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Giant Cell (Temporal) Arteritis: Pathogenesis and investigations

Giant Cell (Temporal) Arteritis: Clinical findings and Complications

Hypokalemia: Clinical Findings

Yu, Yan - Hypokalemia clinical findings - FINAL.pptx Production of Na+/ K+ transporters in cell membranes ? over timeHypokalemia: Clinical FindingsAuthor: Yan YuReviewers:David WaldnerSean SpenceAndrew Wade** MD at time of publicationLegend:Published May 21, 2013 on www.thecalgaryguide.comMechanismPathophysiologySign/Symptom/Lab FindingComplicationsPalpitationsExcitable cells (muscle cells, neurons) depolarize less readilyK+ efflux out of all cells in the body, down its concentration gradientCardiac myocytes experience electrical conduction defects? muscle impulse conductionECG shows characteristic changes:? skeletal muscle contractile abilityRMP now more negative; myocytes take longer to repolarize to RMP(0.5 of R-R interval)?Flatter T-Waves ?Inverted T-waves (with more severe hypokalemia)Purkinje fibers repolarize after the rest of the myocardium has done soU-waves (upward ECG deviations after the T-wave)Cells become hyperpolarized: Inside of cells are more negative relative to outside, ? Resting Membrane Potential (RMP)In the Kidney:Generalized Muscle weaknessK+ diffuse out of Proximal Convoluted Tubule & Collecting Duct cells ? cells retain acidic H+ inside (maintains electrical neutrality)? pH within PCT cells ? glutaminase activity, ? glutamine breakdown, producing HCO3-, which enters the blood? blood pH, [HCO3-], & pCO2 (respiratory compensation)Low Plasma [K+]Abnormally long diastole means that ventricles are overfilled. Contraction takes greater force; sensed by patientsDyspnea, fatigue, dizziness, syncope? cardiac output ? perfusion of tissues, i.e. lungs & brainCardiac arrhythmias: PACs, PVCs, Sinus Bradycardia, paroxysmal atrial/junctional tachycardia, VT (i.e. Torsades de pointes), V-Fib? smooth muscle contractile abilityBowel ileus (bloating, anorexia, nausea/vomiting, absent bowel sounds)? pH in collecting duct intercalated cells ? H+ secretion into the tubuleMetabolic alkalosisParalysis, muscle cramps (in severe hypokalemia)Respiratory muscle failure (? tidal volume, ? pCO2, ? pO2), may even cause death!? depolarizations ? adenyl cyclase activity ? ? sensitivity of collecting duct cells to ADH? ability of nephron to concentrate urineNephrogenic Diabetes Insipidus? urine osmolality, Hypernatremia, Polyuria, Polydipsia? # of aquaporins in the collecting duct membrane"Insulin Resistance": ? ability to import K+ from the blood in response to insulinIn skeletal muscle: 117 kB / 307 word" title="Yu, Yan - Hypokalemia clinical findings - FINAL.pptx Production of Na+/ K+ transporters in cell membranes ? over timeHypokalemia: Clinical FindingsAuthor: Yan YuReviewers:David WaldnerSean SpenceAndrew Wade** MD at time of publicationLegend:Published May 21, 2013 on www.thecalgaryguide.comMechanismPathophysiologySign/Symptom/Lab FindingComplicationsPalpitationsExcitable cells (muscle cells, neurons) depolarize less readilyK+ efflux out of all cells in the body, down its concentration gradientCardiac myocytes experience electrical conduction defects? muscle impulse conductionECG shows characteristic changes:? skeletal muscle contractile abilityRMP now more negative; myocytes take longer to repolarize to RMP("stretches out" the T-wave)! Long QT interval (>0.5 of R-R interval)?Flatter T-Waves ?Inverted T-waves (with more severe hypokalemia)Purkinje fibers repolarize after the rest of the myocardium has done soU-waves (upward ECG deviations after the T-wave)Cells become hyperpolarized: Inside of cells are more negative relative to outside, ? Resting Membrane Potential (RMP)In the Kidney:Generalized Muscle weaknessK+ diffuse out of Proximal Convoluted Tubule & Collecting Duct cells ? cells retain acidic H+ inside (maintains electrical neutrality)? pH within PCT cells ? glutaminase activity, ? glutamine breakdown, producing HCO3-, which enters the blood? blood pH, [HCO3-], & pCO2 (respiratory compensation)Low Plasma [K+]Abnormally long diastole means that ventricles are overfilled. Contraction takes greater force; sensed by patientsDyspnea, fatigue, dizziness, syncope? cardiac output ? perfusion of tissues, i.e. lungs & brainCardiac arrhythmias: PACs, PVCs, Sinus Bradycardia, paroxysmal atrial/junctional tachycardia, VT (i.e. Torsades de pointes), V-Fib? smooth muscle contractile abilityBowel ileus (bloating, anorexia, nausea/vomiting, absent bowel sounds)? pH in collecting duct intercalated cells ? H+ secretion into the tubuleMetabolic alkalosisParalysis, muscle cramps (in severe hypokalemia)Respiratory muscle failure (? tidal volume, ? pCO2, ? pO2), may even cause death!? depolarizations ? adenyl cyclase activity ? ? sensitivity of collecting duct cells to ADH? ability of nephron to concentrate urineNephrogenic Diabetes Insipidus? urine osmolality, Hypernatremia, Polyuria, Polydipsia? # of aquaporins in the collecting duct membrane"Insulin Resistance": ? ability to import K+ from the blood in response to insulinIn skeletal muscle: 117 kB / 307 word" />

Giant Cell (Temporal) Arteritis - Pathogenesis and investigations

Giant Cell (Temporal) Arteritis - Clinical findings and Complications

Hyperosmolar Hyperglycemic State

Hyperosmolar Hyperglycemic State (HHS) Note: HHS is only seen in Type II DM patients! Note: In patients with either DKA or HHS, always look for an underlying cause (i.e. an infection) Author: Yan Yu Reviewers: Peter Vetere Gill Goobie Hanan Bassyouni* * MD at time of publication Alters total body water & ion osmosis Inadequate insulin production, insulin resistance, non- adherence to insulin Tx Relative Insulin deficit Stresses that ↑ Insulin demand: infections, pneumonia, MI, pancreatitis, etc) Hyperglycemia (Very high blood [glucose], higher than in DKA) When blood [glucose] > 12mmol/L, glucose filtration > reabsorption, ↑ urine [glucose] Glucosuria Glucose in filtrate promotes osmotic diuresis: large- volume urine output Polyuria Dehydration (↓ JVP, orthostasis: postural hypotension/ postural tachycardia, ↑ resting HR) Some insulin still present, but not enoughsome glucose is utilized by muscle/fat cells, some remain in the blood Cells not “starved”, but still need more energy ↑ release of Catabolic hormones: Glucagon, Epinephrine, Cortisol, GH Body tries to ↑ blood [glucose], to hopefully ↑ cell glucose absorption Hypothalamic cells sense low intra-cellular glucose, triggering feelings of hunger Polyphagia Note: the presence of some insulin directly inhibits lipolysis; thus, in HHS there is no ketone body production, and no subsequent metabolic acidosis and ketouria (unlike in DKA). If ketones are detected in an HHS patient it’s likely secondary to starvation or other mechanisms. ↓ ECF volume, ↑ ECF osmolarity (i.e. hypernatremia) ↑ Gluconeogenesis ↑ Glycogenolysis (in liver) ↓ Protein synthesis, ↑ proteolysis (in muscle) ↑ Gluconeogenic substrates for liver If the patient doesn’t drink enough water to replenish lost blood volume If pt is alert and Electrolyte imbalance water is accessible Water osmotically leaves neurons, shrinking them Neural damage: delirium, lethargy, seizure, stupor, coma ↓ renal perfusion, ↓ GFR Renal Failure (pre-renal cause; see relevant slides) Polydipsia Note: in HHS, body K+ is lost via osmotic diuresis. But diffusion of K+ out of cells may cause serum [K+] to be falsely normal/elevated. To prevent hypokalemia, give IV KCl along with IV insulin as soon as serum K+ <5.0mmol/L. But ensure patient has good renal function/urine output first, to avoid iatrogenic hyperkalemia! Note: Electrolyte imbalances (i.e. hyperkalemia, hypernatremia) are worsened by the acute renal failure commonly coexisting with DKA/HHS Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 3, 2016 on www.thecalgaryguide.com

central-retinal-artery-occlusion-pathogenesis-and-clinical-findings

Central Retinal Artery Occlusion: Pathogenesis and clinical findings Inflammatory Disease: Cardiogenic Embolism: Hypercoagulable state: Hematologic Disease: (i.e. GCA, SLE, GPA) (i.e. Valvular, arrhythmias, congenital defects) (i.e. OCP, Protein C&S deficiency, ATIII deficiency) (i.e. leukemia/lymphoma, sickle cell, polycythemia) Endothelial cell damage Abnormal blood flow 1` coagulation and/or 1 blood viscosity and creates hypercoagulable state causing localized stasis 4, anti-coagulation inflammation Abbreviations: • GCA — Giant Cell Arteritis • SLE — Systemic Lupus Erythematosus • GPA — granulomatosis with polyangitis • OCP — Oral contraceptive pill • ATIII — Anti-thrombin Ill Thrombus formation Blockage of central retinal artery Central Retinal Artery Occlusion (CRAO) Authors: Graeme Prosperi-Porta Reviewers: Stephanie Cote Usama Malik Johnathan Wong* * MD at time of publication Carotid Artery Atherosclerosis Atherosclerotic plaque dislodges from carotid artery The retina becomes pale 4, perfusion of retinal Slow retinal artery blood Acute retinal edema Ganglion cells and axons from NI, perfusion arterioles due to upstream flow allows for caused by ischemia results death due to ischemia CRAO segmentation of the blood column in a blurred appearance of the retina results in disc pallor seen months after CRAO The choroidal vessels supplying the macula via the posterior ciliary artery become more prominent within a background of retinal pallor

infectious-esophagitis-pathogenesis-and-clinical-findings

Infectious Esophagitis: Pathogenesis and clinical findings HIV/AIDS Radiation therapy Chemotherapy Organ Transplant Antibiotics I/Esophageal motility Tir CD4+ T cells 4,Monocyte and Corticosteroid and granulocyte precursors anti-TNF therapy • • Immunosuppression Note: Bacterial causes of infectious esophagitis are difficult to isolate as they are often polymicrobial in nature and derived from normal oral flora. Cytomegalovirus Infection of endothelial cells and fibroblasts I, Protective flora 4, Pathogen clearance Authors: David Deng Reviewers: Peter Bishay Vadim lablokov Kirles Bishay* MD at time of publication Mechanical stricture Inflammation Ulceration ,..,4 Dysphagia Infectious Viral Bacterial infection infection esophagitis • Fungal infection Odynophagia (i.e. Candida) Herpes Simplex Infection of squamous cells and macrophages Colonization facilitated by use of antacid therapy Nuclear Large Superficial Squamous Macrophage inclusion bodies esophageal ulceration ulcers cell inclusion bodies aggregation Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Spores and pseudohyphae seen on biopsy • Invas.on of underlying blood vessels • White plaques over erythematous base '1' neutrophils due to inflammatory response

non-depolarizing-neuromuscular-blocks-ndnmbs

Authors: Sunny Fong Reviewers: Joseph Tropiano Billy Sun Melinda Davis, MD Non-Depolarizing Neuromuscular Blockers (NDNMBs) Eg. pancuronium, rocuronium, atracurium, vecuronium Abbreviations NDNMBs — Non-Depolarizing Neuromuscular Blockers ACh — Acetylcholine Quick Facts 1° Indication = Skeletal muscle paralysis to facilitate tracheal intubation, and used during indicated surgeries or mechanical ventilation Route of Administration = IV Metabolism & Excretion = Redistribution, hepatic clearance/renal excretion (extent varies greatly by drug). NOT degraded by acetylcholinesterase or pseudocholinesterase See Acetylcholinesterase Inhibitors slide for reversal of NDN M Bs Competitive antagonism at post-synaptic nicotinic receptors on muscles Competitive antagonism at the pre-synaptic nicotinic receptors on neurons Vagolytic effect (esp. pancuronium) Anaphylactic/ anaphylactoid reactions 4, Binding sites for ACh at post-synaptic nicotinic receptors on muscles 4, Binding sites for ACh at pre-synaptic nicotinic receptors on neurons Blockage of vagal muscarinic receptors in sinoatrial nodes IgE antibodies attach to ammonium ion components of NDNMBs Non-immunologic mast cell degranulation (esp. atracurium) 4, Muscle cell depolarization 4, Positive feedback for continued ACh ► release in response to high frequency stimulation Skeletal muscle paralysis Tetanic fade, Train-of-Four fade 4, —• Parasympathetic Tachycardia effects on heart Release of histamine from mast cells and basophils Bronchospasm Hypotension Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications I Published March 3, 2018 on www.thecalgaryguide.com 0€3,0 BY NC SA

non-depolarizing-neuromuscular-blocks-ndnmbs

Authors: Sunny Fong Reviewers: Joseph Tropiano Billy Sun Melinda Davis, MD Non-Depolarizing Neuromuscular Blockers (NDNMBs) Eg. pancuronium, rocuronium, atracurium, vecuronium Abbreviations NDNMBs — Non-Depolarizing Neuromuscular Blockers ACh — Acetylcholine Quick Facts 1° Indication = Skeletal muscle paralysis to facilitate tracheal intubation, and used during indicated surgeries or mechanical ventilation Route of Administration = IV Metabolism & Excretion = Redistribution, hepatic clearance/renal excretion (extent varies greatly by drug). NOT degraded by acetylcholinesterase or pseudocholinesterase See Acetylcholinesterase Inhibitors slide for reversal of NDN M Bs Competitive antagonism at post-synaptic nicotinic receptors on muscles Competitive antagonism at the pre-synaptic nicotinic receptors on neurons Vagolytic effect (esp. pancuronium) Anaphylactic/ anaphylactoid reactions 4, Binding sites for ACh at post-synaptic nicotinic receptors on muscles 4, Binding sites for ACh at pre-synaptic nicotinic receptors on neurons Blockage of vagal muscarinic receptors in sinoatrial nodes IgE antibodies attach to ammonium ion components of NDNMBs Non-immunologic mast cell degranulation (esp. atracurium) 4, Muscle cell depolarization 4, Positive feedback for continued ACh ► release in response to high frequency stimulation Skeletal muscle paralysis Tetanic fade, Train-of-Four fade 4, —• Parasympathetic Tachycardia effects on heart Release of histamine from mast cells and basophils Bronchospasm Hypotension Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications I Published March 3, 2018 on www.thecalgaryguide.com 0€3,0 BY NC SA

Celiac Disease: Complications

Celiac Disease: Complications Autoimmune response to dietary gluten in genetically predisposed individuals 4 Celiac Disease Note: most common presentation with minor symptoms and iron deficiency Modified gluten peptides activates HLA-DQ2 and DQ8 receptors on T cells Activation of B cells to produce anti-tTG2 autoantibodies 1 tanti-tTG2 Release of pro-inflammatory cytokines Villous Atrophy along duodenum and/or jejunum Loss of brush border Loss of enterokinase Defective mucosal barrier enzyme (failure to produce trypsin) Carbohydrate Protein Fat Secretory maldigestion maldigestion malabsorption diarrhea Legend: Fermentation by gut bacteria 1 Gas production Bloating Fat retained in stool Steatorrhea Abdominal pain Pathophysiology Mechanism Sign/Symptom/Lab Finding Growth Retardation Authors: Yoyo Chan Reviewers: Peter Bishay Usama Malik Sylvain Coderre* * MD at time of publication IgA response Autoimmune IgA deposits Lymphocyte response in sub-epidermal skin layer against enamel Dermatitis Herpetiformis (Chronic pruritic blisters) Nutritional deficiency Dental enamel hypoplasia Vitamin D and calcium deficiency Zinc, selenium Folate Iron Osteoporosis deficiency deficiency deficiency Anemia t Risk of miscarriages

Giant Cell Arteritis: Pathogenesis and Clinical Findings

Tonsillitis: Pathogenesis and clinical findings

Tonsillitis: Pathogenesis and clinical findings Group A Streptococci (GAS) infection1,2 Authors: Amanda Marchak Reviewers: Nicola Adderley Jim Rogers Danielle Nelson* * MD at time of publication Viral pathogen1 5-15 years3 Pathogen colonizes the nasopharynx Pathogen colonizes oropharynx4 ** ↑ vascular permeability Leakage of protein and fluid into surrounding tissue Inflammatory cytokine release Inadvertent cellular injury and hemolysis Tonsillar petechiae and erythema Systemic inflammatory cytokines disrupt hypothalamic regulation Fever White blood cell (WBC) activation WBCs infiltrate site of infection WBCs kill pathogen Accumulation and deposition of cellular debris and products of inflammatory response Tonsillar exudate Note: *When GAS is the pathogen, cytokine release and WBC activation is secondary to the release of exotoxins by GAS. Swelling and irritation ↑ lymph drainage to regional nodes Enlarged anterior cervical nodes Cough Note: It is extremely important to distinguish between viral tonsillitis and bacterial tonsillitis. Viral tonsillitis is usually self-limited while GAS tonsillitis can be associated with a number of complications. Notes: Tonsillar tissue Tonsillar edema Nasal tissue6 Nasal congestion Coryza Nasal discharge irritates back of throat Complications5: Peritonsillar abscess, neck abscess, otitis media, sinusitis, pneumonia, scarlet fever, bacteremia, osteomyelitis, meningitis, arthritis, erythema nodosum, hepatitis, acute poststreptococcal glomerulonephritis, acute rheumatic fever, and toxic shock syndrome 1. In general, viral tonsillitis is more common than GAS infection. However, in the absence of cough and coryza (acute, isolated tonsillitis), GAS is more common. 2. While GAS is the most bacterial cause of tonsillitis, it can be caused by other pathogens. 3. GAS tonsillitis is most common in patients of this age group although, rarely, it can occur in adults. 4. When GAS colonizes the oropharynx, the primary location of infection determines how it’s identified. • tonsils primarily effected = tonsillitis • pharynx (throat) primarily effected = pharyngitis (See slide on Group A Streptococci Pharyngitis: Pathogenesis and Clinical Findings) • both = pharyngotonsillitis 5. The listed complications are the result of exotoxins entering systemic circulation or the bacterial infection extending beyond the tonsils. 6. While viral tonsillitis tends to be associated with more upper respiratory tract symptoms, clinical signs and symptoms are NOT reliable for diagnosing GAS tonsillitis. Throat swab or rapid antigen detection test are the standards for diagnosis. Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 5, 2018 on www.thecalgaryguide.com

DiGeorge Syndrome: Pathogenesis and Clinical Findings

DiGeorge Syndrome: Pathogenesis and clinical findings Authors: Danielle Lynch Reviewers: Meghan Jackson, Sean Doherty Yan Yu*, Luis Murguia Favela* * MD at time of publication Note: *TBX1 is most strongly associated with the signs of DiGeorge syndrome, however 30-40 genes reside in the deleted region (e.g. DGCR8 & COMT), though their role is less well understood. Abbreviations: • PA-VSD – pulmonary atresia with ventricular septal defect • TBX1 – T-box Protein 1 • VSD – ventricular septal defect Heterozygous deletion at chromosomal region 22q11.2 The region’s main gene product, TBX1*, exhibits haploinsufficiency: even a heterozygote for this gene product, producing half the normal quantities of TBX1, is insufficient to produce a normal phenotype Abnormal pharyngeal arch development Hypoplastic / aplastic thymus ↓ T cells (lymphopenia) Craniofacial malformations (e.g. tracheomalacia, horizontal Eustachian tubes, cleft palate) Impaired ear and sinus drainage Abnormal conotruncus development Heart defects (e.g. interrupted aortic arch, tetralogy of Fallot, PA-VSD/VSD, truncus arteriosus) Hypoplastic parathyroid glands Hypocalcemia Seizures (usually neonatal onset) Memory Aid: CATCH-22 Cyanotic congenital heart disease Abnormal facies Thymic hypoplasia Cognitive impairment Hypoparathyroidism, hypocalcemia 22q11.2 deletion Abnormal T cell regulation and development Compromised cytotoxic T cells Susceptibility to intracellular pathogens Compromised helper T cells ↓ communication with memory B cells ↓immunoglobulins (progressive hypogammaglobulinemia) Susceptibility to extracellular pathogens Autoimmunity and Atopy Note: There is phenotypic variability in DiGeorge Syndrome. Other features include: thin upper lip, upslanted palpebral fissures, prominent nose, low-set ears, small mouth, hearing impairment, long tapered fingers, scoliosis, vertebral malformations, learning disabilities, and failure to thrive. Viral Infections Bacterial Infections Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 21, 2019 on www.thecalgaryguide.com

chronic-myeloid-leukemia

Chronic Myeloid Leukemia (CML): Pathogenesis and Clinical Presentation Translocation of a Chr 9 segment onto Chr 22, creating a Philadelphia chromosome (Chr 22) containing the BCR-ABL1 fusion gene Mutations from ionizing radiation Other genetic abnormalities Authors: Yan Yu Katie Lin Reviewers: Jennifer Au Crystal Liu Danielle Chang Lynn Savoie* *Indicates faculty member at time of initial publication These genetic abnormalities accumulate in the earliest cell of the blood cell differentiation sequence: the pluripotent hematopoietic stem cell Hematopoietic stem cell division in the bone marrow becomes unregulated 1. Chronic Stage (85% of clinical presentation): Hematopoietic stem cell division/differentiation in the bone marrow results in ↑ production of multiple blood cell lines (detectable on CBC, but patients are usually asymptomatic at this stage) Acquired ↑ genetic abnormalities 2. Accelerated Stage More and more immature precursor cells (”blasts”) divide and accumulate in bone marrow (where 10-19% of blood cells are “blasts”.) Blasts start to spill over into the peripheral blood Acquired ↑ genetic abnormalities 3. Blast crisis (transformation into AML/ALL) Neoplastic blast cells have filled up the bone marrow (where >20% of blood cells are blasts). More blasts spill out into the peripheral blood. Multifactorial causes, most Weight loss, malaise, fever/ with unclear mechanisms Neoplastic division of platelet precursor cells Neoplastic division of WBC precursor cells, especially neutrophil precursors Dividing “blasts” limit the space and resources available for RBC synthesis chills, night sweats Thrombocytosis Leukocytosis: · Neutrophilia, basophilia, & eosinophilia · “Left shift”: ↑ neutrophil & band production · Disorderly WBC differential: i.e. “myelocyte bulge” Trapping of WBC’s in the spleen enlarges the spleen Splenomegaly: · Left upper quadrant pain · Early satiety (large spleen compresses the stomach) · Associated hepatomegaly (if spleen is overfilled & WBCs spill over into liver) Anemia ↓ oxygenation of blood means blood is less red & body tries to compensate Pallor Dyspnea Tachycardia High turnover of these cancerous cells → excess cell lysis Release of intracellular contents (uric acid, K+, LDH) into plasma · Hyperkalemia · High (LDH) Hyperuricemia Gout Acute Kidney Injury Expanding marrow pushing on bone Bone marrow expands into sternum Bone pain Sternal tenderness Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published June 15, 2019 on www.thecalgaryguide.com

Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia (ALL): Pathogenesis and Clinical Presentation Authors: Yan Yu, Katie Lin Reviewers: Crystal Liu, Kara Hawker, Jennifer Au, Lynn Savoie* * MD at time of initial publication Note: ALL is much rarer than AML and is usually seen in children Accumulation of genetic abnormalities in immature lymphoid precursor cells (B/T cell precursors) Neoplastic lymphoid precursor cells (“blasts”) divide and accumulate in bone marrow Abundance of blasts displaces other blood precursors from marrow, inhibiting their development/differentiati on After neoplastic blasts fill up bone marrow, they spill out into blood High turnover of these cancerous cells Multifactorial causes, most with unclear mechanisms Expanding marrow pushing on bone Pancytopenia on CBC 20% of marrow is blasts (on bone marrow aspirate and/or biopsy) Neoplastic blasts continue to divide and accumulate in lymph nodes and spleen (can occur, but not that common) Blasts detected as white blood cells on CBC High rate of cell lysis Weight loss, malaise, fever/chills, night sweats Bone pain (worse than that felt in AML, especially in children) ↓ in neutrophils ↓ in RBCs ↓ in platelets, reduced blood clotting ability Lymphadenopathy Splenomegaly May cause leukocytosis, despite pancytopenia Release of intracellular contents (uric acid, K+, LDH) into plasma Greater chances of infection Anemia Fatigue, shortness of breath, pallor Easy bruising and petechiae on skin Hyperuricemia Hyperkalemia High [LDH] Tumor lysis syndrome Acute kidney injury Gout Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published May 5, 2019 on www.thecalgaryguide.com

Lyme Disease Pathogenesis and Clinical Findings

Lyme Disease: Pathogenesis and clinical findings Authors: Victoria Chang Reviewers: Taylor Woo Crystal Liu Yan Yu* Richard Haber* * MD at time of publication Abbreviations: • OspC – outer surface protein C of B. burgdorferi Tick bite from Borrelia burgdorferi infected Ixodes pacificus (western black-legged tick in British Columbia, Canada) Tick bite from Borrelia burgdorferi infected Ixodes ricinus (tick from European countries) Tick bite from Borrelia burgdorferi infected Ixodes scapularis (Deer tick/black-legged tick in SE Canada and NE United States) Binding of OspC (a surface protein expressed by B. Burgdorferi) to human plasminogen allowing the spirochete to spread from bite site to other host organs and tissues B. burgdorferi spreads through skin and other tissues via bloodstream in human host. If tick bite lasts 36-72 hours or more, this is sufficient time for ticks to transmit the infection. (<36 hours of tick attachment results in a lower rate of infection: 1.2% -1.4%) Lyme Disease A vector-borne, infectious multi-system disease with highest risk in late spring and summer by the spirochete Borrelia burgdorferi Early Disease Stage (<30 days) Macrophages and T-cells produce ↑ inflammatory (TNF- α, IFN-γ) and ↑ anti-inflammatory cytokines, causing eosinophils to concentrate adjacent to the tick bite site Early Disseminated Disease Stage (<3 months) B. burgdorferi attach to host cell integrins Pro-inflammatory response with production of matrix glycosaminoglycans and extracellular matrix proteins which have an affinity to attack collagen fibrils on the heart, nerves, and joints 1. Multiple erythema migrans 2. Meningitis 3. Meningoradiculoneuritis 4. Cranial nerve palsies 5. Carditis 6. Borrelial lymphocytoma Late Disease Stage (>3 months) Ongoing and repeated innate and adaptive host immune response to B. burgdorferi Chronic inflammatory state results in synovial hypertrophy, vascular proliferation, and ↑ mononuclear cell infiltrate in large joints Large joint arthritis (most commonly affecting the knees) Erythema migrans (a slowly expanding red skin patch with partial central clearing resulting in a “target clearing lesion” appearance) at site of tick bite Systemic inflammatory response after dissemination of the spirochete to body tissues and organs Flu-like symptoms (fever, chills, muscle aches, headache, fatigue, joint aches, swollen lymph nodes) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 24, 2019 on www.thecalgaryguide.com References • David A. Wetter and Colin A. Ruff. CMAJ August 09, 2011 183 (11) 1281; DOI: https://doi.org/10.1503/cmaj.101533 • https://www.canada.ca/en/public-health/services/diseases/lyme-disease/causes-lyme-disease.html • Borrelia burgdorferi Infection-Associated Surface Proteins ErpP, ErpA, and ErpC Bind Human Plasminogen. Catherine A. Brissette, Katrin Haupt, Diana Barthel, Anne E. Cooley, Amy Bowman, Christina Skerka, Reinhard Wallich, Peter F. Zipfel, Peter Kraiczy, Brian Stevenson. Infection and Immunity Dec 2008, 77 (1) 300-306; DOI: 10.1128/IAI.01133-08 • https://www.uptodate.com/contents/what-to-do-after-a-tick-bite-to-prevent-lyme-disease-beyond- the-basics • Murray, T. S., & Shapiro, E. D. (2010). Lyme disease. Clinics in laboratory medicine, 30(1), 311–328. doi:10.1016/j.cll.2010.01.003 • Weedon, David. Weedon's Skin Pathology E-Book: Expert Consult-Online and Print. Elsevier Health Sciences, 2009.

