Basic Science Flashcards
What are canaliculi within bone?
System within the lacunar network used by osteocytes to communicate with each other.
What are Haversian canals?
Found in the center of an osteon in compact bone. They contain blood vessels and nerves.
What are Volkmann canals?
They run perpendicular to Haversian canals and connect them to each other.
Mechanism of Rituximab?
Monoclonal antibody to CD20 antigen (inhibits b cells) Used in Rheumatoid patients who are intolerant to methotrexate or DMARDs
Mechanism of Etanercept?
TNF alpha antagonist Tumor necrosis factor receptor immunoglobulin G fusion protein.
What is the mechanism of Methotrexate?
folic acid analogue Binds to dihydrofolate reductase and prevents synthesis of tetrahydrofolate. Usually first line treatment for Rheumatoid.
True or false chlorhexidine gluconate wash the night before surgery decreases surgical site infection?
False.
What bacteria is of concern with soil contamination? What abx coverage should be added?
Clostridia botulinum (anaerobic gram positive bacilli) High dose penicillin
What are the zones of the physis?
What zone of the physis do Salter-Harris fractures occur through?
Hypertrophic zone. Specifically the Zone of calcification within the hypertrophic zone.
Hypertrophic zone can be subdivided into zones of maturation, degeneration, and calcification.
Mechanism of acetominophen?
inhibits prostaglandin E2 production through interleukin-1 beta.
exerts its effects on the central nervous system.
What is the mechanism of fluoroquinolones?
inhibition of DNA gyrase.
What is released from cells within a joint that causes articular surface damage in septic arthrits?
proteolytic enzymes
such as matrix metalloproteinases(MMP)
Have also been implicates in rheumatoid and osteoarthritis.
Toll like receptors such as TRL-2 activate NF-kB pathway that leads to production of MMPs.
What is the most common cause of septic arthritis in adolescents?
Neisseria gonorrhoeae
Gram negative diplococci.
Patients usually have preceding migratory polyarthralgia, multiple joints involved, and small red papules.
Gram stain is negative over 50% of the time.
What will you see on histology from the tissue surrounding a metal on metal hip that has Delayed Type Hypersensitivity?
diffuse infiltrates of both T and B lymphocytes.
What is the function of Osteoprotegrin?
Limits the activity of RANKL.
This promotes osteoblast activity and increases bone formation.
What is Osteonectin?
Secreted by platelets and osteoblasts and functions to regulate calcium and organzing mineral in the bone matrix.
What affect do Bone morphogenic proteins have on inervertebral disk cells and matrix synthesis?
Increase chondrogenic phenotype expression
Increase matrix syntheis.
What causes tumoral calcinosis?
What is the main laboratory abnormaility?
What gentic abnormality is most common?
pathologic deposition of calcium adjacent to joints and occurs in the presence of phosphate dysregulation.
Hyperphosphatemia
FGF-23
Defect in isocitrate dehydrogenase 1 can cause what syndrome?
Maffucci’s syndrome
Deficiency in alpha-1 hydroxylase can lead to?
Hypovitaminosis D.
Genetic defect in Activin A receptor type 1 has been linked to?
Fibrodysplasia ossificans progressiva.
Abnormal ossification of connective tissue at a young age.
What is the function of Linezolid?
prevents the formation of the initiation complex between the 30S and 50S subunits of the ribosome.
Unique in that it disrupts protein synthesis at its origin.
Binds to the 50s subunit of the bacterial ribosome preventing the formation of the initiation complex.
Describe the mechanism of action of the following antibiotics?
Lenezolid
Aminoglycosides
Macrolides
Tetracycline
Chloramphenicol
What is the inheritance pattern of neurofibromatosis?
What embryonic structure is it a disorder of?
What is the mutation of?
autosomal dominant.
neural crest.
Mutated neurofibromin(NF1) gene on chromosome 17q21.
What is the most common genetic disorder caused by a new mutation of a single gene?
Neurofibromatosis type I
On a histology slide how do you differentiate acute vs chronic osteomyelitis?
Acute has live osteocytes(have nuclei) and neutrophils.
Chronic has no nuclei in the osteocytes and lymphocytes. Also has fibrosis of marrow.
What gene mutation is associated with congenital vertical talus?
HOXD10 gene mutation
(transcription factor)
What should be on your differential for congenital vertical talus?
How can you tell the difference between the two?
Oblique talus
the talonavicular subluxation reduces with forced plantarflexion of the foot.
Treatment is observation and shoe inserts. Only some will require pinning.
What two characteristic physical exam findings are found in congenital vertical talus?
rigid rockerbottom deformity
prominent talar head.
What is a normal talocalcaneal angle?
20-40 degrees
> 40 is associated iwth congenital vertical talus.
Olbique talus will reduces with forced dorsiflexion.
Do you need an MRI for congenital vertical talus?
Yes!
Not for the foot but neuraxial imaging should be perfomred to rule out neurologic disorders.
Treatment for a congenital vertical talus?
When?
Serial manipulation can be performed but this is just pre-operative. Still require surgery. Done to stretch dorsolateral soft tissue stuctures. Foot placed in inversion and plantarflexion.
Treatment should be performed as early as possible(6-12 months).
Surgical release, reduction, and pinning: Plantar release, lengthening of peroneals, achilles, and toe extensors. Tib ant transfer to talar neck.
What do you do for a 12 year old with a missed vertical talus?
triple arthrodesis
What do you after excision of an accessory navicular with the tenond that is relfected?
Do not advance the posterior tibial tendon.
Increases downtime and morbidity.
What is a calcaneovalgus foot?
benign soft tissue contracture deformity characterized by hindfoot eversion and dorsiflexion.
Not a congential deformity or dislocation.
Passiviely correctable. One way you differentiate it from vertical talus.
typically resolves spontaneously by 3-6 months. Can do passive stretching exercises.
What is the most common associated condition with calcaneovlagus foot?
What is the most common surgery needed?
Posteromedial tibial bowing.
Most have a LLD. Some will need a surgery to address the LLD.
What transcription factor has been associated with clubfoot?
PITX1
Critical for limb development.
What is the mechanism of botulinum toxin A?
Competitive inhibitor of presynaptic cholinergic receptors.
Finite lifetime, usually does not last longer than 2-3 months.
Helpful in dynamic contractures, little benefit in static contractures.
What is the mechanism of Baclofen?
Not clearly understood.
Thought to act as a GABA agonist.
Intra-thecal administration is preferred to avoid the cognitive impairment of oral administration.
Usually only used for wheelchair bound children with CP.
When are contracture releases or tendon transfers most commonly performed in children with CP?
3-5 years.
Have spasticity but also voluntary muscle control.
What disease occurs from a repeat mutation that leads to lack of the frataxin gene?
How is it inherited?
Friedreich’s Ataxia
Autosomal recessive
Frataxin is a mitochondrial protein involved in iron metabolism and oxidative stress.
Usually wheelchair bound by age 30. Die by age 50 from cardiopmyopathy.
What is the mutation that leads to Marfan Syndrome?
How is it inherited?
Fibrillin-1 (FBN1) gene
Autosomal dominant
Sporadic mutation can occur in up to 30%
What mutations are linked to Larsen’s Syndrome?
Filamin B for autosomal dominant
Carbohydrate sulfotransferase 3 deficiency for autosomal recessive.
What gene mutation leads to spinal muscular atrophy?
survival motor neuron gene (SMN)
Lack SMN-1 protein with severity of disease based on number of functional copies of SMN-II
SMN critical to RNA metabolism and is a mediator of apoptosis.
A telomeric gene deletion.
What does mutation in the androgen receptor gene on chromosome X lead to?
Spinobulbar muscular atrophy.
Trinucleotide CAG expansion.
What is the inheritance pattern of Duchenne Muscular Dystrophy?
X-linked recessive.
What are the orthopaedic manifestations of DMD?
Calf pseudohypertrophy
Scoliosis
Equinovarus foot deformity
Joint contractures.
What are the non-orthopaedic manifestations of DMD?
Cardiomyopathy
Static encephalopathy
How is Becker’s Muscular Dystrophy Similar to Duchenne’s?
How does it differ?
Sex-linked, calf pseudohypertrophy, and CPK is elevated.
Dystrophin protein is decreased instead of absent, Later onset with slower progression. More prone to cadiomyopathy.
Average ate at diagnosis of BMD is 8 years
Average age at diagnosis with DMD is 2 years.
What is the prognosis of Duchenne’s?
Most unable to ambulate independently by age 10
Most are wheelchair bound by age 15
Most die of cardiorespiratory problems by age 20
What is a gower’s sign?
In DMD a child rises by walking hands up legs to compensate for gluteus maximus and quadriceps weakness.
What Lab is markedly elevated in DMD?
How much?
CPK
10-200x normal
What will a muscle biopsy show in DMD?
connective tissue infiltration and foci of necrosis.
Absent dystrophin with staining.
What is the most common skeletal dysplasia?
Achondroplasia
What mutation leads to Achondroplasia?
What is the inheritance pattern?
G380 mutation of FGFR3 (fibroblast growth factor receptor 3, on chromosome 4P)
80% is a sporadic mutation then autosomal dominant.
Gain of function mutation that increases inhibition of chondrocyte proliferation in the proliferative zone of the physis
Results in defect in endochondral bone formation. It is a quantitative cartilage defect.
What zone of the physis is involved in Achondroplasia?
Proliferative zone.
What mutation is associated with multiple epiphyseal dysplasia?
What is the inheritance?
Most common and most severe is COMP gene.
Can also have COL9A1, COL9A2, COL9A3, Matrillin 3, and SLC26A2 (diastrophic dysplasia sulfate transporter gene.
Halp of patients with clinical diagnosis of MED do not have the typical genetic mutations.
Autosomal dominant most common. The SLC26A2 mutation is autosomal recessive. Will present with at least one of the following: Clubfoot, cleft palate, clinodactyly(abnormal curvature of the small finger).
What is the mutation and inheritance of diastrophic dysplasia?
DTDST gene (SLC26A2) on Chromosome 5
Encodes for a sulfate transporter protein.
Leads to undersulfation of cartilage proteoglycan.
What is the mutation that leads to cleidocranial dysplasia?
What is the inheritance pattern?
RUNX2/CBFA1 mutation-transcription factor which regulates osteoblastic differentiation
Autosomal dominant
What is the most common lysosomal enzyme malfunction syndrome?
Morquio syndrome
What is the pathophysiology of lysosomal storage disorders?
