Med PHYS Exam 1.pdf

Physio 1 - Homeostasis, Osmosis, IVFs, Electrical Potentials - 2024 Medical Homeostasis body temperature, blood sugar, fluid pH and balance, electrolyte balance (K+, Cl-, HCO3-, Na+, Mg2+, Ca2+) Negative feedback components of homeostasis...

Physio 1 - Homeostasis, Osmosis, IVFs, Electrical Potentials - 2024 Medical Homeostasis body temperature, blood sugar, fluid pH and balance, electrolyte balance (K+, Cl-, HCO3-, Na+, Mg2+, Ca2+) Negative feedback components of homeostasis SET POINT: target value of control system, for O2 need it for respiration and ATP production CO2 is acidic - will change pH (increases above 40 mg Hg --> brings pH down) - needs to be removed because it is toxic glucose control - under pancreatic control, beta cells secrete insulin in pancreas --> if glucose is increased after meal, insulin secreted to bring it down SENSORS: continuously monitor a controlled variable COMPARATOR: interprets sensory input to determine deviations from set point, initiates counter response when deviations occur EFFECTORS: organ that brings about change - restore set point to normal levels (cardiac muscle, smooth muscle in vasculature, kidney and adrenal glands Insulin will insert GLUT transporters (too big to go through cell alone, requires facilitated diffusion) glycogen is insoluble, can just sit around in cytosol in kidneys: two hormones stimulate to bring back more water in renal tubules (with low BP, kidneys retain more water) ◦ adh synthesized in hypothalamus, sent to anterior pituitary and stored there until needs to be released --> increases aqua porin channels (in distal convoluted tubules --> inserts water channels to reabsorb water) aldosterone (synthesized in adrenal cortex - glomerular area specifically, starts as cholesterol) released in blood, going to act in kidneys and blood vessels aldosterone acts in DCT --> tells kidney reabsorb more salt (wherever salt goes, water follows) NEGATIVE FEEDBACK: when effector initiates a counter response to deviation from normal set point (detected by sensor) Example: Blood pressure control controlled variable: mean arterial blood pressure (MAP) set point: MAP = 95 mm Hg sensor: intravascular pressure sensor located in carotid sinus - carotid sends oxygenated blood to brain so makes it a baro-sensor comparator: CNS site in medulla oblongata effectors: cardiac rate and contractility, vascular tone, urinary fluid excretion ◦ negative feedback: MAP of 110 mm Hg -- signals brain - changes HR, muscle contraction, arterial constriction, renal excretion --> restore normal MAP Example: Glucose control, liver is major storage site of glucose (12-16 hours worth), glucagon in pancreas tells cells that store glycogen to break it down into glucose controlled variable: blood glucose set point: 70 mg/dl Sensor: pancreatic islet cells and hypothalamic CNS cells  comparator: CNS site in hypothalamus Effectors: liver, kidney, muscle and adipose tissue ◦ dietary intake increases blood glucose --> sensed by brain --> stimulates release of insulin from pancreas --> promotes storage of glucose in liver, fat and muscle and utilization of glucose for energy --> kidney will excrete glucose if blood level > 180 mg/dL EXAMPLES OF HOMEOSTASIS core temp - thermo-receptors in hypothalamus (skin blood vessels and sweat glands) ◦ constriction of erector pili muscles (goose bumps) attached to hair follicle, it constricts around the follicle and creates extra layer around skin to trap heat blood gases - peripheral and CSF chemoreceptors ◦ peripheral: carotid artery and aortic arch ◦ regulated by respiratory center in brainstem ◦ CSF bathes cells of nervous system (excitable neurons and non excitable neuroglia) Sodium concentration ◦ sensor in juxtaglomerular apparatus of kidney ◦ regulated by renin-angiotensin system ◦ sodium is most important extracellular ion and solute ‣ triggers RAAS - wherever Na goes, H2O follows, increases water volume ◦ potassium (3.5-5) most important within cell ◦ calcium required for contractions so kept close within cell Fluid balance ◦ water loss: in skin, water vapor in exhaled air, sweating, vomiting, feces ◦ if hypothalamus detects hypertonic extracellular environment ‣ secretes ADH --> tells kidney to reabsorb water from distal convoluted tubules and collecting ducts ‣ activates thirst center of CNS Interstitial fluid bathes body cells in intercellular space Blood plasma bathes blood cells in intravascular space Extracellular: Fluid outside cells Intracellular: fluid inside cells RBCs, WBCs, platelets all in fluid! 66% of TOT body water: ICF, 33% = ECF ◦ 75% of ECF: interstitial fluid ◦ 25% of ECF: blood plasma ◦ most fluid in body is in plasma membrane bound cell 60% body wt in males 50% body wt in females Free exchange of water and small, lipophilic/lipid soluble, uncharged solutes b/ w interstitial fluid and blood plasma across blood capillaries; Concentration gradient is major driver of simple diffusion/osmosis OSMOSIS: water movement driven by water concentration gradient across membrane What happens while sodium is sitting around in blood - water goes into vasculature – blood volume increases, blood pressure increases – CNS medulla notes BP increase, start leakage of fluids in interstitial fluid (swollen gut, swollen face etc. edematous – bc compartment cant withstand all that water and it leaks out) Initiate vasodilation, kidney is now overwhelmed with amount of blood volume – going