Smbj

Front 1

Actinic Keratoses

Back 1

= multiple scattered, thick, scaly erythematous patches and crusts (red to brown in color)
- 3 variants: hypertrophic AK, pigmented AK, actinic chelitis
- Prevalence/incidence varies with: skin type (high in type 1), sun exposed skin, cumulative sun exposure (age)
- Predisposes squamous (may directly progress to this) and basal cell carcinoma
- Treatment: cyrosurgery, topical medications (5-FU), imiquimod, photodynamic therapy, chemical peel, laser surgery. (If progressed to invasive carcinoma, surgery required)

Front 2

Basal Cell Carcinoma

Back 2

- most common non-melanoma skin cancer (except in transplant patients)
- arises from epidermis or follicular epithelium
- occur on sun-exposed skin (most common on face and nose)
- very low metastatic potential (0.1%)
- 3 subtypes: nodular (raised, often pigmented, can be ulcerated), superficial (flat, scaly lesion), morpheaform (sclerosing/scaring, fibrosing --more aggressive)

Front 3

Risk factors for basal cell carcinoma

Back 3

- chronic UVB exposure
- previous ionizing radiation (acne treatment)
- immunosuppression
- inherited syndromes: basal cell nevus syndrome (Gorlin-Goltz), Xeroderma pigmentosum
- chronic arsenism
- mutations in tumor suppressor patch gene
- previous BCC (40% recur in 5 years)

Front 4

Risk factors for non-melanoma skin cancer

Back 4

- male sex
- older age
- fair complexion
- tendency to sunburn easily
- outdoor occupation

Front 5

Squamous cell carcinoma

Back 5

- second most common skin cancer, has definite metastatic potential
- onset generally 55-70, but increasingly in younger individuals, rare before 30
- occurs most on sun-exposed skin
- clinical features: primary tumors may be an enlarging nodule (ultimately ulcerates) or verrucous plaque. May enlarge rapidly, be asymptomatic, recur as nodule or lymphadenopathy

Front 6

Risk factors for squamous cell carcinoma

Back 6

- chronic UVB radiation
- ionizing radiation
- chemical carcinogens: tars, etc
- genetic disorders: basal cell nevus syndrome, xeroderma pigmentosum, others
- immunosuppression: onset at 3-5yrs post transplant (more common than BCC in transplant patients)
- oncogenic HPV
- chronic inflammatory processes: leg ulcers, osteomyelitis, discoid lupus erythematosis

Front 7

Risk factors for skin cancer in transplant patients

Back 7

- Age
- UV exposure
- Type 1-3 skin
- duration of immunosuppression
- intensity of immunosuppression
- HPV infection
- History of skin cancer prior to transplant
- CD4 lymphoma
- may be transplant dependent (higher in cardiac and lung patients, lower in renal, liver patients)

Front 8

Characterisitics of high risk squamous cell carcinoma

Back 8

- recurrent tumors: multiple, rapid
- locations: forehead/temple/ear/lip
- large size: >2cm
- poorly differentiated
- invasion (>4-6mm)
- perineural invasion (wrapped around a nerve)
- in transit cutaneous metastasize along lymph drainage

Front 9

Treatment for BCC and SCC

Back 9

- standard surgical excision
- Mohs micrographic surgery
- Photodynamic therapy
- radiation therapy
- topical therapy for superficial lesions and for field disease: 5-fluorouracil, Imiquimod
- screening and education (aggressive sun protection), vitamin D supplementation

Front 10

5-fluorouracil treatment

Back 10

- applied topically or as a wrap
- used to decrease the the size of pre/cancerous lesions and field disease on hands and forearms especially
- may need to use continuously
- causes reddening and irritation of the skin and actinic keratoses to the point that the peel off. Usually see little or no erythema
- may be useful to combine with alpha/beta hydroxy acids, topical tretinoin

Front 11

Imiquimod

Back 11

- topically applied, non-specific immune modulator (boosts local immune response) for treating precancerous and superficial cancerous lesions and warts of the skin
- safe in transplant recipients
- requires daily application for 6-12 weeks

Front 12

Photodynamic therapy (PDT)

Back 12

- for treatment of field skin disease (actinic keratoses, superficial SCC/BCC)
- topical 20% aminio-levulinic acid (ALA) is applied followed by exposure to blue light with activates it
- exposure to light leads to sunburn effect and peeling of the skin

Front 13

Standard Surgical excision of skin cancers

Back 13

- mainstay of treatment
- take a margin of healthy tissue around the lesion (size of margin determined by size of lesion). Send to path to make sure margins are clean
- Advantages: histologic control, good cure rates
- Disadvatanges: may be more time consuming (may require repeat procedures if margin is involved); patients may perceive larger scars (only guess on margin)

Front 14

Mohs Micrographic surgery

Back 14

- for excision of non-melanoma skin cancers: recurrent lesions, high risk SCC, larger tumors
- requires dermatologic surgeon to also act as a pathologist: analyze frozen sections of tissue during the procedure. Use tissue map to remove additional tissue until all is clear
- Advantages: provides significant tissue conservation, highest cure rates

Front 15

Characteristics of benign nevi

Back 15

= mole
- cells are derived from the same precursor cells as melanocytes (possibly fully differentiated but not migrated).
- generally don't progress to melanoma, but can (if dysplastsic)
Features: generally uniformly pigmented and shaped with symmetrical, defined borders

Front 16

Dysplastic nevi

Back 16

Features: irregular growth patterns, non-uniform pigmentation
- can be sporadic (5-10% of population) or familial
- on their own are benign (though histopatholigically different from classic benign nevi) but can develop into melanoma (20% of sporadic MM--most important precursor)
- 40% of patients with sporadic MM have clinical DN
- DN syndrome: clinically atypical nevi with 2 or more family members with MM--> >50% risk of developing MM

Front 17

Congenital nevi

Back 17

- nevi appear at birth or within the first year of life.
- may be small or large (more concerning)
- risk of MM in a small congenital nevi is unknown
- prophylatic removal during teen years is probably reasonable.
Sub-type: Giant Melanocytic Nevus
- >20cm in diameter, much higher risk of MM (6-10%) especially early in life (<5yrs, the 5-10yrs)
- removal is recommended where possible but often difficult

Front 18

Malignant melanoma

Back 18

- among the most common in young adults; most are invasive and up to 20% develop metastatic disease, curable if caught early but cause >75% of SC deaths

Front 19

Risk factors for malignant melanoma

Back 19

- genetic mutations, ex: CDKN2A (also increases risk for pancreatic cancer, but not common)
- family history of MM or dysplastic nevi
- UVR exposure
- repeated childhood sunburns
- number (>50) and size (>5mm) of melanocytic nevi
- congenital nevi
- multiple (<5-10) dysplatic nevi or dysplastic nevus syndrome
- personal history of MM
- higher socioeconomic status (vacationing?)
- skin types I and II
- equatorial latitudes
- DNA repair defects
- immunosuppression

Front 20

Risk factors for malignant melanoma (grouped by severity)

Back 20

High Risk (>50 fold increase)
- Persistently changing mole
- Multiple dysplastic nevi in patient w/2 family members w/ MM
- Adulthood (vs childhood)
- >50 nevi >2mm in diameter
Intermediate Risk(—1O fold increase)
- F/Hx of MM
- Sporadic dysplastic nevi
- Congenital nevi
- Caucasian (vs. Asian or black)
- Personal Hx of MM
Low Risk (2-4 fold increase)
- Immunosuppression
- Sun sensitivity or excess exposure to sun

Front 21

Clinical subtypes of melanoma

Back 21

- superficial spreading melanoma (SSMM)
- Nodular melanoma (NM)
- Lentigo Maligna Melanoma (LMM)
- Acral Lentiginous Melanoma

Front 22

Superficial spreading malignant melanoma (SSMM)

Back 22

- Most common MM (60-70%)
- Diagnosed most frequently between the ages of 30-50 years
- Most common on trunk in men and legs in women, but can appear anywhere
- Notable radial growth phase (months-years)
- dark brown-black macule w/ irregular borders → patch → nodule (able to invade dermis)
- 1/3rd arise from pre-existing nevus
- Regression within the lesion is common

Front 23

Nodular malignant melanoma

Back 23

- No appreciable horizontal (radial) growth phase (so most aggressive)
- Diagnosed most frequently in the 6th decade, second most common MM (15-30%)
- Trunk » head and neck » other
- twice as common in men as in women
- Presents as blue, black, red nodule most often, usually with rapid growth. Frequently is ulcerated, occasionally amelanotic (nonpigmented). Usually lacks pigment spread

Front 24

Lentigo Maligna MM

Back 24

- In-situ form = lentigo maligna
- 3rd most common MM (5-15%). Most frequent in the 7th decade
- Mostly on sun-exposed areas, esp. face (incidence correlates best with solar elastosis--skin damage from sun)
- Longest radial growth phase (years)
- Brown, black irregular macule → nodule development

Front 25

Acral lentiginous melanoma (ALM)

Back 25

- Most frequently diagnosed in 6→7th decades
- Feet and toes > hands > mucous membranes (nails are often abnormal: absent or growing abnormally in conjunction with pigment; may occur in conjunction with vitiligo)
- 5-10% of all MM, but >70% of MM in blacks, and ~45% in Asians (more common in dark skinned people)
- Irregular macule (may be chronic non-healing) → patch → nodule (after months-years)
- Subungual melanomas (1-3% of MM) are usually
ALM - look for Hutchinson’s sign (pigment on the proximal nail fold, usually with atrophic or poorly growing nail)
- Melanonychia striata (band on pigment in the nail indicating subungual MM) may be early sign
- Diagnosis often missed early on (so end up being more severe cases)

Front 26

ABCDE's of MM diagnosis

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A: asymmetry
B: border irregularity
C: color variability
D: diameter
E: evolution

Front 27

Treatment for MM

Back 27

- perform biopsy: excisional preferred over shave to get full depth (perfom incisional if large lesion)
- Classify with Breslow depth (in mm). If greater that 1mm, it is potentially metastatic (Clark level 2-5), perform sentinel lymphnode biopsy (if positive remove surrounding nodes)
- With path result excise remaining lesion with margin (determined by size of lesion)

Front 28

Clinical stage of MM

Back 28

0: in-situ disease
I and II: disease limited to the skin
III: lymph node disease
IV: metastatic (widespread) disease (prognosis is >12mo depending on location of metastasizes)

Front 29

Sentinel lymph node biopsy

Back 29

- dye injected into tumor, followed to first lymph node which is excised. If positive, surrounding nodes also removed.
- Identifies patients with microscopic metastasizes
- spares 80% of patients from complete lymph node denudation because on 20% are positive.
- important staging tool for disease
- identifies patients for adjuvant therapy and trials

Front 30

Biological effect mechanism of UVR

Back 30

- to have effect UVR must be absorbed by a chromophore (light absorbing molecule; endogenous (DNA)/exogenous (medications))
- Introduction of photon induces electron to jump from unexcited to excited state inducing self-reactivity (vitamin D) or with nearby molecules to form a stable photoproduct which then may initiate signal cascade
- UVR reactivity can result in protein cross-linking (pyrimidine dimers, protein-DNA cross-linking, production of ROS, etc
- The ability of radiation to penetrate is directly proportional to wavelength (lower, less penetration, higher energy). Light may be reflected or scatter or absorbed by layers of skin

Front 31

UVR damage

Back 31

- UVB causes more damage than UVA but both are hazardous
- UVB causes direct DNA damage (causing acute erythema and inflammation: sunburn, determined be total energy exposed to) because DNA absorbs most at that wavelength
- UVA is lower energy but can also cause DNA damage, photoaging, ROS production and immunomodulation
- UVR damage can lead to skin thickening, "photoaging," membrane damage (from ROS), protein damage, cell receptor activation and clustering, increased signal transduction (inactivation of phosphatases), immunosuppression
- DNA damage (cyclobutane pyrimidine dimers, protein-DNA cross-links, oxidative base changes, single strand breaks, deletions, chromosomal aberrations) may lead to cell cycle arrest, DNA repair, or apoptosis. If these mechanisms are compromised then cancer may result

Front 32

UVR impacts on the immune system

Back 32

- immunosuppression occurs at UVR exposed below that required for erythema, reducing surveillance for tumor cells.
- After UVR exposure: Langerhan cells (primary skin APCs) are damaged in ability to present antigen and retreat to the lymph node where they preferentially activate Th2 cells and induce clonal anergy in Th1 cells. Immunomodulatory cytokines are also released after DNA damage and regulatory T cells are generated that inhibit specific cell mediated immunity to an antigen. May also inhibit delayed type hypersensitivity, contact hypersensitivity and tumor rejection
UVR damage also results in the recruitment of neutrophils and mononuclear cells to the site, and increased expression of proteins that promote their recruitment

Front 33

DNA repair of UVR damage

Back 33

Nucleotide excision repair: removes damaged bases (corrects cyclobutane pyrimidine dimers and 46-pyrimidone photoproducts)
- transcription coupled repair: fast, repairs at stalled transcription fork. Only corrects template strand. More important for cell survival
- global genomic repair: results in base excision at any point in the genome at any time; repairs both strands, more relevant for genome integrity
Base excision repair: replaces modified bases
- cell cycle must be arrested which repair occurs (need p53) or apoptosed if repair is not possible (again p53)

Front 34

UVR signature mutations

Back 34

Cyclobutane pyrimidine dimers:
- UVR causes dimerization of adjacent CC residues. When replicated they can not be read, resulting in default AA incorporation, and corresponding TT incorporation.
-signature mutations: C-->T or CC-->TT
- normally repaired by nucleotide excision repair, which is defective in xeroderma pigmentosum
- humans do not have photolyases that repair them in other organisms

Front 35

Acute responses to UVR damage

Back 35

- Sunburn: inflammation/erythema (due to the release of histimine, serotonin, chemokines, PGs, etc), determined by total dose
irrespective of time
- Immune changes: Langerhans migrate to lymph, neutrophils and MNCs recruited, inflammatory chemokines released
- skin hyperplasia: thickening of all the layers, not really photoprotective
- Tanning: pigment darkening and increased distribution of existing melanin (not photoprotective), production of new melanin (delayed tanning. ~72 hrs) in response to MSH (from keratinocytes)
- Vitamin D production: only 10-20% of epidermal provitamin D can be converted in a single exposure

Front 36

Absorption vs Action spectrum

Back 36

Absorption spectrum: the wavelengths that are absorbed by a given molecule or chromophore. (DNA 260-280--UVB range, melanin absorbs well across the spectrum--protective)
- Action spectrum: the wavelengths that cause biological response for a given process (ex: erythema, improvement in psoriasis, DNA damage). It is plotted as wavelength v. the reciprocal of the minimal dose to get an effect. Use the action spectrum to maximize treatment benefits while minimizing UVR damage (psoriasis therapeutic range is different than DNA damage range)

Front 37

5 main functions of the skin

Back 37

- barrier protection: against trauma, chemicals, pathogens, UV light, fluid loss
- thermal regulation: body temperature regulated by heat loss
- immune: physical/chemical barrier to pathogens, coated in protective enzymes
- sensory
- metabolic: vitamin D synthesis

Front 38

Anatomic variation in skin

Back 38

- Thinnest: eyelids (<1mm), thickest: back (>4mm)
- all skin has hair except palms, soles of the feet, glans of the penis, labia minora, dorsal fingers and toes

Front 39

Layers of epidermis

Back 39

- basal layer (stratum basale): rests on the dermis contains stem cells which renew the dermis (skin renewed totally every 28 days)
- spinous layer (stratum spinosum): thickest layer, squamous keratinocytes
- granular layer contains keratohyalin granules
- cornified layer (stratum corneum): outermost layer exposed to the environment, composed of de-nucleated, keratinized cells

Front 40

Abnormal epidermis

Back 40

Scaling diseases:
- ichthyosis: stratum corneum is retained instead of being exfoliated leading to scaly patches over the skin (fish scales)
- psoriasis: improper dermal maturation leads to hypertrophy (plaque) and scaling lesions
Blistering disease:
- epidermolysis bullosa (EB): due to genetic defects in cell attachments causing them to lyse/fall apart and blister mostly on hands and feet (trauma prone areas)
- bullous pemphigoid: auto-antibodies attack the basement membrane separating it (sub-epidermal blisters)
- pemphigus vulgaris: autoantibodies target desmosome components leading to intra-epidermal blisters

Front 41

Cell types present in epidermis

Back 41

- keratinocytes: main component of epidermis
- melanocytes: produce melanin
- langerhan cells: antigen presenting immune cells
- Merkel cells: involved in tactile sense (Merkel cell carcinoma is the most aggressive skin cancer)

Front 42

Melanin synthesis

Back 42

Melanocytes near the basement membrane produce melanin (protective against UVR) from tyrosine/Dopa/dopaquinone (via tyrosinase). Dendritic processes extend to distribute pigment to keratinocytes (everyone has the same number of melanocytes, just activity levels)
Diseases:
- albinism: mutated tyrosinase, normal amount of melanocytes just non-functional
- vitiligo: absence of melanocytes in patches of skin

Front 43

Dermis

Back 43

the dermis functions mainly to support the epidermis. It is predominantly collagen (type I 80% III 10%) also has elastic tissue, hair follicles, sweat glands, blood vessels, nerves (Pacinian and Meissner's corpuscles)
- papillary dermis: just below the epidermis, very thin, composed of organized collagen fibers
- reticular dermis: majority of the dermis, composed of thicker, less regular collagen fibers
Abnormal: solar elastosis (accumulation of abnormal elastin in the dermis from UVR), keloid (overgrowth of collagen in dermis, often as result of trauma)

Front 44

Sweat gland types

Back 44

Eccrine sweat glands: found in all skin, with maximum concentration in the palms, soles, acillae and forehead. The produce watery sweat and function in thermal regulation
Apocrine sweat glands: found only in the axillae, genitals, areolae, external acoustic meatus, and eyelids (glands of moll). In lower mammals the function in scent production (uncertain function in humans)

Front 45

3 phases of hair growth

Back 45

1. anagen phase (85% of the time): active growth, which can last 2-7 years
2: catagen phase (1%): "involuting" phase, in which active growth stops and hair is somewhat reabsorbed. 2-3 weeks
3. telogen phase (15%): resting or shedding phase, ~100 days

Front 46

Function of nails

Back 46

- function to protect distal digits, help grasp thing
- grow ~0.1mm/day
- fingernails grow faster than toenails and growth is faster in the summer than winter

