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First_Aid_Step1. RER, and well-developed Golgi apparatus (arrows in A ). Found in bone marrow and normally do not circulate in peripheral blood. ACTIVATIONADP binding to P2Y12 receptor induces GpIIb/IIIa expression at platelet surface Platelets release ADP and Ca2+ (necessary for coagulation cascade), TXA2 ADHESIONPlatelets bind vWF via GpIb receptor at the site of injury only (specifc) ˜ platelets undergo conformational change EXPOSUREvWF binds to exposed collagen vWF is from Weibel-Palade bodies of endothelial cells and °-granules of platelets INJURYEndothelial damage ˜ transient vasoconstriction via neural stimulation refex and endothelin (released from damaged cell) 4A Temporary plug stops bleeding; unstable, easily dislodged


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First_Aid_Step1. Thrombogenesis Formation of insoluble fibrin mesh. Aspirin irreversibly inhibits cyclooxygenase, thereby inhibiting TXA2 synthesis. Clopidogrel, prasugrel, and ticlopidine inhibit ADP-induced expression of GpIIb/IIIa by irreversibly blocking P2Y12 receptor. Abciximab, eptifibatide, and tirofiban inhibit GpIIb/IIIa directly. Ristocetin activates vWF to bind GpIb. Failure of aggregation with ristocetin assay occurs in von Willebrand disease and Bernard-Soulier syndrome. vWF carries/protects factor VIII; volksWagen Factories make gr8 cars. Platelet ADP (P2Y12) receptor GpIIb/IIIa insertion Subendothelial collagen GpIb GpIIb/IIIa Fibrinogen vWF Thrombin-thrombomodulin complex Protein C Activated protein C Vascular endothelial cells Inside endothelial cells (vWF + factor VIII) Thromboplastin tPA, PGI2 Arachidonic acid Aspirin COX TXA2 vWF Fibrinogen Inside platelets Clopidogrel, prasugrel, ticlopidine Defciency: Bernard-Soulier syndrome Defciency: Glanzmann thrombasthenia Defciency: von


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First_Aid_Step1. tPA, PGI2 Arachidonic acid Aspirin COX TXA2 vWF Fibrinogen Inside platelets Clopidogrel, prasugrel, ticlopidine Defciency: Bernard-Soulier syndrome Defciency: Glanzmann thrombasthenia Defciency: von Willebrand disease Abciximab, eptifbatide, tirofban 4B 4A


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First_Aid_Step1. Hemophilia A: defciency of factor VIII (XR) Hemophilia B: defciency of factor IX (XR) Hemophilia C: defciency of factor XI (AR) Note: Kallikrein activates bradykinin * = require Ca2+ , phospholipid; Fibrin degradation = inhibited by vitamin K antagonist warfarin products (eg, D-dimer) Fibrin mesh stabilizes = activates but not part of coagulation cascade


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First_Aid_Step1. Fibrin mesh stabilizes = activates but not part of coagulation cascade Collagen, basement membrane, activated platelets Tissue factor (extrinsic) pathway Combined pathway Fibrinolytic system ANTICOAGULANTS: LMWH (eg, dalteparin, enoxaparin) heparin direct Xa inhibitors (eg, apixaban) fondaparinux ANTICOAGULANTS: -heparin -LMWH -direct thrombin inhibitors (eg, argatroban, bivalirudin, dabigatran) Tissue factor VII VIIa XII Prothrombin Kallikrein Bradykinin ˜vasodilation ˜ permeability ˜ painKinin cascade HMWK Thrombin Plasminogen Plasmin THROMBOLYTICS: alteplase, reteplase, streptokinase, tenecteplase ANTIFIBRINOLYTICS:aminocaproic acid, tranexamic acid tPA XI XIa IX X II IXa VIIIa VIII with vWF XIIa Xa Va* * IIa I Fibrinogen Aggregation Fibrin monomers Ia Ca2+ XIIIa XIII V Contact activation (intrinsic) pathway –––** * * * # # REGULATORY ANTICOAGULANT PROTEINS: -proteins C and S –C1-esterase inhibitor –––


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First_Aid_Step1. Procoagulation Vitamin K deficiency:  synthesis of factors II, VII, IX, X, protein C, protein S. Reduced vitamin K (active) Inactive II, VII, IX, X, C, S Clotting factors Anti-coagulants -glutamyl carboxylase (vitamin K-dependent) Epoxide reductase Mature, carboxylated II, VII, IX, X, C, S Fibrinogen Fibrin Liver Oxidized vitamin K (inactive) Warfarin inhibits vitamin K epoxide reductase. Vitamin K administration can potentially reverse inhibitory effect of warfarin on clotting factor synthesis (delayed). FFP or PCC administration reverses action of warfarin immediately and can be given with vitamin K in cases of severe bleeding. Neonates lack enteric bacteria, which produce vitamin K. Early administration of vitamin K overcomes neonatal deficiency/coagulopathy. Factor VII (seven)—shortest half-life. Warfarin, Factor II (two)—longest (tallest) half-life. factors VIIa, IXa, Xa, XIa, XIIa. Heparin enhances the activity of antithrombin.


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First_Aid_Step1. Factor VII (seven)—shortest half-life. Warfarin, Factor II (two)—longest (tallest) half-life. factors VIIa, IXa, Xa, XIa, XIIa. Heparin enhances the activity of antithrombin. Principal targets of antithrombin: thrombin and factor Xa. Antithrombin ProteinCpathway pathway Heparin-like molecule (enhances ATIII activity) Thrombin-thrombomodulin complex (endothelial cells) Antithrombin III Protein C Requires protein S Activated protein C Inhibits thrombin (and VIIa, IXa, Xa, XIa, XIIa) Cleaves and inactivates Va, VIIIa resistant to inhibition by activated protein C. tPA is used clinically as a thrombolytic. Liver disease, abetalipoproteinemia Projections of varying size at (“spur cells”) irregular intervals. Liver disease, ESRD, pyruvate Smaller and more uniform (“burr cells”) kinase deficiency projections than acanthocytes Bone marrow infiltration (eg, RBC “sheds a tear” because it’s (“teardrop cells”) myelofibrosis) mechanically squeezed out of its home in the bone marrow


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First_Aid_Step1. Bone marrow infiltration (eg, RBC “sheds a tear” because it’s (“teardrop cells”) myelofibrosis) mechanically squeezed out of its home in the bone marrow MAHAs (eg, DIC, TTP/HUS, Fragmented RBCs (eg, “helmet” cells) HELLP syndrome), mechanical hemolysis (eg, heart valve prosthesis) G6PD deficiency Due to removal of Heinz bodies by cells”) splenic macrophages Hereditary elliptocytosis Caused by mutation in genes encoding RBC membrane proteins (eg, spectrin) Hereditary spherocytosis, Small, spherical cells without autoimmune hemolytic anemia central pallor HbC disease, Asplenia, “HALT,” said the hunter to his Liver disease, Thalassemia target Sickle cell anemia Sickling occurs with low O2 conditions (eg, high altitude, acidosis) Sideroblastic anemias (eg, lead Perinuclear mitochondria with (eg, in ringed poisoning, myelodysplastic excess iron (forming ring in sideroblasts) syndromes, alcoholism) ringed sideroblasts) Require Prussian blue stain to be visualized


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First_Aid_Step1. Functional hyposplenia (eg, sickle Basophilic nuclear remnants (do cell disease), asplenia not contain iron) Usually removed by splenic macrophages Sideroblastic anemias, thalassemias Basophilic ribosomal precipitates (do not contain iron) G6PD deficiency Denatured and precipitated hemoglobin (contain iron) Phagocytic removal of Heinz bodies  bite cells Requires supravital stain (eg, crystal violet) to be visualized Reticulocyte index Also called corrected reticulocyte count. Used to correct falsely elevated reticulocyte count in anemia. Measures appropriate bone marrow response to anemic conditions (effective erythropoiesis). High reticulocyte index (RI) indicates compensatory RBC production; low RI indicates inadequate response to correct anemia. Calculated as: Microcytic, hypochromic anemias MCV < 80 fL.


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First_Aid_Step1. Microcytic, hypochromic anemias MCV < 80 fL. Iron deficiency  iron due to chronic bleeding (eg, GI loss, menorrhagia), malnutrition, absorption disorders, GI surgery (eg, gastrectomy), or • demand (eg, pregnancy)  final step in heme synthesis. Labs:  iron, • TIBC, • ferritin,  free erythrocyte protoporphyrin,  RDW,  RI. Microcytosis and hypochromasia ( central pallor) A . Symptoms: fatigue, conjunctival pallor B , pica (persistent craving and compulsive eating of nonfood substances), spoon nails (koilonychia). May manifest as glossitis, cheilosis, Plummer-Vinson syndrome (triad of iron deficiency anemia, esophageal webs, and dysphagia). -thalassemia α-globin gene deletions on chromosome 16 • α-globin synthesis. cis deletion (deletions occur on same chromosome) prevalent in Asian populations; trans deletion (deletions occur on separate chromosomes) prevalent in African populations. Normal is αα/αα.


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First_Aid_Step1. 2 (α –/α –; trans) or α-thalassemia minor Mild microcytic, hypochromic (αα/– –; cis) anemia; cis deletion may worsen outcome for the carrier’s offspring 3 (– –/– α) Hemoglobin H disease (HbH); Moderate to severe microcytic excess β-globin forms β4 hypochromic anemia 4 (– –/– –) Hemoglobin Barts disease; Hydrops fetalis; incompatible no α-globin, excess γ-globin with life forms γ4 -thalassemia Point mutations in splice sites and promoter sequences on chromosome 11 • β-globin synthesis. Prevalent in Mediterranean populations. -thalassemia minor (heterozygote): β chain is underproduced. Usually asymptomatic. Diagnosis confirmed by • HbA2 (> 3.5%) on electrophoresis.


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First_Aid_Step1. -thalassemia minor (heterozygote): β chain is underproduced. Usually asymptomatic. Diagnosis confirmed by • HbA2 (> 3.5%) on electrophoresis. -thalassemia major (homozygote): β chain is absent  severe microcytic, hypochromic anemia with target cells and increased anisopoikilocytosis C requiring blood transfusion (2° hemochromatosis). Marrow expansion (“crew cut” on skull x-ray)  skeletal deformities (eg, “chipmunk” facies). Extramedullary hematopoiesis  hepatosplenomegaly.  risk of parvovirus B19–induced aplastic crisis.  HbF (αγ ), HbA (αδ ). HbF is protective in the infant and disease becomes symptomatic only after 6 months, when fetal hemoglobin declines. HbS/β -thalassemia heterozygote: mild to moderate sickle cell disease depending on amount of β-globin production. Microcytic, hypochromic anemias (continued)


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First_Aid_Step1. Microcytic, hypochromic anemias (continued) Lead poisoning Lead inhibits ferrochelatase and ALA dehydratase  heme synthesis and  RBC protoporphyrin. Also inhibits rRNA degradation  RBCs retain aggregates of rRNA (basophilic stippling). Symptoms of LEAD poisoning: Lead Lines on gingivae (Burton lines) and on metaphyses of long bones D on x-ray. Encephalopathy and Erythrocyte basophilic stippling. Abdominal colic and sideroblastic Anemia. Drops—wrist and foot drop. Dimercaprol and EDTA are 1st line of treatment. Succimer used for chelation for kids (It “sucks” to be a kid who eats lead). Exposure risk  in old houses with chipped paint.


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First_Aid_Step1. Sideroblastic anemia Causes: genetic (eg, X-linked defect in ALA synthase gene), acquired (myelodysplastic syndromes), and reversible (alcohol is most common; also lead poisoning, vitamin B6 deficiency, copper deficiency, drugs [eg, isoniazid, linezolid]). Lab findings: • iron, normal/ TIBC, • ferritin. Ringed sideroblasts (with iron-laden, Prussian blue–stained mitochondria) seen in bone marrow E . Peripheral blood smear: basophilic stippling of RBCs. Some acquired variants may be normocytic or macrocytic. Treatment: pyridoxine (B6, cofactor for ALA synthase). Interpretation of iron studies  = 1° disturbance. Transferrin—transports iron in blood. TIBC—indirectly measures transferrin. Ferritin—1° iron storage protein of body. aEvolutionary reasoning—pathogens use circulating iron to thrive. The body has adapted a system in which iron is stored within the cells of the body and prevents pathogens from acquiring circulating iron. Macrocytic anemias MCV > 100 fL.