to secrete more water (pee more) beyond peeing more, body cant do much else heart failure/chronically HTN pts, fluid just stays there because no mechanism to get rid of all fluid Kidneys have their own set points (wont get rid of all the water, gets rid of enough by ‘round’) Can give furosemide (anti-diuretic – tells kidney to excrete more water) Hydrochlorothiazide (anti hypertensive) – secretes more fluid from kidneys Ace inhibitors – lisinopril no conversion of angiotensin 1 to angiotensin 2 – no release of aldosterone, so reduce salt and water reabsorption from kidney Renin secreted from kidneys – angiotensin converting enzyme (ACE) HYPERTONIC IVF: promotes osmosis of fluid out of cell to extracellular space causing cell to shrink ISOTONIC IVF: does not promote osmosis, increase extracell volume without changing cell size/conc HYPOTONIC IVF: promotes osmosis of extracell fluid into cell causing cell to swell DKA- diabetic ketoacidosis *after glucose absorbed becomes hypotonic solution +after glucose absorbed becomes isotonic solution HEMORRHAGE capillary endothelium permeable to ware - allows free movement of interstitial fluid into intravascular space --> replacing lost blood plasma ◦ helps maintain blood volume in hemorrhaging pt EFC ~16L ◦ hemorrhaging pt can lose 4 L of EFC before plasma decreases by 1 L ◦ to replace 1 L of plasma volume one must infuse 4 L of ISOTONIC SALINE (0.9% NaCL = normal saline) into intravascular space ELECTRICAL POTENTIALS movement of electrons feeds and drives processes within the cell movement of ions across cell membrane creates charge imbalance between ICF and ECF ◦ causes voltage difference across cell membrane - membrane potential (Vm) ‣ created by potential of cell membrane permeable ions to travel down their concentration gradient ‣ typical nerve cell has resting Vm = -70 mV ‣ EFC by definition is at zero volts: electrical ground ‣ Vm is an electrochemical driving force for diffusion of ions  used to move charged ions OR create communicating electrical signals DIFFUSION AND EQUILIBRIUM POTENTIALS more sodium outside than inside, more potassium inside than outside sodium pump keeps balance Most cells at rest minimal permeability to Na+ or Ca2+ ( significant permeability to K+ - K will flow out of cell until electrical and chemical gradients are equal ◦ EFC K+ concentrations greatly affect IFC K+ concentrations --> to live cell must expend energy to preserve normal chemical/electrical gradients ◦ abnormal IFC concentrations of K+ will result in cell dysfunction/death ◦ EFC K+ concentration in narrow range: normal = 3.5 - 5.0 mmol/L HYPOKALEMIA AND HYPERKALEMIA - both can cause cardiac arrythmias, both affect muscle contraction (affected because of RMP -70mV) so similar clinical signs Hypokalemia decrease in K+ in blood plasma reflects decrease K+ in ECF ICF K+ will migrate out of cell to lower EFC K+ conc clinical signs: muscle weakness and spasms, heart palpitations, fatigue, tingling and numbness Hyperkalemia more serious, MEDICAL EMERGENCY increase in K+ in blood plasma causes increase in K+ in ECF cause: renal failure - unable to excrete excess K+ in blood increase ECF K+ slows K+ flow out of cell --> depolarization --> inactivates Na+ channels required for muscle excitation/ contraction clinical signs: electrical conduction abnormalities, heart palpitations, chest pain, muscle weakness/paralysis, nausea and vomiting Cell Bioenergetics Biological cells must have energy to drive cellular processes & functions Biological cells die when cellular energy production ceases or is insufficient to sustain life Energy used in cellular processes & function is primarily stored in molecular bonds between phosphoric acid molecules & other organic compounds ◦ Because these molecular bonds are very strong - a large amount of energy (10-12 kcal/ mole) is released when bond is hydrolyzed Compounds containing *phosphate bonds are called high-energy phosphate compounds outer membrane: smooth inner membrane: sharp folds, cristae to increase surface area intra-organelle fluid (mitochondrial matrix) gelatin like, perfect medium for enzymes and substrates and ions metabolites: PYRUVATE and FATTY ACIDS - enter mitochondria via membrane porins --> converted to Acetyl-CoA by matrix enzymes of CITRIC ACID CYCLE, yielding some ATP and NADH --> source of electrons for electron- transport chain four electron pumps pumping protons between each other (H+) --> form ATP, create electrochemical gradient ATP Synthase: makes ATP --> flow of protons causes rapid spinning of specific polypeptides in globular ATP synthase complex --> energy of proton flow converted into mechanical energy --> now stored in new phosphate bond of ATP oxidative phosphorylation: ATP synthesis ◦ requires oxygen - 90% of oxygen consumption in body is used for synthesis of ATP ◦ harnesses energy from proton gradient across mitochondrial membranes ◦ acetyl coa becomes lactic acid without oxygen --> STOPS at glycolysis ◦ lactate dehydrogenase (LDH) becomes important metabolite to make lactic acid Oxidation - reduction: produce energy, NAD, NADP, NADPH ox: loss of electrons ◦ combination of substance with O2 ◦ loss of H+ ◦ loss of electrons (-charge) red: gaining of electrons Coenzyme A - High energy compound thioesters: high energy compounds, CoA is most important --> without it cant get into ETC ◦ reduced form of CoA reacts easily with acetic acid to form acetyl-CoA and water Cellular