Front 47

Atopic dermatitis

Back 47

- common, chronic, pruritic eczema that waxes and wanes. Typically presents as a red, inflammed, itchy rash, then may progress to raised painful bumps. Frequently effects the extensor surfaces and face in infants, in older patients may present with lichenification from scratching on flexor surfaces
- complications include: skin infections (broken skin)-- infection with staph can lead to staph impetiginization, infection with HSV can lead to eczema herpticum

Front 48

Atopic dermatitis epidemiology/pathogenesis

Back 48

- most common in developed countries: 10-20% of children, ~1% of adults (tripled in the last several decades)
- onset is usually in the first years of life
- etiology is unclear but likely genetic + environmental components
- pathogenesis is theoretical: patients have hypersensitive skin, lungs and nasal membranes (correlation with allergies , asthma). Possibly: cytoskeleton mutations (filaggrin: aggregates keratin matrix) may cause water loss--> skin dryness; aberrant inflammatory response (lots of Th2 cells); "hygiene hypothesis" or antibiotic use

Front 49

Irritant vs contact dermatitis

Back 49

Irritant: skin comes into contact with a substance that would inflame all skin types if there were sufficient exposure (ex: lye, fecal enzymes)
Allergic: the person has a type IV hypersensitivity response to the substance which does not cause irritation in other people regardless of the exposure level

Front 50

Dermatitis

Back 50

= inflammation of the skin
- histologically epidermis appears edematous (spongiotic). Earliest visible manifestation is widening of the intercellular spaces and accentuation of intercellular bridges
- edema fluid in the epidermis makes the skin swollen or raised and because it is also inflammed, the involved skin is red and itchy

Front 51

Stages of dermatitis/eczema

Back 51

- acute: severe inflammation and edema such that fluid goes to the surface and causes oozing and crusting (prominent vesicles or edematous papules; wet rash
ex: poison ivy). Histologically will have fluid filled vessicles
-subacute: Redness, scaling, fissuring, parched or scalded appearance. Hist: parakeratosis (retain nucleus in strat. corn), hyperplasia of strat spin., elongation/fusion of epidermal ridges, focal vesiculation, intense lymphoctic infiltrate
- chronic: thickened, lichenified skin with excoriations and fissuring. Hist: hyperkeratosis, hypergranulosis, psoriasiform hyperplasia, dermal scaring

Front 52

Lichen Simplex Chronicus (LSC)

Back 52

- patient scratches skin (due to dermatitis or any other chronic itch; ex: dry skin) causing lichenification and further itching (scratch cycle)
- epidermis becomes thickened (acanthotic)
- can complicate any other type of dermatitis

Front 53

Statis dermatitis

Back 53

- occurs in patients with chronic swelling of the lower extremities due to venous insufficiency
- circulation to the skin is compromised causing it to become dry and inflamed, Patient then itches (LSC) aggravating problem
- acute: medial ankle most frequently and severely involved (relatively poor blood flow normally)
- chronic: erythema, redness, red/brown discoloration from deep dermal deposits of extravasated RBCs, dilated superficial veins; lipodermatosclerosis (fat necrosis)
Pathophys: ↑ venous pressure → ↑permeability of dermal capillaries → leakage of fibrinogen and other molecules → fibrin cuffs around dermal capillaries (hallmark of advanced disease) → trapped WBC release inflammatory mediators, growth factors, chemoattractants → leukocytes stay perivascular

Front 54

4 Common causes of allergic contact dermatitis

Back 54

1. Poison ivy (Rhus): from oleoresin in sap of: poison ivy, poison oak, poison sumac, mango rind, lacquer tree, cashew nut, indian marking nut, ginkgo tree fruit pulp
2. Nickel: in jewelry, belt buckles, jean snaps
3. neomycin: most widely used topical antiobiotic (ear/eye drops)
4. formaldehyde: in cosmetics, clothes dyes

Front 55

Define blister

Back 55

- fluid filled separation of the layers of the epidermis or dermis
- normally prevented by intracellular and extracellular cell adhesion
- May be caused by genetic (congenital defects in structural components) or acquired (autoantibodies to structural components) processes

Front 56

Epidermolysis Bullosa

Back 56

= inherited disorder characterized by formation of blisters following friction or trauma
3 types: simplex (less severe, more superficial), junctional (very fatal, can be lethal in early childhood), dystrophic (deeper in skin, causes scaring)

Front 57

Dystrophic epidermolysis bullosa

Back 57

Clinical features:
- upon blister healing milia (keratin filled cyst) and scars (leading to mitten deformities)
- absent or dystrophic nails
- effects mucosal surfaces
- may cause malnutrition, growth retardation, anemia
- may be dominant (more serious) or recessive
- caused be defects in the subepidermal area (collagen VII)

Front 58

Junctional epidermolysis bullosa

Back 58

Clinical features:
- generalized blisters at birth
- periorificial granulation tissue (many occlude the airway in young children -- fatal)
- nail shedding and dystrophy
- enamel defects
- epithelial blistering in respiratory, GI, and GU tracts, mucous membranes
- growth retardation, anemia
- caused by defects in the lamina lucida (laminins, collagen XVII, integrins)

Front 59

Epidermolysis bullosa simplex

Back 59

Clinical features:
- non-scarring
- can be localized to the hands, feet, extremities (on subtype)
- no mucous membrane involvement
Pathophys
- caused by defects in keratin (have disorganized filaments that break easily), superficial epidermis
- leads to cytolysis (usualy below the nucleus of the basal cells
- aggregates of keratin filaments form after rupture
- Dominant: mutation causes a disruption of the polymer structure even if 1 normal allele present (more severe)
- recessive: missing the obligate keratin needed to form the heterodimer, does not form keratin aggregates

Front 60

Pemphigus

Back 60

- IgG autoantibodies target desmogleins (extracellular connection between desmosomes) causing cells to fall apart and intra-epidermal blistering (inflammatory cell invasion, especially eosinophils)
- 2 types: pemphigus vulgaris (desmoglein 3 +/- 1), pemphigus foliaceus (desmoglein 1)
- patients form flaccid, easy to rupture blisters with Nikolsky's sign (easy to move blister). No clear areas of scaring, may be hyperpigmentation

Front 61

Pemphigoid

Back 61

- autoantibodies target proteins of the basement membrane (hemidesmosome) causing blister formation between the dermis and epidermis
- 2 types:
- Bullous pemphigoid: BP antigen 1 and/or 2; forms tense, prurutic blisters that don't rupture easily
- Mucous membrane pemphigoid: BPAG2, laminins, integrins; oral form often presents with gum bleeding red line gingiva, usually does well, no scaring; ocular form scaring fuses the eyelid and eye with fibrous bands that may expand over the cornea, blinding the patient
- occular pemphigoid

Front 62

Diagnostic tools for pemphigus/pemphigoid

Back 62

Biopsy:
- conventional histology (pemphigus will be intra-epithelial, pemphigoid will be below the basal epidermis)
- direct immunofluorescence microscopy (DIF): assay tissue with antibody to antibody, show where located in tissue (p-gus: chicken-wire pattern, p-goid: basement membrane)
Assessment for circulating antibodies
- indirect immunofluorescence (IIF): take antibodies from blood, expose to tissue, see where located (same as above)
- enzyme-linked immunosorbant assay (ELISA): allows quantification of amount antibodies present

Front 63

4 major groups or resident skin bacteria

Back 63

Actinobacteria ~50%; gram +
- Propionibacteria: lipophilic, anaerobic; preferential growth around adnexal structures (hair follicles, sebaceous glands)
- Corynebacteria: pleomorphic bacilli, lipophilic; ubiquitous in soil, moist skin surfaces
- other actinobacteriales
Frimuctes (~25%), gram +
- staphylococci (17%): mostly staph epidermidis, prefers both moist and oily sites, coagulase negative, rare cause of nosocomial infections
Proteobacteria (~17%), gram -
Bacteroidetes (~6 %)

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Resident vs transient bacteria

Back 64

Resident: relatively fixed group which re-establishes after preturbation, commensuals and perhaps symbionts
Transients: arise from the environment and may persist for hours or days before ultimately displaced; may be pathogenic (ex: MRSA hand carriage by healthcare workers)
- Transient flora at one site may be resident at another, and both resident and transient flora may become pathogens

Front 65

Factors that facilitate bacterial growth on skin

Back 65

- moist, oily areas (especially for transient pathogens): skin folds, palms and soles (sweat gland rich)
- occlusion: increases moisture and increases the pH (5 --> 7) resulting in a 10K increase of bacteria in 24hrs
- injury: exposes novel adhesins for pathogen binding (fibronectin, serum protiens (IgG which may bind staph protein A or strep protein G))

Front 66

Skin antimicrobial peptides (AMPs) and their sources

Back 66

Human:
- ex: lysozyme, lactoferin, catestain, calprotectin, cathelicidin, human beta-defensins, etc
- synthesized by keratinoctes and non-resident cells (macrophages). Have multiple functions including antimicrobial
- LL-37, HBD-2 on patients with psoriasis makes them less prone to skin infection, while reduction of these in AD makes those patients more prone
Bacterial:
-phenol soluble modulins (PSM): produced by resident bacterial, protective against Group A strep. S. aureus, E. coli
- serine protease (Esp), lipoteichoic acid (LTA): produced by Staph epi, block biofilm formation (s. aureus colonization of nares), LTA interacts with keratinocytes to block inflammation from epidermal injury (inhibits cytokine production)

Front 67

General scenarios for pathologies associated with normal skin flora

Back 67

2 scenarios:
- Inflammation associated with normal skin flora (ex: toxic shock syndrome)
- inflammation associated with exuberant host response to normal skin flora (ex: acne form propionbacterium)
- Combinations of both.

Front 68

Toxic shock syndrome

Back 68

- linked to the use of super absorbent tampons
- skin occlusion + the specific activity of the synthetic materials stimulated growth of toxin producing S. aureus and the production of toxic shock syndrome toxin
- vaginal wall injury from the tampons also facilitated S. aureus growth and toxin absorption

Front 69

Acne pathogenesis

Back 69

- example of pathology due to normal skin flora from inflammation due to increased host immune response
- Propionibacterium acne normall resides in pores and uses sebum as a nutrient for growth. As sebum production increases (especially during puberty) the number of P. acne bacteria increases in the pore
- Gramp + P. acne in the occluded follicle interact with TLR on local skin monocytes, activating them to produce pro-inflammatory mediators.
- topical and oral antibiotics reduce the density of P. acne colonization in the follicle and microphage activation
- treatment of monocytes with trans-retinoic acid down-regulates the TLR2 expression on monocytes so reduces the inflammatory response

Front 70

Pathogenesis of Malassenzia yeast

Back 70

- a normal skin flora, pathogenesis caused by inflammation due to increased normal flora
- 3 species: M. furfur (#'s peak in adolescence with sebaceous gland activity), P. ovale, P. orbiculare (Pityrosporum especially in warm, humid climates).
- undefined factors trigger overgrowth and converstion from yeast to hyphal forms (branched)
- Tinea versicolor: presentation of hyper or hypo-pigmented patches with readily inducible scale. Mostly on the trunk in a warm environment, usually asymptomatic (may be pruritic)
- Seborrheic dermatitis: flaky white/yellow plaques on oily skin areas, responds to Pityrosporum control (though no quantitative different in P. ovale than normal)
- Pityrosporum folluculitis: acneiform eruptions around follicles, mostly on the trunk; associated with warm climate, antibiotic use, immunosuppressives, increased sebum production, responds to anti-fungals

Front 71

Candida pathogenesis

Back 71

- most common species is C. albicans. Frequently is a constituent of GI tract and mucosal surfaces (less common on skin, but found in warm/wet areas)
- Colonization of the skin is usually associate with marked inflammatory responses (severe pruritus or pain), usually responds to combination anti-fungal/antibiotic therapy
- Intertrigo: inflammation (rash) of the body folds and adjacent areas of skin
- Paryonchia: skin infection around the nails
- Impetigo-like candidiasis: bullous lesions

Front 72

Tools for learning about normal/abnormal skin flora

Back 72

- observation: Ignaz Semmelweiss observed that hand washing could decrease incidence of purpuric fever (related to transient pathogen carriage by physicians)
- Cultivation based tools
- PCR based tools: universal bacterial ribosomal RNA primers (followed by sequencing); helped identify an number of new skin microorganisms in the last 5 years
- Human microbiome project: determine whether individuals share a core human microbiome, whether changes correlate to disease/health, develop technology to support these goals
- Although there has been a lot of progress, over half of the organisms identified on skin represent a limited group of organisms (firmicutes, actinobacteria)

Front 73

Impetigo

Back 73

= a superficial infection of the epidermis that usually involves just the stratum corneum. Transmitted by direct contact, highly contagious. Predisposed by childhood, areas of crowding/heat/humidity
- presents as small vesicles or pustules, erosions with golden, honey colored crust (variants: bullous impetigo, impetiginized eczema)
- causative organisms: staphylococcus aureus (mostly), streptococcus pyogenes (group A beta-strep)
- D/T: skin exam & culture/gram stain; treated with local or systemic antibiotic depending on spread
- complications: rare

Front 74

Bacterial folliculitis

Back 74

= bacterial infection localized the hair follicles. Transmitted by autoinoculation, contact. Predisposed by S. aureus carriage, shaving, irritation, occlusion
- presents as follicular-based slightly pruritic or tender pustules and erythematous papules
- D/T: skin exam & culture/gram stain; treat with topical antiobiotics (oral if extensive/recalcitrant), prevent with antimicrobial washes
- complications: abcesses

Front 75

Hot tub folliculitis

Back 75

= diffuse folliculitis after exposure to waters that are not sufficiently chlorinated. Self-limited.
- causative agent: Pseudomonas aeruginosa
- D/T: exam/stain/culture; may give antibotic for treatment (cipro)

Front 76

Furuncles/carbuncles

Back 76

= inflammatory nodule or abscess around a follicle (boil or risin). Usually a progression from folliculitis; may develop into carbuncle (deeper infection of connecting abscesses). Transmitted by autoinoculation/contact. Predisposed by S. aureus carriage, folliculitis, obesity, immunodeficiency
- Presents as tender, warm, erythematous, fluctuant (movable) or larger, draining plaques
- Causative organism: Staph. aureus
- D/T: exam/stain/culture; treatment is drainage (hot compress or surgical) and oral antibiotic if fever develops; prevent with antimicrobial washes, bleach bath, treating carrier state
- Complications: recurrence, bacteremia (rare)

Front 77

Community acquired MRSA

Back 77

- infection of the skin may cause furunculosis (often recurrent). Often described as a spider bite.
- D/T: culture and sensitivity testing are v. important; treat with Bactrim
- Prevention: treatment of carrier state, antimicrobial washes, bleach baths

Front 78

Dermatophytosis

Back 78

= fungal infection of non-viable, keratinized structures (stratum corneum, hair, nails). Does not invade other tissue.
- presentation is variable by location: feet ("moccasin," scale, hyperkeratosis, +/- pruritis, tow web maceration), nail (discoloration, thickening, debris), skin (annular, erythema, scale, +/- pruritis, demarcated, plaque +/- central clearing), scalp (dry, hyperkeratotic, alopetic patch)
- caused by: filamentous fungi (Microsporum, Trichophyton, Epidermophyton); keratin-eating organisms with keratinases
- Transmission: contact (autoinoculation, p2p, pets, soil)
- D/T: KOH prep, culture, Wood's lamp, biopsy (PAS stain); topical or oral anti-funglas, examine contacts
- complications: rare except nail disfigurement, hair loss
- nomenclature: tinia ____ (location of infection, i.e. Tinea pedis on foot)

Front 79

Verrua (warts)

Back 79

= HPV infection of the basal epithelium stimulating growth of the spinous layer leading to hyperkeratosis, papillomatosis
- Presentation: asymptomatic verrucous, hyperkeratotic lesions skin colored papules (verruca vulgaris), may have thrombosed capillaries (black macules), may be filiform (often facial), or flat (verruca plana)
- Transmission: contact (autoinoculation, P2P, surfaces); predisposing factors (often none), childhood, immune compromised (HIV, transplant)
- D/T: clinical/biopsy (rare); resolve spontaneously (months--years), salicylic acid, plaster, Imiquimod, (duct tape), paring (trimming), cyrosurgery, other surgery (eletro, laser, gross), podophyllin (topical cytotoxin)

Front 80

Molluscum contagiosum

Back 80

= poxvirus infection of the epidermis
- organism: molluscum contagiosum virus
- presentation: small dome shaped papules, central umbilicus/dell
- transmission: skin to skin; predisposing: children, HIV, sexually active young adults
- D/T: clinical, crush prep, biopsy (rare); resolve spontaneously (up to 2 yrs), irritants (imiquimod, cantharidin, cyrosurgery, curettage)

Front 81

Herpes simplex infection

Back 81

= HSV (1 mouth & 2 genital, usually) infection of keratinized skin or mucous membranes
- presentation: painful grouped vesicles or erosions on erythematous base (cold sore, fever blister, genital herpes), may be prodrone period
- Transmission: skin-skin, skin-mucosa, mucosa-skin, STD, may remain latentin neural/lymph cells then reactivate, asymptomatic shedding is common; 80-90% of people are colonized
- D/T: exam, Tzanck prep (stain for multinucleated cells), direct fluorescent antibody, culture, biopsy (rare); self limited, oral antivirals (frequent, immunocompromised, severe), avoid contact with active outbreaks
- complications: rare in immunocompetent, neonatal transmission, dissemination

Front 82

Varicella Zoster

Back 82

= reactivation of varicella zoster virus (chicken pox) that is latent in the ganglia, "shingles," "herpes zoster"
- organism: varicella zoster virus (double stranded, alpha herpes virus)
- presentation: painful dermatomal vesicles, crusted papules, erosions (common on trunk, emerging from spine), unilateral
- NO transmission: reactivation of latent virus (though can transmit chicken pox)
- predisposed by advancing age, stress, immunosuppression
- D/T: exam, Tzanck prep, direct fluorescent antibody, culture, biopsy (rare); treat with oral antivirals ASAP (48-72 hrs), prevent with immunization
- complications: post-herpetic neuralgia (long lasting pain), dissemination, transmission of varicella

Front 83

Scabies

Back 83

= infestation of Sarcoptes scabiei var. hominis. Eruptions caused by delayed (4-8 weeks) Type IV hypersensitivity response to mites tunneling into the stratum corneum
- Presentation: diffuse pruritic, thread-like linear burrows (present with itching). Usually near hands/feet, waistline, genitals, web spacess, axilla
- transmission: skin-skin, skin-fomite; predisposed by nursing homes, childhood