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First_Aid_Step1. Macrocytic anemias MCV > 100 fL. Megaloblastic anemia Impaired DNA synthesis  maturation of RBC macrocytosis, hypersegmented neutrophils nucleus of precursor cells in bone marrow (arrow in A ), glossitis. delayed relative to maturation of cytoplasm. Causes: vitamin B12 deficiency, folate deficiency, medications (eg, hydroxyurea, phenytoin, methotrexate, sulfa drugs). Vitamin B12 Causes: pernicious anemia, malabsorption (cobalamin) (eg, Crohn disease), pancreatic insufficiency, deficiency gastrectomy, insufficient intake (eg, veganism), Diphyllobothrium latum (fish tapeworm).  homocysteine, • methylmalonic acid. Neurologic symptoms: reversible dementia, subacute combined degeneration (due to involvement of B12 in fatty acid pathways and myelin synthesis): spinocerebellar tract, lateral corticospinal tract, dorsal column dysfunction. Folate supplementation in vitamin B12 deficiency can correct the anemia, but worsens neurologic symptoms.


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First_Aid_Step1. Historically diagnosed with the Schilling test, a test that determines if the cause is dietary insufficiency vs malabsorption. Anemia 2° to insufficient intake may take several years to develop due to liver’s ability to store B12 (as opposed to folate deficiency). Nonhemolytic, normocytic anemias Anemia of chronic disease Inflammation (eg,  IL-6)  hepcidin (released by liver, binds ferroportin on intestinal mucosal cells and macrophages, thus inhibiting iron transport)  release of iron from macrophages and • iron absorption from gut. Associated with conditions such as chronic infections, neoplastic disorders, chronic kidney disease, and autoimmune diseases (eg, SLE, rheumatoid arthritis).  iron,  TIBC,  ferritin. Normocytic, but can become microcytic. Treatment: address underlying cause of inflammation, judicious use of blood transfusion, consider erythropoiesisstimulating agents such as EPO (eg, in chronic kidney disease).


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First_Aid_Step1. Aplastic anemia Caused by failure or destruction of hematopoietic stem cells due to: • Radiation and drugs (eg, benzene, chloramphenicol, alkylating agents, antimetabolites) Viral agents (eg, EBV, HIV, hepatitis viruses) Idiopathic (immune mediated, 1° stem cell defect); may follow acute hepatitis  reticulocyte count, • EPO. Pancytopenia characterized by anemia, leukopenia, and thrombocytopenia (not to be confused with aplastic crisis, which causes anemia only). Normal cell morphology, but hypocellular bone marrow with fatty infiltration A (dry bone marrow tap). Symptoms: fatigue, malaise, pallor, purpura, mucosal bleeding, petechiae, infection. Treatment: withdrawal of offending agent, immunosuppressive regimens (eg, antithymocyte globulin, cyclosporine), bone marrow allograft, RBC/platelet transfusion, bone marrow stimulation (eg, GM-CSF).  valine). Mutant HbA is termed HbS. Causes extravascular and intravascular hemolysis.


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First_Aid_Step1.  valine). Mutant HbA is termed HbS. Causes extravascular and intravascular hemolysis. Pathogenesis: low O2, high altitude, or acidosis precipitates sickling (deoxygenated HbS polymerizes)  anemia, vaso-occlusive disease. Newborns are initially asymptomatic because of  HbF and  HbS. Heterozygotes (sickle cell trait) have resistance to malaria. 8% of African Americans carry an HbS allele. Sickle cells are crescent-shaped RBCs A . “Crew cut” on skull x-ray due to marrow expansion from  erythropoiesis (also seen in thalassemias). Complications in sickle cell disease: Aplastic crisis (transient arrest of erythropoiesis due to parvovirus B19). Autosplenectomy (Howell-Jolly bodies)  risk of infection by encapsulated organisms (eg, S pneumoniae). Splenic infarct/sequestration crisis. Salmonella osteomyelitis.


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First_Aid_Step1. Autosplenectomy (Howell-Jolly bodies)  risk of infection by encapsulated organisms (eg, S pneumoniae). Splenic infarct/sequestration crisis. Salmonella osteomyelitis. Painful vaso-occlusive crises: dactylitis (painful swelling of hands/feet), priapism, acute chest syndrome (respiratory distress, new pulmonary infiltrates on CXR, common cause of death), avascular necrosis, stroke. papillary necrosis • hematuria. Hb electrophoresis:  HbA,  HbF, • HbS. Treatment: hydroxyurea ( HbF), hydration. A normocytic anemia that is usually idiopathic and Coombs ⊕. Two types: Warm AIHA–chronic anemia in which IgG causes RBC agglutination. Seen in SLE and CLL and with certain drugs (eg, α-methyldopa). “Warm weather is Good.” + complement causes RBC agglutination upon exposure to cold • painful, blue fingers and toes. Seen in CLL, Mycoplasma pneumoniae infections, infectious Mononucleosis. Spherocytes and agglutinated RBCs A on peripheral blood smear.


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First_Aid_Step1. Spherocytes and agglutinated RBCs A on peripheral blood smear. Warm AIHA treatment: steroids, rituximab, splenectomy (if refractory). Cold AIHA treatment: cold avoidance, rituximab. Direct Coombs test—anti-Ig antibody (Coombs reagent) added to patient’s RBCs. RBCs agglutinate if RBCs are coated with Ig. For comparison, Indirect Coombs test—normal RBCs added to patient’s serum. If serum has anti-RBC surface Ig, RBCs agglutinate when Coombs reagent added. aCorticosteroids cause neutrophilia, despite causing eosinopenia and lymphopenia. Corticosteroids  activation of neutrophil adhesion molecules, impairing migration out of the vasculature to sites of inflammation. In contrast, corticosteroids sequester eosinophils in lymph nodes and cause apoptosis of lymphocytes. Neutrophil left shift  neutrophil precursors, such as band cells A left shift is a shift to a more immature cell in and metamyelocytes, in peripheral blood. the maturation process.


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First_Aid_Step1. Neutrophil left shift  neutrophil precursors, such as band cells A left shift is a shift to a more immature cell in and metamyelocytes, in peripheral blood. the maturation process. Usually seen with neutrophilia in the acute response to infection or inflammation. Called leukoerythroblastic reaction when left shift is seen with immature RBCs. Occurs with severe response (eg, fibrosis, tumor taking up space in marrow). Ferrochelatase and Protoporphyrin, ALA ALA dehydratase (blood) Microcytic anemia (basophilic stippling in peripheral smear A , ringed sideroblasts in bone marrow), GI and kidney disease. Children—exposure to lead paint  mental deterioration. Adults—environmental exposure (eg, batteries, ammunition) • headache, memory loss, demyelination (peripheral neuropathy). B . Most common porphyria. Exacerbated with alcohol consumption. Causes: familial, hepatitis C. Treatment: phlebotomy, sun avoidance, antimalarials (eg, hydroxychloroquine).


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First_Aid_Step1. B . Most common porphyria. Exacerbated with alcohol consumption. Causes: familial, hepatitis C. Treatment: phlebotomy, sun avoidance, antimalarials (eg, hydroxychloroquine). Hemophilia A, B, or C A — • Intrinsic pathway coagulation defect ( PTT). A: deficiency of factor VIII; X-linked recessive. B: deficiency of factor IX; X-linked recessive. C: deficiency of factor XI; autosomal recessive. Hemorrhage in hemophilia—hemarthroses (bleeding into joints, eg, knee A ), easy bruising, bleeding after trauma or surgery (eg, dental procedures). Treatment: desmopressin + factor VIII concentrate (A); factor IX concentrate (B); factor XI concentrate (C). Vitamin K deficiency • General coagulation defect. Bleeding time normal.  activity of factors II, VII, IX, X, protein C, protein S. Hereditary thrombosis syndromes leading to hypercoagulability


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First_Aid_Step1. Vitamin K deficiency • General coagulation defect. Bleeding time normal.  activity of factors II, VII, IX, X, protein C, protein S. Hereditary thrombosis syndromes leading to hypercoagulability Blood transfusion risks include infection transmission (low), transfusion reactions, iron overload (may lead to 2° hemochromatosis), hypocalcemia (citrate is a Ca2+ chelator), and hyperkalemia (RBCs may lyse in old blood units). Leukemia Lymphoid or myeloid neoplasm with widespread involvement of bone marrow. Tumor cells are usually found in peripheral blood. Lymphoma Discrete tumor mass arising from lymph nodes. Presentations often blur definitions. Both may present with constitutional (“B”) signs/symptoms: low-grade fever, night sweats, weight loss. Localized, single group of nodes with Multiple lymph nodes involved; extranodal contiguous spread (stage is strongest predictor involvement common; noncontiguous spread. of prognosis). Better prognosis. Worse prognosis.


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First_Aid_Step1. Characterized by Reed-Sternberg cells. Majority involve B cells; a few are of T-cell lineage. Bimodal distribution: young adulthood and Can occur in children and adults. > 55 years; more common in men except for nodular sclerosing type. Associated with EBV. May be associated with autoimmune diseases and viral infections (eg, HIV, EBV, HTLV). Hodgkin lymphoma Contains Reed-Sternberg cells: distinctive tumor giant cells; binucleate or bilobed with the 2 halves as mirror images (“owl eyes” A ). RS cells are CD15+ and CD30+ B-cell origin. 2 owl eyes × 15 = 30.


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First_Aid_Step1. Plasma cell dyscrasias Characterized by monoclonal immunoglobulin (Ig) overproduction due to plasma cell disorder. Labs: serum protein electrophoresis (SPEP) or free light chain (FLC) assay for initial tests (M spike on SPEP represents overproduction of a monoclonal Ig fragment). For urinalysis, use 24-hr urine protein electrophoresis (UPEP) to detect light chain, as routine urine dipstick detects only albumin. Confirm with bone marrow biopsy. Multiple myeloma Overproduction of IgG (55% of cases) > IgA. Clinical features: CRAB Bone lytic lesions (“punched out” on X-ray A ) • Back pain. Peripheral blood smear shows Rouleaux formation B (RBCs stacked like poker chips). Urinalysis shows Ig light chains (Bence Jones proteinuria) with ⊖ urine dipstick. Bone marrow analysis shows > 10% monoclonal plasma cells with clock-face chromatin C and intracytoplasmic inclusions containing IgG. Complications:  infection risk, 1° amyloidosis (AL).


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First_Aid_Step1. Overproduction of IgM (macroglobulinemia because IgM is the largest Ig). Clinical features: Hyperviscosity syndrome: Retinal hemorrhages Bone marrow analysis shows >10% small lymphocytes with IgM-containing vacuoles (lymphoplasmacytic lymphoma). Complication: thrombosis. syndromes hematopoiesis  defects in cell maturation with bilobed (“duet”) nuclei A . Typically seen of nonlymphoid lineages. Caused by de novo after chemotherapy. mutations or environmental exposure (eg, radiation, benzene, chemotherapy). Risk of transformation to AML. Leukemias Unregulated growth and differentiation of WBCs in bone marrow  marrow failure  anemia ( RBCs), infections ( mature WBCs), and hemorrhage ( platelets). Usually presents with  circulating WBCs (malignant leukocytes in blood); rare cases present with normal/• WBCs. Leukemic cell infiltration of liver, spleen, lymph nodes, and skin (leukemia cutis) possible.


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First_Aid_Step1. A B C D E Chronic myeloproliferative disorders Malignant hematopoietic neoplasms with varying impacts on WBCs and myeloid cell lines. tumor cell lysis, most often in lymphomas/ leukemias. Release of K+  hyperkalemia, Arrhythmias, release of PO 3– • hyperphosphatemia, hypocalcemia due to Ca2+ sequestration Seizures, by PO43–.  nucleic acid breakdown tetany  hyperuricemia  acute kidney injury. hydration, allopurinol, rasburicase. injury Hemophagocytic Systemic overactivation of macrophages and cytotoxic T cells  fever, pancytopenia, lymphohistiocytosis hepatosplenomegaly,  serum ferritin levels. Can be inherited or 2° to strong immunologic activation (eg, after EBV infection, malignancy). Bone marrow biopsy shows macrophages phagocytosing marrow elements A .


