Unit 2 WFA

1) The patient has a Salter-Harris type II fracture. The type II fracture disrupts the physis and extends into metaphysis. A type I fracture is a disruption of the physis without injury to the epiphysis or metaphysis. The separation usually occurs between the physis and metaphysis. A type III fracture is an intraarticular fracture through the epiphysis that extends across the physis to the periphery. In this type of fracture, a portion of the physis separates from its metaphyseal attachment. A type IV injury traverses the epiphysis, physis, and metaphysis and has a high risk for growth plate disturbance. In the type V injury, the physis sustains a crush or compression injury and is at great risk of growth arrest. These injuries are rare. 2) This patient has now developed acute compartment syndrome. Left untreated, acute compartment syndrome can result in muscle contracture, sensory deficits, paralysis, infection, fracture nonunion, and possibly limb amputation. Rhabdomyolysis may occur with muscle ischemia, resulting in myoglobinuria and possible renal failure necessitating dialysis. 3) 1. Inflammatory Phase - Vascular supply is disrupted; hematoma is formed that stops bleeding; immune cells invade the fracture site. 2. Soft Callus Phase - New vessel invasion; hematoma replaced by granulated tissue; precursor cells in fracture site become chondrocytes and fibrocartilage is made; chondrocytes begin to calcify cartilage. 3. Hard Callus Phase - A hard callus is formed by intramembranous ossification peripherally; endochondral ossification replaces the calcified cartilage; woven bone is laid down. 4. Bone Remodeling Phase - Calcified cartilage is replaced by secondary or mature bone; fracture callus is resorbed, and the original shaft is approximated; work performed by osteoblasts and osteoclasts. 4) The patient fractured the lateral tibial plateau and proximal fibula. The common fibular nerve is a branch (part) of the sciatic nerve. The common fibular nerve passes superficially around the posterolateral tibia and fibular head. The fracture injured the nerve and caused transient loss in motor function to the muscles of the anterior and lateral compartments of the leg. The muscles of these compartments dorsiflex and evert the foot, respectively.

A 13-year-old boy presents to the clinic with swelling and pain in his right lateral lower knee. He tells the physician that he was playing superheroes with his friends and jumped off a first-floor roof to replicate a move by his favorite superhero, Black Panther. When asked, the patient reports that his landing was awkward, with an extended leg. Subsequent X-rays reveal a mildly displaced fracture in the lateral tibia (see image below). 1) Identify the Salter-Harris type for the tibial fracture. Identify and describe the major Salter-Harris fracture classification types. 2) The patient's tibia and fibula fractures are treated with closed reduction and casting. One hour later, the patient develops severe deep burning pain and paresthesias of the right foot. Identify this patient's new condition, and explain the risks associated with delayed identification and treatment of this patient's condition. 3) Outline the distinct phases of fracture healing. 4) The patient experiences a transient weakening of dorsiflexion and eversion of his foot during the first ten days after his injury. Soon after he makes a gradual recovery, with a return to full strength. Discuss, in anatomical terms, how this transient motor function deficit occurred as a result of his injury. Relate the injury specifically to the resulting symptoms.

1) Estrogen promotes/accelerates cell proliferation in the growth plate and ultimately causes the fusion of the growth plate once the proliferative potential of the cells is exhausted. The patient generally lacks sufficient estrogen to eventually cause the proliferative potential of the cells to be exhausted. This explains the patient being in the 99th percentile for height. Estrogen replacement therapy will eventually slow long bone growth and promote fusion of the growth plates in this patient to achieve final adult height. 2) Estrogen is an anti-resorptive hormone. Binding of estrogen with receptors on osteoblasts promotes osteoprotegerin (OPG) expression and induces osteoclast apoptosis. OPG is a negative regulator of osteoclast differentiation. In the absence of estrogen, osteoblasts and osteocytes express RANKL, and osteoclast survival increases. Both consequences promote greater osteoclast differentiation and bone resorption, resulting in osteoporosis. 3) Cortical bone remodeling is performed by cutting cones that are aligned to the long axis of the long bone shaft. The cutting cone consists of a front of resorbing osteoclasts followed by bone forming osteoblasts and finally endothelial cells that contribute to the developing blood vessel. The product of a cutting cone is an osteon. Trabecular bone remodeling takes place on the surface of a trabecula/trabeculum. Osteoclasts and osteoblasts work in series at a site (surface) to resorb and add bone, respectively. The product of trabecular bone surface remodeling is parallel lamellae. This patient has estrogen-depleted osteoporosis. Relative bone loss in osteoporosis typically is greater in areas containing trabecular bone than in cortical bone. One possible reason for this is that the available surface area (due to its greater porosity) is much greater in trabecular bone than in cortical bone. Thus, there is more surface area for cellular activity to take place.

A 14-year-old female presents to the pediatric clinic. She is in the 99th percentile for height and is mildly obese (BMI=30 kg/m2). The pediatrician, upon suspicion of an aromatase deficiency, performs a bone mineral density analysis of the girl's spine and hip, which shows osteoporosis. 1) The young female is found to have a genetic aromatase deficiency, which negatively affects the production of estrogen. She is started on hormone replacement therapy with estrogen. Discuss the effect of estrogen on the growth plate and how treatment with hormone replacement therapy will affect her growth in height. 2) Explain why the patient has osteoporosis. 3) Contrast the process of remodeling in cortical and trabecular bone. Predict which bone type would experience greater bone loss (by volume percentage) in this patient and justify your answer.