Front 84

Disease caused by group A strep

Back 84

- Pharyngifis (strep throat)
- Scarlet fever
- Pyoderma (impetigo)
- Cellulitis
- Erysipelas
- Puerpural Sepsis
- Pneumonia
- Necrotizing fasciitis
- Streptococcal Toxic Shock Syndrome (STSS)
- Nonsuppurative sequelae
- Acute Rheumatic Fever
- Glomerulonephritis

Front 85

Microbio of Group A strep

Back 85

- Gram-positive cocci in pairs and chains
- Lancefield Group A
- Catalase-negative, facultative anaerobes
- Many strains produce hyaluronic capsules (copious capsule=mucoid
- Main virulence factor is M protein (anti-phagocytotic surface protein). Immune response is varient specific, so re-infection with different M-protein strains
- Strongly beta-hemoIytic
- Bacitracin susceptible (95% GAS susceptible; 80-90% non-group A strains resistant)

Front 86

Lancefield's streptococcal classification

Back 86

- Group A: strep pyogenes (beta hemolysis)
- Group B: strep agalactiae (beta hemolysis (not as stong as Grp A)
- Groups C & G: various species (variable hemolysis)
- Group D: strep bovis (alpha, gamma hemolysis) (and formerly enterococcus faecalis)

Front 87

Cellulitis

Back 87

= infection involving the deeper dermis, as well as the subcutaneous fat. Manifests as rapidly spreading areas of edema, redness, and heat. May progress to vesicles, bullae, and cutaneous hemorrhage
- Systemic manifestations: fever, tachycardia, confusion, hypotension, and leukocytosis
- Risk factors: obesity, cutaneous damage (trauma, ulceration, fissures, inflammatory dermatoses), edema (venous insufficiency, lymph obstruction, saphenous vein excision)
- organisms: mostly strep A (most common), staph aureus (purulent), or other beta-hemolytic strep
- treat empirically because cultures are rarely successful

Front 88

CA-MRSA skin infections

Back 88

- can cause abscess, cellulitis, furuncles, carbuncles
- not multi-resistant, but usually resistant to erythromycin but susceptible to Bactrim
- SCCmec Type IV type most common
- Panton Valentine Leukocidin (PVL) common: kills leukocytes by pore formation, associated with abscess and necrosis
- Common strains: USA 300, 400

Front 89

Epidermolysis Bullosa: mutation/target vs. blister formation location

Back 89

- Keratin 4 and 14 mutations or antibody targets will lead to blister in the epidermis (EB simplex)
- Laminin 5 mutation/targets will lead to blister involving the basement membrane (junctional EB)
- Collagen VII mutations/targets will lead to blisters below the dermal-epidermal junction (subepidermal), (dystrophic EB)

Front 90

Microfilaments

Back 90

- two-stranded helical polymers of globular G actin with diameter 5-9nm, assembled in a polarized fashion
- compose the cortex to support the plasma membrane and are linked to adjacent cell networks through adherens junctions
- important for cell shape and migration

Front 91

Microtubules

Back 91

- hollow cylinders of tubulin with diameter 25nm (largest). Highly polarized (+/- ends), the minus end located in the centrosome (MTOC)
- involved in the separation of chromosomes, trafficking of proteins and organelles around the cell

Front 92

Intermediate filaments

Back 92

- rope-like fibers of 10nm. Not assembled in a polarized fashion, but are dynamic and re/disassemble under various conditions. Larger family of proteins (>60 humans) are used to form them
- anchor cell desmosomes and hemidesmosomes
- important for resisting mechanical stress in the cell.

Front 93

Classes of intermediate filament genes

Back 93

- Nuclear laminins: expressed in the nuclear lamina
- Vimentin-like proteins: expressed in cells of mesenchymal origin (fibroblasts, endothelia, myocytes)
- Keratins: expressed in cells of epithelial origin
- Neuronal intermediate filaments: expressed in neurons
- Lens intermediate filaments: expressed in the lens of the eye

Front 94

Organization of different intermediate filaments

Back 94

- the central alpha-helical coiled-coil rod domain is conserved between classes, while the amino and carboxy-terminals are globular and highly variable giving different functions and organizations
- Keratin: heterodimers which form a 3D network of filaments to support the nucleus and interact with desmosomes
- Vimentin: homodimers form 3D polymer network similar to keratin
- Neronal: large subunits with carboxyl tails extending outward from the central polymer creating space and controlling axon diameter
- Nuclear lamins: form a 2D sheet underneath the nuclear envelope which interacts with chromatin and other nuclear components

Front 95

Mutations in keratin causing blistering diseases

Back 95

- Keratin filaments form from paired proteins which then form tetromers and polymerize.
- Absence of one of the paired proteins or mutation that interferes with tetromer formation will lead to cytolysis and blister formation.
- recessive: absence or mutation of one of paired proteins preventing the dimer formation
- dominant: mutation in one of the paired proteins that allows dimer formation but interferes with larger polymer formation created weak strands and keratin granule formation

Front 96

Adherens junctions and desmosomes

Back 96

3 gene families contribute to these: transmembrane adhesion proteins (cadherins), cytosolic linking proteins (catenins and filament binding proteins plankins/vinculin), cytoskeleton network (intermediate filaments, actin)
- Adherens junctions and desmosomes use different subtypes of each category
- Both mediate cell-cell adhesion by linking the intracellular actin/keratin networks

Front 97

Hemidesmosomes

Back 97

- form attachments between basal cells and the basement membrane
- attach to the keratin network (5/14) with Plakin linker proteins. Transmembrane integrins attach to laminins in the basement membrane, which is linked to the dermis by collagen VII

Front 98

Gap junctions

Back 98

- 6 connexin proteins for a connexon which align on adjacent cells creating an open pore.
- molecules <1000 daltons can pass between cells
- mediate cell-cell signal and particle transfer

Front 99

Antibody-mediated blistering disease

Back 99

- autoantibodies target proteins in the adhesive connections between cells causing them to separate and blister
- Desmosomes: IgG attacks cadherin proteins to inhibit their attachment to cadherins of neighboring cells. Different cadherins are expressed in different epidermal layers determining where the blister will form (Pemphigus vulgaris: basal layer desmoglein 3). Will have most effect in tissue under high mechanical stress
- Hemidesmosomes: antibodies can target linker proteins, integrins, or laminin causing bullous pemphigoid (basal layer seperates from the basal membrane). (Mutations in the different parts of the hemidesmosome causes epidermolysis bullosa)

Front 100

Gas gangrene/myonecrosis

Back 100

- often occurs after severe penetrating trauma or crush injuries cause interruption of blood supply to tissue allowing colonization of anaerobic bacteria
- mostly caused by clostridium (a spore forming organism that can contaminate open wounds): C. perfringens, C. novyi, and C. histolyticum
- spontaneous (hematogenous) gas gangrene can occur due to C. septicum in patients with GI malignancies or neutropenia
- Therapy: aggressive surgical debridement, penicillin, clindamycin

Front 101

Surgical Site Infections

Back 101

- Most common adverse event in hospitalized patients who have undergone surgery (can'y get patients fully clean: bacteria in glands, etc)
3 types:
- superficial incisional (subcutaneous space)
- deep incisional (deep soft tissue: fascia, muscle)
- organ/space (involves any part of anatomy other than the inicision)
Timing:
- may no become apparent for 5-14 days, so patients may present from home
- Early infections (first 48hrs) often caused by: S. pyogenes (historically a problem during delivery) and clostridium species
Microbio:
- following GI or female GU surgery, or perianal wound: mixed gram +/- flora including facultative and anaerobic organisms
- Following "clean"" procedures (neck/head/trunk/extremity): S. aureus (including MRSA) and strep species (skin flora)

Front 102

Classification of Operative wounds by level of bacterial contamination

Back 102

- clean wound: (<2% infection rate, antibiotics not routine) uninfected, uninflammed operative wound with no entry of respiratory, GI, GU tracts
- clean, contaminated: (10%, require prophylactic antibiotics) entry of respiratory, GI, GU tracts under controlled conditions without unusual contamination
- Contaminated: (20%, require therapeutic antibiotics) open trauma, major breaks in sterile technique, gross spillage GI, incisions with acute inflammation
- Dirty-infected: (40%, require therapeutic antibiotics) old trauma wounds with devitalized tissue and those with clinical infection or perforated viscera

Front 103

Common infections from unusual exposures

Back 103

- Human bite : Eikenella corrodens
- Animal bite: Pasteurella multocida (cats) or Capnocytophagia canimorsus (dogs)
- Fresh water: Aeromonas hydrophila
- Salt water/fish: Erysipelothrix rhusiopathiae
- Aquarium: Mycobacterium marinum
- Spa : Pseudomonas aeruginosa
- Trauma: clostridium (gas gangrene)
- Cirrhosis & salt water: Vibrio vulnificus
- Edema : streptococcus species

Front 104

Vancomycin

Back 104

- effective against G+'s: S. aureus, coag - staph, S. pyogenes, S. pneumo, Enterococci (except VRE); viridans Strep, Corynebacteria, Rhodococcus, C. difficile (given orally)
- indications: severe β-lactam resistant infec or allergy, C. diff colitis (po after failed flagyl)
- inhibits cell wall synthesis in by binding to terminal d-Ala-d-Ala residues and preventing cross linking of the peptidoglycan chains (different site than β-lactams)
- bactericidal (except for enterococci)
- Ineffective against: VRE (plasmid mediated, terminal d-Ala-d-Lac reduces binding affinity); GISA (insenstive S. aureus, thicker cell wall leads to sequesterization); VRSA (interspecies transfer of vanA to multiresistance plasmid probs. from VRE)
- Abs/dist/exct: poor oral bioavailability (stays in gut), must be given IV; CSF limited unless inflammed; renal excretion
- Tox: red man/red neck syndrome (histimine release, not IgE. RX: slow infusion rate, antihistimines), reversible neutropenia; rarely: drug fever, rash, ototoxicity w/ hearing loss

Front 105

Vancomycin MIC in S. Aureus

Back 105

- Resistance classified at 2ug/ml (used to be 4). Clinical failures still occur
- average MIC has been increasing for vanco; unclear why (testing methods, hetero-resistance, dosing, host v. bug, etc)
- Glycopeptide-intermediate SA: Vanco MIC 2-8 ug/ml. Resistance due to increased cell wall, sequesters vanco (usually methicillin resistant also)
- VRSA: fully resistant, have vanA gene on a multi-resistance conjugative plasmid in an MRSA (probably from VRE)

Front 106

Clindamycin

Back 106

- effective against: ANAEROBES (abcesses), most gram + (S. pyogenes, viridans strep (can inhibit toxin production via reduced overal protein synthesis), MSSA, most CA-MRSA, S. pneumo), non-bacterial pathogens (Pneumocystis carinii, Toxoplasm gondii, Babesia)
- indications: anaerobic pulm infec (abscess), polymicrobial intrabdominal/pelvic infec, severe GAP infec, diabetic foot ulcers, CA-SSTI (MRSA, MSSA, GAP), ondontogenic infec (tooth abscess)
- inhibits protein synthesis at 50S ribosomal subunit. Can competitively inhibit macrolides/chloramphenicol (same binding site)
- bacteristatic
- Abs/Dist/Excrt: high oral bioavailablity, distributed to most tissues except brain or CSF, metabolized in the liver and excreted in the urine and bile
- Tox; diarrhea including C. diff induces pseudo-membranous colitis (high effect on gut flora)
- Resistance: altered ribosomal binding proteins (erm A/C genes expressed constitutively or induced by exposure to erythromycin--flattened inhibition zone "D-test"), plasmid mediated inactivation

Front 107

Trimethoprim-sulfamethoxazole

Back 107

- Effective against most gram+/-, Nocardia, Toxoplasma, Pneumocystis carinii, MRSA/MSSA, Listeria, some nosocomial infections, NOT GROUP A STREP
- indications: UTI, prostatitis, PCP, CA-MRSA soft tissue infection, nocardia, listeria meningitis in PCN allergy, nosoc. pneumo due to stenotrophomonas or Burkholderia
- interferes with the folic acid synthesis pathway: sulfonamide blocks PABA→dihydrofolic acid and trimethoprim blocks dihydrofolic acid → tetrahydrofolic acid
- usually bactericidal
- Abs/dist/excr: high oral bioavailability also IV prep available; dist. to most tissues including CSF and placenta; excreted by kidneys after acetylation in liver
- Resistance: decreased cell permeability, drug binding capacity, altered dihydrofolate reductase
- Tox: heme (hemolysis with G6PD deficiency, agranulocytosis, aplastic anemia), hypersensitivity (SJS), kernicterus in infants, increased serum Cr (inhibits secretion), aseptic meningitis, hyperkalemia (inihibits distal K secretion)

Front 108

Enterococcus antibiotic sensitivity

Back 108

- normal flora of the GI, GU tracts
- intrinsically resistant to: penicillins, cephalosporins, aminoglycosides, clindamycin, bactrim
- successful treatment: cell-wall agent (penicillin or vanco) + aminoglycoside
- aquired resistance to: pencillins, aminoglycoside, vancomycin
- VRE: virtually untreatable with conventional agents (also usually resistant to ampicillin), more often E. faecium (than E. faecalis), risks: catheters, antibiotic use, neutropenia

Front 109

linezolid (Zyvox)

Back 109

- effective against gram+s: SA (MSSA/MRSA), coag - staph, S. pyogenes, S. pneumo (including PCN resistant), E. faecalis & E. faecium (VSE and VRE)
- indications: VRE infection, MRSA and CoNS with vanco is contra-indicated, MRSA pneumo
- synthetic oxazolidinone: blocks formation of the 70S initiation complex by interfering with assembly of fMet-tRNA with mRNA
- bacteriostatic
- resistance: 23S rRNA mutation
- same oral/IV bioavailability
- Tox: significant in longterm use, myelosuppression (low platelets), peripheral and/or optic neuropathy, weak MAO inhibitor (seratonin syndrome if given with SSRIs, may potentiate hypertension if given with adrenergic agents)

Front 110

Daptomycin

Back 110

- effective against gram+: SA (MRSA/MSSA/VRSA), S. pneumo (incl PCN-resistant), E. faecalis & E. faecium (incl VRE)
- indications: complicated skin infec, SA bacteremia and right-sided endocarditis, NOT for pneumonia (inhibited in lung by surfactant binding)
- binds cell membrane via Ca++ dependent insertion of lipid tail, rapidly depolarizes cell via ion-conduction, disrupts DNA, RNA and protein synthesis
- rapidly bactericidal in vitro, less effective in vivo
- resistance: rare in vitro, has emerged in SA and Enterococcal infections, mechanism is unknown (possibly loss of chaperone protein)
- daily IV admin only, limited metabolism, 80% urine excretion
- tox: potential for myopathy

Front 111

Common pathogens in skin infections

Back 111

- cellulitis with furuncles, carbuncles, or abcesses: S. aureus
- diffuse cellulitis (unassociated with defined portal): streptococcal
- CA-MRSA: variety of SSTI's: impetigo to necrotizing fasciitis, abscesses and cellulitis are most common (usually a single lesion on extremities)

Front 112

Surgical site infection prevention

Back 112

Skin prep/disinfection (topical antibiotics)
- Povidone-Iondine
- Chlorohexidine: effective against gram +/-, yeast, lipid-enveloped viruses (HIV), NOT spores. Resistance is rare. (binds -charged cell wall, distrupts osmotic equilibrium)
Antimicrobial prophylaxis:
- as indicated for wound type
- must be given preoperatively within an 1hr of incision, discontinued within 24hrs

Front 113

Definition of osteoporosis

Back 113

- skeletal disorder characterized by compromised bone strength predisposing a person to increased risk of fracture
- bone strength primarily reflects the integration of bone density and bone quality (architecture, turnover, mineralization, damage accumulation). Overall risk increase with age for same bone density
- WHO: BMD T score <= -2.5

Front 114

Changes in bone quality with age/osteoporosis

Back 114

Architecture: loss of horizontal trabecular bone. 10% ↓BMD due to ↓trabecular thickness →20% ↓strength OR 10% ↓number → 70% ↓strength
Turnover: ↑destruction to due menopause (low E2)→ development of stress risers (microfractures from mechanical stress) and perforations (gaps make bone no-longer mechanically viable)
Mineralization: ↓turnover → bone continues to accumulate Ca → hypermineralized and brittle (can't disperse mechanical energy)
Damage accumulation: ↓turnover → accumulation of microdamage → loss of strength

Front 115

Normal hormonal control of calcium and bone turnover

Back 115

- PTH (primary mediator of bone turnover) increases serum calcium by activating osteoclasts to ↑ Ca resorption from bones, ↓ renal excretion (and ↑phosphate excretion), ↑ intestinal absorption.
- calcitonin (secreted by the thyroid) acts to ↓ plasma calcium by opposite effects of PTH (though weaker). Also ↓ osteoclast formation
- vitamin D (active form) promotes Ca (and phosphate) absorption from the gut, ↓renal Ca (and phos) excretion. In high doses: ↑bone resorption, in low doses ↑mineralization

Front 116

Changes in bone density with age

Back 116

BMD increases exponentially until puberty, then slows exponentially to a peak BMD around 30. Then slowly tapers until menopause, when it exponentially drops, then more slowly drops in old age.
- BMD is determined by estrogen production (peak at puberty, then gradual increase to 30, and drop off at menopause) and genetic factors (determine peak BMD)

Front 117

Treatments for osteoporosis

Back 117

- calcium and Vit D supplementation (increase risk for MI?)
- estrogen and estrogen agonists/antagonists (EVISTA: antagonist in breast, agonist on bone, ↓B. cancer): E w/o P decreases bone risks w/o increasing breast cancer risk, still thrombosis risk
- Calcitonin: reduces osteoclast formation to maintain bone density
- Bisphosphonates: block osteoclast formation (risk for osteonecrosis of the jaw)
- Anti-RANKL antibody (denosumab): antibody binds and prevents RANKL from being recognized by receptor, thus preventing osteoclast formation and bone resorption (given subQ every 6 months)
- Anabolic agents (Forteo): SHORT bursts of PTH stimulate bone formation, while minimizing resorption
- Cathepsin K inhibitors (in trials): responsible for bone matrix degradation in osteoclast, inhibitions increases bone formation and mass

