Pathology PDF

PATHOLOGY 1. Etiology refers to the underlying causes of disease, while pathogenesis refers to the mechanisms of disease development. 2. Understanding the etiology and pathogenesis of disease is essential for developing treatments and preventive measures. 3. Pathologists use morphological and bioche...

PATHOLOGY 1. Etiology refers to the underlying causes of disease, while pathogenesis refers to the mechanisms of disease development. 2. Understanding the etiology and pathogenesis of disease is essential for developing treatments and preventive measures. 3. Pathologists use morphological and biochemical changes in cells and tissues to diagnose and guide therapy. 4. Cells can adapt to stress or undergo injury and cell death depending on the severity and duration of the stress. 5. Cell death is a crucial event in the evolution of disease and can result from various causes such as ischemia, infections, toxins, and immune reactions. 6. Injurious stimuli can be grouped into categories including hypoxia and ischemia, toxins, infectious agents, immunologic reactions, genetic abnormalities, nutritional imbalances, physical agents, and aging. 7. Hypoxia and ischemia, which deprive tissues of oxygen, are among the most common causes of cell injury. 8. Toxins encountered in the environment, including drugs, can cause cell injury. 9. Infectious agents such as viruses, bacteria, fungi, and protozoans can injure cells. 10. Genetic abnormalities, nutritional imbalances, physical agents, and aging can also contribute to cell injury. 1. Cells exposed to certain chemicals may show adaptive responses, such as hypertrophy of the smooth endoplasmic reticulum (ER). 2. Barbiturates, metabolized in the liver by the smooth ER, can lead to smooth ER hypertrophy and increased enzymatic activity. 3. Smooth ER hypertrophy can result in increased drug metabolism and may cause reduced blood concentration of other medications, such as phenobarbital, when alcohol is consumed. 4. Injured cells can reach a "point of no return" where they undergo irreversible cell death, characterized by the loss of mitochondrial function, plasma membrane integrity, and DNA integrity. 5. Cell death can occur through different mechanisms depending on the severity of the insult. 6. Severe injuries result in accidental cell death known as necrosis, which is the major pathway of cell death in cases of ischemia, toxin exposure, infections, and trauma. 7. Less severe injuries or programmed cell elimination activate regulated pathways that culminate in apoptosis, a controlled form of cell death. 8. Apoptosis eliminates cells with intrinsic abnormalities and occurs during normal development and maintenance of cell numbers. 9. Cellular function can be lost before cell death occurs, and morphological changes of cell injury or death may lag behind loss of function and viability. 10. Necrosis is a form of cell death in which cellular membranes break down, enzymes leak out, and an inflammatory reaction is induced. 1. Severe pathologic conditions can lead to necrosis, where large areas of tissue or entire organs undergo cell death. 2. Different morphological patterns of tissue necrosis can provide clues about the underlying cause. 3. Leakage of intracellular proteins into the circulation can be used to detect tissue-specific necrosis using blood or serum samples. 4. Apoptosis is a pathway of cell death where cells activate enzymes that degrade their own nuclear DNA and proteins. 5. Apoptotic cells break off into fragments called apoptotic bodies, which are rapidly consumed by phagocytes. 6. Unlike necrosis, apoptosis does not elicit an inflammatory reaction. 7. Physiologic apoptosis occurs during normal development to eliminate excess or potentially harmful cells. 8. Apoptosis is regulated by biochemical pathways involving caspases, which are enzymes that cleave proteins. 9. Two main pathways converge on caspase activation: the mitochondrial (intrinsic) pathway and the death receptor (extrinsic) pathway. 10. The mitochondrial pathway is responsible for apoptosis in most situations, involving the release of cytochrome c from mitochondria, caspase activation, and apoptotic cell death. The death receptor pathway is triggered by surface molecules called death receptors. 1. Death receptors, such as type I TNF receptor and Fas (CD95), contain a conserved "death domain" that mediates interaction with proteins involved in cell death. 2. Fas ligand (FasL), expressed on activated T lymphocytes, crosslinks Fas molecules, leading to caspase activation and cell death. 3. In apoptosis, caspase-9 or caspase-8 activation leads to cleavage of additional caspases and subsequent degradation of cellular proteins and nucleus. 4. Apoptotic cells produce "eat-me" signals, such as phosphatidylserine flipping to the outer leaflet of the plasma membrane, which entice phagocytes for efficient clearance. 5. The death receptor pathway eliminates self-reactive lymphocytes and enables cytotoxic T lymphocytes (CTLs) expressing FasL to kill target cells. 6. Necroptosis is a form of cell death initiated by TNF receptors and involves the activation of receptor- interacting protein (RIP) kinases, leading to cell dissolution. 7. Pyroptosis is a form of cell death associated with inflammasome activation, resulting in caspase activation, production of inflammatory cytokines, and apoptosis. 8. Autophagy refers to lysosomal digestion of the cell's own components and is a survival mechanism during nutrient deprivation. 9. Autophagy can lead to atrophy of tissues or, if the cell can no longer cope, eventually result in apoptotic cell death. 10. The cellular response to injurious stimuli depends on the type, duration, and severity of the injury, as well as the cell's type, status, adaptability, and genetic makeup. 1. Reversible cell injury is characterized by cell swelling, fatty change, plasma membrane blebbing, loss of microvilli, mitochondrial swelling, dilation of the ER, and eosinophilia. 2. Necrosis is an accidental form of cell death characterized by increased cytoplasmic eosinophilia, nuclear shrinkage, fragmentation, and dissolution, breakdown of plasma membrane and organellar membranes, abundant myelin figures, and leakage and enzymatic digestion of cellular contents. 3. Different morphologic types of tissue necrosis include coagulative, liquefactive, gangrenous, caseous, fat, and fibrinoid necrosis. 4. Apoptosis is a regulated mechanism of cell death that eliminates unwanted and irreparably damaged cells with minimal host reaction. It is characterized by enzymatic degradation of proteins and DNA, caspase activation, and rapid recognition and removal of dead cells by phagocytes. 5. Apoptosis can be initiated through two major pathways: the mitochondrial (intrinsic) pathway, triggered by loss of survival signals and other cellular stresses, and the death receptor (extrinsic) pathway, initiated by engagement of death receptors by ligands on adjacent cells. 6. The mitochondrial pathway involves the leakage of proapoptotic proteins from the mitochondrial membrane into the cytoplasm, leading to caspase activation. It can be inhibited by anti-apoptotic proteins of the Bcl family. 7. The death receptor pathway is responsible for eliminating self-reactive lymphocytes and damage by cytotoxic T lymphocytes (CTLs). It is initiated by the engagement of death receptors by ligands. 8. Necroptosis is a form of cell death that combines features of both necrosis and apoptosis. It is regulated by specific signaling pathways. 9. Pyroptosis is a type of cell death that can release proinflammatory cytokines and may initiate apoptosis. 10. Autophagy is a cellular adaptation to nutrient deprivation in which cells digest their own organelles to provide energy and substrates. If the stress is too severe, it can result in cell death by apoptosis. 1. Inflammation is a protective response of vascularized tissues to infections and tissue damage. 2. It involves the recruitment of leukocytes and plasma proteins to the site of injury or infection. 3. The mediators of inflammation include phagocytic leukocytes, antibodies, and complement proteins. 4. Acute inflammation is the initial rapid response to infections and tissue damage, while chronic inflammation is a prolonged and destructive form. 5. Inflammatory reactions are induced by chemical mediators produced by host cells in response to injurious stimuli. 6. These mediators promote the recruitment of leukocytes and activate them to eliminate the offending agent. 7. The external manifestations of inflammation are heat, redness, swelling, pain, and loss of function. 8. Inflammatory reactions can cause tissue damage and are associated with various diseases, including autoimmune diseases, allergies, and infections. 9. Anti-inflammatory drugs are used to control the harmful consequences of inflammation. 10. Defective inflammation, as well as excessive inflammation, can lead to serious illness, such as increased susceptibility to infections or immunodeficiency disorders. 1. Inflammation is a beneficial host response to foreign invaders and necrotic tissue, but it can also cause tissue damage. 2. Inflammation involves a vascular reaction and a cellular response, activated by mediators derived from plasma proteins and various cells. 3. The five Rs summarize the steps of the inflammatory response: recognition of the injurious agent, recruitment of leukocytes, removal of the agent, regulation of the response, and resolution/repair. 4. Causes of inflammation include infections, tissue necrosis, foreign bodies, trauma, and immune responses. 