1) Delivering the injection along the anterior aspect of the femoral neck avoids potential trauma to the main arterial supply of the proximal femur. A superior femoral neck injection creates a risk of injuring the retinacular arteries, branches of the medial circumflex femoral artery. These branches are the primary suppliers of blood to the superior proximal femur metaphysis. An inferior-medial femoral neck injection creates a risk of injuring the medial circumflex femoral artery in its course to the posterior capsule. It could also put at risk for injury the inferior retinacular branches of the medial circumflex femoral artery.

A 16-year-old boy presents to his primary care physician with left groin pain several months after a motor vehicle accident in which the dashboard struck his left femur. At the time of the accident, a series of radiographs were taken of the passenger's pelvis, bilateral acetabulum and femurs. No fractures were found, and the hip joint was not dislocated. His PCP orders an MRI and refers him to a PM&R physician for a lidocaine diagnostic injection of his hip joint to rule out an acetabular tear. 1) Discuss the rationale for delivering the injection in the anterior femoral neck aspect of the capsule as opposed to the superior or inferior-medial aspect of the capsule around the femoral neck.

1) The microbe responsible for this disease is Cutibacterium (Propionibacterium) acnes. The central role of P. acnes in acne is to stimulate an inflammatory response. It does this by producing a small peptide within the sebaceous follicles it resides in to attract leukocytes. The bacteria are phagocytized and, after release of bacterial hydrolytic enzymes (lipases, neuraminidase, and hyaluronidase), stimulate a localized inflammatory response. P. acnes releases lipases, neuraminidase, and hyaluronidase as mechanisms of penetrating the cell membrane and degrading host tissue. Lipase production by P. acnes is a major etiological factor, releasing free fatty acids from sebum triglycerides. P. acnes neuraminidase targets the ubiquitous sialic acids on the surface of cells to penetrate cell membranes and cause tissue damage. Finally, hyaluronidases are enzymes that degrade hyaluronic acid, a component of the extracellular matrix of connective tissue. 2) The most important monitoring parameter for a female of child-bearing age taking isotretinoin is pregnancy status. Since isotretinoin is highly teratogenic, a pregnancy test is required at baseline and monthly during treatment. Patients taking isotretinoin should also be monitored for adverse psychiatric events such as mood changes, depression, and suicidal ideation, as these have been reported in patients taking isotretinoin. Finally, routine monitoring of liver function tests, serum cholesterol and triglycerides at baseline and two months into therapy is recommended, since isotretinoin commonly causes elevations of blood lipid levels and liver enzymes. Although usually harmless, these changes can lead to more serious conditions such as pancreatitis and hepatitis. 3) Papular acne consists of papules, which are palpable lesions that are less than 1 cm. Pustular acne has lesions that are elevated and filled with purulent fluid. 4 main processes that lead to acne include: 1. Follicular epidermal hyperproliferation: This is triggered by hormones, mainly androgens, at the beginning of puberty. Excess keratinocytes produce excess keratin, which is sticky and plugs the hair follicle opening, forming a microcomedone (closed at this point). 2. Excess sebum production from sebaceous glands: Oiliness also contributes to the follicle plugging and is associated with androgenic stimulation. 3. Inflammation: Microcomedones continue to fill with sebum, keratin, and bacteria and eventually rupture, causing inflammation. 4. Presence of Proprionibacterium acnes: Sebum breaks down into free fatty acids. This bacterium proliferates with this supply of free fatty acids. In addition to the other inflammatory factors, the P. acnes cell wall proteins cause an immune cascade response, increasing inflammation.

A 16-year-old female presents to her pediatrician with a severe acne outbreak and is visibly distraught about her appearance. She reports spending long hours studying in preparation for her ACT exam and relying on the vending machine and take-out pizza for her sustenance. She has a past medical history of acne vulgaris with no prior treatment other than over-the-counter acne wash. 1) Identify the microbe responsible for this disease and explain how it stimulates an inflammatory response in the host. Include in your discussion the role of the following virulence factors: lipases, neuraminidase, and hyaluronidase. 2) The patient's acne does not respond adequately to topical retinoids or systemic antibiotics, so the pediatrician considers prescribing isotretinoin. Justify at least two parameters the pediatrician should monitor during the treatment period and explain why they should be checked. 3) During physical examination, the patient is noted to have papular and pustular acne on the face, chest and upper back. Differentiate these two types of acne and briefly describe the four main processes that cause acne.