Ataxia Telangiectasia Pathogenesis and Clinical Findings

Ataxia-telangiectasia: Pathogenesis and clinical findings Genetics: Autosomal Recessive, with a defect on gene region 22 and 23 on Chromosome 11q Authors: Merna Adly Reviewers: Kara Hawker Crystal Liu Yan Yu* Laurie Parsons* * MD at time of publication Truncation and loss of the ATM protein, a serine/threonine protein Kinase Impaired ability to phosphorylate ATM, a key protein involved in the activation of the DNA damage checkpoint Impaired DNA damage and apoptosis signals Impaired ATM concentration ability at DNA damaged sites Failure to activate apoptosis in specific neural regions Genomically-damaged cells incorporated into the developing nervous system Progressive spinocerebellar granular neural cell damage and Purkinje Cell degeneration Cerebellar Ataxia (at 12-18 months); involuntary muscle contractions, hypotonia, IQ decline, and abnormal eye movement Loss of ATM leads to mitotic defects and arrest in gamete genetic recombination process Gonadal dysgenesis and delayed puberty DNA damage to tumor suppressors such as p53 and BRCA1 Impaired signaling of downstream cell cycle regulators Impaired genome stability and increased disposition to cancer ↑ Acute Lymphocytic Leukemia of T cell origin (in children) and Chronic Lymphoblastic Leukemia (in adults) Impaired recombination of DNA in immune cells Thymic hypoplasia; humoral & cellular immunodeficiency ↓ or absent functional immunoglobulins IgA, IgE, and IgG2 that function to prevent respiratory infections Respiratory infections with bronchiectasis and pneumonia Cells less able to undergo apoptosis in response to ionizing radiation Accumulation of DNA defects in the cells of sun exposed areas such as skin, hair, and conjunctiva Mucocutaneous telangiectasia on the bulbar conjunctiva and ears between 2-6 years of age May progress to involve periorbital skin, trunk, extremities, body folds, and other mucosal surfaces Sterility DNA damage and genomic instability Premature melanocyte stem cell differentiation Premature graying of skin and hair Abbreviations: • ATM – Ataxia-telangiectasia mutated protein • p53 – Tumor protein 53 • BRCA 1 – Breast cancer susceptibility protein. • IgA, IgE, IgG2 – Immunoglobulins Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 4, 2019 on www.thecalgaryguide.com

Erythema Nodosum pathogenesis and clinical findings

Erythema Nodosum: Pathogenesis and clinical findings Authors: Merna Adly Reviewers: Taylor Evart Woo Crystal Liu Yan Yu* Laurie Parsons* * MD at time of publication Epidermal layer Dermal-Epidermal Junction Dermal layer Subcutaneous Fat Layer Phase 1-5. Septal Fibrosis made of inflammatory cells, such as T lymphocytes, histocytes and eosinophils Genetic Dysregulation Infections (Ex. Streptococcal Pharyngitis) ~28-48% of cases Medications (Ex. Birth Control Pills, Sulfa drugs) ~3-10% of cases Malignancy (ex. Lymphoma) Autoimmune conditions (ex. Sarcoidosis and Inflammatory Bowel Disease) ~11-25% of cases Pregnancy ~1-3% of cases Antigenic Stimuli / Bacteria / Viruses / Chemical Agents all could trigger the following process: Phase 1. Neutrophils Infiltrate the fibrous septa between fat lobules in the subcutaneous fat Phase 2. Neutrophils release reactive oxygen species, leading to oxidative tissue damage and inflammation Phase 3. Opening of inter-endothelial junction and the migration of more inflammatory cells into the septal venules, including macrophages, histocytes, and eosinophils Phase 4. Macrophages secrete inflammatory cytokines, which stimulates the proliferation of more helper T cells (Th1) Phase 5. Th1 cells secrete more cytokines, leading to the further release of Th1 cytokines and mediating the immune complexes deposition in the septal venules of the subcutaneous fat (panniculitis). The Th1 immune reaction is called Type IV Delayed Hypersensitivity Reaction Phase 6. Activated macrophages produce hydrolytic enzymes and transform into multi- nucleated giant cells, called Miescher’s Radial Granulomas. These consist of small, well defined aggregations of small histocytes arranged radially around a small cleft of variable shapes in the septal venules of the subcutaneous fat Phase 1-4. Lesions are red tender nodules, poorly defined, vary in size from 2-6 cm, and usually on shins ( 1st week) Fat Lobules T lymphocytes Macrophages Note: we’ve done extensive research and can’t figure out why erythema nodosum happens mostly on the shins. If you have an answer, please email us! Phase 5. Lesions become tense, hard, and painful; and they change in color into bluish or livid. (2nd week) Phase 6. Lesions become fluctuant as in abscess, but do not ulcerate. Lesions fade to a yellowish color Epidermal layer Dermal-Epidermal Junction Dermal layer Subcutaneous Fat Layer Phase 6. Miescher’s Radial Granulomas Fat Lobules T lymphocytes Macrophages Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 25, 2019 on www.thecalgaryguide.com

iga-vasculitis-henoch-scholein-purpura-pathogenesis-and-clinical-findings

IgA Vasculitis (Henoch-Schönlein purpura) : Pathogenesis and clinical findings Authors: Mia Koegler Nela Cosic Reviewers: Crystal Liu Yan Yu* Martin Atkinson* * MD at time of publication Infectious Agents 50% have preceding upper respiratory tract infections, i.e., influenza virus or Group A Strep Drugs I.e., antibiotics (penicillin, erythromycin), NSAIDs and biologics (tumor necrosis factor α inhibitors) Immunogenetic and cellular predisposition Various genetic polymorphisms alter cell- mediated immune response, IgA levels elevated in 50% of people ↑ Circulating galactose-deficient IgA1 (GD-IgA1). Deficiency in galactosylation of IgAà↓ IgA serum clearanceàadhesion of IgA complexes, which then deposit into the endothelial lining of blood vesselsàattraction of various inflammatory cells to the area: Formation of Secretion of Interleukin 8 (IL8) - cytokine that induces Neutrophils infiltrate Activation of complement immune complexes neutrophilic chemotaxis and macrophage phagocytosis the tissue site factors (C3, C4) Leukocytoclastic vasculitis (histopathologic term for small vessels inflamed by neutrophilic autoimmune response) Inflamed cutaneous vessels become enlarged in clusters Symmetrical palpable purpura (red/purple, non- blanchable papules) distributed on lower limbs and buttocks areas Cutaneous small vessel vasculitis (100%) Inflamed gastric vessels - hemorrhage and edema within bowel wall Gastrointestinal (85%) Colicky abdominal pain (commonly in the periumbilical region), nausea, vomiting Gastrointestinal GI bleeding (hematemesis, melena), Intussusception Glomerular mesangial proliferation and inflammation ↑ mast cell deposition in joints Joints (60-85%) Arthralgia's (common), arthritis (especially knees and ankles) Arthralgia often transient. No permanent sequelae Sympathetic nervous system activation Glomerulosclerosis, tubulointerstitial and podocyte damage Renal tissue ischemia ↑ Na sensitivity in renal tubules (↑ Na and water retention) Renal (10-50%) Increased renin secretion HTN, nephrotic/nephritic syndrome, renal insufficiency Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published September 1, 2019 on www.thecalgaryguide.com

X-linked Severe Combined Immunodeficiency (SCID)

X-linked Severe Combined Immunodeficiency (SCID): Pathogenesis & clinical findings Abbreviations: • Ig: Immunoglobulin • IL: Interleukin • NK: Natural Killer • Th2: T helper 2 cell • Treg: T regulatory cell ↓ IL-15 signaling ↓NK cell differentiation and proliferation ↓ or absent NK cells in the blood, bone marrow and peripheral lymphoid tissues Impaired innate immune system Chronic Stress Response Mutation of the IL2-RG gene encoding the interleukin receptor common gamma chain located on the X-chromosome ↓ IL-2 signaling ↓T cell proliferation Sequence analysis shows mutated, duplicated or deleted IL2-RG gene ↓ IL-7 signaling Global ↓ in lymphocyte survival Absent thymic shadow on X-ray ↑ susceptibility to fungal infections Complete defect in cell mediated and humoral immunity ↓ antibody responses to vaccinations ↑ susceptibility to extracellular pathogens, most notably bacteria Authors: Kyo Farrington Reviewers: Paul Adamiak Jessica Tjong Louis Girard* *MD at time of publication ↓ IL-4 signaling ↓Th2 differentiation ↓T cell help for B cell activation and class switching Dysfunctional B cells Genetic Predisposition ↓ Treg development ↑ risk of developing an autoimmune disease ↓ T cell response to mitogens or anti-CD3 stimulation ↓ or absent T lymphocytes in the blood, bone marrow and peripheral lymphoid tissues ↑ susceptibility to viral infections (often gastrointestinal ones like rotavirus and/or enterovirus) Chronic diarrhea Hypoplastic lymphoid tissues (I.e. tonsils, adenoids, lymph nodes) Hypermetabolic State Failure to thrive ↓ antibody production in response to antigen exposure ↓ IgA, IgM and IgG serum concentrations Note: IL2-RG gene encodes the interleukin receptor common gamma chain, which is a sub-unit common to the receptor complexes for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. The bolded/italicized cytokines contribute most to the pathophysiology of X-linked Severe Combine Immunodeficiency (SCID). Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published October 12, 2019 on www.thecalgaryguide.com

Innate-Immune-Response

Innate immune response: Pathogenesis and clinical findings Authors: Erin Stephenson Reviewers: Jessica Tjong Crystal Liu Nicola Wright* * MD at time of publication Pathogens overcome chemical barriers (e.g., lysozyme, low pH) Pathogens overcome physical barriers (e.g., epithelium, cilia) Trauma Damage-associated molecular patterns Pathogen-associated molecular patterns Examples of tissue-resident macrophages: • Alveolar macrophages – Lung • Histiocytes – Connective tissue • Kupffer cells – Liver Recognition by pattern recognition receptors (e.g., toll-like receptors) • Mesangial cells – Kidney • Microglial cells – Brain • Osteoclasts – Bone Microbe engulfed and exposed to oxidative burst Microbes destroyed Pus Pro-inflammatory chemokines Recruitment of circulating granulocytes and monocytes Pro-inflammatory cytokines (e.g., IL-1β, TNFα, IL-6) Tissue-resident macrophage activation Antimicrobial proteins Unresolved infection/ inflammation Antigen presented to T cells Recruitment of adaptive immune response Enhanced immune responses Acute phase protein production by liver (i.e., C- reactive protein) Prostaglandin production in the hypothalamus Fever Endothelial tight junctions on vasculature disrupted Intravascular fluid leak into extravascular space Edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 19, 2020 on www.thecalgaryguide.com

pharmaceuticals-under-investigation-by-who-for-treating-covid-19-proposed-mechanisms

Pharmaceuticals under investigation by WHO for treating Author: Hannah Yaphe Reviewers: Davis Maclean, Timothy Fu, COVID-19 (Corona Virus Disease 2019): Yan Yu*, Stephen Vaughan* * MD at time of publication Note: This slide is based on literature available up to 03/30/2020. Medicines shown here are those included in the WHO SOLIDARITY trial, which were selected based on in vitro work and clinical data from MERS and SARS. Mechanisms are preliminary and there is insufficient data to support or refute the use of these agents for COVID- 19. Research is ongoing. Viral replication is terminated Fewer new cells infected ↓ activation of inflammatory and immune responses Improvement or halt in progression of clinical signs of infection* *See slide on pathophysiology and clinical findings of COVID19 Proposed Mechanisms COVID-19 Viral Replication Pathway Virus adheres to Angiotensin Converting Enzyme 2 (ACE-2) receptor on body cells Endocytosis of virus in clathrin coated vesicles Vesicles mature through endolysosomal pathway Virus membrane fuses with mature endolysosome releasing viral RNA into cytosol Viral RNA uses host cell ribosomes to make new viral proteins like RNA-polymerase Viral RNA-polymerase incorporates nucleotides from the host cell New viral RNA is produced Viral RNA and proteins packaged into new viral particles Viral particles released from cell Chloroquine or Hydroxychloroquine (CQ, HCQ) Weak basicity leads to ↑ pH of endosomes and lysosomes N-terminal glycosylation of ACE-2 in Golgi is inhibited Abnormal ACE-2 receptor expressed on cell surface Viral membrane cannot fuse with immature endosome Altered virus- ACE-2 interaction impairs entry into host cell Viral contents are not released Interferon-β (IFNβ) (Given with LPV/RTV) Ritonavir (RTV) (given with LPV) Inhibition of CYP450, a drug metabolizing enzyme ↓ degradation of Lopinavir (LPV) ↑ plasma half life and duration of action of LPV Binding to interferon receptor Impaired maturation of endosomes Activation of JAK/STAT pathway Transcription of IFN- regulated genes ↑ expression of antiviral and immunomodulatory proteins Antiviral effects may ↑ response to LPV/RTV (mechanism uncertain) Remdesivir (RDV) RDV is phosphorylated to RDV-triphosphate (RDV-TP) Lopinavir (LPV) Inhibition of viral 3- chymotripsin-like protease Inhibition of viral replication (multiple mechanisms) RDV-TP competes with ATP for binding to viral RNA polymerase Viral protein precursors are not cleaved into mature viral proteins Incorporation of RDV-TP terminates growing RNA Newly formed viral particles can’t infect new cells Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 30, 2020 on www.thecalgaryguide.com

Humoral-Immunity

Humoral immunity: Pathogenesis and clinical findings Authors: Erin Stephenson Reviewers: Jessica Tjong Crystal Liu Yan Yu* Nicola Wright* *MD at time of publication Memory B cells are long-lived detectors Memory B cells sequester in storage sites (e.g. lymph nodes, spleen) or circulate in the blood Memory B cells proliferate and differentiate into plasma cells in response to re- exposure to antigen ↑ Rate and amplitude of secondary immune response on repeat exposure Antigens (Ag) are produced from pathogens (bacteria, viruses, fungi, parasites) or the patient (via trauma, tumor, metabolism), & circulate in plasma, lymph, or other tissue Clonal expansion (proliferation of the activated B cells) ↑ WBCs (lymphocytosis) Autoimmune disease if B cells recognize self-antigen T cell-dependent Ag: Ag-presenting cells (such as dendritic cells or macrophages) present Ag to CD4+ helper T cells and activate them. Activated helper-T cells then stimulate B cells T cell-independent Ag: Ags such as peptides, carbohydrates and lipids may be directly recognized by B cells, triggering their activation Complement: Circulating serum complement proteins detect and bind Ag. Ags tagged with C3 complement fragment bind B cell co-receptor complex and enhance B cell activation. Abbreviations: Ab – Antibody Ag – Antigen Ig – Immunoglobulin WBC – White Blood Cell Naïve B cells Activated B cells (in secondary lymphoid organs, such as the spleen or lymph nodes) Plasma cells first produce IgM Cytokines and T cells stimulate Ig class switching of B cells (changing the heavy chain constant regions of the Ig molecule) Ig production switches from IgM to IgG, IgA, IgE, or IgD IgG is the most common Ig in immune reactions. IgA concentrates at mucosa, IgE degranulates mast cells, IgD helps mature B cells. Differentiation (into memory B cells or plasma cells) Plasma cells produce antibodies, which contribute to immunity in 3 ways: Opsonization: Abs coat pathogens, helping recognition by phagocytes Neutralization: Abs bind to pathogen surface molecules that are needed to invade host cells, thereby neutralizing them Activate Complement: Abs activate complement proteins via the classical pathway (see Complement Activation slide) Clearance of pathogen by adaptive immune response ↑ Serum Ig Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 2, 2020 on www.thecalgaryguide.com

pertussis-pathogenesis-clinical-findings-and-complications

Pertussis: Pathogenesis, clinical findings and complications Authors: Morgan Sosniuk Yan Yu* Reviewers: Jessica Tjong Crystal Liu Timothy Fu Luis Murguia-Favela* * MD at time of publication Bordetella pertussis bacterium enters the airway via droplets B. pertussis binds to ciliated epithelial cells and multiplies, colonizing the nasopharynx B. pertussis produces multiple toxins (e.g. “pertussis toxin”, “tracheal toxin”) which damage mucosal cells Pertussis toxin produces cyclic AMP (cAMP) and disrupts normal intracellular signalling, impairing the immune response initially Pertussis (“Whooping Cough”) Respiratory syndrome consisting of severe fits of paroxysmal coughing and stridor Nasopharyngeal swab produces positive culture and/or positive PCR result (either is diagnostic) Initial immune dampening allows the bacteria to take hold and begin replicating. During this “incubation period”, the bacteria has not yet replicated to the point of causing symptoms. 1. Catarrhal Stage (5-10 days) After a few days, continued damage to nasopharynx epithelial cells stimulates the immune system to ↑ its response once again 2. Paroxysmal Stage (1-2 weeks) Tracheal cytotoxin released by B. pertussis impairs normal cilia function and ciliary beating in the trachea 3. Convalescent stage (2 weeks - months) Immune defenses successfully eliminate the majority of B. pertussis from the respiratory tract ↑ mucus production from goblet cells of the respiratory epithelium Mucus blocks airway, prevents air entry Collapsed lung Rarely, areas of chest or abdominal wall are weakened, allowing contents to bulge out Hernia ↑ proinflammatory cytokine production Mild fever Cold-like symptoms Mild dry cough, runny nose, sneezing, nasal congestion ↓ fluid clearance from the respiratory tract Fluid in the trachea narrows tracheal diameter “Whooping” cough Severe, rapid and sequential coughing fits, followed by characteristic “whooping” sound on inspiration due to a stridor from a narrower trachea Fluid build up in the lungs Environment more susceptible to co-infection Other bacteria colonize the lungs Pneumonia Paroxysmal coughing fits ↓ in frequency and number Cough may sound louder (mechanism unknown) but overall symptoms ↓ Some B. pertussis still remain Residual cough flares This stage may be prolonged in unvaccinated individuals who eliminate the bacterium more slowly Intense cough can break ribsàsharp rib ends puncture lungàair leaks out ↑ pressure on bladder If weak urethral sphincters: Urinary incontinence Cough ↑ intra- abdominal pressure If dripping mucus triggers gag reflex while a cough is contracting abdominal muscles: Vomiting Coughing fits disrupt regular inspiration and ↓ oxygenation Hypoxia If hypoxia is profound enough to affect brain Seizures Abdominal muscles tire from coughing, and coughing fits make it difficult to sleep Extreme fatigue Rarely, violent coughing causes trauma to head Intracranial hemorrhage Vertebral or carotid dissection Cerebral ischemia Coma or death Notes: • B. pertussis is a Gram- negative strict aerobe • An effective vaccine exists to prevent infection by B. pertussis • Pertussis most commonly infects children <18 months prior to completion of scheduled vaccination series, or adolescents with ↓ immunity Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 4, 2020 on www.thecalgaryguide.com Include a sentence! When sending in the final draft of a slide, please include in the email a sentence that describes the slide that you've produced in detail. This will help us boost the relevance of the slide with search engines. E.g., Disease X presents with symptom Y due to pathophysiology Z Pertussis presents with fits of severe paroxysmal coughing due to impaired mucociliary clearance.

Bronchiolitis-updated

Bronchiolitis: Pathogenesis and clinical findings Viral pathogen, most commonly respiratory syncytial virus (RSV) - but can be others such as rhinovirus, adenovirus, parainfluenza, influenza, and coronaviruses - initially colonizes the nasopharyngeal mucosa Virus travels via the epithelium to the lower airways to the terminal bronchioles (small airways) Authors: Nick Baldwin Rebecca Lindsay Reviewers: Kayla Nelson, Yan Yu Timothy Fu, Danielle Nelson* *MD at time of publication Upper airway mucosal inflammation Bronchiolitis (bronchiole inflammation) Apnea (cessation of breathing; via unknown mechanism, potentially apnea reflex) RSV-fusion protein facilitates fusion of the virus to the host cell and directs viral penetration as well as facilitates fusion of the infected cell with its healthy neighbors Forms syncytia (multinucleated cells) Cytokines are released into circulation ↑ thermo- regulatory set- point at the hypothalamus Mild Fever Copious coryza (nasal discharge) Protein and fluid leak into nasopharyngeal interstitium ↑ Capillary permeability Protein and fluid leak into the bronchiole interstitium, accumulating around airway walls Airway wall becomes thickened, more readily apparent on x-ray Peribronchial cuffing (X-ray finding: bronchi appear like thickened ‘cuffs’ when viewed head-on) Inflammation stimulates the upregulation of mucous secreting goblet cells ↑ mucous production Mucous within alveoli ↑ intra- alveolar surface tensionà collapsing alveolar walls During inspiration, air enters the collapsed alveoli if airway is not yet occluded ↑ intra-alveolar pressure causes the alveoli to suddenly pop open Inspiratory crackles on auscultation Syncytia slough off the bronchial epithelium into airways Airways become narrower and occlude Disruption of the ciliated epithelial cells (which transport mucous out of the airways and into the pharynx, to be swallowed or evacuated) ↓ mucous clearance from airways Excess airway mucous triggers cough reflex Cough Interstitial edema Nasal Congestion Air is absorbed distal to occlusion (gas trapping) When all air is absorbed, alveoli collapse (resorptive atelectasis) ↓ gas exchange between blood and air in remaining alveoli ↓ O2 saturation & ↑ CO2 content of blood Narrower airways, especially during expiration, causes audible turbulent airflow Wheeze on auscultation Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published November 29, 2020 on www.thecalgaryguide.com

mrna-vaccines-against-coronavirus-disease-2019-covid-19-production-and-mechanism-of-action

mRNA Vaccines against Coronavirus Disease 2019 (COVID-19): Production and Mechanism of Action Vaccine Production The “spike protein” is known to be a major viral surface Authors: Ryan Brenneis, Yan Yu* Reviewers: Davis MacLean, Hannah Yaphe, Timothy Fu, Stephen Vaughan* * MD at time of publication References 1. ACS Nano 2020, 14, 10, 12522–12537, Publication Date: October 9, 2020, https://doi.org/10.1021/acsnano.0c07197 2. NEJM 2020, Publication Date: December 10, 2020, DOI: 10.1056/NEJMoa2034577 3. Expert Review of Vaccines 2017, 16, 9, 871-881, Publication Date: 2017, DOI: 10.1080/14760584.2017.1355245 4. NEJM 2020, 383, 2439-2450, Publication Date: December 17, 2020, DOI: 10.1056/NEJMoa2027906 5. NEJM 2020, 383, 2427-2438, Publication Date: December 17, 2020, DOI: 10.1056/NEJMoa2028436 6. BMJ 2000, 321, 7271, 1237-1238, Publication Date: November 18, 2000, DOI: 10.1136.bmj.321.7271.1237 Notes: SARS-CoV-2 (RNA virus causing COVID-19) collected from an infected patient (ie. with a nasopharyngeal swab) Various reagents are added to the sample containing both human cells and viral constituents Reagents cause cell/viral membrane lysisàspilling cell contents, viral particles, and viral RNA Fats, proteins, and carbohydrates removed through various washing reagents, leaving nucleic acids (like RNA) Reverse transcriptase polymerase chain reaction produces complementary DNA (cDNA) from viral RNA cDNA library allows for SARS-CoV-2 genome to be mapped through whole-genome sequencing technology SARS-CoV-2’s spike protein DNA sequence is identified, and is used as a template to create synthetic viral spike protein mRNA Extra RNA bases are added to this mRNA strand to promote its stabilityàresulting RNA strand is now called “nucleoside-modified RNA” (“modRNA”) antigen (substance that elicits an immune response) from studies of other coronaviruses (e.g. SARS- CoV-1 and MERS-CoV) Pfizer/BNT162b2 vaccine contents: Moderna mRNA-1273 vaccine: Note: Lipid nano- particles are spherical hollow “balls” made of an outer lipid membrane plus other emulsifiers and membrane stabilizers. Lipid nanoparticles are capable of engulfing smaller molecules (like RNA) and merging with normal cell membranes Spike protein modRNA is then isolated (using a series of precipitation, extraction, and chromatography methods) Final modRNA lipid nanoparticle vaccine is now created and ready for intramuscular injection The modRNA vaccine is injected intramuscularly into a healthy person 2nd dose after 3-4 weeks needed to strengthen the immune response (to a level exceeding the immune response in patients recovered from Covid-19), boosting vaccine efficacy especially in older individuals4,5 Lipid nanoparticle fuses with human cells’ phospholipid membranes via endocytosis, releasing modRNA into the cell’s cytosol modRNA is translated by human ribosomes naturally found in the cell’s cytosol, producing viral spike protein components • • Foreign substance can cause local tissue inflammation The spike proteins encoded by the modRNA of each of the two vaccines are similar It is the proprietary lipid nanoparticle formulation (unknown to the public) that is unique to each vaccine Pain, redness, swelling at injection site (Transient) Proprietary Pfizer/ BioNTech lipid nanoparticle The modRNA encodes a full-length spike protein modified with two proline amino acids (for stability and immunogenicity)2 The modRNA encodes a full-length spike protein modified with two proline amino acids (for stability)1 Proprietary Moderna lipid nanoparticle Encapsulating this modRNA within Pfizer/ BioNTech’s lipid nanoparticle creates the 162b2 vaccine This specific formulation requires colder storage temperatures (-700C) Encapsulating this modRNA within Moderna’s lipid nanoparticle creates the mRNA-1273 vaccine This specific formulation can be stored at slightly warmer temperatures (-200C) Muscles are preferred injection sites as they have greater blood supply than other body tissues Vaccine Action Able to bring in immune cells faster to process foreign antigens6 Able to drain away foreign vaccine material fasterà minimizing local reactions6 Cell-mediated Immunity Spike protein degraded by intracellular enzymes into fragments Humoral Immunity Natural cellular processes release spike protein components from the cell into the bloodstream Spike protein components are engulfed by antigen presenting cells (dendritic cells, B cells, macrophages), fragmented, & bound to unique MHC Class II proteins MHC Class II proteins bring spike protein fragments to the antigen presenting cell’s surface, to present them to circulating naïve CD4+ (helper) T cells Some naïve helper T cells are able to successfully bind to the spike protein-MHC Class II protein complexes Binding activates these spike-protein specific helper T cells Spike protein fragments bound by MHC Class I proteins MHC Class I proteins bring spike protein fragments to the human cell surface MHC Class I proteins present spike protein fragments to naïve CD8+ T cell Naïve CD8+ T cells that able to bind to the spike protein-MHC Class I protein complex become activated, and travel to the lymphatic system to mature MHC = Major Histocompatability Complex; cell surface proteins key to immune function CD = Cluster of Differentiation; glycoproteins on T cell surfaces that are co-receptors and facilitate T cell binding to antigens/MHC complexes. They also distinguish the types of T cells. Some of these T-Cells mature into cytotoxic T cells that now recognize the viral spike protein Cytotoxic T-cells bind to human cells infected with SARS-CoV-2 expressing spike protein or spike protein fragments Cytotoxic T cell releases enzymes perforating infected cell, causing cell death to occur Immune system identifies and destroys human cells infected with SARS-CoV-2, slowing viral spread Other T cell’s can mature into memory T cells (stimulated by cytokines released by helper T cells) Memory T cells travel to lymphatic tissue, awaiting activation from future exposure to spike protein More rapid cell-mediated immune response to future SARS-CoV-2 infection (immunity) Activated helper T cells specific to the viral spike protein secrete cytokines to stimulate immune activity Systemic cytokine releaseàsystemic reactions like fever, chills, fatigue, myalgias (Transient) Some B cells mature into plasma cells that produce IgG antibodies against the viral spike protein Antibodies to spike protein mark SARS-CoV-2, allowing immune system to destroy virus Eradication of SARS-CoV-2 in extracellular compartments Activated helper T cell interacts with naïve B cells in lymphatic tissue Some B cells mature into memory B cells specific to SARS-CoV- 2 spike protein Future exposure to spike protein re-activates memory B cell in lymphatic tissue & creates plasma cells, producing antibodies more rapidly Rapid humoral immune response to future SARS-CoV-2 infection (immunity) Legend: Pathophysiology Mechanism Sign/Symptom/Clinical Finding End Result Published December 19, 2020 on www.thecalgaryguide.com