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First_Aid_Step1. A . Direct thrombin Bivalirudin, Argatroban, Dabigatran (only oral agent in class). inhibitors mechanISm Directly inhibits activity of free and clot-associated thrombin. clInIcal USe Venous thromboembolism, atrial fibrillation. Can be used in HIT, when heparin is BAD for the patient. Does not require lab monitoring. adVeRSe eFFectS Bleeding; can reverse dabigatran with idarucizumab. Consider PCC and/or antifibrinolytics (eg, tranexamic acid) if no reversal agent available. mechanISm Activates antithrombin, which  action of IIa (thrombin) and factor Xa. Short half-life. clInIcal USe Immediate anticoagulation for pulmonary embolism (PE), acute coronary syndrome, MI, deep venous thrombosis (DVT). Used during pregnancy (does not cross placenta). Follow PTT. adVeRSe eFFectS Bleeding, thrombocytopenia (HIT), osteoporosis, drug-drug interactions. For rapid reversal (antidote), use protamine sulfate (positively charged molecule that binds negatively charged heparin).


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First_Aid_Step1. noteS Low-molecular-weight heparins (eg, enoxaparin, dalteparin)—act predominantly on factor Xa. Fondaparinux acts only on factor Xa. Have better bioavailability and 2–4× longer half life than unfractionated heparin; can be administered subcutaneously and without laboratory monitoring. LMWHs undergo renal clearance (vs hepatic clearance of unfractionated heparin) and are contraindicated in renal insufficiency. Not easily reversible. Heparin-induced thrombocytopenia (HIT) type 2—development of IgG antibodies against heparin-bound platelet factor 4 (PF4). Antibody-heparin-PF4 complex activates platelets • thrombosis and thrombocytopenia. Highest risk with unfractionated heparin. HIT type 1 characterized by nonimmunologic milder drop in platelet count, usually asymptomatic. mechanISm Inhibits epoxide reductase, which interferes The EX-PresidenT went to war(farin). with γ-carboxylation of vitamin K–dependent clotting factors II, VII, IX, X, and proteins C,


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First_Aid_Step1. mechanISm Inhibits epoxide reductase, which interferes The EX-PresidenT went to war(farin). with γ-carboxylation of vitamin K–dependent clotting factors II, VII, IX, X, and proteins C, S. Metabolism affected by polymorphisms in the gene for vitamin K epoxide reductase complex (VKORC1). In laboratory assay, has effect on EXtrinsic pathway and  PT. Long half-life. clInIcal USe Chronic anticoagulation (eg, venous thromboembolism prophylaxis, and prevention of stroke in atrial fibrillation). Not used in pregnant women (because warfarin, unlike heparin, crosses placenta). Follow PT/INR. Bleeding, teratogenic, skin/tissue necrosis A , drug-drug interactions.


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First_Aid_Step1. Bleeding, teratogenic, skin/tissue necrosis A , drug-drug interactions. Initial risk of hypercoagulation: protein C has a shorter half-life than factors II and X. Existing protein C depletes before existing factors II and X deplete, and before warfarin can reduce factors II and X production  hypercoagulation. Skin/tissue necrosis within first few days of large doses believed to be due to small vessel microthrombosis. For reversal of warfarin, give vitamin K. For rapid reversal, give fresh frozen plasma (FFP) or PCC. Heparin “bridging”: heparin frequently used when starting warfarin. Heparin’s activation of antithrombin enables anticoagulation during initial, transient hypercoagulable state caused by warfarin. Initial heparin therapy reduces risk of recurrent venous thromboembolism and skin/tissue necrosis. Metabolized by cytochrome P-450. Direct factor Xa inhibitors ApiXaban, rivaroXaban. mechanISm Bind to and directly inhibit factor Xa.


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First_Aid_Step1. Metabolized by cytochrome P-450. Direct factor Xa inhibitors ApiXaban, rivaroXaban. mechanISm Bind to and directly inhibit factor Xa. clInIcal USe Treatment and prophylaxis for DVT and PE; stroke prophylaxis in patients with atrial fibrillation. Oral agents do not usually require coagulation monitoring. adVeRSe eFFectS Bleeding. Reverse with andeXanet alfa. Thrombolytics Alteplase (tPA), reteplase (rPA), streptokinase, tenecteplase (TNK-tPA). mechanISm Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots.  PT,  PTT, no change in platelet count. clInIcal USe Early MI, early ischemic stroke, direct thrombolysis of severe PE.


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First_Aid_Step1. clInIcal USe Early MI, early ischemic stroke, direct thrombolysis of severe PE. adVeRSe eFFectS Bleeding. Contraindicated in patients with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension. Nonspecific reversal with antifibrinolytics (eg, aminocaproic acid, tranexamic acid), platelet transfusions, and factor corrections (eg, cryoprecipitate, FFP, PCC). ADP receptor inhibitors Clopidogrel, prasugrel, ticagrelor (reversible), ticlopidine. mechanISm Irreversibly block ADP (P2Y12) receptor, which prevents subsequent platelet aggregation. Prevent expression of glycoproteins IIb/IIIa on platelet surface. clInIcal USe Acute coronary syndrome; coronary stenting.  incidence or recurrence of thrombotic stroke. adVeRSe eFFectS Neutropenia (ticlopidine). TTP may be seen. Glycoprotein IIb/IIIa inhibitors Abciximab, eptifibatide, tirofiban.


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First_Aid_Step1. adVeRSe eFFectS Neutropenia (ticlopidine). TTP may be seen. Glycoprotein IIb/IIIa inhibitors Abciximab, eptifibatide, tirofiban. mechanISm Bind to the glycoprotein receptor IIb/IIIa (fibrinogen receptor) on activated platelets, preventing aggregation. Abciximab is made from monoclonal antibody Fab fragments. clInIcal USe Unstable angina, percutaneous coronary intervention. adVeRSe eFFectS Bleeding, thrombocytopenia. Platinum agents (eg, cisplatin) Alkylating agents:Azathioprine Ifosfamide 5-fuorouracil Rb, p53 modulate Nitrosoureas (eg, carmustine) Hydroxyurea G restriction point Methotrexate 1 6-mercaptopurine


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First_Aid_Step1. Alkylating agents:Azathioprine Ifosfamide 5-fuorouracil Rb, p53 modulate Nitrosoureas (eg, carmustine) Hydroxyurea G restriction point Methotrexate 1 6-mercaptopurine Nucleotide synthesis DNA RNA Cellular division MTX, 5-FU: ˜thymidine synthesis 6-MP: ˜de novo purine synthesis Hydroxyurea: inhibits ribonucleotide reductase Alkylating agents, platinum agents: cross-link DNA Bleomycin: DNA strand breakage Dactinomycin, doxorubicin: DNA intercalators Etoposide/teniposide: inhibits topoisomerase II Irinotecan/topotecan: inhibits topoisomerase I Vinca alkaloids: inhibit microtubule formation Paclitaxel: inhibits microtubule disassembly Protein


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First_Aid_Step1. Azathioprine, Purine (thiol) analogs Preventing organ rejection, Myelosuppression; GI, liver 6-mercaptopurine  de novo purine synthesis. rheumatoid arthritis, IBD, toxicity. Activated by HGPRT. SLE; used to wean patients Azathioprine and 6-MP are Azathioprine is metabolized off steroids in chronic disease metabolized by xanthine into 6-MP. and to treat steroid-refractory oxidase; thus both have  risk chronic disease. of toxicity with allopurinol or febuxostat. Cladribine Purine analog • multiple Hairy cell leukemia. Myelosuppression, mechanisms (eg, inhibition nephrotoxicity, and of DNA polymerase, DNA neurotoxicity. strand breaks). Cytarabine Pyrimidine analog  DNA Leukemias (AML), lymphomas. Myelosuppression with (arabinofuranosyl chain termination. At higher megaloblastic anemia. cytidine) concentrations, inhibits DNA CYTarabine causes polymerase. panCYTopenia.


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First_Aid_Step1. 5-fluorouracil Pyrimidine analog bioactivated to 5-FdUMP, which covalently complexes with thymidylate synthase and folic acid. Capecitabine is a prodrug. This complex inhibits thymidylate synthase  dTMP  DNA synthesis. Colon cancer, pancreatic cancer, actinic keratosis, basal cell carcinoma (topical). Effects enhanced with the addition of leucovorin. Myelosuppression, palmarplantar erythrodysesthesia (hand-foot syndrome). Methotrexate Folic acid analog that competitively inhibits dihydrofolate reductase  dTMP  DNA synthesis. Cancers: leukemias (ALL), lymphomas, choriocarcinoma, sarcomas. Non-neoplastic: ectopic pregnancy, medical abortion (with misoprostol), rheumatoid arthritis, psoriasis, IBD, vasculitis. Myelosuppression, which is reversible with leucovorin (folinic acid) “rescue.” Hepatotoxicity. Mucositis (eg, mouth ulcers). Pulmonary fibrosis. Folate deficiency, which may be teratogenic (neural tube defects) without supplementation. Nephrotoxicity.


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First_Aid_Step1. Hepatotoxicity. Mucositis (eg, mouth ulcers). Pulmonary fibrosis. Folate deficiency, which may be teratogenic (neural tube defects) without supplementation. Nephrotoxicity. aAll are S-phase specific except cladribine, which is cell cycle nonspecific. Cyclophosphamide, ifosfamide Myelosuppression; SIADH; Fanconi syndrome (ifosfamide); hemorrhagic cystitis and bladder cancer, prevented with mesna (sulfhydryl group of mesna binds toxic metabolites) and adequate hydration. Microtubule inhibitors Cisplatin, carboplatin, oxaliplatin mechanISm Cross-link DNA. clInIcal USe Testicular, bladder, ovary, GI, and lung carcinomas. adVeRSe eFFectS Nephrotoxicity (including Fanconi syndrome), peripheral neuropathy, ototoxicity. Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride (saline) diuresis. Etoposide, teniposide mechanISm Inhibit topoisomerase II  DNA degradation (cell cycle arrest in G2 and S phases).


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First_Aid_Step1. Etoposide, teniposide mechanISm Inhibit topoisomerase II  DNA degradation (cell cycle arrest in G2 and S phases). clInIcal USe Solid tumors (particularly testicular and small cell lung cancer), leukemias, lymphomas. adVeRSe eFFectS Myelosuppression, alopecia. Irinotecan, topotecan mechanISm Inhibit topoisomerase I and prevent DNA unwinding and replication. clInIcal USe Colon cancer (irinotecan); ovarian and small cell lung cancers (topotecan). adVeRSe eFFectS Severe myelosuppression, diarrhea. mechanISm Inhibits ribonucleotide reductase  DNA Synthesis (S-phase specific). clInIcal USe Myeloproliferative disorders (eg, CML, polycythemia vera), sickle cell disease (• HbF). adVeRSe eFFectS Severe myelosuppression, megaloblastic anemia. mechanISm Monoclonal antibody against VEGF. Inhibits angiogenesis (BeVacizumab inhibits Blood Vessel formation). clInIcal USe Solid tumors (eg, colorectal cancer, renal cell carcinoma), wet age-related macular degeneration.


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First_Aid_Step1. clInIcal USe Solid tumors (eg, colorectal cancer, renal cell carcinoma), wet age-related macular degeneration. adVeRSe eFFectS Hemorrhage, blood clots, and impaired wound healing. mechanISm EGFR tyrosine kinase inhibitor. clInIcal USe Non-small cell lung cancer. adVeRSe eFFectS Rash, diarrhea. Cetuximab, panitumumab mechanISm Monoclonal antibodies against EGFR. clInIcal USe Stage IV colorectal cancer (wild-type KRAS), head and neck cancer. adVeRSe eFFectS Rash, elevated LFTs, diarrhea. Imatinib, dasatinib, nilotinib mechanISm Tyrosine kinase inhibitors of bcr-abl (encoded by Philadelphia chromosome fusion gene in CML) and c-kit (common in GI stromal tumors). clInIcal USe CML, GI stromal tumors (GISTs). adVeRSe eFFectS Fluid retention. mechanISm Monoclonal antibody against CD20, which is found on most B-cell neoplasms. clInIcal USe Non-Hodgkin lymphoma, CLL, ITP, rheumatoid arthritis, TTP, AIHA. adVeRSe eFFectS  risk of progressive multifocal leukoencephalopathy.


