Advanced Pathophysiology Advanced Pathophysiology, Exams of Pathophysiology

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Advanced Pathophysiology Epidemiology and Cancer Risk Factors - TONSS Tobacco use Obesity Nutrition (fat, alcohol, fiber, calories) Sun exposure (skin cancer) Sexual exposure to HPV (cervical cancer) Worldwide variation of cancer - North and South America--> Prostate cancer Europe and Asia--> Lung and bronchus North America--> Breast cancer Hall marks of cancer - A TESIA GERD Activating invasion and metastasis Tumor promoting inflammation Evading growth suppressors Sustaining proliferative signaling Inducing angiogenesis Avoiding immune destruction Genomic instability (mutator phenotype) Enabling replicative immortality Resisting cell death Deregulating cellular energetics Hypermethylation - Inactivates transcription of DNA Chronic inflammatory states and cancer - Chronic inflammatory states and cancer- infiltrating cancers provoke a chronic inflammatory reaction, leading some to liken them to "wounds that do not heal." Can cause systemic signs and symptoms, such as anemia due to inflammation-induced sequestration of iron and downregulation of erythropoietin production, fatigue, and cachexia (described later). Direct effects of neoplasms - Include compression or invasion of vital structures and may cause typical pain pattern as well as dysfunction of the involved organ and obstruction of a conduit Indirect effects (Hormone or Peptide secretion) - are heterogeneous and poorly understood. Onset and clinical course are unpredictable. When affecting distant targets uninvolved by tumor, they are collectively termed as paraneoplastic syndromes. These effects are stereotypic syndromes resulting from the elaboration of peptide hormones or cytokines with specific biologic activity. The peptides secreted by a given neoplasm may reflect the tissue of origin or may be the result of activation of latent genes not normally expressed Electrolyte and fluid imbalance, flushing, wheezing, hypogly, hypocalcemia, hyponatremia Examples: SIADH--> small cell lung cancer (Free water and hyponatremia resulting in coma and death) ACTH--> can lead to Cushing syndrome with excessive adrenocorticosteroids, skin fragility, central redistribution of body fat, proximal myopathy with other features Cutaneous effects - GI, Lymphoma, myeloid leukemia GI Rashes, hyperkeratosis (abnormal thickening of the outer layer of the skin), hyperpigmentation in the skin folds, Acanthosis nigricans( dark velvety discoloration in body folds and creases), Leukemia Leser Trelat (of multiple seborrheic keratoses caused by an associated cancer and the rapid increase in their size and number.) Melanosis (skin darkening), skin bullae (blisters), sweet syndrome (painful lesions) Neurologic Effects - Lung - sensorimotor neuropathy, Guillain Barre syndrome (pins and needles), dementia, encephalitis, cerebellar degeneration Swelling, pain, and degeneration Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease — a disease in which the immune system attacks the body's own tissues. The attack occurs at the connection between nerve and muscle (the neuromuscular junction) and interferes with the ability of nerve cells to send signals to muscle cells. Nerve in the immune system attacks the calcium channels on the nerve endings that are required to trigger the release of chemicals. With fewer CA channels , the nerve endings releases less acetylcholine (which works to trigger muscle contraction Hematologic and Coagulopathic Effects - Typical Tumor Types: Adenocarcinomas Anemia, increase in platelets (thrombosis), granulocytes, thrombosis, coagulation Metabolic effects - BRCA1, BRCA2- Hereditary breast and ovarian cancer syndrome Autosomal Recessive Cancer Syndromes - Xeroderma pigmentosum-genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light Bloom syndrome- disorder characterized by a significantly increased risk of cancer and various other features. Signs and symptoms include short stature; sun-sensitive skin changes on the face, hands and/or arms; a high-pitched voice; and distinctive facial features including a long, narrow face, small lower jaw, large nose and prominent ears. Some affected individuals may also have learning disabilities; an increased risk of diabetes; chronic obstructive pulmonary disease (COPD); and recurrent infections of the upper respiratory tract, ears, and lungs during infancy Fanconi anemia-inherited blood disorder that leads to bone marrow failure Genes That Drive Cancer - Two classes of genes: proto-oncogenes and tumor suppressor genes Proto-oncogenes act like "gas pedals" to accelerate cell growth and division Tumor suppressor genes act like "brakes" to inhibit cell growth and division Proto-Oncogenes - Normal cellular genes that are essential for growth Transformed into oncogenes by activating (gain-of-function) mutations Proto-oncogenes may be -Growth factors -Growth factor receptors -Cytoplasmic signaling molecules -Nuclear transcription factors -Proteins involved in cell-cell or cell-matrix interactions Oncogenes--> when the brakes are hit too much in activating