respiration glycolysis ◦ breakdown of glucose to pyruvate or lactate (or both) --> produces ATP ◦ pyruvate converted to Acetyl-Coa using NAD+ oxidation-reduction reaction for energy Fatty acid oxidation ◦ metabolized to acetyl-CoA Amino Acid catabolism ◦ from proteins can be ketogenic or glucogenic  ◦ glucogenic converted to pyruvate ◦ (beta oxidation) ketogenic converted to acetyl-coa and ketone bodies (acetone, acetic acid, betahydroxy buteric acid) gluconeogenesis: non carbohydrate source of energy (fats, amino acids) citric acid cycle ◦ acetyl CoA metabolized to CO2 and H+ while consuming O2 and producing ATP and H2O ◦ CO2 must be removed from body role of respiratory chain mitochondria in conversion of food energy to ATP ◦ oxidation of nutrients (food) leads to generation of reducing equivalents (Acetyl-CoA) for the generation of ATP HYDROLYSIS OF ATP --> ADP and ADP --> AMP produces energy OXIDATION OF ACETYL COA --> produces ATP, CO2, and H2O while consuming H2O CELLULAR RESPIRATION --> O2 must be consumed and CO2 must be removed continuously water used to drive other reactions Intracellular organelles Nucleus: multiple disease are inherited through chromosomal gene expression (transcription, translation) muscular dystrophy: inherited, any muscle in the body can be affected (skeletal, cardiac) --> different inheritance = different severity = different kind of protein (beckers vs. duchenne) Nucleolus: site of DNA to RNA transcription and ribosome production alzheimer's disease: abnormal buildup of proteins in brain ◦ ribosomal DNA deregulated --> ribosomes cannot attach AA's to each other to build proteins --> cannot synthesize enzymes to clear toxic protein buildup cardiovascular disease: nucleolus senses cell. stress --> changes morphology --> hypertrophy (increases tissue mass by increasing cell size) enlargement of nucleolus = increased contractile protein (actin and myosin) synthesis and cell growth --> early indicator of cardiac hypertrophy ◦ mature cardiac cells (myocites) lose ability to undergo mitosis --> heart failure, cardiovascular disease, anemia, need to deliver more oxygenated blood to tissues --> heart is under stress, requires more oxygen to create more energy --> O2 demand of cardiomyocites increases, they enlarge to enable more oxygen Chromosomal DNA (mutations, translocation, etc.) --> removal or inhibition of chromosome, extra copies, recombination or combination of any of these ◦ turner: affects only females, results when one x chromosome is missing or partially missing (XO) ◦ klinefelter: one extra copy of X chromosome is present in males (XXY), phenotypically male, but abnormalities (very tall, gynecomastia, structure of pelvis more gynecoid) ◦ sickle cell anemia: mutation of Hb-beta gene on chromosome 11, inability of Hb to carry oxygen and causes abnormal shape of RBC Rough endoplasmic reticulum (RER) protein synthesis alterations in RER homeostasis (cellular stress) causes abnormal increased protein synthesis, accumulation of misfolded proteins, alterations in calcium balance ◦ alzheimer's, parkinson's ◦ amyotrophic lateral sclerosis (Lou Gehrig's disease) ◦ type 2 diabetes, atherosclerosis ◦ nonalcoholic fatty liver disease, alcoholic liver disease ‣ globular fat inhibits hepatocyte function ◦ cancer Smooth endoplasmic reticulum (SER) no ribosomes steroid hormone production (more in testes, adrenal cortex and ovaries) lipid and carbohydrate synthesis liver has more SER for metabolic and detox processes ◦ stress on SER can interfere with signaling ‣ type 2 diabetes, atherosclerosis ‣ alcoholic and nonalcoholic fatty liver disease ‣ endocrine disorders, cancer Golgi body functions, modifies and segregates proteins for secretion synthesizes lysosomes ◦ neurogenerative diseases  ‣ parkinson's: ribbon formation of Golgi is broken causing malfunction in intracellular functions and altering cytoskeleton ‣ alzheimer's: degenerative disease of brain that causes dementia ‣ amyotrophic lateral sclerosis: progressive disease that atrophies motor neurons of spinal cord and brain Lysosomes - malfunctioning protein --> peroxisome (WBCs) or lysosomes package abnormal protein and uses its hydrolytic enzymes to break it down, ALS parkinson's - buildup of unusable proteins, becomes toxic Tay-sachs - deficiency in enzyme that metabolizes fatty substances ◦ inherited, progressively destroys nerve cells in brain and spinal cord --> mental deficiency and blindness fabry disease - deficiency in alpha-galactosidase gaucher - deficiency in galactocerebrosidase Mitochondrion converts chemical energy in food to ATP regulates immunity, Ca2+ homeostasis, apoptosis ◦ cyanide: disrupts ETC preventing cells from forming ATP using oxygen (cellular respiration) ◦ leigh syndrome: genetic disorder - CNS degeneration caused by abnormal mitochondrial energy production ◦ epilepsy and encephalopathy- certain types Centriole duplication of centrioles necessary for cell division to occur organize mitotic spindles during mitosis abnormalities linked to neurodegeneration, autoimmune disorders, and solid breast tumors ◦ increase centrioles: hallmarks of cancer ◦ structural defects: linked to changes in expression of genes ◦ cytoskeleton of cell allows for transcellular movement --> without centrioles, no movement Microtubule long hollow structures form part of cytoskeleton give shape to cell protein subunits alpha tubulin and beta tubulin in cytoplasm ◦ assist movement of