Adenovirus-Vector-Vaccines-Against-COVID19-Production-and-Mechanism-of-Action

Adenovirus Vector Vaccines Against COVID-19: Production and Mechanism of Action Johnson & Johnson Adenovirus type 26 (Ad26), a mild human adenovirus, is isolated Previous exposure to Ad5 or Ad26 may have sensitized immune system to the adenovirus vector1 Potential for human adenovirus vaccine to fail due to previous exposureàimmunity not built against spike protein CanSino Adenovirus type 5 (Ad5), a mild human adenovirus, is isolated Oxford/AstraZeneca Chimpanzee adenovirus AZD1222 (ChAdOx1), previously shown to be safe & to elicit an immune response in humans2, is isolated Vaccine Production SARS-CoV-2 (virus causing COVID-19) synthetic DNA library sequenced from viral RNA using reverse transcriptase polymerase chain reaction and whole genome sequencing technology Spike protein DNA sequence isolated from SARS-CoV-2 genome A promoter sequence is added to the spike protein DNA sequence, allowing human RNA polymerase to recognize and transcribe the spike protein DNA when introduced into human cells Recombinant genetic technology inserts the modified spike protein DNA into a plasmid: a circular piece of DNA that acts as a shuttle allowing for the insertion of new genes (such as the spike protein gene) into host genomes (like the adenovirus vector DNA genome) Adenoviral DNA isolated using various lytic & washing reagents (chemicals that break open cell membranes and remove non- nucleic acid cellular materials) Adenoviral DNA sequenced using whole genome sequencing, then modified as follows: Chimpanzee virus negates possibility of previous immunity to the viral vector1 Chimpanzee viral vector more likely to successfully generate immune response to the spike protein E1 region of adenoviral genome E3 region of adenoviral genome deleted to create deleted to block viral replication3 room for insertion of SARS-CoV-2 spike protein DNA3 Adenovirus used in the final vaccine cannot replicate within human cells and cannot cause human disease References 1. ACS Nano 2020, 14, 10, 12522–12537, Publication Date: October 9, 2020, https://doi.org/10.1021/acsnano.0c07197 Modified adenoviral DNA genome is reinserted into The viral vector & the spike protein plasmid are mixed together, and DNA recombination the adenovirus particle, creating the “viral vector” technology inserts the spike protein gene from the plasmid into the adenovirus DNA2 Adenovirus containing transcribable SARS-CoV-2 spike protein DNA is introduced into a special cellular culture, allowing the virus to replicate despite its modified DNA2, 3 Authors: Ryan Brenneis, Yan Yu* Reviewers: Davis MacLean, Hannah Yaphe Stephen Vaughan* * MD at time of publication 2. Nature 2020, 586, 578–582, Publication Date: October 20, 2020, https://doi.org/10.1038/s41586- 020-2608-y 3. Frontiers in Immunology 2018, 9, 1963, Publication Date: September 19, 2018, doi: 10.3389/fimmu.2018.01963 4. NPJ Vaccines 2020, 5, 69, Publication Date: July 27, 2020, doi: 10.1038/s41541-020-00221-3 5. The Lancet 2020, Publication Date: Dec. 8, 2020, https://doi.org/10.1016/S0140-6736(20)32623-4 6. BMJ 2000, 321, 7271, 1237-1238, Publication Date: November 18, 2000, DOI: 10.1136.bmj.321.7271.1237 7. NEJM 2021, Publication Date: Jan. 13, 2021, DOI: 10.1056/NEJMoa2034201 Adenovirus containing transcribable SARS-CoV-2 spike protein DNA is isolated and concentrated to a high enough level for administration as a vaccine Adenoviruses have an outer protein layer (called a capsid) to protect its DNA DNA is more stable than mRNA due to deoxyribose sugar backbone and intermolecular bonds between strands Enhanced stability compared to mRNA lipid nanoparticle vaccines Can be stored at 2-8°C for up to 3-6 months Muscles are preferred injection sites as they have greater blood supply than other body tissues Immune cells arrive faster to The viral vector vaccine is injected intramuscularly into a healthy person process foreign antigens6 Foreign substance can cause local tissue inflammation Pain, redness, swelling at injection site (Transient) Note: The Johnson and Johnson vaccine may be 90% effective after a single dose7 Foreign vaccine material drains away fasterà minimizing local reactions6 2nd dose after 28 days recommended to strengthen the immune response (to a level exceeding the immune response in patients recovered from Covid-19), boosting vaccine efficacy especially in older individuals5 Vaccine Action Cell-mediated Immunity Spike protein degraded by intracellular enzymes into fragments Adenovirus surface antigens interact with human cellular receptors, allowing viral entry into human cell via endocytosis3 Adenovirus vector travels to cell nucleus, merges with nuclear envelope and injects its DNA (including the spike protein DNA) into the nucleus RNA polymerases in the nucleus transcribe the viral DNA, making messenger RNA (mRNA) for SARS-CoV-2 spike protein mRNA is transported back into the cytosol & translated by ribosomes naturally found there, producing full length SARS-CoV-2 spike protein Humoral Immunity Natural cellular processes release spike protein components from the cell into the bloodstream Spike protein components are engulfed by antigen presenting cells (dendritic cells, B cells, macrophages), fragmented, & bound to unique MHC Class II proteins MHC Class II proteins bring spike protein fragments to the antigen presenting cell’s surface, to present them to circulating naïve CD4+ (helper) T cells Some naïve helper T cells are able to successfully bind to the spike protein-MHC Class II protein complexes Binding activates these spike-protein specific helper T cells Spike protein fragments are bound by MHC Class I proteins MHC Class I proteins bring spike protein fragments to the human cell surface MHC Class I proteins present spike protein fragments to naïve CD8+ T cell Naïve CD8+ T cells that able to bind to the spike protein-MHC Class I protein complex become activated, and travel to the lymphatic system to mature3 MHC = Major Histocompatability Complex; cell surface proteins key to immune function CD = Cluster of Differentiation; glycoproteins on T cell surfaces that are co-receptors and facilitate T cell binding to antigens/MHC complexes. They also distinguish the types of T cells. Some of these T cells mature into cytotoxic T cells that now recognize the SARS-CoV-2 spike spike protein Cytotoxic T cells bind to human cells expressing spike protein or spike protein fragments (e.g. future COVID-19 infection) Cytotoxic T cells release enzymes perforating infected human cells, causing cell death to occur Immune system can now more quickly identify & destroy human cells showing signs of COVID-19 infection Some T cell’s can mature into memory T cells (stimulated by cytokines released by helper T cells) Memory T cells travel to lymphatic tissue, awaiting activation from exposure to spike protein in the future More rapid cell-mediated immune response to future SARS-CoV-2 infection (immunity) Activated helper T cells specific to the viral spike protein secrete cytokines to stimulate immune activity Systemic cytokine releaseàsystemic reactions like fever, chills, fatigue, myalgias (Transient) Note: Duration of cellular/ humoral immunity is unknown Some B cells mature into plasma cells that produce IgG antibodies against the viral spike protein Antibodies to spike protein mark SARS-CoV-2, allowing immune system to destroy virus Eradication of SARS-CoV-2 in extracellular compartments Activated helper T cell interacts with naïve B cells in lymphatic tissue Some B cells mature into memory B cells specific to SARS-CoV- 2 spike protein Future exposure to spike protein re-activates memory B cell in lymphatic tissue & creates plasma cells, producing antibodies more rapidly Rapid humoral immune response to future SARS-CoV-2 infection (immunity)3 Legend: Pathophysiology Mechanism Sign/Symptom/Clinical Finding End result Published February 11, 2021 on www.thecalgaryguide.com

AAA-Pathogenesis

Abdominal Aortic Aneurysm (AAA): Pathogenesis Different parts of the aorta have different embryologic origins Atherosclerosis Hypertension Age > 65 Progressive deterioration of aorta structural integrity over life span Connective Tissue Disease Structurally abnormal protein or protein organization in aorta Autoimmunity Infection (e.g Chlamydia, Mycoplasma pneumoniae, Helicobacter pylori, human cytomegalovirus, herpes simplex virus) Antigens (substance that causes immune response) on virus or bacteria resemble local proteins in abdominal aorta Antibodies produced in response to infection inappropriately target host cells in the aorta Antibodies tag cells in the abdominal aorta for destruction by T-lymphocytes Immune-mediated destruction of aorta Smoking Genetics Unclear mechanisms Subacute (not clinically detectable) inflammation of aortic tissue Inflammatory cytokines are released and immune cells are recruited ↑ pressure on aorta and other vessel walls Infiltration of vessel wall by lymphocytes and macrophages Production of enzymes that break down elastin & collagen proteins (which provide most tensile strength to aorta) Aorta susceptible to damage Degradation of aortic connective tissue Biomechanical stress on vessels Authors: Olivia Genereux Davis Maclean Reviewers: Jason Waechter* Amy Bromley* Yan Yu* *MD at time of publication The exact mechanisms are complex, debatable, and an area of intensive research – the 3 mechanisms and associated pathophysiology presented here are generally thought to be the main causes of abdominal aortic aneurysms Infrarenal aorta has poorly developed vaso vasorum (dedicated blood supply to vessel wall) Infrarenal aorta relies solely on nutrient diffusion from aortic blood that crosses abdominal aorta Infrarenal aortic wall has fewer “lamellar” units (fibromuscular units) than other regions of the aorta Infrarenal aorta is less elastic & less able to distribute stress Loss of smooth muscle cells & thinning of tunica media Destruction of elastin in tunica media Normal layers of the aortic wall ↓ aortic tensile strength (ability to withstand stretching) Aorta expands and dilates due to internal pressure Tunica Intima (inner-most tissue layer of aorta) Tunica Media (layers of elastic tissue (elastin) and muscle fibers) Adventitia (thin outermost collagenous layer) (longitudinal section) Aortic aneurysms are usually infrarenal (85%) Abdominal Aortic Aneurysm Infrarenal aorta more prone to ischemia and has impaired repair potential Abnormal, irreversible dilation of a focal area of abdominal aorta (area of aorta between diaphragm & aortic bifurcation) to twice the diameter of adjacent normal artery segment Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published February 27, 2021 on www.thecalgaryguide.com

Bacterial-Osteomyelitis

Bacterial Osteomyelitis: Pathogenesis and clinical findings Authors: Mehul Gupta Reviewers: Stephen Vaughan* Yan Yu* * MD at time of publication Iatrogenic: Penetrating medical procedure introduces bacteria directly to bone Systemic immune reaction Macrophages, neutrophils and dendritic cells are activated by recognizing bacterial pathogen associated molecular patterns (PAMPs) Trauma: Penetrating injury or open fracture introduces bacteria directly to bone Hematogenous: Blood carries bacteria from distant site of infection to bone Contiguous: Neighboring site of infection seeds bacteria directly to bone Bacterial Osteomyelitis Innate Immune cells and local mast cells release vasoactive cytokines Capillaries dilate to ↑blood flow to affected area and become more permeable to allow for exit of immune cells and plasma contents Localized Immune response Poorly understood mechanismsàinnate immune systems unable to clear the bacteria in some individualsàchronic infection Immune cells produce pyrogenic intermediates (i.e. PGE2, IL-6, and IL-1) Pyrogenic intermediates travel through the bloodstream to the hypothalamus and alters the body’s thermal setpoint Fever Immune cells produce inflammatory cytokines (i.e. TNFα and IL6) Systemic inflammatory cytokines result in the production of Non-specific acute- phase reactants High Serum CRP and ESR Warmth Erythema Progressive blood vessel occlusion by immune cellular and bacterial debris causing infarct and necrosis of bone More permeable capillaries allow plasma to leak into surrounding periosteal tissue More permeable capillaries allow macrophages and neutrophils to exit the capillaries at the site of infection Immune cells phagocytize bacteria, producing an of opaque off-white fluid Pus Immune cells sequester necrotic bone tissue into a regional abscess within medullary bone Sequestrum seen as localized opacity on CT or late X-ray imaging ↑ Osteoclast activity to remove damaged medullary bone and ↑ Osteoblast activity to reform new bone Osteoclasts and osteoblasts remodel and deposit new bone in area surrounding necrotic tissue Swelling ↑ Periosteal fluid applies ↑ pressure to surrounding nerve endings Bone Pain manifesting as refusal to use limb New layer of bone formed Positive Bone Scan in area of infection Abbreviations: • IL – Interleukin • PGE2 – Prostaglandin E2 • TNFα – Tumor necrosis factor alpha Involucrum / Periosteal Reaction: seen as regional luminance surrounding sequestrum on CT or late X-ray imaging Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 21, 2021 on www.thecalgaryguide.com

Dry-Eye-Syndrome-Pathogenesis

Dry Eye Syndrome (Keratoconjunctivitis sicca): Pathogenesis The Pathophysiology of Dry eye disease is complex and an area of active investigation – The mechanism and causes presented here represented the highest yield causes and mechanism for students Post laser eye surgery Disruption of corneal nerves ↓ corneal sensitivity Damage to trigeminal nerve, the sensory innervation of the eye (due to: Herpes Zoster, tumor, trauma, etc) Blepharitis (eyelid inflammation) Many medications can cause dry eye via multiple mechanisms presented here (e.g. ↓ corneal sensitivity, Meibomian gland dysfunction, lacrimal gland atrophy) Sex Hormones (e.g. androgens & estrogens) play a complex and poorly understood role in mediating dry eye disease (net effect is that women are more often affected by dry eye) Obstructed meibomian glands Eyelid damage Gland atrophy These items represent general causes of meibomian gland dysfunction – exact causes are numerous, their pathophysiology is beyond the scope of this slide Contact lens (long term use) Corneal nerve adaptation to chronic mechanical stimulation Autoimmune disease (e.g. Sjögren's syndrome) Chronic inflammatory infiltration of the lacrimal gland (and salivary gland) Autoimmune Lymphocytic infiltration Inflammatory cytokine release Autoantibody production Cell death and apoptosis Lacrimal gland degeneration Meibomian gland dysfunction (Located along the eyelid margins, these glands produce meibum, an oily substance that prevents evaporation of the tear film) ↓ meibum secretion Loss of lipid layer covering the eye, ↓ the barrier that blocks evaporation of tear film Tear Film instability Lifestyle Extended reading or TV or electronic device uses Exposure Keratopathy (any condition causing dryness due to incomplete or inadequate eyelid closure, e.g. Bell’s Palsy) ↓ activity of the afferent portion of corneal reflex arc (responsible for reflex tearing: tearing in response to irritation of the eye) Mechanical damage to goblet cells secrete mucins – a substance that lubricates the eye and preserves tear film ↓ blink rate ↑ time and area ↓ normal reflex tearing for evaporation Dry climate Wind exposure Infiltrative diseases (e.g. sarcoidosis) Lacrimal gland infiltration ↓ Lacrimal gland secretion of the the watery aqueous layer of the tear film (Aqueous deficient dry eye) Deficient or unstable tear film (Evaporative dry eye) ↑ tear evaporation Direct damage to lacrimal gland (e.g. infection or trauma of the eye) Authors: Davis Maclean, Yan Yu*, Michael Penny, O.D. Reviewers: Natalie Arnold, Saleel Jivraj, O.D., Adam Muzychuk*, Victor Penner* *MD at time of publication Hyperosmolar Tear Film (hyperosmolarity = ↑ solutes and ↓ solvent) (Further) Tear Film instability Corneal and conjunctival epithelial cells dry out, including goblet cells (which secrete mucins – a substance that lubricates the eye) Inflammatory immune response àRecruitment and activation of CD4+ (Helper) T-Cells, further produce cytokines Further irritation and damage to ocular surface structures (cornea, conjunctiva and Meibomian glands) and lacrimal glands See Calgary Guide: “Dry Eye Syndrome (Kerato- conjunctivitis sicca):Clinical Findings” for signs and symptoms Dry Eye Syndrome (Keratoconjunctivitis sicca): A multifactorial disease of the ocular surface and tears characterized by loss of tear film homeostasis, tear film hyperosmolality and inflammation Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 7, 2021 on www.thecalgaryguide.com

covid-19-pathophysiology-and-clinical-findings

COVID-19 (Corona Virus Disease 2019): Pathophysiology and Clinical Findings Authors: Ryan Brenneis, Yan Yu* Reviewers: Ciara Hanly, Yonglin Mai (􏰄􏰁􏰃)*, Stephen Vaughan* * MD at time of publication -Respiratory failure -Septic shock -Multiple organ dysfunction Critical Respiratory droplet production (cough, sneeze, talking, breathing) by human host or animal vector infected with SARS-CoV-2 Note: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the name of the betacoronavirus (a positive sense, single stranded RNA virus). COVID-19 is the name of the disease caused by this virus. rate, ↓ oxygen saturation -Bilateral interstitial infiltrates on Chest X-ray, progressively worsening Small droplets (<5μm in diameter) are aerosolized and become airborne Inhalation of aerosolized particles that are suspended in air Patient exposed to the virus (SARS-CoV-2) Droplet contacts the mucus membranes (eyes, nose, mouth) of recipient Live viral particles can adhere to inanimate objects called fomites (e.g. doorknobs) Symptoms are on a continuum -Worsening dyspnea: ↑ respiratory -Fever -Cough -Myalgia, fatigue -Nausea/vomiting -Diarrhea -Loss of taste/smell Recipient touching infected fomite subsequently touches any of their mucus membranes Mild Moderate Severe Virus spreads in the body via 1) mucus membrane spread to surrounding cells and 2) entering the blood Virus adheres to angiotensin-converting enzyme 2 (ACE-2) receptor on body cells, mimics ACE-2, & gains access into cell COVID-19 Symptomatic infection with SARS-CoV-2 Viral proliferation in cells of tissues with more ACE-2 receptors: lungs (type II pneumocytes); vasculature (endothelial cells), kidneys (proximal tubular epithelium), heart (myocardium), GI tract (enterocytes) Cell death and ↑ in inflammatory cytokines triggers immune response Neutrophils move to lungs, release reactive oxygen species and cytokines Alveolar/capillary damage Fluid accumulates in interstitium and alveoli ↑ Distance for O2 to diffuse from alveoli to capillaryà ↓ blood O2 saturation Cytokines induce the hypothalamus to release prostaglandins ↑ body temperature set point to fight infection Virus disassembles, releasing viral RNA, which uses host cell’s ribosomes to make new viral proteins like RNA-polymerases Newly made viral RNA-polymerases use cell’s own nucleotides to synthesize new viral RNA Bilateral ground-glass opacities (CT lung) & interstitial infiltrates on Chest X-ray Dyspnea Airway irritation Cough Myocardial cell damage ↑ Troponin ↑ skeletal muscle cell damage Viral RNA & proteins packaged into new viral particles New virus assembled and released from cell, killing the cell and contributing to disease symptoms Average incubation period (time from initial infection to symptom onset) is 4-5 days; can be up to 14 days Heart tries to compensate for Fever Myalgia hypoxemiaà↑ cardiac output Arrhythmogenic and strain on myocardium state Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 22, 2020, updated Aug 18, 2021 on www.thecalgaryguide.com

asthma-pathogenesis

Asthma: Pathogenesis Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Ciara Hanly Yonglin Mai (􏰁􏰃􏰄) Naushad Hirani* * MD at time of publication Genetic factors (i.e. HLA gene mutations, defects in bronchial airway epithelium) Environmental factors (i.e. excess hygiene, fewer siblings, antibiotics within the first two years) Asthma: Defined as airway hyper-responsiveness causing variable and reversible airflow obstruction Atopy: predisposition to allergic hyper-sensitivity in airways First exposure to triggers* sensitizes helper T cells Stimulation of B-cells to produce IgE, which binds to mast cell surfaces Activated Helper-T cells & IgE-sensitized mast cells now line the airways Triggers of airway hyper- responsiveness include: Upper respiratory tract infections (URTIs) Allergens (pollen, animal dander, dust, mold, etc) Air pollution, cigarette smoke, other chemicals Drugs (aspirin, NSAIDs, Beta- blockers) Cold air Exercise Early response (0-2 hrs) Delayed response (3-4 hrs) Allergens cross-link IgEs on mast cells Activated mast cells & helper T cells release cytokines Mast cells release histamines, leukotrienes, and other inflammatory mediators Induce maturation of granular WBCs like eosinophils Eosinophils migrate into: Vascular permeabilityà edema of airway mucosa Goblet cell hyperplasia à­ mucus secretion Bronchial smooth muscle contraction Airway obstruction Second exposure to triggers Asthma Airways Bronchiole constriction Eyes Conjunctivitis Nose Rhinitis Note: Delayed response presents within 3-4 hrs, peaks within 6-8 hrs, and resolves within 24 hrs Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 17, 2012, updated Aug 19, 2021 on www.thecalgaryguide.com

Pneumoconioses

Pneumoconioses: Pathogenesis and Clinical Findings Authors: Austin Laing Reviewers: Yan Yu* Tara Lohmann* * MD at time of publication Bronchogenic carcinoma and mesothelioma Inhalation of asbestos (Asbestosis) Inhalation of carbonaceous dust (Carboconiosis) Inhalation of metal dust (Metaloconiosis) Inhalation of silica dust (Silicosis) “-Coniosis”: disease which comes from inhaling dust particles Internalized asbestos fibers disrupt cellular processes through a complex series of theorized mechanisms Inhaled dust particles (1-5μm in size) are trapped and deposited in the alveolar airspaces Alveolar macrophages ingest dust particles, which activates the macrophages and sometimes causes apoptosis Activated macrophages create an inflammatory microenvironment by releasing pro-inflammatory cytokines, chemokines and reactive oxygen species Inflammatory products (e.g. reactive oxygen species) damage alveolar epithelial cells, causing activation and release of inflammatory cytokines into the alveolar space Inhaled dust particles, inflammatory products & other pro- tussive mediators activate airway vagal afferent receptors Activated receptors stimulate the cough center located in the medulla oblongata Cough Alveolar capillaries vasoconstrict in response to hypoxia à↑ Pulmonary vascular resistance Pulmonary Hypertension Right heart must pump blood into lungs against higher pressure àcardiomyocyte growth (via sarcomeres formed in parallel within myofibrils)àconcentric hypertrophy of right heart Cor Pulmonale (right heart failure due to pulmonary hypertension) Asbestos fibers accumulate in the airspace and translocate to the pleural surface Macrophage apoptosis: ↓ alveolar macrophages Fibroblasts are recruited to the alveolar wall and are activated Activated fibroblasts produce and deposit collagen in the extracellular space between alveoli Thickening of tissue between alveoli and capillaries ↑ the diffusion distance of atmospheric and blood gasses ↓ Diffusion of CO2 from blood to alveoli and ↓ diffusion of O2 from alveoli to blood ↑ Respiratory rate to maintain minute ventilation due to ↓ lung volumes and diffusion limitations Dyspnea and Exertional Hypoxemia ↓ Innate immune response in the lungs Chest X-Ray: Nodular and reticulonodular opacities are seen in varying lung regions depending on the underlying inhaled dust Excessive collagen deposition ↓ lung compliance and ↓ lung expansion ↓ Diffusing capacity for carbon monoxide (DLCO) on pulmonary function test ↓ Arterial oxygen contentà ↑ deoxyhemoglobin and ↓ oxyhemoglobin ↑ Deoxyhemoglobin within the vasculature causes the skin and mucous membranes to appear blue Cyanosis ↑ Risk of respiratory infections. Mycobacterial infections (e.g. tuberculosis) associated primarily with silicosis ↓ Inhalation volume ↓ Expiratory volume Hypoxemia ↓Total lung capacity (TLC) and ↓ residual volume (RV) on pulmonary function test ↓Forced vital capacity (FVC) and ↓ forced expiratory volume in 1 second (FEV1) on pulmonary function test Note: Forced Vital Capacity: the volume of air that can forcibly be blown out after full inspiration Forced Expiratory Volume in 1 second: the volume of air that can forcibly be blown out in first 1 second, after full inspiration Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published September 12, 2021 on www.thecalgaryguide.com

Hypersensitivity-Pneumonitis

Hypersensitivity Pneumonitis: Pathogenesis and clinical findings Authors: Zarrukh Baig, Zaini Sarwar Reviewers: Natalie Morgunov, Sadie Kutz, Laura Byford-Richardson, Ciara Hanly, Yonglin Mai (麦泳琳)*, Kerri Johannson* * MD at time of publication Farming and Compost Farmer’s Lung (Common) Bird and Animal Proteins Bird Fancier’s Lung (Common) Water Contamination and Ventilation Organic antigen identified by dendritic cells Manufacturing and Chemical Workers Grain and Flour Processors Notes: Immune complex - Production of IgG antibodies (Type III hypersensitivity) Cell mediated - Sensitization of helper T cells (Type IV hypersensitivity) • Thereare3typesofhypersensitivity pneumonitis: acute, subacute, chronic • InacuteHP,removalofincitingantigen results in resolution of symptoms within days. *Lymphoplasmocytic interstitial infiltrate with bronchiolocentric distribution on pathology Epithelial injury (exact mechanism unknown) *Organizing pneumonia Dyspnea, tachypnea, and crackles Abbreviations: • HP – Hypersensitivity Pneumonitis • PFT – Pulmonary Function Test ↑ Neutrophils, mast cells, macrophages, CD8+ T cells, & inflammatory cytokines • *TriadofmainfindingsforsubacuteHP Systemic release of cytokines disrupts hypothalamic regulation Fever Macrophages ingest antigens *Poorly formed granulomas on pathology Tissue breakdown from neutrophils activates fibroblasts, which deposit collagen CT: Normal or diffuse ground- glass opacity (acute) Chronic deposition of collagen replaces normal lung parenchyma by scar tissues (Chronic Findings) Neutrophil elastase breaks down lung elastic fibers Tissue destruction of alveolar walls creates larger air spaces CT: Emphysema CT: Honeycombing (End stage Iung disease) Pathology: Advanced interstitial fibrosis PFT: Restrictive pattern ↓FEV1, ↓FVC, and ↓ DLCO Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published September 1, 2016, updated October 5, 2021 on www.thecalgaryguide.com

