Patho II – Flashcard

PAGE 137: Several different proteins are involved in DNA replication. One protein unwinds the double helix, one holds the strands apart, and others perform different distinct functions. The most important of these proteins is the enzyme known as DNA polymerase. This enzyme travels along the single DNA strand, adding the correct nucleotides to the free end of the new strand (see Figure 4-2, B). Besides adding the new nucleotides, the DNA polymerase performs a proofreading procedure. After the new nucleotide has been added to the chain, the DNA polymerase checks to make sure that its base is actually complementary to the template base. If it is not, the incorrect nucleotide is excised and replaced with a correct one.

PAGE: 146: Aneuploid cells are defined as those that do not contain a multiple of 23 chromosomes. An aneuploid cell containing three copies of one chromosome is said to be trisomic (a condition termed trisomy). The most well-known example of aneuploidy in an autosome is trisomy of the twenty-first Chromosome: Down syndrome was formerly called mongolism, but this inappropriate term is no longer used. Individuals with this disease typically have intelligence quotients (IQs) between 25 and 70. The facial appearance is distinctive, with a low nasal bridge, protruding tongue, and flat, low-set ears.

PAGE: 154: The penetrance of a trait is the percentage of individuals with a specific genotype who also exhibit the expected phenotype. Incomplete penetrance means that individuals who have a disease-causing allele may not exhibit the disease phenotype at all, even though the allele and the associated disease may be transmitted to the next generation. Huntington disease is a well-known autosomal dominant condition and its main features are progressive dementia and increasingly uncontrollable movements of the limbs. One of the key features is that symptoms/signs are not usually seen until age 40 or later, thus known as age-dependent penetrance. Most genetic diseases exhibit variable expressivity. Expressivity is the extent of variation in phenotype associated with a particular genotype. If the expressivity of a disease is variable, the penetrance may be complete but the severity of the disease can vary greatly. A well-known example of variable expressivity in an autosomal dominant disease is type 1 neurofibromatosis, or von Recklinghausen disease. The expression of this gene can vary from a few harmless café-au-lait spots ("coffee with milk," describing the light brown color) on the skin to malignant tumors, scoliosis, seizures, gliomas, hypertension, learning disabilities, and neuromas.

PAGE 154: The most common lethal autosomal recessive disease in white children, cystic fibrosis. Because an individual must be homozygous for a recessive allele to express the disease, the carriers are phenotypically normal. Because most recessive alleles are maintained in normal carriers, they are able to survive in the population from one generation to the next.

PAGE 174: An autosomal dominant form of breast cancer accounts for approximately 5% of breast cancer cases in the United States. Genes responsible for this form of breast cancer have been mapped to chromosomes 17 (BRCA1) and 13 (BRCA2). Women who inherit a mutation in BRCA1 or BRCA2 experience a 50% to 80% lifetime risk of developing breast cancer. Breast cancer aggregates strongly in families. If a woman has one affected first-degree relative, her risk of developing breast cancer doubles.

PAGE 158: Pedigrees for X-linked recessive conditions show the following distinctive features: 1. The trait is seen much more often in males than in females because females must inherit two copies of the recessive allele (one from each parent) to express the disease, while males need only inherit one copy (from their mother) to express the disease. 2. Because a father can give a son only a Y chromosome, the trait is never transmitted from father to son. 3. The gene can be transmitted through a series of carrier females, causing the appearance of a "skipped generation." 4. The gene is passed from an affected father to all his daughters, who, as phenotypically normal carriers, transmit it to approximately half their sons, who are affected.