proteins and organelles within cell ◦ form spindles that transport chromosomes during mitosis ◦ partially compose cilia and flagella of sperm ◦ primary ciliary dyskinesia: inherited problem with cilia formation --> abnormal movement of cilia ‣ ependymal cells: line ventricles of brain --> hydrocephaly, cant move CSF ‣ reproductive tract: ectopic pregnancies ‣ respiratory tract: cant move mucus, it will accumulate, obstruct airways, protects so without movement of mucus --> chronic pneumonia, lung infections ‣ Cilia are made of microtubules, translocation of organs during embryological development --> dependent on ciliated movement --> severe forms of ciliary dyskinesia --> situs invertus (organs are on opposite site of the body) ‣ Dextrocardia (heart on right side) ‣ infertility: loss of motility of sperm cells ‣ alzheimer's, parkinson's and amyotrophic lateral sclerosis: decrease microtubule activity causes loss of neuronal axonal transport needed to maintain efficient neuronal activity Microfilaments smaller version of microtubules actin filaments wound in a spiral allow for intra-cell movements and support cell structure keep cell organelles bound in one place allow for muscle contraction by binding to myosin (thicker filament, contractile protein) ◦ giant axonal neuropathy: rare genetic disorder, affects both CNS and PNS Cytoplasm within cell membrane 85% water maintain cell shape, intracellular movement/material exchange dehydration: loss of cellular water causes cell to collapse --> cell shape determines cell function!! (Crenation) Cell (plasma) membrane outer membrane that surrounds cell cytoplasm and intracellular structures physical barrier, selective permeability, endo and exocytosis, cell signaling cell growth, metabolism and regulation ◦ defects: cancer, hemolytic disease, cystic fibrosis ‣ hemolytic disease: abnormal structure of RBC can lead to anemia ‣ HIV, Rh tag on RBC can cause hemolytic disease --> problem with cell recognition and signaling ‣ malaria causes hemolysis of cells ‣ cystic fibrosis: sodium chloride channel causes defect in cell function (in resp tract accumulation of mucus --> infection) Membrane Protein may be embedded (integral) or peripheral provides passage or selective permeability contributes to preservation of electrochemical gradients ◦ cystic fibrosis: transmembrane conductance regulator protein (CFTR) regulates flow of chloride and sodium across cell membrane in lungs and GI tract --> regulates water flow ‣ gene allows for formation of transmembrane protein (Na-Cl protein channel allows for mucus formation in GIT< reproductive tract, respiratory tract, GU tract) ‣ consistency of mucus is dependent on Na-Cl channels --? issue with proteins means issue with mucus --> sticky mucus blocks everything (including secretions of proteins) ◦ malformed CFTR protein results in abnormally thick cellular secretions (mucus, pancreatic enzymes) causing obstruction of airways and duct systems Skeletal Muscle develop force by contraction muscle columns (fascicles) --> bundles of muscle cells (fibers) each multi-nucleated cell behaves as single unit --> contains many myofibrils each repeated striated pattern segment = sarcomere (fundamental unit of skeletal muscle) sarcomere ◦ Z line (Z disc) binds sarcomere at each end ◦ thin filaments - project from each Z line toward centre of sarcomere ‣ made of actin, main regulatory proteins (tropomyosin and troponin proteins) ◦ thick filaments (A bands)- in center of sarcomere, overlapped by thin filaments, composed of myosin protein sarcomere arrangement ◦ line up end to end within single myofibril ◦ A bands: darker areas, correspond to thick filaments ◦ I bands: lighter areas, correspond to thin filaments without overlapping thick filaments thin filaments: overlap and insert between thick filaments Motor unit: 1 motor neuron muscle fibers (inn. by branches of motor neuron) ◦ small motor unit ‣ motor neurons branch to only few muscle fibers ◦ large motor unit ‣ motor neurons branch to many muscle fibers ◦ fine control muscles ‣ many small motor units (hand and eye muscles ◦ coarse control muscles ‣ fewer large motor units (postural trunk muscles) Sliding Filament Theory (skeletal muscle contraction) thin filaments pulled over thick filaments ◦ causes shortening of muscle fiver mechanism of skeletal muscle contraction ◦ relaxed: tropomyosin-troponin complexes block myosin attachment site on actin and prevent cross-bridge binding (1,2)  stimulation of muscle: increases intracellular Ca2+ --> binds troponin --> exposes myosin attachment sites on actin (3) contracting muscle: mysoin cross bridges bind to actin using energy from ATP hydrolysis and cycle through cross- bridge structural changes with attachment, detachment and reattachment (power stroke) causing sliding of thin and thick filaments rigor mortis: no more ATP so myosin heads cant be released from actin binding - no muscle relaxation once ATP production ceases and cross bridges are locked in place Hydrolysis of ATP: allows for cycle to continue Force of skeletal muscular contraction controlled by frequency of action potentials = temporal summation ◦ low frequency: briefly contracts then relaxes ◦ high frequency: muscle cannot relax between stimuli --> tetanic contraction ‣ cross bridge attachments are maximal = tetany controlled by number of active motor neurons = spatial summation ◦ small motor units --> reach only few muscle fibers, but easily