Appendix I · Self-Assessment Tracker and Answer Guide

Falling cardiac output lowers mean arterial pressure; baroreceptors detect the fall and sympathetic outflow rises; α₁-mediated cutaneous vasoconstriction shunts blood from skin to core. Pallor and coolness are the visible cost. The variable defended is mean arterial pressure, and specifically perfusion of brain and heart — the skin is sacrificed because it tolerates ischemia far better. (Draws on Ch. 1, 5, 13, 19.)

Small, nonpolar, and lipid-soluble; gases and steroids qualify. Hence O₂ and CO₂ diffuse freely, and steroid hormones cross to reach intracellular receptors — which is why steroid receptors are inside the cell and peptide receptors are on the surface. (Draws on Ch. 2, 3, 16.)

Cardiac myocytes are amitotic in any meaningful number and have no satellite cell population; skeletal muscle has satellite cells that can fuse and regenerate. Cardiac repair is therefore fibrosis — dense irregular connective tissue laid down by fibroblasts. Scar is non-contractile and non-conducting, which explains both the fall in ejection fraction and the arrhythmia risk after infarction. (Draws on Ch. 4, 9, 18.)

It must be nourished by diffusion from underlying connective tissue, so it is thin or arranged with its dividing cells near the basement membrane; and it requires a basement membrane to anchor it and to filter what reaches it. Clinically, an epithelial tumor becomes dangerous when it breaches the basement membrane, because that is where it gains access to blood and lymph. (Draws on Ch. 4, 20.)

Blood clotting (Ch. 17), terminated when the vessel is sealed and anticoagulant mechanisms dominate; the action potential's Na⁺ influx (Ch. 11), terminated by channel inactivation and K⁺ efflux; labor via oxytocin and cervical stretch (Ch. 28), terminated by delivery. Each needs an external endpoint, which is exactly why positive feedback is dangerous when the endpoint never arrives. (Draws on Ch. 1, 11, 17, 28.)

The kidney performs the 1α-hydroxylation that converts 25-OH-vitamin D to calcitriol. Less calcitriol means less intestinal calcium absorption, so ionized calcium falls, so the calcium-sensing receptor triggers PTH release; chronically elevated PTH drives osteoclastic resorption via RANKL. Rising FGF23 from osteocytes suppresses calcitriol further. The result is secondary hyperparathyroidism and progressive bone loss. (Draws on Ch. 6, 16, 26.)

Dense regular connective tissue is largely collagen with few cells and a poor blood supply; muscle is highly vascular with satellite cells. Healing rate tracks vascularity and cellularity. The same logic predicts that cartilage, which is avascular, heals worst of all. (Draws on Ch. 4, 7, 9.)

Muscle atrophy from loss of mechanical loading and reduced protein synthesis; bone density loss because osteocytes sense reduced strain and bone remodels toward the loads it experiences (Wolff's law); and joint stiffness from loss of synovial fluid circulation, which depends on movement because cartilage is avascular and fed by imbibition. (Draws on Ch. 6, 7, 9, 10.)

HMG-CoA reductase inhibition reduces synthesis not only of cholesterol but of downstream isoprenoids including coenzyme Q10, impairing mitochondrial function in tissue with very high oxidative demand — skeletal muscle. Creatine kinase rises when sarcolemmal integrity fails, just as troponin rises from damaged cardiac muscle for the same structural reason. (Draws on Ch. 3, 9, 24.)

The keratinized stratified squamous barrier itself (innate, physical); the acid mantle at pH 4–6 plus antimicrobial peptides and lysozyme in secretions (innate, chemical); and Langerhans cells, which are dendritic antigen-presenting cells that link to adaptive immunity by carrying antigen to lymph nodes. (Draws on Ch. 5, 20.)

Referred pain. Visceral afferents from the heart enter the spinal cord at T1–T5 alongside somatic afferents from the chest wall, arm, and — via cervical inputs — the jaw. The cortex has no dedicated map for visceral origin, so it attributes the signal to the somatic territory sharing those segments. (Draws on Ch. 11, 12, 13, 18.)