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First_Aid_Step1. clInIcal USe Non-Hodgkin lymphoma, CLL, ITP, rheumatoid arthritis, TTP, AIHA. adVeRSe eFFectS  risk of progressive multifocal leukoencephalopathy. Bortezomib, carfilzomib mechanISm Proteasome inhibitors, induce arrest at G2-M phase and apoptosis. clInIcal USe Multiple myeloma, mantle cell lymphoma. adVeRSe eFFectS Peripheral neuropathy, herpes zoster reactivation. Tamoxifen, raloxifene mechanISm Selective estrogen receptor modulators (SERMs)—receptor antagonists in breast and agonists in bone. Block the binding of estrogen to ER ⊕ cells. clInIcal USe Breast cancer treatment (tamoxifen only) and prevention. Raloxifene also useful to prevent osteoporosis.


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First_Aid_Step1. clInIcal USe Breast cancer treatment (tamoxifen only) and prevention. Raloxifene also useful to prevent osteoporosis. adVeRSe eFFectS Tamoxifen—partial agonist in endometrium, which  the risk of endometrial cancer. Raloxifene—no  in endometrial carcinoma (so you can relax!), because it is an estrogen receptor antagonist in endometrial tissue. Both  risk of thromboembolic events (eg, DVT, PE) and “hot flashes.” mechanISm Monoclonal antibody against HER-2 (c-erbB2), a tyrosine kinase receptor. Helps kill cancer cells that overexpress HER-2 through inhibition of HER-2 initiated cellular signaling and antibody-dependent cytotoxicity. clInIcal USe HER-2 ⊕ breast cancer and gastric cancer (tras2zumab). adVeRSe eFFectS Dilated cardiomyopathy. “Heartceptin” damages the heart. Dabrafenib, vemurafenib mechanISm Recombinant uricase that catalyzes metabolism of uric acid to allantoin. clInIcal USe Prevention and treatment of tumor lysis syndrome. Bleomycin, Busulfan


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First_Aid_Step1. Dabrafenib, vemurafenib mechanISm Recombinant uricase that catalyzes metabolism of uric acid to allantoin. clInIcal USe Prevention and treatment of tumor lysis syndrome. Bleomycin, Busulfan Nonspecific common toxicities of nearly all cytotoxic chemotherapies include myelosuppression (neutropenia, anemia, thrombocytopenia), GI toxicity (nausea, vomiting, mucositis), alopecia. Musculoskeletal, Skin, and Connective Tissue “Rigid, the skeleton of habit alone upholds the human frame.” “Beauty may be skin deep, but ugly goes clear to the bone.” “The function of muscle is to pull and not to push, except in the case of the genitals and the tongue.” “To thrive in life you need three bones. A wishbone. A backbone. And a funny bone.”


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First_Aid_Step1. This chapter provides information you will need to understand certain anatomical dysfunctions, rheumatic diseases, and dermatologic conditions. Be able to interpret 3D anatomy in the context of radiologic imaging. For the rheumatic diseases, create instructional cases or personas that include the most likely presentation and symptoms: risk factors, gender, important markers (eg, autoantibodies), and other epidemiologic factors. Doing so will allow you to answer the higher order questions that are likely to be asked on the exam. `mUsCUlosKElEtal, sKin, and ConnECtiVE tissUE—anatomy and physiology Rotator cuff muscles Shoulder muscles that form the rotator cuff: SItS (small t is for teres minor). Supraspinatus (suprascapular nerve)— abducts arm initially (before the action of the deltoid); most common rotator cuff injury (trauma or degeneration and impingement • tendinopathy or tear [arrow in


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First_Aid_Step1. A ]), assessed by “empty/full can” test nerves)—internally rotates and adducts arm Innervated primarily by C5-C6. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 447 Axillary (C5-C6) Fractured surgical neck of humerus Flattened deltoid Anterior dislocation of humerus Loss of arm abduction at shoulder (> 15°) Loss of sensation over deltoid and lateral arm Musculocutaneous Upper trunk compression  biceps (C5-6) reflex (C5-C7) Weakness of forearm flexion and supination Loss of sensation over lateral forearm Radial (C5-T1) Compression of axilla, eg, due to crutches or Wrist drop: loss of elbow, wrist, and finger sleeping with arm over chair (“Saturday night extension palsy”)  grip strength (wrist extension necessary for Midshaft fracture of humerus maximal action of flexors) Repetitive pronation/supination of forearm, eg, Loss of sensation over posterior arm/forearm and due to screwdriver use (“finger drop”) dorsal hand


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First_Aid_Step1. Median (C5-T1) Supracondylar fracture of humerus  proximal “Ape hand” and “Pope’s blessing” lesion of the nerve Loss of wrist flexion, flexion of lateral fingers, Carpal tunnel syndrome and wrist laceration thumb opposition, lumbricals of index and  distal lesion of the nerve middle fingers Loss of sensation over thenar eminence and dorsal and palmar aspects of lateral 31⁄2 fingers with proximal lesion Ulnar (C8-T1) Fracture of medial epicondyle of humerus “funny bone” (proximal lesion) Fractured hook of hamate (distal lesion) from fall on outstretched hand Radial deviation of wrist upon flexion (proximal lesion) Loss of wrist flexion, flexion of medial fingers, abduction and adduction of fingers (interossei), actions of medial 2 lumbrical muscles Loss of sensation over medial 11/2 fingers including hypothenar eminence Humerus fractures, proximally to distally, follow the ARM (Axillary • Radial • Median)


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First_Aid_Step1. Loss of sensation over medial 11/2 fingers including hypothenar eminence Humerus fractures, proximally to distally, follow the ARM (Axillary • Radial • Median) MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 448 Erb palsy (“waiter’s tip”) Klumpke palsy (claw hand) Wrist drop Winged scapula Deltoid paralysis “Saturday night palsy” (wrist drop) Di⁄culty fexing elbow, variable sensory loss Decreased thumb function, “Pope’s blessing” Intrinsic muscles of hand, claw hand Erb palsy (“waiter’s Traction or tear Infants—lateral Deltoid, Abduction (arm tip”) of upper trunk: traction on neck supraspinatus hangs by side) C5-C6 roots during delivery medially rotated) Biceps brachii Flexion, supination Herb gets DIBs (arm extended and on tips pronated) Klumpke palsy Traction or tear Infants—upward Intrinsic hand Total claw hand: of lower trunk: force on arm muscles: lumbricals normally C8-T1 roots during delivery lumbricals, flex MCP joints and


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First_Aid_Step1. Klumpke palsy Traction or tear Infants—upward Intrinsic hand Total claw hand: of lower trunk: force on arm muscles: lumbricals normally C8-T1 roots during delivery lumbricals, flex MCP joints and Adults—trauma interossei, extend DIP and PIP (eg, grabbing a thenar, joints tree branch to hypothenar break a fall) Thoracic outlet Compression Cervical rib Same as Klumpke Atrophy of intrinsic syndrome of lower trunk (arrows in A , palsy hand muscles; and subclavian Pancoast tumor ischemia, pain, vessels, most and edema commonly due to vascular within the compression scalene triangle Winged scapula Lesion of long Axillary node Serratus anterior Inability to anchor thoracic nerve, dissection after scapula to thoracic roots C5-C7 mastectomy, cage  cannot (“wings of stab wounds abduct arm heaven”) above horizontal position MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 449


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First_Aid_Step1. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 449 Wrist region Scaphoid, Lunate, Triquetrum, Pisiform, A Hamate, Capitate, Trapezoid, Trapezium A. (So Long To Pinky, Here Comes The Thumb) 1st MC Hamate is the most commonly fractured carpal bone, Trapezium typically due to a fall on an outstretched hand. Complications of proximal scaphoid fractures include avascular necrosis and nonunion due to retrograde blood supply from a branch of the radial artery. Fracture not always seen on initial x-ray. Dislocation of lunate may cause acute carpal tunnel syndrome. Plane of section MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 450 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 451


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First_Aid_Step1. Plane of section MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 450 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 451 Distortions of the hand At rest, a balance exists between the extrinsic flexors and extensors of the hand, as well as the intrinsic muscles of the hand—particularly the lumbrical muscles (flexion of MCP, extension of DIP and PIP joints). “Clawing”—seen best with distal lesions of median or ulnar nerves. Remaining extrinsic flexors of the digits exaggerate the loss of the lumbricals  fingers extend at MCP, flex at DIP and PIP joints. Deficits less pronounced in proximal lesions; deficits present during voluntary flexion of the digits. Note: Atrophy of the thenar eminence (unopposable thumb  “ape hand”) can be seen in median nerve lesions, while atrophy of the hypothenar eminence can be seen in ulnar nerve lesions. Actions of hip muscles


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First_Aid_Step1. Actions of hip muscles MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 452 Obturator (L2-L4) Sensory—medial thigh Motor—obturator externus, adductor longus, adductor brevis, gracilis, pectineus, adductor magnus Pelvic surgery  thigh sensation (medial) and adduction Femoral (L2-L4) Sensory—anterior thigh, medial leg Motor—quadriceps, iliacus, pectineus, sartorius Pelvic fracture  leg extension ( patellar reflex) MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 453 Superficial peroneal nerve: Sensory—dorsum of foot (except webspace between hallux and 2nd digit) and brevis Deep peroneal nerve: Motor—tibialis anterior Sensory—sole of foot Motor—biceps femoris (long head), triceps surae, plantaris, popliteus, flexor muscles of foot Motor—gluteus medius, gluteus minimus, tensor fascia latae Trauma or compression of lateral aspect of leg, fibular neck fracture


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First_Aid_Step1. Motor—gluteus medius, gluteus minimus, tensor fascia latae Trauma or compression of lateral aspect of leg, fibular neck fracture Knee trauma, Baker cyst (proximal lesion); tarsal tunnel syndrome (distal lesion) Iatrogenic injury during intramuscular injection to superomedial gluteal region (prevent by choosing superolateral quadrant, preferably anterolateral region) PED = Peroneal Everts and Dorsiflexes; if injured, foot dropPED Loss of sensation on dorsum of foot Foot drop—inverted and plantarflexed at rest, loss of eversion and dorsiflexion; “steppage gait” TIP = Tibial Inverts and Plantarflexes; if injured, can’t stand on TIPtoes Inability to curl toes and loss of sensation on sole; in proximal lesions, foot everted at rest with loss of inversion and plantar flexion Trendelenburg sign/gait— pelvis tilts because weight-bearing leg cannot maintain alignment of pelvis through hip abduction


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First_Aid_Step1. Trendelenburg sign/gait— pelvis tilts because weight-bearing leg cannot maintain alignment of pelvis through hip abduction Lesion is contralateral to the side of the hip that drops, ipsilateral to extremity on which the patient stands MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 454 Knee exam Lateral femoral condyle to anterior tibia: ACL. Medial femoral condyle to posterior tibia: PCL. LAMP. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 455 Ankle sprains Anterior TaloFibular ligament—most common ankle sprain overall, classified as a low ankle sprain. Due to overinversion/supination of foot. Anterior inferior tibiofibular ligament—most common high ankle sprain. Always Tears First. Neurovascular pairing Nerves and arteries are frequently named together by the bones/regions with which they are associated. The following are exceptions to this naming convention.


