferation of normal cells usually due to excessive hormonal stim. or growth factors on target cells eg;enlarged prostate. Cervical dysplasia is often detected on Papanicolaou (Pap) smear and is categorized as:  CIN I–mild dysplasia (a few cells are abnormal, Figure A)  CIN II–moderate to marked dysplasia (Figure B)  CIN III–severe dysplasia to //carcinoma-in-situ// (early, noninvasive cancer, Figure C)  Similarly, epithelial cells lining the bronchi of the lung can become dysplastic when repetitively exposed to cigarette smoke. In the breast, excessive hormonal stimulation can result in atypical hyperplasia in the ducts. All of these examples of dysplasia have been linked to the development of neoplasia (cancer) in these tissues, although mild to moderate dysplasia may be reversible if the inciting stimulus is removed.
 * //__10. Describe the cellular adaptations and the causative factors for each of the cellular adaptions:
 * Dysplasia;** (not a true "adaptive" change); abnormal changes in size, shape and organization of mature cells. AKA; atypical hyperplasia. A common site for the occurrence of dysplasia is the cervix when it is subjected to chronic inflammation or infection (such as human papillomavirus).

**// __ 11. Examine the mechanism of cellular injury that can occur as a result of the following causes: __ //** //** hypoxia, free radicals, and reactive oxygen species. ( ** Huether 66-75) Module 3; // //** There are four common themes regarding cell injury & cell death regardless of the injuring agent; ATP depletion, O2 & O2-derived free radicals, calcium alterations, and defects in membrane permeability. hypoxia, free rads, & reactive O2 species are forms of cell injury. **// //** Hypoxic injury ; lack of sufficient oxygen; #1 common cause of cellular injury. Can result from decreased O2 in air, loss of Hemoglobin or it's function, decrease in production of RBC, decrease in resp. or cardiac fx, and poisoning of oxidative enzymes w/in cells. Most common cause; **ischemia; **(reduced blood supply).**////** Ischemic hypoxia can be progressive (like gradual narrowing of arteries) or sudden acute anoxia (total lack of O2-emboli or thrombosis). W/ progressive, the cells may be able to adapt (see #10) but w/ sudden, cell death can occur in minutes if O2 is not restored. **// One of the most recognizable forms of hypoxic injury is **cardiac ischemia** that results from atherosclerotic blockage of coronary arteries. In the presence of arterial blockage, the following sequence of ischemic events occurs:
 * Metaplasia**; replacement of normal cells by another cell type b/c of persistent irritation or low-level injury. The new cell is better able to withstand that injury. eg; Ciliated columnar cells lining bronchi die w/ chronic cig. use. They are replaced w/ non-ciliated stratified squamous cells that can survive the smokey environment.
 * Within a minute after adequate blood flow ceases, ATP decreases and the ischemic tissues begin anaerobic metabolism which is inefficient at providing adequate energy for cells and results in the production of lactic acid.
 * Cells begin to lose their ability to maintain important functions such as membrane electrolyte pumps and protein synthesis.
 * If blood flow is not restored quickly, cells will swell, //vacuolate// (form vacuoles), and eventually suffer membrane, cytoskeleton, and DNA damage that is irreversible.
 * S****EE PAGE 67 in HUETHER AND DO ACTIVITY IN MODULE #3B. I am learning the above and memorizing the activity. Huether's book gets into it deep but the module is less intense. Don't know what we need to know, but this shit confuses me!**


 * Free radicals ** are produced by cells and are crucial to normal cellular metabolism. A free radical is an electrically charged atom or group of atoms that has an unpaired electron, making it unstable. Free radicals can form injurious chemical bonds with proteins, lipids, and carbohydrates. The most commonly described free radicals are called reactive oxygen species (ROS).

Free radicals are generated by three major pathways as listed in your textbook: Another important source of free radicals in the body is inflammatory cells such as polymorphonucleocytes (e.g., neutrophils), which use free radicals within lysosomes to digest foreign invaders, but can release free radicals into tissues and cause bystander cellular damage. Restoration of blood flow to tissues that have been ischemic can also cause cellular damage called **reperfusion injury**. In this case, restoration of needed oxygen is accompanied by oxidative stress with the generation of toxic oxygen radicals which damage cellular membranes and mitochondria. Antioxidants and antiinflammatory drugs may help limit this form of damage.
 * Absorption of energy (e.g., in radiation injury)
 * Redox reactions (e.g., in reperfusion injury)
 * Enzymatic metabolism of chemicals or drugs