1) Paget's disease classically progresses through osteolytic, mixed osteolytic/osteoblastic, and late osteosclerotic phases. The osteolytic phase is characterized by increased osteoclastic activity resulting in numerous resorption pits populated by osteoclasts which are abnormally large and have increased numbers of nuclei. The mixed phase is characterized by increased but disorganized osteoclastic as well as osteoblastic activity. Osteoclasts persist in the mixed phase, but many of the bone surfaces at this point are also lined by plump osteoblasts. The newly formed bone may be woven or lamellar, but eventually it is all remodeled into lamellar bone. In the final osteosclerotic phase, osteoclastic activity is quiescent, but some osteoblastic activity persists. Histologically, the hallmark of mature Paget's disease is evidence of disorganized bone formation characterized by haphazard cement lines as seen in the figure above. Coarsely thickened trabeculae and soft, porous cortices lack structural stability and make the bone vulnerable to fractures. 2) A) AP & lateral radiographs (2-view X-rays) of the left humerus B) Radionuclide whole-body bone scan

A 68-year-old man presents to the emergency department and states "I think I broke my arm". He indicates that he was working in the yard using a pickaxe to dig a hole, and he felt a snap in his left upper arm while hoisting the tool. He denies direct trauma to the area. His medical history is significant for chronic back pain which has been increasing in recent months. Upon physical examination, the patient demonstrates tenderness and deformity of the left mid humerus, mild kyphosis, and some bowing of the femurs and tibias bilaterally. Laboratory evaluation reveals a significantly elevated alkaline phosphatase, confirmed upon further studies to be bone-specific. An initial imaging test is performed which demonstrates a pathological fracture of the left humerus. Based upon this finding, the radiologist recommends additional local imaging of the fractured area and a "whole-body" scan. The "whole-body" scan demonstrates multiple "hot" lesions of the axial skeleton and skull. An image-guided biopsy of the fractured area is then performed. The image-guided biopsy demonstrates changes consistent with Paget's disease of bone with no evidence of malignancy, as shown. 1) Describe the three phases of the evolution of Paget's disease of bone and correlate the histologic features of each phases with the associated abnormal physiology. 2) A) Identify the most appropriate initial imaging test that the primary care physician should order in a patient with such a presentation. B) Identify the imaging modality recommended for the "whole-body scan"?

1) Most hyaline cartilage has a perichondrium that is vascularized and contains an inner layer with mesenchymal stem cells which are a source for new chondroblasts for repair. On the other hand, fibrocartilage has no perichondrium, and therefore has a limited ability to regenerate. 2) The patient has a right anterior fibular head somatic dysfunction. To perform a post-isometric relaxation muscle energy technique, the right fibular head would be supported while the right ankle/foot is plantarflexed and inverted to induce posterior fibular head motion into the patient's restrictive barrier. The patient would be instructed to dorsiflex, evert, and externally rotate their ankle/foot while the physician provides an isometric resistance. The physician would maintain this contraction for 3-5 seconds, then have the patient relax. The physician would then move the ankle/foot into further plantarflexion and inversion to move the fibular head motion further posterior into the new restrictive barrier. This is repeated a total of 3-5 times, the patient is returned to neutral, and fibular head motion is then reassessed. 3) Going from largest to the smallest in hierarchy, the major structural protein of a tendon is a collagen type I heterotrimer. Collagen type I copolymerizes with type V collagen and other fibril-associated collagens with interrupted triple helices (FACIT) that self-assemble to form a tendon fibril. The smallest structures visible in electron microscopy are collagen triple helices. Bundles of tendon fibrils form fibers which make up a tendon fascicle. A tendon's fascicle is wrapped by loose connective tissue called an endotenon. Multiple fascicles are then wrapped by connective tissue called an epitenon to form a complete tendon. 4) The three steps of tendon repair are inflammation, proliferation/recruitment of stem cells, and remodeling. Remodeling begins with type III collagen secretion, which is followed by secretion of type I collagen to form more mature tendinous tissue. The usual surgical repair or conservative approaches such as physical therapy still produce fibrovascular scars which are mechanically weak compared to uninjured tissue. It has been shown in many animal studies that controlled mechanical stress of healing tendons results in better outcomes though the timing and magnitude of the load is debated. Increased cellular proliferation of fibroblasts and mesenchymal stem cells and their collagen production has been found to be upregulated in tendons exposed to static or cyclic uniaxial tension.

A 16-year-old female presents to her primary care physician with right knee pain. She is a soccer player and states that the pain started two days ago after getting hit on the outside of his knee. On physical exam, the patient appears to be limping when bearing weight on the right leg. There is a visible knee effusion with medial joint line tenderness. She exhibits pain when valgus stress is applied to the knee at 30 degrees of flexion. She also has medial joint line pain with passive flexion and extension of the knee with external tibial rotation (McMurray's exam). The tibia also translates forward 8mm with no endpoint (Lachman's/Anterior drawer). Osteopathic structural exam findings include right fibular head motion that is restricted with posteromedial joint glide and with enhancing maneuvers of ankle plantar flexion and inversion; the fibular head moves freely into anterolateral joint glide with ankle dorsiflexion and eversion. 1) Contrast the structure of fibrocartilage of a meniscus to hyaline cartilage found elsewhere in the body. Identify how these differences relate to growth and repair of articular cartilage. 2) Outline the performance of post isometric relaxation muscle energy to treat this patient's fibular head somatic dysfunction (name the dysfunction). 3) Describe the structural hierarchy of the tendon, including its major collagen subtypes. 4) Briefly, outline the process of tendon healing and describe the role of mechanical stress on the healing process.