excitable ◦ large motor units --> reach many muscle fiber, but less excitable ‣ stronger stimulation from CNS required to activate large motor neurons to achieve high force of contraction Skeletal Muscle Diversity slow and fast twitch  types of myosin and other proteins --> different contraction speeds of muscle fiber types different proportions of slow and fast twitch fibers ◦ postural muscles: mores slow twitch (maintain tone and resist fatigue) ◦ extraocular muscles: more fast twitch (required to make fast, brief movements) genetic differences - better sprinter (fast twitch) or long distance (slow twitch) distribution of fiber types is affected by motor neuron firing patterns and can be modified by training (endurance training = more slow twitch fibers) oxidative (more oxygen) because of glycolysis - fast twitch have more glycogen than slow twitch glycolysis - 2 ATP muscle has its own stores of oxygen -- myoglobin, not Hb Tetanus toxin produced by Clostridium tetani toxin travels to spinal cord and blocks inhibitory nerves allowing rapid fire of excitatory motor neurons rapid fire --> causes uncontrolled muscular contraction lethal from respiratory distress Duchenne Muscular Dystrophy dystrophin: important scaffolding protein between sarcolemma (covering membrane) and myofilaments formation of abnormal dystrophin x-linked inheritance - more common in genetic males causes progressive muscle inheritance and eventually death from respiratory failure Neuromuscular Junction Membrane potentials RMB - base value of transmembrane voltage in cell voltage (biological) - difference in charge between interior and exterior of cell excitable tissue (nerve and muscle) - presence of membrane potentials is fundamental to function of cells, ability to generate and propagate electrical signals in form of action potentials non excitable cells - also have membrane potentials but not necessary for their function Vm: composite of several diffusion potentials --> membrane usually permeable to more than 1 ion ◦ Depolarization: membrane potential difference is decreased ◦ Hyperpolarization – membrane potential difference is increased ◦ Repolarization – membrane potential returns to original state following either depolarization or hyperpolarization Action Potential constant electrical signal that can be propagated over long distances without decay all or none impulse when excitable cell membrane is depolarized beyond threshold voltage (-50mV) phase of rapid depolarization opening of voltage gated Na+ channels peak voltage achieved when rapid depolarization abruptly ends and cell membrane enters repolarization phase - closure of Na + channels Action Potential Conduction and Myelination faster in larger diameter nerve - less electrical resistance faster in myelinated nerves ◦ in peripheral nerves, myelin sheath interrupted at regular intervals by uncovered nodes of ranvier ◦ saltatory conduction faster than continous demyelination ◦ interferes with nerve conduction velocity and affects normal function ◦ can be fatal ‣ MS - CNS and gray and white matter disease chronic inflammatory demyelinating disease - episodic neurologic dysfunction inflammatory and degenerative components triggered by environmental factors, or genetically susceptible pt ‣ Guillain- Barre syndrome - PNS disease acute inflammatory neuropathy of sensory and motor nerves  may be triggered by acute infectious illness some forms are demyelinating Synaptic Transmission Electrical synapse: conduct action potentials from cell to cell directly through non selective ion pores (gap junctions) chemical synapse: release of neurotransmitter ◦ action potential of presynaptic cell --> neurotransmitter released and interacts with receptors of postsynaptic cell ◦ action potentials in presynaptic nerve terminals cause ca2+ entry through voltage gated CA2+ channels which triggers release of neurotransmitter by exocytosis ◦ mechanisms of neurotransmitter receptor binding termination ‣ diffusion ‣ enzymatic degradation (acetylcholinesterase) ‣ uptake of neurotransmitter into same nerve ending or another Neuromuscular Junction synapse between motor neuron and skeletal muscle cell each skeletal muscle cell has only one neuromuscular junction near cell midpoint motor neurons branch to activate a group of muscle fibers = motor unit motor neuron neurotransmitter = acetylcholine post synaptic muscle cell membrane: high density of nicotinic acetylcholine receptors ◦ non selective Na+ and K+ channels ◦ when Na+ and K+ channels are opened: depolarization of muscle cell membrane = muscle contraction Substances that affect neuromuscular transmission botulinum toxin - irreversibly inhibits acetylcholine release ◦ overactive bladder ◦ migraine ◦ muscle spasticity ◦ axillary hyperhidrosis ◦ wrinkles d- Tubocurarine and pancuronium - plant origin inhibits acetylcholine binding (reversible competitive antagonist at nicotinic acetylcholine receptor) inhibits action of acetylcholine --> flaccid paralysis of sk muscle --> used during general anesthesia Neostigmine inhibits acetylcholinesterase in synaptic space --> prolongs action of acetylcholine ◦ neuromuscular blockade reversal (after general anesthesia) Hyperkalemia membrane potential of cardiac cells maintained by concentration gradient of K + Excess K+ in the serum (ECF) = decreased concentration gradient With decreased concentration gradient flow of positive charges (K+) into the cell occurs slowly with