//**12. Describe cellular injury caused by infection and inflammation. (**module 4H, )// //**  13. Discuss the manifestations of cellular injury, including hydropic changes, pigment changes, and electrolyte changes. (**Module 5, Huether 82-86**)**// //**In many cases, cellular injury results in the  ** accumulation ** ( ** infiltration ** ) ** of substances within cells and tissues such as water, electrolytes, lipids and carbohydrates, proteins, pigments, calcium,  and  uric acid **. ** Most of these substances are found normally in the cellular environment but become concentrated because of increased production and storage or decreased breakdown (catabolism). //      Hydropic changes;      **Cellular swelling** is a common degenerative change resulting from many types of cellular injury. One example is hypoxic injury. Hypoxic injury disrupts the ability of mitochondria to produce adenosine triphosphate, which in turn prevents normal functioning of the membrane “pumps” that regulate electrolyte and water transport. Although this process is often reversible if oxygen delivery is restored, **oncosis** can occur and can result in cell death.     **Look at figure 3-20 Huether p.83.** Basically no O2 leads to decrease of ATP, w/out ATP Na+ and Potas pump stops working so Na+ and H2O move into cell (potass moves out), Osmottic pressure increases( w/ increased conc. of solute in cell it starts to "pull" more H2O into cell), Cisternae of endoplasmic ret. distend, rupture and form vacuoles. The result is Oncosis or cell swelling. (Module 5d and 5H, huether 83-84)**Lipids;** Certain metabolic disorders result in abnormal **intracellular accumulations of lipids They ** are seen in several inherited central nervous system (CNS) disorders (also called **lysosomal storage diseases**). Three inherited CNS lysosomal storage diseases are:    *Tay-Sachs disease     *Niemann-Pick disease     *Gaucher disease Intracellular lipid accumulation can also be seen in spleen, liver, and acquired tissue injury like the **fatty change** seen with **alcoholic** **liver** disease. **Fatty change** in the liver is most commonly associated with alcohol abuse. Ethanol is toxic to hepatocytes and directly affects mitochondria, resulting in intrahepatocyte accumulation of microvesicular fat described as alcoholic foamy steatosis. This process is reversible with discontinuation of alcohol intake, but it can lead to cirrhosis.
 * Infections **can cause injury by several mechanisms. Virulent organisms can directly invade and destroy cells or may release toxins that are damaging to cells. In addition, the body may injure itself in an effort to fight the invading organism through inflammatory and immune reactions.**
 * Inflammatory injury **can occur when the activation of the body’s innate defense mechanisms results in either an exaggerated or a misdirected response that damages healthy tissues. Innate immunity (inflammation) can damage healthy tissue when there is release of chemicals such as toxic radicals or lysosomal enzymes, or when growth factors cause inappropriate growth of tissues that compromises tissue function (remodeling). Hypersensitivity reactions occur when antibodies or immune cells attack healthy tissue, the most well-known example of which is allergy.**
 * Inflammation includes activation of phagocytic cells, some of which don't differentiate between the bad guys and the good guys, histamine proteases, and complement system. **

Mechanisms that contribute to lipid accumulations in the liver due to exposure to ethanol include:
 * 1) Increased movement of free fatty acids into the liver
 * 2) Preferential conversion of fatty acids to triglycerides
 * 3) Increased synthesis of triglycerides
 * 4) Decreased synthesis of apoproteins
 * 5) Failure of lipids to bind to apoproteins
 * 6) Decreased transport of lipoproteins out of the cell


 * Glycogen** is a form of sugar that can accumulate in tissues and cause vacuolation and injury to cells. Results from excessive vacuolation of the cytoplasm. There are 11 known forms of inherited glycogen storage diseases. Depending on the specific inherited disorder, glycogen storage diseases cause abnormalities of the liver, muscle, immune system, and serum glucose. Most common cause of glycogen accumulation is Diabetes mellitus.

**Electrolytes;** **Calcium;** Ca+ salts accumulate in both injured, esp. injured mitochondria, and dead tissues.In addition, various pathologic processes in the lungs, kidneys, stomach, and pancreas can lead to calcium salt clumping, forming hard calcium deposits that interfere with cellular function. 2 types:
 * Pigments; (**Huether 84-85**);**can be normal of abnormal, endogenous (produced w/in body) or exogenous (produced outside of the body; eg; tattoo, mineral dusts)
 * Melanin;** accumulates in epithelial cells (keratinocytes) of skin and retina. Protects skin against exposure to sunlight and is essential in prevention of skin cancer.
 * Hemoproteins;** among the most essential of normal endogenous pigments. The include **hemoglobin** and the oxidative enzymes, the **cytochromes**. Hemoprotein accumulations in cells are excessive storage of iron, which accumulate in tissues when there is an excess amount of iron present. Excess iron can result from the release of heme into the tissues from red blood cell injury (e.g., bruising), increased iron intake (e.g., multiple transfusions), or an inability to properly process the heme molecule in the liver.
 * Hemosiderin** is a yellow-brown pigment derived from hemoglobin.   **Hemosiderosis** is a condition in which excess iron is stored as hemosiderin (an abnormal pigment) in tissues and organs. This can be an acquired or genetic disorder. Common in people w/ repeated blood transfusions or prolonged parenteral admin of iron. Also assoc w/ increased dietary iron, excessive ETOH(wine). Accumulation of iron damages the liver and can cause cirrhosis.       **Bilirubin** is normal yellow-green pigment of bile derived from metabolism of hemoglobin. Excess bilirubin w/in cells and tissues cause jaundice. Jaundice occurs when there is excessive amounts of hemoglobin being metabolized (e.g., hemolysis of red blood cells), or when there is inadequate removal of bilirubin from the body (e.g., liver disease or biliary obstruction).
 * **Dystrophic calcification** occurs in dead and dying tissues, granulomas, atherosclerosis, and heart valve injury. Dystrophic calcification can also occur in tumors, which may make them easier to see on radiographs. For example, one way that breast cancer can sometimes be detected is by finding characteristic calcifications on mammography.
 * **Metastatic calcification** occurs when there is a high level of calcium in the blood (hypercalcemia) that then deposits in normal tissues. Hypercalcemia and resultant metastatic calcification can be caused by hyperparathyroidism, vitamin D intoxication, Addison disease, sarcoidosis, and tumors that cause bone destruction.

The most common form of urate accumulation occurs in a type of arthritis known as **gout**. Gout results from high levels of urate crystals forming in tissues, especially joints, causing intense inflammation and a very painful arthritis that frequently affects the big toe. Urate can also accumulate in the subcutaneous tissues forming what are called //gouty tophi//.
 * Urate** or **Uric acid** is an end product of protein metabolism. It accumulates in tissues as the result of a number of disorders that affect the activity of urate oxidase (breaks down urate) or in situations that cause massive protein degradation.