5. Epithelial cells, tissue macrophages, dendritic cells, leukocytes, and other cell types express receptors that sense microbes and necrotic cells. 6. Acute inflammation can lead to the elimination of the noxious stimulus and tissue repair or persistent injury resulting in chronic inflammation. 7. Increased vascular permeability allows plasma proteins and leukocytes to enter sites of infection or tissue damage, leading to edema. 8. Lymphatic vessels and lymph nodes are involved in inflammation and can show redness and swelling. 9. Vasodilation, induced by inflammatory mediators like histamine, causes erythema and stasis of blood flow. 10. Increased vascular permeability is induced by histamine, kinins, and other mediators, creating gaps between endothelial cells and allowing fluid passage. 11. Leukocytes are recruited from the blood into extravascular tissue and migrate to the site of infection or tissue injury. 12. Leukocyte recruitment involves loose attachment and rolling on endothelium, firm attachment, and migration through interendothelial gaps. 13. Cytokines promote the expression of selectins and integrin ligands on endothelium, increase integrin avidity, and promote leukocyte migration. 14. Tissue macrophages and other cells produce cytokines in response to pathogens or damaged tissues. 15. Neutrophils are the predominant early inflammatory infiltrate and are later replaced by monocytes and macrophages. 16. Leukocytes eliminate microbes and dead cells through phagocytosis and destruction in phagolysosomes, using free radicals and granule enzymes. 17. Neutrophils can form extracellular nets to trap and destroy microbes, and granule enzymes may be released into the extracellular environment. 18. The mechanisms that eliminate microbes and dead cells can also damage normal tissues. 19. Anti-inflammatory mediators terminate the acute inflammatory reaction when it is no longer needed. 20. Vasoactive amines, mainly histamine, cause vasodilation and increased vascular permeability. 21. Arachidonic acid metabolites (prostaglandins and leukotrienes) play roles in vascular reactions, leukocyte chemotaxis, and other inflammatory reactions. 22. Cytokines, produced by various cell types, mediate multiple effects in leukocyte recruitment and migration during inflammation. 23. Complement proteins, activated by microbes or antibodies, contribute to leukocyte chemotaxis, opsonization, phagocytosis, and cell killing. 24. Kinins, produced by proteolytic cleavage, mediate vascular reactions and pain during inflammation. 1. Chronic inflammation can result from unresolved acute inflammation or be chronic from the start. 2. It is caused by microbes that resist elimination, immune responses against self and environmental antigens, and certain toxic substances. 3. Chronic inflammation is characterized by coexisting inflammation, tissue injury, attempted repair through scarring, and immune response. 4. Macrophages, lymphocytes, plasma cells, and other leukocytes are part of the cellular infiltrate in chronic inflammation. 5. Cytokines produced by macrophages and lymphocytes, particularly T lymphocytes, play a role in mediating chronic inflammation. 6. Granulomatous inflammation is a distinct pattern of chronic inflammation induced by T cell and macrophage activation. 7. Cytokines such as TNF and IL-1 stimulate the production of prostaglandins in the hypothalamus, leading to fever. 8. Cytokines, including IL-6, stimulate the synthesis of acute-phase proteins, such as C-reactive protein, in the liver. 9. Cytokines called CSFs stimulate the production of leukocytes from precursor cells in the bone marrow, leading to leukocytosis. 10. In severe infections, septic shock can occur, characterized by a fall in blood pressure, disseminated intravascular coagulation, and metabolic abnormalities. 11. Different tissues have varying regenerative capacities based on the proliferative potential of their constituent cells. 12. Cell proliferation is controlled by the cell cycle and can be stimulated by growth factors and interactions with the extracellular matrix. 13. Liver regeneration is an example of repair by regeneration, triggered by cytokines and growth factors in response to liver mass loss and inflammation. 14. Repair occurs through connective tissue deposition and scar formation when the injured tissue cannot regenerate or the structural framework is damaged. 15. Repair involves clot formation, inflammation, angiogenesis, granulation tissue formation, fibroblast migration and proliferation, collagen synthesis, and connective tissue remodeling. 16. Macrophages play a critical role in orchestrating the repair process by eliminating harmful agents and producing cytokines and growth factors. 17. TGF-β is a potent fibrogenic agent, and the balance between fibrogenic agents, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs) influences ECM deposition. 18. Cutaneous wound healing involves inflammation, granulation tissue formation, and ECM remodeling. 19. Wound healing can occur through primary union (first intention) or secondary union (secondary intention), with secondary healing involving more extensive scarring and wound contraction. 20. Factors like infection, diabetes, and the type, volume, and location of the injury can influence the wound healing process, and excessive ECM production can lead to keloids and tissue fibrosis. 1. The health of cells and tissues relies on the circulation of blood, which supplies oxygen and nutrients and removes waste. 2. Pathological conditions can disrupt the balance and lead to edema, the accumulation of fluid in tissues due to the movement of water into extravascular spaces. 3. Edema can have varying effects depending on its severity and location, ranging from minor discomfort to life-threatening conditions like hypoxia when fluid fills the lungs. 4. Hemostasis is the process of blood clotting that prevents excessive bleeding after blood vessel damage. 5. Inadequate hemostasis can result in hemorrhage, while inappropriate clotting or clot migration can cause thrombosis or embolism, potentially leading to tissue infarction. 6. Hyperemia is an active increase in blood volume within a tissue due to arteriolar dilation, as seen in inflammation or exercising muscles. 7. Congestion is a passive increase in blood volume caused by impaired venous outflow, occurring systemically in cardiac failure or locally due to venous obstruction. 8. Congested tissues have an abnormal blue-red color (cyanosis) due to the accumulation of deoxygenated hemoglobin, and chronic congestion may lead to cell death, fibrosis, and hemorrhages. 9. Edema is the accumulation of interstitial fluid, and effusions refer to fluid collections in body cavities. 10. The movement of fluid between vascular and interstitial spaces is influenced by vascular hydrostatic pressure and colloid osmotic pressure, with alterations in these forces leading to edema. 1. Edema occurs when fluid moves from blood vessels into interstitial spaces. 2. Edema can be protein-poor (transudate) or protein-rich (exudate). 3. Causes of edema include increased hydrostatic pressure, increased vascular permeability, decreased colloid osmotic pressure, decreased synthesis or increased loss of albumin, and lymphatic obstruction. 4. Endothelial injury exposes the basement membrane, leading to platelet adhesion through GpIb receptors binding to VWF. 5. Platelet activation involves secretion of granule contents, changes in shape and membrane composition, and activation of GpIIb/IIIa receptors. 6. Activated platelets form crosslinks with fibrinogen through GpIIb/IIIa receptors, resulting in platelet aggregation. 7. Thrombin promotes fibrin deposition and solidifies the platelet plug. 8. Coagulation involves a cascade of enzymatic conversions of proteins. 9. Tissue factor is the primary initiator of coagulation at sites of injury. 10. Coagulation is restricted to sites of injury by various mechanisms, including phospholipid surfaces provided by activated platelets or endothelium. 11. Thrombomodulin on endothelial cells converts thrombin into an anti-coagulant. 12. Fibrinolytic pathways help regulate coagulation. 13. Thrombosis is usually related to endothelial injury, abnormal blood flow, or hypercoagulability. 14. Thrombi can propagate, resolve, become organized, or embolize. 15. Thrombosis causes tissue injury through vascular occlusion or embolization. 16. Emboli are masses carried by the blood to distant sites, often originating from dislodged thrombi. 17. Pulmonary emboli primarily originate from lower-extremity deep vein thrombi and can cause various complications. 18. Systemic emboli mainly arise from cardiac sources and their consequences depend on the site of lodging. 19. Fat embolism, amniotic fluid embolism, and air embolism are other types of embolism with specific causes and manifestations. 20. Infarcts are areas of ischemic necrosis caused by arterial or venous occlusion, with hemorrhagic or pale appearances respectively. 1. Immunity refers to protection against infections. 2. The immune system is composed of cells and molecules that defend the body against pathogens. 3. Defects in the immune system can lead to immunodeficiency diseases and make individuals vulnerable to infections. 4. The immune system can also cause tissue injury and hypersensitivity disorders. 5. The chapter discusses diseases caused by both insufficient and excessive immune responses. 6. Amyloidosis is a disease characterized by the deposition of abnormal proteins in tissues. 7. The immune response consists of innate immunity and adaptive immunity. 8. Innate immunity is the immediate response to infections and involves inflammation as a major reaction. 