SFI Exam I

Patch Clamp for voltage-gated Sodium channel

- Time on X-axis - Current on Y-axis - voltage step from -70 mV to -20 mV - opening characteristics of one Na+ channel - the Na+ channel opens with slightly different latency in each trace, and the sum of all seven is shown at the bottom - the macroscopic current we see in the cell is the result of the summed average of the currents of many thousands of channels - total duration of the trace is 20 ms - Na+ channel is most likely to open very quickly after the voltage step is made - V-gated Na+ channels are fast-opening ion pores Na+ channels exhibit inactivation - A V-gated Na+ channel has three conformations: Open, closed-inactivated, and closed - characteristic is essential for the propagation of action potentials down an axon. A stimulus pulse is given --> V-gated channel senses this voltage step and opens - Channel opening increases conductance (G) and we see an increase in Na+ current (I) Just after the peak of the current, the channel closes and enters its closed-inactivated state - confirmation is dependent on both time and voltage The channel remains inactive until the cell repolarizes and enters its closed confirmation Closed-inactivated channel and closed channel create a period of time where another AP cannot happen: basis for refractory period - When the channel is closed-inactivated, no spike can happen, regardless of how much the voltage changes - In closed state, a spike can be initiated but it would require a stronger depolarizing stimulus voltage gated Na+ channels show both voltage and time dependent changes

Schwann Cell

- enclose multiple unmyelinated axons within invaginations/canals in their cytoplasm - Myelinate a single axon As a Schwann cell wraps around the axon --> cytoplasm is progressively reduced and the inner layers fuse - 1 Schwann cell = 1 internode per axon - Small pockets of cytoplasm called Schmidt-Lanterman clefts are found in PNS - Schmidt-Lanterman incisures occur in the compact myelin. - These clefts are regions within compact myelin in which the cytoplasmic faces of the enveloping myelin sheath are not tightly juxtaposed. Organization of Schwann cell interactions w/both unmyelinated and myelinated axons in PNS nerves - Schwann cell processes completely envelop the axons - the external aspect of the Schwann cell in enclosed in a continuous basal lamina that extends across the Node of Ranvier - arrangements permits the Schwann cell to control the ionic environment surrounding the axon

Neurotransmitter Release Overview

1. Action potentials depolarize presynaptic membrane 2. Voltage-gated Ca2+ channels (VGCC) on presynaptic membrane open 3. Intracellular [Ca2+ ]'s increase ~1000-fold 4. Ca2+ sensors in fusion machinery triggers vesicle fusion to synaptic terminal PM 5. NTs released into synaptic cleft

Norepinephrine (NE) Synthesis, Release, Inactivation Termination/Removal

1. Active transport (uptake) of tyrosine into cell synaptic terminal 2. Tyrosine converted into L-DOPA by enzyme tyrosine hydroxylase in cytoplasm - (rate limiting step) 3. L-DOPA is converted to dopamine by enzyme DOPA-decarboxylase in cytoplasm 4. Dopamine (DA) is actively transported into storage vesicles 5. Inside vesicle, DA is converted into norepinephrine (NE) by the enzyme DA-b-hydroxylase (DBH) 6. Exocytosis/release of NE into synaptic space due to Ca2+ influx; NE diffuses across the cleft and binds to its postsynaptic receptor 7. Re-uptake of NE into presynaptic terminal by a NE transporter 8. NE in cytoplasm can be metabolized in mitochondria by the enzyme monoamine oxidase (MAO) 9. NE also can diffuse from synaptic cleft, enter the circulatory system and be metabolized by MAO and catechol-O-methyltransferase (COMT) in the liver (PNS) - In PNS , NE is degraded in the liver by MAO and COMT - main way NE is degraded in the periphery 10. NE that enters the postsynaptic cell can be metabolized by COMT

Serotonin (5-HT) Synthesis, Release & Inactivation

1. Active transport of tryptophan into cell synaptic terminal 2. Tryptophan converted to 5-hydroxytryptophan by enzyme tryptophan-5-hydroxylase - rate limiting step 3. 5-hydroxytryptophan is converted to serotonin (5-HT; 5-hydroxytryptamine) by enzyme aromatic L-amino acid decarboxylase (AADC) 4. Serotonin is actively transported into storage vesicles 5. Exocytosis/release of serotonin into synaptic space due to Ca2+ influx; serotonin diffuses across the cleft and binds to its postsynaptic receptor 6. Re-uptake/removal of serotonin by specific presynaptic transporter (SERT) 7. Serotonin is metabolized by MAO or reloaded into vesicles

Acetylcholine Synthesis, Release & Inactivation

1. Choline AcetylTransferase (ChAT) - synthesized in soma, transported to terminal (made by cholinergic neurons only) 2. Acetyl Coenzyme-A (Acetyl CoA) - produced in mitochondria 3. Choline actively transported into terminal by a transport molecule (Rate-limiting step) - Na+ dependent symporter 4. Acetylcholine (ACh) synthesized in cytoplasm by ChAT (biosynthetic enzyme) - choline + Acetyl CoA 5. Active transport of ACh into vesicle 6. Exocytosis/release of ACh into synaptic space due to Ca2+ influx 7. Removal/degradation: - Hydrolysis of ACh by acetylcholine esterase (AChE) into choline and acetic acid w/re-uptake of choline into presynaptic terminal - AChE is produced and tethered to the postsynaptic cell - AChE is target of nerve gases (sarin), insecticides, and drugs (physostigmine)

Regulation of Muscle Tension: 1. Length/Tension Relationship

Length-tension relationship in a whole muscle differs from that of a single myofiber Total tension of a muscle = sum of the forces of its active and passive elastic elements. Active tension: - due to the actin/myosin crossbridges in sliding filament theory, there is a point of maximum active tension - tension seen for normal sarcomere contraction, (this is the l/t graph from before, where at specific length get max force from max overlap). Passive tension: - due to elasticity of muscle components (tendency of the stretched sarcomeres, tendons to return to their original shape) - when entire muscle unit comes into play, "parallel" elastic element --> parallel because is synergistic with active component. - recoil produced tension - This is an intrinsic tension Total tension = active + parallel tension - Two elements work together within the muscle unit so when added together, sort of balance each other out, corresponds to almost a flat line **When you have a total muscle unit, increasing the length will do almost nothing to the tension, x-intercept of this is your resting length in the body - Resting length does not allow you to change strength by changing length in contrast to cardiac and smooth muscle

Principles of Screening (Characteristics of Good Screening Test)

1. Disease - Should have significant effect on quality or length of life - Acceptable and effective treatment exists - Asymptomatic period during which the disease is (more) treatable - Early treatment (pre-clinical stage) yields better outcomes than delayed treatment (after symptoms develop) - Exampe: testicular cancer does NOT abide by the 4th bullet so not screened for, early detection does not actually yield better outcomes 2. Test - Is a screening test available? - Is test acceptable to patients? - Is the test sufficiently sensitive to detect pre-clinical disease? (few false negatives) - Is the test sufficiently specific to minimize false-positive results? 3. Population - Is the prevalence of the disease high enough to justify screening? - If disease is uncommon, then most positive screening tests will be false positives (low PPV) - Is there access to relevant medical care? - Is the population willing to comply with further work-up and treatment?

Lymphatic System Function 1

1. Draining of Interstitial Fluid - Return of Tissue Fluid/Lymph to circulation Lymph can get in, but not out (one way openings) - Ends of endothelial cells overlap - When ISF pressure greater than lymph, cells separate - Fluid enters lymphatic capillary - When pressure of lymph is greater, cells adhere more closely so lymph cannot flow out (cannot flow backwards) Anchoring filament: - edema causes pulling and greater opening of capillaries - More interstitial fluid can then return during edema (get it out of ISF space)

Ionotropic Receptors

Ligand-gated ion channel (direct gating) Produces a change in postsynaptic potential Fast synaptic transmission (milliseconds) Selectivity of ion channel receptors determines whether effect will be inhibitory or stimulatory - depolarization --> if permeable to Na+ (excitatory) - hyperpolarization --> if permeable to Cl- (inhibitory) Kinetics of NT binding determines length of channel opening and duration of effect

Components of an Ion Channel

1. Gate (ex. if it is voltage-sensitive or activated by a ligand) 2. Ion Selectivity Filter - use size and loose interior binding sites to select for ions - alteration of few specific aa residues lining channel pore can change the specificity of the channel and affect the permeability of the membrane for an ion 3. Typically there are glycoproteins 4. Anchor proteins to keep them stabilized to the lipid bilayer 5. Voltage sensors or ligand binding site

Catecholamine Synthetic Pathways

1. L-Tyrosine converted to L-DOPA by Tyrosine Hydroxylase in cytoplasm of synaptic terminal - rate limiting step - highly regulated enzyme - Tyrosine Hydroxylase is made in soma 2. L-DOPA is converted to Dopamine by DOPA decarboxylase (AADC - aromatic L-amino acid decarboxylase) 3. Dopamine transported into vesicle 4. Dopamine is converted to norepinephrine by Dopamine beta-hydroxylase (DBH) - this reaction occurs within the synaptic vesicle - Norepinephrine (NE) is the only NT produced inside synaptic vesicle - DBH inside vesicle identifies NE neurons Only in epinephrine neurons & adrenals 5. Norepinephrine leaks out from vesicle into cytoplasm 6. Norepinephrine is converted to epinephrine by phenylethanolamine N-methyl-transferase (PNMT) in the cytoplasm 7. Epinephrine is transported into the vesicle

Pitfalls of Evaluating Screening Tests

1. Lead time bias 2. Length time bias 3. Overdiagnosis bias

Cellular Components of CNS

1. Neurons 2. Glial Cells - Astrocytes - Oligodendrocytes - Microglia III. Other Cell Types - Ependymal cells - line the cerebrospinal filled (CSF) ventricles and central canal of the spinal cord, ciliated columnar shape and play in production, regulation, movement of CSF, apical surface is covered in a layer of cilia, which circulate CSF around the CNS, apical surfaces are also covered with microvilli, which absorb CSF - Choroid Plexus Cells (produces CSF): population of modified complex of ependymal cells and capillaries form a structure called the - Pial cells - delicate innermost layer (pia mater) of meninges. Other two meningeal membranes are arachnoid and dura mater. The pia mater is a thin fibrous tissue that is permeable to water and small solutes. It allows blood vessels to pass through and nourish the brain. When the pia mater becomes irritated and inflamed the result is meningitis - Vascular cells

Interpretation of Clinical Significance

1. No evidence of significant and clinical change, keep doing things the same way! 2. There is a trend in effect size, but is the sample size too small? 3. Statistically significant but no clinical significance 4. Statistically significant and practical clinical significance, suggest a change in practice

Functional Divisions of the Nervous System Diagram

1. Somatic Somatic and special sensory receptors, somatic sensory neurons --> CNS --> Somatic motor neurons (voluntary) --> Skeletal muscle 2. Visceral/Autonomic Autonomic (visceral) sensory receptors, autonomic sensory neurons --> CNS --> Autonomic motor neurons (involuntary); sympathetic and parasympathetic divisions --> smooth muscle, cardiac muscle, glands/Enteric motor neurons - Parasympathetic - Sympathetic 3. Enteric NS Enteric sensory receptors, enteric sensory neurons in GI tract and enteric plexuses --> CNS/Enteric motor neurons (involuntary) in enteric plexuses --> smooth muscle, glands, endocrine cells of GI tract

Peripheral Nerves

1. Spinal Nerves - extend from spinal cord 2. Cranial Nerves - extend from brain stem

Types of Significance

1. Statistical Significance - P-Values, Confidence Intervals - Answers: How likely is your sample statistic based on the null hypothesis? 2. Practical Significance (Magnitude) - Effect Sizes - Answers: How large is your estimate/difference? 3. Clinical/Educational Significance - Medical Knowledge - Answers: How much value/meaning is there in the above values to the body of knowledge?

Bradford Hill Criteria for Causality

1. Strength of Association - Odds Ratio/Relative Risk 2. Consistency - Results similar from study to study 3. Specificity - Specific cause yields a specific disease - Specific mechanism for multiple diseases 4. Temporal Relationship - Exposure precedes outcome 5. Biologic Gradient - Dose response demonstrated - (increase in exposure leads to increase in effect) 6. Plausibility - Agree with current understanding of pathologic process 7. Coherence - Fit with current knowledge about the disease process 8. Experiment - Clinical trials support causation 9. Analogy - Data from other areas support causation

Criteria for Neurotransmitters

1. Synthesized in the neuron 2. Released in response to presynaptic depolarization and the release is Ca2+ dependent. 3. Specific receptors exist on the postsynaptic cell that bind the molecule. 4. Specific mechanisms exist which terminate its actions. - Destroy or take back up Acetylcholine (ACh) Norepinephrine (NE) Epinephrine (E) Serotonin (5-HT)

Criteria for Neurotransmitters and Important NT in ANS

1. Synthesized in the neuron. 2. Released in response to presynaptic depolarization in a Ca++ dependent fashion 3. Specific receptors exist on post-synaptic cell that bind the molecule. 5. Specific mechanisms exist which terminate its actions. Type 1. Amino acids - glutamate, glycine, GABA 2. Biogenic amines - acetylcholine, catecholamines (dopamine, norepinephrine, epinephrine), serotonin, histamine 3. Neuropeptides - VIP, endorphins 4. Adenosine 5. Gaseous - NO **important transmitters in the autonomic nervous

Summary of NMJ Action Potential

1. Terminal end of motor neuron takes up Ca2+ after depolarization 2. Vesicles exocytose ACh 3. ACh reaches ACh receptors of muscle fiber and binds producing an EPP 4. EPP triggers an AP and a wave of depolarization is sent along the muscle cell membrane, down the T-tubules and into the triad 5. Depolarization reaches the voltage-sensitive DHP receptor (L-type Ca2+ channel) and activates it 6. The DHP receptor "tickles" and activates the Ryanodine receptors (calcium-release channels) 7. Ca2+ is released from the SR into the sarcoplasm

Main Points of Sensitivity, Specificity, PPV, and NPV

1. The correct interpretation of a test result depends on the characteristics of the population from which the patient came. 2. For a particular test, the sensitivity and specificity remain constant even when the population characteristics change. 3. For a particular test, the PPV and NPV change when the population characteristics change. - If the prevalence of the disease is higher - the PPV will increase - if the prevalence of the disease is lower - the PPV will decrease - you can increase in the PPV by increasing the specificity of the test (get a better test!)

Measurement of TBW

1. Tritiated water (3H2O) 2. Deuterium oxide (D2O)

Types of Carrier Protein Transport

1. Uniport: Transport of a single substance 2. Symport: Transport of more than one substance in same direction (cotransport) 3. Antiport: Transport of more than one substance in opposite directions (countertransport or exchange)

Adrenergic (NE and EPI) Receptors

1. alpha-adrenergic receptors: (activated by EPI, NE) alpha1 receptors mediate excitatory smooth muscle responses: - mydriasis - radial muscle contraction - constriction of blood vessels everywhere (smooth muscle contraction) - piloerection 2. beta-adrenergic receptors: beta1 receptors mediate: (activated by EPI, NE) - increased heart rate and myocardial contractility (cardiac muscle contraction) - increased renin release beta2 receptors mediate: (activated by EPI only) (Beta2 receptors are not innervated by SNS neurons, they are stimulated by circulating EPI) - bronchodilation (smooth muscle relaxation) - vasodilation in skeletal muscle blood vessels (smooth muscle relaxation) - liver - increased glucose release

Circulatory System and Lymphatics

10% of fluid found in plasma does not return back into systemic circulation via venous return This 10% becomes the lymph

Lymphatic System Function 2

2. Transport of Dietary Lipids - from GI to blood stream GI has large SA to be efficient at absorption Villi and inner layers of the wall of small intestine Absorptive cell with microvilli Intestinal villi: - consist of blood capillaries and lymphatics - Lymphatics = lacteal (lacteus= milky) - Function: transport triglycerides (fats) from GI to blood - Bypass liver during first go around! - Fat in lymph makes it creamy white = chyle (juice) By-pass of Liver: Portal Circulation - drains straight to thoracic duct --> left subclavian --> superior vena cava --> right atrium - bypass liver filtering - fat/triglycerides goes straight to heart into systemic circulation

Lymphatic System Function 3

3. Protecting against invasion/Immune Response Lymphocyte Activation - adaptive immune response

Probability

A number that describes how likely it is that an event will occur

Amyotrophic Lateral Sclerosis/Poliomyelitis

Loss of alpha motor neurons Decrease of size of compound action potential

Embryonic Development of CNS

Lumen of Neural Tube (neural canal) forms the Ventricular System Neuroepithelial Cells lining the Neural Tube form CNS Neural Tissue **Optic Vesicles (level of diencephalon) --> Retina of eye is a part of CNS Diencephalon surrounds the 3rd Ventricle

Lymphatic System General Terminology and Structure

Lymph = clear water Tissue fluid = lymph Composition: - Fluid (lymph) - Vessels (lymphatics) - Structures and organs that contain lymphatic tissue - Red bone marrow (site of lymphocyte production) Function: 1. Draining interstitial fluid 2. Transport of dietary lipids 3. Protecting against invasion

Lymph Bodies, Trunks, and Ducts

Lymph nodes - appear throughout body in groups (~500) - Superficial/deep - Filter lymph: enters at one end, out the other - Site where lymphatic and immune systems intersect - Bubo (Gr.bubōn, groin) - Location & direction of flow important in diagnosis/prog-nosis of cancer spread by metastasis - Cancer in lymph nodes not tender - Inflamed lymph nodes feel tender Thoracic Duct drains all lower body below umbilicus and left upper body to the left of medial line - empties into left subclavian vein Right Lymphatic Duct drains right upper body to right of medial line - empties into right subclavian vein

Lymphatic System Pathological Definitions

Lymphadenopathy: Any disease of lymph node Lymphedema: Swelling due to accumulation of lymphatic fluid in loose connective tissue Lymphoma: Any neoplasm (tumor) of the lymphoid tissue, whether benign or malignant Lymphangitis: - infection caused by severe trauma, elephantitis, parasitic infiltration all of which damage the lymphatic vessels causing severe Lymphedema - Elephantitis: parasite colonizes/inhabits lymphatic vessels causing blockage of lymphatic vessels impairing drainage back to venous system and severe fluid accumulation - Post-radical mastectomy: removal of axillary lymph nodes affect drainage from the arms, results in painful lymphedema after cancer surgery

Receptor Clustering at Post Synaptic Membrane (End Plate in Muscle)

AChRs cluster at the motor end plate AChRs need help of scaffolding proteins - two important ones are agrin and dystrophin Dystrophin - links/anchors muscle membrane/receptors/channels to the actin cytoskeleton, giving structure to the NMJ - Gene defects can result in Duchenne muscular dystrophy - Duchenne gene is the second-longest gene in the genome Agrin - extracellular mediator, activates MuSK, a tyrosine kinase, which then goes on to activate rapsyn, an intracellular component which aggregates the receptor - found on nerve terminal and tell the muscle membrane to form a new NJM

Periodic Health Examination (PHE)

AKA the "physical" Consists of one or more visits with a primary care clinician to assess a patient's overall health status and risk factors for preventable disease Opportunity to deliver screening tests and other preventive services (e.g., immunizations) tailored to patient's age, sex, and risk factors Long tradition Limited evidence

Lymphatic Vessel Formation

Lymphatic vessels begin as close-ended vessels called lymphatic capillaries Converge to form larger tubes called lymphatic vessels Resemble veins, but have thinner walls and more valves At intervals, lymph flows through lymphatic tissue structures, lymph nodes

Main Neurotransmitters of ANS

Acetylcholine (cholinergic neurons): 1. preganglionic neurons of SNS and PNS 2. postganglionic neurons of PNS 3. postganglionic neurons of SNS that innervate sweat glands - sympathetic cholinergic fibers (special case) 3. alpha-motoneurons of Somatic NS that innervate skeletal muscle Norepinephrine (adrenergic neurons) and Epinephrine: 1. postganglionic neurons of SNS release norepinephrine 2. adrenal medulla secretes: (neuroendocrine cells - chromaffin cells-specialized post ganglionic neurons) - norepinephrine - 20% - epinephrine - 80%

Sliding Filament Theory

Actin: Individual G (globular) actin monomers line up to create filamentous actin (F-actin). Two filaments intertwine to create functional-actin filament. Filament is found w/tropomyosin along length of the actin active sites, and troponin at certain regulatory points. Troponin has three subunits. 1. Troponin T - (T for tropomyosin) attaches troponin complex to tropomyosin 2. Troponin I - (I for inhibition) lock in place tropomyosin to inhibit actin/myosin interaction 3. Troponin C - (C for Ca2+) binds Ca2+, causing tropomyosin to move out of the way so actin/myosin interaction can occur - 4 calcium binding sites - 2 high affinity sites occupied all the time - 2 low affinity sites that allow triggering of sliding filament when calcium increases Myosin: - 2 chains of light meromyosin - tails - 2 heads of heavy meromyosin - heads - Myosin has two hinged regions - Heads have an actin binding site and an ATP binding site (can hydrolyze ATP - ATPases - The energy released from ATP hydrolysis allows hinged area attached to backbone via a cross bridge to do a 45 degree angle motion. - Ca2+ comes from the SR, goes into the cytoplasm (sarcoplasm) - Ca2+ binds to troponin C and causes the tropomyosin to move off actin active site - allows sliding to happen since actin can now interact with myosin Clinical correlation: when cardiac muscle breaks down in a heart attack, troponin gets into the blood stream and can be measured in the blood.

