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Advanced Pathophysiology
Chapter 1: Introduction to Pathophysiology - Risk - Factor that when present increases the chance of disease Not stressors, but conditions or situations that increase the likelihood of encountering a stressor Prevalence - A measure of disease that allows us to determine a person's likelihood of having a disease. Therefore, the number of prevalent cases is the total number of cases of disease existing in a population. A prevalence rate is the total number of cases of a disease existing in a population divided by the total population Indicates how widespread the disease is Incidence - A measure of disease that allows us to determine a person's probability of being diagnosed with a disease during a given period of time. Therefore, incidence is the number of newly diagnosed cases of a disease. An incidence rate is the number of new cases of a disease divided by the number of persons at risk for the disease. Conveys information about the risk of contracting the disease. Ratio - The quantitative relation between two amounts showing the number of times one value contains or is contained within the other. Primary Prevention - Altering susceptibility or reducing exposure for susceptible persons *Both illness and disease are absent
example: vaccinations, healthy lifestyles Secondary Prevention - Early detection, screening, and management of disease *Illness absent, disease present example: screenings and testings Tertiary Prevention - Rehabilitation, supportive care, reducing disability, and restoring effective functioning *Both illness and disease present example: education Epidemiology - study of the patterns of disease involving populations; examining the occurrence, incidence, prevalence, transmission, and distribution of diseases in large groups of populations/people Endemic - A disease theat is native to a local region Epidemic - When a disease is disseninated to many individals at the same time (spread to many people at the same time) Pandemic - Epidemics that affect large geographic regions, perhaps spreading worldwide. (spread to large geographic areas)
Chemical mediator in the inflammation response of the body Adrenal corticosteroid critical to maintenance of homeostasis May synergize or antagonize effects of catecholamines Chapter 3: Cell Structure and Function - Endocrine Communication - Hormones traveling in the bloodstream Long range signaling Neurocrine Communication - Neurons firing information through synapses Signals travel a very small distance between neuron and target cell Paracrine Communcation - Signaling through the extraceullar fluid between cells in a tissue Localized areas of communication Autocrine Communcation - Localized signaling in which the secreting cell is also the target cell Feedback to self Describe an Action Potential - Rapid, self-propagating electrical excitations of the membrane Mediated by voltage-gated ion channels that open (sodium flows into the cell) and close in response to voltage changes across the membrane Triggered by membrane depolarization
Propagated by sequential opening of voltage-gated sodium channels in adjacent sections of membrane. The action potential is regenerated in adjacent sections of membrane as more sodium channels open. The initial segment repolarizes as sodium channels close and potassium ions move out. Cardiac muscles: repolarization is prolonged from calcium influx Na+ initiates the action potential Only cells with voltage-gated channels have action potentials (not nerve cells) Describe a Resting Action Potential - Electrical charge when there is no net ion movement across plasma membrane Major determinant: Ratio of Internal-to-External [K+] This is dominated by potassium (K+) Take Home Message About Action Potentials - Resting Membrane Potential Dominated by K+ Upstroke of Action Potential --> Na+ Repolarization --> K+ In cardiac tissue, plateau --> Ca++ Depolarization - As the sodium rushes back into the cell the positive sodium ions raise the charge inside the cell from negative to positive. Once the interior of the cell becomes positively charged, depolarization of the cell is complete. This triggers the action potential
Disorganized appearance of cells because of abnormal variations in size, shape, and arrangement -Represents an adaptive effort gone astray -Significant potential to transform into cancerous cells (preneoplastic lesions) -Result from a persistant injury Metaplasia - Replacement of one differentiated cell type with another -Common cause: adaptation to persistent injury, with replacement of a cell type that is better suited to tolerate injurious stimulation -Fully reversible when injurious stimulation is removed -Result from persistent injury Necrosis - Usually occurs as a consequence of ischemia or toxic injury Necrosis occurs when the injury is too severe or prolonged to allow adaptation -Usually from a disruption in blood supply Local and systemic indicators of cell death -Pain -Elevated serum enzyme levels -Inflammation (fever, increased WBC, malaise) -Loss of function Coagulation Necrosis - Most common type of necrosis Process that begins with ischemia Ends with degradation of plasma membrane