Twins Mechanisms and Complications

Twins: Mechanisms and Complications Single ovum ovulatedàOvum fertilized by single sperm Single zygote develops into a single embryo, but for unknown mechanisms, cells in this embryo can separate from one another, causing the embryo to “split” Risk factors for dizygotic twins: ↑ follicle-stimulating hormone (age >35, family history) Allows multiple follicles to mature IVF (multiple embryo transfer) Ovulation induction/ superovulation fertility medications Embryo splits during days 0-3 Embryo splits during days 4-8, after trophoblast cells (outer layer of blastocyst) have already invaded the endometrium and formed part of the placenta Each embryo forms its own amniotic sac, both fed by 1 placenta Monochorionic (1 placenta) Diamniotic (2 amniotic sacs) Monozygotic Twins Embryo splits during days 9-12, when both placental and amniotic sac development have started The embryos must now develop within a shared amniotic sac & placenta Monochorionic (1 placenta) Monoamniotic (1 amniotic sac) Monozygotic Twins Two ova ovulatedàEach ovum fertilized by a separate sperm Cells still undifferentiated at this stage, allows each embryo to develop it’s own placenta and amniotic sac Dichorionic (2 placentas) Diamniotic (2 amniotic sacs) Monozygotic Twins Two embryos develop that implant separately into the endometrium and develop their own placenta and amniotic sac Dizygotic Twins (Dichorionic, Diamniotic by default) Complications of all types of twins: Overdistention of the uterus Weakened uterine muscles leading to uterine atony Postpartum Hemorrhage (see relevant slide) Larger placental mass without ↑ placental blood flow Placental hypoperfusion (plus other complex mechanisms) Gestational Hypertension and Pre- Eclampsia ↑ plasma volumeà diluting red blood cells, plus ↑ fetal iron consumption from mother’s stores Anemia High β- HCG Mechanism unknown Hyperemesis Gravidarum Operative Delivery Preterm Birth Insufficient maternal nutritional supplies Abnormal placental vascular connections Fetal Death Interplacental vascular connections lead to uneven distribution of nutrients and blood flow Twin-Twin Transfusion Syndrome (growth discordance between twins, see relevant slide) Note: all complications are more likely in monozygotic twins Umbilical cords become entangled within shared amniotic sac Cord Entanglement Authors: Jemimah Raffé- Devine, Yan Yu* Reviewers: Brianna Ghali Jadine Paw* *MD at the time of publication Uterine crowding ↑ risk of fetal malpresentation Less space in uterus for continued growth Congenital Anomalies Intrauterine Growth Restriction Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 18, 2021 on www.thecalgaryguide.com

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Authors: Lauren D. Lee, Harry C. Liu* Reviewers: Mehul Gupta, Brian Rankin, Julia Chai, Stephen Williams Yan Yu* Laurie Parsons* *MD at time of publication Pathogenesis and clinical findings Genetic susceptibility Certain HLAs (e.g., HLA-B*58:01, HLA-B*57:01, and HLA-A*31:01) HLA alleles encode for MHC structure and may influence how specific drugs/drug metabolites interact with T cell receptors and MHC proteins on antigen-presenting cells Exposure to offending drug E.g., Aromatic anticonvulsants (lamotrigine, carbamazepine, and phenytoin), allopurinol, and sulfonamides Drug-specific CD4+ and CD8+ T cells produce tumor necrosis factor-alpha and interferon gamma ↑ activated T-cells 2-6 weeks after drug exposure Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Latent Viral infection Latent viruses (HHV-6, HHV- 7, CMV, and EBV) concealed in regulatory T-cells Reactivation of latent viruses may be contributory or secondary to T cell activation by drugs Eosinophilia +/- atypical lymphocytes T helper type 2 cells recruit and activate eosinophils by releasing cytokines Activated leukocytes create a humoral immune and allergic response Dysfunction of regulatory T cells, resulting in failure to control unwanted immune responses against “self” Autoimmune processes with single- or multi-organ involvement CMV- Cytomegalovirus EBV- Epstein-Barr Virus HHV- Human Herpesvirus HLA- Human Leukocyte Antigens MHC – Major Histo- compatibility Complex Endocrine system mechanism of dysfunction unclear but may be linked to autoreactive T cells Autoimmune Type 1 thyroiditis diabetes Lymphadenopathy Fever Facial edema Liver lobular inflammation, dispersed foci of necrotic hepatocytes, granulomatous infiltrates consisting of eosinophils Hepatitis Kidney Interstitial edema and infiltrates of lymphocytes, histiocytes, eosinophils, and plasma cells Acute interstitial nephritis Lung increased pulmonary infiltrate and edema Morbilliform Skin Eruption Spongiosis Epidermal layer Dermal- Epidermal Junction Dermal layer Interface dermatitis Skin eruption (morbilliform to diffuse erythema with follicular accentuation) Interstitial pneumonitis Pleural effusion Eosinophilic infiltration Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 19, 2021 on www.thecalgaryguide.com

COPD-发病机制

COPD: 发病机制 作者: Yan Yu 审稿人:Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人:Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 /012 (如a1-抗胰蛋白酶缺乏) 阻止肺组织损伤的能力↓ +,-. (如长期吸烟、环境污染、感染) 肺内产生自由基 34*5 肺抗蛋白酶的失活 ↑氧化应激，炎性细胞因子，蛋白酶功能 支气管的持续、反复损伤 炎性细胞浸润， 杯状细胞增殖， 气道上皮纤毛 尤其中性粒细 黏液产生↑ 细胞死亡 气道弹性↓ (弹性回缩 肺实质的蛋白水解破坏↑ 维持气道开放 肺泡永久性异常 的结构支持↓ 扩张 胞 力) 肺气体潴留 气道狭窄与 肺过度 肺大泡 气道黏液潴留，成为感染 狭窄 病灶 塌陷 充气 肺气肿 (容易肺泡 破裂) 气道纤维化和 %&'()* 慢性阻塞性肺疾病(COPD) 临床表现 并发症 (参阅相关幻灯片) (参阅相关幻灯片) 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Clinical Findings Lung tissue Chronic Obstructive Pulmonary Disease (COPD) damage ↓ elastic recoil to push air out of lungs on expiration Lungs don’t fully empty, air is trapped in alveoli (lung hyperinflation) ↑ lung volume means diaphragm is tonically contracted (flatter) If occurring around airways Airflow obstruction ↑ mucus production ↓ number of epithelial ciliated cells to clear away the mucus (the cells have been killed by airway inflammation) Chronic cough with sputum Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Naushad Hirani* Juri Janovcik* * MD at time of publication During expiration, positive pleural pressure squeezes on airwaysà↑ obstruction ↓ ventilation of alveoli ↓ oxygenation of blood (hypoxemia) ↓ perfusion of body tissues (i.e. brain, muscle) Fatigue; ↓ exercise tolerance Total expiration time takes longer than normal Prolonged expiration More effort needed to ventilate larger lungs Respiratory muscles must work harder to breathe Turbulent airflow in narrower airways is heard on auscultation Expiratory Wheeze Diaphragm can’t flatten much further to generate deep breaths To breathe, chest wall must expand out more Dyspnea Shortness of breath, especially on exertion Breathes are rapid & shallow If end-stage: Chronic fatigue causes deconditioning Muscle weakness & wasting Barrel chest If end-stage: diaphragm will be “flat”. Continued Patient tries to expire against higher mouth air pressure, forcing airways to open wider Pursed-lip breathing Patient breathes with accessory muscles as well as diaphragm to try to improve airflow inspiratory effort further contracts diaphragmà pull the lower chest wall inwards Hoover’s sign (paradoxical shrinking of lower chest during inspiration) Tripod sitting position (activates pectoral muscles) Neck (SCM, scalene) muscles contracted Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: ! 45 (on ABGs) Ventilation- perfusion mismatch High A-a gradient (calculated from ABGs) Low, flat diaphragm, >10 posterior ribs (on frontal CXR) High TLC and VC (on spirometry) • • PaO2: partial pressure of O2 in arterial blood PaCO2: partial pressure of CO2 in arterial blood • In the setting of fever and productive cough, especially if lung field opacifications are seen on CXR: consider sputum gram stain and culture to rule out pneumonia. Air does not block X-ray beams, will appear black on X-ray film Chronic hypercapnia makes breathing centers less sensitive to the high PaCO2 stimulus for breathing, & more reliant on the low PaO2 stimulus (“CO2 retention”) Give O2 carefully to these patients (high PaO2 may suppress patients’ hypoxic respiratory drive, ↓ their breathing, & ↑↑↑ PaCO2) ↑ retrosternal air space (on lateral CXR) Hyper-lucent (darker) lung fields, ↓ lung markings (on frontal CXR) • Arterial Blood Gasses (ABGs) • Chest X-Ray (CXR): frontal and lateral Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"#$ 气流阻塞 肺泡通气↓ 呼气时，胸膜腔正压挤压气 道à 阻塞↑ 作者: Yan Yu 审稿人: Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者:Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 慢性阻塞性肺疾病 (COPD) 肺组织损伤 没有弹性回缩力将 气体排出肺 肺实质与血管分布减少导 致气体交换面积↓ 弥散功能↓ (肺功能检查) 更多的CO2残留 并扩散到血液中 高碳酸血症: PaCO2 > 45 (动脉血气) 血流灌注通气不良的肺泡 时无法获得足够的氧气 总呼气时长较正常长 FEV1/FEV < 0.7 (肺功能检查) 肺无法完全排空 更多空气潴留在肺部 (肺过度充气) 低氧血症: PaO2 < 70mmHg (动脉血气) 通气-灌注不匹配 肺泡-动脉氧分压差↑ (可通过动脉血气分析计算得出) 横膈低平， 下移至第10肋后端 及以下部位 (胸部正位片) TLC与VC增大 (肺功能检查) 缩写: • • FEV1: 1秒用 • VC:肺活量 PaO2: 动脉血 力呼气量 氧分压 空气不会阻挡X射线， 在X光片上呈现为黑色 慢性高碳酸血症使呼吸中枢对PaCO2 刺激呼吸的敏感性下降 & 更依赖于低PaO2的刺激 (“二氧化碳潴留”) 给患者吸氧时需注意(高PaO2 可能会抑制患者低氧时对呼吸的 刺激，使呼吸驱动↓ & PaCO2↑↑↑ ) • FVC: 用力肺 • 活量 • TLC:肺总量 慢阻肺相关检查 : PaCO2: 动脉 血二氧化碳 分压 胸骨后间隙↑ (胸部侧位片) 肺纹理↓ • 肺功能检查 • 动脉血气分析(Arterial Blood Gasses, ABGs) • 胸部正侧位片 • 当患者发热和湿咳，特别是胸片上见肺野不清晰时: 肺透亮度↑, (胸部正位片) 考虑进行痰革兰氏染色及痰培养以排除肺炎可能 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Complications Lung inflammation Chronic Obstructive Pulmonary Disease (COPD) Airway obstruction ↓ inhaled air in alveoli and terminal bronchioles Rupture of emphasematous bullae on surface of lung Inhaled air leaks into pleural cavity and is trapped there Pneumothorax Feeling a loss of control over one’s life, and hopelessness for the future Goblet cell proliferation, ↑ mucus production Death of airway epithelium ciliated cells ↓ oxygenation of the blood passing through the lungs Chronic hypoxemia Kidneys compensate by ↑ erythropoietin (EPO) production ↑ Hemoglobin and red blood cell synthesis Polycythemia (secondary) Hypoxic alveoli cause the pulmonary arterioles perfusing them to reflexively vasoconstrict Since most alveoli in the lungs are hypoxic, hypoxic vasoconstriction occurs across entire lung Vasoconstriction ↑ blood pressure within lung vasculature Pulmonary hypertension ↑ workload of the right ventricle (to pump against higher pressures) To compensate, the right ventricle progressively hypertrophies and dilates, but over time its output ↓ Cor pulmonale (Right heart failure in isolation, not due to Left heart failure) Mucus trapped in airways, serve as nidus for infection Acute exacerbation of COPD (AECOPD) Pneumonia The chronic, systemic inflammation in COPD is a hyper-metabolic state that consumes calories Macro-nutrient deficiency Trouble with respiration lead to inactivity and deconditioning Wasting, muscle atrophy More inactivity and deconditioning perpetuates the cycle Depression Author: Yan Yu Reviewers: Jason Baserman Naushad Hirani* Juri Janovcik* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"# 肺部炎症 杯状细胞增殖， 气道上皮纤毛 粘液产生↑ 细胞死亡 黏液潴留呼吸道，成为感 染的病灶 慢性阻塞性肺疾病 (COPD) 气道阻塞à 吸入肺泡和终末细 肺大疱破裂 吸入的空气渗入 并潴留于胸腔 气胸 感觉生活失控，对未 来感到绝望 抑郁 作者: Yan Yu 审稿人: Jason Baserman, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 支气管的空气 ↓ 流经肺的血液进行气 缺氧的肺泡à灌注肺泡的肺小动 慢性阻塞性肺疾 病急性加重期 (AECOPD) 肺炎 体交换↓ 慢性低氧血症 肾脏合成促红细胞 生成素进行代偿↑ 血红蛋白与红 细胞合成↑ 红细胞增多症 (继发性) 脉发生反射性血管收缩 肺大部分肺泡缺氧à整个肺 都出现缺氧性血管收缩 肺血管收缩 à 肺血管压力↑ 肺动脉高压 ↑ 右心室负荷(泵血时对抗高压) 为了代偿，右心室逐渐肥大和扩张， 但随着病程进展，右心室输出量 ↓ 肺心病 (单独出现右心衰竭，非左心衰) COPD所致的慢性全身 呼吸困难导致活 性炎症会使机体处于高 动量减少和活动 代谢状态，消耗能量 耐量降低 宏量营养 素缺乏症 消瘦，肌肉萎缩 运动量下降和活动耐量 的降低造成恶性循环 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com " title="COPD: 发病机制 作者: Yan Yu 审稿人:Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人:Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 /012 (如a1-抗胰蛋白酶缺乏) 阻止肺组织损伤的能力↓ +,-. (如长期吸烟、环境污染、感染) 肺内产生自由基 34*5 肺抗蛋白酶的失活 ↑氧化应激，炎性细胞因子，蛋白酶功能 支气管的持续、反复损伤 炎性细胞浸润， 杯状细胞增殖， 气道上皮纤毛 尤其中性粒细 黏液产生↑ 细胞死亡 气道弹性↓ (弹性回缩 肺实质的蛋白水解破坏↑ 维持气道开放 肺泡永久性异常 的结构支持↓ 扩张 胞 力) 肺气体潴留 气道狭窄与 肺过度 肺大泡 气道黏液潴留，成为感染 狭窄 病灶 塌陷 充气 肺气肿 (容易肺泡 破裂) 气道纤维化和 %&'()* 慢性阻塞性肺疾病(COPD) 临床表现 并发症 (参阅相关幻灯片) (参阅相关幻灯片) 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Clinical Findings Lung tissue Chronic Obstructive Pulmonary Disease (COPD) damage ↓ elastic recoil to push air out of lungs on expiration Lungs don’t fully empty, air is trapped in alveoli (lung hyperinflation) ↑ lung volume means diaphragm is tonically contracted (flatter) If occurring around airways Airflow obstruction ↑ mucus production ↓ number of epithelial ciliated cells to clear away the mucus (the cells have been killed by airway inflammation) Chronic cough with sputum Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Naushad Hirani* Juri Janovcik* * MD at time of publication During expiration, positive pleural pressure squeezes on airwaysà↑ obstruction ↓ ventilation of alveoli ↓ oxygenation of blood (hypoxemia) ↓ perfusion of body tissues (i.e. brain, muscle) Fatigue; ↓ exercise tolerance Total expiration time takes longer than normal Prolonged expiration More effort needed to ventilate larger lungs Respiratory muscles must work harder to breathe Turbulent airflow in narrower airways is heard on auscultation Expiratory Wheeze Diaphragm can’t flatten much further to generate deep breaths To breathe, chest wall must expand out more Dyspnea Shortness of breath, especially on exertion Breathes are rapid & shallow If end-stage: Chronic fatigue causes deconditioning Muscle weakness & wasting Barrel chest If end-stage: diaphragm will be “flat”. Continued Patient tries to expire against higher mouth air pressure, forcing airways to open wider Pursed-lip breathing Patient breathes with accessory muscles as well as diaphragm to try to improve airflow inspiratory effort further contracts diaphragmà pull the lower chest wall inwards Hoover’s sign (paradoxical shrinking of lower chest during inspiration) Tripod sitting position (activates pectoral muscles) Neck (SCM, scalene) muscles contracted Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"#$ 慢性阻塞性肺疾病 (COPD) 如果出现在气道周围 气流阻塞 肺不能完全排空 气体，气体潴留 于肺泡(肺过度 充气) 总呼气时长大于 正常时长 呼气相延长 肺组织损伤 呼气时，将空气排出肺外 的弹性回缩力↓ 肺不能完全排空气体， 气体潴留于肺泡内 (肺过度充气) 肺容积↑，膈肌紧张 性收缩(膈肌平坦) 呼气时，胸膜腔正压挤压气道 à 气道阻塞↑ 肺泡通气↓ 血液氧合↓ (低 氧血症) 身体组织灌注 量↓ (比如脑、 肌肉) 疲劳; 运动耐量↓ 黏液生成↑ 清除黏液的上皮纤 毛细胞数量↓ (受 气道炎症损伤) 慢性咳嗽伴咳 痰 作者: Yan Yu 审稿人: Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 容积较大 的肺需要 更加努力 才能通气 呼吸肌必须 更用力才能 呼吸 听诊闻及狭窄气 道中的湍流气流 呼气喘鸣音 呼吸困难 气促，尤其是劳累 膈肌无法进一步收缩以 产生深呼吸 呼吸浅快 为了呼吸， 胸壁必须延 展得更大 桶状胸 晚期病人: 患者试图在较高的口 慢性疲劳导致 患者动用辅助呼吸肌和膈肌呼吸， 腔内气压下进行呼气， 活动耐量下降 从而使气道更开放 以改善气流 晚期病人:膈肌 “平坦” ，持续吸气进一步压 缩膈肌à 向内拉季肋部胸壁 胡佛征 (吸气时，胸廓下侧季肋部内收) 缩唇呼吸 肌肉无力 & 消瘦 端坐呼吸 (调动胸肌) 颈部肌肉收 缩(胸锁乳 突肌、斜角 肌) 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Findings on Investigations Chronic Obstructive Pulmonary Disease (COPD) Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Naushad Hirani* Juri Janovcik* * MD at time of publication Airflow obstruction Lung tissue damage ↓ ventilation of alveoli Blood perfusing ill- ventilated alveoli does not receive normal amounts of oxygen During expiration, positive pleural pressure squeezes on airwaysà↑ obstruction) No elastic recoil to push air out of lungs Loss of lung parenchyma and vasculature ↓ surface area for gas exchange ↓ diffusion capacity (on spirometry) Hypoxemia: PaO2 < 70mmHg (on ABGs) Abbreviations: • FEV1: Forced expiratory volume in 1 second • FVC: Forced vital capacity • TLC: Total lung capacity • VC: Vital Capacity Investigations for COPD : • Spirometry (Pulmonary function test) Total expiration time takes longer than normal FEV1/FEV < 0.7 (on spirometry) Lungs don’t fully empty More air trapped within lungs (hyperinflation) More CO2 remains and diffuses into the blood Hypercapnia: PaCO2 > 45 (on ABGs) Ventilation- perfusion mismatch High A-a gradient (calculated from ABGs) Low, flat diaphragm, >10 posterior ribs (on frontal CXR) High TLC and VC (on spirometry) • • PaO2: partial pressure of O2 in arterial blood PaCO2: partial pressure of CO2 in arterial blood • In the setting of fever and productive cough, especially if lung field opacifications are seen on CXR: consider sputum gram stain and culture to rule out pneumonia. Air does not block X-ray beams, will appear black on X-ray film Chronic hypercapnia makes breathing centers less sensitive to the high PaCO2 stimulus for breathing, & more reliant on the low PaO2 stimulus (“CO2 retention”) Give O2 carefully to these patients (high PaO2 may suppress patients’ hypoxic respiratory drive, ↓ their breathing, & ↑↑↑ PaCO2) ↑ retrosternal air space (on lateral CXR) Hyper-lucent (darker) lung fields, ↓ lung markings (on frontal CXR) • Arterial Blood Gasses (ABGs) • Chest X-Ray (CXR): frontal and lateral Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"#$ 气流阻塞 肺泡通气↓ 呼气时，胸膜腔正压挤压气 道à 阻塞↑ 作者: Yan Yu 审稿人: Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者:Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 慢性阻塞性肺疾病 (COPD) 肺组织损伤 没有弹性回缩力将 气体排出肺 肺实质与血管分布减少导 致气体交换面积↓ 弥散功能↓ (肺功能检查) 更多的CO2残留 并扩散到血液中 高碳酸血症: PaCO2 > 45 (动脉血气) 血流灌注通气不良的肺泡 时无法获得足够的氧气 总呼气时长较正常长 FEV1/FEV < 0.7 (肺功能检查) 肺无法完全排空 更多空气潴留在肺部 (肺过度充气) 低氧血症: PaO2 < 70mmHg (动脉血气) 通气-灌注不匹配 肺泡-动脉氧分压差↑ (可通过动脉血气分析计算得出) 横膈低平， 下移至第10肋后端 及以下部位 (胸部正位片) TLC与VC增大 (肺功能检查) 缩写: • • FEV1: 1秒用 • VC:肺活量 PaO2: 动脉血 力呼气量 氧分压 空气不会阻挡X射线， 在X光片上呈现为黑色 慢性高碳酸血症使呼吸中枢对PaCO2 刺激呼吸的敏感性下降 & 更依赖于低PaO2的刺激 (“二氧化碳潴留”) 给患者吸氧时需注意(高PaO2 可能会抑制患者低氧时对呼吸的 刺激，使呼吸驱动↓ & PaCO2↑↑↑ ) • FVC: 用力肺 • 活量 • TLC:肺总量 慢阻肺相关检查 : PaCO2: 动脉 血二氧化碳 分压 胸骨后间隙↑ (胸部侧位片) 肺纹理↓ • 肺功能检查 • 动脉血气分析(Arterial Blood Gasses, ABGs) • 胸部正侧位片 • 当患者发热和湿咳，特别是胸片上见肺野不清晰时: 肺透亮度↑, (胸部正位片) 考虑进行痰革兰氏染色及痰培养以排除肺炎可能 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Complications Lung inflammation Chronic Obstructive Pulmonary Disease (COPD) Airway obstruction ↓ inhaled air in alveoli and terminal bronchioles Rupture of emphasematous bullae on surface of lung Inhaled air leaks into pleural cavity and is trapped there Pneumothorax Feeling a loss of control over one’s life, and hopelessness for the future Goblet cell proliferation, ↑ mucus production Death of airway epithelium ciliated cells ↓ oxygenation of the blood passing through the lungs Chronic hypoxemia Kidneys compensate by ↑ erythropoietin (EPO) production ↑ Hemoglobin and red blood cell synthesis Polycythemia (secondary) Hypoxic alveoli cause the pulmonary arterioles perfusing them to reflexively vasoconstrict Since most alveoli in the lungs are hypoxic, hypoxic vasoconstriction occurs across entire lung Vasoconstriction ↑ blood pressure within lung vasculature Pulmonary hypertension ↑ workload of the right ventricle (to pump against higher pressures) To compensate, the right ventricle progressively hypertrophies and dilates, but over time its output ↓ Cor pulmonale (Right heart failure in isolation, not due to Left heart failure) Mucus trapped in airways, serve as nidus for infection Acute exacerbation of COPD (AECOPD) Pneumonia The chronic, systemic inflammation in COPD is a hyper-metabolic state that consumes calories Macro-nutrient deficiency Trouble with respiration lead to inactivity and deconditioning Wasting, muscle atrophy More inactivity and deconditioning perpetuates the cycle Depression Author: Yan Yu Reviewers: Jason Baserman Naushad Hirani* Juri Janovcik* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"# 肺部炎症 杯状细胞增殖， 气道上皮纤毛 粘液产生↑ 细胞死亡 黏液潴留呼吸道，成为感 染的病灶 慢性阻塞性肺疾病 (COPD) 气道阻塞à 吸入肺泡和终末细 肺大疱破裂 吸入的空气渗入 并潴留于胸腔 气胸 感觉生活失控，对未 来感到绝望 抑郁 作者: Yan Yu 审稿人: Jason Baserman, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 支气管的空气 ↓ 流经肺的血液进行气 缺氧的肺泡à灌注肺泡的肺小动 慢性阻塞性肺疾 病急性加重期 (AECOPD) 肺炎 体交换↓ 慢性低氧血症 肾脏合成促红细胞 生成素进行代偿↑ 血红蛋白与红 细胞合成↑ 红细胞增多症 (继发性) 脉发生反射性血管收缩 肺大部分肺泡缺氧à整个肺 都出现缺氧性血管收缩 肺血管收缩 à 肺血管压力↑ 肺动脉高压 ↑ 右心室负荷(泵血时对抗高压) 为了代偿，右心室逐渐肥大和扩张， 但随着病程进展，右心室输出量 ↓ 肺心病 (单独出现右心衰竭，非左心衰) COPD所致的慢性全身 呼吸困难导致活 性炎症会使机体处于高 动量减少和活动 代谢状态，消耗能量 耐量降低 宏量营养 素缺乏症 消瘦，肌肉萎缩 运动量下降和活动耐量 的降低造成恶性循环 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com " />

