Goal 1 - (1) Histological function and characteristics of Skin - Self Study

1a. Recognize gross & microscopic features and the nomenclature of skin lesions.
Components Characteristics
Squamous Epithelial  AKA: Keratinocytes → Tightly "glued" via desmosome cell junctions, and produce keratin proteins
Cells that help with protection. Also secrete Ck's and defensins needed for cutaneous immune response
Melanocytes  W/ in epidermis are derived from Neural crest → contain Melanosomes that make melanin (absorbs
UV radiation) via tyrosine precursor; Give skin pigment
Langerhans Cells  Intraepidermal DC, first line of defense against microorganisms, migrate from skin to LN as an APC
for TC's
Lymphocytes  APC in LN ⭐️ TC's (CD4, CD8, Treg) , contain CLA (cutaneous Lymphocyte Antigen) & receptors (CCR4
and CCR10). Keratinocyte CK's draw TC's to skin.
 BC's present in low amount and participate in Humoral Response
Afferent Nerve's  Sensation: Pleasure/ Pain, touch, vibration, itchiness, temperature
Efferent Nerves  ANS: Regulate sweat glands and effector pili muscles
Epidermis: Physical barrier, Vit D synthesis, Sensation, Heat regulation

 R → Stratum Corneum: Dead thin skin cells which do not contain nucleus;
 Stratum Lucidum: Dead thick skin
 B → Granular Layer: Keratinocytes w/ dark blue coarse granules (dead organelles)
 G → Stratum Spinosum: Keratinocytes, cytoplasmic melanocyte process, LCDC's, Merkle Cells, spiny
process → desmosomes
 Y→ Basal Layer: Basal cells that divide and migrate to surface, replacing lost squamous cells;
Melanocytes

Dermis  Deep to epidermis

 Sebaceous Glands: In thin skin, produces sebum that nourishes hair, forms water proof layer,
defends
 Contains Propionibacterium (g+ve rod), commensalism ( 1 benefits, 2nd isn't benefited or
harmed)
 ⭐️ by androgen/estrogen hormones → hypertrophy → Acne
 Sweat glands: Eccrine gland (palms, soles, forehead), Apocrine gland (Axillary and anogenital)
 Erector Pili muscles, mechanoreceptors for pressure
Macro-Lesion Characteristics
Macule < Patch  Flat, circumscribed lesion, color different then skins
 Macule < 5mm < Patch
Onycholysis  Separation of nail plate from bed
Papule < Nodule  Elevated dome-shaped, or flat topped lesion
 papule < 5mm < Nodules
Plaque  Elevated flat-topped lesion, > 5mm. Might be d/t coalescent papules; common in psoriasis

Scale  Dry, horny, plate-like growth. Unusually d/t cornification

Vesicle, Bulla  Fluid filled lesion; Blister. Vesicle < 5mm < Bulla
  As seen in Pemphigus Vulgaris

Excoriation  Traumatic lesion through epidermis, often self induced → Deep Scratch
Lichenification  Thickened rough skin, resulting from repeated rubbing
Micro-Lesion Characteristics
Acanthosis  Diffuse epidermal hyperplasia of keratinocytes

Dyskeratosis  Abnormal, premature keratinization within cells below the stratum granulosum
Erosion  Discontinuity of the skin showing incomplete loss of the epidermis
Exocytosis  Infiltration of the epidermis by inflammatory cells
Hydropic swelling  Ballooning; Intracellular edema of keratinocytes, often seen in viral infections
Hypergranulosis  Hyperplasia of the stratum granulosum, often due to intense rubbing
Hyperkeratosis  Thickening of the stratum corneum, often associated with a qualitative abnormality of the keratin
Lentiginous  A linear pattern of melanocyte proliferation within the epidermal basal cell layer
Papillomatosis  Surface elevation caused by hyperplasia and enlargement of contiguous dermal papillae
Parakeratosis  Keratinization with retained nuclei in the stratum corneum. On mucous membranes, parakeratosis is
normal.
Spongiosis  Intercellular edema of the epidermis
Ulceration  Discontinuity of the skin showing complete loss of the epidermis revealing dermis or subcutis
Vacuolization  Formation of vacuoles within or adjacent to cells; often refers to basal cell-basement membrane
zone area

Goal 2 - Infectious Diseases of Skin and Soft tissue

 Pyogenic Infections: Folliculitis, Furuncle, Carbuncles, Abscess, Impetigo, Cellulitis, Erysipelas
 Toxin mediated skin conditions: Bullous Impetigo/ Staphylococcal Scalded Skin Syndrome, Toxic Shock
Syndrome, Scarlet Fever, Ecthyma gangrenosum, Necrotizing fasciitis, Gas gangrene
 Skin Lesions: Maculopapular rash, Vesicular rash, Scaly rash, Warty lesions and Nodulo-ulcerative lesions
2a. Differentiate between these conditions based on their classical presentation, pathogenesis and definitions
Pyogenic Infections Presentation and Pathogenesis
Folliculitis  Inflammation of the follicle
 d/t: traumatic implantation of organisms around hair follicle, or Trauma d/t friction and rubbing
 Staph aureus (g+ve), Staphylococcus Epidermidis (g+ve), Pseudomonas aeruginosa (g-ve)
 (Think of a 1-2 day old shaved beard)

Furuncle  AKA Boil: Lesion extends beyond hair follicle → Raised painful lesion
 d/t: SA, S. Epidermidis (g+ve), PA (g-ve)

Carbuncle  When several Furuncles coalesce together, especially seen in diabetics

 d/t: SA, S. Epidermidis (g+ve), PA (g-ve)

Abscess  Painful, fluctuant, red, tender swelling

 d/t: #1 SA (lactating breast), S. Epidermidis (Stitch abscesses), E. coli, PA, Mixed infections, and
Non-sporing anaerobes
Impetigo  Pustular lesions w/ dried discharge forming old varnished appearing, honey colored crust
 d/t: SA, Strep P.
 ↑R: children, overcrowding, poor personal hygiene
 Non bullous → Pyogenic
 Bullous → Toxin Mediated

Cellulitis  Acute INFL of skin (dermis) & subcutaneous tissues w/ indistinct edges and regional LN
enlargement along w/ Malaise, fever and chills. Originates from skin lesion or trauma, bacterial
invasion of blood possible
 d/t: #1 Strep P., SA, PA, Vibrio Vulnificus (sea water exposure), Erysipelothrix rhusiopathiae
(violaceous lesions)
 Can progress to Necrotizing Fasciitis
 In Diabetics, PA can cause cellulitis and osteomyelitis in foot b/c of shoe sole colonization
Erysipelas  Acute infection of dermis (salmon red rash w/ well demarcated edges) and superficial lymphatics
(LAP)
 d/t: Strep p.
 Whale/ Seal Finger: Violaceous lesions in wounds that are exposed to fish, whales, seals
(occupational)
 d/t: Erysipelothrix rhusiopathiae

Toxin-Mediated Presentation and Pathogenesis

Bullous Impetigo  Diffuse superficial epidermal peeling; sloughing of skin with erythematous rash and fever
& S. Scalded Skin  d/t: SA exfoliative exotoxin
Syndrome  MOA: exotoxin's are serine proteases that split IC bridges (cadherin desmoglein 1) in the
stratum granulosum of epidermis

Toxic Shock Syndrome  Severe headache, sore throat, fever (up to 105ºF), rashes spread from face to rest of body.
Desquamation seen at palms and soles. Dehydration and watery diarrhea → Shock and death
 D/t: SA (TSST-1 toxin), GpA Strep. Pyogenes (Streptococcal pyrogenic exotoxin)
Scarlet Fever  CF: Strawberry tongue, circumoral pallor, sandpaper rash (blanching), palms & soles spared.
Necrotizing fasciitis assoc.
 d/t: Strep. TSS → SPE toxin (strep. Pyrogenic exotoxin)
 ↑R: diabetics, IMCO, anticancer tx.

Necrotizing Fasciitis  Severe, destructive lesion of fascia, and underlying muscle and fat. Rapid spread/ growth of
organism → Multiple Organ failure → Death. Prodocution of CO2 → Crepitus
 d/t: Flesh eating bacteria (anaerobe) , but may be mixed. #1 Group A Strep (GAS)
 Differential Dx: Gas Gangrene

Ecthyma Gangrenosum  Skin infection commonly seen in IMCO pts. Single or multiple round/oval lesions w/ halo of
erythema and necrotic center. Heal w/ scar formation
 d/t: PA enters host via break in skin, Invades BV, Exotoxin A → Infarction and necrosis
 ↑R: Immunosuppressed, chemotherapy, neutropenic
Gas Gangrene  AKA Clostridial myonecrosis: Fast-spreading, life-threatening, necrotic infection → severe damage
to skin, CT, fascia and muscles.
 d/t: Clostridium spp. Infection

2b. Differentiate between the causal organism causing infections in the patient based on their physical
properties.
Infectious Agent Properties
Staph. Aureus  Infections: Systemic: bacteremia, endocarditis, Pneumonia, emphysema, Osteomyelitis, septic
arthritis
 Localized: Impetigo, folliculitis, furuncle, carbuncle, abscess, mastitis, wound infections
 Toxin mediated: Food poisoning, S. scalded skin syndrome, TSS
 ↑R: children, overcrowding, poor personal hygiene, Infected tampons, infected dressing/
surgical packing
 Morph: G+ve cocci in clusters, non-motile, non-sporing
 Culture: Catalase +ve, Coagulase +ve, (s. epidermidis -ve)
 Nutrient agar: golden yellow opaque colonies
 Blood agar: Beta hemolysis
 Mannitol salt agar: yellow colonies (SA in food poisoning)
 Virulent factors: Protein A: surface component that binds Fc of Ig, evades opsonization
 Enzymes: Coagulase (fibrinogen→ fibrin; well circumscribed abscess can evade
phagocytosis), Fibrinolysin (dissolves fibrin clots), Lipase (hydrolyzes lipids; important in
chronic furunculosis), Hyaluronidase (Hydrolyzes hyaluronic acids in CT, allowing spread)
 Toxins: Cytotoxins (Hemolysin/ Panton-Valentine Leukocidins): Form pores in cells,
erythrocytes, and leukocytes
o Exfoliative Toxin (efoliatin): See S. Scalded Skin Syndrome in 2.a.
o TSST-1: Super antigen, see TSS in 2.a
o Enterotoxins (A-E): Food poisoning
 Tx: methicillin sensitive SA: Cephalexin; Amoxycillin + Clavulanic acid; Ampicillin + clox. or diclox.
 MRSA (altered PBP): Vancomycin; clindamycin; linezolid; rifampin
 Prevention: Avoid contamination of active SA skin lesion; Regular hand washing; Regular
screening for MRSA carrier state (nasal or cutaneous swabs),
 Rx: Mupirocin ointment for carrier state, Vancomycin for persistent carriers
Streptococcus Pyogenes -  Infections: Pyoderma, impetigo, cellulitis, erysipelas, scarlet fever, necrotizing fasciitis, TSS
Group A Strep - GAS  Acquired from other people → Colonized skin → bacteria enters w/ minor breaks
 ↑R: lower socioeconomic status, very young, very old, diabetic
 Morph: G+ve, cocci in clusters
 Culture: Catalase -ve, Bacitracin sensitive
 Blood agar: Beta hemolysis
 Virulent Factors:
 Enzymes: Hyaluronidase, Streptokinase (dissolves fibrin clots), Strep DNase (Liquifies
pus); Responsible for cutaneous lesions that are spreading and invasive in nature
(cellulitis)
o C5a Peptidase → evasion of phagocytosis
 Toxin: Streptolysin O → O2 labile, pore forming, antigenic
o Streptolysin S → O2 Stable, nonimmunogenic
o SPE A-C pyrogenic/ Erythrogenic toxin: behaves like TSST, responsible for diffuse,
erythematous rash (scarlet fever; pharyngitis)
 Tx: Penicillin or Amoxycillin, or Cephalexin
 Complications: Acute Post-strep Glomerulonephritis (APSGN): Edema, hematuria, proteinuria,
HTN following prior skin (impetigo), or throat (pharyngitis)
 Nephrogenic strains: M types (49,55,57,60) → AGN
 Common in adults, and children (6-10yrs), appearing 1-4 weeks after Strep infection.
 Type III HS: Immune complex deposition on glomerular basement membrane
 Dx: Anti-DNase detection
Pseudomonas Aeruginosa  Infections: #1 Burn infection, Wound infection (osteomyelitis), folliculitis
 ↑R: Open wounds in burn pt's and diabetics, exposure to contaminated water
 Morph: Aerobic, G-ve bacilli, grape-like fruity odor. Pigment producing: Pyocyanin (fluorescein),
Pyoverdine
 Culture: Oxidase +ve
 Nutrient agar: Green pigmented colonies
 MacConkey's Agar: Non lactose fermenting, pale colonies
 Virulent factors: Enzymes: Elastases, and phospholipase C
 Toxins: Exotoxin A: INH protein synthesis by ADP ribosylation of EF-2
 Tx: Piperacillin + Aminoglycosides
 Prevention: Avoid flowers in hospitals, and avoid moisture & environmental source
contamination
Vibrio Vulnificus  Infections: Cellulitis
 Exposure to sea water/ brackish water
 ↑R: Areas near gulf of Mexico, and US' east and west coast, Pearl diving, shucking oysters, shell
fish, clams
 Morph: G-ve curved rod, halophilic, contains polysaccharide capsule
 Culture: Oxidase +ve
 Tx: Tetracyclines, 3rd generation cephalosporins
 Complications: Septicemia; ↑Mortality in pts w/ hepatic disease