1) The patellar reflex tests the L2, L3, and L4 nerve roots. The spinal reflex arc (stretch reflex) is initiated by the tap of the patellar tendon, which passively stretches the muscle spindle and distorts the central region of the intrafusal fibers. This stimulates the sensory group Ia afferent neurons to generate receptor potentials and subsequent action potentials into the spinal cord. In the spinal cord, these sensory group Ia afferent neurons terminate directly onto the alpha motor neuron of the agonist muscle, the rectus femoris, and stimulates excitatory postsynaptic potentials. This initiates action potentials down the alpha motor neuron to stimulate the release of acetylcholine and contraction of the quadriceps. At the same time, branches of the sensory group Ia afferent neurons terminate on and excite interneurons that initiate an inhibitory postsynaptic potential of the alpha motor neuron of the antagonist muscle, the hamstring, causing relaxation. This reciprocal innervation allows for the knee to flex. This relieves the stretch on the muscle spindle, which decreases the electrical activity of the sensory group Ia afferent neurons and terminates the reflex. 2) An upper motor neuron is considered the neuron that begins in the motor (or premotor) cortex of the cerebrum and synapses with a lower motor neuron. A lower motor neuron is the neuron in the motor pathway that leaves the central nervous system through the ventral horn of the spinal cord. Therefore, it is the second neuron in the pathway found primarily in the peripheral nervous system. This patient is suffering from a lower motor neuron lesion indicated by the hyporeflexia, decreased muscle tone, muscle weakness, and a negative Babinski sign. Therefore, the cell bodies affected in this patient are located in the ventral horn of the spinal cord. 3) One of the more commonly used muscle energy types uses the principle of post-isometric contraction to help stretch and relax spasmed, restricted muscles. The patient's elbow will be positioned into extension towards the restrictive barrier. The patient is asked to flex their elbow (towards the freedom of motion) while the physician provides an isometric resistance for 3-5 seconds. The patient is asked to stop and relax, and after pausing for a few seconds, the physician will stretch the biceps slightly as they move the elbow into further extension towards the new restrictive barrier. This sequence is repeated a total of 3-5 times, after which the physician will apply a passive stretch to the biceps, return the patient's arm to a neutral position, and reassess biceps tone and elbow range of motion. 4) The post-isometric muscle energy technique involves the inverse myotatic reflex in which there is activation of the Golgi tendon organ (GTO). When the GTO is activated, the Ib sensory afferent fibers are stimulated. These neurons fire and synapse onto inhibitory and excitatory interneurons. The inhibitory interneurons will inhibit the alpha motor neuron that supply the homonymous muscle. The excitatory interneurons will activate the alpha motor neurons that supply the antagonist muscle. This will result in relaxation of the patient's bicep.

A 19-year-old female was referred for evaluation of weakness of her left leg that has progressed for two weeks after a motor vehicle accident. Neurologic examination reveals normal pain sensation in all extremities. No weakness is appreciated in her upper extremities, and biceps and triceps reflexes are 2+. Voluntary movement is markedly decreased in the left leg and normal in the right leg. The patellar and Achilles reflexes are significantly decreased (1+) on the left but normal on the right. Negative Babinski sign bilaterally. Muscle tone is decreased in the left leg and normal on the right. Slight muscular atrophy of the left lower extremity is noted. 1) Identify the nerve root(s) being tested by the patellar reflex. Explain the mechanisms involved in the patellar reflex arc. 2) Differentiate an upper motor neuron and a lower motor neuron anatomically. Indicate the location of the neuronal cell bodies affected by the patient's injury. Justify your response. 3) After using an assistive device (a walker) for several days during the course of her rehabilitation and general conditioning, the patient reports mild soreness in her bilateral biceps area with restriction of motion in elbow extension. Outline and describe the technique principles, including positioning, motions/forces, and basic steps in sequential order involved in treating this patient's concern utilizing post-isometric relaxation muscle energy. 4) Explain the physiologic mechanisms of the reflex arc that are activated with the post-isometric relaxation muscle energy technique that the patient received.

1) The expression of the morphogen retinoic acid (RA) and Hox transcription factors produced by the lateral plate mesoderm are critical in the induction of limb outgrowth. These factors induce the expression of the transcription factors called Tbx5(or 4) which initiates the expression of FGF10. FGF10 induces the development of the apical ectodermal ridge (AER) and the AER's expression of FGF8/4. FGF8 and 4 expression produces a continued expression of FGF10 and therefore limb outgrowth occurs in a proximal to distal direction. Exposure to any teratogen during weeks three to seven can result in major abnormalities in limb development as these processes take place during these times. It is believed that increased levels of topical retinoic acid can decrease the level of retinoic acid for the induction of limb outgrowth (a negative feedback loop). 2) There are several muscles that attach to the ischial tuberosity. They include each of the hamstring muscles (semimembranosus, semitendinosus, and biceps femoris-long head), the inferior gemellus, and the adductor magnus muscle. The inferior gemellus laterally rotates the femur. The adductor magnus adducts, flexes, and medially rotates the femur as well as extends the femur. The hamstring muscles act to extend the thigh and flex the leg. Based on the actions of the muscles that attach to the ischial tuberosity, the patient would likely have difficulty in medial and lateral rotation of the femur as well as extending the thigh and flexing the leg. The patient would also have weakness in adducting the leg.