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First_Aid_Step1. Neurovascular pairing Nerves and arteries are frequently named together by the bones/regions with which they are associated. The following are exceptions to this naming convention. Surgical neck of humerus Axillary Posterior circumflex MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 456 Motoneuron action T-tubules are extensions of plasma membrane in contact with the sarcoplasmic reticulum, allowing potential to muscle for coordinated contraction of striated muscles. contraction


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First_Aid_Step1. Action potential opens presynaptic voltage-gated Ca2+ channels, inducing acetylcholine (ACh) release. Postsynaptic ACh binding leads to muscle cell depolarization at the motor end plate. Depolarization travels over the entire muscle cell and deep into the muscle via the T-tubules. Membrane depolarization induces conformational changes in the voltage-sensitive dihydropyridine receptor (DHPR) and its mechanically coupled ryanodine receptor (RR) • Ca2+ release from the sarcoplasmic reticulum into the cytoplasm. Tropomyosin is blocking myosin-binding sites on the actin filament. Released Ca2+ binds to troponin C (TnC), shifting tropomyosin to expose the myosin-binding sites. The myosin head binds strongly to actin, forming a crossbridge. Pi is then released, initiating the power stroke. During the power stroke, force is produced as myosin pulls on the thin filament


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First_Aid_Step1. A . Muscle shortening occurs, with shortening of H and I bands and between Z lines (HIZ shrinkage). The A band remains the same length (A band is Always the same length). ADP is released at the end of the power stroke. Binding of new ATP molecule causes detachment of myosin head from actin filament. Ca2+ is resequestered. ATP hydrolysis into ADP and Pi results in myosin head returning to high-energy position (cocked). The myosin head can bind to a new site on actin to form a crossbridge if Ca2+ remains available. Sarcomere (Z line to Z line) MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 457 Types of muscle fibers Acetylcholine, bradykinin, etc MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 458 Muscle proprioceptors Specialized sensory receptors that relay information about muscle dynamics.


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First_Aid_Step1. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` anatomy and physiology SECTION III 458 Muscle proprioceptors Specialized sensory receptors that relay information about muscle dynamics. Membranous Bones of calvarium, facial bones, and clavicle. Woven bone formed directly without cartilage. Later ossification remodeled to lamellar bone. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 459 Cell biology of bone Osteoblast Builds bone by secreting collagen and catalyzing mineralization in alkaline environment via ALP. Differentiates from mesenchymal stem cells in periosteum. Osteoblastic activity measured by bone ALP, osteocalcin, propeptides of type I procollagen.


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First_Aid_Step1. Osteoclast Dissolves (“crushes”) bone by secreting H+ and collagenases. Differentiates from a fusion of monocyte/macrophage lineage precursors. RANK receptors on osteoclasts are stimulated by RANKL (RANK ligand, expressed on osteoblasts). OPG (osteoprotegerin, a RANKL decoy receptor) binds RANKL to prevent RANK-RANKL interaction  osteoclast activity. `mUsCUlosKElEtal, sKin, and ConnECtiVE tissUE—pathology Overuse injuries of the elbow Metacarpal neck Also called boxer’s fracture. Common fracture fracture caused by direct blow with a closed fist (eg, from punching a wall). Most commonly seen in 4th and 5th metacarpals A . Entrapment of median nerve in carpal tunnel (between transverse carpal ligament and carpal bones)  nerve compression  paresthesia, pain, and numbness in distribution of median nerve. Thenar eminence atrophies B but sensation spared, because palmar cutaneous branch enters hand external to carpal tunnel.


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First_Aid_Step1. B but sensation spared, because palmar cutaneous branch enters hand external to carpal tunnel. Suggested by ⊕ Tinel sign (percussion of wrist causes tingling) and Phalen maneuver (90° flexion of wrist causes tingling). Associated with pregnancy (due to edema), rheumatoid arthritis, hypothyroidism, diabetes, acromegaly, dialysis-related amyloidosis; may be associated with repetitive use. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 460 Clavicle fractures Common in children and as birth trauma. Usually caused by a fall on outstretched hand or by direct trauma to shoulder. Weakest point at the junction of middle and lateral thirds; fractures at the middle third segment are most common. Presents as shoulder drop, shortened clavicle (lateral fragment is depressed due to arm weight and medially rotated by arm adductors [eg, pectoralis major]).


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First_Aid_Step1. “Unhappy triad” Common injury in contact sports due to lateral force applied to a planted foot. Consists of damage to the ACL A , MCL, and medial meniscus (attached to MCL). However, lateral meniscus involvement is more common than with ACL and MCL injury. Presents with acute pain and signs of joint instability. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 461 Plantar fasciitis Inflammation of plantar aponeurosis characterized by heel pain (worse with first steps in the morning or after period of inactivity) and tenderness. Developmental Abnormal acetabulum development in newborns. Major risk factor includes breech presentation. dysplasia of the hip Results in hip instability/dislocation. Commonly tested with Ortolani and Barlow maneuvers (manipulation of newborn hip reveals a “clunk”). Confirmed via ultrasound (x-ray not used until ~4–6 months because cartilage is not ossified).


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First_Aid_Step1. Legg-Calvé-Perthes Idiopathic avascular necrosis of femoral head. Commonly presents between 5–7 years with disease insidious onset of hip pain that may cause child to limp. More common in males (4:1 ratio). Initial x-ray often normal. Osgood-Schlatter Also called traction apophysitis. Overuse injury caused by repetitive strain and chronic avulsion of disease the secondary ossification center of proximal tibial tubercle. Occurs in adolescents after growth spurt. Common in running and jumping athletes. Presents with progressive anterior knee pain. 462 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology


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First_Aid_Step1. 462 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology Achondroplasia Failure of longitudinal bone growth (endochondral ossification)  short limbs. Membranous ossification is not affected  large head relative to limbs. Constitutive activation of fibroblast growth factor receptor (FGFR3) actually inhibits chondrocyte proliferation. > 85% of mutations occur sporadically; autosomal dominant with full penetrance (homozygosity is lethal). Associated with  paternal age. Most common cause of short-limbed dwarfism. Trabecular (spongy) and cortical bone lose mass despite normal bone mineralization and lab values (serum Ca2+ and PO43−). Most commonly due to  bone resorption related to  estrogen levels and old age. Can be 2° to drugs (eg, steroids, alcohol, anticonvulsants, anticoagulants, thyroid replacement therapy) or other conditions (eg, hyperparathyroidism, hyperthyroidism, multiple myeloma, malabsorption syndromes, anorexia).


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First_Aid_Step1. Diagnosed by bone mineral density measurement by DEXA (dual-energy X-ray absorptiometry) at the lumbar spine, total hip, and femoral neck, with a T-score of ≤−2.5 or by a fragility fracture (eg, fall from standing height, minimal trauma) at hip or vertebra. One time screening recommended in women ≥ 65 years old. Prophylaxis: regular weight-bearing exercise and adequate Ca2+ and vitamin D intake throughout adulthood. Treatment: bisphosphonates, teriparatide, SERMs, rarely calcitonin; denosumab (monoclonal antibody against RANKL). Can lead to vertebral compression fractures A —acute back pain, loss of height, kyphosis. Also can present with fractures of femoral neck, distal radius (Colles fracture). Central expansion Restricted of intervertebral intervertebral disc foramen MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 463


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First_Aid_Step1. Central expansion Restricted of intervertebral intervertebral disc foramen MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 463 Osteopetrosis Failure of normal bone resorption due to defective osteoclasts  thickened, dense bones that are prone to fracture. Mutations (eg, carbonic anhydrase II) impair ability of osteoclast to generate acidic environment necessary for bone resorption. Overgrowth of cortical bone fills marrow space  pancytopenia, extramedullary hematopoiesis. Can result in cranial nerve impingement and palsies due to narrowed foramina. X-rays show diffuse symmetric sclerosis (bone-in-bone, “stone bone” A ). Bone marrow transplant is potentially curative as osteoclasts are derived from monocytes. Defective mineralization of osteoid (osteomalacia) or cartilaginous growth plates (rickets, only in children). Most commonly due to vitamin D deficiency.


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First_Aid_Step1. Defective mineralization of osteoid (osteomalacia) or cartilaginous growth plates (rickets, only in children). Most commonly due to vitamin D deficiency. X-rays show osteopenia and “Looser zones” (pseudofractures) in osteomalacia, epiphyseal widening and metaphyseal cupping/fraying in rickets. Children with rickets have pathologic bow legs (genu varum A ), bead-like costochondral junctions (rachitic rosary B ), craniotabes (soft skull).  serum PO43− . Hyperactivity of osteoblasts  ALP. Also called Paget disease of bone. Common, localized disorder of bone remodeling caused by  osteoclastic activity followed by  osteoblastic activity that forms poor-quality bone. Serum Ca2+ , phosphorus, and PTH levels are normal.  ALP. Mosaic pattern of woven and lamellar bone (osteocytes within lacunae in chaotic juxtapositions); long bone chalk-stick fractures.  blood flow from • arteriovenous shunts may cause high-output heart failure.  risk of osteosarcoma.


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First_Aid_Step1. Hat size can be increased due to skull thickening A ; hearing loss is common due to auditory foramen narrowing. Stages of Paget disease: activity Treatment: bisphosphonates. Avascular necrosis of bone Infarction of bone and marrow, usually very painful. Most common site is femoral head (watershed zone) A (due to insufficiency of medial circumflex femoral artery). Causes include Corticosteroids, Alcoholism, Sickle cell disease, Trauma, SLE, “the Bends” (caisson/decompression disease), LEgg-Calvé-Perthes disease (idiopathic), Gaucher disease, Slipped capital femoral epiphysis—CASTS Bend LEGS. Branch of obturator artery MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 464 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 465 Anaplastic small blue cells of neuroectodermal origin (resemble lymphocytes) F .


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First_Aid_Step1. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 465 Anaplastic small blue cells of neuroectodermal origin (resemble lymphocytes) F . Differentiate from conditions with similar morphology (eg, lymphoma, chronic osteomyelitis) by testing for t(11;22) (fusion protein EWS-FLI1). “Onion skin” periosteal reaction in bone. Aggressive with early metastases, but responsive to chemotherapy. 11 + 22 = 33 (Patrick Ewing’s jersey number). MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 466 Joint Findings Osteophytes (bone spurs), joint space narrowing, subchondral sclerosis and cysts. Synovial fluid noninflammatory (WBC < 2000/mm3). Development of Heberden nodes B (at DIP) and Bouchard nodes C (at PIP), and 1st CMC; not MCP. Erosions, juxta-articular osteopenia, soft tissue swelling, subchondral cysts, joint space narrowing. Deformities: cervical subluxation, ulnar finger deviation, swan neck


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First_Aid_Step1. Erosions, juxta-articular osteopenia, soft tissue swelling, subchondral cysts, joint space narrowing. Deformities: cervical subluxation, ulnar finger deviation, swan neck D , boutonniere E . Involves MCP, PIP, wrist; not DIP or 1st CMC. *Extraarticular manifestations include rheumatoid nodules (fibrinoid necrosis with palisading histiocytes) in subcutaneous tissue and lung (+ pneumoconiosis • Caplan syndrome), interstitial lung disease, pleuritis, pericarditis, anemia of chronic disease, neutropenia + splenomegaly (Felty syndrome), AA amyloidosis, Sjögren syndrome, scleritis, carpal tunnel syndrome. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 467 Findings Acute inflammatory monoarthritis caused by precipitation of monosodium urate crystals in joints A . Risk factors: male sex, hypertension, obesity, diabetes, dyslipidemia, alcohol use. Strongest risk factor is hyperuricemia, which can be caused by:


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First_Aid_Step1. Underexcretion of uric acid (90% of patients)—largely idiopathic, potentiated by renal failure; can be exacerbated by certain medications (eg, thiazide diuretics). Overproduction of uric acid (10% of patients)—Lesch-Nyhan syndrome, PRPP excess,  cell turnover (eg, tumor lysis syndrome), von Gierke disease. Crystals are needle shaped and ⊝ birefringent under polarized light (yellow under parallel light, blue under perpendicular light B ). Serum uric acid levels may be normal during an acute attack.