Erysipelothrix  Infections: Erysipeloid (Whale/ Seal finger): dermatitis of hands

Rhusiopathiae  Exposure to fishes, whales, seals, pigs → Occupational
 Morph: G+ve bacilli
 Culture: Catalase -ve
 Tx: Penicillin

Clostridium Spp.  Infection: C. Perfringens → Gas Gangrene (clostridial myonecrosis); Food poisoning
 ↑R: Road traffic injuries, puncture wounds, GSW, War injuries, septic abortion, compound
fractures
 Morph: Anaerobic G+ve bacilli (Box car appearance), non-motile. Sub terminal, resistant spore.
Sensitive to glutaraldehyde, formaldehyde and ethylene oxide
 Culture: Blood Agar: Double zone of hemolysis
 Egg Yolk Agar: Nagler's Reaction: Neutralization test for the detection of alpha-toxin.
 o 1st half of plate contains anti-alpha toxin Ab's that INH alpha toxin → no growth
o 2nd half of plate has active lecithinase that will hydrolyzes phospholipids in agar →
Pearly opacity
 Litmus Milk Medium: Purple milk will turn pink and "stormy" b/c of fermentation
 Toxins: Alpha toxin (lecithinase, similar to PLC), and 11 others
 Tx: Surgical amputation if needed; ↑dose Penicillin therapy, or Penicillin + Clindamycin;
Hyperbaric O2 chamber
 Complications: In Gas gangrene: Accumulation of gases w/ in tissue space → Crepitus and ↑
area of anoxic damage.
 ↑Vascular permeability and extravasation → Shock, renal failure and death
 Prevention: Proper wound care, and prophylactic antibiotics

Rash Infective Agents Properties

Measles/ Rubeola  At Prodrome: ↑fever & CCCP (cough, coryza, Conjunctivitis, and photophobia → 2 days later
Koplik spots appear (mucus membrane lesions) on the buccal mucosa across from mol ars →
Rash spread starts below ears then spread over the body
 d/t: Measles/ Rubeola Virus

Measles/ Rubeola Virus  Infection: Measles; Respiratory droplet transmission in 5-15 year old most common;
communicable 4 days before and after rash onset; incubation period = 10-12 days
 Inhaled droplets replicate in Resp. tract (RT) → LN spread → Viremia (wide dissemination:
Conjunctivae, RT, UT, LN, CNS) → Rash → Recovery or complication
 ↑R: Unvaccinated, malnourished and IMCO
 Morph: Paramyxoviridae Family → Morbillivirus → Measles Virus
 ssRNA virus, helical symmetry, non-segmented. Hemagglutinate
 Culture/lab: RT-PCR and dx via ELISA (IgM detection & 4x titer ↑ of measles specific Ab)
 LN biopsy: Warthin-Finkeldey Cells → Multinucleate syncytia w/ acidophilic nuclear and
cytoplasmic Inclusions
 Virulent Factors: Nucleocapsid → Nuclear Proteins (NP)
 H protein: VAP on envelope, binds Protein R's and has hemagglutinating activity NP
proteins
 Tx: Treat symptoms
 Complication: Bacterial superinfections, encephalitis
 Subacute sclerosing panencephalitis (SSPE): Serious, late, neurologic condition d/t
persistent virus and an abnormal immune response, or mutant form of virus.
 Giant Cell Pneumonia in children lacking TC immunity : Lymphoid tissue shows
Multinucleate Syncytia Formation. Cells dubbed Warthin-Finkeldey Cells w/ acidophilic
nuclear and cytoplasmic inclusions. Encephalitis.
 Prevention: Measles-Mumps-Rubella Vaccine: Live attenuated vaccine administered at 15mo. -
24 mo., again at 4-6yrs or before 12yrs; 95% livelong immunization
 CI: Prego, IMCO, Gelatin/neomycin allergy; Admin. Ig to ↓R/severity of infection
 ↑dose Vitamin A: ↓R of mortality
Rubella/ German Measles/  "Little Red" virus infecting neonates (congenital abnormalities); children (3 day rash, swollen
3 day Measles glands); Adults (Rash and arthritis or arthralgia)
 d/t: Rubella Virus
Rubella Virus  Infection: Rubella/ German measles/ 3 day measles; suboccipital, post-auricular LN enlarged/
tender
 neonates < 20 wks. → Congenital Rubella (Deafness, Cardiac, CNS, TCP Purpura, HSM)
 Children: Benign w/ 2-3 wk. incubation → 3 day maculo-papular/ Macular rash; swollen
glands
 Adults: more severe dz. → arthritis or arthralgia, & rash
 ↑R:
 Morph: Togaviridae Family → Rubella virus
 +ve ssRNA virus; enveloped
 Culture/Labs: Serology for IgM anti-rubella Ab
 Virulent Factors:
 Tx: Supportive
 Complication: Congenital defects when contracted via in-utero transmission
 Prevention: Live attenuated MMR Vaccine

5th disease/ Slapped Cheek  Infection first causing erythematous rash on cheeks → Reticulate/ lacy rash on trunk and
Dz./ Erythema Infectiosum extremities. Associated w/ Arthralgia and LAP. Adults present w/ fever, joint pain (ImComplex
Deposition), milder rash
 d/t: Parvo B19 virus

Parvovirus B19  Infection: 5th disease/ Slapped Cheek Dz./ Erythema Infectiosum. Transmitted via resp. droplets,
or vertical transmission when pregnant
 Virus binds P-antigen (globoside), and co-receptor (a5b1 integrin) of immature RBC's
 ↑R: children, parents/teachers of infected children, pregnant women, and Chronic anemia pt's.
 Morph: ssDNA; non-enveloped
 Culture/labs:
 Virulent Factors:
 Tx: Supportive
 Complication: Hydrops fetalis w/ vertical transmission; Aplastic Crisis in sickle cell anemia
(progenitor destruction)
 Prevention:
6th Disease/ Roseola  Rapid onset fever for few days → suddenly returns to normal → 2 days later maculopapular rash
Infantum/ Exanthema on trunk and spreads to rest of body
Subitum  d/t: HHV 6 or 7

Human Herpes Virus (HHV)  Infection: 6th disease/ Roseola infantum/ Exanthema Subitum. Transmitted via close contact
6&7  ↑R:
 Morph: dsDNA Virus, enveloped
 Culture/labs: serology for Ab
 Virulent Factors:
 Tx: Ganciclovir (HHV6)
 Complication: Febrile seizures in children (HHV6); Latency of virus in CD4 cells
 Prevention:
Chicken Pox  Infection of epithelial cell, fibroblast, TC, Neurons → Viremia causes asynchronous and
centripetal skin lesions (maculopapular → vesicular→ pustular w/ crusting → Scab) to form
primarily on head and trunk
 d/t: Varicella Zoster Virus
Shingles  Reactivation of latent VZV infection, viral particles causing new symptoms known as Herpes
zoster Presenting w/ dermatomal distribution of vesicles w/ sever pain
 ↑R: Old age, pre-AIDS phase, Organ transplant recipients
 HZ Opthalmicus: Involvement of trigeminal nerve → affected forehead, cornea, upper eyelid,
scalp, nose dorsum
 Ramsay Hunt Syndrome (Herpes Zoster Oticus): Herpes rash around mouth, ear, nose, and neck
→ causing facial muscle paralysis, hearing loss, ear pain, dizziness

Varicella Zoster Virus  Infection: Chicken Pox → Herpes zoster/ shingles; caused by respiratory droplets; tendency for
latency in the dorsal root ganglia; cell to cell spread via syncytia
 Incubation period: 10-21 days
 Morph: Herpes virus → VZV: dsDNA, enveloped
 Culture/labs: Viral DNA by PCR; Antigen Detection; Fluorescent Ab to membrane antigen (FAMA
- test for skin lesions)
 Tzanck smear from scraping ulcer base: Giant cells w/ syncytia formation
 Virulent Factors:
 Tx: Acyclovir, Famciclovir, valacyclovir, VZV Ig's
 Host immunity most relies on CD8 and NK's
 Complication: Interstitial Pneumonia, Herpes Zoster
 Prevention: Live attenuated vaccine: OKA strain → ⭐️Cell mediated and humoral immunity
Herpes Simplex Virus  Infection: Manifest as Herpetic whitlow, eczema herpeticum, Herpes gladiatorum
 Herpetic lesion: Clustered vesicles on erythematous base
 Morph: Herpes Virus → HSV: dsDNA, enveloped
 Culture/labs: PCR for DNA detection, Viral antigen Detection, Tzanck Smear: Multinucleate Giant
Cell
 Tx: Acyclovir

Coxsackie Virus A16  Infection: Hand-Foot-Mouth disease → Feco-oral transmission → Mild fever, vesicular
exanthems on hand, feet, mouth and tongue
 Morph: Picornaviridae family → Coxsackie Virus: (+ve) ssRNA, nonenveloped
 Virulent Factors:
 Tx: symptomatic