9. Adaptive immunity is a specialized and powerful response that neutralizes and eliminates pathogens. 10. The innate immune system includes epithelial barriers, phagocytic cells, dendritic cells, natural killer cells, complement proteins, and pattern recognition receptors. Here is a 20-point summary based on the information provided in the text: 1. The innate immune system recognizes microbes and damaged cells through receptors like Toll-like receptors. 2. Lymphocytes are responsible for adaptive immunity and produce diverse receptors for antigens. 3. T lymphocytes express T-cell receptors (TCRs) that recognize peptide fragments of antigens presented by MHC molecules. 4. B lymphocytes express membrane-bound antibodies and can be activated to become plasma cells that secrete antibodies. 5. Natural killer (NK) cells kill infected or damaged cells and are prevented from killing healthy cells by inhibitory receptors. 6. Antigen-presenting cells (APCs) capture and present antigens for recognition by lymphocytes, with dendritic cells (DCs) being the most efficient APCs. 7. The immune system is organized into generative lymphoid organs (bone marrow and thymus) and peripheral lymphoid organs (lymph nodes, spleen, mucosal lymphoid tissues). 8. The innate immune system responds rapidly to microbes and includes epithelial barriers, phagocytes, NK cells, and complement proteins. 9. Innate immunity does not have antigen specificity or memory, unlike adaptive immunity. 10. Adaptive immunity develops slowly but has specific and memory responses. 11. DCs capture antigens and transport them to lymph nodes, where they are recognized by naïve lymphocytes. 12. Lymphocytes are activated, proliferate, and differentiate into effector and memory cells. 13. Cell-mediated immunity involves T lymphocytes and targets cell-associated microbes. 14. Humoral immunity is mediated by antibodies and is effective against extracellular microbes. 15. CD4+ helper T cells assist B cells in antibody production, activate macrophages, recruit leukocytes, and regulate immune responses. 16. CD4+ T cells perform their functions through secreted proteins called cytokines. 17. CD8+ cytotoxic T lymphocytes kill cells expressing foreign antigens in the cytoplasm, such as virus- infected or tumor cells. 18. Antibodies secreted by plasma cells neutralize microbes, promote phagocytosis, and confer passive immunity to neonates. 19. Antibodies can block the infectivity of pathogens. 20. Antibodies are part of humoral immunity and work against extracellular microbes in circulation and mucosal lumens. 1. Immediate (type I) hypersensitivity is also known as an allergic reaction or allergy. 2. Type I hypersensitivity is triggered by environmental antigens (allergens) in genetically susceptible individuals, leading to strong TH2 responses and IgE production. 3. IgE binds to the FcεRI receptor on mast cells, and reexposure to the allergen causes cross-linking of IgE and FcεRI, activating mast cells and releasing mediators. 4. Histamine, proteases, other granule contents, prostaglandins, leukotrienes, and cytokines are key mediators involved in the immediate vascular and smooth muscle reactions and the late-phase reaction (inflammation). 5. Clinical manifestations of type I hypersensitivity can range from local symptoms like rhinitis to systemic reactions like anaphylaxis, which can be fatal. 6. Antibodies can opsonize cells, with or without complement proteins, and target them for phagocytosis by macrophages, leading to depletion of the opsonized cells. 7. Antibodies and immune complexes can deposit in tissues or blood vessels, activating complement or engaging Fc receptors of leukocytes, causing an acute inflammatory reaction and tissue injury. 8. Antibodies can bind to cell surface receptors or essential molecules, leading to functional derangements without cell injury. 9. Cytokine-mediated inflammation involves activation of CD4+ T cells, secretion of cytokines (e.g., IFN- γ, IL-17), macrophage activation, tissue damage, fibrosis, and leukocyte recruitment. 10. Delayed-type hypersensitivity is a T cell-mediated inflammatory reaction often associated with macrophage activation and granuloma formation. 11. CD8+ cytotoxic T lymphocytes (CTLs) recognize and kill cells expressing target antigens, and they also secrete IFN-γ. 12. Tolerance to self antigens is a fundamental property of the immune system, and breakdown of self- tolerance leads to autoimmune diseases. 13. Central tolerance involves the elimination of self-reactive immature T and B lymphocytes in the generative lymphoid organs. 14. Peripheral tolerance includes functional inactivation (anergy), suppression by regulatory T lymphocytes, or apoptosis of mature lymphocytes recognizing self antigens in peripheral tissues. 15. Factors contributing to the breakdown of self-tolerance and the development of autoimmunity include susceptibility genes and environmental triggers like infections and tissue injury. 16. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by autoantibodies against self antigens and the formation of immune complexes. 17. Major autoantibodies in SLE target nuclear antigens, and other autoantibodies react with red blood cells, platelets, and phospholipid-protein complexes. 18. SLE can manifest as nephritis, skin lesions, arthritis, hematologic abnormalities, and neurologic abnormalities. 19. The underlying cause of self-tolerance breakdown in SLE is unknown but may involve excessive generation or persistence of nuclear antigens, inherited susceptibility genes, and environmental triggers. 20. UV irradiation is one possible environmental trigger for SLE, causing cellular apoptosis and release of nuclear antigens. 1. Sjögren syndrome is an inflammatory disease that primarily affects the salivary and lacrimal glands, causing dryness of the mouth and eyes. 2. The disease is believed to be caused by an autoimmune T-cell reaction against an unknown self antigen expressed in these glands or immune reactions against the antigens of a virus that infects the tissues. 3. Systemic sclerosis, also known as scleroderma, is characterized by progressive fibrosis involving the skin, gastrointestinal tract, and other tissues. 4. Fibrosis may result from the activation of fibroblasts by cytokines produced by T cells, but the triggers for T cell responses are unknown. 5. Endothelial injury and microvascular disease are commonly present in the lesions of systemic sclerosis, possibly causing chronic ischemia, but the pathogenesis of vascular injury is not known. 6. Rejection of solid organ transplants is primarily initiated by host T cells recognizing the foreign HLA antigens of the graft. 7. Types of rejection of solid organ grafts include hyperacute rejection, acute cellular rejection, acute antibody-mediated (humoral) rejection, and chronic rejection. 8. Hyperacute rejection occurs when preformed anti-donor antibodies bind to the graft endothelium immediately after transplantation, leading to thrombosis and graft failure. 9. Acute cellular rejection involves T cells destroying graft parenchyma and vessels through cytotoxicity and inflammatory reactions. 10. Acute antibody-mediated (humoral) rejection is characterized by antibodies damaging the graft vasculature. 11. Chronic rejection, dominated by arteriosclerosis, is caused by T cell activation and antibodies, leading to vascular lesions and parenchymal fibrosis. 12. Treatment of graft rejection relies on immunosuppressive drugs that inhibit immune responses against the graft. 13. Transplantation of hematopoietic stem cells (HSCs) requires careful matching of donor and recipient and is often complicated by graft-vs-host disease (GVHD) and immune deficiency. 14. Inherited mutations in genes involved in lymphocyte maturation or function, or in innate immunity, can cause diseases such as X-SCID, autosomal recessive SCID, X-linked agammaglobulinemia (XLA), Di George syndrome, X-linked hyper-IgM syndrome, common variable immunodeficiency, and selective IgA deficiency. 15. X-SCID is characterized by failure of T cell and B cell maturation due to a mutation in the common γ chain of a cytokine receptor. 16. Autosomal recessive SCID results in failure of T cell development and a secondary defect in antibody responses, often caused by a mutation in the gene encoding ADA. 17. XLA is characterized by a failure of B cell maturation and absence of antibodies due to mutations in the BTK gene. 18. Di George syndrome is characterized by the failure of thymus development, resulting in T cell deficiency. 19. X-linked hyper-IgM syndrome leads to a failure to produce isotype-switched high-affinity antibodies due to mutations in genes encoding CD40L or activation-induced cytosine deaminase. 20. Common variable immunodeficiency is characterized by defects in antibody production, with the cause unknown in most cases. 21. Selective IgA deficiency results in a failure of IgA production, with an unknown cause. 22. Deficiencies in innate immunity include defects in leukocyte function, complement, and innate immune receptors. 23. These immune deficiency diseases present clinically with increased susceptibility to infections in early life. 24. Virus entry into cells requires CD4 and coreceptors, which are receptors for chemokines. 25. Virus entry involves binding of viral gp120 and fusion with the cell mediated by viral gp41 protein. 26. The main cellular targets for viral infection are CD4+ helper T cells, macrophages, and dendritic cells. 27. Viral replication includes integration of the provirus genome into the host cell DNA and triggering of viral gene expression by stimuli that activate infected cells. 