A 27-year-old female with moderate to severe acne consults with her obstetrician/gynecologist before using tretinoin, a topical retinoic acid, to treat her acne. The patient and her spouse plan to start a family in the next one to two years. The patient is concerned because she has read online that retinoids can induce birth defects. 1) Discuss the role of retinoic acid and fibroblast growth factors in normal proximal to distal limb development. Describe how tretinoin impairs embryologic limb development. 2) On the way home from the appointment with her obstetrician/ gynecologist the patient was involved in a motor vehicle accident. Radiography reveals a fracture to the ischial tuberosity. Indicate the muscles that would be affected based on the location of the fracture. Describe the impact of the fracture on the potential dysfunction of the identified muscles in this patient.

1) RUNX2, a transcription factor, promotes the differentiation of mesenchymal cells into osteoblasts during intramembranous ossification. In endochondral ossification, RUNX2 also promotes differentiation of mesenchymal cells of the perichondrium into osteoblasts. These cells deposit bone mineral that becomes the bone collar. RUNX2 also promotes chondrocyte hypertrophy within the growth plate and stimulates Indian hedgehog production, as part of the PTHrP-Ihh signaling axis. 2) Indian hedgehog is secreted by hypertrophic chondrocytes and promotes the proliferation of chondrocytes in the proliferative zone. FGFr3 is expressed by chondrocytes in the proliferative zone. When activated by a ligand, such as FGF-18, this pathway inhibits or slows down chondrocyte proliferation in the proliferative zone. Thus, two signaling pathways work against each other. A point mutation to FGFr-3 caused achondroplasia in this patient. This point mutation caused the receptor to be constitutively active (always activated). Since activation of FGFr-3 inhibits chondrocyte proliferation, constitutive activity caused the growth plate to fuse early because no new chondrocytes will be available to differentiate and add to growth in length.

A 27-year-old male with achondroplasia presents to his primary care physician with a chief complaint of transient tingling, numbness, and weakness in bilateral lower extremities. The symptoms generally develop after exercise and subside with rest. Standing postural exam reveals increased thoracic kyphosis, increased lumbar lordosis, and tibial bowing. 1) Differentiate the role of RUNX2 in endochondral and intramembranous ossification. 2) Characterize the roles of Indian hedgehog and fibroblast growth factor receptor-3 (FGFr3) in the proliferative zone of the growth plate and explain how a point mutation in the local signaling of FGFr3 led to the development of achondroplasia in this patient.

1) The patient's skin lesion is a silvery, scaly, dry, well-demarcated plaque on a mildly erythematous base, which is located on the extensor surface of his right elbow. 2) Tacrolimus is an immunosuppressant macrolide antibiotic that binds to the immunophilin FK-binding protein (FKBP) to inhibit calcineurin phosphatase activity. Calcineurin inhibition prevents the activation of the T cell-specific transcription factor, nuclear factor of activated T-cells (NF-AT), which increases IL-2 and other cytokines. Therefore, tacrolimus inhibits IL-2-mediated inflammation and plaque buildup in patients with psoriasis. Long-term use of tacrolimus ointment and other calcineurin inhibitors should be avoided due to the increased risk of skin cancer and lymphoma. It is not recommended for infants or adult patients who are pregnant or breastfeeding. It is also contraindicated for those that have active skin infections, hepatic disease or are immunosuppressed.

A 31-year-old male presents to his primary care physician for evaluation of an arm rash. He states that the rash has been gradually worsening for the last two months and describes it as itchy. He states he has not tried any topical creams or other treatments because he "wanted to get it checked out first." 1) Briefly describe the morphology of this patient's skin lesion using accurate medico-anatomical terminology. 2) Explain the rationale for use of tacrolimus ointment for psoriasis and outline precautions and contraindications that limit its use.

1) This patient has bowel incontinence and saddle anesthesia. This is clinically significant and pathognomonic for cauda equina syndrome due to a central posterior herniated disc. 2) The nerve root affected would be the L5 nerve root. Typically, L5 pain can radiate into the posterior buttock, lateral buttock, posterior lateral thigh, posterior lateral calf, dorsum of foot and or second web space between the 1st and 2nd digits of the foot. The general rule is that when an IV disc protrudes, it usually compresses the nerve root numbered one inferior to the herniated disc. Therefore, with an L4-L5 disc herniation, the L5 nerve is compressed, potentially causing sciatic pain. 3) Erector spinae group of muscles (spinalis, longissimus and iliocostalis) acting bilaterally extend the vertebral column. Multifidus and rotatores, belonging to the transversospinalis group of muscles extend the spine. Unilateral action of iliocostalis, longissimus, rotatores and multifidus causes rotation. These back muscles are innervated by posterior rami of spinal nerves. 4) ME is classified as a direct technique because it engages a restrictive barrier. ME uses the post-isometric contraction relaxation reflex as the physiologic basis for its efficacy as a treatment technique. This mechanism of action is based on the isometric contraction of the muscle, which increases tension on the Golgi tendon organ proprioceptors within the muscle tendon. The post-isometric contraction relaxation causes a reflex inhibition of the muscle, allowing it to be lengthened towards a new restricted barrier. This contraction and post contraction relaxation and move to the new restricted barrier is repeated for several cycles to normalize physiologic motion. In this case, allowing for improved lumbosacral motion.