Incomplete gylcosaminoglycan breakdown products (mucopolysaccharides accumulating and causing dysfunction in various organs.
What are the CRTAP and LEPRE1 genes associated with?
Severe, lethal forms of OI not associated with primary structural defect of type I collagen.
What is the difference between the AD and AR forms of Osteogenesis Imperfecta?
AD forms (Types I and IV) are milder.
AR forms (Types II and III) are more severe
What is the result of COL 1A1 and COL 1A2 gene mutations?
Osteogenisis Imperfecta
Causes abnormal collagen corss-linking via a glycine substitution in the procollage molecule.
What is different about Type V, VI, and VII Osteogenesis Imperfecta?
They have abnormal bone on microscopy and similar phenotype but no Type I collage mutation.
What is the structure of Type I collagen?
Triple Helix structure- possible because of glycine at every 3rd amino acid residue.
Two alpha-1 chains coded by genes COL1A1
One alpha-2 chain coded by gene COL1A2
What will you see on histology slides for Osteogenesis Imperfecta?
Increased diameter of haversion canals and osteocyte lacunae
replicated cement lines
Increased number of osteoblasts and osteoclasts
decreased number of trabeculae
decreased cortical thickness.
What is the most common pattern of inheritance for osteopetrosis?
benign autosomal dominant.
Also malignant autosomal recessive and intermediate autosomal recessive forms.
May skip generations. 75% gene penetrance.
What is Albers-Schonderg disease?
autosomal dominant osteopetrosis Type II.
Anemia, pathologic fractures, and premature osteoarthritis.
What is a risk factor for having a child with down syndrome?
Advanced maternal age. 1 in 250 in mother > 35 years.
What genetic mutation is associated with Trisomy 21?
COL6A1 and COL6A2 which code for Type VI Collagen.
Component of skeletal muscle extracellular matrix
Contributes to generalized joint laxity.
What HLA markers are associated with JIA?
DR4 with polyarticular
DR8, DR5, and DR2. Associated with pauciarticular
What percent of JIA patients are RF seropositive?
<15%
What is the classical form of Ehler’s Danlos syndrome?
What mutation?
What inheritance pattern?
Type 1 and Type II
Hyperextensible skin, widened atrophic scars, and joint hypermobility.
COL5A1 or COL5A2 mutation. Type V collage
Autosomal dominant.
What factor is decreased or absent in Hemophilia A?
Factor VIII
What factor is decreased or absent in Hemophilia B?
Factor IX.
Less common for.
How is Hemophilia inherited?
X-linked recessive.
Typically affects males only.
Ther is a rare form with a autoimmune etiology with no genetic inheritence.
What is a Bethesda Assay used for?
Measures the amount of factor VIII or IX antibody in the blood
<5 BU = low levels
> 5 BU = high levels
What labs findings are seen in a patient with hemophilia?
PTT prolonged with PT normal
LFTs normal
What is the signifigance of IgG antibodies to clotting factor proteins being present in a patient with Hemophilia?
Inhibits the response of therapeutic factor replacement.
Present in 4-20% of patients
Relative contraindication fur surgery.
What factor levels would you watn in a hemophiliac patient with the following issues:
Acute hematomas?
Aute hemarthrosis and soft tissue surgery?
Skeletal surgery?
Increase levels to 30%
Increase levels to 40-50%
Increae levels to 100% for the first week following surgery and then maintian > 50% for the second week.
What is responsbile for the major source of nutrition to the physis?
Perichondrial artery.
Mutations in DMPK and CNBP gene are responsible for what disease process?
Myotonic dystrophy
A mutation of what gene leads to absence of the dystrophin protein?
What disease process does this lead to?
Xp21 Gene
Duchenne’s Muscular dystrophy
What is the percent chance of septic arthritis based on 0,1,2,3, or all 4 of Kocher’s Criteria?
.2%
3%
40%
- 1%
- 6%
Criteria are ability to bear weight, fever >101.3 or 38.5, WBC >12, and ESR >40
In what patients are capnocytophaga canimorsus infections seen?
Dog bites
Rare, but potentially fatal in splenectomy patients
Mortality rate of 30-60% in immunocompromised
Causes cellulitis, sepsis, endocarditis, meningitis, DIC, ARDS, and death.
What is the first line antibiotic for Pasteurella multocida?
Amoxicillin/clavulanic acid
Commercial name is Augmentin
What condition is associated with HLA-B8
DISH
What percent nerve elongation will diminish a nerve’s microcirculation?
What percent will disrupt axons?
8%
15%
What 25-hydroxy vitamin D level is considered to be deficient?
<20ng/ml
What secretes Stromelysin and plasmin?
Both are metalloproteinases that are secredted by chondrocytes and have degradative action against cartilage.
What role does sclerostin play in bone metabolism?
Inhibits the WNT pathway and leads to decreased bone mass.
What is the function of Peroxisome proliferator-activated receptor gamma (PPARG)
Regulator of mesenchymal progenitor cells that induces adipocyte formation.
Osteoarthritis and formation of osteophytes is thought to be mediated by the differentiation of quiescent chondrocytes through what signaling pathway?
Indian hedgehog (Ihh)
What medication works by binding to and enhancing the ability of antithrombin III?
Unfractionated heparin works by promoting the ability of antithrombin III to inhibit factors IIa, III, and Xa.
Risks are bleeding and heparing induced thrombocytopenia (HIT).
The reversal agent is protamine sulfate.
What does the picture demonstrate?
The D-test.
This should be performed when erythromycin-resistant MRSA is identified as a pathogen and clindamycin is being considered as the antibiotic to be used.
Inducible clindamycin resistance can occur. It theh pathogen is an inducible strain a zone of inhibition in the shape of the letter D will occur. This is considered a positive test.
What is a CAMP test?
Used to identify group B Beta-hemolytic streptococci
What is an Etest?
used to determine the MIC(minimum inhibitory concentration and whether or not a specific strain of bacteriurm is susceptible to the action of a specific antibiotic.
what disease is associated with a mutation in the GNAS gene?
Fibrous dysplasia
What is Metabolic Syndrome?
Collectio of medical comorbidities that are known to be risk fractors for developing cardiovascular disease.
Increased risk of knee pain and OA with these patients.
Includes: Central obesity, dyslipidemia, HTN, and elevated fasting glucose levels.
What are the differences between Aging and Osteoarthritis in articular cartilage for categories listed in the image?
What does an increased adductor moment during gait lead to progression of what disease process within the limb?
Increased adductor moment during gait is associated with progression of knee osteoarthritis
Increased medial compartment pressures.
What are the four types of Gell-Coombs Reactions?
Type I- Allergic (Anaphylaxis)
Type II- Cytotoxic, antibody dependent. Ex Grave’s Disease or hemolytic anemia
Type III- Immune complex diseases such as serums ickness or SLE
Type IV- delayed type
What does Sclerostin do?
Direct antagonist of the WntB-catenin pathway and thus a key regulator of the formation of mineralized bone matrix and bone mass.
Anti sclerostin antiboides result in inactivation of sclerostin, therby promoting the anabolic Wnt/B-catenin pathway and resulting in increased bone density.
What factor stimulates differentiation and proliferation of myofibroblasts?
TGF-beta- leads to production of scar tissue.
Muscle regeneration occurs 7-10 days after injury. Facilitated by IGF-1, FGF, and NGF.
What is the function of tobramycin
It is an aminoglycoside.
Disrupts protein synthesis through irreversibly binding to 30S ribosomal subunit.
Leads to altered cell membrane permeability, disruption of the cell envelope, and eventual cell death.
What is the inheritance of amniotic band syndrome?
Sporadic
What is Anakinra used for?
What is its mechanism?
Disease-modifying antirheumatic drug.
Interleukin IL-1 receptor antagonist that blocks the binding of IL-1 to its cell membrane
Prevents this pro-inflammatory cascade.
What is the mechanism of tranexamic acid?
Antifibrinolytic that prevents the activation of plasmin from the inactive zymogen plasminogen.
Plasmin breaks down fibrin which is factor Ia.
Common X-Linked disorders include?
Hemophilia A
Duchenne muscular dystrophy
Becker’s muscular dystrophy
Hunter’s sundrome
Spondyloepiphyseal dysplasia (SED) tarda
What cellular structures are increased in bone cells relative to other cells?
Endoplasmic reticulum, Golgi apparatus, and mitochondira.
Allows for synthesis and secretion of bone matrix.
What is the most specific marker for osteoblasts?
Osteoclacin
What is Cbfa1(core binding factor alpha-1)/Runx2?
key transcription factor associated with osteoblast differentiation
What factors are involved in osteoblastic differentiation?
BMP- stimulates mesenchymal cells to become osteoprogenitor cells.
cbf alpha 1: RUNX2
Stable beta-catenin
PDGF
IDGF
What effect does estrogen have on bone production?
inhibits bone resorption and stimulates bone production by inhibiting adenyly cyclase.
What effect to glucocorticoids have on osteoblas bone production?
inhibit collage and bone matrix production.
What role does 1,25 dihydroxyvitamin D have in bone production.
Involved in osteoblast bone production.
Stimulates matrix and alkaline phosphatase synthesis
Production of bone specific proteins (Osteocalcin)
What do osteoblasts secrete than inhibits osteoclasts?
Osteoprotegrin (OPG)
OPG binds to RANKL on osteoblasts, preventing RANK activation
What activates the Jagged1-Notch pathway on osteoblasts?
What does this pathway regulate?
Parathyroid hormone
Hematopoietic stem cells
What is the origin of osteoclasts?
originate from myeloid hematopoietic cells from monocyte/macrophage cell lineage.
monocyte progenitors fuse together to form mature multinuclear cells. -> multinucleated giant cells
What is tartrate resistant acid phosphate?
Secreted by osteoclasts to lower the Ph (utilizing carbonic anhydrase) and increases the solubility of hydroxyapatite crystals
What role does Cathepsin K play in bone regulation?
major proteolytic enxyme that digests organic matrix at ruffled border.
In simple terms what is the mechanism of bisphosphonates?
Prevents osteoclasts from formin ruffled border and producing acid hydrolases
At what zone does the osteoclast attach to the bone matrix?
Sealing zone
Attach via integrins (avB3, a2B1, avB1) they are receptros for vitronectin that is found on the bone surface.
Arg-Gly-Asp (RGD) sequence allows extracellular bone proteins to bind directly to integrins.
What signaling factors activate osteoclasts?
Inhibit?
RANKL and IL-1
Calcitonin and IL-10
Is there a difference between mineralized bone matrix degradation and organic bone matrix degradation by osteoclasts?