Rock Mountain Spotted  Flu like illness w/ 2-14 day incubation period: fever, headache, malaise, myalgia, vomiting, along
fever w/ Maculo-papular rash (which then becomes petechial) spreading from distal extremities to
trunk & face
 Other S&S: Arthritis, conjunctivits, hepatitis, meningo-encephalitis, shock, death
 d/t: R. Rickettsii
R. Rickettsii  Infection: Rocky Mountain Spotted Fever: Microbe adheres to endothelial cells lining capillaries
→ Phagocytosed→ escape endosome (PLD) → Binary fission reproduction → Cell Lysis or infect
adjacent cell
 Necrosis of endothelium, Leaky BV's: perivascular infiltration, thrombosis → rash
 ↑R: Outdoor activities (hiking/camping…), April - June, in OK, TN, NC, SC
 Morph: G-ve, OIC, coccobacillus
 Vector: Dermacentor andersonii (wood tick); D. Variabilis (dog tick)
 Culture/labs: Direct fluorescence Microscopy: Antigen in lesions; ELISA & Immuno-Fluorescent
Ab test: Checking for rising titer; Weil Felix test: Heterophile agglutination test to detect Ab
(cross rxn); PCR: early phase detection; Labs: TCP, anemia, abnormal liver fxn test,
hypoalbuminemia
  Virulent Factors:
 Tx: Doxycycline
 Complication: DIC, Septic Shock
 Prevention:
Dengue  Infection causing hemorrhagic lesions in skin: In prodrome, viremia causes flu like symptoms and
involvement of vasculature
 "Breakbone fever" w/ maculopapular and hemorrhagic rash, retro orbital, muscle and
joint pain
 d/t: Dengue Virus
Dengue Virus  Infection: Dengue
 ↑R: Endemic in S. Asia, SE Asia, africa, SA, Mexico, Carib, Texas, and florida
 Morph: Flavivirus Family → Dengue: +ve ssRNA, enveloped
 Vector: Aedes Mosquito
 Culture/Labs: PCR, ELISA (IgM detection)
 Virulent Factors:
 Tx: Supportive care
 Complication: Occurring in those previously infected w/ different serotype of dengue: Non-
neutralizing Ab's enhance Mx's virus uptake → ⭐️TC → CK release →
 Dengue Hemorrhagic Fever: Vasculature rupture → Bleeding and ↑permeability
 Dengue Shock Syndrome: Persistent vomiting , severe abdominal pain, mucosal bleeding,
difficulty breathing, Hypovolemic shock, rapid ↓Platelet count, ↑Hematocrit. High
Mortality rate
Sarcoptes Scabiei  Infection: Scabies: Pruritic tracks or papules seen on hands, wrists, axillary folds, genitals
 Itch Mite will burrow into upper layers of dermis → Lays eggs → Larval and nymph stage
→ adult mites
 ↑R: Overcrowded, unhygienic conditions: wartime, day cares, prisons, nursing homes
 Morph: Eight-legged arthropods w/ sac like bodies and no antennae
 Culture/Labs:
 Tx: 5% Permethrin Cream (elmite); Gamma Benzene Hexachloride
 Complication: ICO Host: Norwegian scabies: extensive crusted dermatitis; Secondary pyoderma
infection may be seen

Scaly, warty and nodulo-ulcerative lesions

Type of lesion Type of infection Causitive agent and Properties
Macular Scaly Superficial Mycoses/ Malassezia Furfur/ Pityrosporum Orbiculare : Spread via direct/indirect, person to person,
Tinea Versicolor transfer of keratinized material, common in tropic's
- Infection of Stratum Corneum, hair and nails; Non destructive lesion w/ litlte host
response
CF: Small hypo/hyper-pigmented macules, primarily upper body. Well demarcated
patches, may be raised & covered w/ fine scale
- Morph: Lipophilic, spherical/oval, thick yeast
- Labs: Wood's lamp examination: Lesion will fluoresce w/ yellowish color upon exposure
to wood's lamp.
- Microscope: Skin scrapings in 10% KOH, "cig. butt like hyphae, and Meat ball like spores."
-Culture: synthetic mycologic media, supplemented w/ olive oil: yeast growth in 5-7 days
at 30 C
Tx: Topical azoles, selenium sulfide shampoo
Scaly Cutaneous Mycoses/ Candida infections:
Dermatophytosis CF: Pruritic rash w/ erythematous scaly lesions in moist skin areas (groin, axilla, toe webs,
(Tineas) breast folds). Onychomycosis and paronychia (nail). Chronic muco-cutaneous candidiasis
→ TC deficiency association
Labs: Gram Stain: G+ve yeast cells and pseudohyphae
-Microscope: 10-20% KOH: Budding yeast like cells and pseudohyphae
-Saboraud Dextrose Agar: Creamy pasty colonies
 -Germ tube test: Candida Albicans identificaiton - yeast cell incubated in human serum at
37C → germ tube formation
Tx: Topical imidazoles like clotrimazole

2c. Indicate the predisposing/ risk factors for acquiring these infections and modes of transmission.
 See 2.a & 2.b: ↑R
2d. Correlate the virulence factors of the microorganisms with their mechanism of action or cytopathic effects with the
pathophysiology in the host.
 See 2.b: Virulent Factors/ Toxins
2e. Identify other sites that may be associated with infection, complications and events that lead to the complications.
 See 2.b: Complications
2f. Choose the appropriate clinical specimen and laboratory investigation/ test to confirm the diagnosis/ causal organism
 See 2.b: Cultures
2g. Select the most appropriate antimicrobial agent and explain its mechanism of action.
 See 2.b: Tx
2h. Indicate the appropriate general/ prophylactic preventive measures.
 Good Hygiene; See 2.b: Prevention

Goal 3 - Zoonotic Infectious Diseases of Skin and Soft Tissues

 See Zoonotic Tables

Goal 4
4a. Acute and chronic inflammatory dermatoses, and their clinical features, this includes:
Acute inflammatory Characteristics
dermatosis
Acute Eczema Dermatitis Subdivided by 5 initiating factors: 1) Allergic Contact, 2) Atopic, 3) Drug related, 4) photoeczeamouts,
5) Primary irritant
Path: Type 4 HS reaction: In skin, foreign reactive chemicals modify self proteins to act as haptens →
Uptake by LHC's → LHC presents antigen to TC (⭐️ effector, memory TC differentiation) → Re-
exposure to antigen → Memory TC home to location. 24 hr process, responsible for erythema &
pruritis.
Morph: Red, papulovesicular, oozing and crusted lesions (If persistent, Acanthosis, hyperkeratosis
can form scaling plaques). Spongiosis (intercellular edema of the epidermis), characteristic feature →
intraepidermal vesicles
Tx: hydrocortisone

Erythema Multiforme
Erythematous lesion w/ diverse array of morphology; self limited HS reaction, any age → death of
squamous cells. Associated w/ 4 conditions:
1 - Infections: Herpes simplex, mycoplasma, histoplasma, coccidomycosis, typhoid
2 - Drugs: sulphonamides, penicillin, barbiturates, antimalarials, hydantoin, allopurinol,
acetaminophen
3 - cancer: carcinomas and lymphomas
4 - collage vascular disease: SLE, dermatomyositis, and PAN
Path: Keratinocyte injury mediated by skin homing cytotoxic TC's
Morph: erythematous targetoid lesions over trunk, spreading to extremities; macules, papules,
vesicles and bullae

Steven-Johnson Syndrome Progression from Erythema multiforme, involvement of mucosal surface, along w/ fever. Secondary
infection of t/ lesion can lead to sepsis.
 - Bullous lesions involving mucous membrane

Toxic Epidermal Necrolysis Progression from Steven-Johnson syndrome: Diffuse necrosis and sloughing of skin and mucous
membranes, involving more than 30% of the body surface. Potentially life threating, and most
commonly drug induced.
- Bullous detachment of skin

Chronic Inflammatory Characteristics

Dermatosis
Psoriasis Autoimmune origin (HLA-C association), or Trauma induced (Koebner phenomenon). Systemic
Association: Myopathy, enteropathy, AIDS
Path: CD4 sensitization → Keratinocyte death (CD8 mediated) → Accum. TC secrete CK's TNFa,
IFNgamma, IL12, → Keratinocyte proliferation → Hyperkeratosis
C/F: Elbows, knees, scalp, lumbosacral areas, penis, nails → Most frequently affected areas. Lesion is
a well demarcated salmon colored plaque, covered by silver scales. Nail: yellowish, w/ pitting
onycholysis
Auspitz sign: multiple minute bleeding points when scale lifted from plaque.
Psoriatic Arthritis: Can produce severe deformities
Micro: Epidermal Hyperplasia (acanthosis), Parakeratosis (scale), Munro microabscess:
accumulation of Neutrophils in the epidermis, seen w/ in the parakeratotic stratum corneum
Tx: High potency topical Corticosteroids, UV light w/ psoralen, or immune modulating, therapy
(retinoid methotrexate cyclosporine, TNFinh adalimumamb etanercept imiximab

Lichen Planus 6P's: Pruritic, purple, polygonal, planar, papules, plaques.

-Papule w/ white lace like pattern → Wickham Stria
Lesion sites: Elbows and wrist, oral mucosa
Path: Cell mediated cytotoxic immune response is possible. Post inflammatory hyperpigmentation
may be seen. Spontaneous resolves 1-2 years after onset. Anucleate, necrotic basal cells, Civatte or
colloid bodies, may be seen in papillary dermis
Histo: Interface dermatitis: dense infiltration of lymphocytes at the dermoepidermal junction. Saw
tooth appearances. Hyperkeratosis, hypergranulosis

4b. Distinguish various blistering (bullous) disease's etiologic factors, Specific pathologic basis and CF

Bullous Diseases Characteristics

Pemphigus AI destruction of desmosomes b/w keratinocytes in epidermis and mucosal epithelium, 4-6th decade
occurrence, 80% Pemphigus Vulgaris type. Commonly involving Mucosa (mouth ulcers), and skin
especially scalp, face, axilla, groin, trunk and points of pressure
 Path: IgG against desmoglein (Intercellular adhesion molecules); type II Hypersensitivity → Suprabasal
Acantholysis of stratum spinosum keratinocytes → blistering. Basal cell layers remain attached giving
tombstone appearance.
Nikolsky sign: Separation of epidermis on stroking the skin.
C/F: Eroded plaques w/ dry crust formed d/t easy rupture of thin bullae
Immunofluorescence: IgG deposition along membranes give off reticular/ fishnet like appearance
Tx: Systemic involvement Rx prednisone

Bullous Pemphigoid AI destruction of Hemidesmosomes (connects basal cell keratin to underlying BM), seen in the elderly.
Involve Skin and mucosa: inner thighs, flexor surfaces of forearm, axillae, groin, lower abdomen.
Path: IgG (BPAGs) against hemidesmosomes → separation of basal keratinocytes from BM. Tense sub
epidermal blister that fails to rupture b/c roof consist of full thickness epidermis. Ulcers form when
blister ruptures
Immunofluorescence: IgG deposition in singular linear pattern (BM involvement)

Dermatitis AI deposition at tips of dermal papillae, seen predominantly in males ~30-40yrs. Can occur in celiac
Herpetiformis disease and responds to gluten free diet. Characterized by urticaria and group vesicles. Seen on extensor
surfaces of elbows, knees, upper back and buttocks
Path: Predisposition → IgA ab to dietary gluten (from wheat protein gliadin) → Cross reaction w/ reticulin
(component of anchoring fibrils, tethering BM to superficial dermis → injury/ inflammation → blister

