Patho___Exam__1_Study_Guide.pdf.pdf

Exam #1 Study Guide Module 1 – Ch: 1-2 Cellular biology, membrane physiology, action potentials, skeletal and smooth muscle contraction, altered cellular tissue, and biology of aging Positive and negative feedback – what are they? Understand basics of what they do and how they affect physiology • •...

Exam #1 Study Guide Module 1 – Ch: 1-2 Cellular biology, membrane physiology, action potentials, skeletal and smooth muscle contraction, altered cellular tissue, and biology of aging Positive and negative feedback – what are they? Understand basics of what they do and how they affect physiology • • Negative feedback: promotes stability o Cancels out the original response – original stimulus or response is cancelled out at the end o Body must sense a change and attempt to return to normal - restores homeostasis o Ex: increased blood glucose – body increases insulin production – lowers blood glucose/homeostasis is restored Positive feedback: promotes a change in one direction; instability; disease o Exaggeration or more of the original response o May be unstable or normal o Normal Ex: oxytocin release during childbirth stimulating labor contractions; platelets and blood clotting cascade Explain the structure of the membrane and the organization of its polar and non-polar components, including lipids and proteins • Membrane structure: phospholipid bilayer o • • Negative, hydrophobic tails inward; positive, hydrophilic heads outward Proteins o Provide selectivity to the membrane o Integral: channels, pores, carriers, enzymes, receptors, second messengers – spread through entire membrane o Peripheral: enzymes, intracellular signal mediators Carbohydrates o Negative charge of carbo chains repels other negative charges o Involved in cell-cell attachments/interactions - often act as receptors o Play a role in immune reactions • Cholesterol – Fat/Lipids o Present in membranes in varying amounts o DECREASES membrane fluidity and permeability (except in plasma membrane) o INCREASES membrane flexibility and stability Cell energy and ATP production basics • Breakdown of carbs into glucose, proteins into amino acids, and fats into fatty acids • Glucose, amino acids, and fatty acids are processed into acetyl-coA • Acetyl-coA reacts with oxygen to produce ATP (aerobic process) o 38 ATP created per molecule of glucose degraded o Only 2 ATP created without oxygen (anaerobic) • ATP is chemical fuel for cellular processes • Adenosine + 3 phosphate groups = ATP • o Bonds between 2nd and 3rd phosphates contain abundant energy o ATP converted to ADP produces energy o Mitochondrial enzymes reconvert ADP and liberated phosphate to ATP o 3 R’s: rupture, release, recycle 3 uses of ATP o Membrane transport, synthesis of chemical compounds, and mechanical work Transport of molecules through the membrane; diffusion and what affects it; facilitated diffusion; active transport; osmosis and what it is • • Molecules transported through membrane o Intracellular: K more abundant o Extracellular: Na more abundant Membrane permeability and ion permeability o High permeability: easily move across membrane ▪ o Low permeability: more difficult to move across membrane ▪ 2 Water, carbon dioxide, oxygen Chloride, potassium, sodium • • Ion permeability o Conductance: depends on probability that channel is open o Characteristics: ▪ Un-gated (passive movement): determined by size, shape, distribution of charge ▪ Gated: • 3 voltage (ex: voltage dependent Na channels) • Chemically (ex: nicotinic ACh receptor channels) - substance binds to open gate Diffusion: movement of ions/substances/molecules; down a concentration gradient o From higher to lower concentration, from higher to lower pressure o Will not occur if the membrane is non-permeable to the molecule ▪ • • Na and K will naturally want to diffuse in and out but cannot without channels because they are not permeable through the membrane o Lipid soluble (non-charged) substances move more readily o No energy required; no carrier required o Factors that affect net rate of diffusion: ▪ 1. concentration difference ▪ 2. electrical potential – charge difference on each side of membrane ▪ 3. pressure difference – higher pressure results in increased energy to cause net movement from high to low pressure Facilitated diffusion: molecules move along its electrochemical gradient attached to a “carrier” protein molecule that facilitates its passage o Diffusion depends on concentration of the carrier molecule – can reach Tmax depending on concentration of the carrier molecule o Does not move against electrochemical gradient o No energy required Osmosis: movement of fluid across a membrane; passive transport from an area of lower solute concentration into an area of higher solute concentration o Water moves down it’s concentration gradient o Osmotic pressure: difference in solute concentration across the membrane creates osmotic pressure difference – this is driving force for movement of water o Hypotonic (low solute); hypertonic (high solute) ▪ o • Osmosis stops when enough fluid has moved through the membrane to equalize the solute concentration on both sides of the membranes Active transport o Primary active transport: molecules are pumped against a concentration gradient at the expense of energy (ATP) ▪ o Secondary active transport: transport driven by the energy stored in the concentration gradient of another molecule or driver molecule (often Na+) ▪ • Created originally by primary active transport – indirect use of energy PRIMARY ACTIVE TRANSPORT EXAMPLES o o o Na+ K+ ATPase “Sodium Potassium Pump” ▪ PRIMARY ACTIVE TRANSPORT ▪ Carrier protein located on the plasma membrane of all cells ▪ Na/K ATPase = enzymes that converts ATP to ADP to release energy ▪ Regulates osmotic balance by maintaining Na+ and K+ balance – preventing cells from swelling and bursting • Pump K+ in and pump Na+ out • Requires one to two thirds of cells energy • Also establishes negative electrical voltage inside the cells which is the basis for nerve function – aka: resting membrane potential Ca2+ ATPase ▪ Present on the cell membrane and sarcoplasmic reticulum ▪ Maintains low intracellular Ca2+ concentration H+ ATPase ▪ 4 Direct use of energy Found in parietal cells of gastric glands (HCl secretion) and intercalated cells of renal tubules (controls blood pH) ▪ • Concentrates H+ ions where they are needed SECONDARY ACTIVE TRANSPORT EXAMPLES o Co-transport: substance is transported in the same direction as the driver (Na+) ion ▪ o Counter-transport: substance is transported in the opposite direction as the driver (Na+) ion ▪ o Na+ moves down concentration gradient (out to in) – that energy brings substance (AA, glucose, HCO3-) against its concentration gradient (out to in) Na+ moving down concentration gradient (out to in) - creates energy to bring substance (Ca2+, H+, Cl-/H+) against its concentration (in to out) Clinical connection: cardiac glycosides (digoxin) – inhibit the Na/K ATPase pump – calcium can’t move out of the cell via secondary transport because Na is not being pumped into the cell via Na/K pump – intracellular Ca increases – Ca needed for contractility leads to