28. The progression of infection involves acute infection of mucosal T cells and dendritic cells, viremia with dissemination of the virus, latent infection of cells in lymphoid tissue, and continuing viral replication and progressive loss of CD4+ T cells. 29. Mechanisms of immune deficiency in viral infections include loss of CD4+ T cells through T cell death during viral replication and chronic stimulation-induced apoptosis, decreased thymic output, and functional defects. 30. Defective macrophage and dendritic cell functions are also observed in viral infections. 31. Destruction of the architecture of lymphoid tissues occurs in late stages of viral infections. 32. Treatment of viral infections often involves antiviral drugs that target specific steps in the viral life cycle. 33. HIV is an example of a viral infection that leads to profound immune deficiency and AIDS. 34. The HIV virus targets CD4+ T cells and progressively destroys them, leading to aweakening of the immune system. 35. The loss of CD4+ T cells in HIV infection is due to a combination of viral replication, chronic immune activation, and direct viral cytopathic effects. 36. The immune deficiency caused by HIV infection increases the risk of opportunistic infections and certain types of cancer. 37. Antiretroviral therapy (ART) is the standard treatment for HIV infection to suppress viral replication and restore immune function. 38. ART involves the use of combinations of antiretroviral drugs that target different steps in the viral life cycle. 39. Early initiation of ART and adherence to treatment are crucial for achieving viral suppression and preventing disease progression. 40. Ongoing research aims to develop new strategies for the prevention, treatment, and cure of HIV/AIDS. 1. HIV infection progresses through different phases: acute HIV infection, chronic (latent) phase, and AIDS. 2. Acute HIV infection is characterized by manifestations of acute viral illness. 3. During the chronic phase, the virus disseminates, the host immune response is activated, and there is progressive destruction of immune cells. 4. AIDS refers to the severe immune deficiency that occurs in advanced stages of HIV infection. 5. Full-blown AIDS manifests with several complications, mostly resulting from immune deficiency. 6. Opportunistic infections are common in individuals with AIDS. 7. Tumors, particularly those caused by oncogenic viruses, can occur in individuals with AIDS. 8. Neurologic complications of unknown pathogenesis can occur in AIDS patients. 9. Antiretroviral therapy (ART) has significantly reduced the incidence of opportunistic infections and tumors in individuals with HIV/AIDS. 10. However, ART can also have numerous complications. 11. Amyloidosis is a disorder characterized by the deposition of proteins that tend to aggregate and form insoluble fibrils. 12. Amyloidosis can result from excessive production of prone-to-aggregate proteins, mutations that produce improperly folded proteins, or defective degradation of extracellular proteins. 13. Amyloidosis can be localized or systemic and is associated with various primary disorders. 14. Monoclonal B-cell proliferations can lead to amyloid deposits consisting of immunoglobulin light chains. 15. Chronic inflammatory diseases like rheumatoid arthritis can cause deposits of amyloid A protein. 16. Alzheimer's disease is associated with amyloid β protein deposits. 17. Familial conditions can result in amyloid deposits consisting of mutated proteins, such as transthyretin in familial amyloid polyneuropathies. 18. Hemodialysis patients can develop deposits of β2-microglobulin due to defective clearance. 19. Amyloid deposits cause tissue injury and impair normal function but do not elicit an inflammatory response. 1. Cancer is the second leading cause of death in the United States after cardiovascular diseases. 2. Cancer is not a single disease but a group of disorders characterized by abnormal growth regulation. 3. Some cancers, like Hodgkin lymphoma, are highly curable, while others, like pancreatic cancer, are usually fatal. 4. Understanding the molecular basis of cancer is crucial for controlling and treating the disease. 5. Cancer is caused by genetic mutations and epigenetic changes that affect key genes regulating cellular processes. 6. Genetic alterations in cancer cells are heritable and subject to Darwinian selection, leading to the dominance of cells with advantageous mutations. 7. Mutations and epigenetic alterations give cancer cells certain properties known as cancer hallmarks, which determine their behavior and response to therapies. 8. Basic research has revealed cellular and molecular abnormalities underlying cancer, leading to advancements in diagnosis and treatment. 9. Neoplasia refers to abnormal growth of cells that continue to replicate independently of normal regulatory influences. 10. Tumors are classified as benign or malignant based on their potential clinical behavior, with benign tumors remaining localized and malignant tumors invading adjacent structures and spreading to distant sites. 1. Benign and malignant tumors can be distinguished based on differentiation, growth rate, invasiveness, and spread. 2. Benign tumors resemble the tissue of origin and are well differentiated, while malignant tumors are poorly or undifferentiated. 3. Benign tumors grow slowly, while malignant tumors grow faster. 4. Benign tumors have a capsule and are well circumscribed, while malignant tumors invade surrounding tissues. 5. Benign tumors remain localized, while malignant tumors are locally invasive and metastasize to distant sites. 6. Cancer incidence varies with age, geography, and genetic background. 7. Environmental factors like infectious agents, smoking, alcohol, diet, obesity, reproductive history, and carcinogen exposure contribute to cancer risk. 8. Chronic inflammation and hormonal stimulation increase the risk of cancer in certain tissues. 9. Morphologic changes in epithelial cells may indicate an increased risk of cancer (precursor lesions). 10. The risk of developing cancer is influenced by interactions between environmental exposures and genetic variants. 11. Mutations in cancer cells can be driver mutations (pathogenic) or passenger mutations (neutral). 12. Passenger mutations can become driver mutations under selective pressure, such as treatment with effective drugs. 13. Tumor cells acquire driver mutations through point mutations and chromosomal abnormalities. 14. Gene rearrangements lead to overexpression of oncogenes or generation of fusion proteins. 15. Deletions often affect tumor suppressor genes, while gene amplification increases expression of oncogenes. 16. Dysregulation of miRNAs (microRNAs) can contribute to carcinogenesis. 17. Epigenetic changes can silence tumor suppressor genes and DNA repair genes. 18. Proto-oncogenes are normal cellular genes that promote cell proliferation. 19. Oncogenes are mutant or overexpressed versions of proto-oncogenes that function autonomously. 20. Oncoproteins promote uncontrolled cell proliferation through various mechanisms. 21. RAS mutations commonly occur in human cancers, leading to unchecked signaling. 22. Overproduction or unregulated activity of transcription factors promotes cell proliferation. 23. Translocation of MYC gene leads to overexpression and unregulated expression of target genes controlling cell cycling and survival. 24. Mutations activate cyclin genes or inactivate negative regulators, driving uncontrolled cell cycle progression. 25. Mutations in cyclins, CDKs (cyclin-dependent kinases), and CDK inhibitors contribute to various cancers. 26. Both copies of RB gene must be dysfunctional for tumor development. 27. RB controls the G1-to-S transition of the cell cycle and arrests cells in G1. 28. Loss of cell cycle control is fundamental to malignant transformation in most cancers. 29. Oncogenic DNA viruses can disable RB by encoding proteins that bind to it. 30. TP53 (p53) is activated by cellular stress and controls cell cycle arrest, DNA repair, senescence, and apoptosis. 31. TP53 mutations are found in 70% of human tumors. 32. Li-Fraumeni syndrome patients inherit one defective copy of TP53 and have an increased risk of developing various tumors. 33. Oncogenic DNA viruses can incapacitate p53 by binding to it. 1. TGF-β inhibits cell proliferation by activating growth-inhibiting genes and suppressing growth- promoting genes. 2. TGF-β function is compromised in many tumors due to mutations in its receptors or inactivation of SMAD genes. 3. E-cadherin maintains contact inhibition, which is lost in malignant cells. 4. The APC gene regulates the destruction of β-catenin, a growth-promoting transcription factor. 5. Loss of APC leads to the accumulation of β-catenin in the nucleus, promoting cell growth. 6. In familial adenomatous polyposis syndrome, mutations in the APC gene result in the development of colonic polyps and eventual colon cancer. 7. Warburg metabolism favors glycolysis over oxidative phosphorylation and is induced by certain driver mutations. 8. Many oncoproteins induce or contribute to Warburg metabolism, while tumor suppressors oppose it. 9. Stress-induced autophagy can be evaded or corrupted by cancer cells to provide nutrients for growth and survival. 10. Mutated IDH can cause the formation of oncometabolites that alter the epigenome, leading to oncogenic gene expression changes. 11. Cancer cells evade cell death through abnormalities in the intrinsic pathway of apoptosis, such as loss of p53 function. 12. Overexpression of anti-apoptotic proteins like BCL2 protects cancer cells from apoptosis. 