PAGE 164: Well-established measures are used to answer this question. 1. The incidence rate is the number of new cases of a disease reported during a specific period (typically 1 year) divided by the number of individuals in the population. 2. The prevalence rate is the proportion of the population affected by a disease at a specific point in time. This rate, and the incidence rate, can be used to compare population variations in disease frequency. For example, the prevalence rate of acquired immunodeficiency syndrome (AIDS) is larger than the yearly incidence rate because most people with AIDS survive for at least several years after diagnosis. 3. Relative risk is a common measure of the effect of a specific risk factor. It is expressed as a ratio of the incidence rate of the disease among individuals exposed to a risk factor divided by the incidence of the disease among individuals not exposed to a risk factor. Page 165: EXAMPLE: The incidence of death from lung cancer was 1.66 (per 1000 person-years) in heavy smokers (more than 25 cigarettes daily), but it was only 0.07 in the nonsmokers. The ratio of these two incidence rates is 1.66/0.07, which yields a relative risk of 23.7 deaths. Thus, it is concluded that the risk of dying from lung cancer increased by about 24-fold in heavy smokers compared with nonsmokers.

PAGE 174: Type 1 diabetes, which is characterized by T-cell infiltration of the pancreas and destruction of the insulin-producing beta cells. In addition to T-cell infiltration of the pancreas, autoantibodies are formed against pancreatic cells; the latter can be observed long before clinical symptoms occur. These findings, indicate that this is an autoimmune disease.

PAGE 183 & 189 1. Epigenetics bridges DNA information and function by modifying gene expression without any alteration in DNA sequence. 2. Epigenetic modification can cause individuals with the same DNA (IDENTICAL TWINS) to have different disease profiles - For example the occurrence of asthma in only one of a pair of identical twins. 3. As twins age, they demonstrate increasing differences in methylation patterns of their DNA sequences, causing increasing numbers of phenotypic differences. 4. Environmental factors, such as diet and exposure to certain chemicals, may cause epigenetic modification. 5. Unlike DNA sequence mutations, which cannot be directly altered, epigenetic modifications can be reversed. EXAMPLE: 5-azacytidine

PAGE: 186 Hypermethylation is seen in miRNA genes that bind to the ends of mRNAs, degrading them and preventing their translation. When miRNA genes are methylated, their mRNA targets are over-expressed, and this over-expression has been associated with metastasis.

PAGE: 187 For some human genes, a given gene is transcriptionally active on only one copy of a chromosome (e.g., the copy inherited from the father). On the other copy of the chromosome (the one inherited from the mother), the gene is transcriptionally inactive. This process of gene silencing, in which genes are silenced depending on which parent transmits them, is known as imprinting, and the transcriptionally silenced genes are said to be "imprinted." A well-known disease example of imprinting is Prader-Willi Syndrome: When this deletion is inherited from the father, the child manifests Prader-Willi syndrome, whose features include short stature, hypotonia, small hands and feet, obesity, mild to moderate mental retardation, and hypogonadism

PAGE 196: If the epithelial barrier is damaged, a highly efficient local and systemic response (inflammation) is mobilized to limit the extent of damage, protect against infection, and initiate repair of the damaged tissue.

PAGE 199: Directs leukocytes to the inflamed area. The complement cascade can be activated by at least three different means, and its products have four functions: (1) anaphylatoxic activity resulting in mast cell degranulation (2) leukocyte chemotaxis (3) opsonization (4) cell lysis

PAGE 210/211: Phagocytosis is the destruction of microorganisms and cellular debris. Once the phagocytic cell enters the inflammatory site, the process of phagocytosis involves four steps: (1) opsonization (recognition of the target and adherence of the phagocyte to it); (2) engulfment (ingestion or endocytosis) and formation of phagosome; (3) fusion with lysosomal granules within the phagocyte (phagolysosome); and (4) destruction of the target FIGURE 7-15 Process of Phagocytosis. Phagocytes The primary role of most granulocytes (neutrophils, eosinophils, basophils) and monocytes/macrophages is phagocytosis; the process by which a cell ingests and disposes of damaged cells and foreign material, including microorganisms.