greater contraction for cardiac muscle because of excess Ca Diffusion potentials • • 5 The potential difference generated across a membrane when an ion diffuses down its concentration gradient o Only can be generated if membrane in question is permeable to that ion o Magnitude of the diffusion potential depends on the size of the concentration gradient ▪ Every substance has the potential to want to diffuse down its concentration gradient ▪ Ex: Na diffusing out to in o Measured in mV o Sign (- or +) depends on the charge of the diffusing ion Equilibrium potentials o The diffusion potential that exactly balances or opposed the tendency for diffusion down the concentration difference o The chemical and electrical driving forces acting on an ion are equal and opposite and no further net diffusion occurs o Nernst potential (equilibrium potential of a specific ion) o May be concentration gradient but electrical neutrality overpowers o Ex: ▪ If membrane was only permeable to K (in to out based on concentration gradient) – equilibrium potential would be –94 mV ▪ If membrane was only permeable to Na (out to in based on concentration gradient) equilibrium potential would be +61 mV Resting membrane potential • RMP: the difference in electrical charge or voltage between the inside and outside of a cell – the voltage of a resting, non-signaling neuron o -70 to –85 millivolts o Result of the composition of ECF and ICF ▪ Sodium has greater concentration in ECF; Potassium greater in ICF ▪ Concentration difference maintained by active transport (Na/K pump) • Na+ and K+ both positive • 3K+ out and 2Na+ in = net –1 inside the cell o Creates diffusion potential for Na+ in and K+ out ▪ HOW/WHY is RMP closest to Nernst potential of K+ (-94 mV)?: Resting plasma membrane is more permeable to K than to Na – K diffuses easy from high concentration ICF to low concentration ECF – results in more negative charge inside the cell ▪ **RMP is closest to the equilibrium potential for the ion with the highest permeability Understand the process of nerve action potentials and steps involved • Action potentials: basic mechanism for transmission of information in the nervous system and in all types of muscle o • 6 Rapid depolarization (upstroke) followed by repolarization of the membrane potential Basic characteristics o Constant amplitude o All or none events o Initiated by depolarization o Involve changes in permeability o Rely on voltage-gated ion channels o Has constant conduction velocity ▪ • Terminology o Depolarization: process of making the membrane potential less negative/more positive o Hyper-polarization: process of making the membrane potential more negative/less positive o Threshold potential: the membrane potential at which occurrence of the AP is inevitable ▪ o • “all or nothing” Overshoot: portion of the AP where the membrane potential (cell interior) is positive ▪ • Fibers with large diameters conduct faster than small fibers During repolarization o Undershoot: “hyper-polarizing after-potential" - portion of the AP following repolarization where the membrane potential is more than it’s RMP o Inward current: flow of positive charge into the cell – depolarization – Na+ flow into the cell during the upstroke of the AP o Outward current: flow of positive charge out of the cell – hyper-polarization – K+ flow out of the cell during the downward stroke of the AP Steps o Voltage gated Na+ channels open – “Na+ activation gates open” o Na+ rushes in – cell becomes more positive o Threshold potential is reached, and AP occurs o Na+ gates close – “Na+ deactivation gates close” – K+ gates open o K+ moves out of the cell – cell becomes more negative o Back to RMP Refractory periods “rest” o After an action potential during which a new stimulus cannot be elicited o Shortly after repolarization, the sodium channels become inactivated and no amount of excitatory signal applied to them will open the inactivation gates o The only condition that will allow them to reopen is for the membrane potential to return to or near the original resting membrane potential Myelinated vs. unmyelinated fibers – know the basic differences and purpose of myelin • Myelination o 7 Myelin: lipid substance, electrical insulator ▪ Decreases ion flow through the membrane ▪ Unmyelinated fibers: have Na+ channels along entire fiber that require activation – results in much slower and less efficient transmission of AP’s o Schwann cells: surround the nerve axon forming a myelin sheath o Sheath is interrupted every 1-3 mm: Node of Ranvier ▪ These nodes are the only sites where AP’s can occur – must jump from node to node ▪ Called saltatory conduction ▪ Na+ channels are concentrated at the nodes ▪ Produce increased velocity of transmission and energy conservation because of decreased surface area for signal to move Neuromuscular junction physiology - know basic process in order • • • Where the myelinated axon of a motor neuron meets the muscle fiber and where a chemical synapse occurs o Motor end plate: structure on the muscle fiber where synapse occurs o Synapse fires at motor end plate and moves in both directions along muscle fiber STEPS: o 1. action potential travels down the motor neuron to the presynaptic terminal o 2. depolarization of presynaptic terminal opens Ca++ channels – Ca++ flows into the terminal o 3. causes exocytosis of ACh o 4. Ach binds to motor end plate receptors (nicotinic ACh receptors) on the motor end plate after diffusing across cleft – produces an end plate potential – if the energy is sufficient... o 5. channels open for Na+ and K+ are opened in the motor end plate o 6. depolarization occurs – action potential occurs – generated in the adjacent muscle tissue o 7. ACh is degraded into choline and acetate by AChEsterase; choline is taken back to presynaptic terminal on an Na+-choline cotransporter to be re-used What stops depolarization at the motor end plate? o 8 When ACh is broken down by AChE, ACh unbinds from their receptors and the Na+/K+ pumps close – hyperpolarization occurs • Clinical connection o o Inhibitors ▪ Curariform drugs: block nicotinic ACh receptors by competing for ACh binding site; reduces amplitude of end plate potential and therefore no AP occurs ▪ Botulinum toxin: decreases the release of ACh from nerve terminals; insufficient stimulus to initiate an AP Stimulants ▪ ACh-like drugs (methacholine, carbachol, nicotine): bind and activate nicotinic ACh receptors • ▪ o 9 These drugs aren’t destroyed by AChE – results in prolonged effect Anti-AChE (neostigmine, physostigmine, diisopropyl fluorophosphate or “nerve gas”): inactivate AChE – prevents breakdown of ACh - depolarization able to keep occurring/prolongs effect Myasthenia gravis ▪ Auto immune disease characterized by presence of antibodies against the nicotinic ACh receptors which destroys them ▪ ACh has nothing to bind to – results in weak end plate potentials ▪ Symptoms: skeletal muscle weakness and fatigue ▪ Treatment: anti-ChE (neostigmine); increases amount of ACh in NMJ so it can bind to what nicotinic receptors are left – prolong any effect it possibly can with so little receptors https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and-physiology/introductionto-muscles/v/neuromuscular-junction