COPD-临床表现

COPD: 临床表现 作者: Yan Yu 审稿人:Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人:Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 /012 (如a1-抗胰蛋白酶缺乏) 阻止肺组织损伤的能力↓ +,-. (如长期吸烟、环境污染、感染) 肺内产生自由基 34*5 肺抗蛋白酶的失活 ↑氧化应激，炎性细胞因子，蛋白酶功能 支气管的持续、反复损伤 炎性细胞浸润， 杯状细胞增殖， 气道上皮纤毛 尤其中性粒细 黏液产生↑ 细胞死亡 气道弹性↓ (弹性回缩 肺实质的蛋白水解破坏↑ 维持气道开放 肺泡永久性异常 的结构支持↓ 扩张 胞 力) 肺气体潴留 气道狭窄与 肺过度 肺大泡 气道黏液潴留，成为感染 狭窄 病灶 塌陷 充气 肺气肿 (容易肺泡 破裂) 气道纤维化和 %&'()* 慢性阻塞性肺疾病(COPD) 临床表现 并发症 (参阅相关幻灯片) (参阅相关幻灯片) 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Clinical Findings Lung tissue Chronic Obstructive Pulmonary Disease (COPD) damage ↓ elastic recoil to push air out of lungs on expiration Lungs don’t fully empty, air is trapped in alveoli (lung hyperinflation) ↑ lung volume means diaphragm is tonically contracted (flatter) If occurring around airways Airflow obstruction ↑ mucus production ↓ number of epithelial ciliated cells to clear away the mucus (the cells have been killed by airway inflammation) Chronic cough with sputum Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Naushad Hirani* Juri Janovcik* * MD at time of publication During expiration, positive pleural pressure squeezes on airwaysà↑ obstruction ↓ ventilation of alveoli ↓ oxygenation of blood (hypoxemia) ↓ perfusion of body tissues (i.e. brain, muscle) Fatigue; ↓ exercise tolerance Total expiration time takes longer than normal Prolonged expiration More effort needed to ventilate larger lungs Respiratory muscles must work harder to breathe Turbulent airflow in narrower airways is heard on auscultation Expiratory Wheeze Diaphragm can’t flatten much further to generate deep breaths To breathe, chest wall must expand out more Dyspnea Shortness of breath, especially on exertion Breathes are rapid & shallow If end-stage: Chronic fatigue causes deconditioning Muscle weakness & wasting Barrel chest If end-stage: diaphragm will be “flat”. Continued Patient tries to expire against higher mouth air pressure, forcing airways to open wider Pursed-lip breathing Patient breathes with accessory muscles as well as diaphragm to try to improve airflow inspiratory effort further contracts diaphragmà pull the lower chest wall inwards Hoover’s sign (paradoxical shrinking of lower chest during inspiration) Tripod sitting position (activates pectoral muscles) Neck (SCM, scalene) muscles contracted Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: ! 45 (on ABGs) Ventilation- perfusion mismatch High A-a gradient (calculated from ABGs) Low, flat diaphragm, >10 posterior ribs (on frontal CXR) High TLC and VC (on spirometry) • • PaO2: partial pressure of O2 in arterial blood PaCO2: partial pressure of CO2 in arterial blood • In the setting of fever and productive cough, especially if lung field opacifications are seen on CXR: consider sputum gram stain and culture to rule out pneumonia. Air does not block X-ray beams, will appear black on X-ray film Chronic hypercapnia makes breathing centers less sensitive to the high PaCO2 stimulus for breathing, & more reliant on the low PaO2 stimulus (“CO2 retention”) Give O2 carefully to these patients (high PaO2 may suppress patients’ hypoxic respiratory drive, ↓ their breathing, & ↑↑↑ PaCO2) ↑ retrosternal air space (on lateral CXR) Hyper-lucent (darker) lung fields, ↓ lung markings (on frontal CXR) • Arterial Blood Gasses (ABGs) • Chest X-Ray (CXR): frontal and lateral Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"#$ 气流阻塞 肺泡通气↓ 呼气时，胸膜腔正压挤压气 道à 阻塞↑ 作者: Yan Yu 审稿人: Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者:Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 慢性阻塞性肺疾病 (COPD) 肺组织损伤 没有弹性回缩力将 气体排出肺 肺实质与血管分布减少导 致气体交换面积↓ 弥散功能↓ (肺功能检查) 更多的CO2残留 并扩散到血液中 高碳酸血症: PaCO2 > 45 (动脉血气) 血流灌注通气不良的肺泡 时无法获得足够的氧气 总呼气时长较正常长 FEV1/FEV < 0.7 (肺功能检查) 肺无法完全排空 更多空气潴留在肺部 (肺过度充气) 低氧血症: PaO2 < 70mmHg (动脉血气) 通气-灌注不匹配 肺泡-动脉氧分压差↑ (可通过动脉血气分析计算得出) 横膈低平， 下移至第10肋后端 及以下部位 (胸部正位片) TLC与VC增大 (肺功能检查) 缩写: • • FEV1: 1秒用 • VC:肺活量 PaO2: 动脉血 力呼气量 氧分压 空气不会阻挡X射线， 在X光片上呈现为黑色 慢性高碳酸血症使呼吸中枢对PaCO2 刺激呼吸的敏感性下降 & 更依赖于低PaO2的刺激 (“二氧化碳潴留”) 给患者吸氧时需注意(高PaO2 可能会抑制患者低氧时对呼吸的 刺激，使呼吸驱动↓ & PaCO2↑↑↑ ) • FVC: 用力肺 • 活量 • TLC:肺总量 慢阻肺相关检查 : PaCO2: 动脉 血二氧化碳 分压 胸骨后间隙↑ (胸部侧位片) 肺纹理↓ • 肺功能检查 • 动脉血气分析(Arterial Blood Gasses, ABGs) • 胸部正侧位片 • 当患者发热和湿咳，特别是胸片上见肺野不清晰时: 肺透亮度↑, (胸部正位片) 考虑进行痰革兰氏染色及痰培养以排除肺炎可能 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Complications Lung inflammation Chronic Obstructive Pulmonary Disease (COPD) Airway obstruction ↓ inhaled air in alveoli and terminal bronchioles Rupture of emphasematous bullae on surface of lung Inhaled air leaks into pleural cavity and is trapped there Pneumothorax Feeling a loss of control over one’s life, and hopelessness for the future Goblet cell proliferation, ↑ mucus production Death of airway epithelium ciliated cells ↓ oxygenation of the blood passing through the lungs Chronic hypoxemia Kidneys compensate by ↑ erythropoietin (EPO) production ↑ Hemoglobin and red blood cell synthesis Polycythemia (secondary) Hypoxic alveoli cause the pulmonary arterioles perfusing them to reflexively vasoconstrict Since most alveoli in the lungs are hypoxic, hypoxic vasoconstriction occurs across entire lung Vasoconstriction ↑ blood pressure within lung vasculature Pulmonary hypertension ↑ workload of the right ventricle (to pump against higher pressures) To compensate, the right ventricle progressively hypertrophies and dilates, but over time its output ↓ Cor pulmonale (Right heart failure in isolation, not due to Left heart failure) Mucus trapped in airways, serve as nidus for infection Acute exacerbation of COPD (AECOPD) Pneumonia The chronic, systemic inflammation in COPD is a hyper-metabolic state that consumes calories Macro-nutrient deficiency Trouble with respiration lead to inactivity and deconditioning Wasting, muscle atrophy More inactivity and deconditioning perpetuates the cycle Depression Author: Yan Yu Reviewers: Jason Baserman Naushad Hirani* Juri Janovcik* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"# 肺部炎症 杯状细胞增殖， 气道上皮纤毛 粘液产生↑ 细胞死亡 黏液潴留呼吸道，成为感 染的病灶 慢性阻塞性肺疾病 (COPD) 气道阻塞à 吸入肺泡和终末细 肺大疱破裂 吸入的空气渗入 并潴留于胸腔 气胸 感觉生活失控，对未 来感到绝望 抑郁 作者: Yan Yu 审稿人: Jason Baserman, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 支气管的空气 ↓ 流经肺的血液进行气 缺氧的肺泡à灌注肺泡的肺小动 慢性阻塞性肺疾 病急性加重期 (AECOPD) 肺炎 体交换↓ 慢性低氧血症 肾脏合成促红细胞 生成素进行代偿↑ 血红蛋白与红 细胞合成↑ 红细胞增多症 (继发性) 脉发生反射性血管收缩 肺大部分肺泡缺氧à整个肺 都出现缺氧性血管收缩 肺血管收缩 à 肺血管压力↑ 肺动脉高压 ↑ 右心室负荷(泵血时对抗高压) 为了代偿，右心室逐渐肥大和扩张， 但随着病程进展，右心室输出量 ↓ 肺心病 (单独出现右心衰竭，非左心衰) COPD所致的慢性全身 呼吸困难导致活 性炎症会使机体处于高 动量减少和活动 代谢状态，消耗能量 耐量降低 宏量营养 素缺乏症 消瘦，肌肉萎缩 运动量下降和活动耐量 的降低造成恶性循环 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com " title="COPD: 临床表现 作者: Yan Yu 审稿人:Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人:Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 /012 (如a1-抗胰蛋白酶缺乏) 阻止肺组织损伤的能力↓ +,-. (如长期吸烟、环境污染、感染) 肺内产生自由基 34*5 肺抗蛋白酶的失活 ↑氧化应激，炎性细胞因子，蛋白酶功能 支气管的持续、反复损伤 炎性细胞浸润， 杯状细胞增殖， 气道上皮纤毛 尤其中性粒细 黏液产生↑ 细胞死亡 气道弹性↓ (弹性回缩 肺实质的蛋白水解破坏↑ 维持气道开放 肺泡永久性异常 的结构支持↓ 扩张 胞 力) 肺气体潴留 气道狭窄与 肺过度 肺大泡 气道黏液潴留，成为感染 狭窄 病灶 塌陷 充气 肺气肿 (容易肺泡 破裂) 气道纤维化和 %&'()* 慢性阻塞性肺疾病(COPD) 临床表现 并发症 (参阅相关幻灯片) (参阅相关幻灯片) 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Clinical Findings Lung tissue Chronic Obstructive Pulmonary Disease (COPD) damage ↓ elastic recoil to push air out of lungs on expiration Lungs don’t fully empty, air is trapped in alveoli (lung hyperinflation) ↑ lung volume means diaphragm is tonically contracted (flatter) If occurring around airways Airflow obstruction ↑ mucus production ↓ number of epithelial ciliated cells to clear away the mucus (the cells have been killed by airway inflammation) Chronic cough with sputum Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Naushad Hirani* Juri Janovcik* * MD at time of publication During expiration, positive pleural pressure squeezes on airwaysà↑ obstruction ↓ ventilation of alveoli ↓ oxygenation of blood (hypoxemia) ↓ perfusion of body tissues (i.e. brain, muscle) Fatigue; ↓ exercise tolerance Total expiration time takes longer than normal Prolonged expiration More effort needed to ventilate larger lungs Respiratory muscles must work harder to breathe Turbulent airflow in narrower airways is heard on auscultation Expiratory Wheeze Diaphragm can’t flatten much further to generate deep breaths To breathe, chest wall must expand out more Dyspnea Shortness of breath, especially on exertion Breathes are rapid & shallow If end-stage: Chronic fatigue causes deconditioning Muscle weakness & wasting Barrel chest If end-stage: diaphragm will be “flat”. Continued Patient tries to expire against higher mouth air pressure, forcing airways to open wider Pursed-lip breathing Patient breathes with accessory muscles as well as diaphragm to try to improve airflow inspiratory effort further contracts diaphragmà pull the lower chest wall inwards Hoover’s sign (paradoxical shrinking of lower chest during inspiration) Tripod sitting position (activates pectoral muscles) Neck (SCM, scalene) muscles contracted Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"#$ 慢性阻塞性肺疾病 (COPD) 如果出现在气道周围 气流阻塞 肺不能完全排空 气体，气体潴留 于肺泡(肺过度 充气) 总呼气时长大于 正常时长 呼气相延长 肺组织损伤 呼气时，将空气排出肺外 的弹性回缩力↓ 肺不能完全排空气体， 气体潴留于肺泡内 (肺过度充气) 肺容积↑，膈肌紧张 性收缩(膈肌平坦) 呼气时，胸膜腔正压挤压气道 à 气道阻塞↑ 肺泡通气↓ 血液氧合↓ (低 氧血症) 身体组织灌注 量↓ (比如脑、 肌肉) 疲劳; 运动耐量↓ 黏液生成↑ 清除黏液的上皮纤 毛细胞数量↓ (受 气道炎症损伤) 慢性咳嗽伴咳 痰 作者: Yan Yu 审稿人: Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 容积较大 的肺需要 更加努力 才能通气 呼吸肌必须 更用力才能 呼吸 听诊闻及狭窄气 道中的湍流气流 呼气喘鸣音 呼吸困难 气促，尤其是劳累 膈肌无法进一步收缩以 产生深呼吸 呼吸浅快 为了呼吸， 胸壁必须延 展得更大 桶状胸 晚期病人: 患者试图在较高的口 慢性疲劳导致 患者动用辅助呼吸肌和膈肌呼吸， 腔内气压下进行呼气， 活动耐量下降 从而使气道更开放 以改善气流 晚期病人:膈肌 “平坦” ，持续吸气进一步压 缩膈肌à 向内拉季肋部胸壁 胡佛征 (吸气时，胸廓下侧季肋部内收) 缩唇呼吸 肌肉无力 & 消瘦 端坐呼吸 (调动胸肌) 颈部肌肉收 缩(胸锁乳 突肌、斜角 肌) 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Findings on Investigations Chronic Obstructive Pulmonary Disease (COPD) Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Naushad Hirani* Juri Janovcik* * MD at time of publication Airflow obstruction Lung tissue damage ↓ ventilation of alveoli Blood perfusing ill- ventilated alveoli does not receive normal amounts of oxygen During expiration, positive pleural pressure squeezes on airwaysà↑ obstruction) No elastic recoil to push air out of lungs Loss of lung parenchyma and vasculature ↓ surface area for gas exchange ↓ diffusion capacity (on spirometry) Hypoxemia: PaO2 < 70mmHg (on ABGs) Abbreviations: • FEV1: Forced expiratory volume in 1 second • FVC: Forced vital capacity • TLC: Total lung capacity • VC: Vital Capacity Investigations for COPD : • Spirometry (Pulmonary function test) Total expiration time takes longer than normal FEV1/FEV < 0.7 (on spirometry) Lungs don’t fully empty More air trapped within lungs (hyperinflation) More CO2 remains and diffuses into the blood Hypercapnia: PaCO2 > 45 (on ABGs) Ventilation- perfusion mismatch High A-a gradient (calculated from ABGs) Low, flat diaphragm, >10 posterior ribs (on frontal CXR) High TLC and VC (on spirometry) • • PaO2: partial pressure of O2 in arterial blood PaCO2: partial pressure of CO2 in arterial blood • In the setting of fever and productive cough, especially if lung field opacifications are seen on CXR: consider sputum gram stain and culture to rule out pneumonia. Air does not block X-ray beams, will appear black on X-ray film Chronic hypercapnia makes breathing centers less sensitive to the high PaCO2 stimulus for breathing, & more reliant on the low PaO2 stimulus (“CO2 retention”) Give O2 carefully to these patients (high PaO2 may suppress patients’ hypoxic respiratory drive, ↓ their breathing, & ↑↑↑ PaCO2) ↑ retrosternal air space (on lateral CXR) Hyper-lucent (darker) lung fields, ↓ lung markings (on frontal CXR) • Arterial Blood Gasses (ABGs) • Chest X-Ray (CXR): frontal and lateral Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"#$ 气流阻塞 肺泡通气↓ 呼气时，胸膜腔正压挤压气 道à 阻塞↑ 作者: Yan Yu 审稿人: Jason Baserman, Jennifer Au, Naushad Hirani*, Juri Janovcik* 译者:Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 慢性阻塞性肺疾病 (COPD) 肺组织损伤 没有弹性回缩力将 气体排出肺 肺实质与血管分布减少导 致气体交换面积↓ 弥散功能↓ (肺功能检查) 更多的CO2残留 并扩散到血液中 高碳酸血症: PaCO2 > 45 (动脉血气) 血流灌注通气不良的肺泡 时无法获得足够的氧气 总呼气时长较正常长 FEV1/FEV < 0.7 (肺功能检查) 肺无法完全排空 更多空气潴留在肺部 (肺过度充气) 低氧血症: PaO2 < 70mmHg (动脉血气) 通气-灌注不匹配 肺泡-动脉氧分压差↑ (可通过动脉血气分析计算得出) 横膈低平， 下移至第10肋后端 及以下部位 (胸部正位片) TLC与VC增大 (肺功能检查) 缩写: • • FEV1: 1秒用 • VC:肺活量 PaO2: 动脉血 力呼气量 氧分压 空气不会阻挡X射线， 在X光片上呈现为黑色 慢性高碳酸血症使呼吸中枢对PaCO2 刺激呼吸的敏感性下降 & 更依赖于低PaO2的刺激 (“二氧化碳潴留”) 给患者吸氧时需注意(高PaO2 可能会抑制患者低氧时对呼吸的 刺激，使呼吸驱动↓ & PaCO2↑↑↑ ) • FVC: 用力肺 • 活量 • TLC:肺总量 慢阻肺相关检查 : PaCO2: 动脉 血二氧化碳 分压 胸骨后间隙↑ (胸部侧位片) 肺纹理↓ • 肺功能检查 • 动脉血气分析(Arterial Blood Gasses, ABGs) • 胸部正侧位片 • 当患者发热和湿咳，特别是胸片上见肺野不清晰时: 肺透亮度↑, (胸部正位片) 考虑进行痰革兰氏染色及痰培养以排除肺炎可能 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com COPD: Complications Lung inflammation Chronic Obstructive Pulmonary Disease (COPD) Airway obstruction ↓ inhaled air in alveoli and terminal bronchioles Rupture of emphasematous bullae on surface of lung Inhaled air leaks into pleural cavity and is trapped there Pneumothorax Feeling a loss of control over one’s life, and hopelessness for the future Goblet cell proliferation, ↑ mucus production Death of airway epithelium ciliated cells ↓ oxygenation of the blood passing through the lungs Chronic hypoxemia Kidneys compensate by ↑ erythropoietin (EPO) production ↑ Hemoglobin and red blood cell synthesis Polycythemia (secondary) Hypoxic alveoli cause the pulmonary arterioles perfusing them to reflexively vasoconstrict Since most alveoli in the lungs are hypoxic, hypoxic vasoconstriction occurs across entire lung Vasoconstriction ↑ blood pressure within lung vasculature Pulmonary hypertension ↑ workload of the right ventricle (to pump against higher pressures) To compensate, the right ventricle progressively hypertrophies and dilates, but over time its output ↓ Cor pulmonale (Right heart failure in isolation, not due to Left heart failure) Mucus trapped in airways, serve as nidus for infection Acute exacerbation of COPD (AECOPD) Pneumonia The chronic, systemic inflammation in COPD is a hyper-metabolic state that consumes calories Macro-nutrient deficiency Trouble with respiration lead to inactivity and deconditioning Wasting, muscle atrophy More inactivity and deconditioning perpetuates the cycle Depression Author: Yan Yu Reviewers: Jason Baserman Naushad Hirani* Juri Janovcik* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 7, 2013 on www.thecalgaryguide.com COPD: !"# 肺部炎症 杯状细胞增殖， 气道上皮纤毛 粘液产生↑ 细胞死亡 黏液潴留呼吸道，成为感 染的病灶 慢性阻塞性肺疾病 (COPD) 气道阻塞à 吸入肺泡和终末细 肺大疱破裂 吸入的空气渗入 并潴留于胸腔 气胸 感觉生活失控，对未 来感到绝望 抑郁 作者: Yan Yu 审稿人: Jason Baserman, Naushad Hirani*, Juri Janovcik* 译者: Zihong Xie (谢梓泓) 翻译审稿人: Yonglin Mai (麦泳琳), Zesheng Ye (叶泽生) * 发表时担任临床医生 支气管的空气 ↓ 流经肺的血液进行气 缺氧的肺泡à灌注肺泡的肺小动 慢性阻塞性肺疾 病急性加重期 (AECOPD) 肺炎 体交换↓ 慢性低氧血症 肾脏合成促红细胞 生成素进行代偿↑ 血红蛋白与红 细胞合成↑ 红细胞增多症 (继发性) 脉发生反射性血管收缩 肺大部分肺泡缺氧à整个肺 都出现缺氧性血管收缩 肺血管收缩 à 肺血管压力↑ 肺动脉高压 ↑ 右心室负荷(泵血时对抗高压) 为了代偿，右心室逐渐肥大和扩张， 但随着病程进展，右心室输出量 ↓ 肺心病 (单独出现右心衰竭，非左心衰) COPD所致的慢性全身 呼吸困难导致活 性炎症会使机体处于高 动量减少和活动 代谢状态，消耗能量 耐量降低 宏量营养 素缺乏症 消瘦，肌肉萎缩 运动量下降和活动耐量 的降低造成恶性循环 图注: 病理生理 机制 体征/临床表现/实验室检查 并发症 2013年1月7日发布于 www.thecalgaryguide.com " />

Asthma clinical findings

Asthma: Clinical Findings Asthma Episodic airway constriction and airflow obstruction, due to hyper- responsiveness to certain triggers (see slide on asthma pathogenesis) Author: Yan Yu Reviewers: Jason Baserman Jennifer Au Yonoglin Mai (麦泳琳) Naushad Hirani* * MD at time of publication Variable, sporadic airway obstruction in response to triggers Associated allergic eosinophil response Eosinophils infiltrate: Skin If severe: ↓ ventilation of alveoli ↓ oxygenation of blood (hypoxemia) During expiration, positive pleural pressure squeezes on airwaysà↑↑ airway obstruction Heart rate ­ to improve perfusion of tissue Tachycardia Respiratory centers ­ rate of breathing to compensate Tachypnea Gas is trapped within alveolià hyperinflates lungs Ventilating larger lungs needs more effort Patients need to voluntarily contract their expiratory muscles faster and more forcefully to effectively expire Narrower airways àturbulent airflow, heard on auscultation Expiratory Wheeze (high-pitched expiratory sound) Nose Rhinitis/ sinusitis Runny nose, sneezing, etc Atopic dermatitis Skin rash, hives Eyes Conjunctivitis Red itchy eyes, visual blurring Episodic dyspnea (shortness of breath) Chest tightness During severe attacks: Note: Asthma attacks often have two phases: • An immediate attack (within 0-2 hours of the trigger, due to acute release of histamine from mast cells) • A delayed attack (due to eosinophil infiltration of airways, presents within 3-4 hours after exposure to the trigger, peaks within 6-8 hours, and resolves within 24 hours). Keep the possibility of a delayed attack in mind when treating patients in Emergency! Note: Symptoms often worse at night or early in the morning. Note: Asthma should be suspected in children experiencing dyspnea with multiple episodes of Upper Respiratory Tract Infections or Croup. Patient compensates by activating accessory respiratory muscles to ↑ thoracic volume Visible contraction of neck muscles (Scalene, sternocleidomastoids) ↑↑↑ airway obstruction on expiration, lungs take more time to empty Prolonged expiratory phase of breathing Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 17, 2012 and updated Dec 4, 2021 on www.thecalgaryguide.com

necrotizing fasciitis

Necrotizing Fasciitis: Pathogenesis and Clinical Findings Authors: Alyssa Federico, Amanda Eslinger, Matthew Harding, Mehul Gupta Reviewers: Heena Singh, Yan Yu*, Donald Graham*, Duncan Nickerson* * MD at time of publication Diabetes Loss of protective sensation in lower extremities Peripheral vascular disease Poor arterial perfusion causes necrosis of tissue Immune compromised host Increased susceptibility to infection Bacteria introduced to tissue Pharyngitis Blood carries bacteria from throat to other tissue (hematogenous spread) Laceration Recent surgery Injection Burn Blunt force trauma Childbirth Lower extremity wounds Bacteria enters tissue through open wound Infection of muscle fascia Local immune response Production of exotoxins by bacteria Disruptions of protective skin barrier Bacteria introduced into tissue during injury Necrotizing Fasciitis Type I infection: mixed aerobic and anaerobic bacteria Type II infection: group A streptococcus Type III infection: marine organisms, clostridial infections Type IV infection: fungal organisms Poor blood supply of muscle fascia allows for progressive spread of infection Systemic immune response Pyrogens produced by immune system Pyrogens travel through the bloodstream to the hypothalamus and alters the body’s thermal setpoint Transmission of bacteria from infected tissue to blood Sepsis Streptolysin (exotoxin) causes blood clot formation Blood clots in vessels Tissue ischemia in epidermis, dermis, subcutaneous fat, muscle fascia, and/or muscle Stimulation of programmed cell death Tissue destruction Pain more severe than clinical findings ↓ blood flow fails to meet tissue’s needs Tissue death Build up of gas in subcutaneous tissue from bacteria metabolism Crepitus ↑ serum creatinine kinase from protein breakdown ↑ blood flow to infected tissue Warmth Erythema Immune cells release vasoactive cytokines into the blood Capillary vasodilation Fluid and proteins shift from cells and capillaries to interstitial space Blood vessel dilation ↓ perfusion of vital organs Organ failure Hypotension ↑ heart rate to perfuse vital organs Tachycardia Bacteria releases toxins which are taken up into the bloodstream Immune cells produce inflammatory cytokines Circulating toxins activate T cells, over- activating the systemic immune response Toxic Shock syndrome Infection ↑ white blood cell production in bone marrow ↑ white blood cells Destructionof peripheral nerve endings Insensitivity to pain Tissue hypoxia à anaerobic metabolism Poor perfusion of lungs impairs gas exchange Tachypnea Cytokines affect dopamine production in the basal ganglia Acute malaise Production of non-specific acute phase reactants ↑ C reactive protein and erythrocyte sedimentation rate Fluid-filled blisters Edema Fever Compartment syndrome (see relevant Calgary Guide slide) Amputation ↑ serum lactate Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First published Nov 20, 2013, updated Dec 19, 2021 on www.thecalgaryguide.com

Minimal Change Disease

Minimal Change Disease: Pathogenesis and clinical findings Authors: Jessica Krahn Reviewers: Timothy Fu Brooke Fallis Yan Yu* Juliya Hemmet* * MD at time of publication Damage induced by cytokines, not immunocomplexes Lack of abnormal immunocomplexes (antibody-antigen complexes) present in serum Immunofluorescence test negative Idiopathic/Primary Minimal Change Disease No identifiable extraglomerular disease process causes this condition Secondary Minimal Change Disease Infections, NSAIDS, neoplasms via unclear mechanisms Minimal change to glomerulus seen on light microscopy Podocyte effacement seen on electron microscopy Abnormal T Cell activation and release of cytokines (sometimes called permeability factors) that are toxic to podocytes Podocyte foot processes efface (become flattened) or fuse together Damage to negatively charged foot processes damages the charge barrier of the glomerulus that repels negatively charged molecules ↑ filtration of larger negatively charged molecules, such as low-molecular weight proteins like albumin, from the blood into the renal tubular filtrate Induces ↑ hepatic lipoprotein synthesis and ↓ lipoprotein catabolism Hyperlipidemia (↑ serum LDL, VLDL, and triglycerides) ↑ lipid filtration through glomerulus Lipiduria (fatty casts) Hypo-albuminemia ↓ oncotic pressure in capillaries Fluid leaks into interstitial space ↑ Filtration of Proteins C and S and antithrombin Hypercoagulable state Proteinuria ↑ Filtration of immunoglobulins Immunosuppression Infections ↑ Filtration of Plasminogen Plasminogen converted to plasmin in the cortical collecting duct via urokinase- type plasminogen activator Plasmin activates the epithelial sodium channel ↓ intravascular volume Hypotension Pre-Renal Acute Kidney Injury Underfill edema (see slide) Thrombosis Edema (especially peri- orbital, scrotal, labial, and extremities) Overfill edema (see slide) ↑ Na+ and water reabsorption Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 30, 2021 on www.thecalgaryguide.com