Yes
Hydroxyapatite crystals dissolved by HCL secreted through ruffled border into resorption lacuna for Mineralized matrix.
Lysosomal cysteine proteinases, MMPs, and Cathepsin K for organic bone matrix degradation
What determines the function of osteoprogenitor cells?
Environment:
Low strain and high oxygen tension = osteoblasts
Intermediate strain and low oxygen tension = cartilage
High strain = fibrous tissue
What is responsible for tensile strength in bone?
Collagen
40% of bone is organic and 90% of that is Type I collage
triple helix composed of one alpha-2 and two alpha-1 chains.
What is responsible for the compressive strength of bone.
Proteoglycans (organic)
Composes of glycosaminoglycan-protein complexes.
Calcium hydroxyapatite (inorganic)
What is the inorganic component in bone?
Calcium hydroxyapatite (Ca10(PO4)6(OH)2- provides compressive strength
Osteocalcium phosphate brushite
What are the three main types of proteins involved in bone matrix?
Osteoclacin: Most abundant non-collagenous protein (10-20% of total). Produced by mature osteoblasts. Promotes mineralization and formation of bone. Marker of bone turnover. Can be measured in serum or urine.
Osteonectin: secreted by platelets and osteoblasts. Believed to have a role in regulating calcium or oganizing mineral in matrix.
Osteopontin: Cell binding protein
What is the blood supply to long bones?
Nutrient artery system
Metaphyseal-epiphyseal system
Periosteal system
Bone receives 5-10% of cardiac output
What system supplies the major blood supply to a long bone?
What about when it is immature?
Nutrient artery system.
Supplies the inner 2/3 of mature bone via the haversion system.
Immature bone recieves the majority from the periosteal system. Flow is centripetal (outside to inside)
How does direction of predominate blood flow differ within a bone for the following:
Arterial
Venous
Mature
Immature
Fracture
centrifugal (inside to outside)
Centripetal (outside to inside)
Centrifugal
Centripetal
Centripetal. Nutrient artery system is disrupted and periosteal system predominates.
What predominately stimulates osteoclast in a normal process?
Pathologic process?
RANKL
PTH (such as metastatic disease)
What is osteoprotegrin?
decoy receptor produced by osteoblasts and stromal cells that binds to and sequesters RANKL.
What molecules inhibit Osteoclasts?
Osteoprotegerin
Calcitonin
Estrogen- decrease in RANKL
TGF-beta
IL-10
What molecules stimulate bone resportion?
RANKL
PTH
IL-1- stimulates osteoclast differentiation
1,25 dihydroxy vitamin D
Prostaglandin E2- activates adenylyl cyclase and stimulates resorption
IL-6 (myeloma)
MIP-1A (myeloma)
When does peak mone mass occur?
What population has greater bone mass?
For the hip between ages 16 and 25.
Greater in men and African Americans.
What is the rate of bone loss after skeletal maturity in adults?
Women after menopause?
.3-.5% per year
2-3% per year for untreated woemn during the 6th-10th years after menopause
What are the dietary requirements for calcium:
Lactating women.
Pregnant women, postmenopausal women, and patients with a healing bone fracture.
Adolescents and young adults
Adults
Children
2000 mg/day
1500 mg/day
1300 mg/day
750 mg/day
600 mg/day
What is the mechanism of PTH in:
Bone?
Kidney?
Intestine?
Bone- Stimulates osteoblasts to secrete IL-6, IL-1, and other cytokines to activate osteoclasts and increase resorption of bone. Increases osteblast production of M-CSF and RANKL which increases number of osteoclasts. Osteoclasts do no express receptor for PTH.
Kidney- Stimulates enzymatic conversion of 25-OH-vitamin D3 to 1,25-(OH)2-vitamin D3 (active hormone form) which: increases resoprtion of Ca++ in kidney (increasing serum Ca++). Increases excretion of PO4- from kidney (decreasing serum phosphate)
Intestine- No direct action. Indirectly increase Ca++ absorption by activating 1,25-(OH)2-vitamin D3
What can recombinant calcitonin be used to treat?
Paget disease
Osteoporosis
Hypercalcemia
What kind of tumors secret calcitonin?
medullary thyroid tumors and multiple endocrine neoplasia type II tumors.
What is the origin and function of calcitonin?
Produced by clear cells in the parafollicles of the thyroid gland (C cells)
inhibit the number and activity of osteoclasts.
Osteoclasts have a receptor for calcitonin.
What has to happen before the ingested form of vitamin D is the active metabolite?
two hydroxylations in the liver and the kidney needed to form 1,25-(OH)2-vitamin D3
What is the function of Vitamin D in:
Liver
Kidney
Bone
Liver- activated vitamin D3 converted to 25-(OH)-vitamin D3
Kidney- 1,25-(OH)2-vitamin D3 (active hormone form) can be inactivated to 24,25-(OH)2-vitamin D3. This inactivity occurs with decreased levels of PTH or increased levels of serum Ca++,P.
Vitamin D parallels that of PTH by increasing reabsorption of Ca in the kidneys.
Bone- 1,25-(OH)2-vitamin D3 stimulates terminal differentiation of osteoclasts. Once they are mature osteoclasts vitamin D3 does not have an effect and they respond to cytokines released by osteoblasts.
1,25-(OH)2-vitamin D3 promotes the mineralization of osteoid matrix produced by osteoblasts
Peak bone mass attainement in both men and women is most dependent on what sex-steroid?
Estrogen
Therapeutic estrogen for women:
increases risk of?
decreases risk of?
Increases risk of heart disease and breast cancer
Decreases the risk of hip fracture and endometrial cancer(if combined with cyclic progestin)
Someone on therapeutic estrogen will have changes in what lab values?
Decrease in urinary pyridoline
Decrease in serum alkaline phosphatase
What function does thyroid hormone have bone formation?
Regulartes skeletal growth at the physis by stimulating:
Chondrocyte growth
type X collagen synthesis
Alkaline phosphatase activity
Thyroid hormoes such as therapeutinc thyroxine increase bone resorption and can lead to osteoporosis.
What effect does growth hormone have on the physis?
Effects the proliferative zone of the physis and in cases of oversecretion or increased response can lead to Gigantism.
What effect does growth hormone have on serium calcium?
Increased absorption in the intestine
Decreases urinary excretion
Function is interdependent with insulin, somatomedins, and growth factors (TGF-B, PDGF, mono/lyphokines)
What is the function of anabolic steroids on bone mass?
Increases bone loss by:
Decreasing Ca++ absorption in intestine through a decrease in binding proteins
Decreasing bone formation (cancellous more so than cortical bone) by decreasing collage synthesis and inhibiting osteoblast activity.
Limb bud development is under control of?
Fibroblast growth factor.
Enlargement of the limb bud is due to interaction between the apical ectodermal ridge and the mesodermal cells in the progress zone.
First identifiable by transvaginal ultrasound at 8 weeks.
What proteins are involved in chondrogenesis at sites of future joints during embryonic development?
WNT4
WNT14
growth and differentiation factor 5 (also known as cartilage-derived morphogenetic protein 1)
What is the difference in gain of funcion in FGFR2c affinity for FGF2 and Loss of function in FGFR2c specificity for FGF2?
Gain of function in FGFR2c affinity for FGF2 ->patients with severe craniofaacial features and mild hand syndactyly.
Loss of function in FGFR2c specificity for FGF2 leads to it being able to bind FGF10 which is expressed more in hands ->mild craniofacial featurs and severe hand syndactyly.
What signaling center and growth factor are involved in Proximodistal limb development?
Signaling center = Apical ectodermal ridge
Most important growth factor is FGF8
Issues in these areas will lead to proximal limb truncation such as radial absence or dysplasia. Can also lead to central deficiency such as a cleft hand.
What signaling center is needed for anteroposterior (radioulnar) limb growth?
Zone of polarizing activity- along posterior (ulnar) part of limb bud.
Signaling molecule Shh is critical.
Normal is high concentration on posterio (ulnar side) and low concentration on anterior (radial) side.
Abnormal upregulation of Shh in the ZPA can lead to polydactly
Downregulation leads to loss of ulnar digits.
Upregulation in the anterior side can lead to loss of thumb.
What role does HOX genes have in limb development?
Anterior-posterior (radioulnar) patterning together with Shh
Regulate somatization of the axial skeleton, essentially patterning digit formation.
What is the third signaling center invovled in limb development?
What does it control?
non-AER limb ectoderm/ Wnt signalling center (progress zone, PZ)
Dorsoventral axis.
Dorsal limb expresses WNT7a to regulate dorsal patterning. Responsible for dorsal features such as nails.
Ventral ectoderm expresses en-1 (engrailed-1 protein, antagonistic to WNT7a) allows ventral limb development.
What happens if there is a duplication of the zone of polarizing activity?
Mirror-image duplication of the limb.
The spinal column originates from what embryonic sturctures during development?
Paris of mesodermal sturctures known as somites
Develop in a cranial to caudal direction on either sife of the notochord and neural tube.
Process is dependent on the presence of the paraxis gene
Somite layers:
SCLEROTOME- layer will become the vertebral bodies and annulus fibrosus
MYOTOME- will lead to myoblasts
DERMATOME- becomes skin
For spine and spinal cord development what eventually develops from the following sturctures:
Neural crest?
Neural tube?
Notochord?
Neural crest- forms PNS, pia mater, spinal ganglia, and sympathetic trunk.
Neural tube- forms spinal cord
Notochord- forms nucleus pulposus and anterior vertebral body
Sclerotome fors the remainder of the vertebral bodies and the annulus fibrosus.
What are the three ossification centers of the vertebrae?
Centrum- anterior vertebral body.
Neural arch- posterior elements, pedicles, small portion of anterior vertebra.
Costal element- (anterior part of lateral mass, transverse process, or rib.
Where does endochondral bone formation occur?
Embryonic long bone formation
longitudinal physeal growth
non-rigid fracture healing (secondary healing)
What type of collagen is associated with endochondral ossification?
Type X collagen
What is the Hueter-Volkmann Law?
Compression across the growth plate slows longitudinal growth.
Tension accelerates longitudinal growth.
What transcription factors are involved in the regulation of chondrocytes?
Sox-9: Considered a major regulator of chondrogenesis, regulates several cartilage-specific genes during endochondral ossification, including collagen types II, IV, and XI and aggrecan.
PTHrP: Delays differentiation of chondrocytes in the zone of hypertrophy.
What is the Groove on Ranvier?