13. Follicular B-cell lymphomas often have high levels of BCL2 due to a specific translocation. 14. Inhibitors of MDM2 and BCL2 family members are being developed as therapeutic agents to induce cancer cell death. 15. Telomerase activation allows tumor cells to maintain telomere length and avoid mitotic catastrophe. 16. Vascularization of tumors is controlled by angiogenic and anti-angiogenic factors produced by tumor and stromal cells. 17. Hypoxia triggers angiogenesis through the action of HIF-1α on VEGF transcription. 18. Various factors, including p53, RAS, MYC, and MAPK signaling, regulate angiogenesis. 19. Tumor invasion involves loosening of cell-cell contacts, degradation of the extracellular matrix (ECM), attachment to novel ECM components, and migration of tumor cells. 20. Inactivation of E-cadherin leads to loss of cell-cell contacts in tumor cells. 21. Proteolytic enzymes secreted by tumor and stromal cells degrade the ECM and release growth factors. 22. Metastatic sites can be predicted based on the location of the primary tumor, and some tumors show organ tropism. 23. The immune system can recognize tumor cells as non-self and destroy them. 24. Antitumor activity is mediated by cell-mediated mechanisms, with tumor antigens presented on MHC class I molecules and recognized by CD8+ CTLs. 25. Tumor antigens can include products of mutated genes, overexpressed proteins, and antigens produced by oncogenic viruses. 26. Immunosuppressed patients have an increased risk of cancer, particularly virus-induced cancers. 27. Tumors can evade the immune system through selective outgrowth of antigen-negative variants, reduced expression of histocompatibility molecules, and immunosuppressive factors. 28. TGF-β and PD-1 ligands are examples of immunosuppressive factors expressed by tumor cells. 1. Inherited mutations in DNA repair genes increase the risk of cancer development. 2. Patients with HNPCC syndrome have defects in the mismatch repair system, leading to colon carcinomas and microsatellite instability. 3. Xeroderma pigmentosum patients have a defect in the nucleotide excision repair pathway, making them susceptible to skin cancers induced by UV light. 4. Syndromes like Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia, as well as mutations in BRCA1 and BRCA2, are associated with defects in the homologous recombination DNA repair system and increased sensitivity to DNA-damaging agents. 5. Mutations in genes involved in genomic instability, such as RAG1, RAG2, and AID, play a role in the development of lymphoid neoplasms. 6. Chemical carcinogens can directly damage DNA and lead to mutations and cancer. 7. Carcinogens can be direct-acting agents or require metabolic conversion to become carcinogenic. 8. Tumorigenesis can be enhanced by exposure to promoters that stimulate the proliferation of mutated cells. 9. Examples of human carcinogens include alkylating agents, benzo(a)pyrene, azo dyes, aflatoxin, and tumor promoters. 10. Ionizing radiation can cause chromosome breakage, rearrangements, and point mutations, contributing to carcinogenesis. 11. UV radiation induces the formation of pyrimidine dimers in DNA, leading to skin cancers. 12. HTLV-1 is a retrovirus associated with T cell leukemia, and its viral protein Tax promotes cell proliferation and survival. 13. HPV is associated with benign warts and cervical cancer, and its oncoproteins E6 and E7 bind to tumor suppressors p53 and RB, respectively. 14. High-risk strains of HPV have oncoproteins with higher affinity for their targets than low-risk strains. 15. EBV is implicated in the development of Burkitt lymphomas, Hodgkin lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and certain sarcomas. 16. EBV gene products stimulate B-cell proliferation pathways and compromise immune competence, leading to the development of lymphoma. 17. Immunosuppressed patients have an increased risk of cancer, particularly virus-induced cancers. 18. Polymorphisms of endogenous enzymes like cytochrome P-450 can influence carcinogenesis by altering the conversion of indirect-acting carcinogens to active carcinogens. 19. Exposure to promoters can stimulate cell proliferation and enhance the effects of mutagens or initiators in tumorigenesis. 20. Tumor promoters act by stimulating cell proliferation directly or through tissue injury and regenerative repair. 21. HPV oncoproteins E6 and E7 neutralize the tumor suppressors p53 and RB, respectively, contributing to oncogenicity. 22. UV radiation induces the formation of pyrimidine dimers in DNA, leading to mutations and skin cancers. 23. HTLV-1 viral protein Tax enhances cell proliferation, survival, and interferes with cell cycle controls, increasing the risk of T-cell leukemia. 24. EBV gene products stimulate B-cell proliferation pathways and compromise immune competence, leading to lymphoma development. 25. Immunosuppressed individuals have a higher risk of virus-induced cancers. 1. HBV and HCV infections are responsible for 70-85% of hepatocellular carcinomas worldwide. 2. Chronic inflammation, hepatocellular injury, and reactive oxygen species production contribute to the oncogenic effects of HBV and HCV. 3. HBx protein of HBV and HCV core protein activate signal transduction pathways involved in carcinogenesis. 4. H. pylori infection is implicated in gastric adenocarcinoma and MALT lymphoma. 5. H. pylori-induced gastric cancers result from chronic inflammation, gastric cell proliferation, and DNA damage caused by reactive oxygen species. 6. H. pylori pathogenicity genes, including CagA, may stimulate growth factor pathways contributing to gastric cancer development. 7. H. pylori infection leads to polyclonal B-cell proliferations, eventually resulting in monoclonal B-cell tumors (MALT lymphoma) due to accumulated mutations. 8. Cachexia, characterized by progressive weight loss, weakness, anorexia, and anemia, is caused by cytokines released by the tumor or host. 9. Paraneoplastic syndromes occur due to the ectopic production and secretion of bioactive substances by tumors, causing systemic symptoms unrelated to tumor spread or appropriate hormones. 10. Tumor grading is based on cytologic appearance and reflects differentiation and aggressiveness. 11. Tumor staging assesses tumor extent based on size, lymph node involvement, and distant metastases and is more clinically relevant than grading. 12. Tumor markers like PSA can be used for population cancer screening and monitoring recurrence after treatment. 13. Molecular analyses aid in diagnosis, prognosis, detection of minimal residual disease, and identification of hereditary cancer predisposition. 14. Molecular profiling of tumors through RNA expression, DNA sequencing, and copy number analysis helps in stratification for targeted treatment and prognostication. 15. Various sampling approaches, including excision, biopsy, fine-needle aspiration, and cytologic smears, are used for tumor diagnosis, while immunohistochemistry and flow cytometry assist in classification based on distinct protein expression patterns. 1. Differentiated cells have distinct structures and functions regulated by epigenetic modifications and lineage-specific gene expression programs. 2. The cytoskeleton, composed of proteins, plays a crucial role in maintaining cell shape, polarity, and movement. 3. Cells communicate and interact with each other through junctions, facilitating mechanical links and receptor-ligand recognition. 4. Intercellular signaling is important for embryonic development, tissue organization, and adaptive responses to threats. 5. Loss of cellular communication can lead to unregulated growth (cancer) or ineffective responses to stress. 6. Cells receive signals from pathogens, damaged cells, cell-cell contacts, cell-ECM contacts, and secreted molecules. 7. Signaling pathways are complex and involve multiple primary and secondary effects, contributing to the final biological response. 8. Signaling can result in enzyme activation or inactivation, nuclear or cytoplasmic localization of transcription factors, and actin polymerization or depolymerization, among other effects. 9. Transcription factors are activated or inactivated by signaling pathways, influencing gene expression. 10. Feedback inhibitory or stimulatory loops can be activated as part of signaling pathways. 1. The completion of the Human Genome Project revealed that humans have around 25,000 protein- coding genes, fewer than previously estimated. 2. Next-generation sequencing technologies enable rapid and cost-effective sequencing of the human exome, facilitating personalized medicine in the treatment of genetic diseases. 3. Hereditary disorders are transmitted through generations, while congenital diseases are present at birth, but not all congenital diseases are genetic. 4. Genetic abnormalities can affect protein structure and function, disrupting cellular homeostasis and contributing to disease. 5. Mutations in protein-coding genes can result in point mutations, frameshift mutations, or trinucleotide repeat mutations. 6. Structural variations, such as copy number changes or translocations, can also alter protein-coding genes and affect protein function. 7. Alterations in non-coding RNAs, such as microRNAs and long non-coding RNAs, play important regulatory roles in gene expression. 8. Genetic disorders can be categorized into Mendelian disorders, complex disorders, diseases arising from chromosomal abnormalities, and other genetic diseases with non-classic inheritance patterns. 9. Mendelian disorders result from mutations in single genes and show high penetrance. 10. Complex disorders involve multiple genes and environmental influences, while diseases arising from chromosomal abnormalities result from changes in chromosome number or structure. 