PAGE 213 Local versus systemic inflammation All the local manifestations of acute inflammation (i.e., swelling, pain, heat, and redness) result from vascular changes and the subsequent leakage of circulating components into the tissue. The systemic changes associated with the acute inflammatory response are fever, leukocytosis (a transient increase in the levels of circulating leukocytes), and plasma protein synthesis (increased levels of circulating plasma proteins). PAGE 215 Resolution and Repair Destruction of tissue is followed by a period of healing that begins during acute inflammation and may not be complete for as long as 2 years. The most favorable outcome of healing is tissue regeneration with complete return to normal structure and function. If damage is minor, no complications occur, and destroyed tissues are capable of regeneration, it is possible to return injured tissues to an approximation of their original structure and physiologic function. This restoration is called resolution. If extensive damage is present, injury occurs in tissues not capable of regeneration, infection results in abscess or granuloma formation, or fibrin persists in the lesion, resolution is not possible and repair takes place instead. Repair is the replacement of destroyed tissue with scar tissue. Impaired inflammation & wound healing The older adult population is also at risk for impaired inflammation and wound healing. In some cases, impaired healing is not directly associated with aging in general but can instead be linked to a chronic illness such as cardiovascular disease or diabetes mellitus. In addition, many older adults require medications such as anti-inflammatory steroids that can interfere with the healing process.

Humoral immunity: Antibody circulates in the blood and binds to antigens on infectious agents. This interaction can result in direct inactivation of the microorganism or activation of a variety of inflammatory mediators (e.g., complement, phagocytes) that will destroy the pathogen. Antibody is primarily responsible for protection against many bacteria and viruses. This arm of the immune response is termed humoral immunity. Cellular immunity: T cells also undergo differentiation during an immune response and develop into several subpopulations of cells that react directly with antigen on the surface of infectious agents. Some develop into T cells that can stimulate the activities of other leukocytes via cell-to-cell contact or through the secretion of cytokines. Others develop into T-cytotoxic cells (Tc cells) that attack and kill targets directly. Targets for Tc cells include cells infected by a variety of viruses, as well as cells that have become cancerous. This arm of the immune response is termed cellular immunity. The humoral and cellular immune responses are interdependent at many levels. In the end, the success of an acquired immune response depends on the functions of both the humoral and the cellular responses, as well as the appropriate interactions between them. For Example: Th1 cells help develop cellular immunity, Th2 cells help develop humoral immunity, and Th17 cells increase the inflammatory response. For example, antigens derived from viral or bacterial pathogens and those derived from cancer cells are hypothesized to induce a greater number of Th1 cells, whereas antigens derived from multicellular parasites and allergens are hypothesized to result in production of more Th2 cells.

Adaptive immunity can be either active or passive, depending on whether the antibodies or T cells are produced by the individual in response to antigen or are administered directly. Active acquired immunity (active immunity) is produced by an individual either after natural exposure to an antigen or after immunization, whereas passive acquired immunity (passive immunity) does not involve the host's immune response at all. Rather, passive immunity occurs when preformed antibodies or T lymphocytes are transferred from a donor to the recipient (breast milk). This can occur naturally, as in the passage of maternal antibodies across the placenta to the fetus, or artificially, as in a clinic using immunotherapy for a specific disease.

PAGE 252: The symptoms of some infectious diseases result directly from toxins produced by infecting bacteria. Protective antibodies can bind to the toxins, prevent their interaction with cells, and neutralize their biologic effects. For example, group A streptococcal bacteria produce a toxin, streptolysin O, that destroys cells, particularly erythrocytes and leukocytes. The infected individual produces an antibody that can neutralize this toxin (antistreptolysin O) and also be detected in laboratory tests as a useful diagnostic tool for group A streptococcal infections.

PAGE 263: Hypersensitivity is an altered immunologic response to an antigen that results in disease or damage to the host. Hypersensitivity reactions can be classified in two ways: by the source of the antigen that the immune system is attacking (allergy, autoimmunity, alloimmunity; Table 9-1) and by the mechanism that causes disease (types I, II, III, and IV; see Table 9-3). The most rapid and severe immediate hypersensitivity reaction is anaphylaxis. Anaphylaxis occurs within minutes of reexposure to the antigen and can be either systemic (generalized) or cutaneous (localized).