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First_Aid_Step1. Crystals are needle shaped and ⊝ birefringent under polarized light (yellow under parallel light, blue under perpendicular light B ). Serum uric acid levels may be normal during an acute attack. symptoms Asymmetric joint distribution. Joint is swollen, red, and painful. Classic manifestation is painful MTP joint of big toe (podagra). Tophus formation C (often on external ear, olecranon bursa, or Achilles tendon). Acute attack tends to occur after a large meal with foods rich in purines (eg, red meat, seafood), trauma, surgery, dehydration, diuresis, or alcohol consumption (alcohol metabolites compete for same excretion sites in kidney as uric acid  uric acid secretion and subsequent buildup in blood). tREatmEnt Acute: NSAIDs (eg, indomethacin), glucocorticoids, colchicine. Chronic (preventive): xanthine oxidase inhibitors (eg, allopurinol, febuxostat).


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First_Aid_Step1. tREatmEnt Acute: NSAIDs (eg, indomethacin), glucocorticoids, colchicine. Chronic (preventive): xanthine oxidase inhibitors (eg, allopurinol, febuxostat). Previously called pseudogout. Deposition of The blue P’s—blue (when Parallel), Positive calcium pyrophosphate crystals within the birefringence, calcium Pyrophosphate, joint space. Occurs in patients > 50 years old; Pseudogout both sexes affected equally. Usually idiopathic, sometimes associated with hemochromatosis, hyperparathyroidism, joint trauma. Pain and swelling with acute inflammation (pseudogout) and/or chronic degeneration (pseudo-osteoarthritis). Most commonly affected joint is the knee. Chondrocalcinosis (cartilage calcification) on x-ray. Crystals are rhomboid and weakly ⊕ birefringent under polarized light (blue when parallel to light) A . Acute treatment: NSAIDs, colchicine, glucocorticoids. Prophylaxis: colchicine. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 468


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First_Aid_Step1. A . Acute treatment: NSAIDs, colchicine, glucocorticoids. Prophylaxis: colchicine. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 468 Septic arthritis S aureus, Streptococcus, and Neisseria gonorrhoeae are common causes. Affected joint is swollen A , red, and painful. Synovial fluid purulent (WBC > 50,000/mm3). Gonococcal arthritis—STI that presents as either purulent arthritis (eg, knee) or triad of polyarthralgia, tenosynovitis (eg, hand), dermatitis (eg, pustules). MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 469 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 470 Libman-Sacks Endocarditis—nonbacterial, verrucous thrombi usually on mitral or aortic valve and can be present on either surface of the valve (but usually on undersurface). LSE in SLE.


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First_Aid_Step1. Libman-Sacks Endocarditis—nonbacterial, verrucous thrombi usually on mitral or aortic valve and can be present on either surface of the valve (but usually on undersurface). LSE in SLE. Lupus nephritis (glomerular deposition of DNA-anti-DNA immune complexes) can be nephritic or nephrotic (causing hematuria or proteinuria). Most common and severe type is diffuse proliferative. Common causes of death in SLE: Renal disease (most common), Infections, Cardiovascular disease (accelerated CAD). In an anti-SSA ⊕ pregnant woman,  risk of newborn developing neonatal lupus  congenital heart block, periorbital/diffuse rash, transaminitis, and cytopenias at birth. RASH OR PAIN: Rash (malar


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First_Aid_Step1. In an anti-SSA ⊕ pregnant woman,  risk of newborn developing neonatal lupus  congenital heart block, periorbital/diffuse rash, transaminitis, and cytopenias at birth. RASH OR PAIN: Rash (malar A or discoid B ) Arthritis (nonerosive) Serositis (eg, pleuritis, pericarditis) Hematologic disorders (eg, cytopenias) Oral/nasopharyngeal ulcers (usually painless) Renal disease Photosensitivity Antinuclear antibodies Immunologic disorder (anti-dsDNA, anti-Sm, antiphospholipid) Neurologic disorders (eg, seizures, psychosis) Lupus patients die with Redness In their Cheeks. Mixed connective Features of SLE, systemic sclerosis, and/or tissue disease polymyositis. Associated with anti-U1 RNP antibodies (speckled ANA). 1° or 2° autoimmune disorder (most commonly in SLE). Diagnosed based on clinical criteria including history of thrombosis (arterial or venous) or spontaneous abortion along with laboratory findings of lupus anticoagulant, anticardiolipin, anti-β2 glycoprotein I antibodies.


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First_Aid_Step1. Treatment: systemic anticoagulation. Anticardiolipin antibodies can cause false-positive VDRL/RPR. Lupus anticoagulant can cause prolonged PTT that is not corrected by the addition of normal platelet-free plasma. symptoms Pain and stiffness in proximal muscles (eg, shoulders, hips), often with fever, malaise, weight loss. Does not cause muscular weakness. More common in women > 50 years old; associated with giant cell (temporal) arteritis. Findings  ESR,  CRP, normal CK. tREatmEnt Rapid response to low-dose corticosteroids. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 471 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 472


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First_Aid_Step1. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 471 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` pathology SECTION III 472 Raynaud phenomenon  blood flow to skin due to arteriolar (small vessel) vasospasm in response to cold or stress: color change from white (ischemia) to blue (hypoxia) to red (reperfusion). Most often in the fingers A and toes. Called Raynaud disease when 1° (idiopathic), Raynaud syndrome when 2° to a disease process such as mixed connective tissue disease, SLE, or CREST syndrome (limited form of systemic sclerosis). Digital ulceration (critical ischemia) seen in 2° Raynaud syndrome. Treat with calcium2+ channel blockers. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 473


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First_Aid_Step1. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 473 Scleroderma Systemic sclerosis. Triad of autoimmunity, noninflammatory vasculopathy, and collagen deposition with fibrosis. Commonly sclerosis of skin, manifesting as puffy, taut skin A without wrinkles, fingertip pitting B . Can involve other systems, eg, renal (scleroderma renal crisis; treat with ACE inhibitors), pulmonary (interstitial fibrosis, pulmonary HTN), GI (esophageal dysmotility and reflux), cardiovascular. 75% female. 2 major types: Diffuse scleroderma—widespread skin involvement, rapid progression, early visceral involvement. Associated with anti-Scl-70 antibody (anti-DNA topoisomerase-I antibody) and anti-RNA polymerase III. Limited scleroderma—limited skin involvement confined to fingers and face. Also with CREST syndrome: Calcinosis cutis C , anti-Centromere antibody, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia. More benign clinical course.


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First_Aid_Step1. ` mUsCUlosKElEtal, sKin,and ConnECtiVEtissUE—dERmatology Skin layers Skin has 3 layers: epidermis, dermis, subcutaneous fat (hypodermis, subcutis). Epidermal layers: Come, Let’s Get Sun Burned. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 474 Tight junctions (zonula occludens) A –prevents paracellular movement of solutes; composed of claudins and occludins. Adherens junction (belt desmosome, zonula adherens) B –forms “belt” connecting actin cytoskeletons of adjacent cells with CADherins (Ca2+-dependent adhesion proteins). Loss of E-cadherin promotes metastasis. Desmosome (spot desmosome, macula adherens) C –structural support via intermediate filament interactions. Autoantibodies to desmoglein 1 and/or 3 • pemphigus vulgaris. D –channel proteins called connexons permit electrical and chemical communication between cells.


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First_Aid_Step1. D –channel proteins called connexons permit electrical and chemical communication between cells. E –connects keratin in basal cells to underlying basement membrane. Autoantibodies • bullous pemphigoid. (Hemidesmosomes are down “bullow.”) Integrins–membrane proteins that maintain integrity of basolateral membrane by binding to collagen, laminin, and fibronectin in basement membrane. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 475 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 476 Seborrheic dermatitis Erythematous, well-demarcated plaques A with greasy yellow scales in areas rich in sebaceous glands, such as scalp, face, and periocular region. Common in both infants (cradle cap) and adults, associated with Parkinson disease. Sebaceous glands are not inflamed, but play a role in disease development. Possibly associated with Malassezia spp. Treatment: topical antifungals and corticosteroids.


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First_Aid_Step1. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 477 Acne Multifactorial etiology—• sebum/androgen production, abnormal keratinocyte desquamation, Cutibacterium acnes colonization of the pilosebaceous unit (comedones), and inflammation (papules/pustules A , nodules, cysts). Treatment: retinoids, benzoyl peroxide, and antibiotics. Pseudofolliculitis Foreign body inflammatory facial skin disorder characterized by firm, hyperpigmented papules and barbae pustules that are painful and pruritic. Located on cheeks, jawline, and neck. Commonly occurs as a result of shaving (“razor bumps”), primarily affects African-American males.


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First_Aid_Step1. Psoriasis Papules and plaques with silvery scaling H , especially on knees and elbows. Acanthosis with parakeratotic scaling (nuclei still in stratum corneum), Munro microabscesses.  stratum spinosum,  stratum granulosum. Auspitz sign ( I )—pinpoint bleeding spots from exposure of dermal papillae when scales are scraped off. Associated with nail pitting and psoriatic arthritis. Rosacea Inflammatory facial skin disorder characterized by erythematous papules and pustules J , but no comedones. May be associated with facial flushing in response to external stimuli (eg, alcohol, heat). Phymatous rosacea can cause rhinophyma (bulbous deformation of nose).


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First_Aid_Step1. Seborrheic keratosis Flat, greasy, pigmented squamous epithelial proliferation of immature keratinocytes with keratin-filled cysts (horn cysts) K . Looks “stuck on.” Lesions occur on head, trunk, and extremities. Common benign neoplasm of older persons. Leser-Trélat sign L —rapid onset of multiple seborrheic keratoses, indicates possible malignancy (eg, GI adenocarcinoma). Verrucae Warts; caused by low-risk HPV strains. Soft, tan-colored, cauliflower-like papules M. Epidermal hyperplasia, hyperkeratosis, koilocytosis. Condyloma acuminatum on anus or genitals N . Urticaria Hives. Pruritic wheals that form after mast cell degranulation O . Characterized by superficial dermal edema and lymphatic channel dilation. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 478 Vascular tumors of skin Glomus tumor Benign, painful, red-blue tumor, commonly under fingernails C . Arises from modified smooth muscle cells of the thermoregulatory glomus body.


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First_Aid_Step1. Vascular tumors of skin Glomus tumor Benign, painful, red-blue tumor, commonly under fingernails C . Arises from modified smooth muscle cells of the thermoregulatory glomus body. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 479 Cellulitis Acute, painful, spreading infection of deeper dermis and subcutaneous tissues. Usually from S pyogenes or S aureus. Often starts with a break in skin from trauma or another infection D . Varicella zoster virus Causes varicella (chickenpox) and zoster (shingles). Varicella presents with multiple crops of lesions in various stages from vesicles to crusts. Zoster is a reactivation of the virus in dermatomal distribution (unless it is disseminated). Hairy leukoplakia Irregular, white, painless plaques on lateral tongue that cannot be scraped off J . EBV mediated. Occurs in HIV-positive patients, organ transplant recipients. Contrast with thrush (scrapable) and leukoplakia (precancerous).


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First_Aid_Step1. J . EBV mediated. Occurs in HIV-positive patients, organ transplant recipients. Contrast with thrush (scrapable) and leukoplakia (precancerous). MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 480 pathophysiology Potentially fatal. Most commonly seen in older adults. Type II hypersensitivity reaction. IgG antibodies against desmoglein-1 and/or desmoglein-3 (component of desmosomes, which connect keratinocytes in the stratum spinosum). Less severe than pemphigus vulgaris. Most commonly seen in older adults. Type II hypersensitivity reaction. IgG antibodies against hemidesmosomes (epidermal basement membrane; antibodies are “bullow” the epidermis). gRoss moRphology Flaccid intraepidermal bullae A caused by Tense blisters C containing eosinophils; oral acantholysis (separation of keratinocytes, “row mucosa spared. Nikolsky sign ⊝. of tombstones” on H&E stain); oral mucosa is involved. Nikolsky sign ⊕.


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First_Aid_Step1. immUnoFlUoREsCEnCE Reticular pattern around epidermal cells B . Linear pattern at epidermal-dermal junction D . MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 481 D . adverse drug reaction. Toxic epidermal necrolysis (TEN) EF is more severe form of SJS involving > 30% body surface area. 10–30% involvement denotes SJS-TEN. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 482 Acanthosis nigricans Epidermal hyperplasia causing symmetric, hyperpigmented thickening of skin, especially in axilla AB . Associated with insulin resistance (eg, diabetes, obesity, Cushing syndrome, PCOS), visceral malignancy (eg, gastric adenocarcinoma). Actinic keratosis Premalignant lesions caused by sun exposure. Small, rough, erythematous or brownish papules or CD . Risk of squamous cell carcinoma is proportional to degree of epithelial dysplasia. Rule of 9’s The extent of a burn injury can be estimated as a percentage of the body surface area. H .