Urate can also accumulate because of high levels of protein being metabolized like that which is seen with induction chemotherapy. This condition is called the //“tumor lysis syndrome”// in which high levels of urate can cause kidney failure after chemotherapy for certain cancers.  //**  14. Discuss the cellular mechanisms of normal degenerative changes of aging.**// //**There are three basic theories described under this proposed mechanism of aging: **//
 * Programmed aging **– cells have a finite lifespan with a finite number of possible replications such that the DNA eventually loses the capacity to facilitate mitosis.**
 * Somatic mutation **– repetitive injury to the DNA causes progressive mutations that interfere with the ability of the cell to repair itself and maintain DNA and protein synthesis.**
 * Catastrophic or error-prone **– the enzymes responsible for transcription and translation become increasingly abnormal, leading to increasing errors in protein synthesis.**


 * There are two main concepts described with theories of aging involving cellular control:**
 * Neuroendocrine changes **– with aging, there is an increased rate of hormonal degradation, decreased rate of hormone synthesis, or a decrease in cellular hormone receptors.**
 * Alterations in immunity **– with aging, there is decreased immunity to invaders and cancer and increased autoimmunity (immune system attacks self).**


 * Aging affects cells, tissues, and the entire body system.**
 * Cellular changes **include atrophy, hypertrophy and hyperplasia, metaplasia, dysplasia, and neoplasia. DNA mutations (breaks, deletions, and additions) lead to altered protein synthesis and decreased cellular function.**
 * Tissue changes **include stiffness of arterial, pulmonary, and musculoskeletal systems. Arteriosclerosis develops with decreased tissue perfusion.**
 * Systemic changes **include decreased endocrine and immune function; decreased pulmonary, cardiac, and gastric function; and decreased bone and muscle mass.**

Frailty **is wasting as one ages. Decreased muscle function and strength leads to increased risk for falls, decreased mobility, and a gradual decline in functionality. There is a decline in some growth factors such as estrogen, androgen, insulin-like growth factor, and growth hormone with an associated increase in inflammatory cytokines such as tumor necrosis factor alpha. Addressing the difficulties of frailty can contribute greatly to quality of life for the elderly.**

//**15. Discuss the two functional fluid compartments of the body. Module 2b**//**//From a general physiologic perspective, the body has two major compartments: //**
 * Flesh compartment**, which consists primarily of non-water–containing elements such as fat and bone, and**
 * Fluid compartment**, which consists primarily of water**
 * On average, the body consists of one-third flesh and two-thirds water. Although this proportion can vary as a function of body age, size, and fat content, it yields a useful diagnostic tool (the “two-thirds rule”), defined as follows. In most clinical situations, an approximation of body fluid volume content as two-thirds of body weight is sufficient for calculating excesses and deficits in body water composition.**

**__//16. Describe the causation, pathophysiologic process, and clinical manifestations of edema. //__**(patho 101-102, Mod 3,#2h)<span style="background: rgb(170, 255, 170) none repeat scroll 0% 50%; -moz-background-clip: -moz-initial; -moz-background-origin: -moz-initial; -moz-background-inline-policy: -moz-initial;"><span style="color: rgb(0, 136, 0);">
 * **Volumes of Body Fluid Compartments as a Percentage of Total Body Weight** ||
 * [[image:http://coursewareobjects.elsevier.com/objects/pathophysiology/huether4e/Module03/Table_1_clip_image001.gif width="1" height="1"]] || **Infant** || **Adult Male** || **Adult Female** ||
 * **Extracellular fluid** || [[image:http://coursewareobjects.elsevier.com/objects/pathophysiology/huether4e/Module03/Table_1_clip_image001_0000.gif width="1" height="1"]]30 || 20 || 15 ||
 * [[image:http://coursewareobjects.elsevier.com/objects/pathophysiology/huether4e/Module03/Table_1_clip_image001_0001.gif width="1" height="1"]]Intracellular fluid || 45 || 40 || [[image:http://coursewareobjects.elsevier.com/objects/pathophysiology/huether4e/Module03/Table_1_clip_image001_0002.gif width="1" height="1"]]35 ||
 * **Total** || 75 || 60 || 50 ||

Causation:


 * Edema** is the accumulation of fluid within the interstitial spaces. This results from fluid movement from the capillaries or lymphatic channels into the tissues as a result of:


 * Increased capillary hydrostatic pressure
 * Lowered plasma oncotic pressure
 * Lymphatic channel obstruction
 * Increased capillary membrane permeability
 * pathophysiologic process:**

Hydrostatic pressure increases as a result of venous obstruction or salt and water retention. Venous obstruction causes hydrostatic pressure to increase behind the obstruction pushing fluid from the capillaries into the interstitial spaces. Thrombophlebitis (inflammation of veins), hepatic obstruction, tight clothing around the extremities, and prolonged standing are common causes of venous obstruction. Congestive heart failure and renal failure are associated with salt and water retention, which cause plasma volume overload, increased capillary hydrostatic pressure, and edema.Lost or diminished plasma albumin production (liver disease or protein malnutrition) contributes to decreased plasma oncotic pressure. Plasma proteins are lost in glomerular diseases of the kidney, serous drainage from open wounds, hemorrhage, burns, and cirrhosis of the liver. The decreased oncotic attraction of fluid within the capillary causes filtered capillary fluid to remain in the interstitial space, resulting in edema. Capillaries become more permeable with inflammation and immune responses, especially with trauma such as burns or crushing injuries, neoplastic disease, and allergic reactions. Proteins escape from the vascular space and produce edema through decreased capillary oncotic pressure and interstitial fluid protein accumulation.The lymphatic system normally absorbs interstitial fluid and a small amount of proteins. When lymphatic channels are blocked or surgically removed, proteins and fluid accumulate in the interstitial space causing lymphedema. 2 For example, lymphedema of the arm or leg occurs after surgical removal of axillary and femoral lymph nodes for treatment of carcinoma. Inflammation or tumors may cause lymphatic obstruction, leading to edema of the involved tissues.