1. Autosomal dominant disorders affect males and females equally and can be transmitted by both sexes. 2. Autosomal dominant disorders often involve dysfunctional receptors and structural proteins. 3. Autosomal recessive diseases occur when both copies of a gene are mutated and frequently involve enzymes. Males and females are affected equally. 4. X-linked disorders are transmitted by heterozygous females to their sons, while female carriers are usually unaffected due to random inactivation of one X chromosome. 5. Marfan syndrome is caused by a mutation in the FBN1 gene, affecting connective tissues and activation of TGF-β. Clinical features include skeletal, ocular, and cardiovascular abnormalities. 6. Prevention of cardiovascular disease in Marfan syndrome involves drugs that lower blood pressure and inhibit TGF-β signaling. 7. There are six variants of Ehlers-Danlos syndrome (EDS), each caused by a distinct mutation affecting collagen synthesis or assembly. Clinical features include fragile skin, hypermobile joints, and organ ruptures. 8. Familial hypercholesterolemia is an autosomal dominant disorder caused by mutations in the gene encoding the LDL receptor or PCSK9. It results in elevated serum cholesterol and increased risk of atherosclerosis. 9. Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene, leading to chloride ion transport defects. It affects multiple organs, with cardiopulmonary complications being the most common cause of death. 10. CFTR mutations can result in severe or mild disease manifestations, and molecular therapies targeting mutant CFTR protein can be beneficial. 11. Phenylketonuria (PKU) is an autosomal recessive disorder caused by a lack of the enzyme phenylalanine hydroxylase. Untreated PKU can lead to severe mental retardation and other clinical features. 12. PKU can be managed by restricting the intake of phenylalanine in the diet. 13. Female patients with PKU who discontinue dietary treatment can give birth to children with malformations and neurologic impairment due to transplacental passage of phenylalanine metabolites. 1. Galactosemia is an autosomal recessive disorder caused by a lack of the GALT enzyme, resulting in the accumulation of galactose-1-phosphate and its metabolites in tissues. 2. Clinical features of galactosemia include jaundice, liver damage, cataracts, neural damage, vomiting and diarrhea, and E. coli sepsis. Dietary restriction of galactose can prevent severe complications. 3. Tay-Sachs disease is caused by the inability to metabolize GM2 gangliosides due to a lack of the β subunit of lysosomal hexosaminidase. It leads to severe mental retardation, blindness, motor weakness, and early death. 4. Niemann-Pick disease types A and B result from a deficiency of sphingomyelinase. In type A, sphingomyelin accumulation in the nervous system causes neuronal damage, while type B does not involve neuronal damage. 5. Niemann-Pick disease type C is caused by a defect in cholesterol transport, leading to the accumulation of cholesterol and gangliosides in the nervous system. It presents with ataxia, dysarthria, and psychomotor regression. 6. Gaucher disease is characterized by a lack of the lysosomal enzyme glucocerebrosidase, resulting in the accumulation of glucocerebroside in mononuclear phagocytic cells. Clinical features vary depending on the type, with hepatosplenomegaly and bone erosion being common in type 1. 7. Mucopolysaccharidoses (MPSs) involve the accumulation of mucopolysaccharides in various tissues. Coarse facial features are a common manifestation, and specific subtypes like Hurler syndrome and Hunter syndrome have distinct clinical presentations. 8. Inherited deficiencies of enzymes involved in glycogen metabolism can result in the storage of glycogen in different tissues. Von Gierke disease leads to hepatic glycogen storage due to a lack of hepatic glucose-6-phosphatase. 9. McArdle disease is a myopathic form of glycogen storage disease caused by a lack of muscle phosphorylase, resulting in storage in skeletal muscles and exercise-induced cramps. 10. Pompe disease is characterized by a lack of lysosomal acid maltase, affecting multiple organs, with heart involvement being predominant. 11. Down syndrome is caused by an extra copy of genes on chromosome 21, typically due to trisomy 21. It presents with severe mental retardation, facial abnormalities, cardiac malformations, higher risk of leukemia and infections, and early-onset Alzheimer's disease. 12. Deletion of genes at chromosomal locus 22q11.2 leads to malformations affecting the face, heart, thymus, and parathyroids, resulting in DiGeorge syndrome and velocardiofacial syndrome. 13. Lyon hypothesis states that in females, one X chromosome, either maternal or paternal, is randomly inactivated during development. 14. Klinefelter syndrome is characterized by the presence of two or more X chromosomes and one Y chromosome due to sex chromosome nondisjunction. It leads to testicular atrophy, sterility, reduced body hair, gynecomastia, and eunuchoid body habitus. 15. Turner syndrome involves partial or complete monosomy of genes on the short arm of the X chromosome, commonly caused by the absence of one X chromosome (45,X) or mosaicism. Clinical features include short stature, webbing of the neck, cardiovascular malformations, amenorrhea, lack of secondary sex characteristics, and fibrotic ovaries. 1. Pathologic amplification of trinucleotide repeats can cause neurodegenerative disorders like fragile X syndrome and Huntington disease. 2. Fragile X syndrome is characterized by mental retardation, macroorchidism, and abnormal facial features due to the loss of FMR1 gene function. 3. Fragile X syndrome occurs when the FMR1 gene expands from 52-200 CGG repeats to over 4000 repeats during oogenesis. 4. Fragile X tremor/ataxia can develop in individuals with FMR1 gene premutations and leads to abnormal neuronal function. 5. Imprinting involves the silencing of certain genes during gametogenesis, and diseases can result from the loss of the functional allele through deletions. 6. Prader-Willi syndrome is caused by the deletion of the paternal chromosomal region 15q12 and is characterized by mental retardation, short stature, obesity, and hypogonadism. 7. Angelman syndrome is caused by the deletion of the maternal chromosomal region 15q12 and is characterized by mental retardation, ataxia, seizures, and inappropriate laughter. 8. Congenital anomalies can result from genetic, environmental, or multifactorial causes. 9. The timing of in utero insults influences the extent of congenital anomalies, with earlier events having a greater impact. 10. Neonatal respiratory distress syndrome (RDS) occurs in premature infants due to insufficient pulmonary surfactant. 11. RDS can be treated with steroids, surfactant therapy, and improved ventilation techniques, but long-term sequelae include retinopathy of prematurity and bronchopulmonary dysplasia. 12. Sudden infant death syndrome (SIDS) is the unexplained sudden death of infants and is likely due to delayed development of arousal reflexes and cardiorespiratory control. 13. Prone sleeping position is a recognized risk factor for SIDS, and the "Back to Sleep" program has reduced its incidence. 14. Fetal hydrops refers to the accumulation of edema fluid in the fetus, and causes can be nonimmune (chromosomal abnormalities, cardiovascular defects) or immune (less common due to Rh antibody prophylaxis). 15. Erythroblastosis fetalis, characterized by circulating immature erythroid precursors, is associated with fetal anemia-related hydrops. 16. Neuroblastomas and related tumors arise from neural crest-derived cells in the sympathetic ganglia and adrenal medulla. 17. Prognostic factors for neuroblastomas include age, stage, MYCN amplification, and ploidy. 18. Wilms tumor is the most common renal neoplasm in childhood. 19. Denys-Drash syndrome, Beckwith-Wiedemann syndrome, and WAGR syndrome are associated with an increased risk of Wilms tumor. 20. Wilms tumor has morphologic components including blastema, epithelial, and stromal elements. 21. Nephrogenic rests are precursor lesions of Wilms tumors. 22. Mutations in the RAS-MAP kinase pathway are common in relapsed neuroblastomas. 23. Neuroblastomas secrete catecholamines, and their metabolites can be used for screening patients. 24. Wilms tumor and other childhood neoplasms can be associated with specific genetic syndromes involving WT1 and IGF2 genes. 1. Many diseases are influenced by environmental factors, including the air, food, water, and toxic agents people are exposed to in various settings. 2. The personal environment, including factors like tobacco use, alcohol ingestion, drug consumption, and diet, can have a significant impact on human health. 3. Environmental diseases are caused by exposure to chemical or physical agents in the ambient, workplace, and personal environments. 4. Work-related illnesses are a major cause of global mortality, exceeding road accidents and wars combined. 5. Environmental diseases create a heavy burden on individuals and societies, particularly in developing countries. 6. Major disasters and chronic exposure to contaminants can lead to environmental diseases, while malnutrition is also a pervasive issue, with millions of people affected. 7. Toxicology studies the effects of toxic agents, including chemicals and physical agents, on health. 8. The metabolism and distribution of xenobiotics (exogenous chemicals) in the body play a role in their toxicity. 9. The cytochrome P-450 system is an important cellular enzyme system involved in the metabolism of xenobiotics. 