gradual depolarization of the cell membrane The threshold voltage is never reached so an action potential is not generated When too many cardiac cells slowly depolarize simultaneously this can cause a fatal arrhythmia Myasthenia Gravis autoimmune disease - antibodies against nicotinic acetylcholine receptor reduces number of functioning receptors action potential not propagated easily causes muscle weakness neostigmine (pyridostigmine) - inhibits acetylcholinesterase - prolongs action of acetylcholine at nmj corticosteroids to reduce autoimmune reactions Genetics: Inheritance Patterns Autosomal Dominant - single copy of abnormal gene causes disease or trait affected relatives are in every generation males and females have equal chance of passing on mutation 50% chance of inheritance for each child Autosomal Recessive - must haver 2 copies of abnormal gene to show disease or trait usually only 1 generation affected (homozygous) both parents must be carriers (heterozygous) of mutation for offspring to be affected 25% chance of inheritance for each child carriers are heterozygous for mutation and can transmit to next generation, but parents are not completely affected affected (homozygous) individuals always transmit mutation to next gen if able to reproduce X- linked recessive no male to male transmission female carriers have milder symptoms than affected males males have only one x chromosome, but contains mutation inheritance risk for each child ◦ 100% for daughters (being at least a carrier) of affected/carrier fathrs ◦ 50% for daughters and sons of affected/ carrier mothers ◦ 0% for sons of affected/carrier fathers Y linked only males can carry y chromosome so Y linked mutations can only be transmitted from father to son Complex disease most diseases that are major public health burdens (diabetes, cardiovascular disease, cancers, asthma), multifactorial because caused by both genetic and environmental factors clustering of disease in multiple family members and relatives that does not follow predictable inheritance pattern later age of onset and variable expression of disease --> difficult to predict combined genetic and environmental influences --> can be protective, neutral or harmful ◦ protective environmental modifications (diet, exercise, medication, screening) --> prevent or delay expression of disease ◦ medical professionals must recognize variable expression to identify increased risks in time to establish preventive care Complex inheritance clustering of biologically related conditions in a family risk estimates based on empiric data ◦ # of relatives affected with condition (or related conditions) ◦ How closely one is related to the affected individual(s) ◦ Similarity of the shared environment ◦ Location of disease or body system involved ◦ Severity of the condition in the affected relative  ◦ Age at onset in the affected relative ◦ Sex of the affected relative Genetics and environment in autism developmental disability significantly affecting verbal and nonverbal communication and social interaction no single mutation that causes autism genotypes may be affected by environment (prenatal or early childhood exposures) environmental risk factors for autism: infection during pregnancy, maternal nutrition, parental age at conception, prematurity, exposure to medications like valproic acid Genetics: Mutations, Penetrance, Expressivity Impact of Genetic Disease Spontaneous Miscarriage - chromosome abnormality present in ~50% of all recognized first trimester pregnancy losses newborn infants - 2-3% have at least one major congenital abnormality, at least 50% caused by genetic factors childhood - genetic disorders account for 50% of all childhood blindness, deafness and severe learning disabilities adult life - 1% of all cancer is single-gene inheritance; 5-10% of common cancers (colon, breast, ovary) have strong hereditary component Genetic Disease Types single gene: alkaptonuria (protein metabolism), albinism (defective melanin), cystinuria (protein metabolism) chromosomal: trisomy 21 multifactorial/polygenic: cleft lip and cleft palate, diabetes mellitus, alzheimer disease acquired genetic disease: cancer Mutations - can be beneficial, harmful or neutral change in DNA sequence that causes disease --> unlike polymorphism, variation without disease Example Normal DNA reads: “get the red hat ” Mutation 1 reads: “get the red cap” (2 base pair change) There is no real change in meaning caused by this mutation Probably results in a neutral mutation Mutation 2 reads: “get the red cat” (only 1 base pair change) There is significant change in meaning caused by this mutation Potentially results in a harmful mutation Mutation 3 reads: “get the big hat” (3 base pair change & different location within sequence) There is significant change in meaning caused by this mutation *** Potentially beneficial mutation (in very sunny or wet environment / you have a big head) Mutation types Germline mutation ◦ occurs during formation of gametes - gametogenesis (ovum or sperm) ◦ every cell in new person's body will have mutation if cell was used in conception Somatic cell mutation ◦ after conception (joining of ovum and sperm) ◦ some cells of person's body will have mutation and others will not (mosaicism) Point ◦ change in one base of gene sequence AAA GGG TTT → A TA GGG TTT frameshift ◦ change that causes order of 3 bases (codon) to be read out of order which codes for a different