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First_Aid_Step1. CD . Risk of squamous cell carcinoma is proportional to degree of epithelial dysplasia. Rule of 9’s The extent of a burn injury can be estimated as a percentage of the body surface area. H . MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 483 Entire head 9% Entire torso 18% Entire arm (L) 9% Entire arm (R) 9% Entire abdomen 18% Perineum 1% Total 100% Entire leg (L) 18% Entire leg (R) 18% 4.5 4.5 4.5 4.5 1 9 9 9 9 4.5 9 9 9 9 4.5 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` dERmatology SECTION III 484 Skin cancer Basal cell carcinoma more common above upper lip Squamous cell carcinoma more common below lower lip Sun exposure strongly predisposes to skin cancer.


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First_Aid_Step1. Skin cancer Basal cell carcinoma more common above upper lip Squamous cell carcinoma more common below lower lip Sun exposure strongly predisposes to skin cancer. Basal cell carcinoma Most common skin cancer. Found in sun-exposed areas of body (eg, face). Locally invasive, but rarely metastasizes. Waxy, pink, pearly nodules, commonly with telangiectasias, rolled borders A , central crusting or ulceration. BCCs also appear as nonhealing ulcers with infiltrating growth B or as a scaling plaque (superficial BCC) C . Basal cell tumors have “palisading” (aligned) nuclei D . Keratoacanthoma Seen in middle-aged and elderly individuals. Rapidly growing, resembles squamous cell carcinoma. Presents as dome-shaped nodule with keratin-filled center. Grows rapidly (4-6 weeks) and may spontaneously regress E .


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First_Aid_Step1. E . Melanoma Common tumor with significant risk of metastasis. S-100 tumor marker. Associated with dysplastic nevi; fair-skinned persons are at  risk. Depth of tumor (Breslow thickness) correlates with risk of metastasis. Look for the ABCDEs: Asymmetry, Border irregularity, Color variation, Diameter > 6 mm, and Evolution over time. At least 4 different types of melanoma, including superficial spreading F , nodular G , lentigo maligna H , and acral lentiginous (highest prevalence in African-Americans and Asians) I . Often driven by activating mutation in BRAF kinase. Primary treatment is excision with appropriately wide margins. Metastatic or unresectable melanoma in patients with BRAF V600E mutation may benefit from vemurafenib, a BRAF kinase inhibitor. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` phaRmaCology SECTION III 485 `mUsCUlosKElEtal, sKin, and ConnECtiVE tissUE—phaRmaCology vasodilation.


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First_Aid_Step1. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` phaRmaCology SECTION III 485 `mUsCUlosKElEtal, sKin, and ConnECtiVE tissUE—phaRmaCology vasodilation. DinoprostoneEpoprostenol CarboprostAlprostadil COX-2 ONLY Celecoxib NF-˜B I˜B COX-1, COX-2 ENDOPEROXIDE SYNTHESIS (cyclooxygenase)KetorolacNaproxenGlucocorticoids (corticosteroids) COX-2 COX-1 Cyclic endoperoxides ThromboxaneProstaglandinsProstacyclin •platelet aggregation •vascular tone •uterine tone •uterine tone •platelet aggregation •vascular tone PGI2 PGE1 TXA2PGF2˜PGE2 •vascular tone Aspirin (irreversible) Other NSAIDs (reversible) Diclofenac Ketorolac Ibuprofen Naproxen Indomethacin is a neutrophil chemotactic agent. inhibits platelet aggregation and promotes Neutrophils arrive “B4” others. Platelet-Gathering Inhibitor. mEChanism Reversibly inhibits cyclooxygenase, mostly in CNS. Inactivated peripherally.


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First_Aid_Step1. mEChanism Reversibly inhibits cyclooxygenase, mostly in CNS. Inactivated peripherally. CliniCal UsE Antipyretic, analgesic, but not anti-inflammatory. Used instead of aspirin to avoid Reye syndrome in children with viral infection. adVERsE EFFECts Overdose produces hepatic necrosis; acetaminophen metabolite (NAPQI) depletes glutathione and forms toxic tissue byproducts in liver. N-acetylcysteine is antidote—regenerates glutathione. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` phaRmaCology SECTION III 486 mEChanism NSAID that irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) by covalent acetylation  synthesis of TXA2 and prostaglandins.  bleeding time. No effect on PT, PTT. Effect lasts until new platelets are produced. CliniCal UsE Low dose (< 300 mg/day):  platelet aggregation. Intermediate dose (300–2400 mg/day): antipyretic and analgesic. High dose (2400–4000 mg/day): anti-inflammatory.


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First_Aid_Step1. CliniCal UsE Low dose (< 300 mg/day):  platelet aggregation. Intermediate dose (300–2400 mg/day): antipyretic and analgesic. High dose (2400–4000 mg/day): anti-inflammatory. adVERsE EFFECts Gastric ulceration, tinnitus (CN VIII), allergic reactions (especially in patients with asthma or nasal polyps). Chronic use can lead to acute kidney injury, interstitial nephritis, GI bleeding. Risk of Reye syndrome in children treated with aspirin for viral infection. Toxic doses cause respiratory alkalosis early, but transitions to mixed metabolic acidosis-respiratory alkalosis. Treatment of overdose: NaHCO3. mEChanism Reversibly and selectively inhibits the cyclooxygenase (COX) isoform 2 (“Selecoxib”), which is found in inflammatory cells and vascular endothelium and mediates inflammation and pain; spares COX-1, which helps maintain gastric mucosa. Thus, does not have the corrosive effects of other NSAIDs on the GI lining. Spares platelet function as TXA2 production is dependent on COX-1.


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First_Aid_Step1. CliniCal UsE Rheumatoid arthritis, osteoarthritis. adVERsE EFFECts  risk of thrombosis, sulfa allergy. Nonsteroidal Ibuprofen, naproxen, indomethacin, ketorolac, diclofenac, meloxicam, piroxicam. anti-inflammatory drugs mEChanism Reversibly inhibit cyclooxygenase (both COX-1 and COX-2). Block prostaglandin synthesis. CliniCal UsE Antipyretic, analgesic, anti-inflammatory. Indomethacin is used to close a PDA. adVERsE EFFECts Interstitial nephritis, gastric ulcer (prostaglandins protect gastric mucosa), renal ischemia (prostaglandins vasodilate afferent arteriole), aplastic anemia. mEChanism Reversibly inhibits dihydroorotate dehydrogenase, preventing pyrimidine synthesis. Suppresses T-cell proliferation. CliniCal UsE Rheumatoid arthritis, psoriatic arthritis. adVERsE EFFECts Diarrhea, hypertension, hepatotoxicity, teratogenicity. Bisphosphonates Alendronate, ibandronate, risedronate, zoledronate.


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First_Aid_Step1. CliniCal UsE Rheumatoid arthritis, psoriatic arthritis. adVERsE EFFECts Diarrhea, hypertension, hepatotoxicity, teratogenicity. Bisphosphonates Alendronate, ibandronate, risedronate, zoledronate. mEChanism Pyrophosphate analogs; bind hydroxyapatite in bone, inhibiting osteoclast activity. CliniCal UsE Osteoporosis, hypercalcemia, Paget disease of bone, metastatic bone disease, osteogenesis imperfecta. adVERsE EFFECts Esophagitis (if taken orally, patients are advised to take with water and remain upright for 30 minutes), osteonecrosis of jaw, atypical femoral stress fractures. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` phaRmaCology SECTION III 487 mEChanism Recombinant PTH analog.  osteoblastic activity when administered in pulsatile fashion. CliniCal UsE Osteoporosis. Causes  bone growth compared to antiresorptive therapies (eg, bisphosphonates).


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First_Aid_Step1. CliniCal UsE Osteoporosis. Causes  bone growth compared to antiresorptive therapies (eg, bisphosphonates). adVERsE EFFECts  risk of osteosarcoma (avoid use in patients with Paget disease of the bone or unexplained elevation of alkaline phosphatase). Avoid in patients who have had prior cancers or radiation therapy. Transient hypercalcemia. Allopurinol Competitive inhibitor of xanthine oxidase  conversion of hypoxanthine and xanthine to urate. Also used in lymphoma and leukemia to prevent tumor lysis–associated urate nephropathy.  concentrations of xanthine oxidase active metabolites, azathioprine, and 6-MP. Pegloticase Recombinant uricase catalyzing uric acid to allantoin (a more water-soluble product). Probenecid Inhibits reabsorption of uric acid in proximal Prevent APainful Flare. convoluted tubule (also inhibits secretion of penicillin). Can precipitate uric acid calculi. Allopurinol, Febuxostat Febuxostat Inhibits xanthine oxidase.


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First_Aid_Step1. Allopurinol, Febuxostat Febuxostat Inhibits xanthine oxidase. NSAIDs Any NSAID. Use salicylates with caution (may decrease uric acid excretion, particularly at Diuretics,low doses). low-dose salicylates Glucocorticoids Oral, intra-articular, or parenteral. Colchicine Binds and stabilizes tubulin to inhibit microtubule polymerization, impairing neutrophil chemotaxis and degranulation. Acute and prophylactic value. GI, neuromyopathic side effects. Urine Probenecid, high-dose salicylates Tubular reabsorption Etanercept Fusion protein (decoy receptor for TNF-α + IgG1 Fc), produced by recombinant DNA. Etanercept intercepts TNF. Infliximab, adalimumab, certolizumab, golimumab Anti-TNF-α monoclonal antibody. Rheumatoid arthritis, psoriasis, ankylosing spondylitis Inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriasis Predisposition to infection, including reactivation of latent TB, since TNF is important in granuloma formation and stabilization.


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First_Aid_Step1. Can also lead to drug-induced lupus. MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ` phaRmaCology SECTION II 488 “We are all now connected by the Internet, like neurons in a giant brain.” “Anything’s possible if you’ve got enough nerve.” —J.K. Rowling, Harry Potter and the Order of the Phoenix “I like nonsense; it wakes up the brain cells.” —Dr. Seuss “I believe in an open mind, but not so open that your brains fall out.” “The chief function of the body is to carry the brain around.” “Exactly how [the brain] operates remains one of the biggest unsolved mysteries, and it seems the more we probe its secrets, the more surprises we find.”


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First_Aid_Step1. Understand the difference between upper motor neuron (UMN) and lower motor neuron (LMN) findings and the underlying anatomy. Know the major motor, sensory, cerebellar and visual pathways and their respective locations in the CNS. Connect key neurological associations with certain pathologies (eg, cerebellar lesions, stroke manifestations, Brown-Séquard syndrome). Recognize common findings on MRI/ CT (eg, ischemic and hemorrhagic stroke) and on neuropathology (eg, neurofibrillary tangles and Lewy bodies). High-yield medications include those used to treat epilepsy, Parkinson disease, migraine, and pain (eg, opioids). Neural development Notochord induces overlying ectoderm to differentiate into neuroectoderm and form neural plate. Neural plate Neural plate gives rise to neural tube and neural crest cells. Day 18 Notochord becomes nucleus pulposus of intervertebral disc in adults. Notochord Neural fold


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First_Aid_Step1. Neural plate Neural plate gives rise to neural tube and neural crest cells. Day 18 Notochord becomes nucleus pulposus of intervertebral disc in adults. Notochord Neural fold Alar plate (dorsal): sensory; regulated by TGF-β (including bone morphogenetic protein [BMP]) Same orientation as spinal cord Basal plate (ventral): motor; regulated by Regional specification Telencephalon is the 1st part. Diencephalon is the 2nd part. The rest are arranged alphabetically: of developing brain mesencephalon, metencephalon, myelencephalon. Neural tube defects Neuropores fail to fuse (4th week)  persistent connection between amniotic cavity and spinal canal. Associated with maternal diabetes and folate deficiency. α-fetoprotein (AFP) in amniotic fluid and maternal serum (except spina bifida occulta = normal AFP). acetylcholinesterase (AChE) in amniotic fluid is a helpful confirmatory test.