Acetylcholine – role in skeletal muscle excitation – see above Calcium role in skeletal muscle contraction; tropomyosin function and troponin • Skeletal muscle contraction: interaction between action potential and muscle fiber = excitation contraction coupling o What’s important? CALCIUM https://www.khanacademy.org/science/biology/human-biology/muscles/v/tropomyosin-and-troponin-andtheir-role-in-regulating-muscle-contraction https://www.khanacademy.org/science/health-and-medicine/circulatory-system/heart-musclecontraction/v/calcium-puts-myosin-to-work • Muscle filaments: contains myofibrils surrounded by SR and are invaginated by T tubules o Sarcomere: functional contracting unit of the muscle fiber o Thick filaments: myosin o Thin filaments: actin, tropomyosin, troponin o Sarcoplasmic reticulum Ca++ ATPase pumps Ca++ from the ICF of the muscle into the interior of the SR for storarge ▪ This keeps ICF Ca++ concentration low when muscle is at rest ▪ Stored in bound form to calsequestrin to maintain a low free Ca++ concentration inside the SR and that reduces the work of the pump so there is more energy for contraction • Actin: protein • Myosin: “heads” - proteins; walk along actin o • • Pull towards middle of actin – contraction – z discs come closer to center Tropomyosin: protein that coils around the actin and is “nailed on” by troponin o 10 ▪ Blocks myosin head from being able to attach to and be able to “walk up” actin Troponin: protein that “nails on” tropomyosin; made up of 3 globular proteins o When calcium attaches, troponin releases tropomyosin and myosin can walk up actin and muscle can contract o Troponin C: where calcium binds to move tropomyosin out of the way – contraction can occur o Troponin I: inhibits the interaction of actin and myosin by covering myosin binding site o Troponin T: the “nail”; attaches the troponin to the tropomyosin • With calcium: calcium binds to troponin – moves tropomyosin out of the way – myosin can work – muscles can contract • Without calcium: calcium cannot bind to troponin – tropomyosin stays in place – myosin is blocked from “crawling up” actin to work and contract muscle • o Calcium is re-accumulated in the SR by the Ca++ ATPase of the SR membrane o No calcium – troponin C returns to tropomyosin – tropomyosin nailed back on actin – myosin not able to attach – skeletal contraction unable to occur – relaxation Clinical correlation o Tetanus: sustained contraction – muscle is continuously stimulated and there is insufficient time for the SR to re-accumulate calcium – intracellular calcium concentration remains high – continued binding of calcium to troponin – myosin able to act on actin and contract Excitation and contraction of smooth muscle, calcium, and calmodulin • • Smooth muscle: produce motility, maintain tension o Found in walls of hollow organs (GI tract, bladder, uterus), walls of vasculature, and smaller muscles (ureters, bronchioles, eye muscles o Made of smaller fibers (diameter and length); contain both actin and myosin; no striation; more thin actin than thick myosin; no troponin complex Contraction process o Activated by Ca++ ions and ATP o Use dense bodies (same function as z-discs) o Contains “side polar” cross-bridges that hinge and pull (inside of sliding like skeletal muscle) ▪ o Can be stimulated by multiple types of signals: hormones, nerves, stretch o Contain many types of receptor proteins that can initiate the contractile process (AP) ▪ o o 11 Does not have NMJ ACh and norepinephrine = 2 major transmitters • Both excitatory and inhibitory • When ACh excites, norepinephrine inhibits; vice versa • Receptors determine whether smooth muscle is inhibited or excited and determines which NT will be excitatory or inhibitory Excitation contraction coupling of smooth muscle (AKA CONTRACTION) ▪ No troponin ▪ Interaction of actin and myosin is controlled by binding of calcium to calmodulin ▪ Calcium-calmodulin regulates myosin-light-chain-kinase which regulates cross-bridge cycling Relaxation ▪ Occurs when intracellular calcium falls below the level needed to form calciumcalmodulin complexes Atrophy, hypertrophy, dysplasia – know what they are and what effect they have on cells • Atrophy: decrease in cellular size o Most commonly affects skeletal muscle, heart, secondary sex organs, brain o MOA: decreased protein synthesis and/or increased protein catabolism o Physiologic atrophy: occurs with early development ▪ o Pathologic atrophy: decreases in workload, use, pressure, blood supply, nutrition, hormonal stimulation, and nervous stimulation ▪ • Ex: disuse atrophy (bedridden – skeletal muscle atrophy), aging (brain cells, gonads) o Atrophic muscle cell contains less ER, fewer mitochondria and myofilaments o Atrophy accompanied by autophagy (self-eating) - hydrolytic enzymes: isolated in autophagic vacuoles to prevent uncontrolled cellular destruction Hypertrophy: increase in cellular size o Most commonly affects cells of the heart and kidney o Physiologic hypertrophy: caused by increased demand, stimulation by hormones, and growth factors ▪ o Ex: muscle growth with weightlifting, uterus enlargement via hormones during pregnancy Pathologic hypertrophy: results from chronic hemodynamic overload ▪ 12 Ex: thymus gland during childhood Ex: HTN or heart valve dysfunction ▪ • Cardiac hypertrophy triggered by two types of signals • Mechanical signals: stretch – increased workload • Trophic signals: growth factors and vasoactive agents Hyperplasia: increase in the number of cells o Results from increased rate of cellular division; response to injury o MOA: production of growth factors – stimulate remaining cells to synthesize new cell components and divide; or by stem cells o Physiologic hyperplasia: NORMAL ▪ ▪ Compensatory hyperplasia: adaptive mechanism that enables certain organs to regenerate • Ex: Liver regeneration, callus formation, wound healing • Occurs in epidermal and intestinal epithelia, hepatocytes, bone marrow cells, and fibroblasts Hormonal hyperplasia: occurs chiefly in estrogen-dependent organs – uterus and breast • o • 13 Pathologic hyperplasia: ABNORMAL ▪ Abnormal proliferation of normal cells – response to excessive hormonal stimulation of effects of growth factors on target cells ▪ Cells: pronounced enlargement of nucleus, clumping of chromatin, presence of one or more enlarged nucleoli ▪ Ex: endometrial hyperplasia – imbalance of estrogen and progesterone that causes excessive menstrual bleeding under the influence of regular growth-inhibition controls; if controls fail – cells can undergo malignant transformation Dysplasia: abnormal changes in the size, shape, and organization of mature cells o • Ex: estrogen stimulates endometrium to grow and thicken for reception of fertilized ovum; pregnancy – hyperplasia and hypertrophy enables uterus to enlarge Not a true adaptive process – r/t hyperplasia and often called atypical hyperplasia ▪ Most often found in epithelia ▪ Dysplasia does not mean cancer ▪ Dysplasias that do not involve the entire thickness of epithelium may be reversible ▪ Carcinoma in situ: dysplastic changes that penetrate the basement