What pathologic process is invovled with this area?
Zone of the physis periphery
During the first year of life, the zone spreads over the adjacent metaphysis to form a fibrous circumferential ring bridging from the epiphysis to the diaphysis.
The ring increase the mechanical strength of the physis and is responsible for appositional (width) bone growths. Supplies chondrocytes to periphery.
Osteochondroma
What are the steps of formation for embryonic long bone formation?
Vascularization- vascular buds invade the mesenchymal model
Primary ossification centers form at 8 weeks.
Cartilage model forms- grows through appositional (width) and interstitial (length) growth.
Marrow forms
Secondary ossification centers form
What is Wolff’s Law?
Bone remodels in response to mechanical stress.
How are Piezoelectric charges involved in bone remodeling?
Bone remodels in response to electric charges.
Compression side is elctronegative and stimulates osteoblast formation.
Tension side is electropositive and stimulates oteoclasts.
What is the mechanism by which cortical bone remodels?
Osteoclastic resorption > layering of osteoblasts > layering of lamellae > cment line laid down
Osteoclast make up head of cutting cone, followed by capillaries and then osteoblasts which lay down the osteoid to fill the cutting cone.
Sclerostin inhibits osteoblastogenesis to decrease bone formation.
How does cancellous bone remodel?
Osteoclastic resorption
Osteoblastic deposition of layers of lamellae
What % strain corresponds to following kinds of healing:
Primary bone healing?
Secondary bone healing?
Fibrous non-union?
<2%
2-10%
>10%
What are the stages of secondary bone healing?
Inflammation
Repair
Remodeling
What effect does NSAIDs have on bone healing?
COX-2 causes repression of runx-2/osterix, which are critical for differentiation of osteolastic cells.
Controversial on how clinically significant this effect is on bone healing.
Does Low intensity pulsed ultrasound decrease time to union?
Decrease non-union?
What is the benefticial ultrasound signal?
Yes
Yes
Healing rates for delayes unions/nonunions has been reported to be close to 80%
30 mW/cm2 pulsed wave.
What are the four main delivery modes for bone stimulators?
All are modes of electrical stimulation
Direct current- decreas osteoclast activity and increase osteoblast activity by reducing oxygen concentration and increasing local tissue pH.
Capcitively coupled electrical fields (alternating current, AC)
Pulsed electromagnetic fields
Combined magnetic fields
What percent of patients with nonunion were found to have matabolic issues?
vitamin D debiciencies?
84%
66%
protein malnourishment decreases fracture callus strength.
What effect does gastric bypass have on bone healing?
Duodenal bypass leads to decreased clacium absorption.
Decreased Ca/Vit D levels, secondary hyperparathyroidism, and increased Ca resorption from bone.
Need to treat with Ca/Vit D supplementation.
Gastric banding does not lead to these abnormalitites because the duodenum is not bypassed.
What effect does diabetes mellitus have on bone healing?
Decreased cellularity and strength of the fracture callus.
Delayed endochondral ossification.
Fracture healing takes 1.6 times longer in diabetic patients versus non-diabetic patients.
True or fale patients with HIV have higher prevalence of fragility fractures and associated delayed healing?
True
Contributing factors:
anti-retroviral medication
poor intraosseous circulation
TNF-Alpha deficiency
Poor nutritional intact
How much is pseudoarthrosis in spine fusion increases by smoking?
500%
Smokers cna also take 70% longer to heal open tibial shaft fractures versus non-smokers.
What are contraindications to bone stimulators?
synovial pseudoarthroses
nonunions that move
greater than 1 cm between fracture ends
What are the direct effects of bone stimulators which stimulate bone growth?
Increasing expression of BMP7
Increasing expression of BMP2
Increasing expression of TGF-beta1
Increasing osteoblast proliferation
What is the source, receptor class, and function for the following growth factors?
What is the signalling pathway and cellular targets of BMP?
Targets undifferentiated perivascular mesenchymal cells.
Activates a transmembrane serine/threonine kinase receptor that leads to the activation of intracellular signalling molecules called SMADs
SMADS lead to different cellular responses
What are the contraindications to use of BMP?
Pregnancy
Allergy to bovine type I collagen or recombinant human rhBMP-2
Infection
Tumor
Skeletal immaturity
FDA approved use for BMP-2 and BMP-2
BMP-2: single level ALIF from L2-S1 levels in degenerative disc disease together with the lumbar tapered fusion device (LT Cage; Medtronic)
BMP-7: Long bone non-unions where autograft can’t be used. Alternative to autograft in patients (with osteoporosis, smoking, or diabetes) requiring revision posterolateral/intertransverse lumbar fusion for whom autologous bone and bone marrow harvest are not feasible or are not expected to promote fusion.
What is the most abundant growth factor in bone?
IGF-1
Products of the GH-IGF-1 system induce proliferation without maturation of the growth plate and thus induce linear skeletal growth.
May have a role in enhancing bone formation in defects that heal via intramembranous ossification.
True or false IGF-2 is more potent that IGF-1
True
Stimulates type I collagen production, cartilage matrix synthesis, cellular proliferation, and bone formation.
What effect does peroxisome proliferator-activated receptor gamma (PPAR-gamma) have?
adipogenic differentiation of mesechymal precursor cells in vitro.
Organize from fastest to slowest rates of resorption of the following materials:
Hydroxyapatite
Tricalcium phosphate
Calcium Sulfate
Fastest to slowest
Calcium sulfate > tricalcium phosphate > hydroxyapatite
Define osteoconductive?
Material acts as a structural framework for bone gowth.
Define Osteoinductive?
Material contains factors that stimulate bone growth and induction of stem cells down a bone forming lineage.
BMP is an example.
Define Osteogenic?
Material directly provides cells that will produce bone including primitive mesenchymal stem cells, osteoblasts, and osteocytes.
What synthetic graft material is associated with increased serous wound drainage?
Calcium sulfate.
What disease has the highest risk of transmission with use of fresh frozen allograft?
Hep B 1 in 63,000
Hep C 1 in 100,000
HIV 1 in 1,000,000
Allografts are tested for HIV, HBV, HCV, HTLV-1, and syphilis.
Describe The Vitamin D Pathway
7-Dehydrocholesterol is stored in the skin where UV exposure converts it to previtamin D3
25-hydroxyvitamin D3:
When calcium is low, PTH levles become elevated which activates 1-alpha-hydroxylase in the kidney. This converts 25-hydroxyvitamin D to the active Vitamin D (calcitriol)
Laboratory level study of choice to determine Vitamin D deficiency.
Describe the PTH Pathway.
Function of PTH
Increase serum Ca++ and decrease serum phosphate in response to hypocalcemia/hypomagnesemia via:
Increased bone resorption of calcium and phosphate (bone is destroyed)
PTH receptor is on the osteoblasts which secretes IL-1 to activate osteoclasts
Increase kidney resorption of calcium in distal convoluted tubule
Decrease kidney resorption of phosphate
Increase 1,25-(OH)2 vitamin D production
Myasthenia gravis patients have a shortage of what?
Ach receptors.
What happens when acetylcholine bind to its receptor?
depolarization of the sarcoplasmic reticulum and release of calcium into muscles cytoplasm.
Calcium binds to troponin leading to a configuartion change of tropomyosin.
Exposing myosin-binding sites on actin filament
Actin forms cross-bridges to myosin, and the ATP breakdown, the two fibers contract past one another.
Describe the composition of the sarcomere?
FILAMENTS: Thick myosin filaments and thin actin filaments.
BANDS: H band is myosin only
I band is actin olnly
Z line flanks each sarcomere and acts as site of attachment for actin filament
DURING MUSCLE CONTRACTION:
A ban stays the same length. I band reduces in length. H zone reduces in length.
What type of muscle contraction is a plyometric?
Rapid lengthening followed by contraction of muscle groups (e.g. jumping up and down on boxes)
Describe the difference between Type I and Type II muscle fibers
What are the three energy systems?
ATP-CP anaerobic system- ATP, less than 20 seconds, no lactic acid, does not use oxygen
Lactic anaerobic system (lactic acid metabolism)- 20 to 120 seconds. hydrolysis of one glucose molecule.
Aerobic system- used in longer duration and lower intensity exercises. Krebs cycle generates ATP from glucose and fatty acids through oxidative phophorylation.
What are the most abundant cells early on after acute injury?
Neutrophils
Generates free radicals that possibly increase muscle damage.
True or false wheelchair propulsion requires 9% more energy than ambulation in normal subjects?
True
Which amputation in a patients is the best candidate for a myoelectric prostheses?
Midlength transradial amputation.
What is the most common through knee or above knee prosthesis for children?
Constant friction (single axis) knee.
Patients can walk on uneven terrain.
Not recommended for older or weaker patients.
Only allows a single speed of walking
With regard to prosthetic complications what is choke syndrome?
Obstructed venous outflow due to a socked that is too snug.
Acute phase- red, indurated skin with orange-peel appearance.
Chronic phase- hemosiderin deposits and venous stasis ulcers.
For the various foot alignment abnormalities describe the effect?
Inset foot
Outset foot
Anterior foot placement
Posterior foot placement
Dorsiflexed foot
Plantar-flexed foot
Inset foot- varus strain, circumduction and pain
Outset foot- valgus strain, borad-based gait and pain
Anterior foot plaement- stable increased knee extension with patellar pain
Posterior foot placement- unstable increased knee flexion
Dorsiflexed foot- Increased patellar pressure
Plantar-flexed foot- Drop-off and increased patellar pressure
For transtibial prostheses what is the cause of the following:
Swing-phase pistoning?
Stance-phase pistoning?
Swing phase pistoning- ineffective suspension system
Stance phase pistoning- poor socket fit
Stump volume changes -> stump sock may need to be changed.
What is the main cell type in both tendons and ligaments?
Fibroblasts.
Both tendons and liaments show low vascularity and cellularity.
What are the extracellular components of ligaments and tendons?
What is the number one component by dry weight?
Water, Type I collagen, elastin, lipids, proteoglycans and epiligament coats (present in some ligaments not all is analogous to epitenon.
Type 1 collage is 70% by dry weight.
How does ligament and tendon composition differ?
Ligaments have lower percentage of collagen than tendons.
Ligaments have a higher percentage of proteoglycans and water.
Ligaments have less organized collagen fibers.
Ligaments have rounder fibroblasts.
What is Hysteresis?
Energy dissipation.
When tissue is loaded and unloaded, the unloading curve will not follow the loading cruve.
The difference between the two curves is the energy that is dissipated.