mutation--> not normal and cancer inducing Representative oncogenes activated in human tumors. - The epidermal growth factor receptor (EGFR) binds a number of extracellular ligands and in cooperation with its homolog HER2 signals proliferative and apoptotic pathways. Overactivity of EGFR or HER2 can lead to unregulated control of growth and apoptotic signaling. EGFR/HER2--> Breast, ovarian, gastric cancer, amplication EGFR or HER1 is mutated or amplified in nearly half of all glioblastomas is amplified in a fraction of breast cancers and other epithelial cancers, and is mutationally activated in a fraction of lung cancers RAS genes - Point mutations of RAS family genes constitute the most common type of abnormality involving proto-oncogenes in human tumors Tumor Suppressor Genes (ts) - -Contribute to cancer when inactive -Both copies of ts genes are inactivated when cancer develops -One can inherit a defective copy of tumor suppressor gene at much higher risk for cancer development -The two important ts genes are Rb and p53 Neoplasia p53- Guardian of genome - Most common tumor-suppressor gene defect identified in cancer cells -More than ½ of all types of human tumors lack functional p53 -p53 is a transcriptional factor for cell cycle and DNA repair genes p53 is a cellular stress monitor -Accumulates only after stress -Binds to damaged DNA and stalls division to allow for DNA repair -May direct cell to initiate apoptosis Cancer cells with mutant p53 are genetically unstable because they are unable to: Carry out efficient DNA repair Undergo apoptosis p53 - Activation of normal p53 by DNA damaging agents or by hypoxia leads to cell cycle arrest in G1 and induction of DNA repair by transcriptional upregulation of the cyclin dependent kinase inhibitor CDKN1A and GADD45 genes. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53 triggers either apoptiosis or senescence. In cells with loss or mutations of the p53 gene, DNA damage does not induce cell cycle arrest or DNA repair, and genetically damaged cells proliferate, giving rise eventuallly to malignant neoplasms Rb gene - -Normally "master brake" for the cell cycle -Blocks/stops cell division -An inactivating mutation of the Rb gene removes restraint on cell division and replication occurs -Defective Rb gene - common in some cancers - retinoblastoma, osteosarcoma, lung cancers The hypophosphorylated RB in complex with the EE2F transcription factors binds to DNA, recruits chromatin remodeling factors and inhibits transcription of genes whose products are required for the S phas of the cell cycle. When RB is phosphorylated, it releases E2F that activates transcription of S phase genes. Virtually all cancer cells show dysregulation of the G1-S checkpoint as a result of mutation in one of four genes that regulate the phosphorylation of RB Neoplasia Cell Cycle Checkpoints - G1- Check for cell size, nutrients, growth factors, DNA damage (oncogenes, Rb) G2- check for cell size, DNA replication (oncogenes) S phase checkpoint- DNA repaired p53 Spindle Assembly Checkpoint- Check for chromosome attachment to spindle BRCA1 and BRCA2 Genes - -Tumor suppressor genes -Associated with Hereditary breast and ovarian cancer - HBOC syndrome -Family history and inherited defect in BRCA1 and BRCA2 increases risk of breast cancer -Several hundred mutations of BRCA1 and BRCA2 known; some are more common A 40-year-old woman presents for the evaluation of a left-sided breast lump. She does have a strongly positive family history, with her mother and one older sister both having had breast cancer. Physical examination is notable for a 2-cm lump in the left breast. A biopsy shows invasive ductal carcinoma. The tumor is positive for estrogen receptor expression and HER2 gene amplification. A. What genetic factors may have been involved in this patient's risk for developing breast cancer? - Linkage analysis has identified genetic markers that are known to confer a high risk of developing breast cancer. Two such genes in particular have been found, BRCA1 and BRCA2. Both are involved in repair of DNA. Inherited mutations of BRCA1 or BRCA2 are associated with a lifetime risk of developing breast cancer of up to 80%. Mutations in these genes are also associated with a high incidence of ovarian cancer and can lead to increased incidences of prostate cancer, melanoma, and breast cancer in males. What are the two major subtypes of breast cancer? - There are two major subtypes of breast cancer. Ductal carcinomas arise from the collecting ducts in the breast glandular tissue. Lobular carcinomas arise from the terminal lobules of the glands. Describe the distinction between invasive breast cancer and carcinoma in situ? - While it is still contained by the basement membrane, the tumor is called carcinoma in situ. Invasive carcinoma occurs when tumor cells breach the basement membrane. Both ductal and lobular carcinomas may be either in situ or invasive. By definition, an in situ tumor does not carry a risk of spreading to the lymph nodes or of creating distant metastases. Finding an in situ tumor raises the affected individual's risk of developing a subsequent breast