NSAIDs and the Kidney Nephrotoxicity

NSAIDs and the Kidney: NSAID induced Nephrotoxicity Non-steroidal anti-inflammatory drugs (NSAID) Authors: Kyle Moxham Mehul Gupta Reviewers: Emily Wildman Yan Yu* Adam Bass* * MD at time of publication Inhibition of Cyclooxygenase COX-1 (expressed in kidney) and COX-2 (expressed in kidney and sites of inflammation) NSAID induced nephrotoxicity: associated with chronic NSAID usage independent of dosage COX inhibition ↑ conversion of arachidonic acid (AA) to leukotrienes, causing systemic T-cell dysfunction (unknown mechanism) Type IV systemic hypersensitivity (delayed T helper cell mediated) reaction to drug exposure T cells release inflammatory cytokines into the bloodstream (see Calgary Guide slide on NSAIDs and the Kidney: Mechanism of Action and Side Effects) T cells infiltrate the renal interstitium, sparing the glomeruli and blood vessels Overproduction of cytokines by T cells causing inflammation, tissue damage, and cell death, of the renal intersitium Drug Induced Acute interstitial nephritis (AIN): a type of immune-mediated tubulointerstitial injury Activated T-cells infiltrate the glomerulus and cause podocyte injury (epithelial cells attached to the glomerular basement membrane) Membranous nephropathy: nephrotic syndrome involving autoimmune glomerular basement membrane thickening & complete podocyte effacement (seen on kidney biopsy) Minimal change disease: nephrotic syndrome caused by autoimmune podocyte effacement (seen on kidney biopsy) Cytokine mediated activation and proliferation of immune cells like macrophages and eosinophils Cytokines travel to hypothalamus, causing change in the body’s thermal set point Fever Podocyte effacement allows for serum proteins to across the glomerulus into the tubular lumen (see Calgary Guide slide on Nephrotic Syndrome for full mechanisms) Repeated NSAID exposure causing recurrent unrecognized AIN and damage of the kidney Chronic interstitial nephritis /analgesic nephropathy Infiltrating immune cells (predominantly neutrophils) are filtered into/enter the renal tubules, and form clumps (“casts”) within the tubulesà casts are then released into urine WBC cast on urinalysis ↑ Blood eosinophils Immune cells infiltrate the dermis and epidermis of the skin Rash Abnormal quantities of protein present in urine Protein present in the blood is improperly filtered into the filtrate at the glomerulus Protein- Creatinine Ratio >3.5mg/mg Proteinuria >3.5g/d Hypo- albuminemia ↓ plasma oncotic pressure resulting in fluid extravasation into the interstitium (see Calgary guide slide on Edema for full mechanisms) Pitting Edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 13, 2022 on www.thecalgaryguide.com

Langerhans Cell Histiocytosis

Langerhans Cell Histiocytosis: Pathogenesis and clinical findings Precursor cells differentiateàClonal expansion of abnormal (constitutive MAPK activation) CD1a+/CD207+ (Langerhans cell phenotype surface receptors) dendritic cells in tissue(s) Somatic BRAFV600E mutation: BRAF is a kinase in the MAPK pathway Other somatic (non- reproductive cell) mutations Idiopathic (unknown cause) Mutation(s) can occur in one of these precursor cell types* Hematopoietic stem cell (earliest cell of blood cell differentiation) in bone marrow Committed dendritic cell (type of myeloid antigen-presenting cell) precursor in bone marrow or blood Committed dendritic cell precursor in tissue Constitutive activation of the MAPK pathway (signalling pathway that regulates variety of cellular processes) in one of these precursor cell types *Note: Based on the “misguided myeloid differentiation” modelàthe earlier the mutation(s) occur in the myeloid cell differentiation pathway, the more severe the disease. Langerhans Cell Histiocytosis Accumulation of abnormal CD1a+/CD207+ dendritic cells (Langerhans Cell Histiocytosis cells or LCH cells) with an inflammatory background in one or more organs Authors: Ran (Marissa) Zhang Reviewers: Mehul Gupta Kiera Pajunen Yan Yu* Lynn Savoie* * MD at time of publication ↑ recruitment & activation of T cells, macrophages, eosinophils in tissue(s) around the body ↓ CCR7 & CXCR4 (chemokine receptors) expression on LCH cellsàinhibits migration of LCH cells to lymph nodes ↑ BCLXL (an apoptosis regulator protein) expression on LCH cellsà inhibits apoptosis of LCH cells Immune cell infiltration & ↑ pro-inflammatory chemokine/cytokine release à dysregulated local & systemic inflammation Accumulation of LCH cells in tissue(s) around the body Inflammatory lesion (an area of abnormal tissue) formation in one or more organs: In pituitary stalk Mass effectà obstruction of antidiuretic hormone (complex mechanisms) In liver Invasion & accumulation of cells foreign to liverà expands liver Chronic local inflammation Scarring of bile ducts ↓ bilirubin clearance from liveràbuildup into serum ↑ serum bilirubin Jaundice In cortical bone Cytokine production à↑ osteoclast (cells that break down bone) activity ↑ rate of bone loss Osteolytic bone lesions In bone marrow Unclear mechanism but likely due to macrophage activation ↑ phagocytosis (ingestion & destruction) of blood cells In spleen Invasion & accumulation of cells foreign to spleen Forms aggregates that expand the red pulp (functions as the blood filter in spleen) Splenomegaly In skin Unclear mechanisms Variable presentations: most commonly pinpoint erythematous (red) papules or erythematous plaques with crusting & scaling Hepatomegaly • BRAF- B-Raf proto-oncogene, serine/threonine kinase • CCR7- C-C motif chemokine receptor type 7 • CD1a- Cluster of differentiation 1A • CD207- C-type lectin domain family 4 member k • CXCR4- C-X-C chemokine receptor type 4 • LCH- Langerhans Cell Histiocytosis • MAPK- Mitogen-activated protein kinase Diabetes Insipidus Abbreviations: • BCLXL- B-cell lymphoma-extra large Anemia, thrombocytopenia &/or neutropenia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 13, 2022 on www.thecalgaryguide.com

Vitiligo Pathogenesis and Clinical Findings

Vitiligo: Pathogenesis and clinical findings Authors: Wisoo Shin Reviewers: Lauren Lee Stephen Williams Ben Campbell Laurie Parsons* Yan Yu* * MD at time of publication Genetic predisposition Variants in over 30 susceptibility loci Environmental exposure UV light, monobenzone, phenol, catechol Production of IgG auto- antibodies to melanocyte-specific proteins Auto-antibodies bind to melanocytes and trigger antibody-dependent cellular cytotoxicity: marking melanocytes for destruction by Fc- receptor bearing immune cells such as neutrophils Impaired mitochondrial function in melanocytes ↑ Susceptibility of melanocytes to oxidative stress ↓ E-cadherin or ↑ anti- adhesion molecule expression in melanocytes ↓ Adhesion of melanocytes to keratinocytes ↑ Clearance of melanocytes from epidermis ↑ Reactive oxygen species production within melanocytes Activation of apoptosis and senescence signaling pathways Pressure or friction Melanocytes excrete exosomes (melanocyte- specific antigens, microRNA, heat shock proteins) that, through complex mechanisms, stimulate the immune system’s CD8+ T-cells to destroy melanocytes Melanocytes enter apoptotic or senescent state ↓ Functional melanocytes ↓ Melanin production Overall loss of functional melanocytes Vitiligo Normal Skin Pigmented Epidermis Dermal- Epidermal Junction Dermis Autoimmune destruction of melanocytes Depigmented Epidermis Melanocytes Immune-mediated destruction of melanocytes (by both neutrophils and CD8+ T cells) A depigmenting skin disorder characterized by selective loss of melanocytes Depigmentation in areas of ↑ pressure, friction and/or trauma Nonsegmental vitiligo Smooth unpigmented macules or patches in bilateral, often symmetric pattern Somatic mosaicism (mutation limited to a subset of cells) in zygote during development Segmental vitiligo Smooth unpigmented macules or patches in unilateral pattern not crossing midline Vitiligo Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published February 15, 2022 on www.thecalgaryguide.com

isotretinoin-systemic-retinoid-mechanisms-and-side-effects

Isotretinoin (Systemic Retinoid): Mechanisms and Side Effects Isotretinoin Authors: Ayaa Alkhaleefa Reviewers: Mehul Gupta, Ben Campbell Stephen Williams, Lauren Lee, Yan Yu*, Laurie Parsons* * MD at time of publication ↑ Apoptotic signaling in sebocytes Inhibits androgen nuclear receptors responsible for sebum secretion ↓ Sebaceous lipogenesis ↑ Apoptotic signaling in neural crest cells during embryonic development Alterations in hindbrain, neural crest, otic anlage, and reduced pharyngeal arch in embryo Craniofacial, cardiac, thymic, and central nervous system malformations in fetus Isotretinoin isomerizes to all-trans retinoic acid (ATRA) ATRA enters cell nucleus and binds retinoic acid receptors and retinoic X receptors ATRA induces tumour necrosis factor-related apoptosis-inducing ligand ↑ Apoptotic signaling in epidermal keratinocytes ↑ Expression of FoxO1 ↑ Expression of p53 (tumour suppressor) Release of caspases 3, 6, 7, and 9 ↑ Cell cycle inhibitors p21 and p27 ↓ Pro-survival proteins (Survivin) Sebaceous gland involution Sebum suppression C. acnes unable to break down sebum into pro- inflammatory lipids ↓ Colonization with C. acnes Teratogenicity ↑ Cornification (death) of epidermal keratinocytes ↓ Corneodesmosomes (main adhesive structures of the stratum corneum) ↓ Cohesion of corneocytes (dead keratinocytes) ↓ Corneocyte buildup in pilosebaceous follicles C. acnes unable to populate and release cytokines in corneocytes Epidermis Dermis Pilosebaceous follicle ↓ Stratum corneum thickness ↑ Trans-epidermal water loss Dryness, peeling & inflammation of lips (cheilitis), skin (dermatitis) & mucosa (mucositis) ↓ Comedogenesis Sebum Hair follicle Dermal- Epidermal Junction Sebaceous gland (sebocytes) Death of sebocytes in pilosebaceous follicles Reduction of number and size of acne lesions Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 20, 2022 on www.thecalgaryguide.com

irritable-bowel-syndrome-ibs-pathogenesis-and-clinical-findings

Irritable Bowel Syndrome (IBS): Pathogenesis and clinical findings Authors: Ben Campbell Reviewers: Mehul Gupta Kiana Hampton Yan Yu* Edwin Cheng* * MD at time of publication Note: *Several signaling pathways in the gut are believed to play a role in IBS. The serotonin pathway is represented here for illustrative purposes, and it is a common target of therapy. Pathogenesis is multifactorial, not fully understood, and may arise from any one or a combination of these factors Genetic factors are believed to influence many of these pathways Environmental factors Gut infection, ischemia, injury, chronic low-level inflammation, altered microbiome Abnormal gut chemical milieu (cytokines, lymphocytes, mast cells, hormones) One common pathway: altered quantity or activity of serotonin-releasing enterochromaffin * cells and serotonin reuptake transporters in gut Serotonin is a key stimulator of gut muscle contraction and sensory signaling Altered bowel motility Bowel motility can ↑, ↓ or alternate ↑/↓ Psychosocial factors Anxiety, depression, adverse experiences, dysregulated stress response Brain can alter normal reflexes of enteric nervous system (e.g. via hypothalamic stress hormone release) ↑ Activity of sensory receptors in gut + recruitment of formerly ”silent” receptors Altered visceral bowel sensation Visceral hypersensitivity Complex mechanisms ↓ Brain’s ability to modulate pain signals from gut; ↑ vigilance to pain Irritable Bowel Syndrome Disorder of brain-gut interaction with gastrointestinal manifestations Not a predominantly inflammatory condition During times of ↑ bowel motility: No lesions in gut mucosa (Absence of ”red flags” for organic disease) ↑ Impacts of other factors that precipitate diarrhea Dietary sensitivity (e.g. to intake of fermentable oligo/di/ monosaccharides and polyols— FODMAPs—which draw water into gut lumen by osmosis) ↑ Impacts of other factors that precipitate constipation Dietary sensitivity (e.g. to inadequate intake of motility- promoting fibre) During times of ↓ bowel motility: ↑ Time for water absorption from feces and bacterial fermentation ↑ Hard stool and trapped gas in bowel ↑ Number and sensitivity of active pain receptors (nociceptors) in gut Hyperalgesia ↑ Response to painful stimulus Stretch receptors in gut stimulate pain in normally unconscious neural pathways Allodynia Pain in response to normal stimulus ↑ Peristalsis ↓ Time for water absorption from feces ↑ Water volume in gut lumen ↑ Stretch / stimulation of visceral afferent nerves in gut Absence of bloody stool and anemia Absence of nocturnal symptoms and inflammatory markers Constipation Bloating Diffuse abdominal pain All symptoms may exacerbate psychosocial factors Bowel distension Diarrhea Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 30, 2022 on www.thecalgaryguide.com

hypercalcemia-pathogenesis

Hypercalcemia: Pathogenesis Malignancy Thiazide Diuretics Immobilization Granulomatous Diseases (e.g., sarcoidosis, tuberculosis, fungal infections) Ectopic (outside of kidney) production of 1-α-hydroxylase 1-α-hydroxylase converts calcidiol to calcitriol (aka 1,25-OH Vitamin D or active Vitamin D) ↑ 1-25 OH Vitamin D ↑ Absorption of Ca2+ in the small intestine ↑ Vitamin D Intake Dietary Vitamin D is converted to calcidiol (aka 25- OH Vitamin D or inactive Vitamin D) in the liver Primary Hyperparathyroidism ↑ or normal* serum parathyroid hormone (PTH) level Tumour released Parathyroid Hormone related Peptide (PTHrP) mimics natural PTH (PTH level itself is low) Tumour produces bone- reabsorbing substances (IL-6, IL-1, RANKL) Paget’s Disease Osteoblasts produce abnormally high levels of RANKL Block Na+/Cl- cotransporter (NCC) on distal convoluted tubule (DCT) cells of the nephron ↓ Na+ and Cl- transport from lumen into DCT cells ↓ Intracellular Na+ in DCT cells + To compensate Na , ↑ Ca-ATPase and 3:Na:Ca exchanger activity on DCT cells (moves 3 Na+ into cell, 1 Ca+ out into peritubular capillary) ↑ Ca+ moving into bloodstream ↓ Mechanical stimulation of osteocytes ↓ Signaling of osteoblasts (cells that form bone) ↓ New bone formation ↓ Ca2+ incorporation into bone ↑ Ca2+ in plasma ↑ reabsorption of Ca2+ from the distal portion of nephron back into the blood ↑ 1-α-hydroxylase production in the proximal convoluted tubule Milk Alkali Syndrome Ca2+ intake exceeding 2000 mg per day leads to unregulated gut Ca2+ absorption into the blood PTH binds to osteoblasts on the surface of bone Osteoblasts produce RANKL to stimulate osteoclast function ↑ Osteoclast (cells that breakdown bone) activity ↑ Bone breakdown Ca2+ within bone is released into the bloodstream Osteolytic bone metastases Hyperthyroidism ↑ Catabolic thyroid hormones ↑ RANKL: OP ratio, RANKL promotes bone breakdown by stimulating osteoclast growth while OP (osteogenic protein) promotes bone formation Hypercalcemia Hypercalcemia Authors: Alexander Arnold, Peter Vetere, Huneza Nadeem Reviewers: Mark Elliott, Ran (Marissa) Zhang, Yan Yu*, Hanan Bassyouni* * MD at time of publication See Hypercalcemia: Clinical Findings slide *Note: A normal PTH value is abnormal in the context of hypercalcemia, since hypercalcemia would normally negatively feed back to suppress PTH production. Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published February 11, 2014, updated Aug 11, 2022 on www.thecalgaryguide.com

asthma-how-treatments-work-and-common-side-effects

Asthma: How Treatments Work and Common Side Effects • Relievers: Used as needed to ↓ symptoms during attacks • Controllers: Used daily to ↓ frequency and severity of attacks Note: Please see slide on Asthma: Pathogenesis • Exacerbation: Used emergently in acute exacerbation Short-acting Beta Agonists (Reliever) Long-acting Beta Agonists (Controller) Short-acting Muscarinic Antagonists (Exacerbation) Long-acting Muscarinic Antagonists (Controller) Magnesium Sulfate (Exacerbation) Monoclonal Antibodies (Controller) Leukotriene Receptor Antagonists (Controller) Inhaled Corticosteroids (ICS) (Controller) Systemic Corticosteroids (Exacerbation) Binding to beta-2 adrenergic receptors and subsequent intracellular signal cascade in bronchial smooth muscle Off-target binding occurs in other systemic cells Inhibition of muscarinic acetylcholine receptors in airway muscle cells ↓ Activation of the inositol triphosphate (IP3) intracellular pathway (IP3 pathway normally functions to mobilize intracellular Ca2+ stores) Inhibition of Ca2+ channels on airway smooth muscle surface ↓ Influx of Ca2+ Binding and inactivation of inflammatory signal molecules (IgE, IL-5) Inhibition of leukotriene receptors in lung and immune cells Steroid binds to nuclear receptors within cells ↓ Gene expression/synthesis of immune mediators (ex. cytokines) Stimulation of Na/K ATPase (which transports K into cells) Hypokalemia Palpitations Tachycardia Muscle cramps Tremor Authors: Chunpeng Nie Reviewers: Sravya Kakumanu, Ben Campbell, *Tara Lohmann * MD at time of publication ↓ Activation of mast cells (by ↓ IgE) and eosinophils (by ↓ IL-5/leukotrienes) ↓ Release of inflammatory cytokines by these cells (↓ Type 2 inflammatory response in airways) ↓ Permeability of airway vasculature ↓ Microvascular leakage into airway Inadvertent sympathetic nervous system activation Bronchial smooth muscle cells have ↓ Ca2+ release from intracellular stores (i.e. from sarcoplasmic reticulum) ↓↓ Cytoplasmic Ca2+ Myosin (muscle protein) unable to be activated for muscle contraction ↓ Smooth muscle contraction in bronchioles Bronchodilation ICS cause ↓ immune cell activity in the oropharynx Susceptibility to infection and irritation of the oropharynx from inhaled particles and pathogens Hoarseness Thrush Systemic corticosteroids cause ↓ immune cell activity in whole body ↑ Susceptibility to any infection Many other side effects Similar effects on other muscles in the body outside bronchi Dry mouth Urinary retention Constipation ↓ Mucosal edema ↓ Airway Mucus Airflow improvement ↑ Peak flow, ↑ Oxygenation, ↓ Dyspnea Legend: Pathophysiology Mechanism Treatment Effect Complications Published October 9, 2022 on www.thecalgaryguide.com

chronic-pancreatitis-complications

Chronic pancreatitis: Complications Hypothesis: Cytokines stimulate hypersecretion of secretory proteins (lithostathine, GP2) from acinar cells in exocrine pancreas (early in disease course) Proteins precipitate and form aggregates within pancreatic ducts Accumulation of protein aggregates and localized fibrosis block pancreatic ducts Rupture of acinar cells near blocked ducts → release of intracellular enzymes and fluid Accumulation of enzyme- rich fluid within pancreas Intra-pancreatic pseudocysts (differ from pseudocysts in acute pancreatitis, which are primarily extra-pancreatic) Chronic Pancreatitis Recurrent episodes of acute pancreatitis leading to irreversible fibroinflammatory pancreatic damage Inflammatory cytokines are continuously released from damaged pancreas over years Cytokines damage endothelium of intra- and peri-pancreatic blood vessels (including splenic vein, which runs posteriorly behind pancreas and allows for its venous drainage) Thin and weakened vessel walls balloon outwards from pressure of blood flow Pseudoaneurysms Venous stasis (low blood flow) → ↑ concentration of clotting factors Obstruction of peripancreatic ducts Author: Ashar Memon Reviewers: Yan Yu*, Kiana Hampton, Sylvain Coderre* * MD at time of publication Exocrine insufficiency (↓ secretion of digestive enzymes, e.g., Lipase, into gastro-intestinal tract) ↓ digestion of foods and absorption of nutrients (including fats) ↓ absorption of fat-soluble vitamin D Metabolic bone disease (a group of disorders of decreased bone mineralization) Blood vessels dilate and swell from increased blood flow Gastric varices Cytokines perpetually activate pancreatic stellate cells (stellate cells produce proteins that remodel extra- cellular matrix) Pancreatic stellate cells increase amounts of collagen and other extra- cellular matrix molecules in pancreas → Fibrosis Pancreatic proteolytic enzymes (e.g., trypsin) in fluid-filled pseudocysts digest walls of adjacent blood vessels Fibrotic tissue and pseudocysts compress peripancreatic structures (including splenic vein) Cytokines stimulate apoptosis of hormone- producing pancreatic Islet cells (e.g., beta cells) Endocrine insufficiency (↓ production and secretion of pancreatic hormones) Damaged endothelial cells of splenic vein trigger coagulation cascade (See Calgary Guide slide on Coagulation Cascade) Splenic vein thrombosis ↑ resistance to blood flow through splenic vein Cytokines stimulate apoptosis of acinar cells in exocrine pancreas Malnutrition ↓ secretion of insulin ↓ cellular uptake and metabolism of glucose → hyperglycemia Diabetes mellitus Collateral blood vessels develop around stomach so blood can circumvent splenic vein and relieve splenic vein hypertension Duodenal obstruction Biliary obstruction Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 18, 2022 on www.thecalgaryguide.com

thiazide-diuretics-mechanism-of-action-and-adverse-side-effects

Thiazide Diuretics: Mechanism of Action and Adverse Side Effects Thiazide diuretics Authors: Huneza Nadeem Reviewers: Ran (Marissa) Zhang, Julian Midgley* * MD at time of publication Thiazides in circulation enter the proximal convoluted tubule (PCT) cells by basolateral Organic Acid Transporter 1 (OAT1) ↑ Intracellular thiazide availability for apical OAT4 exchangers OAT4 reabsorb urate in lumen in exchange for thiazide that is excreted ↑ Urate in serum Hyperuricemia Uric acid build up in joints Gout Block the Na-Cl cotransporter (NCC) in the distal convoluted tubule (DCT) of the nephron Impaired water excretion, vasopressin release, and ↑ water intake (mechanisms unclear) Hyponatremia Lack of intracellular Na+ needed to drive the Na+/K+ ATPase (moves 2 K+ into cell, 3 Na+ out into peritubular capillary) ↓ Intracellular Na+ drives Ca-ATPase and 3:Na:Ca exchanger activity (moves 3 Na+ into cell, 1 Ca+2 out into peritubular capillary) ↑ Ca+2 in serum Hypercalcemia See Hypercalcemia: Clinical Findings slide ↓ Na+ and Cl- reabsorption into proximal DCT cells ↑ Na+ in DCT filtrate by ∼3-5% Water follows Na+ to maintain balanced osmotic pressure ↑ Water available for excretion Mild Diuresis ↓ Blood volume Hypotension ↑ Na+ filtrate delivery to cortical collecting duct (CCD) Epithelial sodium channels (ENaC)s on principal cells of the CCD transport Na+ from filtrate into the principal cells ↑ Intracellular Na+ drives Na/K+ ATPase activity on principal cells (moves 2 K+ into cell, 3 Na+ out into peritubular capillary) ↑ Intracellular K+ drives H/K+ ATPase activity on intercalated cells (moves 1 H+ into cell, 1 K+ out into tubular filtrate) ↓ K+ in serum Hypokalemia See Hypokalemia: Clinical Findings slide Acute response to high dose thiazide diuretics (mechanism unclear) Hyperlipidemia Hypokalemia induces hyperpolarization of pancreatic beta cells ↓ Number of voltage gated Ca+2 channels open given intracellular charge ↓ Ca+2 influx prevents exocytosis mediated insulin release ↓ Glucose uptake in the body Hyperglycemia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 18, 2022 on www.thecalgaryguide.com

type-ii-proximal-renal-tubular-acidosis-pathogenesis-and-laboratory-findings

Type II/Proximal Renal Tubular Acidosis: Pathogenesis and Laboratory Findings Authors: Wazaira Khan* Reviewers: Huneza Nadeem, Ran (Marissa) Zhang, Julian Midgley* * MD at time of publication Overview of bicarbonate reabsorption in the proximal tubule (PT): Serum bicarbonate (HCO3-) is filtered by the glomerulus and enters PT lumen H+ ATPase and sodium- hydrogen exchanger 3 (NHE3) on luminal surface of PT cell secrete H+ into PT lumen H+ combines with HCO3- in PT lumen to form carbonic acid (H2CO3) H2CO3 is broken down to H2O and CO2 by luminal membrane carbonic anhydrase 4 CO2 diffuses into PT cell CO2 reacts with H2O to form H2CO3 in PT cell, catalyzed by cytosolic carbonic anhydrase 2 H2CO3 rapidly breaks down intracellularly to form HCO3- and H+ HCO3- is reabsorbed into plasma by sodium bicarbonate transporter (NBCE1) on basolateral surface of PT cell HCO3- is available for use to buffer plasma H+ H+ is available intracellularly for use by H+ ATPase and NHE3 exchanger Mutation encoding NHE3 exchanger ↓ H+ secretion into PT lumen Galactosemia, Wilson disease, cystinosis, tyrosinemia, glycogen storage disorders Dent disease, Lowe syndrome Infiltrative disorders e.g., amyloidosis, multiple myeloma, monoclonal gammopathies Drugs e.g., tenofivir, ifosfamide, cisplatin Carbonic anhydrase inhibitors ↓ H2CO3 breakdown to H2O and CO2 Mutation encoding CAII enzyme, carbonic anhydrase inhibitors ↓ H2CO3 production in PT lumen ↓ CO2 diffusion into PT cell ↓ H2CO3 production in PT cell ↓ HCO3- production in PT cell ↓ HCO3- reabsorption by PT cell into plasma Type II/Proximal Renal Tubular Acidosis (RTA) Defective HCO3- reabsorption in proximal tubule Normal anion gap metabolic acidosis (NAGMA) See NAGMA slide Accumulation of toxic metabolites systemically, including in the PT Disruption of endocytosis and intracellular transport systemically, including in the PT Accumulation of light chain/amyloid deposits in PT Interfere with PT’s ability to reabsorb ions/molecules • • • • Fanconi Syndrome: generalized PT dysfunction Defective tubular reabsorption of other ions/molecules to varying degrees, including phosphate, glucose, sodium and amino acids Tubular proteinuria Phosphaturia Glucosuria ↑ Na+ secretionàhypovolemia Mutation encoding NBCE1 transporter ↑ HCO3- delivery to distal nephron K+ in distal nephron lumen binds to HCO3- K+ is lost through osmotic diuresis Hypokalemia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 24, 2022 on www.thecalgaryguide.com