set of AAs AAA GGG TTT → A TA AGG GTT T.. insertion - as in frameshift - generally result in nonfunctional proteins deletion ◦ sequence of DNA is lost during DNA replication (any # of nt can be deleted - abnormality of single protein or entire piece of chromosome) Duplication ◦ area of DNA is duplicated - total of 3 copies of that area ◦ extra DNA"instructions" often cause birth defects or developmental problems Nonsense - creates STOP codon which may stop synthesis of protein or create a partial  protein (either result may cause disease) Mutation causes radiation - short wavelengths electromagnetic waves (x and gamma) and high energy particles (alpha and beta particles, and neutrons) chemical mutagens - cigarette smoke, formaldehyde and benzene, some basic dyes, some food preservatives (nitrates and nitrites) - stomach cancer, char of barbecuing - stomach cancer infectious agents - HPV (oral and genital cancers), H. pylori (stomach cancer) DNA repair - cleavage of DNA strand, removal of damaged region, insertion of new bases and sealing break ◦ some mutations are not eliminated by DNA repair Chromosomal Abnormalities Translocation ◦ portions of chromosome broken off and attach to different location ◦ if no genetic info lost --> balanced translocation - often causes no problems ‣ if person reproduces - extra copy of original broken area of chromosome may be passed to offspring --> unbalanced translocation (possible birth defects) Ring ◦ portions of chromosome break off and free ends attach to form ring ◦ genetic info may be lost or inaccessible - problems in person inversion ◦ 2 breaks in one chromosome and free portion inverts (flips) prior to reinsertion ◦ if no genetic info lost, person may be unaffected ‣ abnormal copies made during gamete production may cause infertility problems or early pregnancy loss genetic penetrance ◦ rate at which mutant genotype can be recognized through phenotypic traits ◦ phenotypic characteristic must be defined ‣ for example - gene mutation + every individual > 40 yo with an abnormal bone density scan and 7/10 individuals meet this definition --> penetrance would be 70% ◦ penetrance may vary by definition ‣ for type 1 osteogenesis imperfecta: penetrance may be 90% if criteria are: gene mutation + individual >40 yo with abnormal bone density scan OR positive lab tests for abnormal collagen synthesis --> collagen deficiency = connective tissue problem ◦ penetrance may vary by age ‣ disease or trait may begin to show as one ages (Multiple Endocrine Neoplasia Type 1 -  7% by age 10, 100% by age 60) ◦ penetrance may vary with environmental factors ‣ trait for increased synthesis of LDL cholesterol may not show if one eats a low fat diet and avoids meat Genetic Expressivity extent to which mutant genotype affects phenotype - including affected tissues and severity of those effects EXAMPLE- Type 1 Osteogenesis Imperfecta - variable expressivity ◦ 2 individuals with same mutated gene may have different phenotypes ◦ condition is autosomal dominant inheritance but disease can skip generation ◦ individual in skipped generation is obligate carrier but displays no signs of severe disease ◦ blue scleras and short stature or multiple fractures and deformities and limited to wheelchair mutation is penetrant in both individuals but expression is variable reduced penetrance and variable expressivity can occur in individuals who cary same mutated gene ◦ differences due to ‣ effects of modifier genes ‣ environmental interactions ‣ chance (unknown factors) Mutation rate and prevalence of genetic disease DNA sequence mutations ◦ 20% chance of harmful mutation per new person ◦ only 1% has identifiable disease caused by single gene defect Harmful mutations of many single genes are lethal very early in development and lead to pregnancy loss and are never clinically apparent harmful mutations in some genes do not cause an easily recognizable abnormality of phenotype Selected Genetic Diseases single gene inheritance ◦ MENDELIAN OR MONOGENETIC ◦ mutations occur in DNA sequence of single gene ◦ ~5000 known single gene disorders ◦ single gene disorders have different patterns of genetic inheritance ‣ autosomal dominant ‣ autosomal recessive ‣ x linked (sex linked) - can recessive or dominant ‣ y linked (sex linked) ◦ examples ‣ sickle cell anemia phenotype: painful crises and poor tissue oxygenation associated with sickling of RBCs anemia caused by increase in RBC destruction (hemolysis) increased susceptibility to infections because spleen becomes damaged and immune functions are compromised ◦ get trapped in tiny capillaries, autosplenectomy occurs (death of spleen) genetic mechanism: autosomal recessive ◦ caused by single nonsense mutation (LYS to VAL) resulting in abnormal beta globin gene of hemoglobin ◦ beta chain is not producing normal Hb chain --> can't carry oxygen properly, tissues will starve of oxygen --> don't have ATP ◦ any person of color (higher incidence of malaria in Asia and Africa --> development as response to malaria) ‣ cystic fibrosis phenotype: recurrent pulmonary infections, ◦ thick mucous secretions occur in lungs blocking airways ◦ exocrine pancreatic insufficiency (decrease of pancreatic enzymes) --> blockage of hydrolytic enzymes --> cant get where they need to be to digest food --> they stay in pancreas (it eats itself!!!) ◦ male infertility due to blockage or absence of vas deferens ◦ mucus is blocking ducts (endocrine will secrete