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First_Aid_Step1. Spina bifida occulta Failure of caudal neuropore to close, but no herniation. Usually seen at lower vertebral levels. Dura is intact. Associated with tuft of hair or skin dimple at level of bony defect. Meningocele Meninges (but no neural tissue) herniate through bony defect. Myelomeningocele Meninges and neural tissue (eg, cauda equina) herniate through bony defect. Myeloschisis Also called rachischisis. Exposed, unfused neural tissue without skin/meningeal covering. Anencephaly Failure of rostral neuropore to close  no forebrain, open calvarium. Clinical findings: polyhydramnios (no swallowing center in brain). +/− Tuft of hair Skin defect/thinning Skin thin or absent Skin


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First_Aid_Step1. +/− Tuft of hair Skin defect/thinning Skin thin or absent Skin Holoprosencephaly Failure of the embryonic forebrain (prosencephalon) to separate into 2 cerebral hemispheres; usually occurs during weeks 5–6. May be related to mutations in sonic hedgehog signaling pathway. Associated with other midline defects including cleft lip/palate (moderate form) and ★ cyclopia (severe form). risk for pituitary dysfunction (eg, diabetes insipidus). Can be seen with Patau syndrome (trisomy 13). Monoventricle MRI reveals monoventricle A and fusion of basal ganglia (star in A ). Lissencephaly Failure of neuronal migration resulting in a “smooth brain” that lacks sulci and gyri. May be associated with microcephaly, ventriculomegaly. Chiari I malformation Ectopia of cerebellar tonsils inferior to foramen magnum (1 structure) A . Congenital, usually asymptomatic in childhood, manifests in adulthood with headaches and cerebellar symptoms. Associated with spinal cavitations (eg, syringomyelia).


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First_Aid_Step1. Chiari II malformation Herniation of cerebellar vermis and tonsils (2 structures) through foramen magnum with aqueductal stenosis  noncommunicating hydrocephalus. Usually associated with lumbosacral myelomeningocele (may present as paralysis/sensory loss at and below the level of the lesion). More severe than Chiari I, usually presents early in life. Dandy-Walker Agenesis of cerebellar vermis  cystic enlargement of 4th ventricle (arrow in B ) that fills the malformation enlarged posterior fossa. Associated with noncommunicating hydrocephalus, spina bifida.


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First_Aid_Step1. Syringomyelia Cystic cavity (syrinx) within central canal of spinal cord (yellow arrows in A ). Fibers crossing in anterior white commissure (spinothalamic tract) are typically damaged first. Results in a “capelike,” bilateral, symmetrical loss of pain and temperature sensation in upper extremities (fine touch sensation is preserved). Associated with Chiari I malformation (red arrow in A shows low-lying cerebellar tonsils), scoliosis and other congenital malformations; acquired causes include trauma and tumors. Most common location cervical > thoracic >> lumbar. Syrinx = tube, as in “syringe.”


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First_Aid_Step1. Posterior fossa malformations A˜erent Lateral spinothalamic tract (pain, temperature) Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Posterior fossa malformations Expanding syrinx (can a˜ect multiple dermatomes) Anterior white commissure compressed by syrinx Dorsal root Posterior fossa malformations Posterior fossa malformations ganglion Loss of pain and temperature sensation at a˜ected dermatomes (C5-T4 shown here) 1st and 2nd pharyngeal arches form anterior 2/3 (thus sensation via CN V3, taste via CN VII).


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First_Aid_Step1. Loss of pain and temperature sensation at a˜ected dermatomes (C5-T4 shown here) 1st and 2nd pharyngeal arches form anterior 2/3 (thus sensation via CN V3, taste via CN VII). 3rd and 4th pharyngeal arches form posterior 1/3(thus sensation and taste mainly via CN IX, extreme posterior via CN X). Motor innervation is via CN XII to hyoglossus (retracts and depresses tongue), genioglossus (protrudes tongue), and styloglossus (draws sides of tongue upward to create a trough for swallowing). Motor innervation is via CN X to palatoglossus (elevates posterior tongue during swallowing). Taste—CN VII, IX, X (solitary nucleus). Pain—CN V3, IX, X. Motor—CN X, XII. The Genie comes out of the lamp in style.


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First_Aid_Step1. Taste—CN VII, IX, X (solitary nucleus). Pain—CN V3, IX, X. Motor—CN X, XII. The Genie comes out of the lamp in style. Neurons Signal-transmitting cells of the nervous system. Permanent cells—do not divide in adulthood. Signal-relaying cells with dendrites (receive input), cell bodies, and axons (send output). Cell bodies and dendrites can be seen on Nissl staining (stains RER). RER is not present in the axon. Neuron markers: neurofilament protein, synaptophysin. Astrocytes Most common glial cell type in CNS. Physical Derived from neuroectoderm. support, repair, extracellular K+ buffer, removal Astrocyte marker: GFAP. of excess neurotransmitter, component of blood-brain barrier, glycogen fuel reserve buffer. Reactive gliosis in response to neural injury.


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First_Aid_Step1. of excess neurotransmitter, component of blood-brain barrier, glycogen fuel reserve buffer. Reactive gliosis in response to neural injury. Ependymal cells Ciliated simple columnar glial cells line the ventricles and central canal of spinal cord. Apical surfaces are covered in cilia (which circulate CSF) and microvilli (which help with CSF absorption). Specialized ependymal cells (choroid plexus) produce CSF. Myelin  conduction velocity of signals transmitted down axons  saltatory conduction of action potential at the nodes of Ranvier, where there are high concentrations of Na+ channels. In CNS (including CN II), myelin is synthesized by oligodendrocytes; in PNS (including CN III-XII), myelin is synthesized by Schwann cells. Wraps and insulates axons (arrow in A ):  space constant and  conduction velocity. COPS: CNS = Oligodendrocytes, PNS = Schwann cells.


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First_Aid_Step1. Wraps and insulates axons (arrow in A ):  space constant and  conduction velocity. COPS: CNS = Oligodendrocytes, PNS = Schwann cells. Schwann cells Promote axonal regeneration. Derived from Each “Schwone” cell myelinates only 1 PNS neural crest. axon. Injured in Guillain-Barré syndrome. Oligodendrocytes Myelinate axons of neurons in CNS. Each Derived from neuroectoderm. oligodendrocyte can myelinate many axons “Fried egg” appearance histologically. (∼ 30). Predominant type of glial cell in white Injured in multiple sclerosis, progressive matter. multifocal leukoencephalopathy (PML), leukodystrophies. Pacinian corpuscles Large, myelinated fibers; adapt Deep skin layers, ligaments, High-frequency vibration, quickly joints pressure Merkel discs Large, myelinated fibers; adapt Finger tips, superficial skin Pressure, deep static touch (eg, slowly shapes, edges), position sense


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First_Aid_Step1. Merkel discs Large, myelinated fibers; adapt Finger tips, superficial skin Pressure, deep static touch (eg, slowly shapes, edges), position sense Endoneurium—thin, supportive connective Endo = inner tissue that ensheathes and supports individual Peri = around myelinated nerve fibers. Epi = outer Perineurium (blood-nerve Permeability barrier)—surrounds a fascicle of nerve fibers. Epineurium—dense connective tissue that surrounds entire nerve (fascicles and blood vessels). Reaction of neuronal cell body to axonal injury. Changes reflect  protein synthesis in effort to repair the damaged axon. Characterized by: Displacement of the nucleus to the periphery Dispersion of Nissl substance throughout cytoplasm Wallerian degeneration—disintegration of the axon and myelin sheath distal to site of axonal injury with macrophages removing debris.


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First_Aid_Step1. Dispersion of Nissl substance throughout cytoplasm Wallerian degeneration—disintegration of the axon and myelin sheath distal to site of axonal injury with macrophages removing debris. Proximal to the injury, the axon retracts, and the cell body sprouts new protrusions that grow toward other neurons for potential reinnervation. Serves as a preparation for axonal regeneration and functional recovery. Neurotransmitter changes with disease Acetylcholine Basal nucleus of Meynert Three membranes that surround and protect the CSF flows in the subarachnoid space, located brain and spinal cord: between arachnoid and pia mater. Dura mater—thick outer layer closest to Epidural space—potential space between skull. Derived from mesoderm. the dura mater and skull/vertebral column Arachnoid mater—middle layer, contains containing fat and blood vessels. Site of blood web-like connections. Derived from neural collection associated with middle meningeal crest. artery injury.


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First_Aid_Step1. Arachnoid mater—middle layer, contains containing fat and blood vessels. Site of blood web-like connections. Derived from neural collection associated with middle meningeal crest. artery injury. Pia mater—thin, fibrous inner layer that firmly adheres to brain and spinal cord. Derived from neural crest. Prevents circulating blood substances Circumventricular organs with fenestrated (eg, bacteria, drugs) from reaching the CSF/ capillaries and no blood-brain barrier CNS. Formed by 3 structures: allow molecules in blood to affect brain Tight junctions between nonfenestrated function (eg, area postrema—vomiting after capillary endothelial cells chemotherapy; OVLT [organum vasculosum


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First_Aid_Step1. Tight junctions between nonfenestrated function (eg, area postrema—vomiting after capillary endothelial cells chemotherapy; OVLT [organum vasculosum Astrocyte foot processes neurosecretory products to enter circulation Glucose and amino acids cross slowly by carrier-(eg, neurohypophysis—ADH release). mediated transport mechanisms. Infarction and/or neoplasm destroys endothelial Nonpolar/lipid-soluble substances cross rapidly cell tight junctions • vasogenic edema. via diffusion. Hyperosmolar agents (eg, mannitol) can disrupt the BBB • permeability of medications. Coordinated by nucleus tractus solitarius (NTS) in the medulla, which receives information from the chemoreceptor trigger zone (CTZ, located within area postrema in 4th ventricle), GI tract (via vagus nerve), vestibular system, and CNS. CTZ and adjacent vomiting center nuclei receive input from 5 major receptors: muscarinic (M1), dopamine (D2), histamine (H1), serotonin (5-HT3), and neurokinin (NK-1) receptors.


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First_Aid_Step1. CTZ and adjacent vomiting center nuclei receive input from 5 major receptors: muscarinic (M1), dopamine (D2), histamine (H1), serotonin (5-HT3), and neurokinin (NK-1) receptors. 5-HT3, D2, and NK-1 antagonists used to treat chemotherapy-induced vomiting. H1 and M1 antagonists treat motion sickness; H1 antagonists treat hyperemesis gravidarum. Sleep physiology Sleep cycle is regulated by the circadian rhythm, which is driven by suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian rhythm controls nocturnal release of ACTH, prolactin, melatonin, norepinephrine: SCN • norepinephrine release  pineal gland • melatonin. SCN is regulated by environment (eg, light). Two stages: rapid-eye movement (REM) and non-REM. Alcohol, benzodiazepines, and barbiturates are associated with  REM sleep and N3 sleep; norepinephrine also  REM sleep. Benzodiazepines are useful for night terrors and sleepwalking by  N3 and REM sleep.


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First_Aid_Step1. Thalamus Major relay for all ascending sensory information except olfaction. Limbic system Collection of neural structures involved in The famous 5 F’s. emotion, long-term memory, olfaction, behavior modulation, ANS function. Consists of hippocampus (red arrows in A ), amygdalae, mammillary bodies, anterior thalamic nuclei, cingulate gyrus (yellow arrows in A ), entorhinal cortex. Responsible for Feeding, Fleeing, Fighting, Feeling, and Sex. A . Input: inferior cerebellar peduncle from spinal cord Output: The only output of cerebellar cortex = Purkinje cells (always inhibitory)  deep nuclei of cerebellum  contralateral cortex via superior cerebellar peduncle Deep nuclei (lateral  medial)—Dentate, Emboliform, Globose, Fastigial Lateral lesions—affect voluntary movement of extremities (lateral structures); when injured, propensity to fall toward injured (ipsilateral) side.