Caused by ischemia/infarction Atrophy - Cells shrink and reduce their differentiated functions in response to normal and injurious factors -General causes: disuse, denervation, ischemia, interruption of endocrine signals, persistent cell injury -Results from decreased functional demand or chronic ischemia Results from decreased functional demand or chronic ischemia Proliferation - A rapid and often excessive spread or increase Cell Differentiation - How generic embryonic cells become specialized cells. This occurs through a process called gene expression. Gene expression is the specific combination of genes that are turned on or off (expressed or repressed), and this is what dictates how a cell functions. Endocytosis - The process of capturing a substance or particle from outside the cell by engulfing it with the cell membrane. The membrane folds over the substance and it becomes completely enclosed by the membrane. At this point a membrane-bound sac, or vesicle, pinches off and moves the substance into the cytosol. There are two main kinds of endocytosis: (1) Phagocytosis, or cellular eating, occurs when the dissolved materials enter the cell. The plasma membrane engulfs the solid material, forming a phagocytic vesicle. (2) Pinocytosis, or cellular drinking, occurs when the plasma membrane folds inward to form a channel allowing dissolved substances to enter the cell Exocytosis -
Meiosis Crossing over errors: chromosome portions lost, attached upside-down, or attached to wrong chromosome Mitosis Opportunities for chromosomal breakage & rearrangement Generally due to an abnormal number of chromosomes and/or alterations to the structure of one or more chromosomes Usually a result of separation during meiosis Monosomy - Daughter cell with a deficiency of 1 chromosome Usually not compatible with life Polysomy - Daughter cell with too may chromosomes May result in viable detus Nearly always associated with severe disability Those involving extra/missing sex chromosome not as debillitating Trisomy 21 (Down Syndrome) - Extra copy of 21st chromosome that occurs almost 12 times per 10,000 live births Most common chromosomal disorder Leading cause of mental retardation Protruding tongue, low-set ears, epicanthal folds, poor muscle tone, short stature; congenital heart deformities, increased susceptibility to respiratory infections, leukemia Clearly associated with advanced maternal age Cri du Chate Syndrome - Deletion of short arm of chromosome 5
Severe mental retardation, round face, congenital heart anomalies Cry resembles a cat crying Some live to adulthood and thrive better than those with trisomies Klinefelter Syndrome - Most common sex chromosome abnormality (occurs in 1 out of 1,000 births) Affects males Usually 1 extra X chromosome; sometimes more than 1: XXY, XXXY, XXXXY Abnormal sexual development and feminization Lack of secondary sex characteristics during puberty Associated signs include: lack of testosterone, testicular atrophy, infertility, feminine hair distribution/gynecomastia, tall stature, long arms/legs, high-pitched voice, and impaired intelligence These patients are usually on testosterone therapy Turner Syndrome - (1:3000 live female births) Monosomy X: 1 normal X chromosome; no Y chromosome Female phenotype with no developed ovaries Second X chromosome missing or structurally abnormal; usually from father's chromosome Rarely survive to birth Associated signs: short stature, webbed neck, wide chest, congenital heart defects, failure to develop secondary sexual characteristics Multiple X Females (XXX) - Relatively common Menstrual abnormalities; retardation tendency with more than 4 X chromosomes Double Y Males (XYY) - Relatively common
-Two carriers have 1 in 4 chance of having affected offspring and 2 in 4 chance of having carrier offspring Often associated with consanguinity, the mating of family members (familial aspect of two carriers having same recessive gene) Often involve abnormal enzymatic functions Cystic Fibrosis - Most common of the autosomal recessive dissorders (occuring in 1 out of 3,700 births) Production of abnormally thick secretions in glandular tissues from a defect in chloride transport across the cell membrane Cystic fibrosis transmembrane conductase regulator (CFTR) is a transmembrane protein that transports chloride from the cytoplasm into the lumen of the bronchiole. Mutations in the CFTR transporter gene are believed to cause the thick secretions typical of cystic fibrosis. Water is just going in one direction so it is much drier in patients with Cystic Fibrosis Phenylketonuria - Inborn error of metabolism: cannot metabolize phenylalanine (lack enzyme phenylalanine hydroxylase); test for this disorder at birth We test for this in newborns right abfter birth (this disease can be managed with diet) Tay Sachs Disease - Lysosomal storage disease Mutation on chromosome 15 Deficiency of lysososmal enzyme: hexosaminidase A Ashkenazi Jews Ganglioside accumulates in the cells, particularly the central nervous system, causing progressive destruction of neurons and brain cells