Granulomatosis with Polyangiitis Pathogenesis

Granulomatosis with polyangiitis: Pathogenesis Author: Oswald Chen Reviewers: Ben Campbell *Liam Martin * MD at time of publication Drugs Thiol- and hydrazine-containing medications (e.g., hydralazine, propylthiouracil, allopurinol) Environmental exposures Silica dust, cigarette smoke, infections (Staphylococcus aureus) Genetic factors Alpha-1 antitrypsin deficiency, proteinase 3 gene mutation ↑ Production of cytokines and antineutrophil cytoplasmic antibodies (ANCAs) (mechanism unknown) Cytokines bind to endothelial cells (that line blood vessels) and neutrophils, priming them Proteinase 3 (PR3), an enzyme that degrades extracellular matrix proteins, migrates from neutrophil granules to neutrophil cell surface Circulating ANCAs bind to PR3 on neutrophils PR3 stimulates maturation of dendritic cells in lungs Dendritic cells present antigen (PR3) to naïve CD4+ T cells in peripheral lymph nodes T cells differentiate into type 1 and type 17 helper T cells (Th1 and Th17 cells) Th1 and Th17 cells secrete cytokines (interferon γ (INF-γ) and tumor necrosis factor α (TNF-α)) in lungs Secreted cytokines trigger macrophage maturation Formation of granulomas (giant cells with central necrosis surrounded by plasma cells, lymphocytes, and dendritic cells) primarily in lungs and upper airways ANCA-activated neutrophils release proinflammatory cytokines, attracting more neutrophils to endothelium (blood vessel wall) ANCA-activated neutrophils undergo firm adhesion to endothelium ANCAs stimulate ↑ secretion of proteolytic enzymes and reactive oxygen species from neutrophils Endothelial damage and tissue injury Granulomatosis with polyangiitis (GPA) ANCA-associated vasculitis affecting medium and small-sized arteries, associated with necrotizing granulomas Constitutional symptoms with involvement of multiple organ systems (see slide on clinical findings) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 4, 2022 on www.thecalgaryguide.com Granulomatosis with polyangiitis: Clinical findings Inflammation-mediated endothelial damage and granuloma formation (see slide on pathogenesis) Granulomatosis with polyangiitis (GPA) Author: Oswald Chen Reviewers: Ben Campbell *Liam Martin * MD at time of publication ANCA-associated vasculitis affecting medium and small-sized arteries, associated with necrotizing granulomas Constitutional symptoms Fever, unintentional weight loss, night sweats, arthralgias Skin involvement Inflammation of cutaneous vessels Systemic inflammation obstructing blood flow, with granulomatous lesions primarily in upper airways and lungs Ear, nose, and throat involvement ↑ C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) (markers of inflammation) Necrotizing granulomas on biopsy of affected tissue Positive PR3-ANCA/c-ANCA blood test (antibodies present in ~90% of patients, described in GPA Pathogenesis slide) Renal involvement Inflammation of renal vessels Rupture of basement membrane (layer that filters blood from glomerular capillaries into Bowman’s capsule) Pauci-immune glomerulonephritis (see Nephritic Syndrome slide) Rapidly progressive glomerulonephritis Eye involvement Inflammation of ocular tissue Conjunctivitis Scleritis/ episcleritis (painful red eye) Lower respiratory tract involvement Inflammation of pulmonary vessels Vessel occlusion and ischemia Skin necrosis Vessels burst and blood pools under skin Round and retiform (net- like) palpable purpura of lower extremities Granulomatous destruction of nasal cartilage Collapse of nasal bridge Saddle nose deformity Inflammation of paranasal sinus and nasal cavity vessels ↓ Perfusion of lungs Dyspnea Damage to interstitial capillaries Hemoptysis Diffuse alveolar hemorrhage Rhinitis/ sinusitis Granulomatous obstruction of eustachian tube Otitis media (see Otitis Media slide) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 4, 2022 on www.thecalgaryguide.com

Acute and Chronic Gastritis: Pathogenesis and clinical findings

Acute and Chronic Gastritis: Pathogenesis and clinical findings Author: Oswald Chen Reviewers: Vina Fan, Ben Campbell, Eldon Shaffer* * MD at time of publication Infectious Helicobacter pylori (most common) Noninfectious NSAIDs, alcohol, gastric reflux Stress Critical illness, trauma Gastric ulceration (see Peptic Ulcer Disease slide) ↓ Gastric mucosal defense (↓ secretion of prostaglandins and mucus) Acid erodes gastric mucosa Inflammatory cells (primarily neutrophils) infiltrate site of injury Acute Gastritis Acute inflammation of gastric mucosa Inflammatory cells (primarily lymphocytes and plasma cells) accumulate in gastric mucosa Autoimmune Metaplastic Environmental Metaplastic Atrophic Gastritis (AMAG) Atrophic Gastritis (EMAG) Atrophic Gastritis Chronic inflammation of gastric mucosa Inflammatory cells destroy gastric glandular epithelial cells Gastric mucosal atrophy and metaplasia (replacement of gastric mucosal cells with intestinal epithelial cells, commonly goblet cells) Hypochlorhydria (parietal cell loss → ↓ hydrochloric acid secretion) ↓ Iron absorption Iron deficiency anemia (see Iron Deficiency Anemia slide) Activation of chemoreceptors and mechanoreceptors Activation of visceral nociceptors Visceral afferents stimulate chemoreceptor trigger zone of medulla Nausea/ vomiting Autoimmune Associated with human leukocyte antigens HLA-B8 and HLA-DR3, which are proteins expressed on immune cell surface Antibodies destroy parietal cells and intrinsic factor in gastric body and fundus Epigastric pain (typically burning or gnawing) Dyspepsia (abdominal discomfort after eating, often with early satiety and bloating) Parietal cell loss → ↓ intrinsic factor → ↓ vitamin B12 absorption Vitamin B12 deficiency (see Vitamin B12 Deficiency slide) Macrocytic Peripheral anemia neuropathy ↓ Gastric acidity leads to ↓ inhibition of G cells in antrum Hypergastrinemia (↑ gastrin release from G cells) Gastrin binds to cholecystokinin-B (CCK-B) receptors on parietal and enterochromaffin-like (ECL) cells of gastric body ↑ CCK-B signaling leads to ↑ cell proliferation and ↓ cell death (↓ apoptotic activity) Hyperplasia (↑ number of cells) Low-grade dysplasia (disordered growth of epithelium) High-grade dysplasia Carcinoid tumor (0.7% of cases) Malignancy arising from ECL cells Gastric adenocarcinoma (0.3% of cases) Malignancy arising from gastric epithelial cells Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 15, 2022 on www.thecalgaryguide.com

Ischemic Stroke: Pathogenesis

Ischemic Stroke: Pathogenesis Small artery occlusion Acute injury (<20mm diameter) of basal or brainstem penetrating arteries Large artery atherosclerosis Cholesterol plaque ↓ diameter of intra- or extracranial vessel Cardiac embolism Blood clot in heart breaks free, travels to brain Other E.g. volume loss, severe infection Unknown E.g. 2 or more mechanisms Modest ↓ in O2 at penumbra (see figure) Authors: Mizuki Lopez Andrea Kuczynski Illustrator: Mizuki Lopez Reviewers: Sina Marzoughi Usama Malik Hannah Mathew Ran (Marissa) Zhang Andrew M Demchuk* Gary M. Klein* * MD at time of publication Significant ↓ in O2 at ischemic core (see figure) ↑ Anaerobic metabolism ↓ ATP Production Dysfunction of Na+/K+ ATPase pump (for 1 ATP molecule, 3 Na+ moved out of cell, 2 K+ moved into cell) H2O influx following Na+ Cerebral edema Compression of vessels and surrounding tissue damages blood-brain barrier ↑ Permeability of damaged blood-brain barrier Infiltration by peripheral immune cells Immune cells release inflammatory cytokines ↓ Cerebral Blood Flow Penumbra Ischemic core Metabolic demands are greater than supply of ATP Cell death Microglia (resident neural immune cells) activate to clean dead cell debris Microglia release inflammatory cytokines (TNFα, IFγ, IL-1β) Cytokines lead to astrocyte activation (support cells for neurons) Astrocytes release more inflammatory cytokines Inflammation of brain tissue ↑ Na+, Ca2+ influx, K+ outflux ↓ Glutamate (excitatory neurotransmitter) reuptake by astrocytes (support cells for neurons) ↑ Glutamate in extracellular fluid Spreading depolarization from core (unclear mechanism) Activate biochemical pathways including glutamate receptor activation ↑ Glutamate activity Activate glutamate receptors that conduct Ca2+ ↑ Ca2+ influx into neuron Activation of catabolic proteases, lipases, nucleases in neuron Dysfunction of neuronal protein synthesis and activity Neuronal cell death ↑ Volume of dead (infarcted) brain tissue Neurons depolarize and release glutamate Reversal of Na+ Dependent Glutamate Reuptake Transporters on astrocytes (normally 3 Na++ 1 H+ + 1 glutamate into cell, for 2 K+ out) ↑ Glutamate in extracellular fluid Stroke symptoms (e.g. weakness, slurred speech, visual field losses, autonomic dysfunction) (see Ischemic Stroke: Impairment by Localization stroke slide) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 14, 2017; updated November 6, 2022 on www.thecalgaryguide.com

Myelodysplastic Syndrome Pathogenesis and clinical findings

Myelodysplastic Syndrome (MDS): Pathogenesis and clinical findings Authors: Mao Ding Reviewers: Ashar Memon Man-Chiu Poon Yan Yu* * MD at time of publication Stem cells differentiateà accumulation of bone marrow cells with aberrant morphology & maturation Idiopathic (unknown cause) Treatment related: exposure to ionizing radiation, chemotherapeutic agents (e.g., alkylating agents, anti- metabolite, topoisomerase II inhibitors) Environmental toxins (e.g., tobacco, benzene & other organic solvents) Familial predisposition to MDS Acquired somatic (non- reproductive) gene mutations (DNA alterations) Inherited germline (reproductive cells) gene mutations Recurrent mutations cause alteration(s) in one or more protein functions with/without chromosomal abnormalities in hematopoietic stem cell (earliest cell of blood cell differentiation): Mutation in the transcription factor gene RUNX1 impairs regulation of normal hematopoietic (blood cell) development Mutation(s) in epigenetic regulator genes (DNMT3A, TET2) impairs regulation of DNA methylation Mutation in splicing regulator genes (SF3B1) causes mistakes in splicing mRNA moleculesàaberrant translation (production) of proteins Chromosomal abnormalities: deletions (chromosome 5, 7, and/or 20), duplications (chromosome 8), structural abnormalities (inversion of a gene segment) Myelodysplastic Syndrome Mutation-associated clonal disorders of hematopoietic stem cells, causing dysplasia (abnormal development) of one or more myeloid cell lineages (granulocytes, monocytes, red blood cells & platelets) in the bone marrow Genetic mutations or chromosomal abnormalities occur in hematopoietic stem cellsàclonal expansion of abnormal cells in bone marrow Apoptosis (programed cell death) of clonal cells, inhibiting development of granulocytes, monocytes, red blood cells & platelets in the bone marrow Neoplastic myeloid precursor cells (blasts) accumulate in the bone marrow Acute Myeloid Leukemia (AML) > 20% Blasts in the bone marrow Excessive blasts displace other precursor cells & inhibit differentiation Pancytopenia (↓ number of cells of ALL 3 cell lines: platelets, white blood cells & red blood cells) (see Acute Myeloid Leukemia for signs/symptoms/complications) ↓ Number of mature functional blood cells leave the bone marrow to go to peripheral bloodà↓ number of cells of one or more cell lines Bone marrow’s inability to make sufficient blood cells cause extramedullary hematopoiesis (formation/activation of blood cells outside the medulla of bone) at sites such as liver and/or spleen Hematopoietic stem cells migrate to the spleen/liver & differentiate into blood cells Expanding bone marrow physically pushes on bone’s cortex from within, activating nociceptors Multifactorial causes mostly with unclear mechanisms Intracellular granules precipitate inside blasts & the precipitate spills into the blood ↑Division & death of cancerous cells → ↑ cell lysis & release of intracellular contents into plasma Bone pain B symptoms: Weight loss, fever, night sweats Auer Rods (needle- like crystals) seen on blood smear ↑ Serum levels of uric acid, K+, LDH ↓ Red blood cells Anemia fatigue, pallor ↓ White blood cells Leukopenia Recurrent infections ↓ Platelets Thrombo- cytopenia Bruising, bleeding Accumulation of cells within the spleen/liver increase the size of the organ Splenomegaly Hepatomegaly Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 4, 2023 on www.thecalgaryguide.com

Primary Hemostasis

Primary Hemostasis: Normal physiology, disorders, and clinical findings Authors: Mina Mina Reviewers: Parker Lieb Mao Ding Kareem Jamani* *MD at time of publication Normal physiology: Injury to blood vessels from trauma (blunt or penetrating injury) Disorders of primary hemostasis: Collagen and microfibrils (subendothelial elements that are normally protected) are exposed to circulating blood due to vessel injury Storage granules in endothelial cells release large multimers of clotting factor von Willebrand (vWF) when damaged Acquired or inherited reduction in vWF quantity or quality (see vWF deficiency slide) von Willebrand Disease Defect in expression of GpIb interferes with platelet ability to bind to vWF Bernard-Soulier syndrome Defect in platelet membrane glycoproteins IIb and IIIa Glanzmann’s Thrombasthenia Insufficient platelets to form a platelet plug Thrombocytopenia (low platelet count) Disorders of primary hemostasis: problems with formation of a platelet plug Platelet adhesion: vWF binds to collagen and interacts with the platelet surface receptor glycoprotein Ib (GpIb) allowing platelet adhesion Platelet activation: mediated by agonists like ADP, thrombin and collagen Mucocutaneous bleeding (bleeding of the skin and mucous membrane) ↑ Closure time, ↑ bleeding time Platelets change shape and release substances from their granules Conformational changes in platelet cell surface glycoprotein IIb/IIIa ↑Affinity for fibrinogen through GpIIb/IIIa ADP Fibrinogen, vWF, and other substances Thromboxane A2 (see note) Induces aggregation Epistaxis Menorrhagia Note: Petechiae Platelet aggregation: fibrinogen forms bridges between adjacent platelets by binding to activated glycoprotein IIb/IIIa Interaction with coagulation factors: platelets provide a scaffold that allows the activation of phospholipid-dependent coagulation factors Primary hemostasis (formation of a platelet plug) Secondary hemostasis (see slide for normal physiology) Drugs like Aspirin and NSAIDs inhibit Thromboxane A2 synthesis (by inhibiting cyclooxygenase) and thereby inhibit platelet aggregation Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 30, 2023 on www.thecalgaryguide.com

Sarcoidosis pathogenesis and CXR findings

Sarcoidosis: Pathogenesis and chest X-Ray findings Authors: Harshil Shah Reviewers: Mao Ding Tara Shannon Vincent Dinculescu* * MD at time of publication Genetic predisposition Unknown sarcoid antigens Sarcoid antigens interact with pattern recognition receptors on macrophages in the lungs Macrophages become activated Helper T cells and macrophages release cytokines (proteins made by immune cells that modulate cell growth and division) such as tumor necrosis factor to neighboring cells Tumor necrosis factor is a pro- inflammatory cytokine promoting cell survival and proliferation, predominantly in the upper/middle lung for unknown causes More macrophages and helper T cells are activated and accumulate in the mediastinum, peritracheal region, and the upper/middle lung Macrophages and helper T cells promote fibroblasts (cells that produce collagen) in the upper and middle lungs Macrophages in the lungs present the antigen to the helper T cells in lymph nodes Helper T cells become activated and accumulate in the lungs Image Credit: Radiopaedia The right peritracheal and bilateral hilar lymph nodes becomes swollen Inflammatory signals stimulate macrophages to form granulomas (clusters of white blood cells) in the lungs, peritracheal and bilateral hilar lymph nodes X-ray images show visible white opacities in areas of increased densities, such as areas of macrophage and helper T cell concentration Enlarged peritracheal lymph node Stage 1 and 2 Enlarged bilateral hilar lymph node Stage 1 and 2 Interstitial Opacities Stage 2 and 3 Bilateral and symmetric lacey lung markings in upper/middle lungs Decreased lung volume on either sides (higher than normal diaphragm) Collagen accumulate which causes fibrotic tissue (scarred and thickened), replacing healthy tissue Pulmonary fibrosis of upper and middle lung Stage 4 The fibrotic tissue is stiffer, reduces amount of air held in lungs, and has a higher density (appearing white) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 7, 2023 on www.thecalgaryguide.com

Superficial thickness burns

Superficial Thickness Burns: Pathogenesis and clinical findings Author: Amanda Eslinger Elise Hansen Illustrator: Amanda Eslinger Reviewers: Alexander Arnold Sunawer Aujla Yan Yu* Duncan Nickerson* * MD at time of publication Epidermis (Penetrated by superficial burns) Dermis Sub-cutaneous tissue Erythema Radiation Sunlight (most common), x-ray, nuclear emission/explosion Specific to sunlight radiation, UV rays reach keratinocytes in the epidermis p53 tumor suppressor protein is induced in keratinocytes Transient cell cycle arrest Apoptotic pathway is Fire Contact Scald Chemical Electrical Direct damage to keratinocytes Skin erosion and sloughing of skin cells Direct stimulation of nociceptive nerve endings in the epidermis DNA repair mechanisms are activated Mistakes in repair process Malignancy (See ‘Basal Cell Carcinoma’ Slide & ‘Squamous Cell Carcinoma’ Slide) Fluid leaves vasculature and enters interstitial tissues of the skin, causing it to swell Edema Triggers release of endothelin A proalgesic protein Selective excitement of nociceptive nerve ending in epidermis Pain initiated in keratinocytes Keratinocytes apoptose Prostaglandins, arachidonic acid metabolites, substance P & proinflammatory cytokines are released into surrounding tissue ↑ Vascular permeability ↑ bloodflow carries warmth to body area Irritation of endothelial cells in the dermal vascular plexus Release of endothelium derived vasodilators such as nitric oxide Vasodilation, ↑ blood flow through vessels ↑ blood under skin leads to skin appearing red Warmth Pressing on skin occludes blood vessels temporarily, making skin Blanchable underneath appear white immediately after pressure is lifted Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 2, 2013, updated Aug 25, 2023 on www.thecalgaryguide.com

Sugammadex

Sugammadex: Mechanism of action and adverse side effects A direct reversal agent with a high affinity for rocuronium and lesser affinity for vecuronium, capable of reversing even deep neuromuscular blockade. Binds rocuronium and vecuronium (non-depolarizing neuromuscular blocking drugs (nNMBs)) in plasma when administered IV ↓ Concentration of functional nNMBs in plasma Creates a concentration gradient from muscle tissue (high) to plasma (low) nNMBs move from muscle compartment to plasma Sugammadex in plasma encapsulates nNMBs that moved to the plasma ↓ Concentration of functional nNMBs in the plasma ↓ Concentration of nNMBs at the nicotinic acetylcholine receptor within the skeletal neuromuscular junction Reverses neuromuscular blockade created by nNMBs Sugammadex Progesterone is similar in structure to nNMBs Sugammadex binds progesterone ↓ Progesterone activity in the body Progesterone is critical for maintenance of early pregnancy Unknown significance, avoid use in early pregnancy Sugammadex-nNMB complex is cleared by the kidneys Higher concentrations of sugammadex facilitate faster nNMB clearance Unknown mechanisms Post operative nausea and vomiting Headache Bradycardia Cardiovascular Collapse ↓ Effectiveness of progesterone-based contraception for 7 days ↓ Clearance in patients with severe renal impairment Reversal of profoundly deep neuromuscular blockade at higher doses Binds to IgG or IgE receptors on sensitized basophils/mast cells in allergic reactions Activation of basophils/mast cells Degranulation of basophils/mast cells Release of granulation products Anaphylaxis Bronchospasm Hypotension Authors: Arzina Jaffer, Kayleigh Yang Reviewers: Jasleen Brar, Mao Ding Joseph Ahn* * MD at time of publication Movement of limbs or body during anesthesia Coughing during anesthesia Grimacing or suckling on the endotracheal tube Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 16, 2024 on www.thecalgaryguide.com

Avascular Necrosis AVN of the Femoral Head Findings on MRI

Avascular Necrosis (AVN) of the Femoral Head: Findings on MRI Traumatic or atraumatic disruption of blood supply to the proximal femur (for full pathogenesis, see Calgary Guide slide Avascular Necrosis: Pathogenesis and clinical findings) Ischemia of the femoral head (usually unilateral for traumatic and bilateral for non-traumatic) Prolonged anoxia (total oxygen deprivation) within the femoral head Cell death (necrosis) of osteocytes and marrow cells in the femoral head, forming a focal lesion (sequestrum) Histiocytes and giant cells (immune cells) aggregate around the sequestrum, forming a “reactive zone” around the periphery of the sequestrum Apoptotic osteocytes in the anoxic reactive zone cannot be phagocytosed leading to dysregulated bone remodeling and osteosclerosis (hardening of bone and ↑ bone mineralization and density due to ↓ resorption and ↑ bone formation) Femoral head becomes progressively weaker while the mechanical load on it remains the same Progressive femoral head/subchondral bone collapse Osteoarthritis Areas with ↑ fluid content appear darker on T1w images Areas with ↑ fluid content appear brighter on T2w images Areas with ↑ bone density and ↓ fat content appear darker on T1w images Areas with ↑ bone density and ↓ fat content appear darker on T2w images Basic MRI Physiology Edema and inflammation increases fluid content Sclerotic areas have ↑ bone density and thus ↓ fat content Location of Signs Inflamed reactive zones are darker on T1w images Inflamed reactive zones are brighter on T2w images Sclerotic areas are darker on both T1w and T2w images Authors: George S. Tadros Reviewers: Matthew Hobart, Mao Ding Shahab Marzoughi David Cornell* * MD at time of publication T1w Signs on both T1-weighted and T2-weighted images are most commonly seen on the superior anterolateral aspect of the femoral head Single dark band on T1-weighted MRI A single band-like crescentic lesion of low signal intensity is seen on T1-weighted MRI images (white arrows). This band represents the edematous reactive zone between the necrotic and normal tissue, and typically extends to the subchondral plate Double Line Sign on T2-weighted fat-saturated MRI An outer distal low signal intensity line is seen (white arrows) representing reactive bone sclerosis Image source: radiologymasterclass T2w An inner proximal high signal intensity line is also seen (red arrows) representing vascular and repair tissue at the periphery of the sequestrum Image source: radiologymasterclass Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 27, 2024 on www.thecalgaryguide.com

Acute Wound Healing

↓ Blood supply and oxygenation to local skin tissue Ischemia Degradation of intact skin Abrasion (damage by scrape/rub) Puncture (small piercing caused by sharp object) Acute injury to the skin Crush (damage by compression) Acute Wound Healing: Pathogenesis and clinical findings Author: Amanda Eslinger Mina Youakim Reviewers: Heena Singh Shahab Marzoughi Yan Yu Laurie Parsons* * MD at time of publication 8 – 365+ days post-injury Remodeling (↓ blood vessels & organized collagen) Extensively cross-linked type 1 collagen replaces the disorganized collagen laid down in the proliferative phase ↑ Protein content in collagen Scarring (fibrotic tissue replaces previously healthy tissue) Disruption of structure and function of dermis, epidermis and subdermal tissues Subendothelial and endothelial damage activates the coagulation pathway Formation of a platelet plug Bleeding is slowed or stopped by hemostatic plug (hemostasis) Clot unifies wound edges 0 – 7 days post-injury Inflammation (In disrupted skin layers) 4 - 14 days post-injury Proliferation of collagen, extracellular matrix & blood vessels TGF-β attracts fibroblasts to the site of the wound Fibroblast & macrophage stimulate tissue growth & angiogenesis which replaces hemostatic plug Scabbing (protective crust overlying damaged tissue) Re-epithelialization beneath the scab sloughs it off Healing (newly replaced tissue replaces damaged one) In response to irritant, mast cells release histamine Complement activation causing nearby endothelial cells to release prostaglandins Vasodilation occurs around the wound area Localized ↑ vascular supply (reception of blood and fluid from vessels) ↑ Hydrostatic pressure forces fluid from vessels into surrounding tissue Edema (swelling from fluid buildup) Erythema (redness) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First Published Sept 19, 2013; updated Jan 30, 2024 on www.thecalgaryguide.com

Chancroid

Chancroid: Pathogenesis and clinical findings Authors: Mina Youakim Reviewers: Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication Condomless sex Multiple sexual partners Genital injury (i.e. cuts, friction) Micro-abrasions occur in the epidermal tissue of the genital area Sexual Transmission of Haemophilus ducreyi (H. ducreyi) bacteria from an infected sexual partner H. ducreyi enters the epidermis through micro abrasions H. ducreyi infects epithelial cells H. ducreyi secretes Large Supernatant Proteins LspA1 and LspA2 (which inhibit phagocytosis by neutrophils and macrophages) T cells activate and release cytokines IL-6 and IL-8 Neutrophils are recruited to the site of infection Local macrophages form a collar around the base of the papule to try to reach and engulf H. ducreyi ↑ Localized buildup of immune cells While infection persists, H. ducreyi release lipooligosaccharides (LOS) LOS travels to lymph nodes in the inguinal region Lymph nodes synthesize and proliferate T cells specific to H. ducreyi antigen Inguinal lymph nodes swell due to ↑ number of T cells Inguinal buboes (swollen inguinal lymph nodes) Neutrophils surround the bacteria and attempt to engulf it Localized epidermal buildup of neutrophils and H. ducreyi Papules (small protrusions on the skin) Continued build-up of H. ducreyi, neutrophils, dead white blood cells (pus), and macrophages Pustules (pus-filled skin lesion) ↑ Local pressure from growing pustule compresses surrounding vessels ↓ Local blood flow erodes and sloughs off the local epidermal roof Ulcers (open skin sore) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 8, 2024 on www.thecalgaryguide.com

Neonatal Necrotising Enterocolitis in Premature Neonates

Neonatal Necrotising Enterocolitis (NEC) in Premature Neonates: Pathogenesis and clinical findings Prematurity risk factors ↓ Intestinal motility ↑ Intestinal stasis allows bacteria more time to proliferate Bacterial overgrowth in gut ↓ Goblet cells in intestinal epithelium ↓ Intestinal mucus layer production leads to impaired mechanical defense against pathogenic bacteria Immature tight junctions in intestinal epithelium ↑ Permeability of intestinal epithelial barrier ↑ Toll-like receptor 4 (TLR4) expression on intestinal epithelial cells Aberrant bacterial colonization of gut Impaired gut barrier allows for ↑ bacterial translocation across intestinal epithelium TLR4 on intestinal mesentery endothelial cells bind lipopolysaccharides (LPS) on Gram-negative gut bacteria Immune cells release proinflammatory mediators (TNF, IL-12, IL-18) Cytokines mediate ↑ enterocyte apoptosis (including enteric stem cells) and ↓ enterocyte proliferation Intestinal mucosa healing is impaired, leading to local inflammation & injury TLR4 on intestinal epithelial cells binds LPS from Gram-negative gut bacteria Authors: Rachel Bethune Naima Riaz Reviewers: Nicola Adderley Michelle J. Chen Kamran Yusuf* Jean Mah* * MD at time of publication Endothelial nitric oxide synthase expression is reduced Vasoconstriction from ↓ NO reduces blood flow to intestines Prolonged ↓ in O2 perfusion results in irreversible intestinal mucosal cell death (necrosis) Gas escapes into abdominal cavity Leakage of intestinal contents irritates parietal peritoneum Bacteria enter bloodstream Pneumo- peritoneum Abdominal distention Peritonitis Sepsis Blood from tissue damage mixes with intestinal contents Bloody stool Intestinal sensory neurons detect damage and send signals to medullary vomiting centre Bilious vomiting Damaged intestinal cells are unable to absorb nutrients Short gut syndrome Persistent intestinal mucosal injury creates penetrating lesions through intestinal wall Intestinal perforation Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 6, 2019; updated Mar 21, 2024 on www.thecalgaryguide.com