Action Potential General Overview

Action potentials are produced in excitable cells: - neurons - skeletal muscle - smooth muscle - secretory cells, etc - All or nothing events: they will only occur if the membrane potential reaches a certain threshold level (around -50 mV). - Once initiated, the amplitude of each AP will always be the same. - Depolarization phase of the AP is caused by the opening of voltage gated Na+channels that allow Na+ to rush into the cell, making the membrane potential less negative to a positive maximum called overshoot - As sodium rushes in, positive charge is deposited in the cell, causing further depolarization. At threshold, an AP takes off in a rapid, self-sustaining manner: current entering through Na+ channels is sufficient by itself to continue the depolarization in a regenerative cascade of positive feedback. - The voltage gated Na+channels then inactivate at about the same time that delayed rectifier voltage gated K+ channels open, initiating the repolarization phase - opening of these channels allows K+to flow out of the cell, returning the membrane potential back to the resting membrane potential or slightly below - slight hyperpolarization at the end of the AP is called the undershoot and is due to the long lasting activation of these channels after the depolarization that will take a little time to close. RMP of most cells is closer to equilibrium (Nernst) potential for K+ EK than Na+ - cell membrane has a higher permeability for K+(greater number of K+ then Na+ leak channels) and therefore K+has the greatest impact on the overall resting potential (Vm) When threshold is reached and voltage gated Na+channels begin to open, the permeability for Na+goes way up because excitable cells typically have lots of these channels - there are so many voltage gated Na+channels that the voltage at the peak of the AP is close to equilibrium potential of Na+, ENa.

Cohort Studies Advantages v. Disadvantages

Advantages - Complete description of experience - Multiple effects of exposure (risks and benefits) - Calculation of incidence rates - Less prone to bias Disadvantages - Difficult (impossible?) for rare diseases - Expensive (can take years) - Often long follow-up - Exposure may change - Maintaining follow-up can be difficult

Case-Control Studies Advantages v. Disadvantages

Advantages - Good for rare diseases - Good for rare exposures: If account for large number of cases - Relatively quick and easy to do - Relatively inexpensive - Fewer subjects - Multiple causes (exposures) can be studied - Interactions between causes can be studied Disadvantages - Relies on recall of past (Recall Bias) - More susceptible to bias - Recall bias - Selection bias: Are controls at risk for disease? - Validation of exposure difficult or impossible - Selection of controls difficult - Incidence rates cannot be calculated - Look at odds of disease

Lead Time Bias

Affect time to death without affecting ultimate prognosis by diagnosing the disease earlier in its course - Overestimation of survival duration among screen-detected cases (vs usual care) when survival is measured from diagnosis - Reflection/artifact of earlier diagnosis - Overall prognosis of the patient is unchanged - Do not be deceived by 5 year survival rate Increasing 5-year survival rates do not always correlate with fewer deaths - compared 5-year cancer survival and mortality statistics in U.S. in 1950-54 and 1989-1995 - Prostate cancer survival increased from 43 to 93 percent, but mortality rose by 10 percent - Melanoma survival increased from 49 to 88 percent, but mortality rose by 161 percent - Kidney cancer survival increased from 34 to 61 percent, but mortality rose by 37 percent

Afferent and Efferent Neurons

Afferent --> sensory - receive and transmit information from the internal and external environments to the CNS Efferent --> motor - transmit information generated in the CNS to the periphery

How does decreasing alpha affect Alpha, Beta, and Power

Alpha Error decreases Beta Error increases Power decreases

Likelihood Ratio (LR)

Also known as Bayes Factor likelihood that a given test result would be expected in a patient with the target disorder compared to the likelihood that that same result would be expected in a patient without the target disorder. LR = Sn/(1-Sp) TP/FP

Nernst Equilibrium: One Ion Channel

Also known as electrochemical equilibrium Nernst's Equation will give value of equilibrium potential (voltage): Eeq = 60/Z log Xo/Xi - Use for determination of equilibrium potentials for any ion Hypothetical glial cell - intracellular [K+] is 100 mM - extracellular [K+] is 10 mM - This cell has ONLY leakage K channels - Since the cell's membrane has potassium channels, K+will move down its concentration gradient out of the cell entering the extracellular space (inside to outside) - As K+ leaves, the inside will become more negative due to the higher abundance of unbalanced A- - This will continue until the system has reached its electrochemical equilibrium - equilibrium is established when outward flow of potassium due to the concentration gradient is equal to the inward flow of potassium due to the electrical gradient - No net flux at equilibrium - The electrical gradient comes from the net negative charge created each time potassium leaves the cell Note this is not the same as resting membrane potential which is at steady-state, not an equilibrium.) Ek = 60/Z log Ko/Ki Ek = 60/1 log (10/100) Ek = -60 mV - intracellular environment has an electrical voltage (potential) 60 mV less than surrounding extracellular environment - Nernst potential for Na+and Cl-in example cell should not be considered because there are not leak channels for those ions in our example cell Membrane Potential = Equilibrium Potential of K+

Action Potential Summary

An AP is a self-sustaining, regenerative current driven by influx of sodium and efflux of potassium Sequence of events in an AP: - Membrane depolarization opens V-gated sodium channels (-50mV) - Sodium rushes into the cell (down its concentration gradient) - The cell depolarizes which helps to open more sodium channels - Membrane potential is driven up to Erev for Na+ - this limits the duration of the AP in two ways: 1) Sodium Channels inactivate which causes a decrease in GNa 2) Depolarization opens V-gated potassium channels to increase GK - Potassium rushes out to repolarize the cell (down its concentration gradient) - Local circuit currents are produced during an action potential which allow depolarization spreading (propagation) to the nearby membrane. - could potentially produce a retrograde flow of current (AP going the wrong way down an axon) --> prevented by refractory period

Main Hallmarks of Parasympathetic Division

Anatomical Differences - Parasympathetic pathways have relatively short postganglionic fibers - Ganglia lie far from CNS, nearby or within innervated organs - Parasympathetic fibers are more localized and discrete Biochemical Differences - Postganglionic fibers release acetylcholine

Main Hallmarks of Sympathetic Division

Anatomical Differences - Sympathetic pathways have long postganglionic fibers - Ganglia lie close to CNS - Sympathetic fibers branch profusely - divergence Biochemical Differences - Postganglionic fibers predominately release norepinephrine - Few exceptions e.g. sweat glands (acetylcholine)

Axon Properties

Arises from cell body at axon hillock --> Summation and generation of AP at axon hillock Transmits information (Action Potentials) - To other neurons - To effector cells (e.g., muscle) Action Potentials - Due to rapid change in electrical charges across axonal membrane - Ion channels responsible for changes in membrane charge Cytoplasm/axoplasm - Contains dense bundles of microtubules and neurofilaments - Play a key role in transport of metabolites and organelles Typically devoid of ribosomes - Distinguishes axons from dendrites - do not produce proteins - Has smooth ER (SER) Generally neurons have a single axon - Range from short (few mm) to long (>1.5 m) - Accounts for ~99.8% of the total neuron volume

Myasthenia Gravis

Autoimmune disease Antibodies against nicotinic AChR at NMJ --> destroy AChR Reduction of Safety factor via reduction of mepp amplitude and quantal size

Multiple Sclerosis

Autoimmune disease Antibodies attack CNS myelin - oligodendrocytes Global reduction of conduction velocity in CNS

Guillain-Barre Syndrome

Autoimmune disease Antibodies attack peripheral (PNS) myelin - schwann cells Global reduction of conduction velocity in peripheral nerve

Lambert Eaton Myasthenia

Autoimmune disease Antibodies to presynaptic P type calcium channels at NMJ Reduction of Safety factor via reduction of vesicle release and quantal content

Functional Integration of ANS

Autonomic Nervous System - known as vegetative or involuntary nervous system - regulates involuntary responses of smooth muscle, glands, blood vessels, heart, visceral organs - regulates physiologic processes that do not require consciousness 1. ANS controls/helps regulate body temperature, sweating, pupillary constriction, vascular tone, heart rate and contractility, salivation, bronchial secretions and tone, gastrointestinal secretions and motility, water and electrolyte balance, bladder emptying, reproductive functions, etc. 2. Receives and automatically responds to sensory information from the periphery (i.e., from photoreceptors, mechanoreceptors, baroreceptors, chemoreceptors, pain receptors) 3. Controlled by centers in hypothalamus (homeostasis) and brain stem that are influenced by higher brain areas such as the cortex and limbic system

ANS Effects on the Heart, Blood vessels and Kidney

Autonomic Nervous System in the Control of Blood Pressure Parasympathetic Effects (Acetylcholine stimulation of muscarinic receptors) Heart - decreased heart rate (SA node) - decreased conduction through AV node - decreased contractility of atria Sympathetic effects (NE and EPI) Heart (beta1 receptor mediated) - increased heart rate (SA node) - increased conduction through AV node - increased contractility (atrial & ventricular muscle) Blood vessels - arterial and venous constriction (alpha1 receptor mediated) - vasodilation in skeletal muscle b.v. and b.v. to liver (beta2 receptor mediated) Kidney - increased renin secretion (beta1 receptor mediated) - increased blood volume

Anatomy of Heart and Cardiac Conduction

Autonomic tone: continuous basal nerve activity (tonic activity) Parasympathetic tone: SA node - PNS tone (via vagus nerve) - lowers HR below the intrinsic rate of the heart (~100bpm) - withdrawal of PNS tone increases HR Sympathetic tone: Arterioles - SNS tone to arterioles - causes partial constriction of arterioles to maintain blood pressure - Sympathetic stimulation of arterioles can be increased or decreased to increase or decrease blood pressure

Axonal Terminals

Axon Terminals contain Chemical Synapse - Synaptic contacts may occur at axon terminations and along axon length - Composed of pre- and post-synaptic elements and a synaptic cleft Variety of synaptic types - Neuron-Neuron - Neuron-NMJ - Neuron-Secretory cell (gland) Chemical Synapse release Neurotransmitters

Axon/Soma Interface

Axon hillock - graded membrane potentials (EPSP, IPSP) are summated before being transmitted to the axon Initial segment (AIS) - Earliest site of action potential initiation - First ~50-100 μm of the axon

Brain Imaging Techniques

Magnetic Resonance Imaging (MRI) Diffusion Tensor Imaging (DTI) - blood flow patterns

Practical Significance

Magnitude Effect size: Magnitude of the effect, difference or association in the population - measures strength of the relationship between groups - the bigger the effect size, the stronger the independent variables influence on the dependent variable Statistically can be measured by: - Mean difference - Relative Risk - Odds Ratio - Pearson's r (Correlation) Common Effect Sizes Mean Difference: Difference between estimates of 2 groups mWeight(Males) - mWeight(Females) Relative Risk: Rate of incidence between 2 groups - (New Cases/Participants)Intervention/(New Cases/Participants)Control Odds Ratio: Odds of Cases and Non-Cases between 2 groups - 2 groups are usually different by Exposure of Interest - Used a lot in observational studies (Case-Control)

Autonomic Tone

Many parts of the ANS demonstrate continuous basal activity (tonic activity) Parasympathetic Tone: 1. SA node - PNS tone (via vagus nerve) lowers HR below intrinsic rate of the heart (100 bpm); withdrawal of PNS tone increases HR 2. GI tract - PNS tone (via vagus nerve) provides a basal level of gut motility that can be increased or decreased by increasing or decreasing activity of the vagus nerve. Sympathetic Tone 1. Arterioles - SNS tone to arterioles causes partial constriction of arterioles - helps maintain our blood pressure - Sympathetic stimulation of arterioles can be increased or decreased to increase or decrease blood pressure

CNS - PNS Transition

Meninges - Dura Mater - Arachnoid Mater - Pia Mater Transition from CNS to PNS occurs at pia mater CNS (Origin: Neural Tube) PNS (Origin: Neural Crest)

Stages of Lymphedema

Mild: edema is still pitting, limb size is normal or almost normal size in the morning Moderate: tissue is spongy consistency, non-pitting Severe: - irreversible swelling, hardening of tissue (fibroses) - perfect medium for bacteria and recurrent infection - Lymphedema (infection) may result in the following symptoms: rash, red blotchy skin, itchy, discoloration occurs.

Chylothorax

CHYLOUS EFFUSION lymph accumulation surrounding lungs due to ruptured/torn thoracic duct Causes compression of the lung and leads to possible collapsed lung - lung not able to fully expand due to lymph accumulation - is milky (cyclous) because contains fat from GI system in thoracic duct - if not reintroduced to the body could cause malnutrition due to not absorbing fats from lacteals

Cranial Nerves

CN I Olfactory CN II Optic CN III Oculomotor CN IV Trochlear CN V Trigeminal CN VI Abducens CN VII Facial CN VIII Vestibulocochlear CN IX Glossopharyngeal CN X Vagus CN XI Spinal Accessory CN XII Hypoglossal **Components of the parasympathetic nervous system - Have autonomic motor output (visceral) and somatic output (voluntary skeletal)

Anatomical Divisions of the Nervous System

CNS 1. Brain - Forebrain - Midbrain - Hindbrain 2. Spinal Cord - Cervical - Thoracic - Lumbar - Sacral - Coccygeal PNS 1. Somatic Nervous System 2. Visceral/Autonomic Nervous System - Parasympathetic - Sympathetic 3) Enteric Nervous System

CNS and PNS embryonic origins

CNS: originates from the neural tube PNS: originates from the neural crest

Calcium Homeostasis

Ca++ concentration gradients are huge!!! - Extracellular 10-3(1-2 milliMolar) - Intracellular 10-8 (10-50nanoMolar) Physiological effects of Ca2+do not depend upon its total concentration, but rather on its free concentration, or its activity Concentration difference creates a huge driving force pushing calcium into the cel; - 10,000-fold gradient is hard to maintain and requires a lot of energy When Ca2+ enters a nerve, it induces vesicle fusion - most of the Ca2+ is immediately bound to proteins which sequester it in intracellular compartments - For every 1000 Ca2+ions that enter, 1 remains free (free concentration not total). Calcium homeostasis is the result of the three processes 1. Ca2+ Binding - Most Ca2+ binding is accomplished through the action of calmodulin, calcineurin, and calreticulin, and also synaptotagmin (protein that causes vesicle fusion) - Ca2+ may also bind to negative head groups of phospholipids such as PLA2 2. Ca2+Sequestration and release from intracellular stores - Ca2+ is sequestered by mitochondria and smooth ER (SER) - Mitochondria contains mitochondrial calcium uniporter (MCU) and Na+/Ca2+antiport, a low-affinity, high capacity pump - SER contains an ATP-dependent Ca2+ pump which brings in Ca2+ from the cytosol (Ca2+-ATPase) high affinity, low capacity pump - Under normal conditions, Ca2+-ATPase pump is the most important sequestration mechanism. Within the membrane of the SER are two important calcium channels - Specialized intracellular channels in SER (Ryanonidine and IP3 Receptors) control the release from these stores - Caffeine is a potent stimulator of ryanodine receptors which has been shown to increase intracellular calcium in both cardiac myocytes and neurons 3. Ca2+Extrusion - kicking calcium back out of the cell takes a lot of energy (pump against big concentration gradient 1. Ca2+-ATPase - Ca2+-ATPase is same as on in SER, but it is oriented in an opposite direction in PM 2. Na+/Ca2+Antiport - The Na+/Ca2+antiport uses the energy of Na+ gradient to make a 3 Na+ to 1 Ca2+ exchange - 3 Na+ are brought into the cell , 1 Ca2+ is kicked out of the cell

Imaging of Lymphatic System

Can be used as diagnostic technique for diseases FDG PET scan of a patient with multiple myeloma with severe diffuse and focal disease 48-year-old man with esophageal adenocarcinoma status post-esophagogastrectomyand radiation therapy who was referred for evaluation for metastatic disease. His previous PET scan had showed malignancy in the distal esophagus Current FDG PET scan shows no malignancy in the esophagus - There is, however, hypermetabolismin right and left posteromedial basal segments of the lungs (worse on the right), which is most likely related to inflammatory changes secondary to recent radiation therapy

M.A.A.R.I.E. Framework Cohort Study

Cause to Effect Classify on exposure, follow for disease development

Steps in Neurotransmitter (NT) Production & Release

Cell Body 1. NT enzyme biosynthesis in RER 2. NT enzyme transport to Golgi 3. Modification of biosynthetic NT enzymes Axon 4. Transport of enzymes from cell body to presynaptic terminal (anterograde transport) Presynaptic terminal 5. Active uptake/transport of precursor molecules through plasma membrane 6. NT synthesis in cytoplasm & transported into synaptic vesicles (except for NE where the last step of biosynthesis occurs within the vesicle) 7. Exocytosis of NT into synaptic space (mediated by Ca2+ influx) followed by endocytosis of vesicles & removal or inactivation of NT

Spinal Nerves

Cervical - 8 Thoracic - 12 Lumbar - 5 Sacral - 5 Coccygeal - 1 Accessory Structures Cervical and Lumbar Enlargements Conus Medullaris Cauda Equina Filum Terminale

Hyperinsulinism (hyperinsulinemia)

Constant depolarization of pancreatic beta cells Problem w/ATP sensitive Potassium channel (always closed) or L type voltage gated Ca2+ channels (always open) Diabetes Type 2 - rationale for use of sulfonylurea - blocks ATP sensitive K+channel of pancreatic beta cells as first therapy --> release more insulin to combat resistance?

The Lymphatic System: Forces Controlling Flow

Contraction of skeletal muscles: - contractions compress lymphatic vessels Breathing movements: - inhalation creates pressure gradient between abdomen (high) and thorax (low) Smooth muscle cells surrounding lymphatic vessels (peristaltic waves) Gravity

Parasympathetic Division

Cranial outflow from brain innervates organs of head, neck, thorax, and most of abdomen Preganglionic fibers of cranial outflow are contained in cranial nerves III, VII, IX, and X (Vagus) Sacral outflow supplies the rest of abdominal and pelvic organs

Parasympathetic Nervous System Pharm Overview

Craniosacral outflow - preganglionic neuron cell bodies located in brain stem (CN III, VII, IX, X) and in sacral segments of the cord (S2-4) Head and neck innervation - preganglionic axons travel with cranial nerves III, VII and IX to synapse with postganglionic neurons located in four parasympathetic ganglia. Thoracic and abdominal organs - preganglionic axons travel with vagus nerve (CN X) to synapse with postganglionic neurons located in target organ. Pelvic organs - preganglionic axons emerge from sacral segments (S2-4) and form pelvic nerves and synapse with postganglionic neurons located in target organ Long preganglionic (myelinated) fibers Short postganglionic (unmyelinated) fibers emerging from ganglia located close to or within target organ Discrete innervation of target sites PNS is involved in energy restoration and conservation PNS is influenced by higher brain centers.