cancer, in either breast, and of either subtype. Therefore, carcinoma in situ is a marker of heightened susceptibility to developing invasive breast cancer. How is our knowledge of the tumor receptors used in treatment of breast cancer? - There are specific therapies that target receptors present in breast cancer. The amount of estrogen exposure is correlated with breast cancer risk. Antiestrogen therapy has long been used with success in patients with estrogen receptor-positive breast cancer, although half of patients diagnosed with breast cancer are estrogen receptor-negative. More recently, antibodies that target the HER2 receptor, a tyrosine kinase growth factor receptor, are used in tumors with an overexpression of the HER2 receptor. Metastasis - Process by which cancer cells escape their tissue of origin and initiate new colonies of cancer in distant sites -Carried by blood or lymph -Invade surrounding tissue -Enter blood or lymph vessel -Carried to distant site -Escape from lymph/blood vessel to surrounding tissue -Establish a tumor From which tissues do sarcomas arise? - Mild and self limited Prominent local and systemic signs Chronic More diffuse Extends over longer period May result in scar tissue formation or deformity Mainly monocytes/macrophages, and lymphocytes Severe and progressive Less local and systemic sign Inflammation process - Microbes enter the cell -->macrophage, dendritic cell, and mast cell which recognition by macrophages, other sentinel cells in tissues Mediators (amines, cytokines) enter in into the blood vessel causing a recruitment of leukocytes (mono and granulo) --> elimination of microbes, dead tissue--> cytokines, growth factors-- fibroblasts--> repair Vasodilation, increased vascular permeability--> edema Inflammation pathogen/bacterial invasion or tissue damage - Pathogen/Bacterial invasion or tissue damage (AA pathway) Release of histamine by mast cells (plus chemotaxins by damaged cells) Arterial vasodilation & resulting in increased blood flow-erythema/warmth Increased permeability due to widening endothelial cell junctions - tissue exudate- edema Extravasation of leukocytes-neutrophils and macrophage into surrounding tissues Phagocytosis of pathogen/ damaged tissue Resolution of inflammation Vascular Endothelial Cells - -Response to local injury signals: upregulation of protein adhesion molecules (selectin) that "capture" WBC's -Physically alter position to aid movement of WBC's into tissue (diapedesis) -Normal, intact, healthy endothelium possesses anticlotting and antiinflammatory activity -Damage produces mediators that are crucial to mounting a response to tissue damage Principal mechanisms of Inflammation - Principal mechanisms of increased vascular permeability in inflammation and their features and underlying causes Retraction of endothelial -Induced by histamine, other mediator -Rapid and short-lived Endothelial injury -caused by burns, some microbial toxin -Rapid; may be long lived (hours to days) Formation of exudates and transudates. - A, Normal hydrostatic pressure (blue arrow) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrow) , which is equal to the mean capillary pressure. Therefore, the net flow of fluid across the vascular bed is almost nil. B, An exudate is formed in inflammation, because vascular permeability increases as a result of increased interendothelial spaces. C, A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic pressure. Emigration of Leukocytes - The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles in different steps of this process: selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. ICAM-1, Intercellular adhesion molecule 1; PECAM-1 (CD31), platelet endothelial cell adhesion molecule-1; TNF, tumor necrosis factor. Nature of leukocyte infiltrates in inflammatory reactions. - The photomicrographs show an inflammatory reaction in the myocardium after ischemic necrosis (infarction). A, Early (neutrophilic) infiltrates and congested blood vessels. B, Later (mononuclear) cellular infiltrates. C, The approximate kinetics of edema and cellular infiltration. For simplicity, edema is shown as an acute transient response, although secondary waves of delayed edema and neutrophil infiltration can also occur. White cells continue inflammation and signal healing - Excess fluid and proteins are cleared via lymphatic drainage. Macrophages clear dead (apoptosed) neutrophils and other necrotic tissue. Macrophages also release growth factors that stimulate new growth (growth (fibroblasts), as well as angiogenesis Macrophages themselves go through apoptosis. Mechanism of tissue repair - Mechanisms of tissue repair: regeneration and scar formation. Following mild injury, which damages the epithelium but not the underlying tissue, resolution occurs by regeneration, but after more severe injury with damage to the connective tissue, repair is by scar formation. Stpes in repair by scar formation- injury to a tissue such as muscle (which has limited regenerative capacity, first induces inflmation, which clears dead cells and microbes. This is followed by the formation or vascularized granulation tissue