PAGE 263: Type I reactions are mediated by antigen-specific IgE and the products of tissue mast cells. Most common allergies (e.g., pollen allergies) are type I reactions. In addition, most type I reactions occur against environmental antigens and are therefore allergic. Type I reactions are mediated by antigen-specific IgE and the products of tissue mast cells. Most common allergies (e.g., pollen allergies) are type I reactions. In addition, most type I reactions occur against environmental antigens and are therefore allergic. Because of this strong association, many healthcare professionals use the term allergy to indicate only IgE-mediated reactions.

PAGE 266: Type II hypersensitivity reactions are generally characterized by a specific cell or tissue being the target of an immune response. The symptoms of many type II diseases are determined by which tissue or organ expresses the particular antigen. First, the cell can be destroyed by antibody (IgG or IgM) and activation of the complement cascade through the classical pathway. For example, alloimmune reaction to ABO-mismatched transfused blood cells. Second, antibody may cause cell destruction through phagocytosis by macrophages. IgG and also C3b of the complement system are opsonins that bind to receptors on the macrophage. For example, antibodies against platelet-specific antigens or against red blood cell antigens of the Rh system. Third, antibody and complement may attract neutrophils. Fourth is antibody-dependent cell-mediated cytotoxicity (ADCC) (see Figure 9-2, D). This mechanism involves a subpopulation of cytotoxic cells that are not antigen specific (natural killer [NK] cells). For example, in the hyperthyroidism (excessive thyroid activity) of Graves disease, autoantibody binds to and activates receptors for thyroid-stimulating hormone (TSH) (a pituitary hormone that controls the production of the hormone thyroxine by the thyroid). In this way the antibody stimulates the thyroid cells to produce thyroxine.

PAGE 278: AB Because individuals with type O blood lack both types of antigens, they are considered universal donors, meaning that anyone can accept their red blood cells. Similarly, type AB individuals are considered universal recipients because they lack both anti-A and anti-B antibodies and can be transfused with any ABO blood type. When large volumes of whole blood (i.e., cells plus plasma) are transfused, however, antibodies in the donor's blood can bind to antigenic determinants on the recipient's erythrocytes, causing agglutination of the recipient's own cells. Agglutination and lysis cause harmful transfusion

Whereas types I, II, and III hypersensitivity reactions are mediated by antibody, type IV reactions are mediated by T lymphocytes and do not involve antibody (Figure 9-4). Clinical examples of type IV hypersensitivity reactions include graft rejection and allergic reactions resulting from contact with such substances as poison ivy and metals. A type IV component also may be present in many autoimmune diseases. For example, T cells against type II collagen (a protein present in joint tissues) contribute to the destruction of joints in rheumatoid arthritis; T cells against a thyroid cell surface antigen contribute to the destruction of the thyroid in autoimmune thyroiditis (Hashimoto disease); and T cells against an antigen on the surface of pancreatic beta cells (the cell that normally produces insulin) are responsible for beta-cell destruction in insulin-dependent (type 1) diabetes mellitus.8 A type IV hypersensitivity reaction in the skin was thoroughly described first by Ehrlich in 1891 and led to the development of a diagnostic skin test for tuberculosis. The reaction follows an intradermal injection of tuberculin antigen into a suitably sensitized individual and is called a delayed hypersensitivity skin test because of its slow onset—24 to 72 hours to reach maximum intensity. The reaction site is infiltrated with T lymphocytes and macrophages, resulting in a clear hard center (induration) and a reddish surrounding area (erythema).

PAGE 300 From the perspective of the microorganisms that cause disease, the infectious process undergoes four separate stages of progression: colonization invasion multiplication spread

PAGE 324 & 325 HIV is a member of the retrovirus family, which carries genetic information in the form of two copies of RNA. An enzyme, reverse transcriptase (RT), converts RNA into a double-stranded DNA. Another enzyme, an integrase, inserts the new DNA into the infected cell's genetic material. On activation, translation of the viral information may be initiated, forming new virions, resulting in lysis and death of the infected cell, and shedding infectious HIV particles.