Front 118

how estrogen deficiency results in bone loss

Back 118

- estrogen deficiency activates the immune system by increasing oxidatve stress which activates T cells.
- T cells secrete TNF (which increases osteoclast formation) OR activates stromal cells which increase RANKL production.
- RANKL is a cytokine that is essential for osteoclast formation and increase the conversion of osteoclast precursors to active osteoclasts.
- This response is a normal post-partum adapation to increase serum calcium, trigger lactation (RANKL decreases there, allowing for terminal maturation), and re-activate the immune system after giving birth

Front 119

Sclerosteosis

Back 119

- rare skeletal disorder characterized by generalized progressive bone overgrowth leading to tall stature, facial distortion, entrapment of cranial nerves, and raised intracranial pressure (predisposes sudden death)
- bone formation is increased but resorption is not affected or mildly diminished
- results from loss of SOST gene product Sclerostin (normally inhibits WNT signaling that makes bone)

Front 120

Diseases of too little bone

Back 120

Disease due to decreased bone formation or increased resorption resulting in decreased bone strength and more fractures
- osteoporosis (decreased BMD)
- osteomalacia (vitamin D deficiency, demineralization)
- osteogenesis imperfecta (collagen I deficiency, hypermineralization)
- hypophosphatasia (hypomineralization, alk phos deficiency leading to osteomalacia)
- other rare disorders

Front 121

Diseases of too much bone

Back 121

Disorders of decreased bone resorption or increased bone formation. Despite abnormal quantity, abnormal quality makes it susceptible to fracture
- osteopetrosis: multiple types, defective osteoclastic resorption
- osteosclerosis: multiple types, increased bone formation (Progressive diaphyseal dysplasia, Endosteal hyperostosis, fibrodysplasia ossificans progressiva)

Front 122

Diseases of chaotic bone development

Back 122

Disorders in which bone formation and resorption are not coupled/coordinated, resulting in chaotic bone development or remodeling
- Paget's disease
- Juvenile Paget's
- Familial expansile osteolysis
- other rare disorders

Front 123

Sclerosing bone disorders

Back 123

- Disorders of too much bone: decreased resorption or increased formation.
- Despite increased bone quantity, abnormal quality so susceptible to fracture.
- Pathophysiology: Mutations in factors regulating osteoblast or osteoclast differentiation during development or in aduft bone remodeling.
- Other causes: Malignancies (especially prostate cancer) can cause osteoblastic lesions from abnormal expression of osteoblastic factors, fluoride toxicity and bisphosphonates may cause osteosclerosis

Front 124

Differentiation of osteoclasts

Back 124

- hematopoietic stem cells in marrow are activated by cytokines (M-CSF) to become preosteoclasts.
- RANKL activated T-cells produce TNF-α which activates stromal cells to secrete RANKL.
- RANKL promotes preosteoclast fusion, cathespin K development and adherence to bone (RANK-L is modulated by OPG, which is secreted by the placenta during pregnancy)
- RANKL and M-CSF drive further differentiation of preosteoclasts into osteoclasts

Front 125

Features of osteoclasts that allow for function

Back 125

- RANK receptor expression: allows response to RANK-L (major differentiation signal). Deficiency results in less development of functional osteoclasts
- Carbonic anhydrase II: generates H+ needed to acidify bone for resorption
- TC1RG1: transports H+ to bone surface
- CICN7: transports chloride to the bone surface to maintain electoneutrality
- integrin expression, for adherence to bone proteins
- Cathespin K: lysosomal peptidase to digest bone extracellular matrix

Front 126

Differentiation of osteoblasts

Back 126

- derived from pluripotent mesenchymal stem cells
- converted to pre-osteoblasts by Wnt, BMP (bone morphogenic protein) signaling
- pre-osteoblasts are then converted to osteoblasts by BMP OR to condrocytes then osteoblasts.
- osteoblasts then become incorporated in bone as osteocytes or apoptose

Front 127

Autosomal-recessive infantile osteopetrosis (ARO)

Back 127

- severe disorder (presents w/in 1 yr) of bone overgrowth due to lack of resorption resulting dense, brittle bone prone to fracture
Two types: CICN7, TCIRG mutations (normal osteoclast numbers, but defective acidification), RANKL mutation (low osteoclasts)
Complications:
- bone overgrowth into the marrow cavity reducing hematopoietic function causing bleeding, infections, hypersplenism, hemolytic anemia (RBC's lyse in the spleen)
- cranial nerve compression, blindness, deafness, delayed eruption of dentition** (unique to osteoclastic disease)
- death in the first decade if untreated.
Treatment: bone marrow transplantation to provide normal osteoclast precursors

Front 128

Autosomal Dominant Osteopetrosis II (Albers-Schonberg Disease, ADO II)

Back 128

- more benign disorder (late childhood onset) of bone overgrowth due to ineffective resorption
Complications:
- spine sclerosis (predominant diagnostic criteria) "rugger jersey" spine
- fracures in 80% of patients
- scoliosis, skull base scoliosis may cause compression of cranial nerves
- poor tooth formation resulting in dental abscesses and osteomyelitis
Types: variable penetrance and severity due to different mutations. Most are heterzygous for CICN7 but have gene inactivation (only one allele expressed)

Front 129

Pycnodysostosis

Back 129

- very rare autosomal recessive disease of ineffective bone resorption due to Cathespin K deficiciency
Signs/complications:
- disporportionate short stature
- short/clubbed fingers or aplastic, hypoplasia of fingernails
- large cranium, facial dysmorphism (dense orbital ridges, sclerotic base of skull, hypoplasia of facial bones)
- pectus excavatum
- kyphoscoliosis, lumbar lordosis, dense vertebrae with preservation of transverse processes
- recurrent fractures (usually lower limbs)

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Carbonic Anhydrase II Deficiency

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- autosomal recessive disorder causing osteopetrosis due to reduced bone resorption
- skeletal sclerosis diminishes with age at the body finds other ways to deal with bicarbonate
Presentation: (variable)
- renal tubular acidosis and cerebral calcifications
- mental subnormality
- dental malocclusion
- optic nerve compression

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Bone disorders with increased bone formation

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- progressive diaphyseal dysplasia
- Endosteal hyperstosis and related diseases (sclerosteosis, Van Buchem disease, Endosteal hyperostosos)
- Fibrodysplasia ossificans progressiva (soft tissue turns to bone)
- Hereditary multiple exostoses (bone tumors within bone)
- Disorders of unknown etiology: melorheostosis, osteopathia, striata, fibrogenesis imperfecta ossium/axial osteomalacia, pachydermoperiostosis

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Progressive Diaphyseal dysplasia

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- autosomal dominant disease of increased bone growth
- characterized by gradual appearance of symmetric hyperostosis on periosteal and endosteal surfaces of long bones (and other bones less often)
- variable age of onset, severity, and course
- mutation in TGFβ Latency Associated Peptide (LAP, a secreted binding protein) so TGFβ action is unregulated
- Presentation: continued growth (disproportionately long legs, knock need, pseudoclubbing), deafness, perforated nasal septum, torus palitanus, low muscle mass, hypocalcuria, vitamin D deficiency with osteomalacia (not corrected by supplementation)

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Canonical Wnt Pathway

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- pathway that stimulates cell division causing cancers, bone deformation diseases
- normally Wnt inhibits alternative mesenchymal differentiation pathways (adipocyte, chondrocyte) and promotes osteoblast differentiation, proliferation, and mineralization while blocking apoptosis and osteoclast differentiation. (when you age, this pathway becomes less active and produces more adipose, less bone)
- Activating mutations: van Buchem disease, sclerosteosis, endosteal hyperostosis (Worth type):
- Inactivating mutations: osteoporosis, pseudoganglioma syndrome

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Van Buchem disease and sclerosteosis

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- autosomal recessive disease resulting excessive bone growth and density (no fractures because high bone quality)
- Van buchem: progressive asymmetrical enlargement of the mandible without dental dental occlusion (different from osteopetrosis)
- Sclerosteosis: tall, big people of Afrikans descent, syndactyly
- Caused by deactivating mutations of SOST and osteocyte protein inhibitor of the Wnt signaling pathway, resulting in excessive pathway activation
Complications: optic atrophy, facial nerve palsy, deafness, painful pressure points on long bones, selectively endosteal sclerosis, elevate serum alk phos (often)

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Endosteal Hyperostosis (worth type)

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- autosomal dominant, benign disorder of increase bone formation and density (remodeled normally, no fractures due to high structural quality)
- Caused by LRP5 mutation that prevents DKK-1 binding to inhibit the Wnt pathway (results lessened inhibition of Wnt growth signaling)
- Signs: flatten forhead during adolescence, elongated mandible, toras palatinus

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Fibrodysplasia Ossificans Progressiva

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- disease in which soft tissue is progressively ossified in a specific pattern (precipitated by trauma so don't biopsy)
Pathogenesis:
- missense mutation in ACVR/ALK2 type 1 BMP receptor (receptor for TGFβ and BMP: both promote osteoblast differentiation from mesenchymal precursors). Mutation is in the binding site of inhibitor FKBP12, resulting in signaling in absence of ligand and hyper-response to ligand
- same mutation
Presentation:
- in first decade: inflammatory swelling of soft tissues that transform into armament-like encasing of bone, tendon and muscle. TM joints ankylose, hearing is impaired (ossification of middle ear), endochondrial ossification of bones
- cardiac, diaphragm, tongue, extra-occular muscle usually spared
- wheel-chair by 3rd decade, jaw ankylosis, fixed rigid chest wall (restricts breathing), right sided heart failure

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Paget's disease general

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- a localized disorder of bone remodeling creating disorganized woven and lamellar bone resulting in deformity, fracture, and metabolic derangement
Prevalence: 3% in US, more males thank females, late life onset, only 5-20% with symptoms (depends on area involved, extent)
Presentation: 67% polyostotic/33% Monostotic; elevated alk phos w/o explanation, fracture, bone deformity, pain, "cotton-wool" skull
Pathogenesis: likely due to osteoclasts dis-regulation, genetic susceptibility (25%), slow virus? (not proven)

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Mutated genes associated with Paget's disease

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- SQSTM1 Gene: codes for p62 (a scafold protein in Nfκβ processing), mutation believed to cause unregulated Nfκβ signaling (reason for focal changes unclear). Highly penetrant (when fully mutated): 20-50% familial cases, 5-10% sporatic
- RANK gene: receptor for RANK-L, receptor activator of Nfκβ. Mutation impairs cleavage of RANK peptide leading to abnormal cell localizatoin. Associated w/ 3 disease: familial expansile osteolysis, expansile skeletal hyperphosphatasia, early onset familial Paget's. Autosomal dominant (early onset, early tooth loss, deafness, severe Paget's changes)
- OPG Gene: soluble decoy receptors of RANKL, inactivating mutations cause increased RANKL stimulation. Autosomal recessive, associated with Juvenile Paget's (idiopathic hyperphosphatasia, abnormal bone turnover, widespread deformities)
- VCP gene: codes p97 which normally binds ubiquitin in proteosome system. Mechanism unclear, may be related to impaired degradation of osteoclastogenic pathway components. Causes inclusion body myopathy, Paget's, fronto-temporal dementia

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Abnormalities in Paget's disease

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Mostly in osteoclasts: increase in osteoclast number, cell size, number of nuclei (up to 100, 20-50x normal), vitamin D hyper-responsiveness, and increased IL-6 in marrow resulting in increased bone resorption
- Osteoblast are normal but overall remodelling and bone formation is increased but disorganized: Coupled Chaotic Activity (or resorption and formation)

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Paget's Presentation

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Histology:
- osteoclast that are large, numerous, highly poly-nuclear
- "mosaic" or "woven" bone appearance
Clinical:
- bone size is expanded (osteopetrosis and sclerosis), often in the skull ("cotton wool" appearance on x-ray)
- skull involvement: hearing loss (50%, due to ↓BMD in cochlear capsule), increased skull weight, platybasia (base skull weakening causing ↑cerebellar pressure, tonsilar herniation), hydrocephalus (causing ataxia, dementia, incontinence), pagetic steal syndrome (blood shunted to ext carotids), osteoporosis circumscripta (loss of bone around the skull), leontiasis ossea (enlarged face/jaw bones, dental malocclusion, causes hemorrhagic complications in oral surgery)
-spine involvement: "picture frame" vetebral body (cortical thickening with central lytic lesion, focally located in spine)

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Leontiasis ossea

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- uncommon feature of Paget's disease and fibrous dysplasia
- enlargement of facial bones with jaw involvement, dental malocclusion and teeth loss.
- results in hemorrhagic complications of oral surgery and difficult tooth extractions

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Diagnosis of Paget's disease

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- X-ray is diagnositic
- physical exam: skeletal deformity, local warmth over affected bone, hearing loss, dilated scalp veins, high output heart failure, headache on valsalva (impending herniation from platybasia)
Labs: elevated alk phos (though not diagnostic or correlated to symptoms) <2x normal in 50% of patients and normal in 15%. NTx and CTx (collagen breakdown proteins) and bone specific alkaline phos and some urine markers also elevated. Monitor markers to evaluate response
Other tests:
- bone scan with radiolabeled bisphosphonate
- x-rays of involved sites (diagnostic)
- CT for skull involvement including optic and auditory canals
- bone biopsy is rare

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Complications of Paget's disease

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- pain: local metabolic activity o the disease, deformity, nerve compression, disc disease, spinal cord or cranial nerve involvement, secondary arthritis
- fracture: fissure fracture, complete fracture ("chalk-stick")
- neurologic syndromes: compression, vascular steal, deafness, blindness, platybasia
- osteosarcoma (10% in older patients)
- giant cell tumors (ends of long bonds, possible familial correlation)
- hypercalcemia, hypercalciuria (from immobilization)
- gout (23% of patients with Paget's)
- High output heart failure (if 15% of skeleton involved)
- non-skeletal malignancies are not increased

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Treatment of Paget's

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Indications: only for symptomatic patients (most are not)
- analgesics, NSAIDS, COX2 inhibitors to reduce pain
- physical therapy
- orthopedic or neurosurgery
Medications: (indicated by advanced disease, symptomatic patients, asymptomatic patients with involvement of weight bearing bones or near major joint, skull near optic/auditory canals, AlkPhos >2x ULN), prolonged immobilization
- salmon calcitonin (causes osteoclasts to retract and stop resporption, injected analgesic
- bisphonates: kill osteoclasts or atleast detach from bone (risk for jaw osteonecrosis). Effective, currently main treatment option

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Bisphosphonate

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- used in treatment of Paget's and other disease that cause bone fragility
- Different mechanisms depending on type:
-all bind Ca so localize to bones
- targets enzymes that use pyrophosphates and is incorporated in toxic ATP analog causing apoptosis
-disrupts HMG-CoA reductase pathway preventing lipid modification of membrane proteins (prenylation--cause disruption of ruffled border) causing osteoclast apoptosis and cholesterol synthesis in liver
Efficacy:
- induces reduction in AlkPhos, pain
- 60% remission orally, near 100% with IV
- failure with one still often can be treated with another
Complications: risk for osteonecrosis of the jaw

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Clinical correlations of hip anatomy

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- the piriformis fossa is the entry point for the introduction of intramedullary devices into the femur
- two weak spots prone to dislocation: anteriorly between iliofemoral/pubofemoral, posterioly between iliofemoral/isofemoral ligaments
- because of orientation of the ligaments the volume in the hip joint decreases on extension, internal rotation (standing)
- avascular necorsis of the femoral head occurs when the lateral epiphyseal artery is damaged (fracture, dislocation, surgery)
- normal hip has 10-12 degrees of anteversion (in-toeing)
- gluteus minimus has a preponderance for producing heterotropic ossification when damaged during surgery

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Biomechanics of the hip

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- 2 forces across the femoral neck: compressive and tensile. Trabecular bone grows in patterns to resist these
- joint reactive force provided by the iliopsoas compensates for body weight. Can reduce force w/ weight ipsilaterally or cane contralaterally

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Clinical presentation of intra-articular hip pathology

Back 148

Pain:
- common in anterior hip or groin.
- May be referred to anteromedial thigh and knee along L3 dermatome
- Butt pain is uncommon, and usually due to spinal pathology
Ambulatory capacity (ask LOCATES):
- often report difficulty doing rotation of the hip while flexed (in/out of cars, putting on shoes/socks, inability to negotiate stairs reciprocally)
- may have total inability to bear weight--> fracture
Injury:
- High energy: motor vehicle accident
- Low energy: ground level fall
- pathologic: concerning if injury pattern is not consistent with mechanism, there is history of pain the the same location prior to injury, history of cancer

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Hip exam

Back 149

Inspection:
- gait: non ambulatory, ambulatory with limp (antalgic gait, trendelenberg gait, short leg gait), ambulatory without limp
-leg length, posture (seated, standing), deformity
Palpation: eval for bursitis (trochanteric, ischial), range of motion, strength
Special tests: log roll (non-specific), impingement, Trendelenberg (stand on one leg, look for hip drop--> glut. med.), Thomas test (loss of extension when contralateral leg is brought to chest-->iliopsoas, rectus femoris)
Imaging: Xray, CT, MRI (for groin pain/refusal to bear weight after fall + neg. xray), ultrasound, bone scan

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Hip fracture epidemiology

Back 150

= fracture of the proximal femur between the femoral head and the lesser trochanter
- 90-95% occur secondary to low energy mechanisms; >80% occur in women
- Rate increases exponentially with age, occur as a result of multiple risk factors (osteoporosis is a major contributor)
- overall 1yr mortality is 30% b/c of comorbidities that predispose fracture
- treatment goal is return pre-fracture functionality asap

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Hip Fracture types

Back 151

Femoral neck: Garden 1: valgus impacted, 2: non-displaced, 3: minimally displaced, 4: completely displaced; relatively high rate of fracture non-union (blood supply at risk, within the capsule, low surface area across fragments). Treat w/ repair/replace depending on patient
Intertrochanteric (w/ femoral neck 95% of all fractures): high rate of fracture union after internal fixation, an extracapsular fracture, high surface area across fracture: treat with repair
Subtrochanteric: high energy, younger population
Femoral head: rare, high energy trauma, hip dislocation; high rate of non-union (blood supply at risk, bathed in synovial fluid)

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Treatment for femoral neck fracture

Back 152

Repair (internal fixation):
- <50, non-displaced, good bone quality, less vertical fracture pattern, normal joint, normal cognitive function
Replace (arthroplasty):
- elderly, displaced head, bad bone quality, more vertical fracture, arthritic joint, compromised cognitive function

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Factors contributing to osteomyelitis