membrane; preinvasive neoplasms Metaplasia: reversible replacement of one mature cell type by another less mature cell type o Ex: replacement of normal bronchial columnar ciliated epitheial cells by stratified squamous epithelial cells – lose all typical protective mechanisms o A reprogramming of stem cells Reperfusion injury physiology • Restoration of oxygen can cause additional injury – serious complication • Causes excessive reactive oxygen species (ROS), pH alterations, osmotic changes, gap junction changes, inflammatory signaling, and mitochondrial calcium overload o Ex: tissue transplantation; myocardial, hepatic, intestinal, cerebral, renal and other ischemic syndromes including stroke o WBC’s (neutrophils) are especially affected – neutrophil adhesion to endothelium • During ischemic period: excessive ATP consumption – accumulation of purine catabolites (hypoxanthine and xanthine – reperfusion/influx of oxygen is metabolized by xanthine oxidase – makes massive amounts of superoxide and hydrogen peroxide – causes membrane damage and mitochondrial calcium overload • Rapid restoration of intracellular pH – opening of large conductance pore on mitochondrial membrane (mitochondrial permeability transition pore) - massive escape of ATP and solutes – apoptosis • Preventing reperfusion injury: focus on cardio protection o Treatments include the use of antioxidants, blockage of inflammatory mediators, and inhibition of apoptotic pathways Cellular death – necrosis vs. apoptosis • Necrosis: rapid loss of the plasma membrane structure, organelle swelling, mitochondrial dysfunction, and lacking typical features of apoptosis o Includes inflammatory changes o The cellular changes after local cell death and the process of cellular self-digestion (autolysis) o Begins with dense clumping and progressive disruption of genetic material and disruption of the plasma and organelle membranes ▪ • • Membrane integrity is loss and contents leak out – may cause signaling of inflammation in surrounding tissue Apoptosis: programmed cell death; “dropping off” of cellular gragments called apoptotic bodies; active process of cellular destruction o No inflammatory changes o Can occur normally or pathologically o Dysregulated apoptosis: is excessive or not enough; can lead to cancer, autoimmune disorders, neurodegenerative diseases and ischemic injury Autophagy: recycling center; eats itself; self-destructive; survival mechanisms Cellular aging, frailty, somatic death 14 • Aging o Normal, inevitable, universal o Degenerative extracellular changes: ▪ • o Atrophy, decreased functioning, loss of cells (apoptosis) o 4977 deletion/common deletion (mitochondrial DNA) o Tissues/systemic: progressive stiffness and rigidity; sarcopenia – loss of muscle mass and strength Frailty: wasting syndrome of aging; most common in women o • Accumulation of damaged macromolecules, collagen binding and cross linking, increase in free radicals, structural alterations, PVD and oxidative stress Mobility, balance, muscle strength, motor activity, cognition, nutrition, endurance, falls, fractures, and decreased bone density Somatic death: death of the entire person – does not involve inflammatory processes o Postmortem changes ▪ Complete cessation of respirations and circulation ▪ Algor mortis: reduced temp ▪ Livor mortis: purple skin discoloration ▪ Rigor mortis: muscle stiffening ▪ Postmortem autolysis: putrefactive changes associated with the release of enzymes and lytic dissolution – 24-28 hours after death – smell Cellular injury – basic pathophysiology – hypoxia – infiltrations • • • Cellular injury: leads to injury of tissues and organs, determining structural patterns of disease o Reversible or irreversible; acute or chronic; causes cell stress o Can involve necrosis, apoptosis, autophagy, accumulation, or pathologic calcification Pathophysiology: 4 biochemical themes o 1. ATP depletion: changes that all contribute to the loss of integrity of the cell membrane o 2. Oxygen and oxygen-derived free radicals: lack of O2 – key to progression of cell injury – free radicals cause destruction of cell membranes o 3. Intracellular calcium increases: causes intracellular damage by activating enzymes o 4. defects in membrane permeability: found in all forms of cellular injury Cellular injury to cell death o 15 Decreased ATP, failure of pumps, cellular swelling, detachment of ribosomes from ER, cessation of protein synthesis, mitochondrial swelling from calcium accumulation, vacuolation, leakage of digestive enzymes from lysosomes (autodigestion of intracellular structures), lysis of plasma membrane • • Hypoxia (most common injury) o Ischemia: decreased O2 – arteriosclerosis and thrombosis common causes o Anoxia: total lack of O2, sudden obstruction – embolus o Cellular responses: decrease in ATP (anaerobic metabolism doesn’t produce as much ATP) causes failure of sodium-potassium pump and sodium-calcium exchange – osmotic balance failed – cellular swelling Infiltrations/Accumulations: harm cells by crowding organelles and by causes excessive/harmful metabolites o Water – cellular swelling “oncosis” ▪ Most common degenerative change ▪ Caused by shift of extracellular water into the cells – increase intracellular sodium concentration increases osmotic pressure which draws more water into the cell ▪ Reversible, sublethal, early manifestation of almost all cellular injury ▪ Associated with high fever (acute inflammatory response, release of pyrogens), tachycardia (increased need for O2 resulting from fever), leukocytosis (infection), pain (release of bradykinins, obstruction, pressure), hypokalemia o Lipids and carbohydrates – ex: liver - “fatty liver” o Glycogen – excessive vacuolation of the cytoplasm – ex: genetic disorders (glycogen storage diseases) o Proteins – primarily in renal convoluted tubule and in the immune B lymphocytes o Pigments – melanin, hemoproteins, bilirubin o Calcium – dystrophic calcification or metastatic calcification o Urate – uric acid – gout Understand basics of common toxins and their patho; know how they cause cellular alterations (lead, radiation, carbon monoxide, etc.) • 16 Lead o Patho: disruption of Ca++ homeostasis – alters intracellular concentration of Ca++ in many cell types o Alterations in ion transport mechanisms and inhibition of transport proteins such as Na/K pump and Ca++ channels ▪ Lead binds to calcium-activated proteins with high affinity than calcium; competes with calmodulin ▪ Alters NT function, inhibits heme synthesis (ANEMIA), impairs mitochondrial function (decreases cellular energy) o • • Manifestation: nervous, CV, reproductive, endocrine, musculoskeletal, and immune systems ▪ Adults – peripheral nervous system (neuropathy) ▪ Children – central nervous system (brain and spinal cord – affects neuro development) Carbon monoxide o Produces hypoxic injury – directly reduces the oxygen-carrying capacity of blood and promotes tissue hypoxia – CO affinity is 200x more than O2 – quickly binds to hemoglobin o Mild (headache, tinnitus, n/v, weakness); severe (confusion, short-term memory loss, seizures, LOC) - poorer outcomes in adults >35 years old (presence of acidosis and LOC) Radiation o Any form of