Patch Clamp for voltage-gated Potassium channel

Current traces reflect properties of one K+ channel as it responds to a set voltage step. If we sum all the openings, we get the trace at the bottom As for sodium, the macroscopic potassium current we see in a cell is the result of the summed average of the currents of thousands of channels. If we superimposed average trace for a Na+ channel onto this one, we would see that K+ channels open slower (more delay) than Na+ channels - V-gated K+ channels are slow-opening ion pores Potassium channels do not exhibit inactivation - remain keep opening and closing as long as the cell is depolarized. Voltage gated K+ channels open when voltage is changed, do not demonstrate inactivation and close when the membrane potential changes back to normal

How does decreasing variation affect Alpha, Beta, and Power

Decreasing Variation (SD) (Eg. Increasing your N or Improving Precision in Assessment Tool) Alpha Error doesn't change Beta Error decreases Power increases

Neuron Structure

Dendrites Cell body/soma Axon Synapses Extensive plasma membrane Complex specialized cytoskeleton

Somatic Division of PNS

Dermatomes: - Area of skin innervated by one signal spinal nerve/segment - (sensory nerves - afferent) somatic Myotomes: - Muscles innervated by one single spinal nerve/segment - (motor nerves - efferent) somatic

Descriptive v. Inferential Statistics

Descriptive - statistical estimates are calculated to describe characteristics of our sample Inferential - allows us to make a decision about some feature of our sample, such as weather or not a difference b/w two groups is significantly different from 0

Basic Study Designs

Descriptive: Document and communicate experience - Case Reports - Clinical Series Explanatory: Examine etiology - Experimental: Clinical Trials (RCTs) - Observational: Cohort, Case-Control, Cross-sectional

CNS and PNS Interface

Development of Sensory & Motor Divisions of CNS Grey Horns from basal and alar plates Alar Plate --> Dorsal Horn (sensory) Basal Plate --> Ventral Horn (somatic motor), Lateral Horn (visceral motor - autonomic) Inductive influence

Interpretation

Did the authors properly reject or fail to reject null hypothesis? Were both Type I (alpha) and Type II (beta) errors considered? Was an assertion made regarding cause and effect? Was clinical significance considered?

Extrapolation

Did the investigators stay within the limits of the data? Were differences between general population and study population considered? Was there consideration of sub-group differences?

Voltage Gated Calcium Channels (All Types)

Distinguished through voltage clamp experiments on cardiac myocytes - respond differently to voltage changes in the membrane L-Type (Long-lasting) - L-type becoming activated at higher membrane potentials, opening slower, and remaining open longer than T-type - play a role in sustaining an AP T-Type (Transient) - T-type becoming activated at lower membrane potentials, opening faster, and remaining open shorter than L-type - help to initiate APs - due to their rapid kinetics, respond better to rhythmic stimulation - play important roles in rhythmic processes such as maintaining the heart beat, breathing, sleep waves in thalamic neurons and spinal cord pattern generators used in walking KNOW CHART Presynaptic Calcium Channels N-Type Ca2+Channels - N stands for neuronal as it is specific for neurons - involved in NT release but they also fulfill roles in neuronal Ca2+homeostasis (P for Purkinje, and Q/R) - high threshold of activation, relatively slow kinetics similar to N type - P type is the channel present in presynaptic terminal at the Neuromuscular Junction and control the release of ACh

What difference does and doesn't the PHE make?

Does: Increases delivery of screening tests - PHEs increase receipt of Pap smears, colorectal cancer screening with fecal occult blood testing, cholesterol screening Intermediate clinical outcomes - Beneficial effect on patients' worry (reassurance) - Mixed effects on disease detection, health habits, blood pressure, serum cholesterol, BMI Doesn't: - 2019 Cochrane review and meta-analysis of 15 randomized trials of PHEs - PHEs increased number of new diagnoses and treatments - No effects on hospitalization, disability, worry, additional physician visits, absence from work - No effects on cardiovascular mortality, cancer mortality, or all-cause mortality - ie not reducing morbidity and morality by diagnosing and treating more disease and screening --> potentially treating people who do not need to be

Resting Membrane Potentail (RMP)

Due to presence of: - leak channels selective for particular ions (such as Na+ and K+) - impermeable intracellular protein anions Maintained by Na+/K+ ATPase pump -70 mV to -90 mV

Role of Adrenal Medulla and EPI

EPI released by adrenal medulla enhances the effects of locally released NE on alpha and beta1 receptors EPI also stimulates beta2 receptors - circulating EPI produces bronchodilation, glycogen breakdown and vasodilation of blood vessels in skeletal muscles. Vasodilation results in shunting of blood from other tissues to skeletal muscles. In addition to stimulating receptors that are innervated by SNS neurons, circulating EPI also stimulates receptors that are not innervated by SNS neurons

Skeletal Muscle Structure

Each muscle is made of many myofibers which are cells with many nuclei that come from the fusion of myoblasts Each myofiber has many myofibrils which have a long stretch of sarcomeres arranged in series Sarcomeres contain interdigitating thin and thick filaments that form striations - working unit of muscle fiber Thin filaments are made of: actin, tropomyosin, and troponin Thick filaments are made of myosin Thick filaments do not move during muscle contraction, rather, thin filaments slide over the thick causing contraction. A band: Encompasses entire length of myosin; stays same length during contraction I band: contains only actin; shrinks with contraction H band: myosin only; shrinks with contraction Z line: attachment point for actin filaments; from Z line to Z line is 1 sarcomere. M line: midpoint of sarcomere; holds myosin filaments in place

Edema

Edema (swelling) - Excessive accumulation of interstitial fluid - Causes: 1. Obstruction of lymph node or vessel 2. Pregnant uterus 3. Excessive lymph formation and increased permeability of blood capillary after injury (decreased albumin formation due to liver disease --> less capillary oncotic pressure) 4. Increased capillary hydrostatic pressure (HTN) Treatment of Edema: RICE - Rest - Ice - Compression - Elevation Ascites --> very serious outcome of systemic edema in peritoneum

M.A.A.R.I.E. Framework Case-Control Study

Effect to Cause Classify on disease state, track back for exposure

Sequence of Events at NMJ

Electrical events at NMJ 1. Presynaptic Nerve action potential => All or none 2. Postsynaptic End Plate Potential => Graded 3. Postsynaptic Nerve action potential => All or none - Ach binds to Ach Receptor - Open a cationic channel - Many channels opened at the same time produce the End Plate Current - current results in an EPP - Since number of vesicles released each time is variable the resulting EPP will be variable

Synaptic Vesicle Recycling (Endocytosis)

Endocytic Vesicles - A-C: Clathrin coated pits and vesicles form; segregated from active zones & synaptic vesicle fusion and NT release - D-E: Clathrin removed and endocytic vesicles are modified (i.e., SNARE proteins are added to the surface of these vesicles) and recycled as synaptic vesicles for NT release - F: Modified vesicles are 're-loaded' with NTs and ready for the next fusion & NT release Clathrin mediated endocytosis

Peripheral Nerve Structure

Epineurium - encapsulates entire never Perineurium - encapsulates bundle of axons Endoneurium - encapsulates individual axons

Level of ANS Control by CNS

Even though ANS not considered to be under direct voluntary control, many of its activities are regulated by the CNS Levels of CNS control can occur at: - Brain stem and spinal cord - Hypothalamus and amygdala - Cerebral cortex Cerebral Cortex (frontal lobe) Limbic Lobe (emotional input) Hypothalamus (overall integration of ANS - the boss) Reticular Formation of brain stem (Regulation of pupil size, respiration, heart rate, blood pressure, swallowing) Spinal Cord (Urination, Defecation, Erection, ejaculation reflexes)

Sensitivity and Specificity of a Test Depend on the Cutoff

Example: Serum Ferritin as a marker for Iron Deficient Anemia As low end cut off increases, sensitivity increases, but specificity decreases ie as sensitivity increases (increase in TP rate) the FP rate (people who are well but test positive) also increases Where do you draw the line? - Is this disease serious? - Is there an asymptomatic phase? - Is this disease treatable/curable? - How dangerous is the treatment? - Does early treatment improve the outcome?

Dendrites

Extension of cell body Not myelinated Usually branch extensively - Primary, secondary & tertiary dendrites Often possess spines on smaller dendrites Have membrane receptors that receive chemical signals released from other neurons

Extracellular Ca2+ effects on Voltage-Gated Na+ channels

Extracellular Ca2+ concentration regulates activation (opening) of voltage gated Na+ channels Ca2+ changes the way that voltage gated Na+channel senses changes in membrane potential because of charge shielding effects on the voltage sensor Example: if a depolarizing potential is -20 mV, with Ca2+present the channel will sense only -10 mV - When there is a high extracellular [Ca2+], the voltage gated Na+channels require a larger depolarization in order to reach their threshold and generate an AP - low extracellular Ca2+ levels can lead to a perceived membrane potential to be larger than it really is, requiring a smaller depolarization needed for Na+ channels to reach threshold and hyperexcitability. Increased extracellular Ca2+ = decreased excitability Decreased extracellular Ca2+ = increased excitability If Ca2+ drops too low, the nerve or heart cells may fire at inappropriate times. - Ca2+ drop of 50% or more may lead to tetany (high rate action potentials) in peripheral nerves - Paralysis of respiratory muscles may result and death. A right-shift corresponds to an increase in Ca2+, which in turn, makes it increasingly hard to initiate an action potential.

Responses to Stimulation of PNS

Eye (+) - pupillary constriction due to contraction of sphincter muscle (miosis) - smooth muscle response - accommodation - rounding of the lens for near vision - smooth muscle response Glands (+) - contraction = increased secretions from lacrimal, nasal and salivary glands Bronchi - (vagus) (+) - constriction of bronchial smooth muscle - increased bronchial secretions Heart - (vagus) (inhibitory responses) (-) - decreased heart rate (SA node) - decreased atrial contractility - decreased speed of conduction through AV node GI - (vagus - stomach, small intestine, part of large intestine, digestive glands) (+) - increased gastric secretions (HCl = hydrochloric acid) - increased motility - relaxation of sphincters (-) Urinary bladder (+) - contraction of bladder smooth muscle - internal sphincter relaxation (-) Male sexual organs - erection (+)

Responses to Stimulation of SNS

Eyes (+) - pupillary dilation (mydriasis) due to contraction of radial muscle --> different smooth muscle being contracted (radial spokes) Lung Bronchi (-) - SM dilation Heart (+) - increased heart rate (SA node) - increased conduction velocity (AV node/His-Purkinje conduction system) - increased contractility (atrial & ventricular muscle) GI - decreased motility (-) - contraction of sphincters (+) Urinary bladder - decreased contraction of bladder wall muscles (-) - contraction of sphincter (+) Kidney - ↑ renin secretion → ↑ Na+ and water retention (↑ Angiotensin II) Liver - increased metabolism → increased glycogen breakdown and glucose release Fat cells - lipolysis, release of free fatty acids Skin (+) - (pilomotor muscle) - piloerection (hair stands on end) Male sexual organs - ejaculation (+) Blood vessels (+) - constriction - all vascular beds (arteries and veins) Dilation (-) - vessels in skeletal muscles and vessels to the liver Sweat glands (+) - profuse sweating (***cholinergic response) Adrenal medulla - innervated by branch of the greater splanchnic nerve - acts like a postganglionic cell and releases NE (20%) and EPI (80%), which circulate throughout body and thus function as hormones since their target is distant from the release site - allows for a prolonged and more powerful effect.

Passive Diffusion - Fick's Law

Flux: movement of ions from an area of high concentration to low concentration, measured in an amount of particles per time (rate) Fick's Law: Ji= DiA(C1-C2)/x - Ji is the flux for ion i - Diis the diffusion coefficient for i - A is the cross sectional area over which diffusion takes place - (C1-C2) is the concentration difference (gradient) - x - distance over which diffusion takes place Fick's Law applied to the plasma membrane: Jx= Px(Xo-Xi) Px: permeability coefficient - consists of 4 components 1. Lipid/Water Partition Coefficient (beta): ratio of a molecule's solubility in oil to its solubility in water, where a higher number is more lipophilic (0=soluble in H20; 1=soluble in lipid, more flux across hydrophobic PM) 2. Diffusion Coefficient(Dx) - Increasing Dx will increase Jx 3. Membrane thickness (X) - Assumed constant for most membranes (10 nm not considering myelin) 4. Area - typically 1 square/micron Xo and Xi are concentrations of molecule "x" inside and outside of the cell - when Xo exceeds Xi, there is a positive permeability coefficient, net flux of "x" will be into the cell - "x" fluxes in both directions, but the inward flux is more than the outward flux. Solutes are in constant motion

Projected Benefits and Harms: Example PSA Screening

For every 1000 men who have PSA screening every 1 to 4 years for 10 years, 1 man may avoid a prostate cancer death (while another man dies of something else) - 100-120 men have at least one FP test result - treatment of 110 additional men diagnosed with prostate cancer - leads to 29 men developing erectile dysfunction and 18 developing urinary incontinence AAFP / ACPM "Choosing Wisely" Do not routinely screen for prostate cancer using a PSA test or digital rectal exam. - Screening for prostate cancer using PSA may prevent mortality from prostate cancer for a small number of men, while putting many men at risk for long term harms, such as urinary incontinence and erectile dysfunction.

Pathophysiologic Reasoning

Form of clinical decision making that uses: - Pathophysiologic principles - Biochemical literature - Clinical assessment - To draw conclusions about effectiveness of diagnostic and therapeutic interventions

Brain Regions

Frontal Lobes Partiel Lobes Temporal Lobes Occipital Lobes Limbic Lobes (inferior) Cerebellum Brain Stem Anatomical and functional separation

Surface Anatomy of the Face and Sinuses

Frontal Sinus Ethmoid Sinus Maxillary Sinus

Metabotropic Receptors

G-protein coupled receptors (GPCRs) Do not directly form ion pores but can cause opening of neighboring ion channels (indirect gating) Activate second messenger intracellular cascades G-proteins can be stimulatory or inhibitory Slower, longer lasting and more diverse postsynaptic effects (sec-hours) than ionotropic receptors Metabotropic receptor subtypes for a single neurotransmitter can activate different types of G proteins Activation of a single receptor can result in activation of many G protein molecules = amplification of signal and long term effects

Conductance

G=1/R Conductance (G) - inverse of resistance Ohm's Law can be rewritten as I=GV. - Note: G (conductance) is always a positive value - In this equation V really is (V-E) where V is the voltage applied and E is the Nernst potential of the ion channel - If the voltage applied is equal but opposite the Nernst potential V-E will be zero, and there will be no current - This is the conduction pathway of each channel - R (thus G) depends on the number of channels available - An increase in number of channels will decrease the resistance, R, of the membrane, which means conductance, G, will increase

Screening Tests Take Home Points

Good screening tests must meet certain criteria regarding: disease, test, and population Selection, lead time, length time, and overdiagnosis biases can exaggerate benefits of a screening test Only well-designed RCTs that measure mortality can prove that a screening test works PSA-based screening for prostate cancer does not meet criteria for a screening test that should be performed routinely

Sources of Fuel for Muscle Contraction

Humans have 3 major sources of ATP: Glycolysis (anaerobic - glycolytic) Krebs cycle (aerobic - oxidative) Creatine phosphate - Muscles use in limited stores as a third source of ATP. - Creatine phosphate can transfer its phosphate group onto ADP thus making ATP - low capacity emergency storage Glycolytic pathway - glycogen is broken down by phosphorylase (in muscle myophosphorylase) - glycolysis outcome leads to cell acidosis Krebs cycle burns fatty acids - By product of Krebs cycle is CO2 and water, easily diffusible Best way to improve performance is through the aerobic Krebs cycle that uses fatty acids and oxygen - Burning fat isn't a fast process, so we use glycolytic pathway to also make ATP through an anaerobic process - pathway eventually causes lactic acid to build up in the blood - Lactic acid stimulates the pain perception sensory fibers ATP Usage 1 molecule of ATP is required per cycle - ATP is used to dissociate the myosin head, recharging it ATP is used for relaxation - remove calcium back to SR via Ca+ ATPase

Nernst Equilibrium: More than One Ion Channel

Hypothetical Glial Cell - Na+ and K+ leak channels 1:100 ratio - effect of Na+ on the cell is much less than K+ because there is approximately 1 Na+leak channel for every 100 K+leak channel in a typical cell - effect of the influx of Na+ (down its electrochemical gradient) will depolarize (make it less negative) the cell - flow of K+ back into the cell driven by electrical gradient will be diminished (by depolarization due to Na+) while the flow of K+ out of the cell driven by concentration will remain the same - Result of this is: 1) the potassium electrochemical equilibrium is destroyed (RMP is not at Ek any more) 2) net K+current moving outside the cell (IK) and 3) net Na+current moving inside the cell (INa) Will continue until the cell reaches a steady state where IK + INa = 0 Membrane potential = Steady State Fundamental condition that determines RMP Dependent on: - ion concentrations AND - relative number of K and Na leak channels (permeability) Role of Na+/K+ATPase - maintains the RMP concentration gradients of Na+ and K+ inside and outside the cell - creates a high Na+concentration outside - creates high K+concentration inside - since three cations were pumped outside the cell and only two cations were pumped in --> creates a charge difference (pump is electrogenic, creates a positive charge outside the cell and a negative charge inside the cell) - pump will hyperpolarize the cell slightly due to electrogenic property of the pump determining a net outward current Resting Membrane Potential is created by K+ leak channels and Na+leak channels BUT is maintained by Na+/K+ATPase - dynamic balance between K and Na leakage - Close to Nernst potential of K, but offset by Na leak - Primary means by which cells alter their RMP is by changing the relative number of leak channels in their membrane - toxin oubain is a potent inhibitor of this pump. By binding to the α-subunit it inactivates the pump, causing the membrane to depolarize. Hypotheticals 1. Add Na+ leak channels - membrane becomes more permeable to sodium - Na+will flow down its concentration gradient into the cell making it less negative - K+ leak channels are always present and they will increase efflux to try to compensate the Na+ influx - RMP potential becomes less negative, or depolarized, to a less negative value because positive charges are deposited in the cell. 1. Add anion channels (Cl-) - membrane becomes permeable to an anion (that is not very abundant inside the cell) - RMP becomes more negative, or hyperpolarized because negative charges are desposited in the cell.

Case-Control Study

Identify cases of disease (and controls) and look backward to identify exposure Risk factor/exposure identification Assign based on presence or absence of disease Assess for exposure

P-values and Confidence Intervals

If a 95% CI includes the null effect The P-value is >0.05 We would fail to reject the null hypothesis If the 95% CI excludes the null effect The P-value is <0.05 We would reject the null hypothesis -CI for a difference between two means: Does the interval include 0 (null effect)? -CI for a ratio (e.g, OR, RR): Does the interval include 1 (null effect)? P-value and Confidence Intervals answer the question: - "Is there a statistically significant difference between the two treatments?" The confidence interval ALSO answers the question: - "How precisely did this trial determine or estimate the treatment difference?"