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Micro-organism entrance routes:
- hematogenous route (bacteremia)
- direct spread from contiguous site of infection (e.g. diabetic food ulcer
- penetrating wounds (e.g. pseudomonas in deep punctures, pasteurella from cat bites)
Contributing factors:
- trauma
- ischemia
- foreign bodies (e.g. surgical screws)

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Classification of osteomyelitis

Back 154

Acute:
- onset is days to weeks.
- More common in kids (with hematogenous spread especially)
Chronic:
- onset is weeks to months; can persist for years.
- Necrotic bone is common (must be surgically debrided b/c antibiotics can get to infection)
Hematogenous: bacteremic seeding of bone;
- occurs most in children (have well perfused long bones w/ slow flow, fenestrations, few phagocytes and loose periosteum (get subperiosteal infections)) but also older adults (esp. vertebral: very vascular, near Batson's venous plexus (UTI spread)) and IV drug users/patients w/ chronic lines (sternoclavicular, sacroiliac, pubic bones)
- most often involves: humerus, vertebrae (adults), femur, tibia
Contiguous: spread from an adjacent infection.
- Predisposed by traumatic and penetrating injuries, post-op orthopedic surgery, diabetic and ichemic ulcers
- most often involves: calvarium (sinus/scalp infections), mandible (dental abscess), hands (bites), femur, tibia, feet (diabetic ulcers)

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Microbiology of hematogenous osteomyelitis

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Reflects bacteremia causes in different groups:
- Children: S. aureus, Group B strep (newborns), other strep, CoNS
- Elderly: S. aureus, gram negatives (from UTIs)
- Immunocompromised or endemic exposure: fungi, or anything really
- IV drug users: S. aureus, Pseudomonas aeruginosa, Serratia
- Sickle cell: salmonella (not usually systemic in normal patients), S. aureus
- TB: any group but most often presents in the spine

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Staphylococcus aureus

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Identification:
- gram positive cocci in clusters
- rapid growth on blood agar, catalase positive, coagulase positive (differentiate from CoNS), subtle alpha hemolysis, mannitol fermentation, grow yellow colonies (CoNS grey/white)
Infections:
- carrier state: anterior nasopharynx, on skin, vagina, etc
- skin, soft tissue, bone, joints
- post surgery or trauma
- bloodstream infection: metastatic complications (bone and joint, meningitis, endocarditis, pericarditis, lung abscess, pyomyositis)
- toxin mediated disease: food poisoning, scalded skin syndrome, toxic shock syndrome with multi-organ failure
Virulence factors:
- catalase (interferes with phagocytosis)
- clumping factor, techoid acid, Proteins A/B (adherence/attachment)
- lipases (assist in abscess formation)
- leukocidin (pore formation and lysis of phagocytic cells resulting in puss and necrosis)
- toxins: toxic shock syndrome toxin-1, enterotoxins, exfoliative toxins (belong to a class of superantigens the bind HLA class II receptors and lead to dramatic cytokine liberations and systemic toxicity)

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Clinical manifestations of hematogenous osteomyelitis

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- long bones: fever, chills, and malaise + soft tissue swelling and pain, usually children
- Vertebral: neck or back pain and localized tenderness + high ESR/CRP; fever low grade or absent; watch for signs of epidural abscess (neurologic deficits)

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Diagnosis of hematogenous osteomyelitis

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Plain film: become positive after 2-3 weeks (require 50% loss of bone calcium), may take 6-8 in vertebral
- findings: periosteal elevation, areas of demineralization "most eaten" appearance, loss of sharp bony margin, soft tissue swelling, in late stages increased calcification or sclerosis from healing
CT: sensitive method
Bone scan: can detect early disease, false positives can occur, Gallium method preferred for vertebral
MRI: detects early changes and defines soft tissue abnormalities (becoming preferred method)
Bone biopsy: in children/long bone treated empirically (reliably staph/strep), in adults requires operative biopsy

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Treatment of hematogenous osteomyelitis

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Rx:
- empiric antibiotics usually avoided (except kids), require a PICC line for 4-6 weeks of therapy
Surgical debridement (if late in course, usually for long bone not vertebrae)

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Diagnosing contiguous spread osteomyelitis

Back 160

Clinical manifestations: increasing pain, mild fever and minimal drainage from existing wound
Imaging: difficult to interpret due to surrounding soft tissue infection
Microbiology: may be poly microbial--> S. aureus most common, but also strep, enterococci, enterobacteriaceae, pseudomonas aeruginosa, anarobes
Treatment: sample of tissue recommended for culture/path, debridement of necrotic tissue, empiric antibiotic therapy should be avoided, often use outpatient IV therapy

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Diabetic and ischemic osteomyelitis

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Common presentation: painless (due to neuropathy) ulcer that extend to bone (if reaches bone is osteomyelitis by definition). May have mild cellulitis and crepitance with anaerobes or enterobacteriaceae
Microbio: (mixed gram +/- and anaerobes, almost always multimicrobial)
- acute wounds: S. aureus (CA-MRSA is becoming most common and is associated with worse outcomes), β-hemolytic strep
- Chronic wounds: enterococci, obligate anaerobes, P. aeruginosa and Enterobacteriaceae
Treatment: revascularization when possible, hyperbaric oxygen, amputation or debridement often required (sometimes multiple rounds), antibiotics for 4-8 weeks depending on extent of debridement

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Acute septic arthritis

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- generally hematogenous spread, though could be iatrogenic puncture
- Most common bacteria: Staph aureus, Strep, Gram -rods, and N. gonorrhoeae
- Acute monoarticular arthritis (single, warm, inflamed joint) is septic arthritis until proven otherwise
- joint fluid usually has elevated WBC (mainly PMNs) but not specific to infection (Gout can also do this); Gram stain helpful in about 50% and culture positive 80-90%.
Therapy: joint drainage (repeat closed or open) to remove damaging inflammatory cytokines; systemic antibiotics 2-4 weeks

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Disseminated gonococcal disease

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= bacteremia due to gonococcal infection, usually causing arthritis. Most commonly in patients with asymptomatic mucosal infections.
Two clinical syndromes associated (may be overlap between them):
- Bacteremic form: tenosynovitis, dermatitis, polyarthralgia/arthritis, fever; papules and pustular skin lesions (4-40)
- localized joint form: purulent arthritis (1-2 joints)

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Neisseria gonorhoeae

Back 164

Culture: gram negative diplococci, oxidase +, inoculate immediately, growth on GC-chocolate agar in 5% CO2
- DGI strains resist bactericidal action of human serum (serum resistant)—associated with outer membrane Por lA
- DGl culture dx can be challenging. Success in only 50% synovial cultures, <30% blood cultures, 80-90% cervical swabs (women), 50-70% urethral (men)

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3 types of prosthetic joint infections

Back 165

Early (acute, <3mo):
- contiguous virulent infection (eg. S.aureus) seeded at the time of surgery.
- Presents w/ acute onset joint pain, effusion, erythema, warmth, fever
Delayed (chronic, 3-24mo): less virulent contiguous infection (ex: CoNS) seeded at the time of surgery
- Presents with low grade/subtle symptoms, implant loosening, chronic joint pain
Late (>2 yrs): hematogenous spread from a variety of sources (skin, resp, dental, UTI)

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Prosthetic joint infections: causes, diagnosis, treatment

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- occurs when bacteria are trapped under prosthesis forming a biofilm
Bacteria: 2/3 staph (most CoNS, except acute: S. aureus), then strep, gram - rods, entercocci, anaerobes, fungi (rare)
Dx: synovial fluid aspiration and culture, prosthetic tissue culture, sonification of removed prosthesis to dislodge biofilm
Tx: prothetic removal and replacement, debridgement and later replacement, long term antiobiotic (3-6 months) with agents effective against biofilms

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Other forms of arthritis related to infectious disease (not isolated joint infection)

Back 167

Chronic Septic Arthritis
- Mycobacterial: M.Tb and nontuberculous mycobacteria
- Lyme Disease (Borrelia burgdorferi)
- Fungi: Sporothrix, Coccidioides, Cryptococcus, Blastomyces, Candida
Viral agents with associated arthritis
- Often associated with traditional childhood
viruses occurring in adults: Rubella (women), Mumps (men), Parvovirus B19 (women)

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Penicillin binding proteins

Back 168

- target for β-lactam antibiotics
- have transpeptidase or carboxypeptidase activity and the act to regulate cell size and shape
- bacteria have several different proteins each with a different function that bind β-lactams preferentially. That function may be different between individual bacteriums
- numbered according to size, PBP-1 is the largest
- when inhibited by β-lactams at sublethal concentrations alters cell morphology: in E.coli PBP-2 binding causes spherical cells while PBP-3 cause filamentous growth

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Autolysins

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- responsible for cell wall turnover and permit growth
- normally produce weak point to allow for expansion of the cell wall structure.
- stimulated by β-lactams leading to breakdown of peptidoglycan and osmotic fragility and ultimately cell lysis
- autolysins in enterococci work differently so β-lactams are bacteristatic rather than bactericidal

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3 Main site for development of β-lactam resistance

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Porin protein: required to pass through outer membrane and reach cell wall
β-lactamase: hydrolize 4-member ring, preventing it from binding to target
Penicillin binding proteins: altered binding sites and sensitivities

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β-lactamases

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Plasmid mediated β-Iactamases
- Spread via conjugation
- Mutations extended spectrum to include new antibiotics
Chromosomal β-Iactamases
- Present in most bacteria (not necessarily expressed)
- Mutations of regulatory genes cause clinical resistance
- Can “jump” to plasmids

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Bacteria with resistant to β-lactams due to altered PBPs

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MRSA
- resistant to almost all β-lactams
- major pathogen in both hospital and community settings
- have the Mec A gene which codes for PBP2a conferring resistance
Penicillin resistant Streptococcus pneumoniae
- has several "mosaic" PBP's. Resistant mutants are due part from internal mutations and part from acquisition

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Resistance to β-lactams due to reduced permiability

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Nonfermentative Gram-negative Bacilli
- Outer membrane less permeable: pseudomonas 12-100 are less permeable than E. coli b/c E. coli has proteins that scavenge Fe3+ which allows β-lactam binding and entrance
Other resistance mechanisms are more effective when combined with low permeability
- Efflux pumps
- β-lactamases

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Penicillins pharmacology

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- Oral absorption varies
- Excreted by renal tubular cells
- Have short T 1/2 (30-72 minutes), requiring more frequent dosing which is a pain
- Well distributed to most areas of the body
- Enter CNS (5-10% of serum concentration) only if meninges inflamed
- Penicillin G is still effective against β-hemolytic strep and viridans strep, and drug of choice for S. pneumoniae, syphilis, N. meningitidis and many anaerobes (not bacteroides)
- Comes in IV, IM, and PO preparations

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Antistaphylococcal penicillins

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- methicillin (not used), nafcillin, oxacillin (lab), dicloxacillin (PO)
- have bulky side chains that block β-lactamase from hydrolyzing the ring
- can't cross the outer membrane of gram negative bacilli
- active against most streptococci (not the enterococci)

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Aminopenicillins

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- ampicillin, amoxicillin (moderat spectrum PCNs)
- More active than PCN against: enterococci, listeria, H. flu
- limited activity against gram negative bacilli (β-lactamases)
- Amoxicillin preferred over ampicilllin: better oral bioavailability (higher serum levels), less frequent administration (2-3xday)

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Extended spectrum Penicillins

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Includes: aminopenicillins (amoxicillin, ampicillin), carboxypenicillins, ureidopenicillins
- increased affinity to PBP's and increased entry into periplasmic space
- no increased β-lactamase stability (so often given with inhibitor)
- piperacillin prototype drug

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β-lactamase inhibitor combinations

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- inhibitors consist of chemicals structurally similar to β-lactams with weak antibiotic activity but bind irreversible to some bacterial β-lactamases allowing antibiotic to evade hydrolysis
- inhibit most plasmid encoded β-lactamases but not chromosomal ones
- All penicillin-inhibitor combinations have enhanced activity against: S. aureus (not MRSA), H flu, E. coli (most), Klebsiella (many), Moraxella catarrhalis, anaerobes (B. fragilis)
- Combination activity against nosocomial gram negative bacilli depends on the paired penicillin
- Augmentin (PO) = amoxicillin/clavulanic acid: good for URI, sinusitis, otitis, DOC for bite wound prophylaxis, diarrhea common (good anaerobic activity)
- Unasyn (IV) = ampicillin/sulbactam: not good for nosocomial gram negative bacilli; good for mixed infections: odontogenic infections, diabetic foot ulcers, aspiration pneumonia
- Zosyn = piperacillin/taxobactam: same spectrum as unasyn plus activity against nosocomial gram - bacilli (pseudomonas) due to piperacillin activity (chromosomal β-lactamases not inhibited). Good for nosocomial mixed infections (intaabdominal, resp tract)

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Bad nosocomial gram negative bacilli

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SPACE:

Serratia
Pseudomonas
Acinetobacter
Citronbacter or Klebsiella
Enterobacter

Can develop resistance to all PCNs and cephalosporins

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Cephalosporins

Back 180

- Derived from cephalosporin C
- Among the most commonly prescribed antibiotics: good safety profile, broad spectrum of activîty, favorable pharmacokinetics
- Side chains on both rings allow for many substitutions (reduced class-wide allergies)
- Divided into "generations” based on spectrum of activity (doesn't really correlate with structure). In general, have more β-lactamase stability than
penicillins
- Gaps in coverage: Enterococci MRSA, Listeria
Pharmacology: longer/more variable T½ than PCNs, mostly renal elimination, generally good oral bioavailability, variable CSF penetration (poor 1st, 2nd G, good 3rd, 4th)

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First generation cephalosporins

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Cefazolin (ancef)
- Good activity against streptococci and S. aureus
- Active against many community-acquired gram negative bacilli including E. coli, Proteus mirabilis, Kiebsiella
- Good for skin and soft tissue infections
- Most commonly used agent for perioperative prophylaxis
Cephalexin (Keflex)
- A comparable oral agent

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Third Generation Cephalosporins

Back 182

General:
- more gram - less gram + activity than earlier cephalosporins
- S. aureus activity fair but active against S. pneumoniae
- Very active against E. coli, Kiebsiella, Proteus, Providencia, Serratia BUT susceptible to chromosomal β-lactamases
of nosocomial gram-'s
- Good CSF penetration
Ceftriaxone (Rocephin):
- pharmacokinetic difference: T½ of 8 hrs, dose 1/day
- Good for: complicated UTl’s, CA-pneumonia (including pneumococcal), some nosocomial infections,
meningitis
Ceftazidime (Fortaz):
- worst gram positive and anaerobic activity of the 3rds, use only when Pseudomonas present or suspected (nosocomial infections, febrile neutopenia, DOC for Pseudomonas meningitis)

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4th generation cephalosporins

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Cefipime (Maxipime) (only one available)
- Very broad aerobic activity
- Relatively resistant to hydrolysis by chromosomal β- lactamases: active against many Enterobacter and Citrobacter isolates resistant to 3rd gens
- Good anti-pseudomonal activity
- Good gram positive activity including S. aureus (not MRSA)
- Has a role in treating nosocomial gram negative infections where resistance to other drugs is suspected or confirmed

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5th generation cephalosporin

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- new cephalosporin with MRSA activity, "Fifth Generation"
Ceftaroline
- increased binding affinity for PBP2a (mutated PBP in MRSA)
- Active against MRSA and penicillin resistant S. pneumoniae
- Gram negative activity similar to ceftriaxone
- Recently approved by FDA for skin and soft tissue infections, CA-pneumonia
- Clinical role not clear

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Monobactams

Back 185

Aztreonam (Azactam)
- Broad gram negative activity including Pseudomonas aeruginosa
- Not active against Acinetobacter (which can make it so intrinsically resistant)
- Doesn’t bind PBP’s of gram+s or anaerobes
- No apparent IgE cross-reactions with PCNs or cephalosporins (except ceftazidime) so can be used in the PCN/cephalosporin allergic patient (major role)
- In many ways, similar to ceftazidime (same side chain, same T½, same dosing schedule, similar antimicrobial spectrum)

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Carbepenems

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Meropenem (Merrem)
- Widest spectrum of any β-lactam: ability to cross outer cell
membrane, β-lactamase stability (due to stereo-conformation), high affinity to PBP’s
- Exceptionally broad activity including: most gram + cocci (except MRSA, VRE and E. faecium), most anaerobes (inc. B. fragilis), most gram - bacilli (except B. cepacia & S. maltophilia)
- multiple, potentially severe adverse reactions
- should restrict use to specifically indicated cases due growing resistance from carbapenamases

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Carbapenamases

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- most versatile β-lactamases with broad activity, more accurate carbapenem-hydrolyzing activity
- initially were chromosomally encoded, now on plasmids and other mobile genetic elements causing interspecies transfer
KlebsielIa pneumoniae carbapenemase (KPC)
- can hydrolyze β-lactams of all classes
- Located on transferable plasmids, mostly on K. pneumoniae but also reported in Enterobacter and Salmonella
- K. pneumoniae can accumulate and transfer resistance determinants creatin isolates that are often multidrug resistant

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Adverse reactions to β-lactams

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Type I: Immediate (<1hr, not >72), IgE mediated allergy
- urticaria, anaphylaxis, wheezing, laryngeal edema, hypotension
- occurs more in PCNs than CFNs, 0.2-1/10,000 courses, fatal in 1-2/100,000
- pertinent epitope is the PCN nucleus so extensive cross class allergy, but rarely between PCNs and CFNs (but still avoid if possible, monobactams OK)
Type II: IgG, IgM mediated:
- usually in long course of therapy
- drug-induced nephritis, hemolytic anemia, thrombocytopenia, neutropenia
Type III: immune complex mediated (7-14 days into therapy)
- drug fever, serum sickness
Type IV: cell mediated
- contact dermatitis (while PCNs not used topically)
Late allergic reactions (days-weeks)
- idiopathic: maculopapular rash, Exfoliative dermatitis/Stevens-Johnson syndrome, eosinophilia, vasculitis
Others: p-Iactams - Adverse Reactions
Other: diarrhea, enterocolitis, platelet dysfunction (some PCNs and CFNs), sodium overload, seizures (high dose penicillin, imipenem), elevated SGOT, superinfection (more common with broad spectrums), Jarisch-Herxheimer reaction

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Ehler's-Danlos Syndrome (EDS)--Classical