radiation capable of removing orbital electrons from atoms – resulting in the production of negatively charged free electrons and positively charged ionized atoms = ionized radiation o Factors: ▪ o Bystander effects: cells not in the direct radiated field are affected by radiation – horizontal transmission o Genomic instability: generations of cells derived from an irradiated progenitor cell appear normal, but lethal (irreversible) and nonlethal mutations appear – vertical transmission o Genetic changes: gene mutations, mini-satellite mutations, micronucleus formation, chromosomal aberrations (structural or number), ploidy changes, DNA strand breaks, and chromosomal instability – all phases of cell cycle can be affected ▪ • Patho: effects nutritional status – major nutritional deficiencies include magnesium, vitamin B6, thiamine, phosphorus – adversely affect brain and peripheral nerves ▪ Folic acid deficiency – ethanol alters folate homeostasis by decreasing intestinal absorption of folate, increases liver retention of folate, and increases the loss of folate through urinal and fecal excretion ▪ Metabolized to acetaldehyde in the liver – has many toxic tissue effects (CNS) Mercury o 17 Direct or indirect (interaction with reactive products like free electrons, hydroxyl radicals, hydrogen free radicals) Ethanol o • Rate of delivery; field size; cell proliferation (injury manifested early after exposure); oxygen effects and hypoxia (low oxygenation tissue is less sensitive; damage DNA by generation of reactive oxygen species from reactions with free radicals by radiolysis of water); vascular damage (epithelial cell damage – impaired healing, fibrosis, chronic ischemic atrophy) High affinity to proteins leading to tissue damage in the CNS and kidney – many neuro disorders including ALS, Alzheimer's, MS, Parkinson's o Lipid soluble – increase accumulation in the brain – altering neuromotor cognitive, and behavioral functions o Found in fish and dental fillings – pregnant/nursing mothers, young children avoid Module 2 – Ch: 4-6, 12-13 Genetics, genes and common diseases, epigenetics, and cancer Transcription and translation – understand basics of each process • Transcription: RNA synthesized from a DNA template – results in messenger RNA (mRNA) from the base sequence of the DNA molecule o RNA polymerase binds to a promoter site (ID’s beginning of gene) on the DNA ▪ RNA polymerase pulls DNA strands apart to allow DNA bases to be exposed and provide template for the sequence of complementary mRNA nucleotides • o o • Proteins called transcription factors bind to DNA sequences called transcription factor binding sites near genes to regulate the timing of transcriptions and specific tissues in which genes are actively transcribed ▪ Transcription factors can activate of repress expression of genes ▪ Enhancers (DNA sequences) may up-regulate transcription by binding on Termination sequence – RNA polymerase detaches from the DNA and the transcribed mRNA is freed to move out of the nucleus and into the cytoplasm Gene splicing then occurs “proof reading” o 18 Uracil instead of thymine (A/U - C/G) Vital for the introns to be removed precisely – any leftover intron nucleotides or deletion of extron nucleotides may result in a faulty protein being produced – must produce a readable template for protein production to occur • Translation: RNA directs the synthesis of a polypeptide o mRNA interacts with transfer RNA (tRNA) o tRNA has site for amino acid at one end and site for anticodon (sequence of 3 nucleotides) at the other end o The anticodon undergoes complementary base pairing with the appropriate codon in the mRNA – as each codon is processed, an amino acid is translated by the interaction of mRNA and rTNA ▪ Aided by ribosomes (cytoplasmic structures) - site of protein synthesis ▪ Bonds are formed by adjacent amino acids to make a growing polypeptide chain – when ribosome arrives at a termination signal on the mRNA sequence translation ends – mRNA, ribosome, and polypeptide separate from one another – polypeptide is released into cytoplasm to perform required function Mutations - missense, frameshift, silent • Mutation: any inherited alteration of genetic material • Deletions: chromosome breakage or loss of DNA o • Duplications: excess – usually have less consequences • Inversion o 19 Ex) cri du chat syndrome: low birth weight, mentally challenged, microcephaly, heart defects, specific facial features Occurrence of two breaks on a chromosome followed by the reinsertion of the missing fragment at its original site but in inverted order ▪ o o Result in no loss or gain of genetic material - “balanced” - often have no apparent physical effect Usually only offspring get affected ▪ • • • 20 Results in duplications or deletions in the chromosomes of daughter cells Translocation: interchange of genetic material between 2 different (nonhomologous) chromosomes o Robertsonian: long arms of two nonhomologous chromoses fuse at the centromere forming a single chromosome – common in downs syndrome o Normal phenotype but have 45 chromosomes only in each cell ▪ Results: offspring have serious deleitons or duplications ▪ Ex) fusion of 21 and 14 – offspring have extra copy of long arm of 21 – trisomy 21 Missense: when the substitution alters a single amino acid o Nonsense: when the substitution produces any of the 3 stop of nonsense codons o Missense and nonsense can have profound consequences, serious genetic diseases Frameshift: insertion of deletion of one or more base pairs to the DNA molecule – can change an entire reading frame of the DNA sequence o • Ex ABCDEFG might become ABEDCFG Can greatly alter the resulting amino acid sequence and typically results in a premature stop codon Silent: occur when the change the sequence produces the same amino acid in the polypeptide – structure and function remain the same Aneuploidy, polyploidy • Euploid: cells that have a multiple of the normal number of chromosomes o Ex: haploid: one member of each chromosome pair – 23 chromosomes (gametes) o Ex: diploid: two members, the chromosome pair – 46 chromosomes (somatic cells) ▪ Meiosis: formation of haploid cells from diploid cells o When a euploid cell has more than the diploid number of chromosomes it is said to be a polyploid cell o Polyploid: normal in some body tissues – liver, bronchial, epithelial ▪ Ex: triploidy: zygote having 3 copies of each chromosome rather than 2 ▪ Ex: tetraploidy: euploid cells have 92 chromosomes rather than 23 or 46 • • These examples account for 10% of all known miscarriages Aneuploidy: those that do not contain a multiple of 23 chromosomes o o Ex: three copies of one chromosome – trisomy; one copy in diploid cell – monosomy ▪ Monosomy is lethal ▪ Trisomy (13, 18, 21) can survive ▪ **loss of chromosome material is more serious than duplication Usually the result of nondisjunction: an error in which homologous chromosomes or sister chromatids fail to separate normally during meiosis or mitosis Nondisjunction and typical diseases associated with it • Aneuploidy of sex chromosomes o Usually presents less serious consequences than autosomes ▪ • Nondisjunction: the failure of homologous chromosomes