Goal 5 (6)
5a. Disorders of pigmentation and melanocyte etiologic, pathologic basis & clinical characteristics,
Melanocyte disorder Characteristics
Melanocyte Responsible for skin pigmentation and are present in basal layer of the epidermis, derived from the
neural crest. They synthesis melanin in melanosomes using tyrosine as a precursor molecule.
Keratinocytes receive melanin.
Freckle Seen after sun exposure. Circadian darkening/lightening, d/t ↑melanin pigment in basal melanocytes
Lentigo Benign localized hyperplasia of the melanocytes restricted to basal layer, starting in infancy and child
hood. 5-10mm oval, tan macules or patches that are sharply circumscribed. Do not darken on sun
exposure
Melanocytic Nevus Benign, pigmented neoplasms d/t Aquired ⭐️ mutation involving RAS pathway.
Congenital Nevus: Associated w/ hair
Aquired nevus: junctional nevus Begins as nests of melanocytes at the DE junction; most common in
children. It grows by extension into the dermis→ Compound nevus → Junctional component is
eventually lost resulting in an intradermal nevus, most common mole in adults.
Dysplastic Nevi & Melanocytic Nevi w/ architectural and cytological atypia, majority are clinically stable, some may be
Variants precursors of melanoma. ↑R w/ multiple dysplastic nevi.
Dysplastic nevus syndrome: autosomal dominant disorder
C/F: numerous flat macules to slightly raised plaques
Morph: larger than most nevi, pebbly or target like lesions w/ darker raised center and irregular flat
periphery.
Melanoma Malignant melanocyte disorder. Commonly in sun exposed areas of skin; others include oral and
anogenital region, meninges, uvea of eye.
↑R: Sun light(UV rays) exposure leading to pyrimidine dimer formation, Albainsm (↓melanin),
Xeroderma Pigmentosum (NT excision repair defect), dysplastic nevi syndrome.
 Path: LOF mutation disrupting cell cycle control genes: CDKN2A gene mutation which codes for P16 (Loss
of CDK4/6 inhibition and inhibition of Rb gene), P15, and P14 (Loss of MDM2 INH → excess p53
degradation).
GOF: mutation in pro-growth cell signaling pathways: NRAS mutation (10-20%) (↑RAS→ PI3K→ AKT→
(radial, epidermis ↑MDM2 and ↑MTOR → ↑Cell survival), and BRAF mutations (40-50%) (↑braf → Mek→ erk→
limited) ↑CDK4/6→ Proliferation). ⭐️mutations of telomerase: TERT mutations most common
C/F: Mole like growth, asymptomatic, itchy or painful are early manifestations. Important warning signs:
ABCDE's. Asymmetry, Border irregularity, Color dis-uniform, ↑Diameter, Evolution
Radial Growth phase: Horizontal growth along the epidermis and superficial dermis; ↓R
Lentigo Maligna Melanoma: elderly; lesions located to face; Superficial spreading: Most common
subtype, sun exposed skin; Acral/mucosal lentiginous melanoma: Unrelated to sun exposure
Vertical Growth Phase: Vertical growth into deep dermis; ↑R of metastasis. Breslow thickness
(extension depth - granular layer to m) is most important prognostic factor. Nodular appearance→
Vertical; nodular emergence of clone cells w/ metastatic potential
aggregates) Good prognosis: Female gender, extremity location, Few Mitoses, Breslow thickness < 1.7mm
Differentials: Seb Keratosis, Compound/junctional nevus, dysplastic nevi, Kaposi sarcoma, malignant
melanoma
Tx: Vemurafenib - use in BRAF mutation if common V600 E mutation

5b. Interpret the histological characteristics of various benign epithelial Tumors of the skin, their pathologic
basis, cell of origin and clinical characteristics, this includes:
Benign Skin Tumors Characteristics
Seborrheic Keratosis Squamous proliferation in middle aged or older adults. Spontaneous and located on trunk, extremities,
head and neck.
Path: ⭐️mutation in Fibroblast GF Receptor3 (differential Achondroplasia). Hyperplasia of epidermis
C/F: round coin like, waxy plaques, uniformly dark brown, variable in size, stuck on appearance. Seen as
part of a paraneoplastic syndrome: Leser-trelat sign in carcinomas of GIT.
Histo: hyperplasia of epidermis, resembling basal cells; hyperkeratosis, Horn cyst: small keratin filled
cysts and invaginate into main mass called invagination cyst
Acanthosis Nigricans
Fibroepithelial Polyp
(Acrochordon
- [ ] fibroepithelial polyp (acrochordon).

5c. Distinguish between categories of premalignant & malignant epidermal Tumors, and recognize their
pathologic basis, cell of origin & clinical characteristics, this includes:
 Actinic keratosis
 squamous cell carcinoma actin keratosis
 basal cell carcinoma.

5d. Study of a skin tumor resulting from cellular migration into the skin, this includes: Mycosis fungoides and
its cell of origin, clinical characteristics and pathological basis.

Goal 6
 Radio

Goal 7
 Adnexal and Subcutaneous Tissue Disorder

Goal 8
 Congenital Skin Diseases
Goal 9 (7) - Neoplastic disorders of muscles
 Bone
o Osteoblast sit on surface of bone and synthesize type 1 collagen and hydroxyapatite (reinforces collagen) to
form new layers of matrix
 Produce RANKL induces monocyte fusion to create osteoclast
o Osteocytes: found deeper into the bone and are less able to create matrix, and can't multiply. Contain
mechanoreceptors to detect stress and damage and control remodeling
o Osteoclast: Secrete enzymes that break down bone matrix to releases Ca and PO4 back into blood → Useful
in bone remodeling and when blood Ca is low

9a. Outline the morphologic features seen in muscular dystrophies- Duchenne, Becker.
 Dystrophin and dystrophin associated protein complex attach intracellular contractile apparatus to
extracellular connective tissue matrix. Transfer force of contraction to CT
Dystrophy Morphological features
Duchenne  Most common/ severe muscular dystrophy. A dystrophin gene mutation (Robbins frameshift mutation, and
Muscular deletion)
dystrophy  C/F: Normal at birth, symptoms appear at 5 years w/ progressive muscular weakness. Proximal weakness of
shoulder and pelvic girdles. Child becomes wheal chair dependent at around 9.5 years. Contractures, scoliosis,
worsening respiratory reserve and sleep hypoventilation. Trendelenburg gait, gowers sign, calf
pseudohypertrophy (fibroadipose tissue replacement), heart failure arrhythmia, respiratory insufficiency and
pulmonary infections
 Histo: Muscle fibers of various size. Necrosis, degeneration of fibers. Fibrosis, fatty infiltration.
 Lab: Elevated serum creatinine kinase
 Dx: Muscle biopsy, DNA analysis by PCR, Western Blot

A: 3 year old, architecture of fascicular muscle maintained, but variation in size of myofibers is seen. Focal pink
staining → endomysial fibrosis. B: Complete absence of membrane associated dystrophin. C: 9 year old, disease
progression, fatty replacement and more endomysial fibrosis
Becker  Less common, less severe. Altered dystrophin gene. Late onset, variable progression. Relatively normal life span.
Muscular Cardiac involvement is rare.
Dystrophy

9b. Distinguish between Duchenne and Becker muscular dystrophies with reference to clinical features.
 See 9a.

9c. Discuss the genetic basis, clinical features and morphology of myotonic dystrophy
 Myotonia → sustained involuntary contraction of a group of muscles
 ↑CTG Repeat: AD multisystem disorder associated w/ skeletal muscle weakness, cataracts,
endocrinopathy, and cardiomyopathy
 CF: Stiffness, difficult to release the grip, percussion of thenar eminence elicits a myotonia. Cataract,
frontal balding, gonadal atrophy, Ring fibers.


9d. Explain the genetic basis and clinical features of ion channel myopathies –
 Inherited diseases caused by mutations affecting ion channel protein functions. AD w/ variable
penetrance
 C/F: Epilepsy, migraine, movement disorders, cerebellar dysfunction. Peripheral nerve disease and
muscle disease → ↑ or ↓muscle tone (hypertonia, hypotonia)
 Further subclassified based on Potassium levels
o Hyperkalemic
o Hypokalemic Periodic Paralysis: CACNA1S missense mutation in muscle calcium channel
o Malignant Hyperthermia: RYR1 mutation, dysfunctional ryanodine receptor: Hyper metabolic state
that can be triggered by a aesthetics, and succinylcholine.

9e. Hyperkalemic and hypokalemic periodic paralysis, malignant hyperthermia

 See 9D.

9f. Mitochondrial myopathies and discuss the morphologic features and clinical presentation – MELAS, MERRF
Mitochondrial Characteristics: Maternally transmitted mitochondrial DNA. SM involvement manifest as weakness, ↑ serum
Myopathy Creatine Kinase or Rhabdomyolysis
MELAS Mitochondrial Encephalomyopathy, Lactic acidosis, and stroke-like episodes: Recurrent episodes of acute
neurological dysfunction, cognitive changes, muscle involvement, weakness, lactic acidosis
 Mutation in mitochondrial tRNA-Leucine (MTTL1)
MERRF Myoclonic epilepsy and ragged red fibers: Affected individuals have myoclonus, seizure disorder, and evidence of
a myopathy. Ragged Red fibers on muscle biopsy

9g. Noninfectious inflammatory myopathies – Dermatomyositis, Polymyositis, Inclusion body myositis.

Inflammatory Myopathy Characteristics
Dermatomyositis CF: Children/ Adults; bilateral proximal muscle weakness. Skin rash on upper eyelid (heliotrope),
periorbital edema
Path: MAC complex deposition w/ in capillary beds of skin and muscle. Anti-Mi2 Ab: Gottron papules
and heliotrope rash. Anti-Jo1 Ab's: Interstitial lung disease, non erosive arthritis, "mechanic hand skin
rash." Anti-P155/P140 Ab: Paraneoplastic and juvenile cases of disease
Histo: Perimysial & vascular lymphocytic infiltrate; perifascicular fiber atrophy, SM fiber degeneration
and regeneration
Polymyositis CF: Adults; bilateral proximal muscle weakness
Histo: Endomysial lymphocytic inflammation, Skeletal muscle fiber degeneration and regeneration
Inclusion body Myositis Most often myositis seen in late adult hood.
CF: Progressive muscle weakness, worst in quadriceps, and distal upper extremity muscles. Elevated
CK

9h. Discriminate between Myasthenia Gravis and Lambert Eaton Myasthenic syndrome
Myasthenia Gravis AI Dz where Ab's attack post synaptic AcH receptors in NMJ → weakness. Associated w/ thymic hyperplasia
and thymoma
Morph: Type II fiber atrophy, Immune complex and complement deposits found along postsynaptic
membrane
CF: F>M. Muscular weakness; ptosis; diplopia. Weakness worsens w/ repeated contractions. Respiratory
muscle involvement → death
Tx: Anticholinesterase agents, Immunosuppressants (glucocorticoids, cyclosporine, rituximab), thymectomy
Lambert-Eaton Most common presentation → Paraneoplastic syndrome of small cell carcinoma of lung. Ab against calcium
myasthenia channels. Proximal muscular weakness that improves with repeated contractions

9i. Discuss the clinical presentation of drug induced myopathies and agents responsible
Drug Drug induced myopathy characteristic
Statins Unrelated to dose, cumulative dose or statin type
Antimalarials Chloroquine and Hydroxychloroquine
 Interfere w/ lysosomal function and can cause lysosomal storage myopathy: slowly progressive muscle
weakness. Vacuolation predominantly affecting type 1 fibers
 Aggregates of whorled, lamellar membranous structures, including curvilinear bodies
ICU Corticosteroid therapy: relatively selective degradation of sarcomeric myosin thick filaments

9j. Distinguish between achondroplasia and thanatophoric dysplasia

 Abnormal proliferation or maturation of osteoblast, osteoclast, or chondrocytes
Achondroplasia AD - Impaired proliferation of cartilage at growth plate; FGFR3 mutation
CF: Normal sized vertebral column, enlarged head possible. Shortened arms and legs. Normal growth
hormone and IGF1 levels
Thanatophoric Defect in FGFR3 Receptor: Severe limb shortening and bowing, frontal bossing, depressed nasal bridge.
Dysplasia Most common lethal form of dwarfism

9k. Discuss the genetic basis, tissues affected, clinical features and subtypes of osteogenesis imperfecta
 Osteogenesis Imperfecta: AD brittle bone disease. Defective synthesis of Type 1 collagen
o CF: Recurrent pathological fractures d/t osteopenia; Blue sclera; deafness; Laxity of joint ligaments;
Easy bruisability; thin dermis; Dental imperfections
o Subtype 1: Decreased synthesis of pro- alpha 1 chain
o Subtype 2: Abnormal pro-alpha 1 or 2 chains