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- caused by mutations in COL5A1/2 which deal with collagen. Clinical genetic testing available
Major diagnostic criteria: skin hyperextensibility, widened atrophic scars, joint hypermobility (>= 5 on Beighton's Criteria)
Minor diagnostic criteria:
- Smooth, velvety skin, easy bruising, molluscoid pseudotumors: fleshy, heaped-up lesions associated with scars over pressure points
- Subcutaneous spheroids: small, cyst-like, hard shot-like nodules, freely moveable in the subcutis over the bony prominences of the legs and arms.
- Complications of joint hypermobility (e.g., sprains, dislocations/subluxations, pes planus)
- Muscle hypotonia, delayed gross motor development
- Manifestations of tissue extensibility and fragility (eg. hiatal hernia, rectal prolapse in childhood, cervical insufficiency)
- Surgical complications (postoperative hernias)
After diagnosis evaluate to determine extent of disease: clinical exam, joint mobility, motor development, baseline EKG w/ aortic diameter, clotting factors (if easy bruising)

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Hypermobile Ehler's-Danlos Syndrome

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- patients have haploinsufficiency of tenascin X, genes usually unknown so testing is unavailable
Major Diagnostic criteria (all clinical/history)
- joint hypermobility, often confirmed by Beighton scale >=5
- soft skin with normal or only slightly increased extensibility
- abscence of fragility or other significant skin or soft tissue abnormalities
Minor diagnostic criteria:
- positive family history, recurrent dislocations or subluxations, chronic joint limb or back pain, easy bruising, functional bowel disorders (functional gastritis, IBS), neurally mediated hypotension or postural orthostatic tachycardia, high narrow palate, dental crowding
Therapies: (mainly treatment of manifesting symptoms)
- exercise (low resistance to build muscle tone), vitamin C, vitamin D, calcium supplementation, avoid high impact force

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Vascular Ehler's-Danlos syndrome

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- associated with arterial, digestive, uterine fragility or failure
- 1/4th of individuals experience a significant medical problem by age 20, 80% by age 40. Frequently associated with sudden death (median lifespan is 48)
Pathogenesis:
- caused by mutations in proα1(III) chain of collagen III (COL3A1 gene). Clinical genetic testing available
- autosomal dominant: 50% have inherited it, 50% spontaneous.
Major diagnostic criteria:
- thin/translucent skin, extensive bruising, characteristic facial appearance
Minor diagnostic criteria:
- positive family history (or sudden death in close relative), acogeria, hypermobility of small joints, tendon or muscle rupture, talipes equinovarus, early onset varicose veins, spontaneous pneumothorax or hemothorax
Therapy: manage visceral complications, pregnancy, genetic counseling, Celiprolol (β1 blocker/β2 agonist: reduces arterial events)

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Kyphoscoliosis Ehler's-Danlos Syndrome

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Diagnositic criteria:
- generalized joint laxity
- severe hypotonia at birth
- scoliosis at birth, progressive
- scleral fragility and rupture of ocular globe
Pathogenesis:
- deficiency of lysyl hydroxylase (a collagen modifying enzyme)
- autosomal recessive mutations in PLOD1 gene. Clinical genetic testing available

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Arthrochalasia Type Ehler's-Danlos Syndrome

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Diagnostic criteria:
- severe generalized joint hypermobility
- congenital bilateral hip dislocation, developmental hip dysplasia
- tissue fragility and skin
Pathogenesis:
- mutations in COL1A1 or COL1A2 leading to abnormal processing of the amino-terminal end of proα1/2
- autosomal dominant, clinical genetic testing available

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Ehler's-Danlos Syndrome -- Dematosparaxis type

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Diagnostic criteria: severe skin fragility, sagging redundant skin, large hernias
Pathogenesis: autosomal recessive deficiency of procollagen I N-terminal peptidase. No clinical testing available (clinical diagnosis)

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Genes causing Ehler's-Danlos syndrome

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- mutations in genes encoding fibrillar collagens or collagen-modifying enzymes have been identified in most forms of EDS
- genetic and phenotypic heterogeneity
- COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, PLOD1, ADAMTS2, TNXB
- 50% of EHS patients have mutation in COL5A1/2

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Marfan syndrome

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= connective tissue disorder caused by mutations in FBN-1 gene (fibrillin) on chromosome 15 (fibrillin is important for association of elastin fibers, also can bind TGF-β--in excesses with Marfan)
Clinical manifestations:
- cardiovascular: dilatation of the ascending aorta involving the sinuses of Valsalva and/or dissection of the ascending aorta
- ocular: ectopia lentis (displacement of the lens)
- skeletal: pectus carinatum or excavatum (requiring surgery), Walker-Murdoch wrist, Steinberg thumb, scoliosis of >20%
Treatment: TGF-β blockers (in mice reduce aortic aneurysm)--losartan reduces aortic root dilatation. Unclear whether can reverse changes

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Stickler Syndrome

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Clinical features: cleft palate spectrum, midfacial hypoplasia (flattened look), high myopia leading to retinal detachment, hyperextensible joint and early onset arthritis, mitral valve prolapse, adult onset hearing loss
Cause
- caused by mutations in any of 3 collagen genes: COL2A1, COL11A1, COL11A2
- autosomal dominant, testing available

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Osteogenesis Imperfecta (OI)

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= group of heritable conditions often characterized by bone fragility and low bone mass (range of severity, prevalence 7-7/100000)
7 types described, 4 are common
Radiographic findings: wormian bones: sutural bones (in calvarium) >4x6mm, 10+ arranged in mosaic patterns
Inheritance: most types are autosomal dominant, except some rare type III, type VI (uncertain), type VII (recessive)
Genetics:
- most result from mutations that silence one gene resulting in decrease of normal collagen synthesis and/or structural defects in synthesized collagen (II, III, IV)
- most have mutations in genes for type I collagen (COL1A1/2)
Testing:
- analysis of type I collagen in fibroblasts from skin biopsy
- molecular genetic testing also available (though many genes may be involved)
Treatment: treat fractures as you would uneffected people, minimize immobility, encourage PT, intramedullary rodding, bisphosphonates?

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Osteogenesis Imperfecta Types

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Type 1: fractures with minor trauma (not before ambulatory), normal height, no bony deformity, bluish/grey scelrae, 50% develop hearingl loss in aduthood
Type II: severe perinatal lethal form. Multiple fractures in utero, multiple fractures of ribs, minimal calvarial mineralization, platyspondyly, compression of long bones; dark blue scleri
Type III: utero/neonate fractures, dentinogenesis imperfecta (grey/brown/clear teeth that wear down easily), thin ribs, platyspondylym thin gracile bones, "popcord" epiphyses, short stature, blue sclerae, hearing loss
Type IV: mild to mod. bony deformity, variable short stature, possible dentinogenesis imperfecta, sclerae normal to grey, possible hearing loss
Other types: V-VII are quite rare, all are moderate severity, normal sclerae, multiple fractures, normal hearing, no DI. Type V: hypertophic callus, Type VI: rhizomelic shortening, Type VII: bony deformity, mild short stature
In utero: mode of delivery does not effect fracture frequency, higher rate of c-section

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Achondroplasia

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= disease characterized by abnormal bone growth: short stature, large head, facial features with frontal bossing and mid-face hypoplasia
Other characteristics: hypotonia in infancy, delayed motor milestones, normal intelligence/lifespan, risk of infant death due to compression of spinal cord and/or upper airway
Genetics:
- >99% have 1 of 2 mutations in FGFR3: G1138A substitution (98%) or G1138C substiution (1%)
- overaction of FGFR3 signaling may specifically impair chondrocyte function within the epiphyseal growth plates

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Diagnostic approach for bone tumors

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Imaging:
- x-ray and CT are best: show whether lesion is bone or not and whether it is lytic, blastic, or mixed. Can also identify hallmarks: Codman triange, onion skin
- MRI: shows soft tissue involvement
- radionucleotide scan: show metastasizes
Characteristic populations and locations: many bone tumors only appear in certain population group and locations, which can be used to implicate specific diagnsoses

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Treatment for bone tumors

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Benign:
- first treat for pain: benign tumors may cause pain but will resolve on their own.
- If pain persists or other complications arise then remove the lesion
Malignant:
- Osteosarcoma: treat with chemo followed by resection. Patients with >90% tumor necrosis following chemo have much better prognosis (kills metastasizes
- Chondrosarcoma: surgery is primary treatment as these are resistant to chemo and radiation
- Ewing Sarcoma: treated with chemo followed by excision, commonly metastatic at diagnosis

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Translocation associated tumors

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- tumors that are associated with a gene translocation that causes a transcriptional activator to be inappropriately expressed due to loss of proper regulatory domain.
-Ex: Ewing Sarcoma is a translocation between chromosomes 11 and 22 causing an up-regulation

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Osteoid Osteoma

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Benign bone tumor
Age: Males, 10 – 25
Site: Femur and tibia, vertebrae
Symptoms: Pain at night, relieved by aspirin
Histology: nidus – soft and granular to densely sclerotic, peripheral cuff of hemorrhagic tissue, reactive host bone sclerosis, < 2 cm (osteoblastoma if larger)

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Encondroma/Condroma

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“En” if it’s ENside the bone, just chondroma if it’s on the outside
Symptoms: Pathologic fracture, incidental finding
Imaging: “Popcorn” calcifications
Etiology: Originate in the medullary canal, thought to be residual cartilage displaced from the physis
Histology: benign cartilage

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Osteochondroma

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Most common benign bone tumor (usually stop growing at skeletal maturity)
Benign polypoid projections from cortical bone (remains in contiguous meduallary canal)
Histology: Cartilage cap, bone marrow inside
Cartilage cap rarely becomes sarcomatous (concerning if cap >1cm)

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Osteosarcoma

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Population: mostly adolescents (M>F, 400/yr), the older people (M>F, 500/yr)
Location: almost all in metaphysis; kids: 50% knee (femur/tibia), adults: 40% axial skeleton; metastasize then go to the lungs (80%)
Presentation: pain, swelling, weight loss (disseminated disease), increased serum AlkPhos, decreased range of motion, pathologic fracture
4 border types: sclerotic (slow growing into bone, reactive new bone growth), sharp (w/o sclerosis; probs newer/faster so no sclerosis, +/- malignancy), scalloped (chondrosarcoma), ill defined (most concerning, irregular growth, could also be osteomyelitis)
Codman triangle: tumor causes lifting and destruction of the periosteum, causing reactionary formation of new (normal) bone underneath
Types: osteoblastic, fibroblastic, chondroblastic, telangiectatic, parosteal, periosteal, central low-grade, secondary
Prognosis: following surgical resection only (80-90% metastasize), fatal in 80-90% of pulmonary metastasis. Much better if use chemo first to elicit 90% cell death

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Chondrosarcoma

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Population: 35-60yrs old, M=F
Location: trunk, pelvis, long bones
Presentation: pain, swelling
Treatment: resection, resistant to chemo/radiation
3 grades: low, intermediate, high. Rarely will see dedifferentiation (abrupt transition from low to high grade in tumor), VERY poor prognosis (<5% after 5yrs)

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Ewing Sarcoma/PNET

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Population: adolescents/young adults, M>F
Location: paravertebral (ES), extremities (PNET)
Imaging: onion skin appearace
Histology: small round blue cells
Pathogenesis: caused by a t(11;22) (95%) or t(21,22) translocation resulting in gene upregulation

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Metastatic bone cancer

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Most common tumors found in bones (more common than in-situ tumors)
Most common sources: BLTKP: breast, lung, thyroid, kidney, prostate
Lytic: renal, thyroid
Blastic: prostate
Easy to identify because of gland formation in bone

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Major complaints of myopathy

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Common:
- muscle weakness: hip and shoulder girdle weakness, will complain of "hair, chair, stair weakness." Grade strength on 0-5 scale
- myalgia (muscle ache)
- fatigue
- exercise intolerance
- muscle cramping and pain
- muscle wasting (atrophy): due to loss of muscle bulk and replacement with fibrofatty infiltrate
Less common
- bulbar weakness: dysphagia, dysarthria, double vision
- dyspnea (trouble breathing) when diaphragm and skeletal muscle are involved
- rhabydomyolysis
- muscle stiffness

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Localizing clinical muscular symptom to site of lesion

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Diagnosing Myopathy

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Labs:
- creatine kinase (CK): not definitive, but suggestive of muscle breakdown. Normal does not rule out myopathy either (could be endocrine changes or congenital myopathy)
Electrophysiology (nerve conduction studies) and electromyography (EMG)
- used to localize the cause of peripheral weakness
- may assist in selection for what muscle to biopsy (won't tell what type of myopathy, but can indicate presence)
Muscle biopsy

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Different classes of myopathy

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Inherited myopathies:
- Musclular distophy: Duchenne/Becker's, myotonic
- congenital myopathy: centronuclear myopathy
- metabolic myopathy: McArdle's disease,carnitine palmitoyltransferase II deficiency
- mitochondrial myopathy
Aquired myopathy
- Inflammatory myopathy: dermatomyositis, polymyositis, inclusion body myopathy
- toxic myopathy: alcohol, Rx, etc
- Myopathy associated with systemic disease: hypokalemia, hypophosphatemia, etc

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Muscular dystrophy

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= progressive disorders characterized by chronic muscle necrosis (degeneration) and regeneration (which differentiates it from congenital myopathy)
- Hist: variable fiber size, abnormal cells (macrophages present to clear necroticc fibers), regenerating fibers (stain blue b/c of increased DNA content), fibro-fatty infiltration
- Approx 9 different types, most have abnormal proteins, different patterns of inheritance
- may also have involvement of systems outside the skeletal muscle (especially cardio: arrhythmia, dilated cardio myopathy)
- patterns of weakness, exam findings (Gower's maneuver), and family history can help with diagnosis

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Duchenne Muscular dystrophy

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- most common muscular dystrophy in childhood
- X-linked recessive mutation of the dystrophin protein results in absent (<5% of normal) dystrophin (a structural protein associated with transmembrane proteins in the sarcolemma and extracellularly. Loss results in leaky sarcolemma resulting in the inflammation cascade, degeneration, regeneration).
- Onset by 5 yrs, wheelchair bound by 12 (use steriods to prolong walking because of anti-inflammatory effect)
- associated with dilated cardiomyopathy (main cause of morbidity and mortality later in life), also diaphragm weakness and respiratory failure
Clinical: pseudohypertophy of the calfs, lumbar lordosis, heel cord shortening

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Becker's Muscular dystrophy

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- less severe form of dystrophinopathy (Duchenne MD)
- X-linked recessive, 1/30,000 male births
- variable onset between 5-15yo, wheelchair bound after 16 yrs (difference in timing from Duchenne used to differentiate disorders)
- has decreased rather than absent dystrophin production (life expectancy: 40-60's)

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Myotonic Dystrophy type I

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- most common form of muscular dystrophy in adults
- autosomal dominant with maternal anticipation, associated with trinucleotide (CTG) repeat in myotonin protein kinase gene on C19
- characteristics findings: asymmetric, distal weakness with myotonia (impaired relaxation of muscle), frontal balding, cataracts, cardiac conduction defects, central hypersomnolence, endocrine dysfunction (hypergonadism), GI hypomotility

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Congenital myopathy

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- clinically apparent myopathy, static or slowly progressive over time
- general clinical features: hypotonia (don't move well in utero), poor feeding, high-arched palate, delayed motor milestones, joint contractures, respiratory difficulty, pectus carinatum, generally normal CK level because not that much regeneration/degeneration

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Central core disease

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= congenital myopathy characterized on histology by central or eccentric "cores" of area devoid of oxidative enzymes (NADH stain), central nuclei
- autosomal dominant abnormality in the ryanodine calcium channel gene.
- Known association with malignant hyperthermia: fever, muscle rigidity and necrosis, lactic acidosis due to excessive release of calcium by sarcoplasmic reticulum. (generally associated with anesthesia from surgery)

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Metabolic myopathy

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May result from disorders of
- carbohydrate metabolism: glycogen storage diseases
- Fatty oxidation (lipid metabolism)
- oxidative metabolism via electron transport chain--disorders of mitochondrial metabolism

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McArdle's disease

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- AR defect of myophosphorylase deficiency: unable to breakdown glycogen to glucose for use in muscle. Abnormal deposits of glycogen in muscle cells visible on histology.
- Exercise intolerance with premature fatigue, stiffness/weakness in exercising muscles relieved by rest
- Can have rhabdomyolysis with intense exercise
- “second wind” phenomenon: brief rest after onset of myalgia allows resumption of activity

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Carnitine palmitoyltransferase II deficiency

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- congenital myopathy in which carnitine palmitoyltransferase is deficient (a key enzyme for transport of long chain fatty acids from cytosol into mitochondrion)
- Associated with recurrent rhabdomyolysis after prolonged fasting or exercise (these patients will have recurrent admissions)
- most common cause of recurrent myoglobinuria in adults

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Mitochondrial myopathy

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- maternal transmission
- tends to affect tissues with higher basal metabolic rates causing extra-muscular problems: retinitis pigmentosa, brain problems, SN deafness, DM, primary ovarian failure
- also effects bulbar muscles causing ptosis, abnormalities of eye movement
Ex disorders: progressive external opthalmoplegia, MELAS (mitochondrial encepholopathy with lactic acidosis and stroke), MERRF

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Inflammatory Myopathies

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Dermatomyosis:
- humoral immune process against vascular epithelium (deposition of complement C5b9 membrane attack complex resulting in ischemic muscle injury)
- increased risk of malignancy in 4 yrs before and after diagnosis
- heliotrope rash (sun sensitive skin), Grotton's papules (over extensor surfaces)
Polymyositis:
- cell mediated immune response with primary endomysial inflammation involving T-cells and macrophages (lymphocytes invade normal appearing muscle)
Inclusion body myopathy:
- most common aquired myopathy >50yo
- atypical pattern of weakness: asymmetric weakness of finger and wrist flexors, knee extensors, ankle dorsiflexors
- insidious onset: symptoms often last up to 6 years before diagnosis
- Hist: red-brim vacuoles, necrosis with secondary fatty infiltrate

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Causes of toxic (drug induced) myopathies

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- alcohol
- cholesterol-lowering drugs (statins and fibric acid derivatives)
- colchicine (used for gout)
- glucocorticoids
- AZT
(difficult to determine if myopathy is toxic vs. genetic vs. acquired)

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Myopathies associated with systemic disease

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Hypokalemia (causes periodic paralyis)
Hypophosphatemia
Critical illness myopathy
Myopathy associated with endocrine disorders
- Thyroid disease (hypo- and hyperthyroidism)
- Parathyroid disease (hypo- and hyperparathyroidism)
- Adrenal disorders (hypercortisolism and insufficiency)
- Hypopituitarism
-Acromegaly

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Differentiating between causes of muscle pain