 * clinical manifestations :**

> > **__<span style="font-family: Arial,sans-serif;"><span style="color: rgb(0, 0, 0);">17. Examine the regulatory processes for fluid and electrolyte balance in the body. __**(Patho 103-112, Mod 3, #3b)<span style="background: rgb(170, 255, 170) none repeat scroll 0% 50%; -moz-background-clip: -moz-initial; -moz-background-origin: -moz-initial; -moz-background-inline-policy: -moz-initial;"><span style="color: rgb(0, 136, 0);">
 * Swelling
 * Increase in body weight
 * Functional impairment
 * Pain
 * Impairment of arterial circulation

The kidneys and hormones have a central role in maintaining sodium and water balance. Because water follows the osmotic gradients established by changes in salt concentration, sodium and water balance are intimately related. Water balance is regulated primarily by antidiuretic hormone (ADH; also known as vasopressin ); sodium is regulated by renal effects of aldosterone (see p. 104). <span style="font-family: Arial,sans-serif;">//**Water Balance**// Water balance is regulated by the secretion of ADH. ADH is secreted when plasma osmolality increases or circulating blood volume decreases and blood pressure drops. Increased plasma osmolality occurs with water deficit or sodium excess in relation to water (see Figure 4-2, D ). The increased osmolality stimulates hypothalamic osmoreceptors. In addition to causing thirst, these osmoreceptors signal the posterior pituitary gland to release ADH. Thirst stimulates water drinking and ADH increases the permeability of renal tubular cells to water. Water is then reabsorbed into the plasma from the distal tubules and collecting ducts of the kidney (see Chapter 28 ). Urine concentration increases, and the reabsorbed water decreases plasma osmolality, returning it toward normal (see Figure 4-2, E ). With fluid loss (dehydration) from vomiting, diarrhea, or excessive sweating, a decrease in blood volume and blood pressure often occurs. Volume-sensitive receptors and baroreceptors (nerve endings that are sensitive to changes in volume and pressure) also stimulate the release of ADH from the pituitary gland. The volume receptors are located in the right and left atria and thoracic vessels; baroreceptors are found in the aorta, pulmonary arteries, and carotid sinus. ADH secretion also occurs when atrial pressure drops, as occurs with decreased blood volume. The reabsorption of water mediated by ADH then promotes the restoration of plasma volume and blood pressure

<span style="font-family: Verdana,sans-serif;">Three hormones (antidiuretic hormone [ADH], aldosterone, and natriuretic hormones), are primarily responsible for controlling the integrity of sodium and water balance.
 * **<span style="font-family: Verdana,sans-serif;"><span style="color: rgb(255, 255, 255);">Hormone ** || **<span style="font-family: Verdana,sans-serif;"><span style="color: rgb(255, 255, 255);">Action  ** ||
 * <span style="color: rgb(0, 0, 255);">__<span style="font-family: Verdana,sans-serif;">Antidiuretic hormone (ADH) __ || * <span style="font-family: Verdana,sans-serif;">Responsible for water conservation
 * <span style="font-family: Verdana,sans-serif;">ADH is manufactured in the hypothalamus of the brain and stored in the posterior section of the pituitary gland. Its release is regulated on a minute-to-minute basis by a network of osmoreceptors, located throughout the vascular system, that sense when body fluids vary from an isotonic state. ||
 * <span style="color: rgb(0, 0, 255);">__<span style="font-family: Verdana,sans-serif;">Aldosterone __ || * <span style="font-family: Verdana,sans-serif;">Responsible for sodium and potassium regulation
 * <span style="font-family: Verdana,sans-serif;">Serum aldosterone is manufactured as a result of a sequence of hormonal activities that involve the vascular system, heart, and kidney. It acts primarily to control the amount of sodium that is conserved or excreted by the kidney. Serum aldosterone levels will rise if the serum sodium concentration drops or if the vascular compartment loses volume or pressure.
 * <span style="font-family: Verdana,sans-serif;">In contrast, an increase in vascular compartment volume, sodium intake, or blood pressure can lower serum aldosterone concentration, resulting in enhanced sodium excretion by the kidney. This response is mediated by a network of volume receptors that are located throughout the cardiac and vascular systems.
 * <span style="font-family: Verdana,sans-serif;">Aldosterone also regulates the potassium content of the body. However, it does so in a way that is reciprocal or opposite to that of sodium regulation. That is, increased levels of aldosterone result in sodium conservation and potassium excretion, whereas low aldosterone levels result in potassium conservation and sodium excretion. ||
 * <span style="color: rgb(0, 0, 255);">__<span style="font-family: Verdana,sans-serif;">Natriuretic hormones __ || * <span style="font-family: Verdana,sans-serif;">Responsible for stimulating water and sodium excretion
 * <span style="font-family: Verdana,sans-serif;">When the volume receptors of the cardiovascular system detect an increase in blood volume, natriuretic hormones (Atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], C-type natriuretic peptide, and urodilatin) are released from manufacturing sites within the heart and brain. These hormones then act on the kidney to increase the excretion of both sodium and water.
 * <span style="font-family: Verdana,sans-serif;">Under the opposite condition of dehydration, when the body water volume is low, levels of natriuretic hormone become undetectable. ||


 * __18. Examine the inflammatory process, stating the major benefits, characteristics.__** (MS 193-197, Patho 123- ,Mod 4 #4d)

Virtually any injury to vascularized (having a blood supply) tissues will activate inflammation. The classic symptoms of inflammation include redness, heat, swelling, pain, and loss of function. Characteristic microscopic changes also occur within seconds ( Figure 5-1 ). These include the following:

Each of the characteristic changes associated with inflammation is the direct result of the activation and interactions of a host of chemicals and cellular components found in the blood and tissues ( Figure 5-2 ). The vascular changes deliver leukocytes, plasma proteins, and other biochemical mediators to the site of injury, where they act in concert.
 * __1 Vasodilation__** (increased size of the blood vessels), which causes slower blood velocity and increases blood flow to the injured site
 * __2 Increased vascular permeability__** (the blood vessels become porous) and leakage of fluid out of the vessel, causing swelling (edema) at the site of injury; as plasma moves outward, blood in the microcirculation becomes more viscous and flows more slowly, and the increased blood flow and increasing concentration of red cells at the site of inflammation cause locally increased warmth and redness
 * __3 White blood cell adherence to the inner walls of vessels__** and their migration through enlarged junctions between the endothelial cells lining the vessels into the surrounding tissue