9l. Explain the underlying pathogenesis, morphology, clinical and radiologic features of osteopetrosis
 Osteopetrosis - aka Marble bone disease and Albers-Schöngerg disease: a group of rare genetic diseases
that are characterized by reduced bone resorption and diffuse symmetric skeletal sclerosis d/t impaired
function or formation of osteoclast → overgrowth and sclerosis of cortical bone
o AR: Seen in children - severe
o AD: Seen in adults - less severe
 CF: Pathologic fractures
o Anemia: Replacement of marrow cavity; pancytopenia; extramedullary hematopoiesis
o Cranial nerve compression: visual and hearing loss; facial nerve palsy
o Hydrocephalus d/t CSF obstruction
o Erlenmeyer flask deformity; Bones are diffusely sclerotic and distal metaphysis of ulna and radius
are poorly formed

Goal 10 (9)
10a. Classify infectious diseases of bone and joints based on the clinical presentation, symptoms, age, and
anatomical location of the infection
Disease Characteristics
Osteomyelitis  Staph Aureus (90% of cases) infection resulting from hematogenous dissemination to bone, or
secondary infection resulting from trauma to adjacent area.
 Also can be caused by Streptococcus pyogenes, Haemophilus Influenzae.
 Clinical findings:
 Children: cutaneous infection → spread to metaphyseal area of long bones (highly
vascularized area of bony growth); Localized pain over involved bone and high fever; Limping
in pain
 Adults: Vertebral osteomyelitis, long bones rarely involved; intense back pain and fever
 Neutrophils enzymatically destroy bone. Devitalized (dead) bone; lifting of periosteum
impairing blood supply to affected area → Sequestrum; top arrow
 Involucrum: Reactive bone formed around segment of devitalized infected bone in chronic
disease; bottom arrow
 Fracture, intraosseous abscess (brodie's), amyloidosis is common
o Brodie abscess: sequestered focus of infection in the metaphyseal area of long bone;
occurs only in adults
 Soft tissue abscess from ruptured periosteum leads to draining sinus tract to the skin surface:
↑R of squamous cell carcinoma developing at orifice of sinus tract
 Sclerosing osteomyelitis of Garré: Typically in the jaw, extensive new bone formation that obscures
underlying osseous structure
 Osteomyelitis in sickle cell disease: Salmonella Sp. Is most common cause
 Tx fluoroquinolones → ciprofloxacin, in children use
 Tuberculous Osteomyelitis (Pott Disease): Mycobacterial osteomyelitis. Spine involvement in 40%
of cases. Disk and vertebrae destruction → permanent compression fractures → Scoliosis or
kyphosis and neurologic deficits
o Tuberculous arthritis, sinus tract formation, psoas abscess and amyloidosis
 Pseudomonas → diabetic or IV drug abusers
 Pasteurella → Cat or dog bit/ scratches
Septic Arthritis  Staph aureus infection in young children and adults who receive intraarticular injections or who
have mechanically abnormal joints
 Multiple joint involvement indicative of hematogenous spread
 CF: Painful erythematous joint w/ purulent material obtained on aspiration; large joints most
commonly involved
 Neisseria gonorrhoeae most common cause of septic arthritis in sexually active individuals
 CF: History of fever, chills, malaise, sore throat, skin rash, and polyarthralgia, vaginal
discharge
 May produce disseminated gonococcemia
 Most common in young women; Deficiency of C5-C9 → Predisposition to dissemination
 Septic Arthritis (knee); Tenosynovitis (wrists and ankles); Dermatitis (pustules on wrists or
ankles)
 Clinically: Tender, painful, swollen & erythematous joint. Usually monoarticular and seen in knee,
hip and shoulder.
 Route of infection: hematogenous, direct inoculation, spread from adjacent sites
 Joint aspiration: Cloudy aspirate, neutrophils, gram stain
Prosthetic Joint  Coagulase negative staphylococci infection, particularly the hip. Localized pain and mechanical
infections failure of the joint common.
 Tx: joint replacement and antimicrobial therapy
Reactive Arthritis  Reiter syndrome: Triad of arthritis, nongonococcal urethritis or cervicitis, and conjunctivitis
 Cant see, cant pee, cant climb a tree
 Men in their 20s o 30s in 80% of cases → HLA-B27 positive; HIV association. Prior genitourinary
infection (chlamydia), GIT (shigella, salmonella, Yersinia, campylobacter).
 Path: Urethritis or diarrhea → arthritic symptoms w/ in several weeks of inciting bout. Arthritis
episodes usually wax and wane over several weeks to 6 months
 Clinical findings:
 Joint stiffness, low back pain common early symptoms.
 Ankles, knees and feet affected most often → asymmetric pattern
  Synovitis of digital tendon sheath → sausage finger or toe
 Ossification of tendoligamentous insertion sites → Calcaneal spurs and bony out growths
Lyme Arthritis Caused by spirochete: Borrelia burgdorferi which is transmitted by deer tick (ixodes ricinus). Arthritis
develops in 60-80% of untreated individuals w/ disease. Primarily involving large joints (knees,
shoulders, elbows, and ankles - descending order of frequency).
Infected synovium: chronic synovitis marked by synoviocyte hyperplasia, fibrin deposition,
mononuclear cell infiltrates and onion skin thickening of arterial walls

Viral Arthritis Viral infection including: alpha virus, parvovirus B19, rubella, EBV, and hepatitis B and C viruses
Neuropathic Arthropathy Noninflammatory joint disease; secondary to a neurological disease. Joint destruction d/t insensitivity
(Charcot's Joint) to pain
Causes: DM (tarsometatarsal joint); Syringomyelia (shoulder, elbow, wrist joints); Tabes dorsalis (hip,
knee, ankle joint)

10b. Differentiate reactive and septic arthritis with respect to the causal organisms and pathogenesis

10c. Determine the most likely causal organism and describe the routes by which various microbes gain access
to bone/joint.

10d. Indicate the predisposing/ risk factors for acquiring these infections.

10e. Differentiate each causal organism based on their physical properties.

Microbe Characteristics
Staph Aureus Micro: g+ve cocci that form clusters but difficult to identify
Labs: Yellow colonies when cultured, hemolysis on sheep blood agar
Tx: Penicillin w/ beta lactamase; trimethoprim-sulfamethoxazole;
Tetracyclines: doxycycline or minocycline, clindamycin, or linezolid
Hemophilus Micro: G-ve rod
Influenza Labs: (X-factor: Hemin - stimulating growth factor) (V factor: NAD -vitamin) Both factors are needed in order to
facilitate growth of microbe
Tx: broad spectrum cephalosporins for severe infections. Less severe infections can be treated with amoxicillin,
active cephalosporin, azithromycin, doxycycline, or fluoroquinolone.
Prevention via purified capsular PRP immunization
Neisseria Path: Gonococci attach to mucosal cells (Pili, PorB, Opa proteins mediate attachment and penetration) →
Gonorrhoeae penetrate into the cells and multiply → pass through the cells into the subepithelial space where infection is
established.
LOS (lipooligosaccharide) → ⭐️CK release, primarily TNFa → associated symptoms
Micro: g-ve bacteria, diplococci arrangement. Oxidase +ve, catalase +ve
Tx: Dual therapy: Ceftriaxone and either azithromycin or doxycycline

10f. Correlate the virulence factors of the microorganisms and their mechanism of action with
pathophysiology in the host.

10g. Identify other sites that may be associated with infection caused by some of these causal organisms,
complications and events that lead to the complications.

10h. Identify the appropriate clinical specimen and laboratory investigation/ test to confirm the diagnosis/
causal organism.

10i. Select the most appropriate antimicrobial agent and explain its mechanism of action.
10j. Indicate the appropriate general/ prophylactic preventive measures
Goal 11
11a. Compare and contrast rheumatoid and osteoarthritis including the etiology, pathogenesis, morphology,
clinical and radiologic features of each.
Disease Rheumatoid Arthritis: Inflammatory
Etiology Chronic inflammatory AI disorder → produce a non
suppurative proliferative and inflammatory synovitis.
F>M 4:1; 20 and 50 years old
Path Pathologic changes mediated by Ab against self
antigens. CD4 TC's secrete CK's: IFNgamma → ⭐️Mx
and synovial cells. IL17 → recruit Nx and monocytes.
TNF/IL1 from Mx → ⭐️Synovial cell to secrete protease
that destroy hyaline cartilage. RANKL from ⭐️TC →
⭐️bone resorption
Rheumatoid factor: IgM/A ab against Fc fragment of
IgG
Anticyclic citrullinated Peptide antibodies (anti-CCP)
Morph Synovitis: Acute inflammatory reaction w/ edema and
inflammatory infiltrate (neutrophils followed by
lymphocytes and plasma cells). Hyperplasia &
hypertrophy of the synovial lining cells eventuate into
numerous finger like villi. → Granulation tissue
(pannus) extends over articular cartilage (extension of
pannus to subchondral bone results in erosion and
cyst formation leading to deformities of both cartilage
and bone) → Scarring contracture and deformity
result from destructive inflammation of ligaments
tendons and bursae → Subcutaneous Rheumatoid
nodules
Clinical Fatigue, malaise, anorexia, weight loss, fever, myalgia.
Features Swelling of joints and stiffness in morning or after
inactivity. Polyarticular and symmetric joint
involvement (PIPJ, MCPJ, Knee and ankle). Radial
deviation of wrist and ulnar finger deviation. Swan
neck deformity, Boutonniere deformity, Bakers cyst
(popliteal fossa).
Extra-articular manifestations: Pleural/pericardial
effusion, anemia, LAP, Pulmonary Involvement, Neuro
abnormalities. AA amyloidosis deposition
Felt syndrome: splenomegaly, neutropenia, RA
Still disease: Juvenile RA, LAP, HSM, acute onset
marked by fever
Radio Symmetrical involvement, radial deviation of
Features wrist and ulnar fingers
Osteoarthritis: Degenerative
A degenerative joint disease characterized by degeneration of
cartilage that results in structural and functional failure of
synovial joints. Primary: insidiously, In younger it's secondary:
joint deformity, previous joint injury, Diabetes, ochronosis,
hemochromatosis, obesity.
Degeneration of articular cartilage and its disordered repair
1: Chondrocyte injury d/t genetic or biochemical factor
2: Early OA d/t chondrocyte proliferation & secretion of
inflammatory mediators, collagens, proteoglycans (shock
absorption) and proteases → Remodel cartilaginous matrix →
synovium and subchondral bone changes
3: Late OA d/t repetitive injury and chronic inflammation →
Chondrocyte drop out, marked cartilage loss, extensive
subchondral bone changes
Chondrocytes proliferate → form clusters (cloning). ↑Water
content in matrix, ↓[proteoglycan]
Normal horizontally arranged collagen type II fibers are
cleaved→ Fissure and clefts on articular surface(granular soft
articular surface) → chondrocytes die → sloughing of cartilage
→ Pieces fall into joint space (joint mice) → Newly exposed
subchondral bone rubs against opposing bone → Polished
ivory appearance (bone eburnation) → Underlying bone has
fracture gaps where synovial fluid enters → Fibrous walled
cyst form → Mushroom shaped osteophytes with ossifying
fibrocartilage and hyaline cartilage as caps
~50's, Deep achy pain that worsens w/ use. Morning stiffness,
crepitus, limited range of movement. Cervical and lumbar
nerve root compression if spinal foramina is impinged. Joints
involved: Hips, knees, lower lumbar, cervical vertebrae, PIPJ,
DIPJ. Heberden Nodes in DIPJ common in women. NO FUSION
Figure 26-40 Severe osteoarthritis of the hip. The joint space
is narrowed, and there is subchondral sclerosis with scattered
oval radiolucent cysts and peripheral osteophyte lipping
(arrows).
11b. Enumerate the key distinguishing features of juvenile idiopathic arthritis
Disease Key Distinguishing Features
Juvenile A heterogenous group of disorders of unknown cause that present with arthritis before age 16 for at least 6 weeks
Idiopathic When compared to RA, JIA:
Arthritis 1. Oligoarthritis is more common
2. Systemic disease is more frequent
3. Large joints affected more than small joints
4. Rheumatoid Nodules and Rheumatoid factor are usually absent
5. Antinuclear Antibody (ANA) seropositivity is common
Risk Factors: HLA & PTPN22 variants
Caused by: TH1 & TH17, and their mediators: IL1, IL17, TNF, IFNgamma