Negative Predictive Value (NPV)

If the test is negative, the probability that the patient really is free of disease TN/ (TN + FN)

Positive Predictive Value (PPV)

If the test is positive, the probability that the patient really has the disease TP/(TP + FP)

Statistics Used in Cohort Studies

Incidence Rates (I) - Risk - What is the occurrence of disease in a group initially free of the condition? I = # of new cases in some time period/# of persons at risk for disease Relative Risk - How many times more likely are exposed persons to become diseased, relative to non exposed persons? RR = Ie/Ine RR = 1 No difference between exposed and not exposed RR > 1 Exposed at greater risk of disease RR < 1 Exposed at less risk of disease Ex: 100 smokers and 100 non smokers - 5 smokers developed lung cancer - 1 non-smokers developed lung cancer - Ie = 5/100 - Ine = 1/100 RR=.05/.01=5

How does increasing effect size affect Alpha, Beta, and Power

Increasing Effect Size (Changing "Detection" Size) Alpha Error doesn't change Beta Error decreases Power increases

Independent vs. Dependent Variable

Independent variable: - the exposure(s) of interest - Other Names: Explanatory, Predictor, Exposure - Includes any variable that modifies or confounds the relation between the outcome and exposure of interest Dependent variable: - the outcome of interest, that which is affected or caused - Other Names: Response, Outcome - The dependent variable responds to changes in the independent variable

Infant Morality in DC

Infant morality rate has decreased over the years since 2007 Still much higher than national US average - 2016 (7.1% DC vs. 5.87% US) - Infant Mortality rate disparities: higher among blacks and hispanics that whites - Higher in Wards 7, 8 - Lowest in Wards 2, 3

Neurotransmitter Receptors in Relation to EPP

Ionotropic receptors - ligand-gated receptors - ion channels that are directly activated by ligand binding nicotinic AChR: - located at the NMJ but stimulated by nicotine - 5 subunit - two molecules of ACh bind the receptor, a cation channel opens which allows both Na+and K+ to enter the cell - instantaneous, desensitize rapidly Metabotropic receptors - ligand-binding indirectly alters the postsynaptic cell by: 1. activating either a G-protein which then gates the channel OR 2. activating enzymatic pathways to activate second messengers --> second messengers go on to gate channels or do other things within the cell Metabotropic receptor is NOT an ion channel but ultimately may affect ion channel function - muscarinic AChR: Muscarine is a highly toxic toadstool alkaloid which potently stimulates this class of receptor

Quantal Release and Synaptic Vesicles

Miniature End Plate Potentials (MEPPs) - In absence of presynaptic stimulation, small spontaneous depolarizations of postsynaptic cell occurred - due to the spontaneous release of individual vesicles of NT ACh in the synaptic cleft that activates AChR. Quantal Theory of NT Release - MEPPs result from spontaneous, irreducible units of transmitter release called quanta - quantal release of NT produce a MEPP, EPP observed at NMJ is caused by the summation of lots of quanta each equivalent to a MEPP - if you increase the number of quanta, you increase the strength of the EPP, If the EPP is bigger, you increase the likelihood of inducing an action potential in muscle - Safety factor means that the number of vesicles (quanta) release is always larger than that required to reach threshold in the muscle. - Safety factor is compromised in myasthenia patients by circulating antibodies against the AChR that act as an antagonist. Thus MEPPs, or "MINIs" provide us with a great tool to understand the effect of a single synaptic vesicle Quantal size, Qs: response to one vesicle = average MINIs (MEPPS) amplitude - Quantal size can also be measured from distance between peaks of the EPP distribution Quantal content, Qc - average number of vesicles released from activation of a pre-synaptic nerve M = mean amplitude of responses mean amplitude of MINIs

Presynaptic Components

Mitochondria - Supply ATP for steps of vesicle cycle Smooth ER - Regulation of Ca2+ stores - Lipid production (vesicle membranes) Synaptic Vesicles - Small, 30-50 nm - Store non-peptide neurotransmitters - Recycled - Release is regulated by Ca2+ - Fast, spatially precise signaling NO RER --> proteins found in the presynaptic terminal need to be transported from soma/cell body via axonal transport

Hyperexcitability

Lack of relative refractory period Lower AP threshold (less stimulus needed to fire another AP) Caused by 2-AP poison induced block of Voltage gated K channels

Axon Insulation

Large axons are myelinated - CNS = oligodendrocyte - PNS = Schwann cell Smaller axons are less myelinated, while the smallest axons are unmyelinated - All axons still have intimate contact with oligodendrocytes or Schwann cell Myelin serves to increase electrical conduction - Saltatory conduction - Nodes of Ranvier Action potentials travel along an axon in proportion to their diameter (less internal resistance, larger space constant, higher conduction velocity) - Invertebrates evolved to have large axons to accommodate the need for speed. - Vertebrates evolved to produce an electrochemically insulating sheath-the myelin sheath.

Internal Structure of the Spinal Cord

Lateral Horn (Gray Matter) Ventral Horn (Gray Matter) Ventral Root Spinal Nerve Dorsal Horn (Gray Matter) Dorsal Root Dorsal Root Ganglion Spinal Nerve Dorsal (Posterior) Column (White Matter) Ventral (Anterior) Column (White Matter) Lateral Column (White Matter)

Why do physicians often provide ineffective and potentially harmful screening tests?

Legal fear - doctors don't want a bad outcome, do it even though does not show better outcomes for patients Because it just makes sense - Digital rectal exam to detect prostate cancer (most doesn't need to be treated) - Breast self-exam to detect breast cancer (FP) - Testicular exam to detect testicular cancer (FP) - Bimanual pelvic exam to detect ovarian cancer - Chest x-rays to detect lung cancer - Ultrasonography to detect carotid artery stenosis (unnecessary procedural result that could cause morbidity - stroke) However, most evidence contradicts this and that it does more harm than good (anxiety for patient, FPs, money wasted, unnecessary treatment --> potentially harmful)

Sympathetic Division (Thoracolumbar)

More complex than parasympathetic system Innervates more organs Visceral organs Visceral structures in superficial region of body - Sweat glands, hair-raising erector pili muscles of skin, smooth muscles of arteries (vascular SM Two types of ganglia: - Sympathetic trunk ganglia (Paravertebral) - Prevertebral ganglia (Celiac, UM, SM)

Classification of Neurons

Morphology - Unipolar - Pseudounipolar - Bipolar - Multipolar Function - Sensory vs. motor vs. interneuron - Afferent vs. efferent Molecular Prosperities - Excitatory vs. Inhibitory - Type of Neurotransmitter Cells in periphery have less dendrites (less signals to integrate than CNS cerebrum) Interneurons: control the other neurons (little boss controlling the big workers) --> coordinating the signals Bigger cell body: bigger/longer axons

Astrocyte Functions

Most abundant/largest glial cell in CNS --> occupy 20-50% of brain volume "Star-shaped process bearing cells" that are located in both gray and white matter Guide Neuronal migration during development - radial glia cells provide scaffolding for migrating neurons during development Produce & secrete growth factors - Regulate morphology, proliferation, differentiation & survival of neurons Act as a physical barrier (Glial limitans) - conjunction w/CNS endotheliall cells, astrocytes form BBB which restrict entry of proteins and charged molecules into the brain Maintain brain Homeostasis - Regulate extracellular ionic concentrations necessary for membrane depolarization in neurons - Control blood flow by signaling to blood vessels about the need for enhanced delivery of oxygen and glucose-fMRI - Provide energy and substrates needed by neurons for neurotransmission - Rapidly remove neurotransmitters from the synaptic cleft following neurotransmission

Lymph/Tissue Fluid Formation

Most plasma proteins are too large to leave blood vessels Proteins that escape, must return to circulation At a certain point, after tissue pressure builds, lymphatic capillaries open up and fluid allow return to circulation

Recommendations for PHE from Society of General Internal Medicine

"Choosing Wisely" For asymptomatic adults without a chronic medical condition, mental health problem, or other health concern, don't routinely perform annual general health checks that include a comprehensive physical examination and lab testing. "Talk with a trusted doctor about how often you need to be seen."

Osmoles

# of osmotically active particles/mol 1 mole glucose --> 1 osmole 1 mole NaCl --> 2 osmoles

Reye Syndrome and Aspirin Case-Control Study

***

Length Time Bias

- Diagnose less aggressive disease (better prognosis) but miss more aggressive disease (worse prognosis) - Overestimation of survival duration among screen-detected cases due to a relative excess of slowly progressing cases in screen cases - Slowly progressing (indolent) cases are disproportionally identified by screening - Screening preferentially identifies diseases with longer asymptomatic periods, falsely appearing to improve survival Probability of detection: - directly proportional to length of time during which they are detectable - inversely proportional to rate of progression

Mechanics of Muscle Function

Length - Tension Relationship - maximum force of contraction of a sarcomere is achieved when there is maximal overlap between actin and myosin allowing maximal number of crossbridges formed - If filaments are stretched too far apart, no cross bridges can form so no tension is produced - If actin and myosin are too close together, they may form crossbridges but no further shortening is possible, so no tension is produced - optimum position of myosin relative to actin filament is the resting length of the sarcomere, so small deviations in sarcomere length will not greatly influence strength of contraction - not the case in cardiac muscle, where the force of contraction is controlled by altering the resting muscle length Force - Velocity Relation - speed of shortening of a muscle fiber is dependent on the rate of the ATPase of the myosin head (reset myosin head) - two major types of myosin head ATPases, fast and slow, that are found in white and red muscle - force-velocity relationship is produced with a series of isotonic contractions, in which a muscle is held at a constant tension and the velocity of contraction is measured - with minimum force load (the load of only the muscle itself), maximum velocity of shortening will be observed - with a maximum load no shortening will be observed - Overall, as the load decreases, the contraction velocity increases.

Isometric Contraction

Length of the muscle constant Tension/tone is changed The muscle cannot change a prefixed length Muscle tension developed is less than its opposing load - muscle cannot shorten and lift the object with that load tension generated by the sarcomersis used to pull on the tendons. No change in length is seen. An example would be pushing against a wall Muscle length remains the same, and the tone changes.

Anatomy of Neuromuscular Junction (NMJ)

- NMJ is the neuroanatomical contact point (synapse) between nerve and muscle, referred to as the End Plate - chemical synapse (cholinergic) Depolarization of muscle fibers is limited to NMJ through an excitatory postsynaptic potentials (EPSPs) or End Plate Potential (EPP) that travel electrotonically along the postysynaptic muscle fiber - EPP is usually the termed used for NMJ and is a special case of EPSP Presynaptic cell terminal - unmyelinated ending of axon filled with synaptic vesicles (single vesicles are quanta) containing neurotransmitter Acetylcholine (ACh) - most NT-containing vesicles are fused along the inner leaflet of the membrane in parallel rows (active zones) - active zone of vesicles at NMJ contain high concentrations (~100 mM) of the neurotransmitter acetylcholine (ACh), and proteins that facilitate rapid transmitter release when stimulated. - As an AP travels down an axon, it reaches the synaptic terminal and depolarizes the membrane - In the presynaptic terminal, voltage-gated Ca2+channels open and permit an inward flux of Ca2+ - Excitation-secretion coupling: depolarization increases free cytosolic Ca2+ that induces synaptic vesicle fusion on the presynaptic membrane and exocytosis of neurotransmitter (NT) - 20-30 vesicles can be released per EPP, and each individual vesicle (also called "quanta") is capable of activating 1,000 AChR. - Transmitter diffuses across synaptic cleft to the postsynaptic membrane where it binds its receptor to either directly or indirectly alters the conductance of the postsynaptic cell. Synaptic cleft - B/w pre and postsynaptic cells which contains the basal lamina (basal membrane) - lamina contains the enzyme acetylcholinesterase (AChE), which instantly cleaves ACh into choline and acetate after it is released from its receptor terminating its action - AChE is the target for many clinically important agents, including drugs designed to alleviate the symptoms of Myastenia gravis Post Synaptic membrane - membrane folds on top there are ACh receptor ion channels (AChR) at a huge density (10,000 per square micron) ready to be activated by Ach - specializations including junctional folds, transmitter receptors, and scaffolding proteins - Junctional folds serve two purposes: 1. Membrane invaginations increase surface area of the postsynaptic membrane --> more room to insert receptors. 2. Folds decrease distance between the pre and post synaptic cells to help speed neurotransmission and ensure that any NT released gets to its target.

Regulation of Muscle Tension: 4. Increasing # and type of motor units involved

Motor unit: an alpha motor neuron and the fibers that is innervates (receive same stimulus) - strength of motor unit will depends on the number of fibers innervated - brain will recruit more and stronger motor units for a strenuous task --> more motoneurons firing APs, the more muscle fibers contracting and stronger the force Example - Let's say you are extending your hand with no extra weight on it. - This takes very few motor units to perform. - Now stack Guyton texts on top of your hand one by one - will become substantially harder to sustain the weight of the books, and the tension in the muscle must increase. - The brain recruits more motor units, increasing strength of muscle as each book is added. Brain can change the type of motor unit firing - two types of skeletal muscle fibers, red and white - they are a part of two different types of motor units (type I- red, type II- white) - Type I - weaker and slower contractions, produce low contractile force - type II - used for rapid and powerful bursts of energy, produce high contractile force - brain can change the type of motor unit from type I to type II to increase contraction strength. Fast contraction velocity of type II motor units is due to fast ATPase activity - Anaerobic exercise uses type II fast fibers, which is the reason for muscle soreness (high fatigability) after quick bursts of exercise - type II units utilize glycolytic metabolism, leaving the by-product lactic acid behind

Oligodendrocyte Functions

Much smaller than astrocytes Found in both gray and white matter In white matter they are associated with neuronal axons and form myelin insulation around them Major function: MYELINATION of axons - myelin sheath is not continuous along the axon, organized into segments called an internodes - Each internode is followed by an unmyelinated/uninsulated segment called the node of Ranvier followed by another internode - Uninsulated regions have a lower resistance; rich in Na+ channels Action potentials "leap" from node to node - called saltatory conduction - cannot myelinate multiple segments of same axon but can myelinate multiple different axons (up to 30)

Skeletal Muscle Action Potential

Muscle fiber: - ensemble of single myofibrils - covered by a cell membrane - sarcolemma - Sarcolemma invaginates inside muscle fiber and creates T-tubules - T-tubules are deep pits continuous with extracellular environment. - When the AP is generated in the muscle fiber it can travel all over the membrane including down into the T-tubules. - Next to the T-tubules are terminal cisternae of the sarcoplasmic reticulum (SR) - contains a high concentration of calcium bound by calsequestrin - triad: two terminal cisternae and one T-tubule --> important in excitation contraction coupling. Depolarization that comes from the EPP of the NMJ will trigger an AP that will spread along the muscle fiber - Voltage gated Na+ and K+ channels are all over the muscle fiber membrane including down in the T-tubules - As in any action potential, Na+ goes in, K+ comes out - However, due to limited extracellular space in t-tubules, K+ is unable to clear during repolarization, leading to elevated extracellular [K+] and reducing the rate at which K+ is excreted - sequestered K+ temporarily inhibits repolarization and prevents hyperpolarization from occurring - when [K+]o is high the RMP is depolarized!! - temporarily high [K+]o causes a slight hump during the repolarization phase of the skeletal muscle AP - To help with repolarization of skeletal muscle, a leakage Cl- channel exists all over the membrane --> active all the time and it keeps the resting membrane potential (RMP) of muscle ~10 mV more hyperpolarized than in a nerve (-85 or -90 mV). - During repolarization of skeletal muscle, there is no undershoot of the RMP, as there is in nerves, due to the accumulation of K+ in the T-Tubules

Enteric Nervous System Division

Myenteric Plexus Submucosal Plexus Sympathetic Afferent visceral sensory to spinal cord Efferent visceral motor from spinal cord Parasympathetic Afferent visceral sensory to brain (vagus nerve) Efferent visceral motor form vagus nerve

Autonomic Nervous System Terminology/Synapses

NOTE: Both Somatic & Autonomic Peripheral Sensory neurons are located in the DRG 1. Lateral horn 2. Ventral root 3. Spinal nerve 4. White Communicating Ramus 5. Sympathetic Chain Ganglia (Synapse Here) 6. Gray Communicating Ramus OR Sympathetic Nerve 7. Vascular smooth muscle, sweat glands, erector pili muscles 5. Sympathetic Chain Ganglia 6. Splanchnic Nerve 7. Collateral Ganglion (Synapse Here) 8. Neuroeffector junctions on smooth muscle, cardiac muscle, secretory glands, metabolic cells, immune cells 5. Sympathetic Chain Ganglia 6. Splanchnic Nerve 7. Celiac Collateral Ganglion 8. Adrenal Medulla Gland (synapse here) 9. Release of epinephrine and norepinephrine from specialized post ganglionic neurons (endocrine cells of adrenal medulla)

Neurotransmitter Receptors

NT binds to its cognate receptor on effector cell Ion Channels (ionotropic) - ligand gated G-protein coupled receptors (metabotropic) NTs bind with a high degree of specificity A single NT can activate receptors that are ionotropic or metabotropic --> eliciting different cellular responses - Example: ACh activates nicotinic (ionotropic) and muscarinic (metabotropic) Ionotropic and metabotropic receptors can have multiple subtypes - A single NT can activate more than one receptor subtype

Sodium-Potassium ATPase Pump

Na+/K+ pump or sodium pump Primary Active Transport Maintains gradients of Na+ and K+ b/w intracellular and extracellular compartments - Creates large extracellular Na+ concentration - Creates large intracellular K+concentration Important for fluid homeostasis Drives transport of other solutes Antitransporter/countertransporter Electrogenic pump: - 3 Na+ out of cell - 2 K+ in cell

Nervous System: Hierarchical Control

Nervous System are Organized into Functional Units that Exhibit Hierarchical Control All information about environment (external and internal) goes through a peripheral nerve

Neural Crest Origin, Migration & Differentiation

Neural crest cells originate from the Ectoderm-Neural plate border zone Separate from both the ectodermal cells and the neuroepithelial cells forming the neural tube during invagination of the neural folds and closure of the neural tube During migration subpopulations of neural crest cells leave the migratory stream to form: - melanocytes - glial cells (schwann) - neurons initially associated w/ectoderm Steam of migratory cells form all cellular components of the PNS including: - somatic sensory cells in spinal ganglia - neurons in the autonomic and enteric nervous system Other migrating neural crest initially associated with the mesoderm generate a variety of non-neuronal cells: - osteoblasts - adipocytes - chondrocytes Sensory Components (PNS) --> Originate from neural crest - sensory receptors - sensory ganglia and nerves (somatic and visceral) Cerebrum, Cerebellum, Brainstem, Spinal Cord (CNS) Motor Components (PNS) - Visceral Motor System --> Autonomic ganglia and nerves --> Originate from neural crest - Somatic Motor System --> motor nerves --> Originate from spinal neural tube

Cholinergic (ACh), Adrenergic (NE/E) & Serotonergic (5-HT) Receptors

Neurotransmitter --> Receptor --> Type ACh --> Ionotropic --> Nicotinic ACh --> Metabotropic --> Muscarinic NE --> Metabotropic --> α-adrenergic NE --> Metabotropic --> β-adrenergic E --> Metabotropic --> α-adrenergic E --> Metabotropic --> β-adrenergic 5-HT --> Ionotropic --> 5-HT3 subtypes 5-HT --> Metabotropic --> 5-HT1,2,4-7 subtypes

Cholinergic (ACh) Receptors

Nicotinic receptors: (ionotropic) 1. nicotinic neuronal (Nn) receptors mediate: (ganglia) - stimulation of postganglionic neurons of PNS and SNS - stimulation of adrenal medullary cells (chromaffin cells) to release EPI and NE 2. nicotinic muscle (Nm) receptors located at NMJ mediate: - contraction of skeletal muscle fibers Muscarinic receptors (various subtypes): (metabatropic) 1. end organs of PNS - mediate all effects of PNS stimulation listed above 2. sweat glands - innervated by postganglionic cholinergic fibers in SNS