The drug blocks β₁ receptors on SA nodal cells; normally β₁ couples to Gs, raising cAMP, which directly accelerates the funny current (I_f, an HCN channel) and increases Ca²⁺ current. Blocking it slows the pacemaker potential's rise to threshold, lengthening the interval between beats. This is also why beta-blockers blunt the tachycardic response to hypovolemia. (Draws on Ch. 13, 16, 18.)

Circadian disruption flattens and elevates the cortisol rhythm through the HPA axis; sustained cortisol raises blood pressure by permissive potentiation of catecholamine vasoconstriction, by mineralocorticoid receptor cross-activation causing sodium retention, and by promoting insulin resistance and visceral adiposity. Reduced night-time melatonin removes a nocturnal dipping signal. (Draws on Ch. 12, 16, 19, 24.)

Two different calcium pools. Contraction uses intracellular calcium released from the sarcoplasmic reticulum. Extracellular calcium stabilizes voltage-gated sodium channels by screening membrane surface charge; when it falls, sodium channels open at less depolarized potentials, neurons fire spontaneously, and muscles contract involuntarily. Excitability, not contractility, is the affected variable. (Draws on Ch. 6, 9, 11, 16.)

Nervous control is fast (milliseconds) and brief because it is delivered by a wired, point-to-point axon to a specific target and its transmitter is degraded or reuptaken within milliseconds. Endocrine control is slow (seconds to days) and prolonged because it is broadcast through blood to every cell bearing a receptor, and clearance depends on hepatic and renal metabolism. Structure predicts kinetics. (Draws on Ch. 11, 13, 16.)

Both involve tissues with no or minimal cell turnover accumulating irreversible damage over decades: lens crystallins are laid down in utero and never replaced, so oxidative and glycation damage accumulates and scatters light; cochlear hair cells are post-mitotic and are not regenerated after mechanical and metabolic injury. Where there is no turnover, damage is permanent. (Draws on Ch. 4, 15, 30.)

Afferent: the optic nerve (CN II). Efferent: parasympathetic fibers in the oculomotor nerve (CN III) via the ciliary ganglion to the sphincter pupillae. It is consensual because the pretectal nucleus projects bilaterally to both Edinger–Westphal nuclei. A unilateral afferent lesion therefore abolishes both responses when that eye is lit, while a unilateral efferent lesion abolishes only that eye's constriction. (Draws on Ch. 13, 15.)

Plaque rupture exposes subendothelial collagen and tissue factor. Platelets adhere via von Willebrand factor and GPIb, activate, and aggregate through GPIIb/IIIa cross-linking by fibrinogen. Aspirin blocks thromboxane A₂ synthesis via COX-1; a P2Y₁₂ inhibitor blocks the ADP activation pathway. Two independent activation routes require two blocks, because inhibiting one leaves the other able to drive aggregation. (Draws on Ch. 17, 19, 20.)

Saturation measures the percentage of available hemoglobin carrying oxygen, not the amount of oxygen. Content is CaO₂ = 1.34 × Hb × SaO₂ + 0.003 × PaO₂; with hemoglobin low, content is low even at 100% saturation. Delivery is DO₂ = CO × CaO₂, so the only compensation available is raising cardiac output — hence tachycardia. (Draws on Ch. 17, 18, 22; see Appendix H §H.7.)

Right atrium → tricuspid valve → right ventricle → pulmonary valve → pulmonary trunk → pulmonary arteries → lobar and segmental arteries → pulmonary arterioles → pulmonary capillaries (gas exchange) → pulmonary venules → pulmonary veins → left atrium. Note the reversal of the usual convention: pulmonary arteries carry deoxygenated blood and pulmonary veins carry oxygenated blood, because artery and vein are defined by direction relative to the heart, not by oxygen content. (Draws on Ch. 18, 19, 22.)

A ventricle that empties poorly raises end-diastolic pressure, which is transmitted backward to the left atrium and then to pulmonary capillaries. Raised pulmonary capillary hydrostatic pressure shifts the Starling balance toward net filtration; when the filtration rate exceeds the capacity of pulmonary lymphatics to drain it, fluid accumulates in the interstitium and then in alveoli, lengthening the diffusion path and causing hypoxemia and dyspnea. (Draws on Ch. 18, 19, 20, 22.)