__1 Limits and controls tissue damage through the influx of plasma protein systems__ (e.g., clotting system) and white blood cells (e.g., eosinophils) that prevent the inflammatory response from spreading to areas of healthy tissue 2 __Prevents infection by contaminating microorganisms__ through the influx of fluid to dilute toxins produced by bacteria, the influx and activation of plasma protein systems that help destroy and contain bacteria (e.g., complement system, clotting system), and the influx of white blood cells (e.g., neutrophils, macrophages) that “eat” and destroy infectious agents __3 Initiates the adaptive immune response__ through the influx of macrophages and lymphocytes and drainage of microbial antigens by lymphatic vessels to the lymph nodes, where they activate lymphocytes (this process is discussed in Chapter 6, and the lymphatic system is described in Chapter 22 ) __4 Initiates healing__ through removal of bacterial products, dead cells, and other products of inflammation (e.g., by way of channels through the epithelium or drainage by lymphatic vessels) and activate mechanisms of repair
 * __There are several benefits of inflammation .__** They include the following:


 * __19. Describe the role of the mast cell and the plasma protein systems in relation to the inflammatory process__.** (Patho 124, 126 Mod 4,#5 #6)

<span style="font-family: Verdana,sans-serif;"><span style="color: rgb(0, 0, 0);">**The mast cell** is the single most important inflammatory cell in the response to injury. When injured, triggered by chemical agents, or stimulated by the immune system, the mast cell will degranulate and release preformed cytokines from its internal granules. It will also begin synthesizing many important inflammatory cytokines that will be released into the area of injury or insult.

<span style="font-family: Andale Sans for VST,sans-serif;">Acute Inflammatory Response.Inflammation is usually initiated by cellular injury and may be complicated by infection. Mast cell degranulation, the activation of three plasma systems, and the release of subcellular components from the damaged cells occur as a consequence. These systems are interdependent, so that induction of one (e.g., mast cell degranulation) can result in the induction of the other two. The result is the development of the characteristic microscopic and clinical hallmarks of inflammation. The figure numbers refer to additional figures in which more detailed information may be found on that portion of the response. <span style="font-family: Andale Sans for VST,sans-serif;"> <span style="font-family: Andale Sans for VST,sans-serif;">Degranulation (left) and Synthesis (right) of Biologic Mediators by **Mast Cells** during Inflammation. Mast cells are filled with darkly staining granules that contain a large number of biologically active substances. Among these are histamine, which is a major initiator of vascular changes, and a variety of chemotactic factors. These substances are released immediately after stimulation of mast cells.

<span style="font-family: Thorndale for VST,serif;">Three key **plasma protein systems** are essential to an effective inflammatory response. These are the complement system, the clotting system, and the kinin system (__<span style="color: rgb(0, 0, 255);">Figure 5-5 __). Although each system has a unique role in inflammation, they have many similarities. Each system consists of multiple proteins in the blood. <span style="font-family: Thorndale for VST,serif;">Each system contains a few proteins that can be activated by products of tissue damage or infection. Activation of the first component results in sequential activation of other components of the system, leading to a biologic function that helps protect the individual. This sequential activation is referred to as a cascade. <span style="font-family: Thorndale for VST,serif;">The **complement system** consists of a large number of proteins (sometimes called complement components) that together constitute about 10% of the total circulating serum protein.__<span style="color: rgb(0, 0, 255);">3 __ The complement system is extremely important because activated components can destroy pathogens directly and can activate or collaborate with virtually every other component of the inflammatory response. For these reasons, proteins of the complement system are among the body's most potent defenders against bacterial infection. The most important portion of the complement cascade is activation of C3 and C5, which results in a variety of subunits that are (1) opsonins, (2) chemotactic factors, or (3) anaphylatoxins. **Opsonins** are molecules that coat bacteria and increase their susceptibility to being eaten and killed by inflammatory cells, such as neutrophils and macrophages. <span style="font-family: Thorndale for VST,serif;">Complement activation can be accomplished in three different ways (see __<span style="color: rgb(0, 0, 255);">Figure 5-5 __): <span style="font-family: Thorndale for VST,serif;">1 **Classical pathway:** activated by proteins of the acquired immune system (antibodies) <span style="font-family: Thorndale for VST,serif;">2 **Lectin pathway:** activated by certain bacterial carbohydrates <span style="font-family: Thorndale for VST,serif;">3 **Alternative pathway:** activated by gram-negative bacterial and fungal cell wall polysaccharides

<span style="font-family: Thorndale for VST,serif;">The **clotting (coagulation) system** is a group of plasma proteins that, when activated sequentially, form a fibrinous meshwork at an injured or inflamed site.__<span style="color: rgb(0, 0, 255);">6 __ This (1) forms a clot that stops bleeding, (2) traps infectious organisms and prevents their spread to adjacent tissues, (3) keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity, and (4) provides a framework for future repair and healing. The main substance in this fibrinous mesh is fibrin, an insoluble protein produced by the coagulation cascade. <span style="font-family: Thorndale for VST,serif;">The third plasma protein system, the **kinin system,** interacts closely with the coagulation system (see __<span style="color: rgb(0, 0, 255);">Figure 5-5 __). Both the clotting and kinin systems are activated through activated factor XII (factor XIIa). Another name for factor XIIa is prekallikrein activator because it enzymatically activates the first component of the kinin system, prekallikrein. The final product of the kinin system is a small-molecular-weight molecule, **bradykinin,** which is produced from a larger precursor molecule, kininogen. At low doses, bradykinin causes dilation of blood vessels, acts with prostaglandins to induce pain, causes smooth muscle cell contraction, and increases vascular permeability (see __<span style="color: rgb(0, 0, 255);">Figures 5-2 __ and __<span style="color: rgb(0, 0, 255);">5-7 __). Bradykinin induces smooth muscle contraction more slowly than histamine and may be more important during the later phases of inflammation. <span style="font-family: Thorndale for VST,serif;">The three plasma protein systems described previously are highly interactive so that activation of one results in secondary activation of the other two. It is beneficial to the individual to activate all three systems, but it would be detrimental if the systems continued producing potent proinflammatory molecules indefinitely. Therefore, the systems are tightly regulated to control and localize inflammation to the appropriate sites. For instance, during clot formation the enzyme **plasmin** is produced from plasminogen. Plasmin limits clot formation by degrading fibrin and fibrinogen and also can activate the complement cascade through components C1, C3, and C5.