A 33-year-old athletic male was lifting weights in his gym two days ago. He reports that he was trying to target muscles of his back, abs, and waist by adding a rotational component to the lift. As he lifted the weight, he noticed a sharp pain in his low back. Since then he has been unable to sit, cough, or sneeze without pain. In addition, he noticed that he trips over curbs and has difficulty climbing the steps to his second story apartment. He reluctantly confided that he had an "accident" while eating at a restaurant last night. When questioned further he confessed to having "pooped his pants" when he sneezed. Currently his low back pain is an 8/10 and he displays bilateral hip weakness and saddle anesthesia. 1) Indicate whether this patient demonstrates any red flag symptoms of low back pain. If so, briefly describe their potential clinical significance. 2) However, if the MRI indicates that there is only a small posterio-lateral L4-L5 intervertebral (IV)disc herniation and he is experiencing unilateral radicular symptoms, which nerve root(s) would be primarily affected and where would the pain radiate? 3) What are the major intrinsic back muscles that cause extension and rotation of the low back and what is their innervation? 4) If the patient had no red flags, the treating physician could elect to treat this patient with OMT using post isometric contraction muscle energy (ME) for discogenic lumbar pain. Describe the classification, physiologic basis, and rationale for using this technique.

1) This patient is a weightlifter and has developed greater mass and tone on his upper limb muscles. Repeated muscle contraction (due to activities such as routine weightlifting) increases: 1. production of local insulin like growth factor-1 (IGF-1) 2. intracellular Ca2+ concentration. Increased production of local IGF-1 activates phosphatidylinositol-3-kinase (PI3K) resulting in activation of the AKT-mTOR signaling pathway that increases net protein synthesis. In addition, activation of AKT simultaneously inhibits protein degradation through the forkhead box O protein (FoxO)-atrogene pathway. The increase in net protein synthesis through AKT-mTOR signaling pathway and inhibition of protein degradation through FoxO-atrogene pathway increase muscle fiber size due to addition of more myofilaments/myofibrils in parallel within the muscle fiber. The increase in intracellular Ca2+ can stimulate the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) signaling pathway. This increases mitochondrial biogenesis and expression of slow muscle fibers, resulting in increased aerobic capacity of the muscle. Doubling the myofibrillar diameter by adding more sarcomeres in parallel (hypertrophy) may double the amount of force generated. 2) The isotonic contraction is an exercise where the tension (load) is held constant, but the length shortens, producing movement. Because this exercise involves movement that requires bursts of power, the primary skeletal muscle types recruited are the type II (IIx/IIb) muscles. These are the fast twitch glycolytic muscles that contain myosin isoforms that hydrolyze ATP quickly. They are large muscle fibers with large motor units that allow for an increased force of contraction allowing the patient to relatively lift the load to perform the bicep curl.

A 42-year-old male comes to his primary care physician complaining of awkwardness when running or walking. He is a weightlifter and has developed greater mass and tone on his upper limb muscles compared to his lower limbs. The patient indicates increased cramping and weakness in his left leg four months ago but attributed that to a change in his exercise habits. The weakness is progressing despite continued exercise, and now the left leg muscle mass is decreasing. He was last seen for a routine physical examination three years ago, and no abnormalities were noted at that time. On examination, extensor Babinski reflex is absent on the left foot and the left leg muscles are hypotonic and weak. There are no other significant findings. Patient is referred for muscle biopsy and neuromuscular study. Laboratory findings reveal normal muscle biopsy. Electromyography shows abnormal potentials suggestive of lower motor neuron disease in the left leg. Nerve conduction studies are abnormal in the left leg. 1) Explain the physiologic and cellular signaling mechanisms contributing to greater mass and tone of the upper limb muscles in this patient. 2) As a part of his physical therapy training, the patient performs a series of isotonic bicep contraction exercises for 30 seconds to help strengthen his upper body. Explain the type of contraction that is occurring and describe the unique features of the primary skeletal muscle type being recruited.

1) nAChRs are ligand-gated ion channels present on the post-synaptic membrane of the muscle fiber at the neuromuscular junction (NMJ). At rest, the muscle membrane is hyperpolarized, and most of the ion channels are closed. When acetylcholine molecules are released by the presynaptic terminal which innervates the junction, they bind to nAChRs, and the channels open, allowing cations (primarily sodium but also potassium and sometimes calcium) to flow across the membrane. This depolarizes the membrane and is the end-plate potential. This depolarization crosses the threshold for activation of a muscle action potential, meaning it activates voltage-gated sodium channels in the muscle fiber membrane in the areas surrounding the endplate of the NMJ, leading to the muscle action potential. (The action potential will travel quickly throughout the muscle fiber's membrane, triggering intracellular calcium release to then lead to contraction of the fiber.) 2) Cranial nerve III (Oculomotor) was affected. The patient has myasthenia gravis (MG) in which acetylcholine (ACh) receptor antibodies attack the nicotinic receptors found on the postsynaptic skeletal muscle membrane at the neuromuscular junction. The degradation of these receptors inhibits endplate depolarization and subsequent contraction of skeletal muscles. This reduced density of nicotinic receptors, in combination with reduced ACh released at the neuromuscular cleft in skeletal muscles during repetitive stimulation will result in skeletal muscle weakness. This correlates to the patient's symptoms of ptosis. 3) Acetylcholinesterase inhibitors such a pyridostigmine, are used to manage patients with Myasthenia Gravis to assist with muscle activation and contraction. Acetylcholinesterase inhibitors increase the availability of acetylcholine to bind nicotinic acetylcholine receptors at the motor end plate by inhibition of acetylcholinesterase. [To a lesser extent, acetylcholinesterase inhibitors also increase the release of acetylcholine from the motor nerve terminal.] Nondepolarizing drugs, such as rocuronium, produce muscle relaxation for surgeries and intubation, and are competitive acetylcholine antagonists that compete for the same site of action as acetylcholine on the nicotinic acetylcholine receptors. Therefore, acetylcholinesterase inhibitors antagonize non-depolarizing neuromuscular blockade by increasing the availability of acetylcholine at the motor end plate and reducing the probability of rocuronium binding to the receptor.