or sister chromatids to separate noramlly during meiosis or mitosis o • Usually the cause of aneuploidy Autosomal aneuploidy: aneuploidy in all other chromosomes except the sex chromosomes o Trisomy's: 13, 18, 21 can survive; most others can not o Partial trisomy: only an extra portion of a chromosome is present in each cell – not as severe as trisomy's ▪ 21 Y chromosome usually causes no problems since it contains little genetic material; no Y – will survive; no X- will not survive Chromosomal mosaics: trisomy's that occur in only some cells of the body – body has two or more different cell lines – each of which has a different karyotype ▪ Usually formed by early mitotic nondisjunction occurring in one embryonic cell but not in others o Most well-known autosomal aneuploidy is trisomy 21 – Down Syndrome o 97% of Down Syndrome cases are caused by nondisjunction during the formation of the one of the parent's gametes or during early embryonic development – other 3% result from translocations o Characteristics of Down Syndrome: o ▪ IQ 25-70, low nasal bridge, epicanthal folds, protruding tongue, flat low set ears, poor muscle tone, short stature ▪ Congenital heart defects, reduced ability to fight RTI’s, increased susceptibility to leukemia, symptoms similar to Alzheimer’s at earlier age ▪ 75% spontaneously aborted or stillborn – 10-20% only survive 10 years – otherwise life expectancy is 60 years Occurrence increases with advanced maternal age – 95% of nondisjunction occurs in formation of mother’s egg cell Sex chromosome abnormalities – understand the patho basics with turner, Klinefelter, and fragile x syndromes • Sex chromosome aneuploidies are typically less severe • Examples: • o Trisomy X o 45,X (missing a 46th homologous X or Y chromosome - monosomy): Turner Syndrome o 47,XXY (at least two X chromosomes and a Y chromosome in each cell): Klinefelter syndrome Turner syndrome (X,__ or 45,X) o o o • 22 Patho: ▪ Formation of gamete undergoes nondisjunction and the sperm without the X chromosome will have nothing to give and therefore the sex chromosomes will only be X and not typical XX ▪ Only X – always female (x usually inherited from the mom) Characteristics: ▪ Sterile (gonadal streaks rather than ovaries - susceptible to ca), short stature, webbing of the neck, widely spaced nipples, coarctation (narrowing) of the aorta, edema of the feet in newborns, sparse body hair ▪ IQ’s typically normal – some spatial and math reasoning impairment Tx: Estrogen to produce secondary sex characteristics; Human growth hormone to increase stature Klinefelter syndrome (XX,Y) o Patho: ▪ Formation of gamete undergoes nondisjunction of the x chromosomes in the mother (usually) and the gamete has multiple X’s to contribute to the Y and therefore the sex chromosomes will be XXY, XXXY, XXXXY, etc... • o Characteristics: ▪ • The more X chromosomes the more severe the syndrome Male appearance, sterile, gynecomastia, small testes, sparse body hair, high-pitched voice, elevated stature, moderate degree of mental impairment Fragile X syndrome: o Fragile sites: chromosomes develop breaks and gaps o Located on the long arm of the X chromosome o ▪ Elevated number of repeated DNA sequences in the first exon of the fragile X gene – repeats consist of CGG sequences that are duplicated many times ▪ 50-200 repeats are most likely to produce affected offspring ▪ More than 20 other genetic diseases are also caused by this mechanism Substantial cognitive impairment (second behind down syndrome) Recurrence risk for dominant and recessive inheritance • Recurrence risk: the probability that a family member will have a genetic disease • Recurrence risk for autosomal dominant inheritance o Diseases caused by autosomal dominant genes are relatively rare – most cases are the result of new mutations o One parent affected (heterozygote) with one unaffected parent ▪ o Both parents affected (heterozygotes) ▪ o Recurrence risk for each child is 100% o If a child has been born with an autosomal dominant disease and there is no history – the child is a product of a new mutation o Germline mosaicism: during embryonic development of one of the parents a mutation affects all or part of the germline but few or none of the somatic cells of the embryo ▪ 23 Recurrence risk for each child is 75% Both parents affected (homozygotes) ▪ • Recurrence risk for each child is 50% Result: parent carries mutation but does not express disease – can still pass on mutation to multiple offspring Recurrence risk for autosomal recessive inheritance o Must be homozygous to express disease; expressed equally in males and females; observed in siblings but no parents o Diseases are rare although frequency of carriers for recessive diseases can be high ▪ Trait usually appears in the children, not the parents ▪ Consanguinity may be present: marriage between related individuals – related are more likely to share recessive genes o Many recessive diseases, like dominant diseases, are characterized by delayed age of onset, incomplete penetrance, and variable expressivity o Most common recessive disease: cystic fibrosis ▪ Carriers are phenotypically normal and heterozygotes ▪ Both parents are heterozygotes • ▪ One heterozygous carrier parent and one homozygous non-carrier parent • o 25% homozygous normal, 50% heterozygous carriers, 25% homozygous affected 50% homozygous non-carriers, 50% heterozygous carriers Because carrier parents usually are unaware that they both carry the same recessive gene, they often produce an affected child before realization of their condition ▪ Carrier detection tests through genetic testing can ID disease locus for mutation Penetrance, expressivity • Penetrance: percentage of individuals with a specific genotype who also exhibit the expected phenotype o Incomplete penetrance: have disease-causing allele but does not exhibit disease phenotype – still can pass onto next generation ▪ o • • 10% are obligate carriers: have an affected parent and affected children and therefore must carry the allele themselves • Penetrance is 90% in this example Age-dependent penetrance: symptoms of a disease are not seen until later in life ▪ People who have disease have had children before they are aware that they were carriers ▪ Ex: Huntington disease, familial colon cancer, familial breast cancer, hemochromatosis, polycystic kidney disease Expressivity: the extent of variation in phenotype associated with a particular genotype o 24 Ex: retinoblastoma Variable expressivity: penetrance may be complete, but the severity of the disease can vary greatly ▪ Ex: Type I neurofibromatosis (von Recklinghausen disease) • o Autosomal dominant; mutation in normal tumor-suppressor gene leads to tumor formation – expressivity varies and determines severity of tumors/symptoms Can be caused by: ▪ Modifier genes: genes at other loci that can modify the expression of the genes ▪ Environmental factors can also influence the expression of the disease-causing gene ▪ Different types of mutations at a locus can cause variation in severity • Ex: a base substitution resulting in a single amino acid change (a missense mutation) usually produces a mild form of hemophilia – a nonsense