 * __20. Discuss each of the cell types (granulocytes, platelets, lymphocytes and natural killer cells, monocytes) involved in the inflammatory response. Explain their individual roles and relative importance to the process.__** (patho 129-132, mod4 #7)

__**Granulocytes**__ <span style="font-family: Thorndale for VST,serif;">**Read more about each of these on the pages listed above.** <span style="font-family: Thorndale for VST,serif;">__**Platelets**__ <span style="font-family: Thorndale for VST,serif;">**Platelets** are cytoplasmic fragments formed from megakaryocytes. They circulate in the bloodstream until vascular injury occurs. After injury, platelets are activated by many products of tissue destruction and inflammation, including collagen, thrombin, and platelet-activating factor. Activation results in (1) their interaction with components of the coagulation cascade to stop bleeding and (2) degranulation, releasing biochemical mediators such as serotonin, which has vascular effects similar to those of histamine. (Platelet function is described in detail in __<span style="color: rgb(0, 0, 255);">Chapter 19 __.)
 * <span style="font-family: Thorndale for VST,serif;">The primary circulating white blood cells are granulocytes, so called because of the many enzyme-containing granules in their cytoplasm. These include neutrophils, eosinophils, and basophils.
 * <span style="font-family: Verdana,sans-serif;"><span style="color: rgb(0, 0, 0);">**Neutrophils** (polymorphonucleocytes, PMNs) are the first phagocytes to arrive at the inflamed site; they ingest bacteria and debris.
 * <span style="font-family: Verdana,sans-serif;"><span style="color: rgb(0, 0, 0);">**Eosinophils** help control inflammation or act directly on parasites

<span style="font-family: Thorndale for VST,serif;">__**Natural killer cells**__ <span style="font-family: Thorndale for VST,serif;">The main function of **natural killer (NK) cells** is to recognize and eliminate cells infected with viruses and abnormal host cells, specifically cancer cells. Along with Toll-like receptors, NK cells have additional inhibitory and activating receptors that allow them to recognize differences between infected or tumor cells and normal cells. If the NK cell binds to a target cell through activating receptors, it produces several cytokines and toxic molecules that can kill the target.

<span style="font-family: Thorndale for VST,serif;">__**Monocytes**__

<span style="font-family: Thorndale for VST,serif;">Monocytes are the largest normal blood cells and have a nucleus that is often indented or horseshoe shaped. Monocytes are produced in the bone marrow, enter the circulation, and migrate to the inflammatory site, where they develop into macrophages. Monocytes also appear to be the precursors of macrophages that are fixed in tissues (tissue macrophages), including Kupffer's cells in the liver, alveolar macrophages in the lungs, and microglia in the brain.

<span style="font-family: Thorndale for VST,serif;">__**Lymphocytes**__

<span style="font-family: Thorndale for VST,serif;">The body's reaction to antigenic challenges is the immune response, which involves two types of **lymphocytes:** B lymphocytes (B cells) and T lymphocytes (T cells). The **B lymphocytes (B cells)** produce antibodies that enter the blood and react with the antigen, and the **T lymphocytes (T cells)** attack the antigen directly. Both cells are extremely specific, so that each individual B or T cell recognizes only one specific antigen.

 <span style="font-family: Thorndale for VST,serif;">**Phagocytosis** is the process by which a cell ingests and disposes of foreign material, including microorganisms (__<span style="color: rgb(0, 0, 255);">Figure 5-7 __). Cells that perform this process are called **phagocytes.** The two most important phagocytes are neutrophils and macrophages. Both cells are circulating in the blood and must first leave the circulation and migrate to the site of inflammation before initiating phagocytosis. The change of surface molecules described earlier increases the adhesion, or stickiness, between leukocytes and endothelial cells, causing the leukocytes to adhere more avidly to the walls of the capillaries and venules in a process called **margination,** or **pavementing.**__<span style="color: rgb(0, 0, 255);">11 __ Adhesion molecules that are expressed later lead to **diapedesis,** or emigration of the cells through the endothelial junctions that have retracted in response to inflammatory mediators. <span style="font-family: Thorndale for VST,serif;">Once inside the tissue, leukocytes are attracted to the inflammatory site by chemotactic factors. The primary chemotactic factors include many bacterial products, neutrophil chemotactic factor from mast cells, complement fragments C3a and C5a, and products of the clotting and kinin systems. <span style="font-family: Thorndale for VST,serif;">At the inflammatory site, the process of phagocytosis involves five steps: (1) adherence of the phagocyte to its target, (2) engulfment (ingestion or endocytosis), (3) formation of a phagosome, (4) fusion of the phagosome with lysosomal granules within the phagocyte, and (5) destruction of the target (see __<span style="color: rgb(0, 0, 255);">Figure 5-7 __)
 * __21. Describe the process and sequence of phagocytosis and how it can promote the inflammatory process.__** (patho 130, mod 4, 7j)

inflammatory process.__//**
 * //__22. Compare and contrast the roles of cellular products, particularly cytokines, in the

 [Heuther, pp. 135] LOCAL MANIFESTATIONS OF ACUTE INFLAMMATION:  Local inflammation accompanies all types of cellular & tissue injury, whether infected or sterile, & is responsible for initiating healing. Local Characteristics of Acute Inflammation: -Heat & Redness: result of vasodilation & increased blood flow through injured site. -Swelling (edema): occurs as exudate (fluid & cells) accumulate in the tissues. -Pain: accompanies swelling caused by pressure exerted by exudate accumulation, as well as the presence of soluble biochemical mediators such as prostaglandins & bradykinin. Exudate varies in compostition, depending on the stage of the inflammatory response and, to some extent, the injurious stimulus. For example: early or mild inflammation=watery (serous) exudate w/very few plasma proteins or leukocytes (blister fluid). Severe/advanced inflammation=thick and clotted exudate (fibrinous exudate), such as in the lungs of individuals w/pneumonia. If large number of leukocytes accumulate, as in persistent bacterial infections, the exudate consists of pus & is called a purulent (suppurative) exudate. Purulent exudate is characteristic of walled-off lesions (cycst or abcesses). Bleeding causes exudate to be full of erythrocytes=hemorrhagic exudate.