hormones directly into blood, exocrine ducts can be blocked, no hormones secreted) genetic mechanism: autosomal recessive ◦ mutations cause loos of function in chloride channels (allow for mucus secretion in lungs) ◦ very rare in asians ◦ 1:2000 in whites ◦ patients dont grow well - lack of oxygen causes poor development ‣ phenylketonuria phenotype: mental and growth restriction genetic mechanism: autosomal recessive inheritance caused by loss of function through mutations in phenylalanine hydroxylase gene ◦ enzyme necessary for metabolism of phenlyalanine to tyrosine ◦ accumulation of excessive phenylalanine causes phenylketonuria (PKU) which can cause irreversible CNS abnormalities ◦ 1:10,000 ◦ new born screening - if positive --> low protein diet with phenylalanine and aspartame restriction  ◦ failure to diagnose --> cognitive impairments ‣ fragile x syndrome phenotype: mental deficiency (cognitive impairment) ◦ characteristic facial features - microcephaly and enlarged ears ◦ large testes genetic mechanism: x linked inheritance ◦ unstable DNA causes failure to express a gene that encodes for RNA binding protein -->needed for normal brain development 1:1500 males, can be found in females ‣ alpha and beta thalassemia - autosomal recessive alpha: genetic mutations or deletions can cause abnormal alpha chain hemoglobin synthesis ◦ beta hemoglobin accumulates - body can't make alpha chains, so it makes more beta ◦ hemoglobin molecule is abnormal and hemolysis (destruction of RBC) occurs therefore O2 transport is decreased beta: inherited abnormal production of beta chain Hb ◦ alpha hemoglobin accumulates ◦ hemoglobin molecule is abnormal and hemolysis (destruction of RBC) occurs therefore O2 transport is decreased treatment: folic acid supplementation (like sickle cell) ◦ RBC transfusion prn ◦ avoid excessive iron supplementation since iron accumulates as result of hemolysis ‣ excessive iron accumulation in brain and liver potentially causes fatal damage ‣ hemochromatosis: accumulation of Fe, gets stuck inside of cell hepatocytes and brain cells end up flooded with iron, they die ◦ chelation therapy (deferoxamine) or dialysis to remove excessive iron multifactorial genetic inheritance ◦ also called complex or polygenic inheritance ◦ caused by environmental factors and mutations in multiple genes ◦ e.g. breast cancer: susceptibility has been found in chromosomes 6, 11, 13, 14, 15, 17 & 22 chromosome abnormalities - in number or structure ◦ problems during cell division causing deletion of chromosomes, extra copies of chromosomes, abnormal structure of chromosomes ‣ example: down syndrome (trisomy 21)- failure of chromosome 21 to separate during gamete formation causing an extra chromosome in all body cells - affects multiple organ systems ◦ 1:800, increased risk with advanced maternal age ◦ ASD (atrial septal defect) or VSD (ventricular septal defect) ◦ mental and growth restriction ◦ dysmorphic features, high forehead, wide gap between 1st and 2nd toes, single line on palm ◦ internal organ abnormalities - congenital heart disease, thyroid disease turner syndrome (45, XO) missing sex chromosome, female born with only one x chromosome --> affects multiple organ systems ◦ only chromosomal monosomy compatible with postnatal life in humans ◦ 1:2500 girls ◦ usually short stature, phenotype is female, need second x chromosome for  internal female genitalia, wide spaced nipples, webbed neck, blind ended vagina, no dev of uterus ◦ heart defects - valvular disorders ◦ delayed puberty ◦ infertility ◦ learning disabilities klinefelter (47, XXY or XXXY) - phenotypically male, internal organs, super tall, gynecoid pelvis, develop gynecomastia ◦ many signs related to low testosterone levels ◦ males with reduced muscle mass but taller than most other males ◦ fat deposition is female, but male phenotype ◦ delayed puberty ◦ infertility ◦ osteoporosis ◦ small penis and testes --> phenotypically male, but dont develop male genitalia ◦ chromosome imbalance: caused by extra x chromosome in male (has XY chromosome also) ◦ 1:650 boys cri du chat (46, XX or XY, 5p-) known as cry of the cat syndrome, position 5 - microcephaly - ears enlarged due to microcephaly, shriek as part of presentation ◦ low muscle tone at birth but eventually become hypertonic ◦ risk of ear infections and hearing loss ◦ mental and muscular restriction ◦ round or plump face ◦ possible crossed eyes or broad nasal bridge ◦ genetic mechanism: deletion of genetic material on small arm (p arm) of chromosome 5 ◦ 1:15,000 - 1:50,000 mitochondrial genetic inheritance disorders ◦ mutations in non nuclear DNA (mitochondrial) ◦ each mitochondrion contains 5-10 circular pieces of DNA - about 37 genes coding for proteins ◦ oocytes keep their mitochondria during fertilization (sperm cells do not) --> always inherited from female parent! ◦ paternal mitochondrial DNA self-destructs or is consumed by phagosomes shortly after fertilization of oocyte ‣ examples leber's hereditary optic neuropathy (LHON) - an eye disease ◦ acute or subacute blindness ◦ occasionally myopathy or neurodegeneration ◦ mutation of mitochondrial DNA affects ETC function ◦ 1:100,000 - 1:50,000 ◦ inflammation of retinal vessels - feeding oxygen to retinal tissue ‣ starving retinal tissue, causes loss of vision myoclonic epilepsy with ragged red fibers (MERRF) mitochondrial encephalopathy, lactic acidosis and stroke like episodes (MELAS) - rare form of dementia