What is the difference on a stress strain curve between tendons and ligaments?
Tendons carry higher loads and recruit fibers quickly -> Smaller toe region.
Ligaments recruit fibers gradually -> elongated toe region.
Toe region- significant deformation for given load. In this region the crimped and relaxed fibers of the ligament straightened to take load.
What is the difference between where ligaments fail in adults vs children?
Usually midsubstance in adults
Usually at bony insertion in children
Ligament avulsion occurs at juntion of mineralized and unmineralized fibrocartilage layers.
What are the two types of ligament bone insertion?
Indirect (fibrous insertion)
Direct (fibrocartilaginous insertion)
What are the phases of ligament healing?
Factors that impair ligament helaing?
Intra-articular
Increasing age
Immobilization
NSAIDs
Diabetes
Alcohol intake
Decreased growth factors and expression of genes
Factors that improve ligament healing?
Many of these are experimental.
Extra-articular
Compromised immune response. CD$4 knockout mice have faster patellar tendon healing. Depletion of macrophages (source of TGF-B1 that stimulates fibrosis)
Mesenchymal stem cells
Growth factors such as PDGF-BB, GCSF, and BMP-2 and 12.
What are the two main proteoglycans found in tendons?
What are their roles?
After tendon surgical repair when are tendon reparis weakest?
When is maximum strength?
7-10 days
6 months.
Final strength only reaches 2/3 of normal eve years after repair.
What are the five forms of cartilage?
Hyaline or articular cartilage
Fibroelastic cartialge (meniscus)
Fibrocartilage (at tendon and ligament insertion into bone)
Elastic cartilage (trachea)
Physeal cartilage (growth plate)
What makes up the extracellular matrix of hyaline cartilage?
Water 65-80% of mass of cartilage. Water content decreases with normal aging and increases with osteoarthritis.
Collagen- 1-20% of total mass. Type II collagen accounts for 90-95% of the total collage content
Proteoglycans- Make up 10-15% of cartilage. Function to provide compressive strength and attract water.
What are the layers of articular cartilage?
For the following factors how does age change them and how does osteoarthritis change them?
How does healing differ between a superficial cartilage laceration and a deep laceration that extends through the tidemark?
Superficial leads to chondrocyte proliferation but no healing because the cartilage is avascular.
DEEP leads to fibrocartilage healing. Because subchondral bone is penetrated there is stem cell migration and vascular ingrowth.
What transcription factor is critical for mesenchymal stem cell differentiation towards the cartilage lineage?
SOX-9
True or false a disruption in pH can lead to an abnormal cartilage structure?
True
pH of cartilage is 7.4
What besides articular cartilage is composed of hyaline cartilage?
Ribs and nasal septum.
What structures are composed of fibrocartilage?
Pubic symphysis, tendon/ligament junction with bone, annulus fibrosis of the intervertebral disc, and menisci.
Predominantly Type I collagen.
What is the composition of collagen?
Composed of a triple helix:
Two alpha 1 chains
One alpha 2 chain.
Several common amino acid sequences are found in collagen including:
Glycine-X-hydroxyproline
Glycine-Proline-X
Descire the formation of collagen fibers?
Type III collagen is predominantly found in?
What are some related clinical conditions?
skin and blood vessels
Ehler-Danlos syndrome
Dupuytren’s contracture
Where is Type IV collagen found?
Related clinical conditions?
Basement membrane
Renal diseases like Goodpasture’s and Alport syndromes
type VII and VIII are also found in epithelial basement membranes.
What types of collagen occur in small amounts in articular cartilage?
Type V, VI, IX
Where is type X collagen found?
Found in the deep calcified layer of cartilage
Produced only by hypertrophic chondrocytes during endochondral ossification (growth plate, fracture callus, heterotopic ossification).
Increased in early arthrits
Related condition is Schmid metaphyseal chondrodysplasia
What is the function of Type XI collagen?
An adhesive with the function of holding the collagen lattice together in cartilage.
What is the difference between and exon and intron?
Both are parts of genes
exon- coding information
intron- does not code for mRNA
What is a codon?
sequence of three nucleotides (thymine, adenine, guanine, and cytosine)
Each codon correlates to one of the 20 amino acids.
What do the following identify?
Southern blot
Northern blot
Western blot
DNA sequence
RNA sequence
Protein
Briefly describe the cell cycle?
What are the two antigen presenting cells (APC) involved in the acquired immune response?
B cells and dendritic cells
The APC cells above break down the protein antigen and presents the key peptide sequences via the major histocompatibility complex receptors.
Once presented on the surface of the APC, the T-cell receptor recognizes the MHC/antigen complex prior to the T-cell activation.
CD8 T lymphocytes, T helper cells, delta gamma T cells, B cells, and Plasma cells are involved in acquired immune response.
What is benign ethnic neutropenia?
Most common neutropenia in the world
Approximatel 25-50% of people of African descent and some sub-groups in the Middle East found to have low ANC without increased infection risk.
ANC <1.5 x 10(9) cells/L
More common in males, athletes, and children under the age of 5.
Match the following immunoglobulins IgG, IgM, IgA, and IgE with the facts below:
Important in conferring protection against parasites and allergic reactions.
The major class of antibody in external secretions.
The first class of antibody to appear in our serum after exposure to an antigen.
The most abundant immunoglobulin.
IgE-Important in conferring protection against parasites and allergic reactions.
IgA-The major class of antibody in external secretions.
IgM-The first class of antibody to appear in our serum after exposure to an antigen.
IgG-The most abundant immunoglobulin.
Describe Types I, II, III, and IV immuological reactions.
In general how are defective structural proteins and defective enzymes inherited?
Defective structural proteins = autosomal dominant.
Defective enzymes = autosomal recessive.
Name as many examples as you can of orthopaedic conditions that are inherited through an autosomal dominant pattern?
Syndactyly, Polydactyly
Marfan’s Syndrome, Cleidocranial dysostosis, Hereditary Multiple Exostosis
Achondroplasia, MED, Metaphyseal Chondrodysplasia (Schmid and Jansen types)
Kniest dysplasia, Malignant hyperthermia, Ehlers-Danlos syndrome
Osteogensis Imperfecta Type I and IV
Osteochondromatosis/Multiple Hereditary Exostosis and Osteopetrosis (tarda, mild form)
Orthopaedic disroders that are inherited through a autosomal recessive pattern?
Diastrophic dysplasia
Friedreich’s Ataxia
Gaucher disease
Spinal muscular atrophy
Sickle cell anemia
Osteogenesis Imperfecta Type II and III
Hypophosphatasia
Osteopetrosis (infantile and malignant form)
What are examples of sex-linked recessive orthopaedic conditions?
Duchenne muscular dystrophy
Becker’s muscular dystrophy
Hunter’s syndrome
Hemophilia
SED tarda
Usually occur in males only.
What are examples of Sex-Linked dominant orthopaedic conditions?
Hypophosphatemic rickets
Leri-Weill dyschondrosteosis (bilateral Madelung’s deformity
What are some examples of diseases that demonstrate imprinting?
Angelman Syndrome
Prader-Willi syndrome
A genetic phenomenon by which certain genes ae expressed in a parent-of-origin-specific manner
What orthopaedic conditions demonstrate multiple inheritance patterns?
Charcot-Marie-Tooth (AD, AR, Xlink)
Osteopetrosis (AD, AR)
Osteogenesis Imperfecta (AR, AD)
Neurofibromatosis (AD, AR)
SED (AD, Xlink)
What happens to the retinoblastoma protein (pRB-1) in patients with retinoblastoma?
It becomes phosphorylated and is unable to bind to DNA to regulate.
Recessive suppressor
Both alleles must be mutated to have uncontrolled growth
What gene mutation is found in 50% of all tumors, osteosarcoma 20-65% of the time, and in chondrosarcoma?
p53
What is a tumor antigen?
What disease is associated with the following tumor antigens?
CEA
CA-19-9
CA-125
CA-15-3
AFP
Expressed by tumor cells. Used in the diagnosis, monitoring of treatment response, and are being researched for treatment options as anti-cancer vaccines.
CEA: colorectal carcinoma
CA-19-9: pancreatic cancer
CA-125: ovarian cancer
CA-15-3: Breast cancer
AFP: hepatocellular carcinomas
What is a siRNA used for?
It is a small interfering RNA
Blocks translation of mRNA
Useful for loss-of-function experiment designs
For the following diseases what are the translocations and diseases involved?
For the following skeletal dysplasia what is the mutation?
What is cytogenetic analysis used for?
Allows for the detection of gene translocations by evaluating the size and number of chromosomes isolated from the cell nucleus.
Present in up to 95% of sarcomas
How do you calculate stress?
Force/Area
What is the definition of strain?
How do you calculate strain?
relative measure of the deformation of an object
Change in length/original length
How do you calculate toughness?
area under the stress/strain curve
Joules per meter cubed is the units. J/m3
What is Hooke’s Law?
When a material is loaded in the elastic zone, the sress is proportional to the strain.
Describe Youngs modulus of elasticity.
Measure of the stiffness (ability to resist deformation) of a material in the elastic zone.
Calculated by measuring the stress/strain curve in the elastic zone.
A higher modulus of elasticity indicates a stiffer material.
Relative values of Young’s modulus of elasticity: 1. Ceramic (Al2O3) 2. Alloy (Co-Cr-Mo) 3. Stainless steel 4. Titanium 5. Cortical bone 6. Matrix polymers 7. PMMA 8. Polyethylene 9. Cancelous bone 10. Tendon/ligament 11. Cartilage
What is an isotropic material?
What is an anisotropic material?
A material that possess the same mecahnical properties in all directions.
A materail that possess different mechanical properties depending on the direction of the applied load. Ex-ligaments and bones.
What is a viscoelastic material?
A material that exhibits a stress-strain relationship that is dependent on duration of applied load and the rate by which the load is applied (strain rate)
Examples are ligaments and bone
What is fatigue failure and endurance limit as it applies to metals?
Fatigue failure- Failure at a point below the ultimate tensile strength secondary to repetitive loading. Depends on magnitude of sress and number of cycles.
Endurance limit- defined as the maximal stess under which an object is immune to fatigue failure regardless of the number of cycles.
What are the different types of corrosion involved in orthopaedic metals?
Galvanic corrosion- dissimilar metals leads to electrochemical destruction. Mixing metals 316L Stainless steel and cobalt chromium (Co-Cr) has the highest risk of galvanic corrosion.
Crevice corrosion- occurs in fatigue cracks due to differences in oxygen tension. 316L stainless most prone.