 SYSTEMIC MANIFESTATIONS OF ACUTE INFLAMMATION : Fever, Leukocytosis, and Increased Levels in Circulating Plasma Proteins.

 a.) FEVER: is partially induced by specific cytokines known as endogenous pyrogens to differentiate them from pathogen produced exogenous pyrogens. Pyrogens act directly on the hypothalamus the thermostat of the body. Fevers can be beneficial b/c some microorganisms are highly sensitive to small increases in body temp. On the other hand, fever may have harmful side effects b/c it may enhance the host’s susceptibility to the effects of endotoxins associated w/gram-neg bacterial infections.

 b. ) LEUKOCYTOSIS: is an increase in the # of circulating WBCs. During infections, leukocytosis may be accompanied by a “left shift” in the ratio of immature to mature neutrophils, so that the more immature forms of neutrophils, such as band cells, are present in relatively > normal proportions.

 c.)PLASMA PROTEIN SYNTHESIS: mostly the liver produces these circulating proteins that increase during inflammation. Acute-phase Reactants are these proteins and remember they can be pro-inflammatory or anti-inflammatory in nature. W/in 10-40 hrs after the start of inflammation, these reactants reach max circulating levels. Common lab tests for inflammation measure levels of acute phase reactants. Example; an increase in blood levels of acute-phase reactants such as fibrinogen is associated w/ an increased ESR. Although ESR is a nonspecific rxn, it is considered a good indicator of an acute inflammatory response. View Table 5-2,136

__24. Discuss the characteristics of chronic inflammation, focusing on the differences between__ __resolution and repair.__

 Heuther,pp.136] The characteristics of Chronic Inflammation consist of an acute inflammation that lasts 2 weeks or longer, regardless of cause. This may be the result of an unsuccessful acute inflammatory response. For example, if bacterial contamination or foreign objects(dirt,wood splinter, glass) persist in wound, an acute response may be prolonged beyond 2 wks. Pus formation, suppuration (purulent discharge), & incomplete wound healing may characterize this type of chronic inflammation. Chronic inflammation can also occur as a distinct process w/out previous acute inflammation. Mycobacterium causing TB for example may have cell walls w/a very high lipid & wax content, making them insensitive to breakdown by phagocytes. Others survive attack or produce toxins to cause persistent inflammation even after the organism is killed. Finally, chemicals, particulate matter, or physical irritants (inhaled dusts, wood splinters, and suture material) can cause a prolonged inflam. response. See Fig 5-11 p136 for complete picture of chronic inflammation

 RESOLUTION & REPAIR: [Heuther pp142]

 1. Resolution (regeneration) is the return of tissue to nearly normal structure & fxn. Repair is healing by scar tissue formation.

 2. Damaged tissue proceeds to resolution (restoration of the original tissue structure & fxn) if little tissue has been lost or injured tissue is capable of regeneration.

 3. Tissues that sustained extensive damage or those incapable of regeneration heal by the process of repair resulting in the formation of a scar. This is called healing by secondary intention.

 4. Resolution & repair occur in 2 separate phases, the reconstructive phase in which the wound begins to heal & the maturation phase in which the healed wound is remodeled.

 5. Dysfunctional wound healing can occur as a result of abnormalities in either the inflammatory response or the reconstructive phase of resolution & repair.

__25. Describe the body’s countermeasures against pathogens and ways pathogens have found to__ __circumvent these countermeasures.__

 Innate Immunity is the body’s countermeasure against pathogens. This includes Barriers, the Inflammatory Response, and Adaptive (Acquired) Immunity. See Table 5-1 p122 Heuther. True pathogens have devised ways of circumventing these barriers. For example, some bacteria produce thick capsules of carbohydrate or protein that are antiphagocytic, preventing efficient phagocytosis. Others defend themselves by producing toxins that kill neutrophils. B/c the primary immune response may take a week to develop adequately, some pathogens proliferate at rates that surpass the development of a protective response. Viral pathogens bypass many defense mechanisms by hiding w/in cells and away from normal inflammatory or immune responses. In many cases, however, b/c viral agents must spread cell to cell, the developing immune response eventually cures the infection so the disease is self-limiting. However, many viruses (e.g. measles and herpes) are inaccessible to antibodies after initial infection b/c they do not circulate in the bloodstream but instead remain inside infected cells, spreading by direct cell-to-cell contact. Abs that block a virus from attaching to a target cell (neutralizing Abs) are most effective in preventing the initial infection. Other viruses, such as polio and influenza, spread through the blood, are more susceptible to the effects of circulating Abs, and can be controlled by Abs even after the initial infection. Also, some viruses can elude the immune response by undergoing antigenic variation. The virus can change its appearance by altering surface antigens. Influenza infection provides an example of how this occurs. The “flu” virus undergoes yearly antigenic drift resulting from mutations in key surface antigens, etc. Other pathogens such as some parasitic microorganisms use a similar approach and change surface antigens by gene switching. A parasite may carry thousands of genes for different surface molecules that the parasite can switch on and off at frequent intervals. Consequently, the immune system is always trying to catch up by generating new Abs and T cells against the new antigens.

 See Table 7-8 p186 Heuther for easy version!