Lichen Sclerosus

Lichen Sclerosus (genital manifestation): Pathogenesis and clinical findings Authors: Mina Youakim Reviewers: Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) Chronic inflammation (i.e. chronic infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) ↑ Activation of CD4+ and CD8+ T cells released from macrophages (white blood cell) in the perineum and genital skin tissue infiltrate into the dermal-epidermal junction T-cells proliferate in a horizontal linear formation Pro-inflammatory response activation Fibroblasts (contributes to the formation of connective tissue) proliferate and persist producing altered collagen under the epidermis Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the overall skin thickness Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors Localized area appears red Erythema (reddening of the skin) Erosion/ulceration Skin fissures (linear cleavage of skin) Localized histamine release Nitric oxide induces localized vasodilation (↑ blood flow) Normal Skin Lichen Sclerosus Epidermal layer Basal layer Dermal-Epidermal Junction Dermal layer Hypopigmented patches (localized, pale areas of skin) Epidermal atrophy (crinkling paper-type skin appearance) Thinned skin is weakened and prone to physical stress or trauma ↑ fluid in the extracellular space due to capillary leakage from ↑ blood flow Superficial dermal edema (swelling) Fibrotic tissue deposition following healing of damaged tissue Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Dermal layer Scarring Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 25, 2024 on www.thecalgaryguide.com Lichen Sclerosus (genital manifestation): Pathogenesis and clinical findings Authors: Mina Youakim Reviewers: Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) Chronic inflammation (i.e. chronic infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) ↑ Activation of CD4+ and CD8+ T cells released from macrophages (white blood cell) in the perineum and genital skin tissue infiltrate into the dermal-epidermal junction T-cells proliferate in a horizontal linear formation Pro-inflammatory response activation Fibroblasts (contributes to the formation of connective tissue) proliferate and persist producing altered collagen under the epidermis Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors ↑ fluid in the extracellular space due to capillary leakage from ↑ blood flow Superficial dermal edema (swelling) Epidermal atrophy (crinkling paper- type skin appearance) Thinned skin is weakened and prone to physical stress or trauma Localized histamine release Nitric oxide induces localized vasodilation (↑ blood flow) Localized area appears red Erythema (reddening of the skin) Erosion/ulceration Skin fissures (linear cleavage of skin) Normal Skin Lichen Sclerosus Epidermal layer Basal layer Dermal-Epidermal Junction Dermal layer Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Dermal layer Progressive basal layer degeneration thins the overall skin thickness Hypopigmented patches (localized, pale areas of skin) Fibrotic tissue deposition following healing of damaged tissue Scarring Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com Chronic inflammation (i.e. chronic Reviewers: Dermal layer Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication ↑ Activation of CD4+ and CD8+ T cells released from macrophages (white blood cell) in the perineum and genital skin tissue infiltrate into the dermal-epidermal junction T-cells proliferate in a horizontal linear formation Pro-inflammatory response activation ↑ Expression of MicroRNA-155 (enhances pro-inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts (contributes to the formation of connective tissue) proliferate and persist producing altered collagen Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors ↑ fluid in the extracellular space due to capillary leakage from ↑ blood flow Superficial dermal edema (swelling) Epidermal atrophy (crinkling paper- type skin appearance) Thinned skin is weakened and prone to physical stress or trauma Lichen Sclerosus Localized histamine release Nitric oxide induces localized vasodilation (↑ blood flow) Localized area appears red Erythema (reddening of the skin) Erosion/ulceration Skin fissures (linear cleavage of skin) Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Normal Skin Progressive basal layer degeneration thins the overall skin thickness Hypopigmented patches (localized, pale areas of skin) Epidermal layer Basal layer Dermal-Epidermal Junction Fibrotic tissue deposition following healing of damaged tissue Scarring Chronic inflammation (i.e. chronic Reviewers: Dermal layer Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication ↑ Activation of CD4+ and CD8+ T cells released from macrophages in the perineum and genital skin tissue infiltrate into the dermal-epidermal junction T-cells proliferate in a horizontal linear formation Pro-inflammatory response activation ↑ Expression of MicroRNA-155 (short segment of RNA which enhances pro- inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts proliferate and persist producing altered collagen Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the overall skin thickness Hypopigmented patches (localized, pale areas of skin) Epidermal layer Basal layer Dermal-Epidermal Junction Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors Superficial dermal edema (swelling) Epidermal atrophy (crinkling paper- type skin appearance) Localized histamine release Nitric oxide induces localized vasodilation (↑ blood flow) Localized area appears red Erythema (reddening of the skin) Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Normal Skin Lichen Sclerosus Skin fissures (linear cleavage of skin) Erosion/ulceration Fibrotic tissue deposition following healing of damaged tissue Scarring Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Reviewers: Dermal layer Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) Chronic inflammation (i.e. chronic infection, chronic toxin exposure) and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) Elise Hansen Sunawer Aujla Shahab Marzoughi Jori Hardin* * MD at time of publication ↑ Activation and infiltration of CD4+ and CD8+ T cells into the dermal-epidermal junction T-cells proliferate in a band (horizontal linear) formation Pro-inflammatory response activation ↑ Expression of MicroRNA-155 (short segment of RNA which enhances pro-inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts proliferate and persist producing altered collagen Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Sclerotic plaques (localized areas of thickened skin) T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the epidermis Hypopigmented patches (localized, pale areas of skin) Epidermal layer Basal layer Dermal-Epidermal Junction Mast cells respond to increased need for immune cell flow to area Nitric oxide is released when histamine binds to vascular receptors Superficial dermal edema (swelling) Epidermal atrophy (crinkling paper- type skin appearance) Localized histamine release Histamine receptor binding stimulates sensory nerve endings Pruritus (itching) Skin fissures (linear cleavage of skin) Nitric oxide induces localized vasodilation (↑ blood flow) Localized area appears red Erythema (reddening of the skin) Scarring Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Erosion/ulceration Fibrotic tissue deposition following healing of damaged tissue Normal Skin Lichen Sclerosus Chronic inflammation (i.e. chronic Elise Hansen Unknown triggers Genetic predisposition infection, chronic toxin exposure) Medications (e.g. carbamazepine, (HLA-DQ7 and HLA-DR12) and trauma pembrolizumab, nivolumab, ipilimumab) ↑ Activation and infiltration of CD4+ and CD8+ T cells into the dermal-epidermal junction Sunawer Aujla Shahab Marzoughi Name Name* * MD at time of publication T-cells proliferate in a band (horizontal linear) formation Pro-inflammatory response activation (increase in pro-inflammatory cytokines such as Interleukins 1-alpha and 1-beta) ↑ Expression of MicroRNA-155 (short segment of RNA which enhances pro-inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts proliferate and persist producing altered collagen T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the epidermis Hypopigmented patches (localized, pale areas of skin) Histamine receptor binding stimulates sensory nerve endings Localized area appears red Localized histamine release Localized vasodilation (↑ blood flow) Superficial dermal edema (swelling) Pruritus Erythema Collagen deposits and hyalinizes (transforms into acellular translucent material) beneath the epidermal layer Normal Skin Sclerotic plaques (localized areas of thickened skin) Epidermal layer Basal layer Dermal-Epidermal Junction Dermal layer Skin fissures (linear cleavage of skin) Bleeding Erosion/Ulceration Epidermal atrophy (crinkling paper- type skin appearance) Lichen Sclerosus Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Dermal layer Fibrotic tissue deposition following healing of damaged tissue Scarring Lichen Sclerosus (genital manifestation): Pathogenesis and clinical findings Authors: Mina Youakim Reviewers: Elise Hansen Sunawer Aujla Shahab Marzoughi Name Name* * MD at time of publication Pruritus Histamine receptor binding stimulates sensory nerve endings Localized area appears red Erythema Unknown triggers Genetic predisposition (HLA-DQ7 and HLA-DR12) Chronic inflammation and trauma Medications (e.g. carbamazepine, pembrolizumab, nivolumab, ipilimumab) ↑ Activation and infiltration of CD4+ and CD8+ T cells into the dermal-epidermal junction T-cells proliferate in a band formation Pro-inflammatory response activation ↑ Expression of MicroRNA-155 (short segment of RNA which enhances pro-inflammatory response and ↓ expression of tumor suppression genes) Fibroblasts proliferate and persist producing altered collagen T cells release of pro-inflammatory cytokines (interleukins and transforming growth factor β) Localized histamine release Localized vasodilation (↑ blood flow) Superficial dermal edema (swelling) Collagen deposits and hyalinizes beneath the atrophic epidermal layer Hypopigmented patches (localized, pale areas of skin) ↑ Oxidative stress and cell damage Progressive basal layer degeneration thins the epidermis Skin fissures Lichen Sclerosus Epidermal atrophy (crinkling paper- type skin appearance) Sclerotic plaques (localized areas of thickened skin) Bleeding Scarring Erosion/Ulceration Normal Skin Epidermal layer Basal layer Dermal-Epidermal Junction Dermal layer Atrophic Epidermal layer Hyalinized collagen deposits Basal layer degeneration Band of T-cell infiltrate Dermal layer Legend: Published MONTH, DAY, YEAR on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Irritant Contact Dermatitis Pathogenesis and Clinical Findings

Irritant Contact Dermatitis: Pathogenesis and clinical findings Authors: Zaini Sarwar, Mina Youakim Reviewers: Shahab Marzoughi, Ryan T. Lewinson, Yan Yu*, Laurie M. Parsons* * MD at time of publication Repeated/chronic exposure causes damage to cell membranes Skin barrier disruption Chronic non-specific inflammatory response Repetitive keratinocyte cytokine-mediated injury Keratinocytes exhibit ↑ proliferation as a compensatory response Rapid turnover of stratum corneum (outermost layer of the epidermis) Hyperkeratotic skin is less amenable to skin stretching and pressure Skin fissures (cracks in the skin) Irritant agents (abrasives, cleaning solution, oxidative & reducing agents, dust, soils, water) Acute exposure triggers inflammatory response Keratinocytes undergo cytotoxic damage with ↑ neutrophil & cytokine release Common occupational exposures (housekeeping, cleaning, catering, medical/dental, construction) Risk factors (atopy, fair skin, low temperature, low humidity) Stimulation of local nociceptors (free nerve endings extend into the mid epidermis) Perivascular (around the blood vessel) inflammation causes histamine release from mast cells Damaged keratinocytes are destroyed via apoptosis (programmed cell death) Epidermal Necrosis (death of epidermal tissue) Shedding of necrotic tissue Ulceration (deep open wound on skin) Burning pain (uncomfortable stinging sensation) Pruritus (itching) Histamine causes local blood vessel dilation and ↑ blood flow to the area of skin affected Erythema (area appears red from ↑ blood flow) Burning & Itching Spongiosis Neutrophils Neutrophils Histamine causes local blood vessel walls to have ↑ permeability, thereby ↑ leakage of fluid Spongiosis (↑ fluid between keratinocytes in the epidermis) Fluid continues to build up from ongoing inflammation Vesiculation (fluid collections in the epidermis) Long-term skin scratching causes chronic irritation which eventually hardens the skin Lichenification (thick, hardened patches of skin) ↑ Overall keratin production Hyperkeratosis (thickening of the outermost skin layer) Further fluid buildup bursts vesicles leaving behind erosions and dried crust on the epidermis Crust (scaling over the skin) Lichenification Erosions (open sore on skin) Ulcer Epidermis Perivascular Inflammation Hyperkeratosis Dermis Dermal-epidermal junction Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 19, 2016; updated Mar 30, 2024 on www.thecalgaryguide.com

Febrile Neutropenia Pathogenesis and clinical findings

Febrile Neutropenia (Neutropenic Fever): Pathogenesis and clinical findings Administration of cytotoxic chemotherapy for cancer treatment Acquired aplastic anemia Autoreactive T cells destroy bone marrow stem cells Congenital mutations in ELA2 gene (encodes neutrophil elastase) ↑ Neutrophil apoptosis Chemotherapy eliminates beneficial bacterial species from gut microbiota New microbiota composition allows for growth of colonizing bacteria Indwelling catheters inserted to deliver chemotherapy Skin-colonizing bacteria access tissues through catheters Bacteria penetrate tissue barriers Chemotherapy injures gastrointestinal mucosa Broken mucosal barrier increases susceptibility to infections Chemotherapy destroys circulating neutrophils Chemotherapy impairs bone marrow stem cells ↓ Production of neutrophils Neutropenia (Absolute Neutrophil Count (ANC) < 0.5x109 cells/L ↓ Immune cell ↓ Production of engulfment of microbes inflammatory mediators Fewer circulating neutrophils blunts the innate immune response Pathogens enter bloodstream from tissues Systemic infection Authors: Max Lazar Braxton Phillips Reviewers: Naman Siddique Michelle J. Chen Lynn Savoie* * MD at time of publication Dormant viral infections reactivate (e.g. cytomegalovirus, herpes simplex virus) ↑ Susceptibility to common bacterial infections Positive blood bacterial cultures Fever (T ≥ 38.3 oC or sustained T ≥ 38 oC for 1 hour) Immune system mounts an excessive inflammatory response that damages tissues and organs Sepsis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 5, 2018; updated Mar 30, 2024 on www.thecalgaryguide.com

Costochondritis

Costochondritis: Pathogenesis and clinical findings Systemic infection originating in upper respiratory tract (commonly Staphylococcus aureus and Streptococcus bacterial infections) Infection spreads through blood to ribcage and chest wall Age-related degeneration of cartilage within ribcage joints Immune cells present in joints secrete proinflammatory cytokines Cytokines sensitize nociceptors (pain receptors) in joints Repetitive trauma or strain to chest wall muscles (e.g. chronic cough, chest wall injury, overexertion of chest wall muscles) Excessive stretch and tearing of ribcage cartilage and ligaments Autoimmune disease (e.g. rheumatoid arthritis) Antigen presenting cells display self-antigens to CD4+ T cells Mechanical stimuli (e.g. Damaged cells release cytokines Pathogens activate immune cells at site of stretch) activate nociceptors that recruit immune cells inflammation Costochondritis Benign inflammation of the ribcage (costal) cartilage, particularly at the costosternal junctions (connection between sternum and cartilage) and the costochondral junctions (connection between the cartilage and rib) Authors: Michelle J. Chen Reviewers: Raafi Ali Yan Yu* Gerhard Kiefer* * MD at time of publication Cartilage, ligament, or muscle injury Presence of foreign pathogen in costal cartilage Injury or pathogen activates inflammatory cascade in the ribcage cartilage Immune cells proliferate so that they exceed the available space in the cartilage matrix of the ribcage Cartilage swelling compresses intercostal nerves Compression acts as a mechanical stimulus to activate nociceptors Sharp, localized pain reproducible upon palpation over ribcage Immune cells secrete cytokines Cytokines activate nociceptors so that they become more sensitive to mechanical stimuli Muscle or ligament stretch from normal use activates sensitized nociceptors Pain increases with inspiration or cough Natural resolution of inflammation over time Macrophages phagocytose apoptotic cells (immune and cartilage cells) and cellular debris Immune cells release factors that degrade proinflammatory cytokines Fewer cytokines reduce immune cell recruitment into costal cartilage Pain usually self-resolves Immune cells release lipid molecules that bind to the same cells (autocrine signaling) to inhibit further production of inflammatory cytokines and chemokines Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Apr 29, 2024 on www.thecalgaryguide.com

Acute Otitis Media Complications

Acute Otitis Media: Complications Prolonged mucus buildup or swelling in Eustachian tube due to colds/allergies obstructs the Eustachian tube Fluid unable to drain through tube and accumulates in middle ear Acute Otitis Media Infection and inflammation of the middle ear Mastoid air cells are in physical contact with distal middle ear Pathogens move into mastoid air spaces Inflammation & infection in air spaces Mastoiditis Bacterial and immune cell debris (pus) accumulates in mastoid air spaces Untreated middle ear infection allows further bacterial proliferation Persistent effusion causes ion channel changes in inner ear Composition of endolymph and perilymph in inner ear changes Vestibular/Labyrinth dysfunction Feelings of Vertigo imbalance Purulent discharge from middle ear through perforation Otorrhea (ear discharge) ↑ Pressure in middle ear Pressure stretches tympanic membrane Cytokines reach hypothalamus through the bloodstream Hypothalamus responds to stimulation and ↑ thermoregulatory set-point High-grade fever Infection spreads into bloodstream Sepsis Cytokines alter metabolism pathways of neurotransmitters in the brain Cerebral cortex dysfunction Infection spreads to cranium Intracranial complications (e.g., meningitis, brain abscess, thrombus) Author: Jody Platt Stephanie de Waal Reviewers: Yan Yu Elizabeth De Klerk William Kim Annie Pham Michelle J. Chen Danielle Nelson* * MD at time of publication Helper T cells and macrophages release inflammatory cytokines into the bloodstream Perforation of tympanic membrane ↓ Conduction of sound waves Conductive hearing loss Pressure in middle ear diffuses out of perforation ↓ Tympanic membrane stretching Otalgia (ear pain) fades Accumulated debris compresses cranial nerve VII Facial nerve palsy Mastoid abscess Febrile seizures Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 28, 2013, updated Apr 29, 2024 on www.thecalgaryguide.com

Wiskott-Aldrich Syndrome

Wiskott-Aldrich Syndrome (WAS): Pathogenesis and clinical findings X-linked recessive inheritance (mostly males impacted) Spontaneous DNA mutation Genetic mutations in Wiskott-Aldrich Syndrome Protein (WASP) impair actin cytoskeleton remodeling in hematopoietic cells (immature blood cells) Authors: Mina Mina Reviewers: Hana Osman Mao Ding Maharshi Gandhi Shahab Marzoughi Louis-Philippe Girard* * MD at time of publication Megakaryocytes (platelet precursor cells) depend on the cytoskeleton changing shape to form pseudopodia (arm-like projections) which bud off forming cellular fragments (platelets) Abnormal cytoskeleton reorganization leads to ineffective thrombocytopoiesis (production of platelets) Microthrombocytopenia (↓ platelet size and quantity) Issues with formation of a platelet plug due to abnormal platelets (dysfunction of primary hemostasis) Reduced ability for platelet adhesion, activation, and/or aggregation Natural killer cells depend on the cytoskeleton reorganization to form immunological synapses (communication) with body cells in order to have effective surveillance T cells depend on the cytoskeleton remodeling to form pseudopods which allow them to synapse with other cells when a pathogen is encountered Defective immune synapse formation ↓ Cancer immunosurveillance ↑ Risk of malignancy Helper T cells cannot activate B cells which generate antibodies (immunoglobulins) to destroy pathogens Regulatory T cells can not sufficiently downregulate effector cells which typically limit the immune response and prevent autoimmune conditions ↑ Risk of autoimmune diseases Recurrent opportunistic infections Immune dysregulation Impaired immune response ↓ Number and function of T cells Immune responses contribute to Type 2 immune responses Atopic dermatitis (AD; chronic inflammation that causes itchy skin) ↑ Immunoglobulin (Ig) A Epistaxis (nosebleed) Red blood cells leak from capillaries Menorrhagia (heavy menstrual bleeding) Petechiae (small, flat, red spots that appear on the skin) Inflammation in AD triggers release of interleukins (modulatory proteins during inflammatory and immune responses) leading to Immunoglobulin (Ig) class switching ↑ IgE levels Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Apr 20, 2024 on www.thecalgaryguide.com

Scabies pathogenesis and clinical findings

Scabies: Pathogenesis and clinical findings Direct person-person transmission of Sarcoptes Scabiei var. hominis to new host Fertilized females secrete proteolytic enzymes that allow them to burrow through the stratum corneum (2 mm/day) Authors: Heena Singh Amanda Eslinger Nirav Saini Reviewers: Shahab Marzoughi Danny Guo Yan Yu Richard Haber* * MD at time of publication Mechanical irritation and immunological reaction Mast cell activation and histamine release Itch (> 10 Mites) Stratum corneum Stratum lucidum Stratum granulosum Stratum spinosum Stratum basale Females lay 2-3 ova/day which hatch in the stratum corneum in pockets after 3 days The larvae molt and mature for 2 weeks and mate within the pockets of the stratum corneum Following mating, female mites begin burrowing Cycle is propagated as new female mites create more burrows in stratum corneum Superficial, Linear, Tortuous (i.e., Twisted) +/- Scaly Burrows ↑ Exposure to mite antigens such as Sar s 14.3 and Sar s 14.2 Type 2 helper T-cells produce proteins IL-4, IL-5, IL-13 ↑ Serum Immunoglobulin G & E ↑ Eosinophil Count in Peripheral Blood Inappropriate T helper-type immune response in skin (mechanism unknown) Antigens forming from mite feces, ova, or decomposing bodies Type IV hypersensitivity reaction (delayed immune response 2-4 weeks following initial contact) Skin barrier dysfunction from inflammation and histamine release Pre-existing immunosuppression Chronic inflammatory response Allergic reaction to ↑ mite activity at night Uncontrollable Itch (Worse At Night) + Excoriations (Scratch Marks) Urticarial (Hive-Like) Crusted Papules Eczematous Plaques Skin breakdown Opening for bacteria (commonly S. aureus) 2° Bacterial infection Pustules Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 17, 2013; updated Jun 9, 2024 on www.thecalgaryguide.com

Acute Otitis Media Pathogenesis and Clinical Findings in Children

Acute Otitis Media in Children: Pathogenesis and clinical findings Congenital conditions (e.g. Down Syndrome, Pierre Robin syndrome) Exposure to tobacco smoke Impaired macrophage function in nasopharynx Lack of immunizations Lack of breastfeeding Infant does not receive antibodies from breast milk Overcrowding Age 6 – 16 months Immune system deficiencies Close proximity of kids & ↓ sanitation (e.g. daycare) ↑ Infection risk Upper Respiratory Tract Infection (i.e. bacterial (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis), viral) Immature Eustachian tube anatomy which facilitates pathogen transmission to middle ear Author: Jody Platt Stephanie de Waal Reviewers: Yan Yu Elizabeth De Klerk William Kim Annie Pham Michelle J. Chen Danielle Nelson* * MD at time of publication Abnormal anatomical structure (e.g. cleft palate) ↑ Nasopharyngeal streptococcus pneumoniae Lack of immunity to pathogens ↑ Colonization of nasopharynx with bacterial pathogens Inflammation & edema of respiratory mucosa including the nose, nasopharynx, and Eustachian tube Obstruction of the Eustachian tube Air from middle ear resorbs into circulation which creates a low-pressure environment Negative pressure gradient pulls viral/bacterial pathogens into middle ear Degenerating white blood cells, tissue debris, and microorganisms accumulate & develops into purulent effusion Inflammation & infection of middle ear Complications of acute otitis media** ↑ Pressure in middle ear Stretching of tympanic membrane Helper T cells & macrophages release cytokines into the bloodstream Cytokines trigger hypothalamus to ↑ thermoregulatory set-point Effusion behind tympanic membrane Effusion obstructs visualization of ossicles Neutrophils infiltrate middle ear & phagocytose pathogens Pus accumulates behind the tympanic membrane Blood vessels of the tympanic membrane vasodilate Bulging tympanic membrane Otalgia (ear pain) Discomfort disrupts daily activities in young children Fever Irritable Poor feeding Tympanic membrane erythema Painful blisters on tympanic membrane (e.g. Bullous myringitis) Can persist for up to 3 months after infection resolves Loss of tympanic membrane landmarks (i.e. handle of malleus, light reflex) ** See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 28, 2013; updated Aug 25, 2024 on www.thecalgaryguide.com

Pityriasis Tinea Versicolor

Pityriasis (Tinea) Versicolor: Pathogenesis and clinical findings Authors: Kerry Yang Reviewers: Mina Youakim Shahab Marzoughi Jori Hardin* * MD at time of publication ↑ Loosening of the stratum corneum Scaling of skin Hyperhidrosis (↑ sweating) Poor ↑ Sebaceous nutrition gland secretions Development of a lipid- rich environment Use of oils on skin ↑ Environmental heat & humidity Immunosuppression Lipophilic Malassezia (normal constituent of skin flora) yeast cells transform into the pathogenic, mycelial (fungal thread) form, commonly occurring on the trunk, neck, and proximal extremities Malassezia infect the stratum corneum (the outer layer) of the skin ↑ Malassezia – associated ligand – activated transcription factors Rate of different gene transcriptions modified ↑ Melanin production by melanocytes ↑ In melanin more than the ↓ in melanin Hyperpigmented macules, patches, and plaques ↑ Production of the enzyme keratinase ↑ Activation of Langerhans cells (macrophages in the skin) Alteration in the expression of cytokines and chemokines in keratinocytes (epidermal skin cells) ↑ Inflammatory response Activation of cutaneous nerve fibers Itch signal transduction Mild pruritis (itchiness) Ligand-activated transcription factors produced by Malassezia ↑ Degradation of keratin in the skin ↑ Production of dicarboxylic acids by certain Malassezia species Competitively inhibits the rate- limiting enzyme in melanin production tyrosinase ↓ Production of melanin ↓ In melanin more than the ↑ in melanin Hypopigmented macules, patches, and plaques ↑ Production of inflammatory mediators Dyspigmentation Malassezia, particularly M. globosa, M. furfur, and M. sympodialis Loosened Epidermal layer Dermal-Epidermal Junction Dermal layer Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 25, 2024 on www.thecalgaryguide.com

Secondary hypoglycemia Insulin Mediated

Hypoglycemia: Insulin mediated secondary causes Insulinoma (pancreatic beta islet cell tumour) Non-insulinoma pancreatic islet cell disorder (e.g. Non-insulinoma pancreatogenous hypoglycemia syndrome) Nesidioblastosis (pancreatic islet tissues formed from pancreatic duct budding) formation ↑ In number & size of abnormal pancreatic beta islet cells throughout the entire pancreas ↑ Insulin production & secretion by abnormal pancreatic islet cells ↑ Glycogen synthesis Insulin autoimmune syndrome Autoantibodies bind to insulin molecules released post-meal Insulin molecules unable to exert effects Hyperglycemia Promotes insulin release ↓ Plasma glucose concentration ↓ Insulin release & ↓ total insulin levels Insulin molecules dissociate from autoantibodies ↑ Free insulin levels (inappropriate for the ↓ plasma glucose levels) ↓ Glycogenolysis (glycogen breakdown to glucose) Hypoglycemia (serum glucose of <3mmol/L) Intake of insulin secretagogues (e.g. Sulphonylureas, Meglitinide analogues) Binds to adenosine triphosphate (ATP) dependant potassium channels on pancreatic islet cells Inhibit potassium ion efflux through ATP-dependent potassium channels Pancreatic islet cell depolarization Opens voltage-gated calcium channel Calcium influx into pancreatic islet cells ↑ Insulin release ↓ Gluconeogenesis (glucose synthesis from non-carbohydrate compounds) Exogenous insulin intake Suppress endogenous insulin production (by beta cells) Low C-peptide levels (byproduct of endogenous pro- insulin being converted to insulin) 90% caused by somatic mutations of pancreatic beta islet cells 10% due to genetic changes linked to MEN1(Multipl e endocrine neoplasia type-1) gene mutation ↑ Pancreatic islet cells proliferation ↑ Insulin secretion by hyperplastic (increasing in number) pancreatic islet cells Neuroglycopenic symptoms (altered mental status, seizures) Neurogenic symptoms (palpitations, tremulousness, diaphoresis Authors: Iffat Naeem Run Xuan (Karen) Zeng Reviewers: Gurreet Bhandal Luiza Radu Yan Yu* Samuel Fineblit* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 29, 2024 on www.thecalgaryguide.com