Fretting corrosion- A mode of destruction at the contact site from the relative micromotionof two materials or two components. Common at head neck junction in hip arthroplasty. Modular components are at increased risk.
What are the two components of PMMA?
POWDER: Polymer, benzoyl peroxide (initiator), barium sulfate (radio-opacifier), coloring agent (green chlorophyll or blue cobalt).
LIQUID: monomer, DMPT (N,N-Dimethyl para-toluidine, accelerator), hydroquinone (stabilizer)
Reaches ultimate strength at 24 hrs.
Modulus between cortical and cancelous bone.
Strong in compression, poor tensile and shear strength.
How do you calculate the bending rigidity of the following structures?
Solid Cylinder
Hollow Cylinder
Rectangular Object
Solid Cylinder- proportional to the radius to 4th power for a solid cylinder.
Hollow Cylinder- proportional to the radius to the 3rd power. This is sited in orthopaedic literature but not at all true.
Rectangular object- proportional to the (base x height) to the 3rd power.
Pullout strength of a screw is maximized by?
Large outer to inner diameter difference.
Fine Pitch
Most of all by quality of bone.
Pullout strength is proprotionate to outer(major) diameter to the 2nd power.
What will increase locking plate construct stability?
bicortical locking screws.
Increased number of screws
Screw divergence from screw hole < 5 degrees
Longer plate
torsional rigidity of an intramedullary nail is proportional to what?
Radius to the 4th power.
What factors increase stability of conventional external fixators in order of effectiveness?
Contact of ends of fracture
Larger diamter pins
Additional pins
Decreased bone to rod distance
Pins in different planes
Increasing size or stacking rods
Rods in different planes
Increased spacing between pins.
Factors that increase stability of circular (Ilizarov) external fixators?
Larger diameter wires
Decreasing ring diamter
Olive wires
Extra wires
Wires cross perpendicular to each other
Increased wire tension
Placement of two central rings close to fracture
Increased number of rings.
What is secondary osteoporosis?
What population is it more common in male or female?
Osteoporosis caused by things like hypogonadism, glucocorticoid excess, and alcoholism.
Can begin at any age.
What osteoporotic fracture are most common overall and for the following age ranges?
50-60 years
60-70 years
70-80 years
Vertebral body > hip > wrist fractures
wrist
vertebral
hip
What are the four categories of osteporosis risk factors?
Lifestyle
Medications
Genetic polymorphisms
Diseases
Do men or women have a higher risk of mortality after hip fractures?
Men
Is there an increased risk of a second hip fracture in a patient who experiences a hip fracture?
Yes 10-fold increase.
What is the main difference between post-menopausal and senile osteopororsis?
Senile affects both cortical and trabecular bone (still affects trabecular more) while post-menopausal is almost exclusively trabecular.
On histology what leads to increased osteoclast ruffled border?
What leads to a flattened ruffled border?
PTH. 1,25 dihydroxy Vit D3. Prostaglandin E
Bisphosphonates and Calcitonin
What is tetracycline labeling used for in relation to bone biopsy testing?
Helpful in determining if bone condition is osteoporosis or osteomalacia?
Osteoporosis = Normal tetracycline labeling
Osteomalacia = Abnormal tetracycline labeling.
What are the side effects of Teriparatide?
When is it contraindicated?
Teriparatide (Forteo)
Transient hypercalcemia, dizziness, nausea, and headache.
Contraindicated in Paget’s disease due to potential osteosarcoma risk.
What is the mechanism of Forteo?
How is it given?
Forteo or teriparatide is 1-34 amino terminal residues of parathyroid hormone (1-84)
Activates receptors on osteoblasts and renal tubule cells.
Is actually anabolic.
Stimulates intestinal absorption Ca and PO4.
What is the mechanism of Prolia(Denosumab)?
What effect does it have on reduction of fragility fractures?
What are the side effects and contraindications?
Monoclonal Ig2 against RANKL (inhibits binding of RANKL to RANK, like osteoprotegerin)
Reduced vertebral fractures by 68%, hip fractures by 40%, nonvertebral fractures by 20%
Side effects: arhtralgia, nasopharyngitis, back pain.
Contrainidcated in severe hypoclacemia.
What is the mechanism of Romosozumab (Evenity)
What effect does it have on reduction of fragility fractures?
What are the side effects and contraindications?
Humanized monoclonal Ig2 that activates Wnt pathway by binding sclerostin (sclerostin normally inhibits Wnt pathway). Promotes bone formation and inhibits resorption.
Reduced new vertebral fracture by 73% through month 12 and by 75% through month 24.
Given Sub-c injection monthly.
Side effects: Hyperostosis, cardiovascular events, osteoarthritis, and cancer. Watch out for osteonecrosis of the jaw, atypical femoral fractures.
Reserved for post-menopausal women with history of osteoporotic fracture, multiple risk factors who have failed other therapies.
What are the non-nitrogen containing bisphosphonates?
What are their mechanism?
Side effects:
Etidronate, clodronate, tiludronate
Produce toxic ATP analog
Esophagitis, dysphagia, gastric ulcers, osteonecrosis of the jaw, and atypical subtroch fractures.
What are the nitrogen containing bisphosphonates?
What are their mechanism?
Side effects?
Pamidronate. Alendronate (Fosamax). Risedronate (Actonel). Zolendronate (Reclast). Ibandronate (Boniva)
Inhibits farnesyl pyrophosphate synthase (mevalonate pathway)
Esophagitis, dysphagia, gastric ulcers, ONJ, atypical subtroch fractures
What are the associated orthopaedic manifestations of renal osteodystrophy?
Osteomalacia (adults) and growth retardation (children)
AVN
tendinitis and tendon rupture
Carpal tunnel syndrome- deposition of amyloid (B2 microglobulin)
Pathologic fracture- from brown tumors (hyperparathyroidism) or amyloid depotis
Osteomyelitis and septic arthritis.
What is the pathophysiology of the following in renal osteodystrophy?
hypocalcemia?
Hyperparathyroidism and secondary hyperphosphatemia?
Uremia related phosphate retention?
Hypocalcemia- due to the inability of the damaged kidney to convert vitamin D3 to calcitrol (the active form). Because of phosphate retention (hyperphosphatemia)
Hyperparathyroidsim and secondary hyperphosphatemia- cause by hypocalcemia and lack of phosphate excretion by damaged kidney.
Uremia related phosphate retention- The damged kidneys are not able to adquately secret phosphorus. THis causes insoluble calcium phosphate to form in the body which removes calcium from circulation. This leads to the hypocalcemia and secondary hyperparathyroidism and hyperparathyrodism. This it key pahtophysiological step responsible for osteomalacia.
What are the two broad classifications of renal osteodystrophy?
What are symptoms of hypocalcemia?
Abdominal pain
Muscle cramps
Dyspnea
Convulsions/seizures
Mental status changes
What are provocative tests for tetany found in some patiens with renal osteodystrophy?
Trousseau’s Sign- Carpalpedal spasm (painful cramps of the muscles in hands and feet) after blood pressue readings
Chvostek’s Sign- Facial muscle contractions after tapping on the facial nerve.
What is the treatment for renal osteodystrophy
Treat underlying renal condition and or relieve urologic obstruction.
What conditios does the radiographic findings suggest?
What are other radiographic findings?
Image is of a brown tumor that is found in patients with renal osteodystrophy.
Image below is of a looser’s zone
Will also see osteosclerosis from mineralization of osteomalacia bone.
Rugger jersey spine
Soft tissue calcifications
In children will see varus deformity of the femurs. Widened growth plate and zone of provisional calcification.
What will histology of renal osteodystrophy show?
Thinned trabeculae. See below.
Amyloid stains pink on Congo red stain.
Describe the different osteodystrophy conditions based on labs and their genetic inheritance?
What are the orthopaedic manifestations of Rickets?
Brittle bones with physeal cupping/widening
Bowing of long bones
Ligamentous laxity
Flattening of skull
Enlargement of costal cartilage (rachitic rosary)
Kyphosis (cat back)
What do you see on histology of a patient with Rickets?
Disordered and elongated zone of proliferation
Poorly defined zone of provisional calcification
Widened osteoid seams
Swiss cheese trabeculae
Abnormally arranged collagen fibers- run perpendicular to haversian canals.
What will you find on physical exam of a patient with Rickets?
Tibial bowing
Rachitic rosary
Bowing of knees
Retarded bone growth
Muscle hypotonia
Waddling gait
Dental abnormalities- Dleayed dentla eruption and defective enamel
Pathologic fractures
Who is at risk for nutritional Rickets?
Rare now that Vitamin D is added to milk
Presents ar 6 months - 3 years of age
RISK FACTORS: premature infants
Black children > 6 months who are still breastfed
Patients with malabsorption syndromes (celiac sprue) or chronic parenteral nutrition
Asian immigrants
Patients with unusual dietary choices (vegetarian diet)
Describe Vitamin D-resistant (familial hypophosphatemic) Rickets.
What are the three genetic forms.
What is Vitamin D-dependent Rickets?
What is the treatment for Rickets?
Nutritional Rickets- Vitamin D 5000 IV/day for 6-10 weeks
Famililia hypophosphatemic Rickets- Calcitriol. 20-30 mg/kg/day split into 203 doses in children. .5-.75 ug/day split into 2 doses in adults. Phosphate replacement 20-40 mg/kg/day split into 3-5 doses in children. 750-1000 mg/day split into 3-4 doses in adults. Recent research calls into question the addition of phophate.
Type I Vitamin D dependent Rickets- Calcitriol
Type II Vitamin D dependent Rickets- Vitamin D
What is the role of rheumatoid factor in rheumatoid arthritis?
It ias an IgM antiboday that targets native IgG antibodies.
Immune complexes then get deposited in end tissues liek the kidney as part of the pathophysiology.
What is the role of mononuclear cells in RA?
They are the primary cellular mediator of tissue destruction.
What factors are part of the cascade that leads to joint damage in RA?
IL-1, TNF-alpha
CASCADE OF EVENTS INCLUDE:
antigen-antibody and antibody-antibody reactions
microvascular proliferation and obstruction
Synovial pannus formation (histology shows prominent intimal hyperplasia)
Joint subluxation, chodnrocyte death/joint destruction, and deformity
Tendon tenosysnovitis and rupture.
What are associated medical conditions & comorbidities with RA?