11c. Formulate scenarios involving seronegative spondyloarthropathies and discuss with respect to etiologic
and genetic basis, clinical and radiologic features.
 A heterogenous group of disorders triggered by a TC responses against unidentified antigen, manifesting
as:
o pathological changes in the ligamentous attachments (not synovium)
o Involvement of sacroiliac joints, with or w/o other joints
o Absence of rheumatoid factor (Seronegative)
o Association w/ HLA-B27
Spondyloarthropathies Features
Ankylosing Spondylitis Destruction of articular cartilage and bony ankylosis, especially of sacroiliac and apophyseal joints. AKA
Rheumatoid spondylitis and Marie-Strümpell disease
 Pt. becomes symptomatic in 2-3rd decade of life; lower back pain, spinal immobility. Bilateral
sacroiliitis w/ morning stiffness → Fusion of vertebrae (bamboo spine)
 Aortitis w/ aortic Regurge and Uveitis
 Peripheral joint involvement (hip, knees, shoulders) in 1/3 of individuals
 90% HLA-B27 +ve
Reactive Arthritis Reiter syndrome: Triad of arthritis, nongonococcal urethritis or cervicitis, and conjunctivitis
 Cant see, cant pee, cant climb a tree
Men in their 20s o 30s in 80% of cases → HLA-B27 positive; HIV association. Prior genitourinary
infection (chlamydia), GIT (shigella, salmonella, Yersinia, campylobacter).
 Path: Urethritis or diarrhea → arthritic symptoms w/ in several weeks of inciting bout. Arthritis
episodes usually wax and wane over several weeks to 6 months
Clinical findings:
 Joint stiffness, low back pain common early symptoms.
 Ankles, knees and feet affected most often → asymmetric pattern
 Synovitis of digital tendon sheath → sausage finger or toe
 Ossification of tendoligamentous insertion sites → Calcaneal spurs and bony out growths
Enteritis Associated D/t gastrointestinal infection by Yersinia, salmonella, shigella, and campylobacter. LPS on outer cell
Arthritis membrane thought to trigger abrupt arthritis, involving the knee, ankles and sometimes the wrists,
fingers and toes.
 Last for about a year, then clears
Psoriatic Arthritis Chronic inflammatory arthropathy associated with psoriasis that affects peripheral and axial joint,
ligaments and tendons. HLA-B27 association. 3rd-5th decade of life. Sacroiliac joint involvement in 20%
of pt's, but primarily a peripheral arthritis of the hands and feet.
 DIPJ first affected w/ asymmetric distribution (pencil in the cup deformity). Contrast to RA where
PIPJ is affected first. Sausage fingers.
Remissions are more frequent, and joint destruction is less frequent.

11d. Compare and contrast gout and pseudogout with respect to etiopathogenesis and clinicopathologic
features. Metabolic Arthritis
Disease Etiopathogenesis and clinicopathogenesis
Gout Transient attacks of acute arthritis initiated by crystallization of Monosodium Urate within and around
joints.
Primary: Unknown enzyme defect and HGPRT: ↑Uric acid production normal excretion; ↑↑UA
production; Normal UA but ↓excretion
Secondary: Increased NA turnover, chronic renal disease, congenital Lesch-Nyhan syndrome, Thiazide
drug use
Recurrent acute arthritis: Commonly in 1st metatarsophalangeal joint: Podagra. Accompanied w/
Fever, pain, and neutrophilic leukocytosis. MSU phagocytosed by neutrophils in synovial fluid
Chronic Gout: Tophi produced: deposits of MSU in soft tissues around joints; Granulomatous reaction
w/ multinucleated giant cells. Tophi destroy subjacent bone → erosive arthritis
Associated Clinical conditions: Urate Nephropathy, renal stones. HTN, coronary artery disease. Lead
poisoning: interstitial nephritis (interferes w/ uric acid excretion)
Labs: Hyperuricemia, Joint aspiration is confirmatory

Pseudogout AKA: Calcium Pyrophosphate crystal deposition disease, Chondrocalcinosis

Crystals normally get deposited into the articular cartilage of the knee in a linear fashion. Crystals
phagocytosed by neutrophils show +ve birefringence
Associated w/: Diabetes, hypothyroidism, ochronosis

Goal 12
 Acute Pain management → COX inhibition by NSAIDS:
o Nonselective: Acetaminophen, aspirin, ibuprofen, ketoprofen, naproxen
o Selective: Celecoxib: ↑R for MI and other cardiovascular events
o Toxicities: GI upset, Peptic ulcers, kidney damage, diversion of AA to LT pathways (anaphylaxis to ASA)
 Disease modifying antirheumatic drugs:
o Gold Salts: Auronofin, Aurothioglucose, gold sodium thiomalate
o Glucocorticoids: Prednisone
o Other: Etanercept, hydroxychloroquine, leflunomide, methotrexate, penicillamine, sulfasalazine
 Drugs to prevent Gout attacks: Allopurinol, febuxostat, pegloticase, rasburicase, sulfinpyrazone
  Drugs to treat Gout attacks: Colchine, indomethacin, NSAID's

12a. Describe the use of disease modifying antirheumatic drugs (DMARDs) and describe their toxicity.
 Drugs capable of slowing the progression of joint erosion in RA. Have delayed onset of action, and combinations
are more effective
Drug MOA Adverse Effects
Gold Salts Unknown MOA but linked to BM suppression, nephrotic syndrome, proteinuria,
 Auronofin (PO) antimitochondrial activity and cell Flushing, hypotension, tachycardia, skin rash, stomatitis.
 Gold Sodium apoptosis, ↓lysosomal/Mx function. Hematologic, dermatologic, GI, and renal effects
Thiomalate (IV) Therapeutic affects seen 3-6 months after
 Aurothioglucose(IV) initiation
Glucocorticoids: Drug INH PLA2 → INH AA release → no Glaucoma, Lunacy, peptic Ulcers, Cushing's, Osteoporosis,
Prednisone PG, IL, TNF production. Used to induce Cataracts, Opportunistic infections, Retention of NaH20,
remission, and to provide short course Telangiectasia, Insulin resistance, Cause muscle weakness,
therapy during flareups grOwth retardation, I by GH inhibition, Delayed wound
healing, Suppress HPA Axis
Methotrexate  INH dihydrofolate reductase Bone marrow suppression, hair loss, mucositis, worsens
 INH lymphocyte proliferation→ ↓CK's, nodules. Contraindicated in pregnancy
RF Labs: CBC, liver transaminases, creatinine, Hepatitis B/C
 INH PMN leukocyte chemotaxis →
↓cytotoxins
Hydroxychloroquine Stabilized lysosomes and decrease Cinchonism: GI distress and visual dysfunction; Hemolysis in
chemotaxis G6PD deficiency
Labs: CBC, Liver transaminases, creatinine, Eye exam
Sulfasalazine ASA INH COX2, and Sulfapyridine ↓BC ASA: GI distress
function Sulfapyridine: Rash, hemolysis, SLE like syndrome
Labs: CBC, liver transaminases, creatinine
D-Penicillamine Suppress TC and ↓RF Aplastic anemia, Myasthenia gravis
Cyclophosphamide Alkylating agent used in severe cases. Byproduct Acrolein causes Hemorrhagic cystitis; Tx w/
alkylates guanine N7 of DNA and makes it Mesna
nonfunctional
Azathioprine Immunosuppressive in AI Dz → INH BM suppression
purine synthesis
Infliximab MAB → ↓TNF Infusion reactions, infections, rash
Labs: CBC, liver transaminases, creatinine
Etanercept Binds TNF receptor→ INH TNF action Hypersensitivity, infections
Labs: CBC, liver transaminases, creatinine
Leflunomide INH dihydro-orotic acid dehydrogenase→ Alopecia, rash, hepatotoxicity
↓UMP→ ↓RNA→ Pyrimidine synthesis Labs: CBC, liver transaminases, creatinine, Hepatitis B/C
INH
Anakinra IL1 receptor antagonist Injection site reaction, infection
Labs: CBC, liver transaminases, creatinine
Adalimumab (Humira) Recombinant MAB → Binds TNF Infusion reaction
Labs: CBC, liver transaminases, creatinine
Abatacept Costimulation modulator Labs: CBC, liver transaminases, creatinine
 Rituximab prefered if platelet count is belwo 50k

12b. Describe the use of biologics in the management of systemic inflammatory diseases.
 RA confirmation in patients > 18 → Methotrexate therapy for 3 months → Active disease→
o Erosive: Add TNFa INH or abatacept for 2-3 months
 If disease still active, switch to another TNFa INH or other biological agent
 o Nonerosive: Triple therapy: Add sulfasalazine or hydroxychloroquine to methotrexate, or add TNFa INH or
abatacept for 2-3 months
 If disease still active: Stop SSZ and HCQ. Add TNFa INH if Patient is receiving triple therapy. Add other
biologic agent if patient is already receiving TNFa INH
 Before Screening:
o Baseline Labs
o TB screening
o Ensure vaccinations are UTD

Condition Management
Acute Pain Glucocorticoids, NSAIDs (not if in renal failure)
Mild RA NSAIDS, Plaquenil, sulfasalazine, minocycline, methotrexate
Moderate RA Single or combo DMARD's: MTX, anti-TNF agent, Anti-IL1, Leflunomide, azathioprine, Gold, cyclosporine, Mild RA
Tx
Severe RA Combination of DMARD's, steroids, Prosorba column, cyclophosphamide

12c. Describe the pharmacologic treatment of acute and chronic gout. Compare and
contrast the mechanism of action, drug interactions, uses, and toxicity of 3 different drug groups used in gout
Acute Gout Rx MOA AE
Colchicine Binds tubulin→ ↓MT polymerization→ ↓LTB4→ INH Acute: Diarrhea and GI pain
leukocyte/granulocyte migration Long Term: Myelosuppression, peripheral
Rx w/ in 36 hours neuropathy, hematuria, alopecia
Chronic: ↑excretion MOA AE
Allopurinol Allopurinol → Alloxanthine (via XO) → INH XO (suicide Peripheral Neuropathy, stone formation,
substrate) → ↓purine metabolism → ↓ Uric acid Gout exacerbation
Febuxostat Non purine selective INH of XO. GI upset, arthralgia, Hemolytic anemia,
CI: In cancer patients, taking Allopurinol and febuxostat, ↓LFTs
lower 6MP dose or severe liver toxicity CI: Theophylline, azathioprine, 6MP (INH
6MP metabolism.
Chronic: ↓excretion MOA AE
Probenecid INH proximal tubular reabsorption of urate. ↑urate excretion → Urate crystals in kidney
CI: INH secretion of acidic drugs (Penicillin's)
Sulfinpyrazone INH proximal tubular reabsorption of urate. Activity is GFR GI distress, Rash, Nephrotic syndrome, INH
dependent: < 30ml/min platelet aggregation

Goal 13 - Metabolic Bone disorders (13,14)

Prework:
Condition Serum calcium Serum phosphate Serum alkaline phosphate
Hyperparathyroidism ↑ ↓/Normal Normal/↑
Renal Failure (↑Bun, creatine) ↓ ↑ Normal, ↑
Normal/ Osteoporosis Normal Normal Normal
Paget's Disease Normal Normal ↑↑
Vitamin D deficiency ↓ ↓ Normal/↑
Hypoparathyroidism ↓ ↑ Normal
Vitamin D intoxication ↑ Normal/ ↑ ↓
13a. Distinguish primary from secondary osteoporosis in terms of etiology.
 Osteopenia: Decreased bone mass
 Osteoporosis: Osteopenia that is severe enough to significantly ↑R of fracture