Salutatory Conduction

Nodes of Ranvier - points along axon in which myelin is absent - lower membrane resistance (higher conductance) - nodes contain concentrated grouping of voltage gated Na+and K+channels that are absent in the myelinated sections - Node rich in Na+channels - K+ channels are highly concentrated in paranodal axolemma (adjacent juxtaparanoderegion) Nodes create phenomenon of saltatory conduction in which the AP jumps from node to node by quickly by passing a myelinated section and getting a boost at the next node - myelination creates a smaller (ie faster) time constant --> decreasing membrane capacitance, don't need to charge up the membrane (capacitor) and less current is taken from AP propagation, can proceed faster (filling up smaller bucket, instead of big bucket) Many diseases of the nervous system involve pathologic loss of myelin - Multiple Sclerosis (CNS demyelination) - Guillain-Barre (PNS demyelination)

Gate vs. Non-gated Channels

Non-gated channel (Pore) - leak channels - number and type of pore channels are responsible for the resting membrane potential Gated Channel - gated by a door - responsible for other potentials on a membrane such as action potentials and synaptic potentials 1. Voltage-Gated Channels: opens in response to voltage change in membrane 2. Ligand-Gated Channels: binding a ligand to its receptor opens the channel 3. Gap Junction: two hemichannels from adjacent cells simultaneously open and ions pass between adjacent cells - Can be gated by pH Additional examples: mechanical gated, temperature gated, water channels **Movement through channels is by simple diffusion with one exception: - At very high concentrations of ion, a Jmax (flux max) can be found, but this is not physiologically relevant Channels are generally specific for a certain ion (selectivity)

Components of a Formal Hypothesis Test

Null Hypothesis (H0) - Statement about value of a population parameter - Must contain condition of equality (=, >, <) - Example: H0: μ = 0 Alternative (Research) Hypothesis (H1) - Statement that must be true if H0 is false - Does not contain condition of equality (ne, >, <) - Example: H1: μ > 0 Reject or fail to reject H0 based on inferential test statistic, which corresponds to a p-value

Null Hypothesis (One or Two Sided Testing)

Null hypothesis: - H0: μ1 = μ2 (Eg:The Mean of Population) Alternative Hypothesis: HA: μ1 ≠ μ2 (Two-sided test) (Most Common) - No a priori reason to assume directionality of effect (Conservative) - Preferred and expected in most cases OR HA: μ1 > μ2 or μ1 < μ2; (One-sided Test) - Specifically interested in only one direction - Be very cautious in using One-sided Tests! Statistical Testing is done based upon the Null Hypothesis

Statistics Used in Case-Control Studies

Odds Risk = Number with Disease/Number at risk of disease Odds = Number with Disease/Number without Disease **For rare diseases the odds approximates the risk of disease Therefore Odds Ratio --> approximates Relative Risk Odds ratio OR = odds of disease in exposed persons/odds of disease in non exposed persons OR = 1 No difference between exposed and not exposed OR > 1 Exposed more likely to be diseased OR < 1 Exposed less likely to be diseased Example: 6 with lung cancer, 5 who smoked 184 without lung cancer, 95 who smoked odds of disease in exposed persons: 5/95=0.52 odds of disease in non exposed persons: 1/99=0.01 OR = 0.52/0.1 = 5.2

Assessment

Outcomes - Cohort: Disease - Case-control: Exposure Outcomes - Appropriate - Precise - Accurate: Case-control problem - Complete: Cohort problem (lost to follow up) - Unaffected by process: Cohort problem

Overdiagnosis Bias

Overestimation of survival among screen-detected cases due to the inclusion of "pseudo-disease" - Subclinical disease that would not become overt before patient dies of other causes Estimated percentages of cancers overdiagnosed by screening - Prostate cancer (PSA): 50% - Breast cancer (mammography): 33% - Lung cancer (low dose CT): 20%

Interpreting P-values

P-value = 0.08 - Some evidence against the null hypothesis (Marginally significant) P-value = 0.70 - Very weak evidence against the null hypothesis (very likely a chance finding) P-value = 0.007 - Very strong evidence against the null hypothesis (Very unlikely to be a chance finding) Sample Size - Size of p-value is related to sample size - Lis and Jugdutt trials are similar in effect (~ 50% reduction in risk) - But Jugdutt trial has a large sample size, therefore power is greater in Jugdutt trial Effect Size - Size of p-value is also related to the effect size or the observed association or difference - Chiche and Flaherty trials approximately same size (N), but observed difference greater in the Chiche trial

Characteristics of PNS and SNS Responses

PNS - most often involved in discrete or localized responses - in energy restoration and conservation ("rest and digest" responses). SNS - produce massive diffuse responses - leading to increased metabolism and energy utilization (eg., stress response "fight or flight" reaction) -can also respond discretely in some instances

Simple Diffusion

Passive Transport - Movement of a substance down its concentration gradient (downhill) - Requires no energy - Continues until concentration becomes equal on both sides (equilibrium) Rate of diffusion depends on: 1. Concentration gradient 2. Permeability of membrane to substance 3. Surface area Examples: - Lipid soluble substances - blood gases - steroids - can diffuse directly through bilayer

Facilitated Diffusion

Passive Transport Transport of a substance down its concentration gradient facilitated by an integral membrane protein (channel or carrier) Requires no energy Rate of diffusion is faster at lower concentrations compared to simple diffusion due to presence of carrier protein ("facilitated" by carrier protein) Rate of diffusion reaches saturation at higher concentrations Follows features of a carrier mediated transport: - saturation - specificity - competition

How does one prove that a screening test works?

Perform a well-designed, adequately powered RCT - Offer the screening test to one group and not to the other - Follow both groups for 5, 10, or 15 years and measure disease-specific and all-cause mortality - Use intention-to-treat analysis - If mortality rate is lower in the group offered screening, the test works Example: PSA screening for prostate cancer does not work - More Prostate Cancers Diagnosed in Intervention than Control Group - Same Number of Prostate Cancer Deaths - # of PrCa deaths in screening group has never been lower than that in the control group

Power Calculations/Sample Size

Performed using a statistical software program, investigators need to know certain clinically relevant factors to determine sample size. - Alpha (Type I error) (Usually 0.05) - Power (Typically 0.8 or 0.9) - Statistical Significance (One/Two Tailed) - Treatment Effect Size (How big a change is a significant "change") - Standard Deviation(s) (How much Variation is in your response variable?) Make sure to Account for Attrition/Lost To Follow-Up

Conductance vs. Permeability

Permeability is a property of the membrane - number of channels contained in a membrane Conductance refers to the electrical property due to the current of ions through the channels - If no ions are present, the membrane will still have permeability as the channel are always there, but there is no conductance as there is no current

Reflection Coefficient

Permeability of a membrane to a particular solute, compared to water sigma = 1 - (Psolute/Pwater) sigma = 0 ie Psolute = Pwater, solute is highly permeable, meaning that effective osmotic pressure due to that solute will be 0 sigma = 1 ie Psolute very small, solute is impermeable, meaning that it has an effective osmotic pressure Binary decision for physiologists IF YOU ARE DEALING WITH A SOLUTE THAT IS HIGHLY PERMEABLE IT HAS NO EFFECTIVE OSMOTIC PRESSURE ie. urea

Post Synaptic Components

Postsynaptic density (PSD): - localization site for neurotransmitter (NT) receptors - composed of protein scaffolds around receptor-signaling microdomains (stabilized to actin framework) - site linking receptors to their second messengers and molecular signaling pathways Transmembrane proteins tether postsynaptic cell membrane to transmembrane proteins on presynaptic axon - stabilizes pre-/post-synaptic sites

Afterload and Preload

Preload: the initial stretching of the cardiac myocytes prior to contraction (EDV) Afterload: Load against which the heart has to pump (TPR)

Error

Present in all studies Random Error - Can be handled by statistics - Usually affects power Systematic Error—Bias - Non random error - Must be recognized - Can possibly be controlled for (stratifying confounders)

Lymphatic System: Clinical Issues

Principle 1: Know to which lymph node a particular lesion (infection/cancer) will drain to Principle 2: Know what body regions are drained by an enlarged lymph node(s) Principle 3: When multiple lymphatic regions are involved, consider systemic disease

Lymphatics Clinical Issues Principle 1

Principle 1: Know to which lymph node a particular lesion will drain to Lymph Drainage of Breast - Axillary Nodes - Parasternal Nodes Dye can be injected into tissue with lesion to see path of tissue fluid drainage through lymphatics --> can trace possible path of metastasis/spread of cancer and remove those lymphnodes to test for cancer Sentinel Lymph Node: first node to exhibit positive signal of metastasis Lymphatic Drainage of Testis - will drain to abdominally located aortic lymph nodes to do testis development - enter veins to spinal cord and can lead to testicular cancer metastasizing to the brain - will not drain to inguinal lymph nodes

Lymphatics Clinical Issues Principle 2

Principle 2: Know what body regions are drained by an enlarged lymph node(s) Transumbilical Plane Separates Watershed Areas w/respect to lymph drainage Above umbilicus will drain to axillary region Below umbilicus will drain to inguinal region

Lymphatics Clinical Issues Principle 3

Principle 3: When multiple lymphatic watersheds are involved, consider systemic disease enlarged areas not painful

P-value

Probability of obtaining a value of the sample test statistic as extreme as the one actually obtained from the sample data, assuming H0 is true In terms of difference between groups, it represents the probability that the difference between groups happened by chance or sampling error. (If the null hypothesis is true) P<0.05 --> Unusual sample results --> Reject H0 p>0.05 --> Not unusual sample results --> Fail to reject H0 P-Value (2-Tailed) --> 0.025 on each end of distribution Fisher suggested 5% level (p<0.05) could be used as a scientific benchmark for concluding that fairly strong evidence exists against H0 - Was never intended as an absolute threshold --- P <0.05 is an arbitrary cut-point --- Alpha (Type I) Error determined prior to study - Scientific context is critical - Does it make sense to adopt a therapeutic agent because P-value obtained in a RCT was 0.049, and ignore results because P-value was 0.051? Hence important to report the exact p-value - Not < 0.05 or > 0.05

Excitation-Contraction Coupling

Process by which AP in the skeletal muscle (electrical event) generates force (mechanical contraction) *extracellular calcium is NOT necessary for contraction of skeletal muscle fiber if directly stimulated applying electrical stimuli on the surface - However, the NMJ does need Ca2+ in order to release Ach, if Ca2+ is removed during nerve stimulation muscle contraction won't occur as the nerve terminal won't release ACh - cardiac and smooth muscle extracellular Ca2+ is required for contraction Two Important Elements of Triad 1. A voltage gated L-type calcium channel - aka dihydropyridine (DHP) receptor - L-type calcium channels are in T tubules together with the voltage gated Na+ and K+ channels. 2. A calcium-release channel located in membrane of the SR - ryanodine receptor because it is activated by ryanodine. 1. Membrane depolarization at t-tubule opens/activates voltage-gated L-type Ca2+ channel 2. Mechanical coupling b/w L-type Ca2+ channel and Ca2+ release channels causes Ca2+ release channel to open on SR - the calcium permeability of the L-type calcium channel is not important at all in coupling - voltage gated L-type calcium channel protein undergoes a conformational change and acts as an agonist (bind, tickles) the ryanodine receptor (Ca2+ release channel) - physical-mechanical interaction b/w L-type voltage-gated Ca2+ channel and the Ca2+-release channel on SR opens up the Ca2+-release channel 3. Ca2+ exits SR via Ca2+ release channels leading to muscle contraction - Calsequestrin keeps high Ca ++in the SR **4. Ca2+ entering cell via L-type Ca2+ channels also can activate Ca2+ release channels --> this pathway is not essential in skeletal muscle, but does occur to a small degree - slower component is very important in cardiac muscle and smooth muscle, it is due to a consistent calcium-induced calcium release from the SR

Assignment

Random - Blind assignment? Were controls comparable to cases? Confounding - Matching - Statistical

Regulation of Tension in Skeletal Muscle

Regulation of contraction speed: 1. changing ATPase activity 2. changing the force on the muscle Regulation of muscle tension in a contraction (ie crossbridges formed) 1. length/tension relationships 2. hypertrophy 3. increasing the number of stimuli 4. increasing # and type of motor units involved

Confounding Variable

Related to both the exposure and outcome But is the actual underlying cause of the outcome observed Coffee and Bladder Cancer Coffee Consumption --> Cancer Confounding Variable: Cigarette Smoking - associated w/both exposure of interest and outcome but is the actual explanation for the outcome seen

Post-Synaptic Response: Generation of EPP

Reversal Potential Erev of the End Plate Current ACh binding to its receptor (AChR) at motor end plate generates a current through the acetylcholine channel (Nicotinic muscular) which is carried by Na+ and K+ that are almost equally permeable - same conductance (G) At RMP for muscle (-80mV) there is no driving force on K+(remember that the driving force is given by Iion= Vm- Erev) because Erev for K+ is about -90 mV Driving force on Na+ is large because its reversal potential is ~+90 mV When ACh initially binds, Na+ is forced (rushes) into the cell - as it flows in, the cell depolarizes, and the potential moves away from Erev for potassium - driving force on K+is created As sodium continues to influx, potassium efflux increases, but as it does so, the membrane potential of the cell starts to approach Erev for Na+. Eventually the two ions balance each other out and come to rest at a new reversal potential which settles between the reversal potential of both sodium and potassium This occurs at 0mV - point at which there is equal flux of sodium and potassium through the acetylcholine channel If you apply the condition PNa equal to PK to the conductance equation we studied before, it simplify to Vm=(EK+ENA)/2 thus Vm = 0 = Erev

Surface Anatomy of the Lungs

Right Lung (3 Lobes) - Superior - Middle - Inferior - Horizontal Fissure and Oblique Fissure Left Lung (2 Lobes) - Superior - Inferior - Oblique Fissure

Sympathetic Stress Response

SNS is a tonic system Its activity can be increased or decreased organ by organ or as a unit. It is not essential to life, but is necessary in stressful situations such as exercise, excitement, hemorrhage, etc. During stress, SNS is activated and all the physiological responses listed above occur

Anatomical Planes

Sagittal - Median - Divides the body into right/left - Parasagittal Coronal (Frontal) - Divides body into anterior/posterior Horizontal (Transverse/Axial) - Divides body into superior/inferior

Classes of PNS Glia

Schwann Cells (similar to oligodendrocytes) --> myelin sheaths Satellite Cells (similar function to astrocytes) - around the cell bodies (typically in ganglia)

Myelination and Conduction Velocity

Schwann Cells --> myelination in the PNS Oligodendrocytes --> myelination in the CNS Myelination decreases (ie faster) the time constant and therefore increases conduction velocity by: - decreasing membrane capacitance (ie decrease ability for the membrane to steal current from the AP) by increasing the distance between the membrane plates Myelination increases the space constant and therefore increases conduction velocity by: - increasing membrane resistance by insulating the axon to prevent current loss to the environment.

Screening Test Definition

Screening tests detect preclinical disease in patients with no symptoms, so that earlier treatment may be initiated with the goal of improving health outcomes Problems/downsides - hard to make an asymptomatic person feel better - Most persons who are screened do not benefit personally and are more likely to be harmed

Serotonin (5-HT) influences peripheral tissues

Serotonin is a NT that also has CNS and peripheral targets Important in the regulation of: - bone remodeling (SSRI's decrease bone density) - lipolysis - glucose metabolism - bone marrow - gut microbiome

Regulation of Muscle Tension: 3. Increasing the number of stimuli

Single APs will create a twitch with a weak force - With one AP, Ca2+ level goes up then goes quickly down due to the Ca2+ ATPase - The tension has a delay, increase, and then drops - This is called a twitch which isn't very efficient. Brain will send down multiple APs at a higher frequency to generate a greater force of contraction due to Ca2+ released during excitation-contraction coupling does not have enough time to reuptake into the SR - the more Ca2+ present leads to more binding to troponin C, and allowing more cross-bridge formation - This phenomenon is known as tetany and is responsible for a high, sustained maximal force. - Many APs are required for efficiency because the Ca2+ stays up and the cross bridge cycling continues leading to a maximum contraction Series elastic element - After a muscle AP, Ca2+ is released from the SR leading to a muscle contraction - process is not entirely continuous as there is a time delay before Ca2+ release, and an even longer delay before muscle contraction - series elastic element accounts for longer delay before muscle contraction - defined as a slack of the tendons, tissue and muscle fibers that must be taken up before contraction to occur (think of a fishing line that needs to be taut before you are able to reel it in) - series elastic element explains why a single twitch cannot cause maximum tension - A single AP leading to a single muscle twitch does not provide enough tension to take up the "slack". Hence the need for multiple APs

Chemical Synapses

Site of transmission b/w 2 neurons or neuron & target cell Allows for communication between cells - Sender: presynaptic neuron - Receiver: postsynaptic neuron or target cell/organ - Pre + Post = Functional Unit Pass information directionally from a presynaptic neuron to a postsynaptic cell via a chemical (transmitter): a functional unit Presynaptic neuron: Active zone: site of neurotransmitter release at end of axon - vesicles lined up on presynaptic terminal ready for release Synaptic Cleft: - Space (20-40 nm) b.w pre- & post-synaptic cell at a synaptic site Postsynaptic cell: Postsynaptic density: location of NT receptors on postsynaptic cell (a 2nd neuron or effector cell like muscle) Sites of mechanical adhesion: - Contains transmembrane proteins that tether presynaptic and postsynaptic membranes together

Microglia Functions

Smallest of all glia cells NOT derived from the Neural tube but originate from mesenchymal cells derived from yolk sac that migrate into the CNS during development Microglia are the resident "immune-derived" phagocytic cells which are scattered throughout CNS Actively migrate within CNS to monitor environment Proliferate in response the CNS injury Ability to become quickly activated and respond to pathological changes Survey brain for damage or infection - phagocytose debris Important during CNS development & synaptic plasticity: phagocytose degenerating cells during normal developmental programmed cell death and prune synapses through life

Smooth Muscle Contractile Unit

Smooth muscle cells are small and unstriated Smooth muscle (SM) has actin/myosin complex - no sarcomeres - does not exhibit the same highly ordered conformation seen in a skeletal muscle sarcomere SM uses dense bodies to align filaments (no Z-line) - dense bodies are scattered throughout SM - Myosin filaments are extremely thin (same diameter as actin) - Actin filaments are attached to dense bodies scattered throughout the cytosol - allowing sliding and contraction of actin and myosin without a preferential direction Gap junctions between fibers spreads APs, inducing waves of contraction Smooth muscle does not have parallel elastic elements SM sarcoplasmic reticulum (SR) is not very well developed, requiring presence of extracellular Ca2+ for contractions.

Smooth Muscle Calcium Regulation

Smooth muscle has no triads or t-tubules SM contains caveoli ("indentions") on cell membrane which contain voltage gated Ca2+ channels - sarcoplasmic reticulum within smooth muscle cells is insufficient, thus extracellular calcium influx is important in SM. - Smooth muscle has mechanisms to increase intracellular Ca2+ concentration that are not seen within skeletal muscle. Four pathways for Calcium entry: 1. Calcium leak channels: do not participate in E-C coupling 2. Voltage gated Calcium channels 3. Receptor or ligand gated calcium channels 4. Ligand second messenger pathways that stimulate the release of Ca++from the SR 1. Voltage-gated L-type Ca2+ channels (within caveoli) - opened due to APs from muscle cell membrane - Calcium flows into cell down a concentration gradient 2. IP3-gated Ca2+ release or ligand-gated Ca2+ channels. - Hormones or neurotransmitters bind to G protein complex/receptors on muscle cell membrane, causing a signal transduction cascade that will allow Ca influx from the SR - mainly an IP3 activation from the cleavage of PIP2 by PLC - IP3 opens ligand-gated Ca2+channels on SR 3. Ca2+-induced Ca2+ release channels (CICR) also can cause influx of Ca2+ from the SR 4. Store-operated channels, allow influx of extracellular Ca2+ by complex mechanism More points: - SM can utilize extracellular (most important) or intracellular Ca2+ for contraction in contrast to skeletal muscle which relies on intracellular SR levels solely. - Pharmacological control of smooth muscle can be seen by use manipulating the ligand-gated channels or metabotropic receptor regulated channels - Smooth muscles (unitary) generate long action potentials where Ca2+ channels play important roles. The intracellular Ca2+ concentration oscillates in smooth muscle propagating from fiber to fiber (Ca2+ waves) Single-unit smooth muscle can produce gradations of contraction - differs from mechanism for producing gradations of skeletal muscle contraction. - depends on the level of calcium ions in the cytosol. - Many single-unit smooth muscle cells have enough calcium in cytosol to maintain tone (low level of tension) - occurs in absence of APs - Signaling by ANS and hormones alter the strength of self-induced, smooth muscle contractions - Other factors, such as local metabolites, certain drugs, alter the contraction of smooth muscle - All of these influences alter level of calcium ions in the cells' cytosol.