PAGE 339 (1) alarm stage or reaction, in which the central nervous system (CNS) is aroused and the body's defenses are mobilized (e.g., "fight or flight") Initially one becomes alarmed by a stressor that activates the hypothalamus and sympathetic nervous system; (2) stage of resistance or adaptation, during which mobilization contributes to "fight or flight" The resistance or adaptation phase begins with the actions of the hormones cortisol, norepinephrine, and epinephrine; and (3) stage of exhaustion, where continuous stress causes the progressive breakdown of compensatory mechanisms (acquired adaptations) and homeostasis. Exhaustion marks the onset of certain diseases (diseases of adaptation).

PAGE 345: Norepinephrine regulates blood pressure by constricting smooth muscle in all blood vessels. Norepinephrine release promotes arousal, increased vigilance, increased anxiety, and other protective emotional responses.

PAGE 348: Cortisol secretion during stress exerts beneficial effects by inhibiting initial inflammatory effects, for example, vasodilation and increased capillary permeability. Cortisol also promotes resolution and repair. Whether cortisol-induced effects are adaptive or destructive may depend on the intensity, type, and duration of the stressor; the tissue involved; and the subsequent concentration and length of cortisol exposure. In addition, the overall health of the individual has a huge impact on cortisol production - for example nutritional status. Finally, glucocorticoids have been shown to induce T-cell apoptosis. Cortisol acts to suppress the activity of Th1 cells, which leads to a decrease in innate immunity and to the proinflammatory response.

PAGE 365: In general, cancers are named according to the cell type from which they originate (e.g., lip), whereas benign tumors use the suffix "-oma." For diseases associated with a tumor marker, there is indeed a "blood test for cancer." Tumor markers include hormones, enzymes, genes, antigens, and antibodies. Liver and germ cell tumors secrete a protein known as alpha fetoprotein (AFP) into the blood, and prostate tumors secrete prostate specific antigen (PSA) into the blood. During surveillance or diagnosis of cancer as well as following therapy, specific biochemical markers of tumors have proven to be helpful. These tumor markers are substances produced by both benign and malignant cells that either are present in or on tumor cells or are found in blood, spinal fluid, or urine (Table 12-3). If the tumor marker itself has biologic activity, then it can cause symptoms, a phenomenon known as a paraneoplastic syndrome. For example, the adrenal medulla normally secretes the catecholamine epinephrine (adrenaline). Benign tumors of the adrenal medulla (pheochromocytoma) can produce catecholamines (e.g., adrenaline) in vast excess, leading to rapid pulse rate, high blood

27. PAGE 379 Guardians of the Genome These repair mechanisms are directed by caretaker genes, genes that are responsible for the maintenance of genomic integrity. Loss of function of caretaker genes leads to increased mutation rates. If DNA damage is severe, the cell undergoes programmed cell death, or apoptosis, rather than simply dividing with damaged DNA. Inherited mutations can disrupt the caretaker genes that protect the integrity of the genome. Hereditary nonpolyposis colorectal cancer (HNPCC) results from an inherited defect in repairing DNA base pair mismatches that occur occasionally during DNA replication. Affected individuals have an increased rate of small insertions and deletions in DNA, leading to a high rate of colon and other cancers. Page 373: What Are the Driver Mutations? See table 12-4 It is important to distinguish between oncogenes and tumor-suppressor genes. Oncogenes are mutant genes that in their normal nonmutant state direct synthesis of proteins that positively regulate (accelerate) proliferation. Conversely, tumor-suppressor genes encode proteins that in their normal state negatively regulate (halt, or "put the brakes on") proliferation. Inherited mutations that predispose to cancer are almost invariably in tumor-suppressor genes. Page 379

PAGE 384: Chronic inflammation has been recognized for close to 150 years as being an important factor in the development of cancer. Chronic inflammations may result from many causes; for example, solar irradiation, asbestos exposure (mesothelioma), pancreatitis, and infection. Individuals who have suffered with ulcerative colitis for 10 years or more have up to a 30-fold increase in the risk of developing colon cancer. Additionally, some organs appear to be more susceptible to the oncogenic effects of chronic inflammation; for example, the gastrointestinal (GI) tract, prostate, thyroid gland, pancreas, urinary bladder, pleura, and skin.