Bone Density T-Score
Healthy Bone > -1.0
Low Bone Density - Osteopenia -1.0 to -2.5
Osteoporosis -2.5 to -3.0
Severe Osteoporosis < -3.0
Osteoporosis Etiology
Primary Idiopathic, postmenopausal, senile
Secondary Endocrine: Addison disease, Diabetes type 1, Hyperparathyroidism, hyperthyroidism, hypothyroidism,
Pituitary tumors, neoplasia, carcinomatosis, multiple myeloma
GI: Hepatic insufficiency, malabsorption, malnutrition, Vitamin C and D deficiency
Drugs: Alcohol, anticoagulants, anticonvulsants, chemotherapy, corticosteroids
Miscellaneous: Anemia, homocysteine, immobilization, Osteogenesis Imperfecta, Pulmonary disease

13b. Discuss post-menopausal and senile osteoporosis in terms of etiopathogenesis, morphology, CF, Dx, Tx
 Peak bone mass observed during young adulthood
Osteoporosis Etiopathogenesis Morphology CF, Dx, & Tx
Senile  Age: Old age→ Osteoblast have ↓proliferative and Normal bone in CF: Pain, loss of height,
biosynthetic potential; ↓capacity to make bone; low decreased quantity deformities, PE, Pneumonia
turn over variant Cortex is thinned and Dx: Hard to visualize until
 ↓Activity: Normally, mechanical forces stimulate bone Haversian system is 30-40% bone is lost
remodeling (Astronauts & athletes), w/ ↑age, ↓ widened Tx: Exercise, Ca and Vit D
activity intake, bisphosphonates
 Genetic factor: single gene defects; e.g. LRP5, RANKL, (↓osteoclast activity,
RANK, OPG induce apop), Denosumab
 Ca Nutritional state: ↓CA, ↑PTH, ↓Vitamin D → (antiRANKL ab)
Senile Osteoporosis
Post-  Hormonal influence: Accelerated bone loss. ↓Estrogen Normal bone in Same as↑
menopausal → ↑Bone resorption and formation, but latter much ↓quantity
slower; high turnover variant Bones w/ ↑surface area
 ↓Estrogen→ ↑CK's (IL6,1, TNFa)→ most affected: vertebral
↑RANKL(osteoclast recruitment and ⭐️)→ ↓OPG→ bodies → eventual
↓osteoclast proliferation and ↓ osteoclast apoptosis. vertebral collapse
(Normally, estrogen induces osteoclast absorption).

 Other Treatments → Antiresorptive agents

Drug class Drug MOA Indications
Bisphosphonates Etidronate -Structurally similar to pyrophosphate → Binds Osteoporosis, hypercalcemia,
2nd gen: hydroxyapatite binding site on surface of bone tissue. tumor induced osteolysis,
Alendronate -Uptake by osteoclasts during phases of bone multiple myeloma, pagets
Tiludronate resorption → Interfere w/ osteoclast function and disease, hereditary skeletal
Pamidronate promotes osteoclast apoptosis → Reduced bone disorder
Risedronate resorption Toxicicty: Esophagitis (drink
3rd gen: -Nitrogen-containing bisphosphonates also INH activity water and stay upright for 30
Ibandronate of farnesyl pyrophosphate synthase minutes); osteonecrosis of the
Zoledronic Acid -Post translation modification (isoprenylation) of jaw, renal impairment
proteins is INH → Osteoclast apoptosis
Selective Estrogen Raloxifene -Estrogen antagonist in breast, endometrium Osteoporosis in menopausal
modulator -Partial agonist in bone women
Toxicity: ↑R for DVT, hot flashes
Calcitonin -↓ serum Ca2+, ↓Bone resorption, Osteoporosis, hypercalcemia
rhPTH Teriparatide Recombinant human parathyroid hormon → ↑bone 1st line in patients w/ ↑R for
formation (stimulates anabolic activity of osteoblast) fracture

13c. Discriminate between osteopenia and osteoporosis

 Osteopenia: Decreased bone mass
 Osteoporosis: Osteopenia that is severe enough to significantly ↑ the risk of fracture

13d. Discuss the clinic-pathologic changes of Paget Disease including the histologic phases, genetic changes,
complications and diagnostic features of this disorder.
Paget Disease Diagram
Osteitis Deformans: ↑Bone mass that is disordered and structurally unsound. Average age of onset:
~70 y.o.; Unknown etiology but strong association with SQSTM1 gene mutation. Targets the pelvis,
skull, and femur
Path: 3 Histological phases:
1. Osteolytic Stage: Early phase of osteoclast resorption → Shaggy appearing lytic lesion
2. Osteoclastic-Osteoblastic Stage: Late phase: ↑osteoblastic bone formation; markedly ↑serum
alkaline phosphatase. Production of thick, weak bone (mosaic bone)
3. Osteosclerotic stage: Burn out stage
CF: Bone pain/ deformity, pathologic fractures, ↑R
Complications: ↑R for developing osteogenic sarcomas, fibrosarcoma, ↑R for developing high-output
heart failure (d/t arteriovenous connections in vascular bone
Dx: Mosaic pattern; haphazard arrangement of cement lines (hallmark feature). Lytic and sclerotic
areas on Xray
Labs.: ↑Alk phosphatase, urinary hydroxyproline; calcium and phosphorus normal

13e. Compare and contrast osteomalacia and rickets with respect to pathogenesis and clinic pathologic features.
Disease Features
Both ↓Mineralization of newly formed bone; a problem with vitamin D metabolism
D/t: Dietary deficiency, intestinal malabsorption, lack of sunlight, renal and liver disease
Labs: ↓serum Ca and Phosphorous; ↑Alkaline phosphatase
Rickets CF: Craniotabes (frontal bossing), Rachitic rosary, pectus carinatum, lumbar lardosis, bowing of legs
Osteomalacia CF: Bone pain, fractures of hip, vertebra, wrist. Diffuse radiolucency on x-ray

13f. Formulate scenarios resulting in skeletal changes due to hyperparathyroidism with consequent skeletal morphologic
changes.
Hyperparathyroidism → Osteitis Fibrosa Cystica aka → Von Recklinghausen disease
Hyperparathyroidism d/t parathyroid adenoma or hyperplasia → Osteoclast ⭐️→ Bone
resorption
CF: Bone pain, deformity, fractures. (Resorption of radial aspect of middle phalanx of ring and
index finger)
Morph: Fibrous replacement of bone; cystic spaces in bone.
Brown tumors: Cystic enlargement of bone + Fibrosis + hemorrhage

13g. Evaluate the downstream effects of chronic renal insufficiency on the skeletal system- Renal osteodystrophy.
Renal Osteodystrophy
Collectively the skeletal changes that occur in chronic renal disease; including those associated w/ dialysis
Manifestations: Osteopenia/osteoporosis, osteomalacia, secondary hyperparathyroidism, growth retardation
3 major types:
1. High-turnover osteodystrophy: ↑bone resorption > bone formation
2. Low-turnover; aplastic disease: Dynamic bone (little osteoclastic and
osteoblastic activity), less commonly: osteomalacia
3. Mixed pattern disease: areas of high and low turnover
Path: Tubular dysfunction, generalized renal failure. ↓Production of secreted
factors: Less 1,25-OH Vitamin D3, Less BMP-7 (normally induces osteoblast
formation and proliferation) and less Klotho (membrane bound product of kidney
needed to regulate phosphate homeostasis and vitamin D production)

Goal 14 - Vasculitis (12)

Vasculitis is vessel wall inflammation presenting with constitutional signs and symptoms such as fever, myalgia,
arthralgias, and malaise. Caused by:
1. immune mediated inflammation
a. Immune complex deposition, as seen in SLE
i. Drug hypersensitivity vasculitis (e.g. penicillin)
ii. Vasculitis secondary to infections
b. Antineutrophil cytoplasmic antibodies → ANCA's
i. Anti-proteinase-3 → PR3-ANCA (previously c-ANCA). PR3 is a neutrophil azurophilic granule
constituent.
1. Polyangiitis
ii. Anti-myeloperoxidase → MPO-ANCA (previously p-ANCA). MPO is a lysosomal granule constituent
involved in oxygen free radical generation.
1. Microscopic Polyangiitis
2. Churg-Strauss syndrome
c. Antiendothelial Cell antibodies
i. Kawasaki Disease
d. Autoreactive T Cells
2. Direct invasion of vascular walls by infectious pathogens

14a. Describe the vasculitides that occur in large, medium, and small vessels.
Vessel size Vasculitides
Large Giant Cell Arteritis,
Medium Giant Cell Arteritis, Granulomatosis w/ polyangiitis, Churg-Strauss Syndrome, Polyarteritis Nodosa, Buerger Disease,
Behçet Disease, Leukocytoclastic Vasculitis (Veins)
Small Granulomatosis w/ polyangiitis, Churg-Strauss Syndrome, Polyarteritis Nodosa, Leukocytoclastic Vasculitis, Buerger
Disease, Behçet Disease

14b. Distinguish between giant cell arteritis and Takayasu arteritis

Vasculitis Distinguishing characteristics
Giant Cell Arteritis  Most common VT among older individuals. A chronic inflammatory disorder of Medium and small
arteries. Primarily affecting arteries in the head → Temporal arteries especially, and vertebral and
ophthalmic arteries (can lead to permanent blindness). F > M. HLADR4 association
 Polymyalgia Rheumatica association: Systemic flu-like symptoms, proximal muscle pain, peri-
articular pain.
 Path: TC mediated immune response against vessel wall antigens. ↑ Ck production: TNF
 Morph: Intimal thickening → ↓luminal diameter. Classic lesion: Granulomatous inflammation
centered on internal elastic lamina → elastic lamina fragmentation
 CF: ~50 years old. Fever, fatigue, weight loss, facial pain, headache (intense along superficial
temporal artery), ocular symptoms, ↑ESR. Temporal arterial biopsy (2-3cm) positive in 60% of cases
 Tx: Corticosteroids or anti-TNF therapies
 Osmosis: Grandmothers affected most in segmental fashion

Takayasu Arteritis  Granulomatous vasculitis of medium and larger arteries characterized by ocular disturbances,
weakened pulse in upper extremities (pulseless disease). Transmural fibrous thickening of the aorta
(arch and great vessels) → Severe luminal narrowing
 Path: Rapid progression w/ quiescent stage of 1-2 years. Sequele: collagenous fibrosis involving all
layers especially intima. Aortic valve insufficeincy d/t involvement of aortic root → dilation.
 Morph: Narrowing of orifices w/ irregular fibrous thickening of wall. Massive intimal fibrosis
 CF: 15-45 years old. Fever, arthritis, night sweats, myalgia, skin nodules, ocular disturbances (visual
defects, retinal hemorrhages, total blindness). MI d/t narrowing of the coronary ostia
 Osmosis: Asian woman under 40 years old, similar histological presentation as Giant cell, ↑ESR
 Tx: Corticosteroids