Smooth Muscle General Features

Smooth muscle is controlled by involuntary autonomic nervous system - visceral motor Development of force is used: 1. For motion (pilomotors and muscles of nictitating membrane) 2. To expel content of hollow organ (G.I. tract, uterus hearth) 3. To change cross-sectional dimension of tubular organ (airways, blood vessels) 4.T o change dimension of passive organs (ciliary muscles/lens). Comes in two different varieties: 1. Multiunit smooth muscle --> NEUROGENIC - found in areas of our body that require fine motor movement - cell membranes are electrically isolated from each other, allowing finer motor control - has few fibers per motor neuron - do not have APs in the classical way seen in cardiac or skeletal muscle - properties partway between skeletal muscle and unitary smooth muscle. - normally respond to nerve impulse but can be activated to contract in response to certain chemicals - found in the walls of large vessels, large airways of the lungs, ciliary muscle, iris of the eye, pili erector muscles on skin (pilomotor) 2. Unitary smooth muscle --> MYOGENIC - has less precision because more muscle fibers are innervated per motor neuron - muscle fibers have sparse innervation and connect via gap junctions - gap junctions permit lateral spread of APs along length of the muscle, coordinating synchronous contraction - develops nerve-independent contractile activity, initiated by the muscle itself, does not require nervous stimulation for contraction, self-excitable - Characterized by spontaneous pacemaker or slow-wave potentials that spread to entire muscle as it is were a single unit (functional syncytium) - A syncytium is a group of interconnected cells. When an AP develops in one cell, quickly spreads to other cells. All cells in a syncytium contract as a single, coordinated unit - Automatic shifts in ion concentrations in ECF and ICF cause spontaneous depolarizations to threshold potential. - able to respond to sudden stretch as a mechanical stimulus that will elicit contraction - Muscle cells found in G.I tract, uterus, ureters, muscle cells of arterioles, capillary sphincters, most blood vessels, bladder

Comparison of Somatic and Autonomic Motor Systems

Somatic NS Characteristics - Lower motor neurons of somatic NS (GSE) exert direct control over skeletal muscle - Cell bodies originate in ventral gray horn - Axons are heavily myelinated - conduction of impulse is rapid Autonomic (Visceral) NS Characteristics - ANS unit exists as a chain of two motor neurons: preganglionic (located in CNS) and postganglionic (located in PNS) - Cell bodies of pregaglionic originate in lateral gray horn - Preganglionic axons are slightly myelinated, postganglionic neurons lack myelin - Conduction of impulse in ANS is slower than in SNS

Somatic Sensory and Motor Function

Somatic Sensory Receptors - Exteroreceptors: Chemoreceptors, Thermoreceptors, Mechanoreceptors (touch, pressure), Nociceptors, Photoreceptors - Proprioceptors: Movement, joint position Sensory Component - Different DRG neurons convey each type of sensation - These sensory projections are general somatic afferents (GSA) - skin, joint, muscle spindle Motor Component - Different motor neuron groups control Striated Muscle vs Muscle Spindles - Both motor projections are general somatic efferents (GSE). - Alpha and gamma (tension and tone) motor neurons --> muscle, muscle spindle

Referred Pain Phenomenon

Somatic and Visceral Sensory Afferent Projections into the Spinal Cord have partial overlapping Distributions Referred pain: Visceral pain perceived as somatic pain originating from the skin or outer body - Partially due to overlap in nociceptive afferent terminals from somatic nerves in spinal cord - May also be due to reflexive vasoconstriction in the vessels supplying the corresponding somatic segments

Sympathetic & Parasympathetic NTs and Receptors

Somatic lower motor neurons - Cholingeric - Release ACh - Binds nicotinic receptor (Nm) on skeletal muscle Parasympathetic - Preganglionic neuron releases ACh - Binds nicotinic receptor (Nn) on postganglionic neuron - Postganglionic neuron releases ACh - Binds muscarinic receptor on effector/target tissue Sympathetic - Preganglionic neuron releases ACh - Binds nicotinic receptor (Nn) on postganglionic neuron - Postganglionic neuron releases NE or E (adrenergic) - Binds alpha or beta adrenergic receptor depending on effector/target tissue **chromaffin cells are neuroendocrine cells (postganglionic neurons) found mostly in medulla of the adrenal glands. Notice that sympathetic neurons (presynaptic cell) release ACh onto chromaffin cells (postsynaptic cell) which express nicotinic (Nn) receptors. Activation of nicotinic receptors causes the release of E/adrenaline and NE/noradrenaline from the chromaffin cells into the circulation, where these NTs effect multiple organs

Neurotransmitters of Autonomic Nervous System

Somatic: Lower motor neurons (Cholingeric) Nm Autonomic Parasympathetic: - Preganglionic (Cholingeric) Nn - Postganglionic (Cholingeric) M Sympathetic - Preganglionic (Cholingeric) Nn - Postganglionic (Adrenergic) A

Neocortex Functions

Specific Functions are localized within different regions of Neocortex Frontal Lobe - social/emotional behavior, judgement, problem solving - Premotor Cortex - movement of trunk muscles - Motor Cortex - planning/executing voluntary movements - Broca's Area - speech and language production Parietal Lobe - spatial relations - Somatic Sensory Cortex - processes sense of touch and temperature Temporal Lobe - speech, hearing and memory, associates words with images, processes semantics - Primary Auditor Cortex - basics of hearing, pitch, volume Occipital Lobe - visual perception, ability to read - Visual Association Cortex - static and moving objects, pattern recognition

Action Potential Propagation

Speed of propagation is termed conduction velocity - Units are meters/sec - Conduction velocities differ for different axons - Speed depends on internal diameter of axon and internal resistance - Membrane capacitance and myelination - Activation kinetics of the Na+ channel Space Constant - how far an AP can passively travel due to a decrement in voltage - determines how far a current will spread - λ conceptually is the distance an AP can travel before it reaches 37% of its initial strength λ= √Rm/Ri Rm = membrane resistance Ri = internal resistance given as inverse of diameter of cell Ri= 1/d (larger the diameter --> lower internal resistance, smaller the diameter --> greater internal resistance GOAL: Increase the space constant --> increase speed/velocity of AP HOW?: - increasing membrane resistance --> reduce amount of current lost to the surroundings by insulating the axon (myelination) - decreasing internal resistance ie increasing axon diameter Time Constant - amount of time required to charge and discharge the membrane capacitance - cell membrane acts as a capacitor by separating and storing the intra and extracellular charge - time t = τ, the charge on the capacitor is reduced to 37% of its initial value (ie. the smaller the time constant, the faster the capacitor is discharged) τ = Rm x Cm During an AP, the flow of ions actually charges the membrane, and by doing so, the AP becomes weaker - if we could decrease capacitance (reduce the membrane's ability to steal current from the AP), it would speed signal propagation. GOAL: Decrease the time constant --> increase speed/velocity of AP, smaller the time constant, the faster the conduction velocity - Decrease membrane capacitance (Cm) --> myelination - successive layers of myelin thicken the membrane and increase the distance between the plates of the capacitor - capacitance decreases with the distance between plates (membrane thickness) - Myelination also increases membrane resistance (Rm) which would be good to increase the space constant by insulating and preventing current loss, but would increase the time constant :( wouldn't the increase in Rm cancel out the decrease in capacitance? - reduction in Cm via myelination outweighs the increase in Rm having an overall effect of reducing the time constant and increasing conduction velocity

Cross Bridge Cycle

Starting with/myosin attached to actin: 1. ATP binds to myosin head decreasing its affinity for actin Cross bridge is released. 2. ATPase on myosin head hydrolyzes ATP into ADP + Pi. causes myosin head to become perpendicular to actin filaments 3. Ca2+ binds to Troponin C and changes conformation of the troponin/tropomyosin complex exposing actin active sites to myosin heads - myosin head attach to the active site on actin - Ca2+ is required in this step 4. ADP + Pi is released and power stroke occurs - myosin head bends 45 degrees and pulls the actin towards the M line - sarcomere shortens by up to 1 um. - rigor (myosin head bound to actin after power stroke) - New cycle starts when ATP binds to myosin head to release rigor complex (release of the crossbridge) Two important points to remember: 1. Speed of the cycle depends on the speed/efficiency of ATPase on the myosin head 2. Strength of cycle depends on amount of cross bridges formed, which depends on the amount of Ca2+ Calcium Removal (Muscle Relaxation) Ca2+ is removed from sarcoplasm by the Ca2+-ATPase on SR membrane - Intracellular concentrations of Ca2+ decrease to point where there are insufficient amounts to bind to Troponin C - Tropomyosin now returns to its resting position, blocking myosin binding site of actin --> muscle is now relaxed If Ca2+ remained high in a cell, it could go through cell death due to Ca2+ overload. Rigor mortis - actin filament and myosin are attached after power stroke in rigor complex - there is no more ATP to allow release crossbridge - muscle remains in a contracted state without any action potential involved

Epinephrine (E) Synthesis, Release & Inactivation

Steps 1-5 are same as for NE 1. Active transport of tyrosine into cell synaptic terminal 2. Tyrosine converted into L-DOPA by enzyme tyrosine hydroxylase in cytoplasm - (rate limiting step) 3. L-DOPA is converted to dopamine by enzyme DOPA-decarboxylase in cytoplasm 4. Dopamine (DA) is actively transported into storage vesicles 5. Inside vesicle, DA is converted into norepinephrine (NE) by the enzyme DA-b-hydroxylase (DBH) 6. NE leaks from the storage vesicle into the cytoplasm 7. NE is converted into epinephrine (E) by enzyme phenylethanolamine-N-methyltransferase (PNMT) in cytoplasm Steps 8-12; E is transported into the synaptic vesicle, released, undergoes reuptake, and degradation similar to NE

Surface Anatomy of the Neck

Sternocleidomastoid Muscle Posterior Triangle Anterior Triangle

Regulation of Muscle Tension: 2. Hypertrophy

Strength of contraction (tension) of a muscle can be regulated through changes in structure of muscle fibers. 1. Hypertrophy - increase in size of existing muscle fibers - an increase in the number of sarcomeres, but no change in the actual number of muscle fibers --> increases number of crossbridges --> more tension! - This can be accomplished through exercise or steroid use - The converse of hypertrophy is atrophy occurring for example after prolonged bed rest 2. Hyperplasia is an increase in the number of muscle fibers and only occurs in pathological states.

Relative Strengths of Study Designs

Strongest --> Weakest Randomized clinical trial Cohort study Case-control study Case series

Axonal Transport

Structural Components - Neurofilaments - scaffold - Microtubules - railroad/highway - Mitochondria - Transport vesicles Importance: - Maintains function of axon/synapses - Trophic support for neuron (back to cell body) Bi-directional Transport - Anterograde/orthograde - from cell body toward synapse --- Necessary for maintaining structural integrity of axon --- Essential for transporting biosynthetic enzymes & neurotransmitters to axon terminals - Maintains function of axon/synapses - Retrograde - from terminals toward cell body --- Endocytotic vesicles, organelles, proteins are carried back to soma Steps - Large molecule peptides (pre-propeptides) are converted into smaller peptides in the RER (a) - Propeptides and enzymes are packaged into vesicles that are transported to the Golgi, modified, and packaged into vesicles (b) - Vesicles get attached to microtubules and are carried to terminals by fast axonal transport (c) - Propeptides are cleaved to produce smaller peptide transmitters in the terminal (d) - Small molecule transmitters are synthesized in the neuronal terminal and packaged into vesicles (e) - Peptides and neurotransmitters are released into the synaptic cleft by exocytosis (f) - Surplus membrane elements in terminal are carried back to the cell body by retrograde transport (g) - The retrieved vesicular membrane is degraded or recycled (h) Got to get a lot of stuff down the axon - Need a lot of mitochondria --> ATP dependent transport - any mitochondrial diseases are going to have a neurological component because axonal transport is going to be affected

Defense of General Health Checks (PHE)

Studies of PHE in 1960s and 1970s "included little or no cancer screening and employed a battery of tests of little value when used to screen asymptomatic people." Most recent study began in 1999 Modern general health check bears little relationship to "annual physical" At least 55 recommended preventive interventions in adults (not counting immunizations) If not provided during a preventive health visit, then when?

Cell Body/Soma

Support and Metabolic Center Highly active - Transcription/translation - Euchromatic nucleus - Prominent nucleolus - Extensive rough ER (basophilic Nissl substance) & polyribosomes --> neurotransmitter enzyme production - Extensive Golgi complex High energy metabolism - Large # of mitochondria - ATP for transport down axon cytoskeleton Specialized functions - Proteins primarily translated and processed in cell body (also proximal large dendrites) - Produce large numbers of small transport vesicles which contain enzymes and neurotransmitters - Dense network of scaffold proteins (intermediate filaments & microfilaments) and microtubules for structural support Neurofilament --> specific filaments to neurons Glial filaments --> specific to astrocytes

Qualitative Data

Survey Interview Focus groups Anecdotal accounts More detailed and in-depth assessment of situation or problem

Quantitative Data

Survey Data Reporting to public health, CDC, DC Dept. of Health Limited by sample size Endpoints require larger sizes for comparisons Statistical associations may be made

Sympathetic v. Parasympathetic Regulation of Organ Function

Sympathetic - Preganglionic neuron is short - Post ganglionic neuron is long Parasympathetic - Preganglionic neuron is long - Post ganglionic neuron is short (typically on or near effector organ) - Vagus nerve responsible for parasympathetic innervation of abdominal organs

Autonomic Division of PNS

Sympathetic (fight or flight) Parasympathetic (rest and digest)

Anatomical Organization and Origin of ANS

Sympathetic Neurons: - Located in mid spinal cord segments - Thoracic - upper Lumbar (T1-L2) - Thoracolumbar Division Parasympathetic Neurons: - Rostral (Brainstem - CN III, VII, IX, X) - Caudal (Sacral spinal cord S2-S4) segments of the CNS - Craniosacral Division Preganglionic Neuron cell bodies form intermediolateral cell column in Lateral Horn (Origin: Neural Tube)

Excitation-Secretion Coupling

Synaptic delay - Time b/w the arrival of an AP at presynaptic nerve terminal and the production of a postsynaptic response - Measuring the postsynaptic response as a function of presynaptic potential is called the input-output relation What underlies this synaptic delay? 1. time it takes for voltage-gated Ca2+channels to open 2. Ca2+ to induce vesicle fusion and NT release 3. diffusion of ACh across the synaptic cleft - As a presynaptic action potential reaches the nerve terminal (labeled action potential in presynaptic cell), the terminal depolarizes and sodium rushes in - As sodium reaches its reversal potential, a simultaneous inward Ca2+current begins just before the terminal repolarizes (downward deflection labeled inward calcium current) due to a voltage sensitive Ca2+channels opening - As the presynaptic cell repolarizes, the inward Ca2+flux stops - postsynaptic cell action potential doesn't even start until the presynaptic cell is completely repolarized - The End Plate Potential (EPP, labeled with the more general term epsp: excitatory postsynaptic potential) produced by AChR activation begins just after the end of the presynaptic calcium current due to the synaptic delay Let us know take a closer look at the EPP - activation of AChR results into a large depolarization in postsynaptic cell membrane - AChR are permeable to both Na+and K+ - at RMP in the muscle, when the AChR opens, Na+rushes in driven by a large voltage difference from ENa (typically over +60 mV), while little K+exit the cell as EK is close to RMP - EPP produced is normally well over voltage necessary to induce an action potential (threshold) in the muscle cell - excess of voltage is known as the safety factor and is caused by excess number of vesicle release from the presynaptic cell Please note that the EPP (or EPSP) IS NOT an action potential - purpose of EPSP is to depolarize the muscle cell at the NMJ enough such that Voltage gated Na+channels will open to produce the action potential in the muscle - EPP is a graded potential --> size will depend on number of vesicles released that fluctuate

Neurotransmitter Release (Exocytosis)

Synaptic vesicle fusion and NT release is mediated by Ca2+ - Vesicles dock at presynaptic active zone and initiate exocytosis of NTs at presynaptic membrane - Voltage gated Ca2+ channels enriched in active zone - SNAREs: large protein complex that mediates vesicle fusion - Synaptotagmin: Ca2+ sensor protein Tetanus and botulinum toxin inhibit SNARE function! - inhibit NT release

Blood Pressure Wave

Systole - heart contracts to force blood through arteries - need a higher pressure to overcome a higher resistance Diastole - heart relaxes and blood comes into heart from the veins (venous return) SBP (systolic blood pressure) - peak arterial pressure reached when heart contracts - reflects CO (SV x HR) (depends on contractility) - higher contractility = higher SBP - normal range = 90-120 mmHg DBP (diastolic blood pressure) - lowest arterial pressure reached when heart relaxes - depends on resistance in the arteries (afterload) - DBP reflects degree of resistance in vasculature (TPR) - higher resistance = higher DBP - normal = 60-80 mmHg Pulse pressure (PP) - difference between systolic and diastolic pressures - PP = SBP - DBP (normal ≈ 40 mmHg) MBP (Mean Blood Pressure) or MAP (Mean Arterial Pressure) (normal = up to 120/80 mmHg) MBP = DBP + (SBP-DBP)/3 or MBP = DBP + PP/3 Heart spends 1/3 time in systole and 2/3 time in diastole

Specificity

TN/ (TN + FP) If the patient is free of disease, probability that the test will be negative

Sensitivity

TP/ (TP + FN) If the patient has the disease, the probability that the test will be positive

CV Parameters and Relationships

TPR (Total Peripheral Resistance) - resistance of entire systemic circulation (relates to tone in arteries) Afterload - force against which heart contract CO = Cardiac Output (L/min) - amount of blood pumped out of left ventricle per minute (normal at rest = 5 L/min) CO = SV x HR HR = Heart Rate (bpm) (normal resting HR = 70 beats/min) SV = Stroke Volume (L) - amount of blood pumped out of left ventricle each heart beat VR = Venous Return - amount of blood flowing from veins into the heart (right atrium)/minute - higher the VR the higher the preload Venous tone: level of constriction in the veins BP = CO X TPR

Temporomandibular Joint

Temporomandibular Joint Ramus of Mandible

Bayes' Theorem

The correct interpretation of a test result depends on the pre-test probability that the patient has the condition you are testing for Example: If the patient has a very low probability of pregnancy before the pregnancy test is done (male or post menopausal female), a positive test is unlikely to mean that she is pregnant

Sympathetic Nervous System Pharm Overview

Thoracicolumbar outflow (T1-L2,3) - preganglionic neuron cell bodies are located in intermediolateral cell columns (lateral horns) of spinal cord Preganglionic axons can: 1. synapse w/postganglionic neurons in the paravertebral (sympathetic) chain ganglia (approx. 22 ganglia - close to spinal cord) 2. bypass chain ganglia to form splanchnic nerves that synapse with postganglionic neurons in the prevertebral ganglia (celiac, superior and inferior mesenteric) in abdomen 3. bypass all ganglia to form a branch of splanchnic nerves that directly innervates chromaffin cells of adrenal medulla Short preganglionic (myelinated) Long postganglionic (unmyelinated) fibers Innervation is diffuse - the SNS can produce massive responses leading to increased metabolism and energy utilization (ex., "fight or flight" reaction). SNS is controlled by centers in the hypothalamus (homeostasis) and medulla that are influenced by higher brain areas such as the cortex and limbic system