and then the deposition of extracellular matrix. Resolution of Inflammation: Fibroblasts required for wound healing - As an injury begins to resolve, regeneration and/or repair occurs Angiogenesis Fibroblasts readily proliferate in response to stimuli such as fibroblast growth factor Remodeling Mechanisms of fibrosis - Persistent tissue injury leads to chronic inflammation adn loss of tissue architecture. Cytokines produced by macropages and other leukocytes stimulate the migration and proteins. The net result is replacement of normal tissue by fibrosis. When you have too much fibrosis in tissue you end up with a really stiff area and lessens compliance. Does not allow blood to go through Healing by first intention - When the injury involves only the epithelial layer, the principal mechanism of repair is epithelial regeneration, also called primary union or healing by first intention . One of the simplest examples of this type of wound repair is the healing of a clean, uninfected surgical incision approximated by surgical sutures . The incision causes only focal disruption of epithelial basement membrane continuity and death of relatively few epithelial and connective tissue cells. The repair consists of three connected processes: inflammation , proliferation of epithelial and other cells, and maturation of the connective tissue scar Within 24 hours, neutrophils are seen at the incision margin, migrating toward the fibrin clot. They release proteolytic enzymes that begin to clear the debris. Basal cells at the cut edge of the epidermis begin to show increased mitotic activity. By day 3, neutrophils have been largely replaced by macrophages, and granulation tissue progressively invades the incision space. By day 5, neovascularization reaches its peak as granulation tissue fills the incisional space. These new vessels are leaky, allowing the passage of plasma proteins and fluid into the extravascular space. Thus, new granulation tissue is often edematous . During the second week, there is continued collagen accumulation and fibroblast proliferation. By the end of the first month, the scar comprises a cellular connective tissue largely devoid of inflammatory cells and covered by an essentially normal epidermis. Healing by Second Intention - When cell or tissue loss is more extensive, such as in large wounds, abscesses, ulceration, and ischemic necrosis (infarction) in parenchymal organs, the repair process involves a combination of regeneration and scarring. In healing of skin wounds by second intention , also known as healing by secondary union ( Figs. 3-29 and 3-30 ), the inflammatory reaction is more intense, there is development of abundant granulation tissue, accumulation of ECM and formation of a large scar, and wound contraction by the action of myofibroblasts 4.For physicochemical reasons, soluble immune complexes formed at slight antigen excess are not effectively cleared by the reticuloendothelial system and are of a size that allows them to gain access to and be deposited at subendothelial and extravascular sites sensory function - Begins with activation of specialized dendritic processes, sensory receptors, at the ends of sensory afferents that project to the spinal cord Secondary neurons in the cord are activated and carry the signals up the cord to the brain Thalamus relays signals to various brain areas, including the somatosensory cortex in the parietal lobe Neuronal Structure and Function(Cont.) - 1. For sensory cells, action potential generation occurs at the peripheral sensing end (1), located in skin, muscle, joint, or viscera 2. Nerve endings are specific for one modality (touch, vibration, stretch, temperature, tissue damage/pain) 3. The action potential is propagated to the cell body in a ganglion (2) and to the central nervous system terminal (3) where transmitter is released Sensory neuron structure and function - thermo-receptor- heat sensing Meissner's corpuscle- touch nociceptor- pain Pacinian corpuscle- pressure Two mechanisms can bring a neuron to threshold for fast sodium channel opening: - Synaptic transmitters, particularly excitatory synaptic transmitters (such as glutamate and acetylcholine) depolarize the membrane to threshold Sensory inputs depolarize sensory neurons at their specialized nerve endings -Pain -Touch -Photons -Sound waves From either of these mechanisms, if threshold is achieved, an action potential is generated! Sensory cells come to threshold in response to specific stimuli detected at their receptive zones - Functional groups have well-characterized sizes and pathways Large diameter fiber modalities ("dorsal column" systems) Touch, pressure, vibration Limb position (proprioception) Muscle stretch (reflex assessments) Small diameter fiber modalities ("anterolateral" system) Temperature Pain large-diameter myelinated (Aβ), small-diameter myelinated (Aδ), C fibers distinct functional categories of axons - There are two distinct functional categories of axons: primary afferents with cell bodies in the dorsal root ganglion, and sympathetic postganglionic fibers with cell bodies in the sympathetic ganglion. Primary afferents