10. Air pollution, both outdoor and indoor, is a significant cause of morbidity and mortality, affecting various organ systems, particularly the lungs. Summary: 1. Environmental diseases result from exposure to chemical or physical agents in various environments. 2. Xenobiotics, exogenous chemicals, can enter the body through inhalation, ingestion, and skin contact, and can be eliminated or accumulate in tissues. 3. Xenobiotics can be converted into nontoxic or toxic compounds through the cytochrome P-450 system. 4. Common air pollutants include ozone, sulfur dioxide, acid aerosols, and particulate matter. 5. Carbon monoxide (CO) is a deadly air pollutant that binds to hemoglobin and causes systemic asphyxiation. 6. Heavy metals like lead, mercury, arsenic, and cadmium have toxic effects on humans. 7. Smoking is the most preventable cause of death and is linked to various cancers and diseases. 8. Alcohol abuse leads to liver damage, cardiovascular issues, pancreatitis, and increased cancer risk. 9. Therapeutic drugs and nontherapeutic agents can cause drug injuries, with examples including anti- neoplastic agents, antibiotics, HRT, OCs, acetaminophen, and aspirin. 10. Drug abuse involves substances like sedative-hypnotics, psychomotor stimulants, opioids, hallucinogens, and cannabinoids. 11. Ionizing radiation can damage cells, DNA, and vascular structures, leading to various health problems, including increased cancer risk. 12. Severe acute malnutrition (SAM) is a leading cause of childhood deaths, with marasmus and kwashiorkor as primary SAM syndromes. 13. Secondary SAM occurs in chronically ill patients and those with advanced cancer. 14. Anorexia nervosa is self-induced starvation, while bulimia involves food binges and induced vomiting. 15. Vitamins A, D, C, and B family members have important roles in the body, and deficiencies can lead to specific syndromes. 1. Obesity is a disorder of energy regulation and increases the risk of insulin resistance, type 2 diabetes, hypertension, hypertriglyceridemia, and coronary artery disease. 2. Energy balance regulation involves a complex system with afferent signals (insulin, leptin, ghrelin, peptide YY), the central hypothalamic system, and efferent signals. 3. Leptin, regulated by fat stores, plays a crucial role in energy balance by reducing food intake and stimulating specific neurons in the hypothalamus. 4. Obesity is also associated with an increased risk of certain cancers, nonalcoholic fatty liver disease, and gallstones. 1. Infectious diseases remain a significant health problem globally, even with available vaccines and antibiotics. Influenza and pneumonia are among the leading causes of death in the United States. 2. Low-income countries face a high burden of infectious diseases due to limited access to healthcare, unsanitary living conditions, and malnutrition. Lower-respiratory infections, HIV/AIDS, diarrheal diseases, malaria, and tuberculosis are major causes of death in these countries. 3. Prions are abnormal forms of a host protein that cause transmissible spongiform encephalopathies. They include diseases like kuru, Creutzfeldt-Jakob disease (CJD), and bovine spongiform encephalopathy (mad cow disease). 4. Viruses are obligate intracellular parasites that rely on the host cell's machinery for replication. They can cause transient illnesses, persist in the body, or be involved in tumor transformation. 5. Bacteria are prokaryotes with cell walls made of peptidoglycan. They can be classified as gram- positive or gram-negative based on their cell wall structure. Bacteria can be motile, possess pili, and grow extracellularly or intracellularly. 6. Bacterial infections range from common pharyngitis and urinary tract infections to rare diseases like leprosy. Obligate intracellular bacteria like Chlamydia and Rickettsia replicate inside host cells and cause specific pathologies. 7. Chlamydia trachomatis can lead to female sterility and blindness, while Rickettsiae can cause hemorrhagic vasculitis and central nervous system damage. 8. Bacteria of the genus Mycoplasma and Ureaplasma lack a cell wall and are among the smallest free- living organisms. 9. Infectious diseases disproportionately affect children, older adults, individuals with chronic diseases, and those with immunodeficiency states or receiving immunosuppressive drugs. 10. Infections result from a diverse range of infectious agents, including prions, viruses, and bacteria, each with unique characteristics, modes of replication, and clinical manifestations. 1. Infections can be transmitted through contact, respiratory droplets, the fecal-oral route, sexual transmission, vertical transmission, or insect/arthropod vectors. 2. Pathogens can establish infections by overcoming normal host defenses or when host defenses are compromised. 3. Host defenses against infection include the skin, respiratory system, gastrointestinal system, and urogenital tract. 4. Diseases caused by microbes involve a combination of microbial virulence and host responses. 5. Microorganisms can cause cell death or dysfunction by directly interacting with the cell or releasing bacterial products. 6. The absence of an immune response or immunocompromise can affect the severity of infections. 7. Chronic immunological and inflammatory diseases and cancer can be associated with specific microorganisms. 8. Infectious microorganisms must evade host immune mechanisms to proliferate and be transmitted. 9. Strategies include antigenic variation, inactivating antibodies or complement, resisting phagocytosis, escaping the phagosome, viral latency, and suppressing the host adaptive immune response. 10. Host responses to different classes of microbes can help identify possible causal organisms. 11. Neutrophil-rich acute suppurative inflammation is typical of infections with many bacteria and some fungi. 12. Mononuclear cell infiltrates are common in chronic infections and some acute viral infections. 13. Granulomatous inflammation is characteristic of infections with Mycobacterium tuberculosis and certain fungi. 14. Some viruses cause cytopathic and proliferative lesions. 15. Necrosis can result from tissue-damaging toxins produced by certain microbes. 16. Chronic inflammation and scarring are common in many infections. 1. Anemia can be caused by blood loss, increased red cell destruction, or decreased red cell production. 2. Different types of anemia have specific morphologies, such as microcytic, macrocytic, or normocytic with abnormal shapes. 3. Clinical manifestations of anemia can include shortness of breath, organ failure, pallor, fatigue, jaundice, gallstones, iron overload, and bone deformities. 4. Thalassemia is an autosomal codominant disorder that results in microcytic, hypochromic anemia due to reduced hemoglobin synthesis. 5. Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency is an X-linked disorder that makes red cells susceptible to oxidant damage. 6. Immunohemolytic Anemia is caused by antibodies against red cell constituents or antigens modified by haptens. 7. Malaria is an intracellular red cell parasite that causes chronic hemolysis and can be fatal, especially in Falciparum malaria. 8. Hereditary Spherocytosis is an autosomal dominant disorder characterized by loss of red cell membrane, resulting in anemia and splenomegaly. 9. Sickle Cell Anemia is an autosomal recessive disorder where deoxygenated hemoglobin self- associates into long polymers, causing distorted red cells, pain crises, tissue infarction, and hemolytic anemia. 10. Anemia of Diminished Erythropoiesis includes conditions like iron deficiency anemia, anemia of chronic inflammation, megaloblastic anemia, aplastic anemia, and myelophthisic anemia. 11. Iron Deficiency Anemia is caused by chronic bleeding or inadequate iron intake, resulting in insufficient hemoglobin synthesis and microcytic red cells. 12. Anemia of Chronic Inflammation is caused by inflammatory cytokines that sequester iron in macrophages and suppress erythropoietin production. 13. Megaloblastic Anemia is caused by deficiencies of folate or vitamin B12, leading to inadequate thymidine synthesis and defective DNA replication. 14. Aplastic Anemia is caused by bone marrow failure and can result from various causes, including exposure to toxins, drugs, viruses, and inherited defects. 15. Myelophthisic Anemia is caused by the replacement of bone marrow by infiltrative processes such as metastatic carcinoma and granulomatous disease. 16. Lymphoid neoplasms are classified based on the cell of origin and stage of differentiation. 17. Acute Lymphoblastic Leukemia/Lymphoma is a highly aggressive tumor that blocks differentiation and accumulates immature blasts. 18. Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia is a mature B cell tumor that commonly involves bone marrow and lymph nodes. 19. Follicular Lymphoma is a tumor that resembles the growth pattern of normal germinal center B cells and is often associated with a specific translocation. 1. Mantle Cell Lymphoma is a mature B cell tumor that often presents with advanced disease involving lymph nodes, bone marrow, and extranodal sites. 2. Extranodal Marginal Zone Lymphoma is a mature B cell tumor that arises at extranodal sites affected by chronic inflammation due to autoimmunity or infection. 3. Diffuse Large B Cell Lymphoma is a heterogeneous group of mature B cell tumors that share large cell morphology and aggressive clinical behavior. 4. Burkitt Lymphoma is a highly aggressive mature B cell tumor that usually arises at extranodal sites and is associated with translocations involving the MYC proto-oncogene. 