A 45-year-old male is referred to a neurologist by his primary care physician for a two-month history of intermittent, progressive double vision, and persistent ptosis. He works as a computer graphic designer and states that his symptoms worsen by staring at the computer screen but subside with rest. His past medical history is unremarkable. Physical examination by the neurologist reveals impaired lateral movement of the right eye with bilateral ptosis that worsens with repetitive eye movements. Motor, sensory, and reflex examinations are otherwise unremarkable. A serologic test for acetylcholine receptor antibodies is positive. An electromyography (EMG) is performed and indicates decreasing action potential amplitude of the stimulated muscle. A Tensilon test is performed and is positive. 1) Describe the location and role of nicotinic acetylcholine receptors (nAChRs) in the process of a voluntary contraction of a skeletal muscle fiber. Include what happens as a direct result of this role of nAChRs and the following step that is triggered in the process. 2) Identify the affected cranial nerve implicated in the ptosis. Explain what aspect of the normal physiology of the neuromuscular junction is affected by the underlying pathophysiology that led to the patient's ptosis. 3) The patient was prescribed pyridostigmine to manage his condition. Explain why pyridostigmine diminishes neuromuscular blockade caused by rocuronium. Include the mechanisms of action and respective drug classes in your response.

1) In order to train for a marathon, he would have utilized endurance training. With endurance training, the adaptive response of skeletal muscle is due to an increase in the oxidative capacity by increasing the number of mitochondria and enhancing mitochondrial efficiency of all the motor units. The overall benefit with endurance training is the increased capacity of the cardiovascular and respiratory systems to better handle the increased oxygen demand that is needed to sustain the exercise. 2) Low blood insulin levels in our subject while running the marathon would inactivate the enzyme acetyl CoA carboxylase in his type I limb muscle fibers, primarily being used for the marathon. This would lead to a low cellular malonyl CoA production (from acetyl CoA). Low malonyl CoA levels would activate CPT1 (carnitine palmitoyl transferase 1), the rate limiting enzyme for fatty acid oxidation, upregulating the process as the main energy source for type I skeletal muscle fibers. Low malonyl CoA levels would also turn off fatty acid synthesis in this muscle fiber type. High calcium release in the contracting muscle and high ADP levels would also activate alpha ketoglutarate dehydrogenase (essential for the TCA cycle), upregulating mitochondria oxidative phosphorylation, the primary source for ATP production in the type I muscle fibers. 3) During exercise, there is an accumulation of lactic acid and inorganic phosphate (Pi) in the myoplasm of the skeletal myocytes. The accumulation of lactic acid decreases the myoplasmic pH, which disrupts the binding of calcium to troponin. Accumulation of Pi also reduces the sensitivity of calcium to troponin. In addition, it inhibits the efflux of calcium from the sarcoplasmic reticulum reducing the amount of calcium available in the cytoplasm to bind troponin. The combination of both of these prevents the interaction of actin and myosin, ultimately reducing the number of cross-bridges, thereby, inducing motor unit fatigue.

A 45-year-old male is training for an upcoming marathon of 26.2 miles. As he trains, he becomes more confident in his ability to increase the exercising capacity of his skeletal muscles. This improving performance leads him to decide that he will be able to maintain an 8-minute per mile pace, with proper hydration, as he completes the marathon. 1) Identify the type of training that this individual does for his upcoming marathon. Describe adaptive responses to skeletal muscles that occur, and overall benefit associated with this type of training. 2) Discuss the process of hormonal regulation of the primary metabolic pathways upregulated/activated in the specific muscle fiber type that our subject would be primarily using while running the marathon. 3) During a long run, the individual begins to experience symptoms of muscle fatigue at the 20-mile marker. Explain the cellular mechanisms responsible for motor unit fatigue in this individual.