Action Potentials in Smooth Muscle

Three types: 1. Single spike - corresponds to an AP caused by electrical stimulation, a hormone/neurotransmitter action or a muscle stretch 2. Plateau shaped AP - typical pattern of a muscle AP, but repolarization is delayed - delay accounts for prolonged contractions seen in the bladder or uterus. 3. Slow wave APs (Ca2+-mediated slow waves) - extremely slower than other APs, occurring in seconds rather than milliseconds - waves generate long APs where voltage gated Ca2+-channels are closed slowly, allowing the intracellular Ca2+ levels to oscillate and propagate depolarization throughout the entire muscle - type of contraction is seen in rhythmic movements of the intestines - These type of contractions are characteristic of unitary smooth muscle 4. Pacemaker APs - Pacemaker potential - membrane potential of pacemaker cells is characterized by a period of instability at rest during which the conductance to Na is slowly increased until threshold is reached and an AP starts - process continues at rates dependent on cellular environmental conditions - regulated by Temperature, hormones, PH, neurotransmitters, stretch pressure on the fiber, and pO2and pCO2

Quasi-Experimental

Time series, pre/post test

Lymphatic System Distribution

Tissue Distribution - Throughout body Exceptions: - Avascular tissues (e.g., cartilage, epidermis, cornea of eye) - Central nervous tissue - Portions of spleen - Red bone marrow Skin: lymphatic vessels lie in subcutaneous tissue and follow veins Viscera: Generally follow arteries, forming plexuses

Sympathetic Innervation of Systemic Circulation (Blood vessels)

Tonic SNS activity maintains BP TPR (total peripheral resistance) Arteries: ↑ SNS - ↑ Arterial Resistance --> Afterload Veins: ↑ SNS - ↑ Venous Return --> Preload

Primary Active Transport

Transport of solute against its concentration gradient (uphill) Active process --> requires energy (ATP) Energy is used directly to pump solutes Carrier protein has ATPase activity Follows features of a carrier mediated transport: - saturation - specificity - competition Examples - Sodium-potassium ATPase (Na+/K+ pump) - antiport - Calcium ATPase (Ca2+ pump) - Hydrogen-potassium ATPase (H+/K+ pump) - antiport

Secondary Active Transport

Transport of solute is coupled with Na+ transport (down its concentration gradient into cell) and solute is transported against its gradient Na+ is moving down its concentration gradient Driving force for secondary active transport is Na+ concentration gradient created by primary active transport of Na+/K+ ATPase--> Using potential energy of Na+ gradient Na+ moves down its gradient but provides energy for moving the solutes uphill (thus, secondary active) Active process --> requires energy (ATP) Inhibiting Na+/K+ pump, stops this transport Carrier may transport one or more solutes

Causation

Two key elements: 1. Temporal sequence - The cause must precede the effect (ie its consequence in time) 2. Intervention - Change in temporal antecedent with a corresponding change in effect x is a cause of y if the probability that y occurs is increased as a consequence of the presence of x

Contraction in Smooth Muscle

Two modes of cycling Calmodulin-binding mode - mode is similar to cross-bridging in skeletal muscle - both ATP-dependent, bind myosin head to actin with normal angle and power stroke - Smooth muscle does not have troponin and tropomyosin - Influx of calcium causes activation of Ca2+- calmodulin which activates myosin via phosphorylation - Calcium has no direct contact with active or myosin, thus providing smooth muscle with less efficient and much slower contractions than skeletal muscle 1. intracellular Ca2+ concentration rises, and Ca2+ binds to calmodulin (CAM) 2. Ca-CAM complex binds to myosin light chain kinase (MLCK) 3. MLCK phosphorylates myosin (using ATP) 4. phosphorylated myosin forms cross-bridges with actin 5. contraction occurs 6. Myosin light chain phosphatase (MLCP) dephosphorylates myosin, stops the cross bridge cycle Latch mode - unique cycle to smooth muscle - responsible for maintaining a permanent tension/contraction with little ATP consumption. - myosin becomes dephosphorylated by MLCP and changes its strength of binding to the actin filaments by forming latch bridges. - produce much greater strength and endurance, a permanent contraction and consume less ATP - mechanism is seen in bladder, which needs to remain contracted as urine accumulates without expending a lot of energy - similar to rigor mortis.

One vs. Two-Tailed Intervals

Two-tailed test: - equal boundaries on either side of the mean One-tailed test: - one boundary is calculated and the other is infinity - looking at only one direction

Errors Associated with Hypothesis Testing

Type I Error (Alpha): - Rejecting H0 when it is, in fact, H0 is true. - "False positive" - Probability of Type I error is α (alpha), also called the 'significance level' Type II Error (Beta): - Failing to reject H0 when H0 is actually false. - "False negative" - Probability of Type II error is β (beta) Power: Probability of correctly rejecting H0 - 1 - β - Rejecting H0 when H0 is false

Motor Unit Types/Properties of Skeletal Muscle Fibers

Type I motor units: Properties of Nerve: - small cell diameter (neuron) - fast conduction velocity - high excitability - trigger use of "slow twitch" red fibers Properties of Muscle Cells - few fibers innervated (20-35) - moderate fiber diameter - low force of unit - oxidative metabolism (burn fat) - high myoglobin, high concentration of mitochondria, low glycogen content - moderate contraction velocity - low fatiguability - higher threshold for fatigue resistance - low ATPase activity - muscle type for long term movement - utilize this type of muscle for activities requiring endurance (running a marathon, maintaining posture) Type II units Properties of Nerve: - large cell diameter (neuron) - very fast conduction velocity - low excitability - trigger use of "fast twitch" white fibers Properties of Muscle Cells - many fibers innervated (100-150) - large fiber diameter - high force of unit - Glycolytic metabolism - high glycogen content, low # of mitochondria, lack of myoglobin - fast contraction velocity - high fatiguability - utilize fast ATPases to provide rapid and powerful movements Third muscle type: Fast Oxidative-Glycolytic (Type IIa) - hybrid between the two groups - contain properties of both types Clinical correlation: - slow fibers are used in aerobic exercise, burn fat and are make us healthier - Muscle fibers can become fast or slow via training - There are three skeletal fiber types in the human body: Type I, IIx type IIa - During cardio exercise training, there is some fiber type conversion from II to I - During strength training, the fiber type conversion goes from IIx to IIa - Type IIa and I are more efficient fiber types and are better for your body, thus this is a good change - The only way to go in the other direction (i.e. make type IIx) is via disuse atrophy

How Recommendations are made on Preventative Services/Screenings

U.S. Preventive Services Task Force - Independent panel of 16 nationally renowned experts in primary care, prevention, and EBM - Disciplines include family medicine, internal medicine, geriatrics, pediatrics, preventive medicine, Ob/Gyn, nursing, behavioral medicine - Under the Affordable Care Act, determines which preventive services must be fully covered by private insurers How does the USPSTF make a recommendation? The USPSTF judges whether conclusions drawn from the available evidence about a screening test or other preventive service are sufficiently certain to reliably assess the balance of benefits and harms - If yes: Task Force makes a recommendation (graded "A" - "D") - If no: "I" (Insufficient Evidence) on balance b/w benefits and harms

Grade D Recommendations for Screenings

USPSTF recommends against the service Moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits Clinicians should discourage the use of this service Examples of non-recommended screening tests during preventative health exams (where it is not indicated otherwise): - Urinalysis - EKG --> false positive, bad reads, artifact - Chest x-ray --> radiation exposure MerensteinD, et al., AJPM, 2006 examined data from 1997-2002 National Ambulatory Medical Care Survey on use of three USPSTF "D" rated screening tests - Urinalysis ordered at 37% of PHEs - EKG ordered at 9% of PHEs - Chest x-ray ordered at 8% of PHEs - $47-194 million in annual waste - Does not include costs of workup of abnormal results, further testing (e.g., cardiac stress testing, CT scans, etc.)

Grade A and B Recommendations for Screenings

USPSTF recommends this service. "A" - There is high certainty that net benefit is substantial "B" - High to moderate certainty that the net benefit is moderate to substantial Offer or provide this service Examples: Screening Tests that work - Paps/ HPV tests for cervical cancer - Screening for high blood pressure - Screening for alcohol misuse in adults - Screening for depression in adolescents and adults (including pregnancy and postpartum) - Screening for colorectal cancer - Biennial mammography in women age 50-74 years

Anatomical Classification of Neurons

Unipolar Pseudounipolar (off to side - spinal ganglia) Bipolar (retina) Multipolar (most common)

Measuring Resting Membrane Potential (RMP)

Use either: (1) The Goldman-Hodgkin-Katz (GHK) equation (2) The conductance equation We use the equation to calculate RMP at steady state when the membrane is permeable to more than one species of ion. Steady state = no net movement of current INa+ IK+ + ICl-= 0 GHK Equation: Vm = RT/F ln PNa[Na+]o+ PK[K+]o+ PCl[Cl-]i _______________________________________ PNa[Na+]i+ PK[K+]i + PCl[Cl-]o Conductance equation: - based on Ohm's Law for Membrane that is used to describe the direction of current flow when membrane potential and reversal potential of an ion are known I = G(Vm- Erev) - Conductance equation is determined using Ohms law for the Na+and K+currents (INa and IK) - Remembering that at RMP we have a steady-state condition where IK+INa= 0 - conductance equation is the best way to determine Vm for any cell and at any time

Overview of Circulation

Venous System: Low Pressure Capacitance Vessels Arterial System: High Pressure Resistance Vessels

Overview of SNS and PNS on Cardiovascular Parameters that determine BP

Venous tone --> SNS innervation Blood Volume --> Kidneys Contractility --> SNS (ventricular, atrial), PNS (atrial) HR --> influenced by both PNS and SNS TPR --> SNS arterial tone

Voltage-Clamping and The Hodgkin-Huxley Experiments

Voltage Clamp - technique allows one to hold the membrane voltage at a fixed value even when conductance is changing - makes it possible to measure membrane current at constant membrane potential - Because the voltage cannot change, any change in current is a direct result of a change in conductance, i.e. channels opening and closing - Voltage clamp is used to determine the ion fluxes which make up the action potential Y-axis displays current in mA/cm2, so any line dipping below 0 line (and with a negative slope) is negative current --> Sodium is entering the cell After a short time, the current changes direction, passes the 0 line, and increases until it reaches a maximal value determined by the command potential. On this graph, an upward current swing indicates a positive current value --> K+ leaving the cell Current is changing as a function of time - this indicates that the value of GNa and GK are changing b/c V is held constant - Since conductance is always positive, the sign of the current is entirely a function of the sign of the driving force which is given by: (Vm- ENa) for sodium, or (Vm- EK) for potassium From this graph, we can see that there is an inward and outward current. But how do you tell which ion is part of which current? Separation of Currents with TTX and TEA Tetrodotoxin (TTX), Saxitoxin (STX) - Both toxins are highly specific blockers of Na+ channels - possible to block the sodium current to specifically measure the potassium current in an action potential (outward current) tetraethylammonium (TEA) - selectively blocks outward flow of potassium which makes for easy visualization of both the magnitude and time course of the sodium current (inward current)

Threshold

Voltage at which an AP can start Cannot define threshold for a single channel current. Even with a small depolarization, few voltage gated Na+channel will open and produce a small inward current Magic happens when inward current produced by voltage gated Na+channel is large enough to counteract outward current produced by the K+ leakage channel. - When this occurs, the current from the inward flow of Na+causes more depolarization of more channels in a positive feedback, explosive manner generating an AP At the peak of the AP, the voltage gated Na+ channels will inactivate and close, the K+ leakage channels will begin to repolarize the membrane, and delayed voltage gated K+ channels will open allowing faster repolarization of the membrane. The spike only occurs at threshold when the inward rush of Na+ exceeds the outward flux of K+

Voltage Clamp, Current Clamp and the Patch Clamp

Voltage clamp - set a constant voltage and measure the current Current clamp - set a constant current and measure the voltage Patch Clamp - variant of the voltage clamp - allows us to voltage clamp a tiny piece of membrane - a membrane "patch" to study the current produced by single channel activity - patch can be attached to the cell (cell attached) or excised in different recording arrangements (inside-out or outside out)

Action Potential: Clinical Correlation

Voltage-gated Na+ Channels: Genetic Disorders Hyperkalemic periodic paralysis or Paramyotonia congenita - mutation in several aa in the voltage-gated Na+ channel - results in disruption of Na+ flow and muscle fatigue Note transmembrane domain #4 = voltage sensor of Na+ channel Note P loop between transmembrane domain #5 and #6 = selective ion pore, selective for Na+ - Mutations in these areas are often associated to epilepsy Clinically Relevant Na+Channel Blockers - Na+ channels are a popular target for some recreational and pharmaceutical agents - Cocaine and its derivatives (lidocaine and procaine) all act on these channels - Point mutations in the subunits of the sodium channel lead to various neurological disorders.

General Principles: Method

Were aims properly defined? Was a hypothesis proposed? What is the study type and is it appropriate? - Case-control - Cohort - Clinical trial Sampling Method

Results

Were proper adjustments made? - Confounding Variable (stratify) Was a test of significance performed? - p values Was a measure of the precision of the result made? - confidence intervals

Clinical Significance

What about clinical importance? Does the confidence interval lie partly or entirely within a range of clinical indifference? Does it pass the "so what" test? Clinical importance is a medical judgment, not statistical! Clinicians should change practice only if they believe the study has definitively demonstrated a treatment difference and that the treatment difference is large enough to be clinically important. Example: would you recommend a cholesterol-lowering drug that reduced LDL levels by 2 units in one year? Depends on your knowledge of: - Range of otherpossible treatments/interventions - Cost/Benefit Ratio (Clinical/Financial) - Side effects - Feasibility

Innervation of Skeletal Muscle

When a motor neuron enters a muscle, it splits into many unmyelinated branches A terminal fiber runs along a muscle fiber and ends at a NMJ Each muscle fiber is contacted by a single axon But a single motor axon can innervate several muscle fibers When we are born, we have more End Plates than needed - Multiple neurons may contact a single muscle fiber through these End Plates and compete for survival and innervation - ACh receptors are not localized to the motor end plate, they are found all along the length of the cell With time, receptors cluster at NMJ and extra End Plates are pruned off to leave a single survivor which takes control of its muscle fiber. With development, polyneuronal innervation end and each fiber receive only one End Plate Motor cortex exerts control over skeletal muscles - One long axon extends from motor cortex and synapses in the spinal cord on one or more alpha motor neurons - Primary motor cortex itself is controlled by other areas in the forebrain (premotor cortex)

White vs. Gray Matter

White Matter: Myelinated axons (lipid, and fat in the brain, insulation along pathways) - Fiber Tracks w/Myelinated Axons - Oligodendrocytes Gray Matter: cell bodies, dendrites, synaptic terminals - Neuron Cell Bodies - Neuropil: (Dendrites & Synaptic Connections) - Astrocytes & Microglia - Unmyelinated axon segments near Synapses - Synaptic Connections - Astrocytes & Microglia

Capacitance

ability of a circuit element to store charge C = q/V Capacitance pertains to a cell membrane, because it has the ability to store charge - basic biological property of membrane Membrane lipids which make up the bilayer serve as the insulator, and the two parallel plates are represented by the ion-containing solution on either side Capacitance decreases w/distance between plates (membrane thickness) and increase with their size (cell size)

Refractory Period

absolute refractory period - another AP cannot occur because the Na+ channel is closed-inactive relative refractory period - due to the persistent activation of K+ channels, the cell remains hyperpolarized longer than it would normally be - another action potential can occur, but the stimulus must be stronger (more negative, farther away from threshold Closed-inactivated channel and closed channel create a period of time where another AP cannot happen: basis for refractory period - When the channel is closed-inactivated, no spike can happen, regardless of how much the voltage changes - In closed state, a spike can be initiated but it would require a stronger depolarizing stimulus

McArdle Disease

lack of lactate production during anaerobic exercise Genetic defect with lack of myophosphorylase in White Type II skeletal muscle Damage to Type I via production of free oxygen radicals muscle contraction w/no electrical stimulus (not enough ATP to sequester Ca2+ via Ca2+ ATPase back into SR, muscle cannot relax)

Tennis Elbow

local inflammation nerve pinch localized reduction of conduction velocity

Thoracic Duct Structures

much thinner than typically pictured friable, can be lacerated during surgery!

Ion Channel Structure

multiple-pass transmembrane domain-containing chains of aa Primary aa sequence determines channel structure, and different subunits (amino acid chains) of channels fulfill different roles Hydropathy plot - hydrophobic amino acids make up transmembrane domains - hydrophilic amino acids make up cytosolic or extracellular domains - hydropathy plot tells you what residues are hydrophobic or hydrophilic; ion channels have sequences that alternate between hydrophobic and hydrophilic, indicating that the sequence spans the membrane multiple times - hydropathy plot measures the probability of a group of amino acid residues to be found in lipids or water thus determining the sequence of transmembrane domains. Important aspects of the voltage-gated channel structure: - Each subunit (usually b/w 4-6 subunits for a channel) is consists of 6 domains of transmembrane helices - Fifth domain - P loop (or pore domain) - site for loose binding of ions - Changing amino acids in the P loop will alter channel function Several important types of oligomeric channels (made several subunits) : 1. Tetramers: Voltage gated Na+, Ca++, and K+ channels 2. Pentamers: Nicotinic ACh Receptor Channel 3. Hexamers: Connexon - 6 unit structure that makes up half of an entire gap junction channel.

Isotonic Contraction

muscle tone/tensions stays the same change in length of the muscle The muscle shortens and lifts an object without changingstrength muscle tension developed is greater than its opposing load tension that is generated is used to shorten the muscle. Example would be lifting free weights - Lifting a fixed weight requires no change in strength but will get a decrease in the muscle length - Use this type of contraction to test how force alters speed of a muscle change (force-velocity graph above, where V max was at low weight/force). Two types of isotonic contraction: - Concentric (muscle shortening) - Eccentric (muscle lengthening) All movements are a combination of both types of contractions - tension curve increases first with no change in length (isometric - tension utilized to counteract the load of weight, w/o a change in length) - isometric followed by an isotonic contraction - velocity of muscle shortening is inversely proportional to the magnitude of the load

Oncotic Pressure

osmotic pressure due to colloids in a solution; in the case of the plasma, it is the force due to proteins in plasma.