mutation resulting in a stop codon usually produces a more severe form of hemophilia Benign vs. Malignant tumors • Benign tumors o not referred to as cancers; o Usually encapsulated with connective tissue and contain fairly well-differentiated cells and wellorganized stroma o Retain recognizable normal tissue structure and do not invade beyond their capsule nor do they spread to regional lymph nodes or distant locations o Mitotic cells are rarely present o Named according to tissues from which they arise with the suffix “-oma” ▪ o • Not cancer but may be dangerous/life-threatening depending on their size, location, etc – can compress normal tissue, prevent blood flow, or cause necrotic death of normal tissue ▪ Ex: benign meningioma – base of skull – compress adjacent normal brain tissue ▪ Ex: benign endocrine tumors may lead to overproduction of hormones Malignant tumors o Can begin as benign o Characterized by rapid growth rate and specific microscopic alterations including loss of differentiation, absence of normal tissue organization, disorganized stroma o Lack a capsule and grow to invade nearby blood vessels, lymphatics, and surrounding structures – able to spread far beyond the tissue of origin (metastasis) o Anaplasia: loss of cellular differentiation ▪ o Irregularities of size and shape of nucleus, loss of normal tissue structure Named by originating cell type ▪ 25 Ex: lipoma (fat cell benign tumor), leiomyoma (smooth muscle of uterus) Epithelial tissue: carcinoma ▪ Ductal or glandular tissue: adenocarcinoma ▪ Mesenchymal tissue (connective tissue, muscle, bone): sarcoma ▪ Lymphatic tissue: lymphoma ▪ Blood-forming cells: leukemias Anaplasia, metaplasia - see above Carcinoma in situ (CIS) • Refers to preinvasive epithelial tumors of glandular or squamous cell origin • Cancer develops incrementally as it accumulates specific genetic mutations • Localized to the epithelium and have not penetrated the local basement membrane or invaded the surrounding stroma – not yet malignant • Occurs in: cervix, skin, oral cavity, esophagus, bronchus – glandular sites: stomach, endometrium, breast, and large bowel • Three fates o 1. remain stable for a long time o 2. progress to invasive and metastatic cancers o 3. regress and disappear • Vary from low to high grade – high grade most likely to become invasive cancer • Removal is up for debate – depending on risk vs. benefit - “watchful waiting” Carcinogenesis – understand basic patho behind development of cancer • Carcinogenesis = transformation: the process during which a cell becomes a cancer cell o o o o o • Have anchorage independence – don't need anchor points to be able to divide Are immortal Anaplasia occurs – pleomorphic: variable sizes and shapes Allows lactate and its metabolites to be used for the ore efficient production of lipids and other molecular building blocks needed for rapid cell growth Cancer stem cells – self renew – cell divisions create new stem cells o 26 Lacks contact inhibition – will continuously divide and crowd to create tumor Cancer cells always perform glycolysis (anaerobic metabolism) - doesn’t require oxygen – can grow in oxygen deprived environments o • Autonomy: the cancer cell’s independence from normal cellular controls Multipotent: can differentiate into multiple different cell types o o • • Thought to cause relapse, recurrence Treatment: target cancer stem cells THREE GENETIC MECHANISMS THAT HAVE A ROLE IN CARCINOGENESIS o 1. activation of proto-oncogenes resulting in hyperactivity of growth-related gene products called oncogenes o 2. mutation of genes, resulting in the loss of inactivity of gene products that would normally inhibit growth called tumor suppressor genes o 3. mutation of genes, resulting in an over expression of products that prevent normal cell death or apoptosis, thus allowing continued growth of tumors Inflammation and cancer o Chronic inflammation is an important factor in the development of cancer ▪ Cytokine release from inflammatory cells – GF – stimulate cell proliferation ▪ Free radicals – reactive oxidative species ▪ Mutation promotion ▪ Decreased response to DNA damage • 27 Ex: UC leads to colon cancer or chronic viral hepatitis leads to liver cancer Mutations and cancer • Multiple mutations are required before cancer can develop o Clonal proliferation or expansion ▪ o o o o o • 28 Activate growth-promotion pathways Block antigrowth signals Prevent apoptosis Turn on telomerase and new blood vessel growth Allow tissue invasion and distant metastases RAS: intracellular signaling protein – point mutation can turn RAS from proto-oncogene to oncogene o o • As a result of a mutation, a cell acquires characteristics that allow it to have selective advantage over its neighbors – increased growth rate or decreased apoptosis Stimulates cell growth even when growth factors are missing Common mutation in cancers Caretaker genes: encode for proteins that are involved in repairing damaged DNA – maintain genomic integrity o o Loss of function leads to increased mutation rates Some inherited mutations can disrupt caretaker gene function – leading to disease ▪ • Ex: HNPCC – hereditary nonpolyposis colorectal cancer Chromosome instability o Caused by malfunctions in the cellular machinery that regulates chromosomal secregation at mitosis o Results in a high rate of chromosomal loss, heterozygosity, and chromosomal amplification ▪ Accelerate the loss of tumor-suppressor genes and the over expression of oncogenes Proto-oncogenes, oncogenes, tumor suppressor genes – understand what they are and their role • Proto-oncogenes: normal genes that direct protein synthesis and cellular growth; normal function o • Oncogenes: encode proteins in their normal state that positively regulate proliferation; promote unncessary growth o • Mutant genes Tumor suppressor genes: encode proteins that in their normal state negatively regulate proliferation; turn unnecessary growth off o • Non-mutant oncogenes Inhibit growth factor stimulation, block stages of the cell cycle, end differentiation, stimulate cell death Cancer = turmor suppressor genes OFF – oncogenes ON Angiogenesis - “neovascularization” • Growth of new vessels to promote cancer cell and tumor growth • Advanced cancers can secrete angiogenic factors that stimulate own blood vessel growth Role of telomeres in cancer • Body cells are not immortal and can only divide a limited number of times o • Telomeres are protective ends or caps on each chromosome and are placed and maintained by a specialized enzyme called telomerase o o 29 Controlled by telomeres Telomerase is usually active only in germ cells (testes and ovaries) and in stem cells All other cells lack telomerase activity therefore when on germ cells begin to proliferate abnormally their telomere caps shorten with each cell division o o o Short telomeres normally signal the cell to cease cell division If the telomeres become critically small, the chromosomes become unstable and cells die Cancer cells activate telomerase to restore and maintain their telomeres thereby allowing continuous division ▪ o Thought that telomerase is activated by oncogenes and loss of function of certain tumor suppressor