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Myopathic pain
-usually with high Creatinine phosphokinase (CPK) and/or abnormal Electromyography (EMG); weakness common
Polymyalgia syndromes
- Muscle pain without weakness: Pain may interfere with effort
- Pain: Present at rest; ± increased with movement
- Muscle tenderness: Diffuse or Multifocal
- Serum CPK: Normal (no damage)
- No pathologic changes in muscle

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Polymyalgia Rheumatica

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Diagnosis:
- Persistent pain (> 1 month) involving two of: neck, shoulders, pelvic girdle
- Morning stiffness (>1 hour in duration), particularly in muscles of neck, shoulder and pelvic girdles
Abrupt onset of illness (< 2 weeks)
- Age: 50 years
- Erythrocyte sedimentation rate > 40 mm/hr
- Rapid response to low dose prednisone ( 20 mg/day)
- Absence of other disorders
Epidemiology: F>M, age >50 average is 70, higher incidence in patients of northern european descent
Genetics/Pathogenesis:
- HLA-DR association; genetic polymorphism in intercellular adhesion molecule 1, TNF< IL-1
- likely multiple genetic/envi factors (not known) cause activation of the innate immune system including circulating monocytes that produce IL-1, IL-6, TNF
- Labs: elevated ESR/CRP, thrombocytosis, normal CK & aldolase, anemia of chronic disease (normochromic/cytic), negative ANA/RF

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Fibromyalgia

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= soft tissue pain disorder without evidence of inflammation of or tissue pathology
Clinical features:
- widespread pain and tenderness: waxes and wanes and can be migratory
- many non-specific, non-musculoskeletal symptoms also present (ex: fatigue, sleep difficulty, migraine, etc)
Diagnosis:
- history of chronic, widespread pain involving all four quadrants of body and axial skelton
- presence of 11/18 "tender points"
Epidemiology: 4% of pop., 30-55yrs, 10:1 F:M, 8x increased risk w/ 1st degree
Pathogenesis/etiology: unclear, perhaps aberrant CNS pain perception, autonomic dysfunction; physical or emotional triggers may precede/aggrevate symptoms
Treatment: education, Rx for sleep/pain (anti-inflam/analgesics, CNS active), non-Rx (exercise, cognitive behavioral therapy)

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Rheumatoid arthritis

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= a disease of aberrant immune response in a genetically predisposed individual leading to synovial inflammation and destruction of the joint
Epidemiology: 1% of pop., 2.5:1 F:M, peak incidence 35-50yr (in M <45 is unusual), increased risk w/ 1st degree relatives
Genetics: not a disorder of single or high-penetrance genes, genes not sufficient for disease (loss of tolerance, exogenous trigger-smoking, age), association with HLA-DR4 (northern european)

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Rheumatoid arthritis joint destruction

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- involves all structures of the joint (ligaments, tendons, cartilage, bone)
- destruction is a result of increased inflammatory mediators and enzymes in the joint: cytokines (TNF, IL-1, IL-6, RANKL), proteinases (matrix metalloproteinases), cathepsins
Pathogenesis: underyling genetics/environmental factors activated the innate immune system causing antigen loading; antigen presenting cells (dentritics, macrophages, fibroblast-like synoviocytes) migrate to lymph, activate and recruit T cells and B cells (antibody production). Feedback loop of activation perpetuates release of inflammatory cytokines in joint and synoviocyte/osteoclast proliferation
- overall: hypertrophic synovial membrane and synoviocytes with angiogenesis to the joint, then late in disease inflammatory infiltrates (leading to erosion of joint), hypertrophied synovium (pannus), extensive angiogenesis

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Rheumatoid factor (Rf)

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- autoantibody produced in RA with specificity for the Fc fragment o IgG
- not present in all patients with RA, but associated with more severe disease course and extra-articular manifestations
- may be present in healthy patients and those with other inflammatory diseases and infections

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Clinical features of Rheumatoid Arthritis

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Diagnostic criteria: must satisfy 4/7 with duration at least 6 weeks
- morning stiffness (lasting hours)
- arthritis of 3 or more joints
- arthritis of hand joints (usually spares the DIPs, involves MCPs, PIPs)
- symmetric arthritis
- rheumatoid nodules
- serum rheumatoid factor
- radiographic changes
Clinicial features (not diagnostic)
- malaise and fatigue (may be prodrone)
- stiffness, improves with activity
- swelling (effusion/synovial thickening)
- symmetric arthritis
- rheumatoid nodules; usually in RF+, more severe cases; develop at points of pressure, unclear trigger (can clear arthritis but exacerbate nodules)
- deformity: swan-neck, boutonniere, "trigger" finger, arthritis mutilans, MCP subluxation, ulnar deviation, "hammer toes"
Extra-articular manifestations: multiple in many body systems. Occasionally will present with these first (ex: Felty's RA/leukopenia/splenomegaly)
Labs: ↑ESR/CRP, anemia, thrombocytosis, +RF (80-85%), anti-CCP, joint fluid >2000 WBC, Xray: pariarticlar osteopenia, marginal erosions, ulnar deviation, C1-C2 subluxation around dens (causes head drop)

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Osteoarthritis

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= a degenerative joint disease of the elderly caused by any thing that causes alteration of the joint (trauma, infection, crystal disease, neuropathy, etc)
- Focal loss of articular cartilage in part of the synovial joint is accompanied by a hypertrophic reaction in the subchondral bone and margin of the joint. Occurs most in knees, hips, hands, and apophyseal joints of spine
- not a systemic inflammatory disease, but local inflammation plays a role.
Phases:
- Edema and microcracks: edema of intermediate layer of ETC, loss of smoothness, focal loss of chondrocytes (other areas of proloferation)
- Fissuring and pitting: deepened cracks, verical clefts
- erosion: exposure of subchondral bone, mild synovial inflammation, sclerosis of bone, formation of fibrilar cartilage

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Normal vs. aging cartilage

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Normal:
- ETC composed of collagens (II, IX, XI), proteoglycans (aggrecans + glycosamineglycan chains that bind water)
- chondrocytes
Aging
- shorter glycosaminoglycans (decreased water content)
- altered resistance to mechanical loading
- fissure due to stress fractures of the collagen network

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Pathogenesis of osteoarthritis

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- failure of chondrocytes to produce a quality matrix after damage: dedifferentiation of chondrocytes, shift toward types I, III, X cartilage, shortened proteooglycans
- imbalance between synthesis and degradation of extracellular matrix due to increased synthesis of proteinases (MMP's) and decreased synthesis of tissue inhibitors of them (by active chondrocytes)
- synovial cells become inflammed from the intra-articular fragments and become capable of producing MMPs and cytokines (IL-1 and others) that alter the matrix and activate chondrocytes

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Clinical features of osteoarthritis

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- use related joint pain, gelling of the joints after inactivity, loss of range of motion
- bony overgrowths: Bouchard's (PIP) and Heberden's (DIP) nodes, spares MCPs (should be bony and hard, not warm or boggy)
-mal-alignment of joints: varus (loss of medial joint space)/valgus (loss of lateral joint space)
- mild effusions
- crepitus (rough opposing surfaces)
Labs:
- normal: ESR/SED, hemocrit
- joint fluid: <2000 (usually 100's)
- x-rays: bony proliferation (osteophytes and spurring) at the joint margin, asymmetric joint space narrowing, normal mineralization, no divots or chunks

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Mechanism of gout

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Overproduction (10%)
- increased nucleic acid turnover: Paget's disease, psoriasis, hemolytic anemia, myeloproliferative/lymphoproliferative disorders, chemo therapy
- Derangements in purine synthesis: defects in HGPRT (deficiency; scavenges hypoxanthine/guanine) or PRPP synthase (superativity; converts ribose 5-P to PRPP)
Under excretion (90%)
- hereditary factors
- medications: diruetics (decreased renal excretion), cyclosporin, low dose aspirin
- other: lead intoxication, increased organic acids (ketoacidosis, lactic acidosis, alcohol intoxication), hyperinsulinemia (increases tubular reabsorption)

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Pathogenesis of inflammation in gout

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- Intra-articular crystals can induce gout-like attack but are not pathognomonic
- In active flare the immune system is activated by crystals (trying to get rid of it)
- Cryopyrin (NALP3) inflammasome is key in inflammatory response to crystals: results in the production IL-1, IL-18
- Influx of neutrophils leads to development of acute crystal-induced synovitis: Impaired neutrophil influx is found in an in vivo model

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Gout

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- acute and/or chronic inflammatory response to the formation of monosodium urate monohydrate crystals
- hyperuricemia is usually present
- manifestations include arthritis, tophi, renal stone, neuropathy
Epidemiology: onset: males 40-50, postmenopausal women, 5:1 M:F

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Clinical presentation of gout

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Clinical features:
- painful, red swollen joint(s) or bursa (olecranon bursitis)
- appearance of cellulitis or septic joint
- fever and leukocytosis may occur
- First MTP most commonly effected (Podagra) first
- tophi in chronic forms (distal joints, bursa, pinnae)
- variants: episodic monoarticular (very common), polyarticular, tophaceous with joint destruction
- often mistaken for osteoarthritis in elderly women
Joint fluid analysis:
- cell count can be >50,000
- culture (septic arthritis and can co-exist, the former may trigger the latter)
- examination for crystals: needle shaped, yellow parallel to red compensator
X-ray: normal mineralization, punched out erosions with sclerotic borders, overhanging edges

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Innate vs adaptive immunity

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Innate:
- physical barriers (anti-microbial peptides)
- complement
- phagocytic cells: clear pathogens, release inflammatory mediators and chemokiness
Adaptive
- cannot be initiated without the innate
- T cells always require APC's, B cells can be partially activated directly by free antigen (but need terminally differentiated T cells for full activation)
- T cells: CD8 (MHCI), CD4 (MHCII)

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Antigen recognition

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Antigen = any substance that triggers immune response (bacteria, meds, crystals, endogenous proteins, etc)
- B cells can bind antigens directly via B cell receptors located on cell surface (no APC needed) but then need T helper cells for full activation
- T cells recognize antigen bound to MHC on APCs, must also have co-stimulatory activation by CD28 binding to B7

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MHC1 vs MHC II

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MHC I
- nearly ubiquitously express on host cells (except RBCs because no nucleus)
- recognized by cytotoxic CD8 T cells
- coded or by HLA A, B, C
- mutations implicated in ankylosing spondylitis (B27) and acute anterior uveitis (B27)
MHC II
- only presented on APCs (macrophages, dendritic cells)
- presents extracellular pathogens, prepared by phagocytosis and degradation within the APC
- interacts with helper CD4 T cells to initiate activation and clonal exapansion
- coded for by HLA DR, DP, DQ
- mutations implicated in RA (DR4), and Lupus (DR3) leading to defective immune tolerance and autoimmunity

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Mechanisms of immune self tolerance

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Central tolerance:
- clonal deletion of self-reactive lymphocytes within the primary lymphoid organs
- B cells expressing IgM undergo negative selection for self molecules in the bone marrow
- T cells undergo negative selection for self-proteins and positive selection for self MHC in the thymus
Peripheral tolerance:
- terminally differentiated cells in the periphery are deleted if they are not actively stimulated by antigen
- B cells undergo receptor editing (changes specificity for antigen, preventing autoimmunity and increasing avidity for antigen)
**loss of self tolerance leads to autoimmune disease**
Immunologically privileged sites:
- brain, eye, testes, uterus
- high risk of autoimmunity if barrier is damaged because these areas are not self-tolerated
Alteration of proteins by inflammation, drug exposure or normal senesence cause immune response to normal self-proteins
Molecular mimicry: pathogenic antigens that look like self antigens trigger response that then targets self (Rheumatic fever, Guillain-Barre syndrome from camplobacter)

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Antinuclear antibody test

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= screening test for autoreactive antibodies to nuclear components in the patient's serum. Indicates autoimmune disease if positive (very sensitive but not specific)
- traditionally done with immunofluorescence resulting in staining patterns suggestive of the antigens present
Staining patterns:
- speckled: (most common), antibodies against extractable nuclear antigens (Smith, Ro, La)
- diffuse/homogenous: (2nd most common), antibodies against histone and topoisomerase I
- Rim/peripheral: (specific for SLE), antibodies against dsDNA
- Centromere: (relatively specific for CREST/limited systemic sclerosis), antibodies against centromeres (count 23 dots in not in metaphase)
- Nucleolar: (relatively specific for scleroderma), antibodies against nucleoli (RNA associated antigens)
**ANA also now being done with ELIZA because cheaper, only tests for 10 antigens (out of 150), so if negative get fluorescence (gold standard)

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Rheumatoid factor

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= any immunoglobulin that binds to the constant (Fc portion) of IgG, mostly commonly IgM
- not a postitive test for Rheumatoid arthritis (only indicates upregulation of the immune response: inflammation)
- present in 80% of RA patients, but also present in healthy people, also present in other diseases and infections

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Anti-CCP

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= test measuring the level of citrullinated peptides in the blood
- within joints enzyme peptidylarginine deaminase (PAD) converts arginine to citrullin. Citrullinated proteins can bind HLA DR4 with higher affinity, perhaps leading to the development of autoimmune response
- more specific than Rf for RA

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CRP

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= test for inflammation by measuring C-reactive protein (from c-polysaccharide of pneumococcus) synthesized in the liver, which is elevated after injury, peaks after 2-3 days then returns to normal
- indicates chronic inflammation
- more expensive than ESR by but better test

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Mechanism for treatment of inflammation with corticosteroids

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Classical:
- steroid binds to receptor inducing conformational changes that exposes DNA binding domain. Recptors dimerize, travel to nucleus and bind DNA at glucocorticoid response element (GRE) leading to recruitment of Tx factors and RNA polymerases, resulting in upregulation of many proteins, particularly anti-inflammatory ones
- ex: increased lipocortin tx, which acts on phospholipase A2 preventing phosphorylation of arachadonic acid and reducing eicosanoid production
Adapted/protein interference
- glucocorticoid receptor complex binds tx factor family p50 and p65 on NfKB element of DNA, shutting off downstream genes, particularly those that code inflammation
- ex: reduces expression of COX-1 and COX-2 which are required to convert arachidonic acid into protanoids

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Therapeutic/diagnostic uses and adverse effects of corticosteroids

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Therapeutic:
- anti-inflammatory: Classical--blocks ecosinoid production by inhibiting PLA2. Adaptive-- prevents expression of COX1/2
- suppression of immune system: block synthesis/release of inflammatory mediators, supresses activation of T cells/cytokine production, inhibit leukocyte and macrophage function, reduce the number of lymphocytes, monocytes, eosiophils and basophils in circulation
- HRT (horomone replacement therapy): for treating Addison's (adrenal insufficiency) use hydrocortisone IV for primary, cortisol for secondary
Adverse effects
- metabolic: promotes glucose formation in liver and inhibits use in periphery leading to increased protein and fat catabolism which inhibiting Ca++ absorption and osteoblast formation/activity, also causes salt retention and hypertension
-Overdose from over use (Cushings): characteristic body: obese trunk w/ peripheral wasting, lead to peptic ulcers, hypertension, diabetes, physical/mental growth deficits in children. Diagnosed by elevated urine cortisol
- Withdrawl (Addison's): must wean carefully as body becomes dependent on exogenous hormone and does not produce enough leading to acute adrenal insufficiency

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3 Classes of glucocorticoids

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Short acting: weakest anti-inflammatory, high level of salt retaining activity (80% bound to cortocosteroid-binding-globulin in circulation). Best for treating adrenal insufficency
- cortisol
- cortisone
Intermediate acting: intermediate salt/anti-inflammatory activity (use for anti-inflammation/immunosuppression)
- prednisone
- prednisolone
- methylprednisone
Long-acting: most potent anti-inflammatory, minimal salt retention (do not bind CBG in ciruculation so fully active, like aldosterone) (use for anti-inflammation/immunosuppression)
- dexamethasone
- betamethasone

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Classes of NSAIDs

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Non-selective: inhibit both COX1/2
- good as anti-inflammatory, anti-pyretic, analgesic agents because inibit prostoglandins
- slight disadvantage b/c COX-1 not limited to inflammatory sites (essential for prostogladin production and gastric epithelial defense (mucus/bicarb secretion)--> gastric ulcers/bleeding risk)
- Irreversible: aspirin, covalently acetylates COX-1/2. Cell must make new protein to recover
- Reversible: indomethacin, naproxen, sulindac, reversibly bind active site of COX-1/2, shorter term of action good for transient pain
Selective: only inhibit COX-2
- celebrex (celecoxib) and Vioxx (rofecoxib, recently withdrawn for side-effects)
- reduce peptic ulcer risk
- increased risk for cardiovascular issues (MI, CVA, thrombosis), not mechanistically well understood
Unclear mechanism: weak inhibitors of both COX-1/2
- acetominophen: thought to work on specific COX isoform in the brain (not identified)
- good for fever pain, NOT anti-inflammatory

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Targets of gout therapy

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Under excretion of uric acid:
- Probenacid: inhibits renal tubule reabsorption of uric acid
Over production of uric acid:
- Allopurinol: inhibits xanthine oxidase production of uric acids
Inflammation: (good for treating acute attacks, don't address underlying symptoms)
- NSAIDs: prevents inflammatory response to crystals, preventing cylic inflammation activation in acute attack
- colchicine: prevents inflammation cycle in acute attack by inhibiting migration of leukocytes to site

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Colchicine therapy for gout

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Uses: relief from acute gouty attacks, abort pending attacks, prophylaxis when initiating maintenance therapy (which can transiently activate early phase crystal mobilization)
Mechanism: inhibits inflammatory cycle (synovial crystrals trigger inflammation, ↑synovial lactate, ↓pH, ↑crystal deposition, ↑ inflammation...) by disrupting cellular microtubules preventing migration of leukocytes to inflammed tissue
Toxicities: prominent GI distress, bone marrow depression, alopecia, affects all cells that require microtubules, overdose leads to life-threatening hemorrhagic gastroenteritis

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Probenecid therapy for gout

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Uses: chronic maintenance, reduce hyperuricemia, tophi resorption, not for acute attack
Mechanism: weak acid that is uricosuric: blocks anion exhange of uric acid in the renal tubules preventing reabsorption
Toxicities: initiation of therapy can lead to increased frequency/severity of attacks (take colchicine prophylactically when starting). Can lead to deposition of crystals in kidney/ureters (treat with high water intake)

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Allopurinol therapy for gout