5. Multiple Myeloma is a plasma cell tumor characterized by multiple lytic bone lesions, pathologic fractures, and hypercalcemia. 6. Hodgkin Lymphoma is an unusual B cell tumor consisting mostly of reactive lymphocytes, macrophages, and stromal cells. 7. Acute Myeloid Leukemia (AML) is an aggressive tumor comprised of immature myeloid lineage blasts that replace the bone marrow and suppress normal hematopoiesis. 8. Myelodysplastic Syndromes (MDS) are myeloid tumors characterized by disordered and ineffective hematopoiesis that may progress to AML. 9. Myeloproliferative Neoplasms are myeloid tumors in which the production of formed myeloid elements is initially increased, leading to high blood counts and extramedullary hematopoiesis. 10. Disseminated Intravascular Coagulation is a syndrome in which systemic activation of coagulation leads to consumption of coagulation factors and platelets. 11. Immune Thrombocytopenic Purpura is caused by autoantibodies against platelet antigens and can be triggered by various factors. 12. Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome both manifest with thrombocytopenia, microangiopathic hemolytic anemia, and renal failure, but TTP is more commonly associated with fever and CNS involvement. 13. von Willebrand Disease is an autosomal dominant bleeding disorder caused by mutations in vWF, affecting platelet adhesion. 14. Hemophilia A is an X-linked disorder caused by mutations in factor VIII, leading to severe bleeding into soft tissues and joints. 15. Hemophilia B is an X-linked disorder caused by mutations in coagulation factor IX, presenting clinically identical to hemophilia A. 16. Mantle Cell Lymphoma is associated with an (11;14) translocation, resulting in cyclin D1 overexpression. 17. Extranodal Marginal Zone Lymphoma often remains localized for long periods and may regress if the inflammatory stimulus is removed. 18. Diffuse Large B Cell Lymphoma is often associated with rearrangements or mutations of the BCL6 gene and a translocation involving BCL2. 19. Burkitt Lymphoma is nearly always associated with translocations involving the MYC proto- oncogene and may be latently infected by EBV. 20. Multiple Myeloma is characterized by neoplastic plasma cells that suppress normal humoral immunity and secrete nephrotoxic immunoglobulins. 21. Hodgkin Lymphoma consists mostly of reactive lymphocytes, macrophages, and stromal cells, with malignant Reed-Sternberg cells making up a minor part. 22. AML is an aggressive tumor associated with acquired mutations that interfere with myeloid differentiation. 23. MDS is characterized by disordered and ineffective hematopoiesis, often progressing to AML. 24. Myeloproliferative Neoplasms are associated with acquired mutations that lead to constitutive activation of tyrosine kinases, mimicking signals from normal growth factors. 1. The endocrine system consists of organs that work together to maintain metabolic equilibrium. 2. Hormones are molecules secreted by the endocrine system that act on target cells. 3. Hormones can be carried by the blood to reach their target tissues. 4. Hormones can bind to cell surface receptors or intracellular receptors. 5. Hormones that bind to cell surface receptors increase intracellular second messengers and can affect cell function. 6. Lipid-soluble hormones can pass through the plasma membrane and bind to intracellular receptors, affecting gene expression. 7. Endocrine diseases can be caused by underproduction or overproduction of hormones, end-organ resistance, or neoplasms. 8. The pituitary gland is a small structure connected to the hypothalamus and plays a central role in regulating other endocrine glands. 9. The pituitary gland has an anterior lobe and a posterior lobe, and diseases can affect either lobe. 10. Pituitary adenomas are the most common cause of pituitary disorders, and they can be functional or nonfunctioning. 1. The most common cause of hyperpituitarism is an anterior lobe pituitary adenoma. 2. Pituitary adenomas can be macroadenomas or microadenomas, and they can be functional or nonfunctioning. 3. Macroadenomas may cause visual disturbances due to mass effects. 4. Functional adenomas have distinct endocrine signs and symptoms. 5. Mutation of the GNAS gene is a common genetic alteration in pituitary adenomas. 6. Prolactinomas cause amenorrhea, galactorrhea, loss of libido, and infertility. 7. Growth hormone adenomas cause gigantism in children and acromegaly in adults, along with impaired glucose tolerance and diabetes mellitus. 8. Corticotroph cell adenomas cause Cushing syndrome and hyperpigmentation. 9. Pituitary adenomas, including nonfunctioning adenomas, may be associated with mass effects and hypopituitarism. 10. Hashimoto thyroiditis is the most common cause of hypothyroidism in regions with sufficient dietary iodine levels. 11. Hashimoto thyroiditis is an autoimmune disease characterized by the progressive destruction of thyroid parenchyma. 12. Multiple autoimmune mechanisms contribute to thyroid injury in Hashimoto disease. 13. Subacute granulomatous thyroiditis is a self-limited disease associated with pain and granulomatous inflammation in the thyroid. 14. Subacute lymphocytic thyroiditis often occurs after pregnancy, is painless, and is characterized by lymphocytic inflammation in the thyroid. 15. Graves disease is the most common cause of endogenous hyperthyroidism and is characterized by thyrotoxicosis, ophthalmopathy, and dermopathy. 16. Graves disease is an autoimmune disorder caused by autoantibodies to the TSH receptor. 17. Most thyroid neoplasms manifest as solitary nodules, but only a small percentage are neoplastic. 18. Follicular adenomas are the most common benign neoplasms, while papillary carcinoma is the most common malignancy. 19. Various genetic mutations are involved in thyroid carcinogenesis. 20. Follicular adenomas and carcinomas are composed of well-differentiated follicular epithelial cells, with carcinomas showing invasion. 21. Papillary carcinomas are recognized by nuclear features and have a good prognosis. 22. Anaplastic carcinomas are aggressive and have a poor prognosis. 23. Medullary cancers arise from parafollicular C cells and can be sporadic or familial. 24. Primary hyperparathyroidism is the most common cause of asymptomatic hypercalcemia. 25. Most cases of primary hyperparathyroidism are caused by a sporadic parathyroid adenoma. 26. Skeletal and renal manifestations are common in hyperparathyroidism. 27. Secondary hyperparathyroidism is caused by hypercalcemia secondary to renal failure. 28. Malignancies are an important cause of symptomatic hypercalcemia. 29. Symptomatic hypercalcemia can result from osteolytic metastases or the release of PTH-related protein from nonparathyroid tumors. 30. Routine blood testing can detect hypercalcemia in most cases of hyperparathyroidism, even if they are clinically silent. 1. Type 1 diabetes is an autoimmune disease characterized by the destruction of islet beta cells, resulting in absolute insulin deficiency. 2. Type 2 diabetes is caused by insulin resistance and beta cell dysfunction, leading to relative insulin deficiency. It is not associated with autoimmunity. 3. Obesity is closely related to insulin resistance and type 2 diabetes due to factors such as excess free fatty acids, abnormal adipokine levels, and inflammation in adipose tissue. 4. Monogenic forms of diabetes are rare and caused by single-gene defects affecting beta cell function or insulin signaling. 5. Long-term complications of diabetes, including vascular, renal, neurological, and ocular complications, are attributed to the formation of AGEs, activation of PKC, and disturbances in polyol pathways leading to oxidative stress. 6. The most common cause of hypercortisolism is the exogenous administration of steroids. 7. Endogenous hypercortisolism is most often caused by ACTH-producing pituitary microadenomas (Cushing's disease), primary adrenal neoplasms, or paraneoplastic ACTH production by tumors. 8. Morphological features in the adrenal gland associated with hypercortisolism include bilateral cortical atrophy, diffuse or nodular hyperplasia, or adrenocortical neoplasms. 9. Excess androgen secretion can occur due to adrenocortical neoplasms or congenital adrenal hyperplasia (CAH). 10. CAH is a group of autosomal recessive disorders characterized by defects in steroid biosynthesis, often caused by 21-hydroxylase deficiency. 11. Reduction in cortisol production in CAH leads to compensatory ACTH secretion, resulting in androgen excess and virilization effects. 12. Primary adrenocortical insufficiency can be acute (Waterhouse-Friderichsen syndrome) or chronic (Addison's disease). 13. Chronic adrenal insufficiency is commonly caused by autoimmune adrenalitis in the context of autoimmune polyendocrine syndromes. 14. Tuberculosis, opportunistic infections in HIV, and metastatic tumors are other important causes of chronic adrenal insufficiency. 15. Common symptoms of adrenal insufficiency include fatigue, weakness, gastrointestinal disturbances, and high ACTH levels with associated skin pigmentation. 16. Diabetes is characterized by the destruction of islet beta cells, while hypercortisolism is often caused by pituitary adenomas or adrenal neoplasms. 17. Obesity is closely related to insulin resistance and type 2 diabetes. 18. Monogenic forms of diabetes are caused by single-gene defects affecting beta cell function or insulin signaling. 19. Chronic adrenal insufficiency is commonly caused by autoimmune adrenalitis or infections such as tuberculosis. 20. Symptoms of adrenal insufficiency include fatigue, weakness, gastrointestinal disturbances, and skin pigmentation.