Rehumatoid vasculitis
Pericarditis
Pulmondary disease
Felty’s syndrome (RA wiht splenomegaly and leukopenia)
Still’s disease (acute onset of FA with fever, rash, and splenomegaly)
Sjogren’s syndrome (autoimmune condition affecting exocrine glands) Decreased secretions from salivary and tear duct glands. Lymphoid tissue proliferation
What lat test is most sensitive and specific for RA?
Anit-CCP
Postive RF titer is elevated in 75-80% of patients with RA
What my you find on physical exam of a patient with RA?
subcutaneous nodules in 20% (strong association with positive serum RF).
Ulnar deviation with metacarpophalangeal subluxation and swan neck deformity
Hallux valgus, claw toes, and MTP subluxation
Joints become affected at later stage in disease process.
For the following drugs specify when to stop and when to restart with regards to surgical procedures?
What is the diagnostic criteria for Rheumatoid arthritis.
What is the mechanism of leflunomide and what is it used for?
inhibitor of pyrimidine synthesis
DMARD used in treatment of RA
What are the biologic, TNF anatagonist DMARDs?
What is the mechanism and use of ANakinra (Kineret)?
Recombinant IL1 receptor antagonist
DMARD used in the treatment of RA.
What is the mechanism of Rituximab (Rituxan)
Monoclonal antibody to CD20 antigen (inhibits B cells)
Biologic agent used in treatment of RA
What is the mechanism of Abatacept (Orencia)?
Selective costimulation modulator that binds to CD80 and CD86 (inhibits T cells)
Has been used in the treatment of RA
What is the mechanism of Tocilizumab (Actemra)?
IL6 receptor inhibitor (2nd line treatment for poor response to TNF-antagoinst therapy.
HAs been used in treatment of RA
What is the most common extra-articular manifestions of RA?
Rheumatoid nodules. Seen in up to 25% of patients with RA
Associated with aggressive disease.
Found over IP joints, olecranon, and ulnar border of the forearm.
Can eroid through skin.
Can be treated with steroid injections or surgical excision.
What is arthritis mutilans?
digits develop gross instability with bone loss (pencil in cup deformity or wind chime fingers).
Seen in patients with RA or psoriatic arthritis.
Treated with interposition bone grafting and fusion.
What is the operative treatment for early ulnar drift in a patient with RA?
Synovectomy, extensor tendon centralization, and intrinsic release.
When do you perform a MCP arthroplasty vs a MCP fusion for patients with Rheumatoid diseases and severe symptoms?
MCP arthroplasty when there is thumb MCP involvement + thumb IP involvment
MCP fusion when there is only thumb MCP involvement.
What is the pathoanatomy of a Boutonniere deformity?
Synovitis of PIP leads to central slip and dorsal capsule attenuation
Increasing PIP flexion
Lateral bands subluxate volar to axis of rotation of PIP
Oblique retinacular ligament contracture causes extension contracture of DIP.
What is the pathoantomy of a Swan neck deformity in RA?
Terminal tendon rupture from DIP synovitis leads to DIP flexion/PIP hyperextension
FDS, volar plate, and collateral ligament attenuation from synovitis leads to decreased volar support of PIP, and hyperextension deformity.
Lateral band subluxate dorsal to pIP axis of rotation
Contracture of triangular ligament, attenuation of transverse retinacular ligament.
Briefly descirbe Flexor tendon conditions in RA?
Describe Extensor Tendon Conditions in RA?
Name as many of the primary hypercoagulopathies that are inhertied as you can?
MTHFR/C677T/TT gene mutation carries highest risk
Factor V Leiden mutation
Antithrombin III deficiencey
Protein C deficiency
Protein S deficiency
Activated protein C resistance
Elevated factor VIII
Hyperhomocyteinemia
Prothrombin II G20210A
What are secondary or acquired factors that increase risk of thromboembolism?
Malignancy- recently been associated with up to 20% of all new diagnosed VTE
Elevated hormone conditions- recombinant erythropoeitin, hormone replacement, oral contraceptive therapy, and late pregnancy
Elevated antiphospholipid antibody conditions- Lupus anticoagulant and anticardiolipin antibody
History of thromboembolism, obesity, agiing, CHF, varicose veins, smoking, general anesthetics, immobilization, increased blood viscosity, rapid increase in INR following unopposed intiitation of warfarin therapy in arthroplasty patients.
Describe the Extrinsic and Intrinsic coagulation cascades?
What factor is released as a direct result of surgical dissection that leads to clot formation?
Thromboplastin.
For standard patients what is recommended for anticoagulation by the AAOS for:
Upper extremity procedures
Arthroscopy
Isolated fractures at knee and below
No clear evidence for any of these to receive chemoprophylaxis
True or False the AAOS and the American College of Chest Physicians support ASA as a monotherapy in Hip and Knee arthroplasty?
True
For the anticoagulants listed below describe their mechanism?
For the following medications list where in the coagulation cascade they exert their effect:
Unfractionated heparin
Lovenox
Warfarin
Fondaparinaux (Arixtra)
Rivaroxaban (Xarelto) and Apixiban (Eliquis). Same class less common Edoxaban (Savaysa or Lixiana)
Dabigatran (Pradaxa)
What is thei difference in the mechanism of aspirin and NSAIDs?
Aspirin is a irreversible inhibitor of cyclooxygenase enzyme
NSAIDs are reversible inhibitors of cyclooxygenase enzyme
What is the specific mechanism of aspirin?
Acts as an acetylating agent where an acetyl group is covalently and irreversibly attached to a serine resiude in the active site of the cyclooxygenase enzyme.
Inhibits the production of prostaglandins and thromboxanes through irreversible inactivation of the cyclooxygenase enzyme within platelets.
What is the function of thromboxane?
Under normal conditions thromboxane is responsible for the aggregation of platelets that form blood clots.
What is the function of prostaglandins?
Are involved in
The transmission of pain information to the brain
Modulation of the hypothalamic thermostat
Inflammation
Is there a difference in the metabolism of Unfractionated heparin and Low Molecular weight Heparin?
Yes
Unfractionated heparin is metabolized in the liver.
Low molecular weight heparin is metabolized in the kidney.
What is the specific mechanism of warfarin?
Inhibits vitamin K 2,3-epoxide reductase- prevents reduction of vitamin K epoxide back to active vitamin K
Vitamin K is needed for gamma-carboxylation of glutamic aacid for factors- II (prothrombin), VII (first affected), IX, X
Protein C and Protein S
Warfarin can have adverse reactions with what other drugs?
rifampin
phenobarbital
diuretics
cholestyramine
What is the antidote for Dabigatran (Pradaxa)?
Idarucizumab
What dietary supplements have been found to increase the rate of bleeding by haveing an effect on platelets?
Gingko, ginseng, and garlic
What products can increase the effect of Warfarin?
What products can reduce the effect of warfarin?
Omega-3 Fish Oil
Reduced warfarin effect from Coenzyme Q10, Green tea, and St. John’s wort.
What other ways does hypocalcemia present besides neruomuscular irritability?
Cataracts
Fungal infections of the nail
Hair loss
Skin changes- vitiligo and blotchiness of skin
What is the most common cause of hypoparathyroidsim?
What does it result in?
iatrogenic- thyroidectomy most common cause
Decreased production of PTH by chief cells results in:
Decreased plasma calcium levels
Increased plasma posphate levels
Decreased 1,25 (OH)2 Vitamin D levels
No current hormone replacement therapy available. Treatment is aimed at supplementing Vit D and calcium.
For the following disorders describe the changes in Serum Ca, Serum Phos, PTH, and the most common cause:
Hyperparathyroidism
Hypoparathyroidism
Ectopic PTH
Vit D Malabsorption
Hypo vit D with no phosphate excretion frim the kidney
What are the three symptoms of hyperparathyroidsim?
Stones- kidney stones
Bones- Bone pain
Groans- constipations
What are the complications of hyperparathyroidism?
Peptic ulcer disease- Increased gastrin production stimulated by increased ca++
Acute pancreatitis- Increased lipase activty stimulate by increased ca++
CNS dysfunction- anxiety, confusion, coma, result of metastatic calcification of the brain
Osteoporosis- Bone loss occurs as result of bone resorption due to excess PTH. Orthopaedic surgeons should recognize lab abnormalities as patients may present with fragility fractures.
Treatment for Hyperparathyroidism?
ACUTE HYPERCALCEMIA- IV fluids and loop diuretics
SYMPTOMATIC HYPERCALCEMIA- Treated surgically with parathyroidectomy. Complication is post-op hypocalcemia that should be treated with IV calcium gluconate.
What are the three classes of hyperparathyroidism?
What serum lab values are to be expected?
PRIMARY: hypersecretion of PTH by a parathyroid adenoma(90%)/hyperplasia(10%)
SECONDARY: Secondary parathyroid hyperplasia as compensation from hypocalcemia or hyperphosphatemia. Decreaed gut Ca++ absorption with increased phosphorus.
Associated conditions are chronic renal disease and renal osteodystrophy
TERTIARY: parathyroid gland becomes dysregulated after secondary hyperparathyroidism and secrete PTH regardless of Ca++ levels.
What mutation causes hypophosphatasia?
What is the pathophysiology of the disorder?
mutation in the tissue-nonspecific isoenzyme of alkaline phophatase (TNSALP).
Low levels of alkaline phosphate result in decreased synthesis of inorganic phosphate necessary for bone matrix formation.
Osteoid that forms in the hypertrophic zone of the growth plate fails to mineralize
The zone of provisional calcification never forms and growth is inhibited.
Autosomal recessive
This image is consistent with what disease process?
hypophosphatasia
Image shows deossification of bone adjacent to growth plate.
Presentation is similar to Rickets. Genu varum and short stature.
Will also see abnormal dentition
No approved therapies or treatments.
What is Von willebrand’s disease?
Genetic bleeding disorder caused by missing or defective von Willebrand Factor (VWF) a clotting protein.
In what cases should prophylactic antibiotics exceed 24 hours.
In clean and clean contaminated procedures where the incision is closed prophylactic abx should never exceed 24 hours.
Even in the presence of a drain.
What patients should have prophylactic abx prior to dental procedures?
All patients for the first two years after TJA.
Immunocompromised patients
Drug induced innumon suppression
Radiation induced immunosuppression
Inflammatory arthropathies including SLE and RA
COMORBIDITES INCLUDING: previous joint infection, Type I diabetes, malnourishment, hemophilia. HIV, and malignancy.
According to AAOS and ADA there is limited eveidence to support this so need to use clinical judgment.
How and what abx should be administered prior to dental procedures?