Infants born with Tay Sachs disease appear normal until approximately 6 months of age. As the infant matures, motor incoordination, lethargy, muscle flaccidity, and increasing cognitive impairment become apparent. A characteristic that is diagnostic of Tay Sachs disease is a "cherry red spot" seen on the retina on ophthalmological examination. Death usually occurs by age 3 years. Prenatal diagnosis and carrier detection of Tay Sachs disease is possible. Sex Linked Disorders - Carrier female has 1in 2 chance of producing an affected son or carrier daughter Females rarely affected Females affected: homozygous state of affected or carrier mother and affected father Triplet Repeat Mutations - Fragile X syndrome (prototypical example) Long repeating sequence of 3 nucleotides (CGG) More than 200 to >1000 (Normal is 29) Causes mental retardation Premutation: possible to have an intermediate number of inherited repeats, thus increasing risk of mutation in offspring Males more severely affected Multifactorial Diseases - "Run in families" Thought to be produced by an interaction of several genes: polygenic Present a range of severity Difficult to predict based on family history Interaction of several genes and the environment: multifactorial Examples of multifactorial disorders: high blood pressure, cancer, diabetes Examples of multifactorial traits: height, weight, intelligence
Refers to infection of a developing fetus or newborn by any of a group of infectious agents. "TORCH" is an acronym meaning (T)oxoplasmosis, (O)ther Agents, (R)ubella (also known as German Measles), (C)ytomegalovirus, and (H)erpes Simplex. Prenatal Diagnosis of Chromosome Abnormalities - Amniocentesis - about 16 weeks of gestation, amniotic fluid is obtained, fibroblasts are cultured and chromosome abnormalities can be detected; neural tube defects - elevation in α- fetoprotein. Chorionic villus sampling - can be performed at 10 weeks, does not require in vitro culturing because of an adequate number of cells in sample, earlier detection of abnormalities. Clinical diagnosis by whole-genome sequencing of a prenatal sample Fetal Cells in Maternal Blood (FCMB) - Based on enrichment of fetal cells which circulate in maternal blood. Since fetal cells hold all the genetic information of the developing fetus they can be used to perform prenatal diagnosis. Under development and testing. all these test require fetal cells somehow Chapter 7: Neoplasia - Cancer - aka- Neoplasia Abnormality of cellular growth/tumor Associated with altered expression of cellular genes 2nd leading cause of death in the U.S. Most deaths occur in those over the age of 55 Men have a 1:2 chance in developing cancer and women have a 1:3 chance
5-year survival rate is 68% Cancer Grading System - Histologic characterization of tumor cells Degree of anaplasia 3 or 4 classes of increasing degrees of malignancy Greater degree of anaplasia=greater degree of malignant potential Cancer Staging of Tumors - Location and patterns of spread within the host Tumor size Extent of local growth Lymph node and organ involvement Distant metastasis TNM system most widely used T-tumor N-nodes involved M-metastasis Results of staging determine treatment modality Benign Cancer - Does not have potential to kill host, but may be life-threatening because of its location Does not invade adjacent tissue or spread to distant sites Can be easily cued Malignant Cancer - Can kill host if untreated Confirmed by invasive or metastasizing nature
In CML this encodes a kinase that phosphorylates key proteins involved in cell growth. A therapeutic agent, imatinib mesylate, blocks the bcr-abl kinase by competing with the ATP binding site and can induce remissions in patients suffering from CML. Philadelphia chromosome - A balanced translocation of chromosomes 9 and 22, that is commonly found in chronic myelogenous leukemia (CML). CML Translocation of chromosomes 9 and 22 causes two genes to be juxtaposed and creates a new fusion gene: bcr/abl Protein product of bcr/abl spurs cell proliferation & decreases apoptotic cell death Associated with Chronic Myeloid Leukemia Chapter 8: Infectious Process & 9: Inflammation and Immunity - What is the impact of age on immune function? - The old and the young have the Very young: immature immune function Very old: degenerating immune function What are the key cells of the immune system? - Innate Immune System - Require no previous exposure to effectively respond to antigen NK cells- released into circulation that kills cells bigger than themselves by adhering to the cell, poking holes in it, add sodium (cell swells and lysis) and inject enzymes
Phagocytic cells (Neutrophils & Macrophages) Occurs on initial exposure to antigen Overview of the Innate Immune System Response - (1) Bacteria and other pathogens enter the wound (2) Platelets from blood release blood-clotting proteins at the wound site (3) Mast cells secrete factors that mediate vasodilation and vascular constriction. Delivery of blood, plasma, and cells to injured area increases (4) Neutrophils secrete factors and kill and degrade pathogens (5) Neutrophils and macrophages remove pathogens by phagocytosis (6) Macrophages secrete hormones called cytokines that attract immune system cells to the site and activate cells involved in tissue repair (7) Inflammatory response continues until the foreign material is eliminated and the wound is repaired Specific Immune Respose - Respond more effectively to 2nd exposure Highly selective in ability to recognize antigens B and T lymphocytes Slow to develop More efficient on subsequent exposure Adaptive Immune System - A type of specific immunity capable of -Recognizing foreign invaders -Destroying foreign invaders -Retaining memory of the encounter This allows for more effective defense (adaptive) to be achieved after subsequent exposure