Neutrophils arrive within hours to clear necrotic myocytes, then macrophages orchestrate repair by releasing growth factors that recruit fibroblasts. Fibroblasts deposit collagen. Because cardiac myocytes cannot meaningfully proliferate, that collagen is the final tissue. Healing and scarring are therefore the same process, which is why anti-inflammatory intervention after infarction is a trade-off rather than a pure benefit. (Draws on Ch. 4, 9, 18, 20.)

Repeated nocturnal hypoxemia triggers hypoxic pulmonary vasoconstriction — the pulmonary circulation's unique response, which normally matches perfusion to ventilation but becomes global and maladaptive when hypoxia is diffuse. Chronic elevation of pulmonary vascular resistance increases right ventricular afterload, producing right ventricular hypertrophy and eventually failure (cor pulmonale). (Draws on Ch. 18, 19, 22.)

Low pH with low bicarbonate is a metabolic acidosis. Winter's formula predicts PaCO₂ = 1.5 × 15 + 8 = 30.5 ± 2, and the measured 30 falls inside that window, so respiratory compensation is appropriate and no second disorder is present. The lung is compensating, within minutes, by raising alveolar ventilation. (Draws on Ch. 22, 26, 31; Appendix H §H.7.)

Parietal cell acid secretion is stimulated by three converging signals — histamine on H₂, acetylcholine on M₃, and gastrin — but all three converge on one final effector, the H⁺/K⁺-ATPase. Blocking one input leaves the other two; blocking the common final pathway stops secretion regardless of input. Find the final common effector and you find the more complete block. (Draws on Ch. 16, 23.)

GIP from duodenal K cells and GLP-1 from ileal L cells are released by nutrients in the gut lumen and potentiate glucose-stimulated insulin secretion before absorption raises blood glucose. Intravenous glucose bypasses the gut entirely and so triggers no incretin release, producing a smaller insulin response for the same glycemia. It is a feedforward mechanism: the gut warns the pancreas that glucose is coming. (Draws on Ch. 16, 23, 24.)

Hepatic glycogenolysis dominates for the first 12–24 hours (liver glycogen ≈100 g, exhausted in roughly a day); gluconeogenesis from lactate, glycerol, and amino acids rises in parallel and takes over; lipolysis supplies free fatty acids for tissues that can oxidize them; and ketogenesis rises over days so the brain can substitute ketones for most of its glucose need, sparing muscle protein. Glucagon rises and insulin falls throughout. (Draws on Ch. 16, 23, 24.)

Blocking the Na⁺/K⁺/2Cl⁻ cotransporter in the thick ascending limb delivers a large sodium load to the collecting duct. Volume loss activates the RAAS, so aldosterone is high; aldosterone-driven principal cells reabsorb that sodium in exchange for secreting K⁺ and, via intercalated cells, H⁺. Losing potassium gives hypokalemia; losing hydrogen ion generates bicarbonate and gives metabolic alkalosis. Contraction of extracellular volume around a fixed bicarbonate mass adds to it. (Draws on Ch. 16, 26, 31.)

The descending limb is permeable to water and not to solute; the ascending limb actively pumps NaCl out and is impermeable to water. The ascending limb therefore builds a horizontal gradient of about 200 mOsm at any level, and the countercurrent flow multiplies that small gradient vertically into a corticomedullary gradient reaching 1,200 mOsm/kg. If both limbs had the same permeability, the pumping would be immediately dissipated and no gradient could accumulate. (Draws on Ch. 26, 31.)

Vascular: estrogen upregulates endothelial nitric oxide synthase, promoting vasodilation, and shifts the lipid profile by raising HDL and lowering LDL; losing it raises vascular resistance and atherogenic risk. Skeletal: estrogen restrains osteoclast formation and survival largely by suppressing RANKL and increasing osteoprotegerin, so its loss accelerates resorption and produces the rapid bone loss of the first postmenopausal decade. (Draws on Ch. 6, 19, 27, 30.)

Cardiac output rises 30–50% (higher stroke volume and heart rate); plasma volume rises about 45%; GFR rises 40–50% because renal plasma flow rises, which is why creatinine falls in normal pregnancy and a "normal" creatinine may be abnormal. Hematocrit falls — the physiological anemia of pregnancy — because plasma volume expands proportionally more than red cell mass. (Draws on Ch. 17, 18, 19, 26, 28.)