__26. Compare and contrast bacterial, viral, and fungal infections.__

 [Heuther p206] INFECTION: 1. Bacteria injure cells by producing exotoxins or endotoxins. Exotoxins are enzymes that can damage the plasma membranes of host cells or can inactivate enzymes critical to protein synthesis, and endotoxins activate the inflammatory response & produce fever. 2. Septicemia is the proliferation of bacteria in the blood. Edotoxins released by blood-borne bacteria cause the release of vasoactive enzymes that increase the permeability of blood vessels. Leakage from vessels causes hypotension that can result in septic shock. 3. Viruses enter host cells and use the metabolic processes of host cells to proliferate. 4. Viruses that have invaded host cells may decrease protein synthesis, disrupt lysosomal membranes, form inclusion bodies where synthesis of viral nucleic acids is occurring, fuse with host cells to produce giant cells, alter antigenic properties of the host cell, and transform host cells into cancerous cells. 5. Diseases caused by fungi are called

__27. Examine the clinical manifestations of infection.__  Heuther pp191Infectious diseases typically begin w/the nonspecific or general symptoms of fatigue, malaise, weakness, & loss of concentration. Generalized aching & loss of appetite are common complaints. However the hallmark of most infectious diseases is FEVER. Exogenous pyrogens produced by infectious agent may not cause fever directly but induce the production of endogenous pyrogens during inflammation. Endogenous pyrogens include IL-1, IL-6, tumor necrosis factor-alpha, and other cytokines. It is generally accepted that fever has a beneficial effect against infection, although the mechanisms have not been fully established.
 * //__27. Examine the clinical manifestations of infection.__//**


 * //__28. Describe the structural layers and primary function of the skin.__//**

Patho pg 1086: The primary function of the skin is to protect the body from the environment by serving as a barrier against microorganisms, ultraviolet radiation, loss of body fluids and the stress of mechanical forces. Two layers 1) superficial or outer layer of epidermis and 2) a deeper layer of dermis. each layer contains cells that represent progressive stages of skin cell differentiation as the skin grows. See Table 39-1 Layers of the skin: Structure, cell typs and Characteristics

cellulitis and abscesses, including the risk factors associated with their development.__//**
 * //__29. Describe the pathophysiology, clinical manifestations and collaborative management of

Patho pg. 1102: Cellulitis is an infection of the dermis and subcutaneous tissue usually caused by Staphylococcus. can occur as an extension of a skin wound, as an ulcer, or from furuncles or carbuncles. The infected area is usually in the lower extremities and responds to systemic antibodies as well as burow soaks to relieve pain.

pressure ulcers, including the risk factors associated with their development.__//**
 * //__30. Examine the pathophysiology, clinical manifestations and collaborative management of

Patho pg. 1088 Pressure Ulcers are ischemic ulcers resulting from unrelieved pressure, shearing force, friction and moisture. the term decubitus refers to ulcers or pressure sores that develop when an individual lies in the recumbent position for a long time. (see box on pg 1088, Risk Factors)


 * //__31. Examine the depth and extent of injury for first, second, and third-degree burns.__//**

(Patho pg 1110-1111) First degree burn: Involves only the epidermis, no injury to underlying layers. Skin maintains water and bacterial barrier function. Local pain and erythema, no blisters for about 24 hours. heals in about 3 -5 days.

Second degree burn: two categories 1) Superficial partial thickness injuries- involves thin walled, fluid filled blisters that develop within just a few minutes after injury. nerve endings exposed to air, tactile and pain sensors remain intact throughout the healing process, each wound care procedure causing extreme pain. heals in about 3 to 4 weeks. 2) Deep partial-thickness burns- entire dermis sparing skin appendages such as hair follicles and sweat glands. Look waxy white and take weeks to heal. therapy is to surgically remove burn wound and apply the person’s own unburned skin from another body area (autograft). commonly result in hypertrophic scarring with poor functional and cosmetic results.

Third degree burns (full-thickness burns): destruction of entire epidermis, dermis and often underlying subcutaneous tissue. elasticity is destroyed giving the wound a dry, leathery appearance. full thickness burns are painless because all nerve endings have been destroyed

alterations related to severe burn injuries.__//**
 * //__32. Analyze the consequences of body fluid shifts, cardiovascular compromise, and immunologic

(Patho pg 1113-1114) Fluid shift- Hypovolemia is associated with burn shock, is the result of fluid loss and shifting to the interstitial space from the circulating blood volume. caused by an increased capillary endothelial permeability that persists for 24 hours after burn. Cardiac contractility diminished, blood shunts away from the liver, kidney, gut and other viscera which decreases organ function. cellular metabolism is disrupted resulting in membrane permeability and loss of normal electrolyte homeostasis. Insensible water loss dramatically increases both from breath with increased respiration and also skin with water barrier disrupted. Cardiovascular- decreased cardiac output due to myocardial depressant factor and decreased intravascular volume. hypoproteinemia, increased hematocrit and white blood cell count as fluid moves out of intravascular compartment. irreversible shock and death within a few hours if untreated. Immunologic- response to burn injury is immediate, prolonged and severe. end result for individuals surviving burn shock is immunosuppression with increased susceptibility to potentially fatal systemic burn wound sepsis. WBC altered at time when needed to inhibit sepsis, phagocytosis is impaired, cellular and humoral immunity is abnormal. Macrophages, neutrophils and platelets release large amounts of inflammatory cytokines causing peripheral vasodilation, distant organ dysfunction and multiple organ failure. pulmonary edema due to circulating inflammatories.


 * //__33. Describe the collaborative management of burn injuries.__//**

(patho pg 1114) Burn recovery is long and stormy with complications the norm rather then the exception. goal for burn management is wound closure in a manner that promotes survival. three essential elements of survival of a major burn is 1) adequate fluids and nutrition, 2) meticulous wound management, and 3) early surgical excision and grafting. pain is almost always acute and treatment strategies usually differ from chronic pain management. in addition to opioid agents, strategies for treatment might include: anti-anxiety agents, hypnosis, and relaxation techniques. nutritional therapy focuses on early enteral therapy to reduce gut-mediated sepsis. advancements in skin replacement technology are effective and promising