molecules ▪ Telomerase activity restored in about 90% of cancers ▪ Attractive therapeutic target Also associated with aging Metastasis – understand the basic pathophysiology • Metastasis: the spread of cancer cells from the site of original tumor to distant tissues and organs o Requires cells to have many new abilities – invade, survive, proliferate in new environment, recruit new blood vessel growth (angiogenesis) o 3 mechanisms: ▪ • • Pre-requisite for mets, first step • Requires cancer to attach to specific receptors and survive in the specific environment ▪ Metastases to distant organs – through circulation of lymphatics and blood ▪ Direct transportation – direct placement of cancer cells in new location Detachment and invasion o Cancer cells secrete protease o Proteases digest the extracellular matrix and basement membranes ▪ 30 Direct invasion of contiguous organs - “local spread” Create pathways through which cells can move o Metastatic cells withstand physiologic stresses of travel in the blood and lymphatic circulation o Epithelial-mesenchymal transition (EMT) ▪ Many epithelial-like characteristics such as polarity and adhesion to basement membrane are lost – migratory capacity increases – resistance to apoptosis increases – dedifferentiation to a stem cell like state favors growth in foreign microenvironments ▪ and the establishment of metastatic disease Tumor staging basics • Determining the size of the tumor, the degree to which it has locally invaded, and the extent to which it has spread • Stage 1: confined to organ of origin • Stage 2: locally invasive • Stage 3: spread to regional structures • Stage 4: spread to distant sites • TNM system o T: tumor spread ▪ o N: node involvement ▪ o T0 through T3 - increasing by invasion/size of tumor N0 through N2 - increasing by nodal involvement M: metastasis ▪ M0 through M2 - extent of distant metastasis Cancer epidemiology – basics and common risk factors • Occurs in genes but 2/3 of all cancers are caused by environmental/lifestyle factors interacting with genes • Epigenetics: change in genetic expression (phenotype) without DNA mutation o Usually involves factors that silence genes that should be active or activate genes that should be silent • Genetics, epigenetics, and environmental factors interact to cause cancer • Conditions that increase susceptibility to cancer: prenatal exposure, parental exposure before conception, in utero exposure, toxins in breast milk, gene and environment interactions o Developmental plasticity: degree to which development is contingent on its environment ▪ • Risk Factors: o Tobacco – lung, lower urinary tract, upper digestive tract, liver, kidney, pancreas, cervix, uterus, myeloid leukemia o Diet – either alters micro-ribonucleic acid (predisposes an individual to cancer) or suppresses cancer stem cell renewal ▪ 31 Reducing cancer risk must begin early in life Cancer causing: cooked in fat, meat, alkaloids, mold byproducts, high glycemic carbs, preservatives, alcohol, grilled, blackened, fried, refined grains, high calcium ▪ Cancer preventing (improves DNA repair): kiwi, cooked carrots, CoQ10 enzyme, fruits, vegetables, fiber, vitamins A, B6, C, D, E and folate; whole grains; lycopene; legumes/nuts ▪ Obesity – endometrial, colorectal, kidney, esophageal, breast, pancreatic • Increases insulin resistance-producing hyperinsulinemia • Insulin promotes insulin like growth factor o • Adipose tissue secretes adipokines – increase inflammation o Alcohol – oral cavity, pharynx, larynx, esophageal, liver, colorectal, breast, GI o Decreased physical activity o ▪ Decreases insulin and insulin like GF, decreases obesity, decreases inflammatory mediators, improves immune function, increases gut motility ▪ Related to breast, colon, endometrial Infection ▪ o o o HPV (cervical), Hep B/C (liver), H. pylori (stomach), EBV (nasopharynx, Hodgkin disease, non-Hodgkin lymphoma, b-cell lymphoma), herpes virus (Kaposi sarcoma) Sexual and reproductive behaviors and HPVs ▪ HPV type 16 and 18 ▪ Cervical and anal cancers – one half of vaginal, vulvar, and penile cancers ▪ Infects epithelial cells – mutations lead to cancer Ionizing radiation ▪ Associated with acute leukemias, thyroid, breast, lung, stomach, colon, esophageal, urinary tract, multiple myeloma ▪ Enters cells and randomly deposits energy in tissues • Oncogene activation, tumor suppressor deactivation • Chromosomal aberrations and DNA damage • Genomic instability • Bystander effects • Disrupts mitochondria and increases DNA breakage UV radiation and electromagnetic radiation (conflicting research) ▪ 32 Increases risk for prostate cancer Basal cell carcinoma, squamous cell, melanoma • Basal: patch gene mutation • Squamous: TP53 mutation • Melanoma: P16 mutation o Chemicals and occupational hazards ▪ o Asbestos (mesothelioma/lung ca), dyes, rubber, pain (bladder ca), explosives, rubber cement, benzol, dyeing materials (leukemia) Air pollution ▪ Lung cancer ▪ Outdoor: ozone (smog) and particle pollution (pulmonary inflammation, oxidative stress, oxidation of DNA, proliferative response, tissue remodeling with fibrosis, tumor development) ▪ Indoor: worse - (cigarette smoke and radon – lung; inorganic arsenic – bladder, skin, lung) Not technically in study guide X/Y-linked inheritance: involves X and Y chromosomes • Y linked are uncommon because the Y chromosome contains few genes • X –LINKED RECESSIVE • Females: two X - can be: o o o • Homo/normal: Xa Xa Hetero/normal: XA Xa Males: one X – always hemizygous o If inherits an X recessive gene then will express disease because no normal allele is present to counteract the diseased allele o o Disease: Xa Y Normal: XA Y • Occurs more in males than in females • Never transmitted from father to son – father can give only Y • Affected father will give disease to all of his daughters – only has affected X to give o o • 33 Homo/disease: XA XA Daughters will then give to half their sons Given through female carriers – skipped generation Ex: muscular dystrophy – deletion of DMD gene causes dystrophin to not work properly; muscle cells do not survive Paraneoplastic syndromes • • Symptom complexes are triggered by a cancer but are not caused by direct local effects of the tumor mass Are caused by biologic substances released from the tumor (ex: tumor markers – secreting hormones, GF’s), or by an immune response triggered by the tumor • Can be life threatening • Ex’s: lung breast, ovaries, lymphatic Cancer in children o Most childhood cancers originate from the mesodermal germ layer ▪ ▪ Often diagnosed during time of peak physical growth ▪ Boys affected more than girls ▪ Most common are leukemias and brain tumors ▪ o Gives rise to connective tissue, bone, cartilage, muscle, blood, blood vessels, gonads, kidneys, lymphatic system Embryonic tumors: originate during intrauterine life – immature embryonic tissue is unable to mature of differentiate into fully developed cells - “blasts” Etiology ▪ Oncogenes and tumor suppressor genes ▪ Chromosome aberrations and singe gene defects ▪ • Aneuploidy, amplifications, deletions, translocations, fragility • Trisomy 21 – downs – linked to leukemia Familial risk • ▪ Prenatal exposure ▪ Childhood