Amoxicillin or cephalexin 2 grams orally 1 hour prior to procedure
If allergic to penicillin then 600mg orally.
What immunizations should be given to a splenectomized patient?
Pneumococcal
Haemophilus influenze type B
Meningococcal Group C
Influenza
Lifelong prophylactic antibiotics (oral phenoxymethylpenicillin or erythromycin.
What enzymes are targeted by NSAIDs?
What do these enzymes do?
COX-1 and COX-2
There are some COX-2 spefic inhibitors. Celebrex and Vioxx (rofecoxib). Maintains the beneficial effects of COX-1 (maintaining gastric mucosa, regulating renal blood flow, and influencing platelet aggregation). Also can be used in the perioperative period because they do not affect platelet function.
COX enzymes catalyze the formation of prostaglandins and thromboxane from arachidonic acid.
What is the biggest reason concurrent NSAID and anticoagulant use is discouraged.
Greatly increases risk of gastrointetsintal side effects.
Peptic ulcer perforation, bleeding, or obstruction.
NSAIDs also have some cardiac toxicity.
True or false bisphosphonate use following lumbar fusion leads to decreased fusion mass, but no chane in the actual fusion rate?
False
Leads to increased fusion mass but decreased actual fusion rate.
What medication can be given to patients with osteogenesis imperfecta that reduces bone pain and fracture incidence?
Also increases level of ambulation and bone density.
Cyclical IV pamidronate
Nitrogen containing bisphosphonate- inhibits farnesyl pyrophosphate synthase enzyme, required in mevalonate (cholesterol pathway). Inhibits GTPase formation.
What is substance P?
A sensory neurotransmitter that plays an important role in pain.
Depletion of substance P increases the threshold to painful stimuli
Capsaicin is thought to function by decreasing substance P
What is the most accurate method to control pain and avoid respiratory depression in the morbidly obese patient?
PCA which is based on the patients ideal weight.
True or false: Red haired patients often require more anesthesia to maintain MAC levels and higher opioid dosages postoperatively compared to other hair types.
True
What is the mechanism of methadone?
What is its metabolism?
Synthetic diphenylheptaine-derivative opioid receptor agonist
High bioavailability (three times as much as morphine), effective, and inexpensive.
Metabolism: Cytochrome P450
CAUTION: can accumulate to high levels with repeated dosing. Rates of elimination very considerably.
Risk of respiratory depression and cardiac toxicity (torsades de pointes)
What is the mechanism and use of cyclobenzaprine?
Mechansim not fully understood but it is centrally acting and potentiates norepinephrine and binds serotonin receptros.
Useful in decreasing pain during first two weeks after an injury. No proven benefit after first two weeks.
May interact with MAOIs and alcohol.
Describe the mechanism of the various classes of antibiotics?
What are non-orthopaedic effects of anabolic steroids in a patient that should be considered prior to surgery?
Increase of procoagulant factors VII and IX and thromboxane, which leads to hypercoagulability.
Liver function is upregulated as the steroids induce hepatic enzymes and patients are therefore less sensitive to anesthetic agents.
Have a mineralcorticoid effect on the kidnes leading to edema and hypertension. Often have fluid and electrolyte imbalances because of this.
Higher oxygen consumption and CO2 production.
What is associated with a MECP2 mutation?
Rett syndrome?
Inherited in an x-linked dominant fashion.
Will have a C-shaped curve.
What diseases are associated with the following mutations?
GNAS1
CLCN7
TGF-BR2
PHEX
COLIA1
GNAS1- fibrous dysplasia
CLCN7 and TC1RG1- Osteopetrosis
TGF-BR2 and FBN1- Marfan syndrome
PHEX- x-linked hypophophatemic rickets
COLIA1 and COLIA2- Osteogenesis imperfecta
Name 5 TNF-a inhibitor medications?
Etanercept
Infliximab
Adalimumab
Golimumab
Certolizumab pegol
What kind of medication is Imatinib?
Tyrosine-kinase inhibitor
Used to treat Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML)
What is the mechanism of Denosumab?
What are the two commerical forms of Denosumab?
What are they used to treat?
RANKL inhibitor
Prolia- used to treat osteoporosis Xgeva- Used for prevention of skeleton-related events in patients with bone metastases, giant cell tumors, multiple myeloma with bone mets, and hypercalcemia of malignancy.
what disease process is most likely depicted by the radiograph below?
This is a “White line of Frankl”
Seen in scurvy.
also will see bluish-purple hue of the gums with areas of hemorrhages.
Affects the spongiosa layer of the physis most.
What cell produces synovial fluid?
fibroblast-like type B synovial cell.
Type A synovial cells are important phagocytic cells.
The addition of what antibiotic with mexotrexate has been shown to be more effective in the treatment of rheumatoid arthritis?
Doxycycline
Tetracyclines have biologic effects on the inflammatory and immunologic cascade inhibiting collagenase activity.
Collagenase is an enzyme invovled in breaking down macromolecules in the connective tissue, contributing to the pathologic changes of RA.
What disease process is associated with altered BMP-4 signal transduction?
Fibrodysplasia ossificans progressiva
Also known as “stone man disease”
Massive spontaneous heterotopic bone so much that their bodies literally ossify.
What is osteopoikilosis?
Spotted bone disease
Caused by defective LEMD3 gene
What type of collagen production is found during the inflammatory phase of tendon and ligament healing.
Type III
However tendons and ligaments are still predominantly composed of Type I collagen.
What is released by the osteoclasts to resorb bone?
Cathepsin K, Matrix metalloproteinase, and carbonic anhydrase (CA II)
airbags have been found to not have any significant effect on decreasing what kind of injuries?
Pelvic ring injuries.
Decrease closed head injuries, facial fractures, shock, thoracoabdominal injuries, and need for extraction.
What is the mechanism of Linezolid?
Unique inhibition of the bacterial ribosome.
Binds to the site on the 23S ribosomal RNA of the 50S subunit, preventing formation of the 70S initiation complex and interrupting the translational process.
What is the mechanism of action of Rifampin?
Inhibition of DNA-dependent RNA polymerase
That is the mechanism of action of Daptomycin?
Bacterial cell membrane depolarization interrupting DNA, RNA, and protein synthesis.
What products can be given to Jehovah witnesses?
What things are a gray area and dependent upon individaul choice?
What is not accepted?
Crystalloid, starch products such as Hetastarch and Hespan. Colloids are generally accepted.
Cell saver and hemoglobin based oxygen carries are generally accpeted but should check with the individual patient.
Whole blood, PRBC, platelets, white cells, or plasma. Autologous transfusion whether from the patient or donor directed is forbidden.
What is hypophosphatasia?
autosomal recessive disorder caused by an inborn error in the production of alkaline phosphatase (tissue-nonspecific isoenzyme of alkaline phophatase: TNSALP), leading to low alkaline phophatase levels.
Increased urinary phosphoethanolamine is also diagnostic.
What is the cause of myasthenia gravis?
autoimmune antibodies at the NM junction leading to loss of acetylcholine receptors.
Progressive weakness. Rest periods may allow early strength but easy fatigability.
Acetyl cholinesterase inhibitors along with thymectomy can help control symptoms.
What is a high Alveolar-arterial gradient?
What may it incidcate?
> 20mm Hg or 2.7 kPa on aterial blood gas
May indicate pulmonary embolism.
What is Ogilvie Syndrome?
Acute colonic pseudo-obstruction
ASsociated with advanced age, male gender, narcotic pain medications, and patients who have undergone hip arthroplasty.
Diagnosis made with abdominal radiograph that demonstrates dilation of the large intestine.
What is added to whole blood as an anticoagulant during the process of preparation of the PRP before centrifugation?
What is used to initiate platelet activation?
Citrate Dextrose
Calcium chloride and thrombin are added to initiate platelet activation.
Besides Type I collagen what is found in tendons?
Types III, V, VI, and proteogylcans. (5%)
Decorin is the most common proteoglycan in tendons.
What role does quorum sensing play in the development of a bacterial biofilm?
After several bacteria have attached quorum sensing (cell-to-cell communication) allows maturation of the biofilm and expression of genes that activate virulence factors.
What enzyme is blocked by Warfarin?
vitamin K 2, 3-epoxide reductase, the enzyme needed for the reduction of vitamin K epoxide back to its active form.
Active vitamin K is required for the postribosomal synthesis of acitve coagulation factors II, VII, IX, and X, as well as protein S and C.
What disorder is caused by a glycine substitution in the procollagen molecule?
Osteogenesis imperfecta
What are the differences between VDDR type 1 and VDDR type 2?
VDDR (vitamin D-Dependent Rickets.
Type 1 is a deficiency of 1a-hydroxylase
Type 2 is caused by an inactivating mutation of the receptor for 1,25 (OH)2 vitamin D3.
What diseases are involved with the following genes?
ASPL
ATF1
EWS
PAX3
USPR
ASPL- alveolar soft part sarcoma (tX;17)
ATF1- Clear cell chondrosarcoma
EWS- Ewing’s sarcoma (EWS-FLI1) (t11;22) but also
Where are the following mechanoreceptors located in a tendon and what is their function?
Golgi organs- steady state information when underoging large stimulation for prolonged periods
Pacini corpuscles- sensitive, fast adapting mechanoreceptors
Ruffini endings- very sensitive, acan also be long acting
All of the above are in the myotendinous junction.
Free nerve endings are in the enthesis and are responsible for nociception
What disease processes are the following associated with?
USP6- ubiquitin-specific protease 6
CSF-1 colony-stimulating factor 1
MDM2- mouse double minute-2 homolog
PDGFB- platelet-derived growth factor beta
USP6- aneurysmal bone cysts and nodular fasciitis
CSF-1 diffuse pigmented villonodular synovitis
MDM2- low-grade and parosteal osteosarcoma and atypical lipomatous tumors
PDGFB- Dermatofibrosarcoma protuberans
What is the shelf life of freeze dried bone?
The shelf life is limited only by the duration of its sterility as dtermined by the packaging.
usually 5 or more years.
What is the mechanism of abatacept?
Selective costimulation molecule that binds to CD80 and CD86 cells.
Inhibits T cells
Also has been described as a major histocompatibility complet (MHC) receptor antagonist
Commercial name Orencia
Name some of the non-rhizomelic dwarfisms?
Diastrophic dysplasia
Multiple epiphyseal dysplasia
Metaphyseal chondrodysplasia
Spondyloepiphyseal dysplasia
Kniest Dysplasia Chondroectodermal dysplasia/ Ellis-van Creveld syndrome