14c. Discuss Polyarteritis nodosa with reference to morphology, clinical features and treatment
Disease Morphology
Polyarteritis Nodosa (PAN) Systemic necrotizing vasculitis of any organ, except lung. Small/medium sized muscular arteries.
- Type III HS → Immune complex deposition
- Associated conditions: hepatitis B virus antigenemia, HS to drugs (amphetamines)
- Lesions in different stages (acute/healing). Nodosa formation (focal aneurysm).
- Stage 1: Acute lesion w/ fibrinoid necrosis and neutrophils. Stage 2: Healing lesion w/ fibroblast
proliferation. Stage 3: Healed Lesion w/ nodular fibrosis and loss of internal elastic lamina.
- Sequele: Thrombosis and infarction w/ multiple aneurysms (kidneys, heart, GIT).
CF: Young adults, M>F. Fever, weight loss, malaise, hematuria, renal failure HTN, abdominal pain,
diarrhea, GI bleeding, myalgia, arthralgia, microaneurysms, pericarditis, myocarditis, palpable
purpura
Dx: Arteriography, arterial biopsy, biopsy of palpable nodules in skin or organ.
Prognosis: fatal if untreated, if treated: 90% long term remission
Tx: cyclophosphamide
Osmosis: Medium sized vessel, Transmural involvement, String of beads presentation on
angiogram. HTN if renal arteries involved, neur
14d. Mucocutaneous lymph node syndrome(aka Kawasaki Disease): morphology, clinical features and Tx
Disease Morphology
Kawasaki An acute febrile, self limited illness; associated
Disease w/ arteritis of large/medium arteries, coronary
artery commonly affected. If vascular wall is
weakened → aneurysm
Complications: (Coronary) thrombosis,
(coronary) aneurysm , MI, death (1-2%)
Osmosis: Medium artery, ↑clot formation →
Ischemia, Weak artery wall → aneurysms b/c
fibrin makes it less elastic, area bulges out.
↓diameter → ischemia
Clinical Features
Common in children < 4 y.o. boys, in japan, Hi, and US. Crash &
burn (Fever):
Conjunctivitis (limbus sparing)
Rash on all body w/ desquamation
Adenopathy
Strawberry tongue, red mouth
Hands and feet swollen
Test: Anemia, ↑WBC, ↑CRP, ↑ESR, ↑Liver enzymes, wbc in
urine, ↑Pt count
TX: Aspirin (only time use is appropriate), Immunoglobulins

14e. Allergic granulomatosis/angiitis (Churg-Strauss) & granulomatosis/polyangiitis (Wegner’s granulomatosis)

Disease Characteristics
Churg-Strauss Allergic Granulomatosis and angiitis: small vessel necrotizing vasculitis, associated with asthma , allergic
rhinitis, lung infiltrates, peripheral eosinophilia, and extravascular necrotizing granulomas; PAN variant
Path: systemic vasculitis of upper and lower respiratory tract. Granulomas present. MPO-ANCA +ve (pANCA)
Sites: Lung, spleen, kidney sclerosis

Wegner's Granulomatosis w/ polyangiitis: Necrotizing Vasculitis of small arteries and veins, presenting with:
Granulomatosis Classic Triad: Acute necrotizing granulomatous inflammation, focal necrotizing vasculitis (with granulomas),
necrotizing glomerulonephritis. Classically involves nose, sinuses, lungs, and kidneys rapidly progressive
renal failure
Epi: Rare, M>F, 4th-6th decade
CF: Cough, dyspnea, hemoptysis, chronic sinusitis, perforation of nasal septum, otitis media, mastoiditis,
Hematuria
Micro: Fibrinoid necrosis, neutrophils, granulomas
Labs: PR3-ANCA, indicative of disease activity. Urine examination
O: cANCA, Nasopharynx affected: chronic pain, bloody mucus, deformity of nose→ Saddle Nose
deformity. Relapse common
Tx: Corticosteroids and cyclophosphamide

14f. Discuss Behçet disease

Disease Morphology
Behçet disease A Small/Medium vessel neutrophilic vasculitis presenting w/
Triad: Recurrent oral aphthous ulcers, genital ulcers, and uveitis.
- GI and pulmonary manifestations possible.
- Disease mortality related to neuro involvement and aneurysms.
- HLA-B51 Association, predisposed to disease
O: affects all vessel sizes. Blood clots and aneurysms, Joint stiffens, folliculits, meningitis, kidney test.
Pathergy Test (skin lesion at site of prick that doesn’t heal normally)
Tx: Steroids (immunosuppression), TNF antagonist

14g. Describe the cardinal features of microscopic polyangiitis

Disease Features
Microscopic Polyangiitis A necrotizing vasculitis that generally affects capillaries as well as small arterioles, and venules. AKA
Leukocytoclastic vasculitis and hypersensitivity vasculitis
Organs affected: post-capillary venules, skin → palpable purpura
Path: TIIIHS, Immune complex deposition. MPO-ANCA Positive. Can resolve, recur or remain chronic
Cause: Penicillin, sulfonamides, beta hemolytic streptococcal Ag, Hepatitis B ag
Micro: Fibrinoid necrosis of vascular wall (lumen is top arrow), extravasation of RBC's, Nuclear dust
from PMB breakdown (Bottom arrow), Inflammation and destruction is the same in all vessels, As
opposed to PAN
Seen in Henoch-Scholein Purpura
Osmosis: Only kidney and lungs. pANCA
Tx: Corticosteroids and cyclophosphamide
Henoch-Schönlein A systemic immune disorder of unknown cause that is characterized by a purpuric rash, colicky
Purpura abdominal pain, polyarthralgia(Migratory), and acute glomerulonephritis. D/t the deposition of
circulating IgA-C3 immune complex.
- Most common vasculitis in children, seen normally after URTI
- IgA nephropathy (Berger's Disease) may be part of the system complex
CF: Palpable purpura (lower extremeties, buttocks), polyarthritis, abdominal pain (melena), Renal
disease (hematuria)
O: ↑IgA targeting eCell. SS: Purpura that is palpable (around buttocks and legs), IgA nephropathy
Tx: Steroids, NSAIDS (naproxen)

14h. Discriminate between Thromboangitis obliterans and primary Raynaud phenomenon

Disease Characteristics
Thromboangitis Obliterans Segmental , thrombosing, acute and chronic inflammation of medium/small arteries; principally the
(Buerger's) tibial and radial arteries w/ occasional secondary extension into veins and nerves of extremities
Etiology: Strong association w/ cigarette smoking in 25-50 yo's
Path: Thrombosis, organization, recanalization. Microabscess, granulomas, fibrosis of vascular
bundle
CF: Intermittent claudication, superficial nodular phlebitis, Raynaud's phenomenon, distal gangrene
Osmosis: Clots in fingers and toes → autoamputation
Raynaud Phenomenon Arterial insufficiency of digital vessels in response to cold or increased emotion
Seen in: TAO, Takayasu arteritis, cryoglobulinemia, ergot poisoning, thoracic outlet syndrome, cold
agglutinin disease, CREST syndrome

14i. Distinguish between primary and secondary Raynaud phenomenon

Primary Raynaud Phenomenon Secondary Raynaud phenomenon
Exaggerated central and local vasomotor responses to cold or emotion; it affects Vascular insufficiency due to arterial disease
3% to 5% of pop.; young women. It tends to symmetrically affect the extremities, caused by other entities including SLE,
and the severity and extent of involvement typically remains static over time. scleroderma, Buerger disease, or even
Structural changes in the arterial walls are absent except in long-standing disease, atherosclerosis. Clinically, asymmetric
when intimal thickening can develop. The course is usually benign, but chronicity involvement of the extremities and
can lead to atrophy of the skin, subcutaneous tissues, and muscles. Ulceration and progressively worsens in extent and severity
ischemic gangrene are rare. over time.

Goal 15 Neoplastic Disorders

15a. Describe examples of bone forming, cartilage forming, and other common bone tumors including the
clinicopathologic features, radiological features, treatment, and prognosis of each.
15b. Describe the most common benign and malignant bone and bone forming tumors in terms of etiology, genetic
basis, clinical presentation (age, location), radiologic findings, morphology, treatment, and prognosis – Osteoblastoma,
Osteoid osteoma, Osteosarcoma
15c. Describe the most common benign and malignant cartilage forming tumors in terms of etiology, genetic basis,
clinical presentation (age, location), radiologic findings, morphology, treatment, and prognosis – Osteoblastoma,
Osteoid osteoma, Osteosarcoma
15d. Describe the most common bone tumors of unknown origin in terms of etiology, genetic basis, clinical presentation
(age, location), radiologic findings, morphology, treatment, and prognosis – Ewing’s Sarcoma, Giant Cell Tumor,
Aneurysmal bone Cyst
15e. Outline key features of fibrous dysplasia with reference to genetic basis, morphology and associated syndromes.
15f. Describe the tumors that commonly metastasize to bone, the radiologic manifestations of metastatic lesion
involving bone, and the difference
between osteoblastic and osteolytic metastases.
15g. Discuss the location, pathogenesis and clinical features of ganglion cyst.
15h. Compare and contrast key benign and malignant soft tissue tumors including location, age, clinical, morphologic
and radiologic features- lipoma, liposarcoma, nodular fasciitis, superficial and deep fibromatosis.

Goal 17 (8)
 Choline accumulates in nerve ends because of active transport.
 Ach synthesis: Choline + Acetyl-CoA → Acetylcholine via Choline acetyl transferase
 Calcium influx at nerve endings → Ach release → binds Ach receptors (Nicotinic and Muscarinic) at muscle end
plate membrane → Membrane depolarization → Muscle contraction
o Ach release inhibition: Botulism (food poisoning) → muscle weakness and paralysis.
 Botox injection INH ach release → no wrinkles d/t muscle paralysis
o Ach metabolized by acetylcholine esterase
 Reversible Acetylcholine esterase inhibitor: Edrophonium, physostigmine (can cross BBB),
Neostigmine (can not cross BBB)
 Irreversible Ach esterase inhibitors: Ecothiopate, malathion and parathion
o Cholinometric drugs: (direct acting)
 Nicotinic: Nicotine; Muscarinic: bethanechol, methacholine, pilocarpine
o Cholinoreceptor blockers
 Nn (stimulation of autonomic ganglia E and NE): Hexamethonium, mecamylamine
 Nm (stimulation of skeletal muscle): Tubocurarine , atracurium, succylcholine
 Muscarinic: atropine, benzatropine, glycopyrrolate, scopolamine

17a. Compare and contrast the depolarizing and the non-depolarizing competitive neuromuscular junction blocking
drugs.
 Neuromuscular blockers - Skeletal muscle relaxants: Block ach at nicotinic receptor of SM. Muscle relaxation in
anesthesia/ endotracheal intubation
o Non depolarizing → Competitive. Nicotinic receptor antagonist. Block ach → progressive paralysis of SM and
respiratory muscle. No effect on cardiac or smooth muscle, or consciousness
 D-tubocurarine, pancuronium, atracurium, Mivacurium: very short duration of action b/c of plasma
pseudocholine esterase metabolizes it. Reversible by giving more Ach → antidote
 Antidote: neostigmine → ach esterase inhibitor
o Depolarizing → Noncompetitive. Nicotinic receptor agonist. Succinylcholine
 Phase 1: Fasciculation that worsens w/ neostigmine.
 Phase 2: desensitization when adding succinylcholine → becomes unresponsive to Ach.
 Succinylcholine metabolized by plasma pseudocholine esterase → short duration of action

17b. Recognize the cause and management of malignant hyperthermia

 NM blockers cause malignant hyperthermia
o Rare but life threatening. ↑1.8F every 5 minutes
o Muscle rigidity, hyperthermia, HTN, Acidosis, hyperkalemia
o Genetic component + Succinylcholine or d-tubocurarine or inhalational anesthetics
o Rx: Dantrolene
 Spasmolytics: SM relaxant that act on CNS, Spinal cord or muscle itself
o Benzodiazepines: potentiates GABA actions at GABAa receptors to induce tone of spinal motor neurons
o Baclofen: Direct agonist at GABAb Receptor in spinal cord, as good as diazepam w/ less sedation
o Dantrolene: acts directly on SM to decrease contractility by blocking Ca release from Sarcoplasmic
reticulum. Rx for malignant hyperthermia