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Uses: chronic maintenance, reduce hyperuricemia and frequency of acute attacks, good for patients with gouty nephropathy
Mechanism: structural analog of hypoxanthine (and oxdized form alloxanthine/oxypurinol) that competitively binds xanthine oxidase preventing metabolism of purines to uric acid.
Toxicities: initiation of therapy can lead to increased frequency/severity of acute attacks (take colchicine prophylactically when starting). Prevents the inactivation of mercaptopurine by xanthine oxidase (implications for MCP therapy/toxicity)

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NSAIDs for Gout vs. RA

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Same
- have similar analgesic and anti-inflammatory effects in both
- does not treat the underlying disease in either: uricemia in gout, immune self-reactivity in RA
- same risk for side effects, low cost
Differences
- Aspirin is not indicated in gout but is in RA
- NSAIDs are for acute treatment in gout but are used for chronic management of symptoms of RA

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Methotrexate therapy in RA

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Mechanism:
- Inhibits dihydrofolate reductase (decreases the amount of folate in the body, resulting in decreased DNA synthesis)
- Inhibits lymphocyte proliferation and cytokine production
- Interferes with migration of leukocytes
Characteristics:
- Drug of choice for most RA patients
- benchmark against which other agents are compared
- An anchor agent in combination therapies
- Rapid onset of action (benefit observed in 2-3 weeks)

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Etanercept therapy for RA

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Mechanism:
- TNF-α antagonist: Blocks the action of TNF-α, which is a pro-inflammatory cytokine
Characteristics:
- Soluble TNF-α receptor-Fc fusion protein
- Injected subcutaneously twice a week
- Very expensive

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Anakinra therapy in RA

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Mechanism:
- Recombinant IL-1 receptor agonist (IL-1Ra): Competitively inhibits the binding of IL-1 (pro-inflammatory cytokine) to IL-1R1 (IL-1 receptor). IL-1 is a primary cytokine associated with RA
Characteristics:
- given subcutaneously
- response seen within 4-13 weeks

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Abatacept therapy for RA

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Mechanism:
- T-cell co-stimulatory blocker: Binds to CD80/CD86 and blocks their interaction with CD28, a costimulatory signal necessary for full activation of T lymphocyte
Characteristics:
- A fusion protein of the extracellular domain of CTLA4 (CD154) with the human Fc portion
- Good for moderate to severe RA (Those that aren’t benefitted from MTX/TNF antagonist therapies)
- Intravenous infusion
- Response seen within 3 months

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Disease modifying antirheumatic drugs (DMARDs)

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Immunosuppressive agents: MTX, Leflunomide, Azathioprine
Other secondary agents: hydroxychloroquine (antimalarial, best for mild RA w/ NSAID, possible retinopathy)
Gold compounds: auranofin (oral, unclear mechanism, lots of adverse reactions)
Glucocorticoids: prednisone (only as background therapy, infrequent/low dose therapy)
Cytokine antagonists: etanercept, infliximab, anakinra
T-cell costimulatory blockers: abatacept

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Leflunomide therapy for RA

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Mechanism:
- inhibits dihydrofolate dehydrogenase in pyrimidine synthesis, thus preventing DNA replication and the synthesis of RNA in immune cells)
Characteristics:
- mainly an alternative to MTX
- expensive

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2 mechanisms of damage in SLE

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Inflammation:
- autoantibodies form immune complexes that drive complement, triggering inflammation
- innate susceptibility (genes, female gender, environment) lead to abnormal innate and adaptive immune responses to self-antigen leading T/B cell activation and autoantibodies, immune complexes and inflammation. Chronic inflammation and oxidative damage leads to renal failure, atherosclerosis, stroke, pulm fibrosis, etc
Clot formation
- autoantibodies to phospholipids can lead to clots: antiphospholipid syndrome.
- increased risk of both venous and arterial thrombosis
- increased pregnancy morbidity: increased miscarriages esp. 2/3 trimesters
- test with: anti-cardiolipin antibodies (can create false + in syphilis test in these patients), lupus anticoagulant (antiphospholipid antibodies prolong PTT time, but still have tendency for thrombosis, not bleeding)

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Clinical findings of SLE

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SOAP BRAIN MD (need 4/11, mostly for classifying patients for studies)
Serositis: pleuritis or pericarditis (immune mediated inflammation of the serosa in heart and lungs)
Oral ulcers: oral/nasopharyngeal lesions, often painless, any part of the mucosa including hard palate
Arthritis: non-erosive, potential for deformity but not bony damage (looks like RA but w/o erroded joint space)
Photosensitivity: can be triggered on non-exposed surfaces by exposure elsewhere (antibody production), hand rash w/ knuckle sparing
Blood disorder (hematologic): particularly hematologic anemia, leukopenia, lymphopenia, thrombocytopenia
Renal disorder: from inflammatory attack of glomeruli causing proteinuria, cellular casts (red cells through glomeruli)
- ANA
- Immunologic disorder: other autoantibodies present: anti-dsDNA, anti-SM, anti-Ro/La, anti-RNP, anti-phospholipid antibodies
Neurologic disorder: blackout (from inflammation), seizures, psychosis, thrombotic events (CVA)
Malar rash
Discoid rash

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Cutaneous manifestations of SLE

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Isolated cutaneous lupus: skin involvement with no systemic symptoms
- discoid lesions (leave scar) on scalp, face, ears (chonchal bowl), will have overlying keratotic scale, follicular plugging/prominent orifices, atrophy, and variable pigmentation
- more common in women of childbearing age
SLE
- Malar rash: fixed erythema, patches/plaques with naso-labial sparing, no scaring
- Lupus finger rash: erythema on dorsum of hand on distal portion that usually spares joint surfaces
- discoid rash (see above)
- oral ulcers: oral or nasopharyngeal, self-limited, often on hard palate (rather than mobile in aphthous ulcers, painless
- Raynaud's syndrome: cold-induced hypopigmentation/vasoconstriction of the distal digits
Periungual telangiectasia: small dilated blood vessels on the surface of skin in the proximal nail folds
- vasculitis: palpable purpura (due to immune complex formation causing damage to veins and mass extravasation of RBCs)
- photosensitivity: damage on sun-exposed surfaces with sparing on non-exposed surfaces (eyelids, behind ears, submental)

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Histologic findings of SLE

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- fat PMNs with phagocytosed nuclear material
- this occur because the patient has anti-nuclear antibodies in serum that coat nuclear material after a cell has undergone apoptosis. The antibodies then attract PMNs to ingest the material and trigger abnormal immune cascade and inflammation

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SLE

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- a chronic inflammatory systemic autoimmune disease of unknown etiology characterized by production of antibodies to components of the cell nucleus (ANA) and deposition/formation of immune complexes in tissues causing a variety of manifestations (due to diffuse sites of attack)
Epi: 9:1 F:M, peak incidence 15-40 (estrogen probably involved), possible genetic susceptibility (some concordance in twins, <100%), environmental factors (UV light, drugs, smoking, silica, etc)
Complications:
- early: infections, renal failure, CNS involvement, effect of treatment
- late: atherosclerosis and stroke (due to chonic vascular stress and inflammation: arterial inflammation, antiphospholipid syndrome, drugs, hypertension, DM)
- Increased risk for pregnancy: late term miscarriage or transfer of antibodies causing neonatal lupus: risk of congenital heart block, thrombocytopenia, anti-ro antibodies
Treatment: NSAIDs, steroids, hydroxychloroquine, azathioprine, methotrexate, cyclophosphamide, anti-coagulation treatment (if needed), sun avoidance

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Morphea

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= localized cutaneous scleroderma
- not associated with systemic sclerosis
- not life threatening
- affects proximal rather than distal surfaces
- presents as erythematous, palpable plaque, induated skin (firm), often asymptomatic and resolve without treatment
- histologically appears similar to system sclerosis: normal epiderms and stratum corneum, but with extensive collagen deposition in the dermis and loss of epidermal appendageal structures

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Scleroderma

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= disease of unknown etiology characterized by extensive fibrosis, or excessive collagen production in the dermis and other tissue.
- Progression of disease begins with endothelial damage leading to vascular change, promoting inflammation which stimulates a fibrotic response and excessive collagen deposition by fibroblasts

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Systemic scleroderma cutaneous manifestations

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Limited: CREST, only skin, usually distal upper extremities; Diffuse: widespread skin involvement
- Calcinosis: cutaneous deposits of calcium, typically around joints (rock hard nodules, painful to compression), induced by trauma or other connective tissue disease
- Raynaud phenomenon: cold induced episodic vasoconstriction of small arterioles and arteries in the distal fingers. Characteristic progression from white (cyanotic) to blue to red (re-perfusion)
- Esophageal dysmotility
- Sclerodactyly: fibrotic changes surrounding the IP joints in fingers. Begins with edema/inflammation leading to vessel damage (causing ischemia → distal pits and ulcers → necrosis and auto-amputation of digit) and fibrotic skin (loss of appendages and "bound down" dermis→ contractures and waxy/hard appearance)
- Telangiectasias: mat (no visible feeder vessel) rather than spider, also dilated capillary loops in proximal nail folds
Also in diffuse:
- facial disfigurement: microstomia (pursed mouth), lip retraction, beaked nose
- leukoderma: "salt and pepper" discoloration, spares follicular orifice, usually involving face/scalp/upper trunk/arms

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Non-cutaneous manifestations of scleroderma

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- in Diffuse tightening of skin on upper arm and chest (as opposed to distal in Limited)
- in Diffuse risk of severe pulmonary fibrosis: fibrosis in alveoli in lower lungs causes decreased gas transfer, restricted expansion, pulm. vasculopathy, pulm. hypertension (high mortality, but if isolated w/o fibrosis→ CREST). Manifests as dyspnea on exertion (w/in 3 yrs of onset). Test w/ pulm function, x-ray, ascultation
- GI syptoms (both): esophageal dysphagia, reflux (due to fibrosis around neuromuscular complexes→SM atrophy + fibrosis→ dilated, fibrotic, patulous esophagus), gastroparesis (vomiting, constipation, bacterial overgrowth, pseudo-obstructiosn), wide-mouth diverticuli**, vascular abnormalities (watermelon stomach)
- Cardiac: myocardial fibrosis and sclerosis (independent of CAD), also pericarditis (with non-painful effusions), conduction system disease/arrythmias, Raynaud's, dilated capillary loops/ischemic areas
- Renal: scleroderma renal crisis (Diffuse only): malignant hypertension (decreased perfusion leading to renin release), renal insufficiency, microangiopathic hemolytic anemia (RBCs sheard by fibers across the vessel). Used to be fatal to kidneys
- MSK: pain, symmetric arthralgias and arthritis, calcinosis, muscle atrophy and weakness, coarse tendon friction rubs **(diffuse only), osseous resorption of the digital tuft

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2 clinical presentations of scleroderma

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Diffuse:
- onset of changes within 1yr of Raynaud's
- truncal and acral skin involvement
- early and significant interstitial lung disease
- scleroderma renal crisis
- diffuse GI disease and myocardial involvement
- coarse tendon friction rubs
- 30% incidence of anti-Scl-70 antibodies (against topoisomerase)
Limited:
- longer duration of Raynaud's before onset of skin changes (years to decades) and slower progression
- relatively limited skin involvement, mostly distal surfaces, CREST
- significant late incidence of pulmonary hypertension, some GI/cardiac manfiestations
- high incidence of anti-centromere antibody

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Findings associated with poor prognosis in scleroderma

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- diffuse scleroderma vs. limited
- pulmonary fibrosis: irreversibly damage to lungs, reduced function expansion/O2 exchange, pulmonary hypertension (often unnoticed until fatal)
- fibrosis of cardiac tissue: conduction abnormalities→ arrhythmias, fatal cardiac events
- Sleroderma renal crisis: was uniformly fatal to kindeys, now treated with ACE inhibitors `

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Treatment for scleroderma

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Targeted for clinical manifestations:
- Renal: monitor BP, ACE inhibitors
- GI/GERD: PPI, H2 blockers, prokinetic agents
- MSK: NSAIDs, PT/OT, low dose steroids (watch BP/Renal function)
- Raynauds: smoking cessation, keep core warm, calcium channel blockers, angiotensin receptor blockers
- Pulm: immune suppression (cyclophosphamide, steroids), transplant
- Pulm Hypertension: O2, calcium channel blockers, prostacyclin derivatives, endothelin antagonists

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Cutaneous manifestations of dermatomyositis

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- Heliotrope sign: periocular edema and violaceous color
- Gottron's papules(palpable)/sign (not-palpable): erythema on knuckles. Often discrete, flat topped, slightly scaly papules on the DIPs/elbows
- Periungual erythema: dilated capillaries with "bushy tufts" and intermittent ischemic areas
- Cutaneous calcinosis: more severe than scleroderma
- Shawl sign: erythema on chest and back
Histology:
- thickened stratum corneum (hyperkeratosis), hypergranulosis, marked inflammation around the dermal interface (due to lymphocytic attack of the basement membrane)

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Clinical presentation of dermatomyositis

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Clinical features:
- bilateral, symmetric muscle weakeness (PAINLESS): more proximal, more lower extremities (chair/stair weakness), dysphagia (weak pharynx muscles), dysphonia (weak vocal cords)
- interstitial lung disease and progressive weakness of diaphragm (cardiac often involved, rarely symptomatic)
- cutaneous signs: heliotrope sign, Gottron's sign, cutaneous calcinosis, periungual edema, shawl sign
Lab:
- elevated muscle enzymes: CPK, SGOT (serum glutamate oxaloacetate), SGPT (serum glutamic pyruvic transaminase), aldolase (ALD)
- myositis specific antibodies: Anti-Jo-1 (against transfer RNA synthetase: poly or dermomyositis, generally mores severe disease), Anti-Mi2 (against nucleosome, generally better response to treatment/prognosis)
Other studies:
- EMG: for biopsy localization
- MRI w/ STIR: identify inflamed muscle for biopsy
- X-ray: lots of calcifications and corresponding erosions
- Muscle biopsy: inflammatory infiltrate around blood vessels and nearby peripheral muscle fibers (not in fibers as with polymyositis)

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Inflammatory response in dermatomyositis

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- involves both humoral and cell-mediate immune mechanisms
- abnormal immune stimulation (molecular mimicry?) results in B cells and CD4 T cells migration/aggregation in the periphery of affected muscles contributing to the inflammatory response (predominant cells in perivascular area)
- Complement components C5-9 (forming the membrane attack complex) are up-regulated in peripheral muscle
- Together these factors result cytokine release and decreased blood flow leading to ischemia in muscle tissue causing damage (perifasicular atrophy) followed by angiogenesis and muscle repair (in polymyositis muscle fibers are directly attacked by CD8 t cells)

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Treatment for dermatomyositis

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- Corticosteriods: for rapid immune/inflammatory effects
- long-term immunosuppression: MTX, azathiopine
- IV Ig: exact mechanism not understood, used early in disease

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Potentially harmful causes of back and leg pain

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Leg (radicular): (better w/ forward flexion)
- herniated disc: can cause radiculopathy (compression of nerve at that level) leading to clumsiness of hands, gait dysfunction, weakness, bowel/bladder dysfunction (eval w/ T2 MRI)
- spinal stenosis: (worse walking/standing, better sitting/forward flexion--shopping cart sign. Will persist until sitting unlike vascular) central, lateral recess or foraminal stenosis (thickened ligamentum flavum or facet joints)
Chonic back (axial) pain: mosly diagnosed through maneuvers, worse w/ forward flexion
- discogenic: midline pain, worse w/ sitting/forward flexion
- facet: zygapophyseal, tender to palpation
- sacroiliac: usually below L5, present on butt or radiate to legs
(vertebral compression)

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Big challenges of treating JIA, SLE in peds

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- Children are not adults: different H&P, treatment goals, interaction with parents/family/school
- Different clinical presentation than adult forms of disease
- SLE: problems w/ body image w/ disease and treatment
- Problems transferring to adult care (need to master medical, social, education/vocational, financial aspects of disease)

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Clinical and serological differences between RA and JIA

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Age: JIA <16 (peak around 2 and 9, 0.01% pop), RA>16 (peak 35-50, 1% pop)
Serum: JIA 5% Rf+, RA 80-85% Rf+
Different subtypes of JIA:
- Systemic: high fever, rash, hepatosplenomegaly, lymphadenopathy, pericarditis/pleuritis, "salmon colored rash" which waxes/wanes with fever
- oligoarthritis: uveitis (inflamation of the middle eye: iris, choroid, ciliary body)
- Polyarticular: rheumatoid nodules

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4 Spondyloarthropathies

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- Anylosing spondylitis: axial (affects hips and shoulders); bamboo spine (ossification of annulus fibrosus); starts with SI then progresses up
- Psoriatic: peripheral (knees, toes, fingers (DIP)); occular involvement; psoriasis can come before or after; dactylitis (sausage fingers), arthritis mutilans (telescoping, pencil/cup erosions), enthysitis
- Reactive arthritis (Reiter's syndrome): most common in young adults; can't see/pee/climb tree (conjunctivitis, iritus, urethritis, arthritis), sterile joint inflammation after infection; keratoderma blenorrhagicum (soles of feet), circinate balantitis (GU)
- IBD associated arthritis: peripheral and axial, enthesopathy,erythema nodosum, uveitis, pyoderma gangrenosa (sterile inflammation)

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Define oligoarticular

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involving a "few" joints: 1-4

Front 287

Define enthesitis

Back 287

inflammation where tendon inserts on bone

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Define tenosynovitis

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inflammation of tendon sheath

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Define uveitis

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inflammation of the uvea: includes the iris, the choroid, and the ciliary body (all immunopriviledged so inflammation suggests autoimmune process)

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Define Iritis

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(anterior uveitis)
inflammation of the iris, the pigmented portion of the eye surrounding the pupil

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Define conjunctivitis

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inflammation of the membrane that lines the eyelid and covers the surface of the eyeball

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Clinical and immunological characteristics of all spondyloarthropathies

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- all present with enthesitis (inflammation at tendon insertions, ex: achilles)
- ankylosis (fusion of joints) occurs in response to inflammation (TNFα, IL1, etc), bone erosion (disregulated osteoclast activity via MMP1 and cathespin K) and syndesmophyte formation (from disregulated endocondral bone formation)
- HLA-B27 predisposes disease, may be due to molecular mimicry
- Seronegative: do not serum exhibit RF

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Treatments for spondyloarthropathy

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- Anti-TNFs: show benefit in axial arthritis by inhibiting inflammation. May be able to prevent joint fusion (still to new)
- Bisphosphonates: improve patient function and spine mobility by decreasing erosions