include those with large-diameter myelinated (Aβ), small-diameter myelinated (Aδ), and unmyelinated (C)axons. All sympathetic postganglionic fibers are unmyelinated. Central fibers vs Small diameter fibers - Central fibers carrying information about touch, pressure, vibration, muscle stretch, and muscle force have large diameter and travel in the medial part of the dorsal root. Their axons enter the spinal cord, split into two branches. The spinal branch of muscle stretch (muscle spindle) fibers and muscle force (golgi tendon organ) fibers make synapses on motor neurons and interneurons controlling motor neurons. The other branch ascends (travels toward the head) in the dorsal column white matter. Small-diameter fibers carrying information about pain and temperature enter in the lateral division of the dorsal root, make a synapse in the dorsal horn, and the axons of the receiving neurons cross the spinal cord and ascend to the brain via the spinothalamic tract. sensory receptors- ipsa or contra - May travel up the ipsilateral side of the cord or may cross the spinal cord to travel up the contralateral side Touch, pressure, and vibration travel up the ipsilateral side of the cord Pain, itch, and temperature usually cross over and travel to the brain on the contralateral side Intensity of the stimulus is reflected in the rate of action potentials generated Sensory pathways - Sensory Pathways 2 major tracts Dorsal column-medial lemniscal tract: fine touch, vibration, and proprioception Anterolateral tract: pain, temperature, and itch Sensory information from both tracts is transmitted from the thalamus to the same areas of the somatosensory cortex by way of the internal capsule Somatosensory Cortex - Organized in columns of gray matter that correspond to specific body locations Body somatotopically represented in spinal cord and cerebral cortex so that stimulation at specific points results in discrete sensation in the contralateral side Homunculus map: somatotopic representation of the body along a strip of the cortex; creates a distorted human body Steps in nociceptor activation - Events leading to activation, sensitization, and spread of sensitization of primary afferent nociceptor terminals. A. Direct activation by intense pressure and consequent cell damage. Cell damage induces lower pH (H+) and leads to release of potassium (K+) and to synthesis of prostaglandins (PG) and bradykinin (BK). Prostaglandins increase the sensitivity of the terminal to bradykinin and other pain-producing substances. (Thus the effectiveness of aspirin and other nonsteroidal antiinflammatory drugs that block prostaglandin formation by inhibiting cyclooxygenase) B. Secondary activation. Impulses generated in the stimulated terminal propagate not only to the spinal cord but also into other terminal branches where they induce the release of peptides, including substance P (SP). Substance P causes vasodilation and neurogenic edema with further accumulation of bradykinin. Substance P also causes the release of histamine (H) from mast cells and serotonin (5HT) from platelets. Pain pathways- ascending, descending - Ascending pathways transmit pain information to somatosensory AND limbic (F = frontal, C = cingulate) cortical regions Descending pain modulation pathways involve projections to periaqueductal gray matter, relay in the medulla, with terminations in the spinal cord Plasticity of pain fibers. Sensitization occurs peripherally and centerally- name the substances - After inflammation and injury, sensitization occurs both peripherally (prostaglandins and other mediators) and centrally (glutamate and substance P) Hyperalgesia refers to sensitization in which a normally painful stimulus is associated with greatly increased pain sensation. Heightened sense of pain to noxious stimuli Allodynia refers to sensitization in which a normally innocuous stimulus is perceived as painful Central sensitization - Hyperalgesia and allodynia can result from central sensitization. With the induction of central sensitization in the somatosensory pathwyas wiht increases in synaptic efficacy and reductions in inhibitation, a central amplification occurs, enhancing the apin response to the noxious stimuli. Low threshold senory input now activate painful stimuli Chronic neuropathic pain - Spontaneous repetitive AP propagation in absence of noxious stimuli, Reduced Ca conductance and Na channel mutations, Reduced AP thresholds Referred pain - Diagram of the way in which convergence of somatic and visceral nociceptive fibers in lamina VII of the dorsal horn may cause referred pain. When a visceral stimulus is prolonged, somatic fiber facilitation occurs. This leads to activation of spinothalamic tract neurons, and of course the brain cannot determine whether the stimulus came from the viscera or from the somatic area. The efferent and afferent signs are very close at the visceral neuron. Thus patients can get "referred pain." Mechanisms of pain modulation by opioids - Opioid receptors are found on nociceptive terminals in the dorsal horn, where they reduce nociceptive transmission, including reducing substance P release