Human placental lactogen, placental growth hormone, progesterone, and cortisol all antagonize insulin, which keeps maternal glucose higher for longer after meals and preserves a gradient for facilitated diffusion of glucose to the fetus. A mother whose beta cells cannot increase output to overcome that resistance develops gestational diabetes — which is why it appears in the second half of pregnancy, as placental mass and hormone output peak. (Draws on Ch. 16, 24, 28.)

Sensitization typically occurs at delivery, when fetal red cells enter maternal circulation; the primary response is slow and produces mostly IgM, which does not cross the placenta. On re-exposure the secondary response from memory B cells is fast and produces IgG, which crosses the placenta and hemolyzes fetal red cells. It is the clearest illustration in the book of the difference between primary and secondary adaptive responses. (Draws on Ch. 17, 20, 28.)

These are multifactorial traits: many loci of small individual effect interact with environment — diet, sleep, activity, smoking — so inheritance does not follow Mendelian ratios and no single-gene test predicts them. Family history acts as an integrated proxy for shared genotype and shared environment. Prediction is probabilistic, and the modifiable environmental component is large, which is precisely why risk factor management works. (Draws on Ch. 19, 29, 30.)

Stiffer arteries accept the stroke volume with a larger pressure excursion, so systolic pressure and pulse pressure rise while diastolic often falls — isolated systolic hypertension, the characteristic geriatric pattern. Reduced maximum heart rate caps maximum cardiac output, so VO₂max falls; the aged heart also relies more on the Frank–Starling mechanism and on atrial contraction, which is why atrial fibrillation is tolerated poorly in older patients. (Draws on Ch. 18, 19, 24, 30.)

Loss of gastric HCl gives a hypochloremic metabolic alkalosis. Volume depletion activates the RAAS, so aldosterone drives potassium and hydrogen ion secretion, producing hypokalemia and maintaining the alkalosis. Chloride is low because it was lost in the vomitus. Urine chloride is low (<20 mEq/L) because the kidney is avidly retaining it — which is exactly what distinguishes this saline-responsive alkalosis from the saline-resistant kind seen with hyperaldosteronism. (Draws on Ch. 23, 26, 31.)

Minutes: central chemoreceptors in the medulla detect the fall in cerebrospinal fluid pH that CO₂ produces after crossing the blood–brain barrier, and raise ventilation to blow CO₂ off. Days: the kidney increases proximal tubule H⁺ secretion, regenerates bicarbonate, and generates new bicarbonate via ammoniagenesis, raising plasma HCO₃⁻. Speed differs because one system changes a flow rate and the other changes a chemical reservoir. (Draws on Ch. 22, 26, 31.)

The lesion is total peripheral resistance, not pump failure or volume loss. Inflammatory mediators induce nitric oxide synthase in vascular smooth muscle, producing profound vasodilation and capillary leak. Since MAP = CO × TPR, a collapse in TPR lowers MAP even though the baroreflex has driven cardiac output up. The skin is warm because it is dilated, which is the opposite of the cool, pale skin of cardiogenic or hypovolemic shock. (Draws on Ch. 19, 20, 31.)

Insulin resistance and hypertension stiffen the ventricle and the arteries; a stiff ventricle fills poorly and raises filling pressures; reduced renal perfusion and chronically high angiotensin II damage the kidney; the damaged kidney retains sodium (worsening preload) and makes less erythropoietin (anemia); anemia forces a higher cardiac output for the same oxygen delivery, which the stiff ventricle cannot supply. Interruption points: RAAS blockade (ACE inhibitor or ARB) breaks the sodium-retention and remodeling arm; diuresis reduces preload; sodium restriction, glycemic control, and treatment of her sleep apnea each attack a different node. (Draws on Ch. 16, 17, 18, 19, 24, 26, 33.)

All four exist to keep the composition and volume of the extracellular fluid inside a range in which cells can work. The cardiovascular system moves that fluid, the respiratory system sets its CO₂ and O₂, the renal system sets its volume and electrolyte and acid-base composition, and the endocrine system supplies the slow signals that coordinate the other three. Every disease in this book is a failure of that project, and every treatment is an attempt to restore it. (Draws on Ch. 1, 31, 33.)