Ohm's Law

voltage is equal to the current multiplied by the resistance V = IR When a constant voltage (electric potential) across each resistor is equal, current flows through each resistor, but current will be larger across the path of least resistance. Ion channels are very selective for the cations they conduct: - A Na+ channel has very low resistance (high conductance) for sodium ions, higher resistance for K+, and is completely resistive to anions

Sympathetic Innervation of the Kidney

↑ Renin release ↑ Na+/water retention ↑ Blood volume ↑ BP Blood volume is regulated by the kidneys

Causation: Koch's postulates

- Present in every case - Isolated and cultured from patients - Causes disease in inoculated animals - Re-isolated from inoculated animals

Standard Normal Curve

1 SD - 68% 2 SD - 95% 3 SD - 99.7% 1.96 SD --> 95% confidence interval 2.58 SD --> 99% confidence interval

Tonicity

Ability for water to move across the membrane Cell is placed into hypertonic solution: - Cell will shrink as water moves out of cell towards higher concentration of solutes Cell is placed in hypotonic solution - Cell will swell as water moves into cell towards higher concentration of solute Limit of cell swelling - if cell is placed in increasingly hypotonic solution there is a threshold in which the cell will lysis due to osmotic pressure on cell membrane

Surface Anatomy of the Lower Limb Deep Tendon Reflexes

Patellar Ligament (Tendon*) (knee) Calcaneal (Achilles) Tendon (posterior ankle)

Saturation/Saturability in Carrier Mediated Transport

1. Carrier proteins have limited number of binding sites for solute (limited number of carrier proteins) 2. At low solute concentrations, many binding sites are available and rate of transport increases rapidly w/ increasing concentrations 3. At high solute concentrations, rate of transport reaches a plateau, as all the binding sites are saturated (occupied) 4. Point of saturation is called Transport Maximum (Tm) represented by the plateau phase - defined as maximum rate at which the substance can be reabsorbed

Measurement of Plasma Volume

1. Evans blue dye - binds to plasma proteins 2. Radioiodinated albumin only in plasma/capillary compartment

Facilitated Diffusion Examples

1. Glucose transport from inside intestinal epithelial cells/renal tubules into blood 2. Transport of glucose into skeletal muscle & adipose cells by GLUT-4 transporter from blood 3. Transport of fructose gut all the way from the lumen into the blood

Leading Causes of Death in DC

1. Heart Disease 2. Cancer 3. Cerebrovascular Disease (Stroke) 4. Accidents 5. Diabetes 6. Chronic Lower Respiratory Diseases 7. Alzheimer's Disease 8. HIV/AIDS** 9. Assault/Homicide** 10. Influenze/Pneumonia

Calculation of Blood Volume

1. Hematocrit = Fraction of RBC/BV (usually expressed as percent) 2. Blood volume (BV) = plasma volume/1-Hematocrit (expressed here as a fraction) Plasma Volume + RBC volume = Blood Volume

Statistics Conceptual Framework

1. Identify Population 2. Take a Sample 3. Describe the Sample with a statistic 4. Make inferences about the parameter 5. Draw conclusions about the population

Cell Membrane Proteins

1. Integral membrane proteins - intrinsic/transmembrane proteins - e.g. ion channels, transport proteins - span entire cell membrane (transmembrane) - embedded in membrane - Ex: channels, carriers (transporters) 2. Peripheral membrane proteins - extrinsic proteins - not embedded in the membrane - located on one side of cell membrane (intra- or extracellular side) - Ex: ankyrin: anchors cytoskeleton of RBCs to an integral membrane protein, the chloride bicarb exchanger Functions: - transporters (carrier proteins) - channels - receptors - enzymes - antigens

Measurement of ECF Volume

1. Radioisotopes of selected ions (sodium, chloride, sulfate thiocyanate) 2. Nonmetabolizable saccharides (inulin, mannitol, raffinose) - too large to cross PM into ICF 3. Radioactive iothalamate (125I-iothalamate)

Properties of Cell Membrane

1. Selectively permeable 2. Lipid soluble substances (hydrophobic) can cross lipid bilayer (e.g. O2, CO2, steroid hormones) 3. Water soluble substances (hydrophilic) can cross the lipid with the aid of channels/pores, or transported by carrier proteins (e.g. Na+, Cl -, Glucose, H2O) 4. Some substances cannot pass through the bilayer (e.g. red blood cells, large proteins)

Types of Membrane Transport

1. Simple Diffusion 2. Facilitated Diffusion 3. Primary Active Transport 4. Secondary Active Transport 5. Osmosis

Carotid Artery and Jugular Vein

Anterior/Medial to Sternocleidomastoid Muscle Internal Carotid Artery (more lateral) External Carotid Artery (more medial) Common Carotid Artery Internal Jugular Vein

Bias

Any trend in the collection, analysis, interpretation, publication, or review of data that can lead to conclusions that are systematically different from the truth Not all studies are created equal Particularly a problem for observational studies

Surface Anatomy of the Heart

Aortic Valve - Right 2nd intercostal space Pulmonic Valve - Left 2nd intercostal space Tricuspid Valve - Left sternal border Mitral Valve - Left 5th intercostal space - Midclavicular line - Apex of Heart

Cohort Study

Assign based on exposure Assess/measure for disease development Prospective - cohort assembled in present based on exposure/risk and followed forward in time to see if disease develops Retrospective - looking backward, a cohort is assembled and followed through to the present

What drives fluid movement?

B/w ICF and ECF - changes in osmolarity (tonicity) B/w ISF and Plasma - changes in pressure (hydrostatic and oncotic)

Surface Anatomy of the Upper Limb Deep Tendon Reflexes

Biceps brachii tendon (interior elbow) Triceps brachii tendon (exterior elbow)

DC Health Status

Birth Rate - 51.3/1000 women 15-44 - (US 60.3) Death Rate - 725.4/100,000 - 731.9 Life Expectancy at Birth - 78.5 yr - (US 78.7)

Ca2+ ATPase Pump

Ca2+ pump Primary Active Transport Present in cell membranes (Sarcoplasmic reticulum, ER, intestinal epithelial cells) and transports Ca2+ against an electrochemical gradient

Bias and Precision

Chance for error when making estimates or measurements Bias - results from a sampling scheme that introduces a systematic deviation from the true mean - there are no statistical solutions for collecting a biased sample Precision - measure of how closely our observations cluster close to mean or other measure - can increase precision by taking larger samples or reducing measurement error

Meta-Analysis

Combines similar studies (usually RCTs) Two types: - Combine results statistically - Combine data on individual patients

Types of Data

Data type will determine analysis method 1. Nominal: data that represent categories (categorical) 2. Ordinal: data that are grouped in order (age groups, educational levels, staining scores) 3. Interval: like ordinal but intervals b/w each value are meaningful (temperature) but not a meaningful 0 for ratios 4. Discrete: data can only take certain values, counts 5. Continuous: data can take on any value on continuous scale (temperature, height, weight) 6. Ratio: meaningful zero so that ratios are meaningful (Kelvin)

Qualitative Study

Describe patterns of responses to questions - Indepth interviews - focus groups

Case Report

Detailed description of a single case

Case Series

Detailed descriptions of a few cases

Health Disparities

Differences in health outcomes that are closely linked with social, economic, and environmental disadvantage and are often driven by the social conditions in which individuals live, learn, work, and play.

Relationship b/w Osmotic and Hydrostatic Pressure

Diffusional flow - osmotic pressure (pressure from pure solvent flowing towards solutes to reach equilibrium) Hydraulic flow - hydrostatic pressure (pressure to oppose osmotic pressure ie pressure caused by pure solvent moving across membrane) If hydrostatic pressure is applied, and the wall of compartment is stretchable instead of rigid, the compartment wall can stretch to accommodate increased solvent (instead of solvent going back to other compartment)

Quantitative vs. Qualitative Data

Each one tells a different story Should complement each other Strengths and weaknesses to both Does data drive the problem or Does the problem drive the data?

Epidemiologic Studies

Epidemiology - "The study of the distribution, determinants, and dynamics of health and disease in groups of people in relation to their environment and ways of living" Person Place Time

Measurement

Establish validity of a survey or measurement

Carrier Mediated Transport

Facilitated Diffusion Primary Active Transport Secondary Active Transport Transport requires assistance of an integral membrane protein (channel or carrier) due to impermeability of hydrophilic substance through bilayer Three Common Features 1. Chemical Specificity/Stereospecificity - Ex: Transporter for glucose in renal proximal tubule is specific for D-glucose; it cannot transport its stereoisomer L- glucose 2. Competition 3. Saturation

Terms of Action/Movement

Flexion - Decrease in angle of a joint Extension - Increase in angle of a joint Abduction - Movement away from the midline Adduction - Movement toward the midline Medial (Internal) rotation - Rotation toward the midline of body Lateral (External) rotation - Rotation away from the midline of body Pronation - Palm facing inferiorly Supination - Palm facing superiorly

Frequency/Percentiles

Frequencies - Examine the frequencies to estimate the probability - presented most often in histograms to show the frequency of distribution - x-axis - measure (ex: pulse) - y-axis - counts/frequencies (number of adults with that pulse range) Percentiles - measure of where observations fall in the frequency distribution - 25th percentile - data point that has 25% of the observations below it - 50th percentile - median - data point at which 50% of the data are below it, 50% are above it

Pressures Across Capillary

Hydrostatic Pressure Oncotic Pressure Jv = Kf x net filtration pressure Jv = Kf x (HPc-HPi)-(c - i) Kf = S.A. x Lp Jv = Fluid Movement Kf = capillary filtration coefficient HPc = capillary hydrostatic pressure HPi = interstitial fluid hydrostatic pressure c = capillary oncotic pressure i = interstitial oncotic pressure S.A. = surface area Lp = hydraulic permeability Capillary hydrostatic pressure decreases from arterial to venous end of capillary Capillary oncotic pressure remains constant - Arterial end of capillary --> filtration - Venous end of capillary --> absorption

Surface Anatomy of the Thyroid

Hyoid Bone Thyroid Notch Laryngeal Prominence Thyroid Cartilage Cricothyroid Ligament Arch of Cricoid cartilage Thyroid Gland - Isthmus, left lobe, right lobe

Composition/Constituents of Body Fluid Compartments

ICF - Cations: majority K+, Mg2+ little Na+ - Anions: organic phosphates, anionic proteins, little bicarb, little Cl- ECF ISF - Cations: majority Na+, little K+ - Anions: majority Cl-, small bicarb Plasma - Cations: majority Na+, little K+ - Anions: majority Cl-, small bicarb, plasma proteins*** ICF vs. ECF Difference in steady state cation concentrations b/w ICF and ECF is due to the Na/K ATPase pump which establish these gradients --> really important for physiologically process, concentrations will change during physiologic processes (action potentials etc) ISF vs. Plasma Main difference between ISF and plasma is plasma proteins --> very important for plasma oncotic pressure (osmotic colloid) - (continuous) capillary wall does not allow for movement of these plasma proteins to the ISF (easily)

Cost-Effectiveness Analysis

If intervention is effective determines extra cost per unit of improvement One outcome: Cost per quality-adjusted life year (QALY)

Measurement of Body Fluid Compartments

Indicator - Dilution Technique - Measure size of compartments indirectly - Need to select proper indicator To accurately measure the volume of a particular compartment you must know: 1. quantity of indicator or dye to be injected into compartment 2. indicator stays within compartment to be measured 3. indicator disperses throughout compartment C = Q/V Volume of compartment = quantity of substance injected in compartment (Q)/concentration of substance after diffusion (Q/V) Can directly measure: - TBW - ECF - Plasma Can indirectly measure: - ICF (TBW - ECF) - ISF (ECF - plasma)

Life Expectancy in DC

Location: Life expectancy varies greatly between wards Where you live influences/determines life expectancy - Highest in Ward 3 - Lowest in Wards 7, 8 Race/Ethnicity: - Differences in life expectancy b/w races - Black vs. White Males (15 year difference) - Black vs. White Females (9 year difference)

Characteristics of a Distribution

Measures of Central Tendency - Mean - the average - Median - the 50th percentile/middle observation - Mode - most common observation, highest count/frequency Skewness - descriptive measure of distribution symmetry - normal distribution: mean = median = mode - left skew: mean is less than the median - right skew: mean is higher than the median

Osmosis

Movement of water across cell membrane OR selectively permeable membrane due to difference in concentration of solutes Concentration difference of solutes creates an osmotic pressure that pulls/moves water - water follows the solutes! Water continues to move until concentration of solutes become equal on both sides

Osmosis Examples

Movement of water from intestinal lumen into blood when solutes move in same direction; Movement of water from tubular fluid of kidney (nephron tubule) into blood when solutes move in same direction

Social Determinants of Health

Policies and Programs --> Health Factors --> Health Outcomes Health Factors - Health Behaviors (30%) --> exercise, diet, drug/alcohol use, sexual activity, smoking - Clinical Care (20%) - access and quality - Social and Economic Factors (40%) - education, employment, income, family/social support, community safety - Physical Environment (10%) - air/water quality, housing, transit Health Outcomes - Length of life - Quality of life

Homeostasis

Process by which body maintains constancy in internal function in face of changes in external environment

H+/K+ ATPase

Proton pump Exchanger (antiport, countertransport) Primary Active Transport Gastric parietal cells transport H+ into lumen of stomach against its electrochemical gradient to acidify gastric contents

Randomized Control Trials

RCTs ie Gold Standard Patients w/condition are randomized to treatment or comparison/control (placebo or previous treatment) group and followed through time Evaluate therapy/outcomes Lyme example: Does early Tx work? - Doxy 200 mg within 72 hrs of bite prevents EM rash - 87% effective

Peripheral Vascular System

Radial Artery --> Radial Pulse Dorsal Pedis Artery --> Dorsal Pedis Pulse

Measurement of Blood Volume

Radiolabeled red blood cells with chromium51

Measures of Spread/Variability

Range - simplest measure of spread - Largest observation - smallest observation Variance (s^2) - Average of squared deviations from the mean - variance is squared units Standard Deviation (s) - square root of variance - same units as original data Standard Error (SE) - divide standard deviation by square root of n - used to compare the variability of two or more distributions - need to standardize the standard deviation - s is influenced by sample size

Guidelines

Recommendations to clinicians for the care of patients with specific conditions Ex: IDSA guideline on lyme uptodate

Terms of Orientation

Right -- Left Anterior (Ventral) -- Posterior (Dorsal) Superior -- Inferior Medial -- Lateral Proximal -- Distal Superficial -- Deep Supine - lying face up Prone - lying face down

Statistics/Biostatistics

Science of designing experiments, summarizing and analyzing data, and drawing inferences about a population using only a subset of the population Divided into 3 parts: 1. Experimental Design 2. Descriptive Statistics 3. Inferential Statistics (modeling)

Secondary Active Transport Example

Sodium-Glucose Cotransport (SGLT) - symporter/cotransporter - intestinal epithelial apical/luminal surface - Transport of glucose against its concentration gradient into the cell depends on transport of Na+ down its concentration gradient into the cell Set up by Na+/K+ ATPase pump Glucose movement into intestinal epithelial cell would stop if Na+/K+ pump is blocked

Anatomical Position

Standard Reference Position - Standing upright - Head, gaze (eyes), and toes directed anteriorly - Lower limbs together - Palms face anteriorly

Sample Selection

Statistics are only valid when the represent the population of interest through proper sampling techniques. Proper sampling prevents bias: consistent error in a particular direction Simple Random Sample Stratified Random Sample Cluster Sample Systematic Samples

EBM Process

Step 1: Ask a clinical question - Background Questions: single concept - Who, what, when, why, where, how - Foreground Questions: Compare two things Step 2: Search literature - Methods that work better - Methods for particular question types Step 3: Critically evaluate the medical literature - Alone: use worksheets/user's guides - In groups: journal club - Do it yourself: Evidence based practitioners - Or Delegate: Evidence users (of secondary literature) --> uptodate Step 4: Apply to your patient - Decide if applies - patient in population of study? - Present evidence - Shared decision-making approach - Implement

Surface Anatomy of the Thorax

Sternum - Manubrium - Body - Xiphoid process Jugular Notch - superior to manubrium Clavicle Sternal Angle - b/w manubrium and body of sternum Costal Margin Midsternal Line Midclavicular Line Midaxillary line Anterior axillary line Posterior axillary line

Surface Anatomy of the Abdomen

Sternum Costal Margin Inguinal Ligament Four Abdominal Quadrants - Median and Transumbilical planes - RUQ - Liver, Gallbladder, Right Kidney - LUQ - Spleen, Stomach, Left Kidney - RLQ - Ascending Colon, Cecum, Appendix, Right Ovary - LLQ - Descending Colon, Sigmoid Colon, Left Ovary Nine Abdominal Quadrants - Epigastric - Umbilical - Suprapubic

Major Body Fluid Compartments

TBW: 60% of totally body weight - water content of body gradually decreases throughout life (water content is 75% at birth) ICF: 2/3 of TBW (40% of total body weight) Barrier: Cell membrane/phospholipid bilayer ECF: 1/3 of TBW (20% of total body weight) - Plasma fluid: 1/4 of ECF (5%) Barrier: capillary endothelium + BM - ISF: 3/4 of ECF (15%) interstitial space = milieu intérieur - ECM - proteoglycan filaments, collagen fiber bundles, free fluid vesicles

Evidence-Based Medicine

The conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence-based medicine requires integration of individual clinical expertise and patient preferences with the best available external clinical evidence from systematic research EBM is... A way of making decisions A tool for taking care of patients A way to deal with the uncertainty of patient care A method of answering questions about patients A way to improve care A new paradigm of care EMB IS NOT... A formula for medicine A replacement for physician decision making Cookbook medicine A way to deny care to patients

Osmotic Pressure

The hydrostatic pressure applied to a solution separated from pure solvent by a selectively permeable barrier (permeable only to solvent) which will prevent the movement of solvent into the solution Dependent on concentration of particles pi = icRT i = dissociation of ions mmHg = osmolarity (concentration) x 19.3 5790 mmHg = 300 mOsm/L x 19.3 Volume of a Compartment is determined by the # of Osmoles in that compartment

Incidence

The number of new cases of a disease during a specified period of time Incidence rate = (# NEW cases of disease)/(# of people in pop AT RISK) - Population at risk does not include those already with the disease or those who cannot get the disease (for instance women cannot get prostate cancer)

Prevalence

The number of people affected by a disease at particular time Prevalence rate = (# cases of disease)/(# of people in population)

Effective Osmotic Pressure

Tonicity definition = ability for water to move across the membrane part of total osmotic pressure of a solution which governs the tendency of its solvent to pass through a semipermeable membrane (due to impermeable solutes) Dependent on concentration of impermeable solutes/particles pi = (sigma)icRT sigma = reflection coefficient

Confidence Intervals

Two numbers defining a range of values that covers the parameter of interest with a degree of confidence Estimate +/- margin of error Margin of error = critical value x standard error critical value = 1.96 for 95% CI Width of the CI gives an idea about how uncertain we are about the unknown parameter (ie. precision) - wide interval may indicate that more data should be collected before anything very definite can be said about the parameter. CIs are informative since they provide a range of plausible values for the unknown parameter Interpretation: We are 95% confident that the interval captures the true mean

How to combat Bias in studies

Use RCTs to establish efficacy Use interventions where there is clear evidence of patient oriented outcomes (morbidity, mortality, quality of life) Use EBM/process Follow EBM guidelines or protocols Use EBM to power EHR decision support

EBM is a Key Paradigm for Clinical Medicine

Use the medical literature as the basis for clinical decision making "Medicine is the science of uncertainty and an art of probability." EBM Addresses Uncertainty - the answer is out there - A search of the right resources will find it - Measure the probability

Model of Health Care Disparities

What impacts quality of care between minority and non-minority populations? Dissimilarities in Care - Clinical Appropriateness/Need - Health Care Systems - Clinical Encounter: Biases, Stereotyping, and Uncertainty *Differences, disparities, and discrimination: Populations with equal access to health care

How Pathophysiologic Reasoning Fails: The Example Of Hormone Replacement Therapy (HRT)

What we thought based on pathophysiologic principles: - Women - less cardiovascular disease - Estrogen is protective - Estrogen pills should prevent heart attacks - Early Studies: Lower cholesterol levels Women's Health Initiative (WHI) - RCT, followed 5 yr - 16,000 postmenopausal women with a uterus - Compared risks and benefits Results - No difference in first cardiovascular events - No difference in mortality - Increased stroke (increased morbidity) - Risks outweighed benefits

Z-scores and Standard Normal Table

Z-score - calculation involves a shift and rescale transformation - shift: subtracting the mean, new center is 0 - scaling: divide by s, after transformation s = 1 N(0,1) standard normal, normal w/mean 0 and s 1 - no fundamental change in shape, only where it is centered and how far its spread - data that are normally distributed can transformed to a standard normal curve for calculating probabilities

Simple Diffusion v. Facilitated Diffusion Graphs

x-axis: solute concentration y-axis: rate of transport across membrane Simple Diffusion --> linear Facilitated Diffusion --> hyperbolic