1) In the gluteal region, the sciatic nerve (L4-S3) passes inferior to the piriformis muscle and superior to the superior gemellus muscle. The proximal attachments of the piriformis muscle are the anterior surface of sacral segments 2-4 and the sacrotuberous ligament. Its distal attachment is the greater trochanter of the femur. It is innervated by the anterior rami of S1 and S2 (nerve to piriformis). It externally rotates the hip when it is flexed less than 90 degrees and abducts the hip when it is flexed greater than 90 degrees. When hip flexion is greater than 90°, it reverses its action to internal rotation of the hip. It also stabilizes the head of the femur in the acetabulum. Irritation of the piriformis muscle by the patient's wallet caused sciatic nerve compression which resulted in his presentation. 2) A counterstrain tender point would be a discrete area of tissue texture abnormality (that does not radiate) which often exhibits tenderness in a muscle, tendon, or joint and responds to a positional release. Findings of a trigger point are described as a point in a muscle that has the potential to refer pain in a certain predictable distribution, along with other associated criteria, as follows: 1. Taut band palpable (if muscle accessible) 2. Exquisite spot of tenderness of a nodule in a taut band 3. Patient's recognition of current pain concern by pressure on the tender nodule (identifies an active trigger point) 4. Painful limit to full stretch range of motion 5. Visual or tactile identification of a local twitch response 6. Imaging of a local twitch response induced by needle penetration of tender nodule 7. Pain or altered sensation (in the distribution expected from a trigger point in that muscle) on compression of tender nodule 8. Electromyographic demonstration of spontaneous electrical activity characteristic of active loci in the tender nodule of a taut band 3) The OSE findings relate to a tender point located in the body of the piriformis muscle. The physician would locate the anatomical landmarks for treating the piriformis (right sacroiliac joint and the right greater trochanter) and palpate a point of tenderness at the midpoint between these two landmarks. To treat this tender point using counterstrain, the physician would position the patient in a prone position near the edge of the table. They would then contact the tender point and communicate with the patient to establish an objective pain scale ("We are going to call this a 10"). The physician would then maintain contact with the tender point and would position the patient's right hip into flexion less than 90 degrees, abduction, and external rotation to shorten distance between the origin and insertion of the piriformis. The physician would ask the patient to rate the tenderness compared to the original scale and would continue to fine-tune the patient's positioning until 70 percent reduction of tenderness or greater is achieved. Once achieved, the physician will keep the patient in this position for 90 seconds and will then slowly and passively return the patient to a neutral position while maintaining contact on the tender point. The physician will then reassess the tenderness compared to the originally established pain scale.

A 52-year-old male residential contractor presents to his family practice physician with concerns of right buttock pain and tenderness along with general hip pain. He denies a prior history of lower back pain or back injury, and he has no concerns of pain or numbness radiating down his right lower extremity. He reports that the buttock pain started while driving long distances between construction sites. After researching his condition online, he tried lying in the shape of a figure 4 (shown below) to stretch his right buttock and indicates that he feels eventual pain relief with this maneuver. The physician notices that the patient carries his wallet in his right back pocket. On OSE, the physician notes a discrete tender point at the midpoint between the middle of the right sacroiliac joint and the right greater trochanter. 1) Describe the neuromuscular anatomy of the gluteal region that is most likely involved in the patient's symptoms. In your answer identify the relevant muscle(s), attachment sites, innervation and actions as well as the spinal nerve origins of any nerve(s) involved. 2) No sensory or motor abnormalities are noted during physical examination, and the patient's physician does not suspect a neurologic deficit. Briefly describe the characteristics of the tender point elicited in this patient, and contrast this by describing the expected findings of a Travell trigger point in this region. 3) Outline and describe the positioning, landmark contacts, motions, and basic steps in sequential order involved in treating this patient's concern utilizing counterstrain.

1) The anterior and posterior cruciate ligaments together provide stability to the knee joint. The anterior cruciate ligament (ACL) arises from the anterior intercondylar area of the tibia and extends superiorly, posteriorly and laterally to attach to the posterior lateral side of the lateral condyle of the femur. It limits posterior rolling of the femoral condyles on the tibial plateau during flexion. It also prevents posterior displacement of the femur on the tibia and hyperextension of the knee. The posterior cruciate ligament (PCL) arises from the posterior intercondylar area of the tibia. It passes superiorly and anteriorly on the medial side of the ACL to attach to the anterior part of the lateral surface of the medial condyle of the femur. It limits anterior rolling of the femur on the tibial plateau converting to spin. It prevents anterior displacement of the tibia on femur and helps to prevent hyperextension. Based on the rotational movement of the femur on the fixed tibia (planted foot) while simultaneously pushing off (extending knee), the most likely ligament stressed and therefore injured by the patient is his left ACL. The most common mechanism of PCL injury is a posterior force on the tibia when the knee is flexed, and the femur is fixed. 2) Cartilage is a poorly vascularized connective tissue. The ability of cartilage to heal is greatly increased by its proximity to a vascular supply. Meniscal tears have a greater chance for healing if they occur within the outer one third of the meniscus. The inner two-thirds has a very poor chance for healing. The reason for this discrepancy is that the outer one third receives ample arterial blood from the inferior genicular arteries (lateral and medial), which are branches of the popliteal artery. The inner two-thirds of the meniscus is poorly vascularized due to its distance from the genicular arteries. Thus, the inner two-thirds is less likely to heal on its own.

A 55-year-old year male presents to his family practice physician with swelling around his left patellar tendon. He reports that the swelling developed over the last two months. The patient participates in regular athletic activity, such as playing basketball and running. He is diagnosed with left patellar tendinopathy. 1) A year later, the patient injured his left knee while attempting a dribble-fake during a basketball game. He first faked left then attempted to push off his left leg from a flexed and externally rotated position to an extended left knee position. The patient felt instantaneous left knee pain, heard a pop and fell to the ground, writhing in pain. When he attempted to stand on his left leg, it felt like his "knee was going to give out." Describe the anatomy (attachment sites and orientations) and functions of the anterior and posterior cruciate ligaments in the knee. Identify, based on the movements described above, which ligament was injured. Justify your answer. 2) As part of his knee injury, the patient tears the posterolateral outer one-third of his meniscus. During surgery to repair his cruciate ligament tear, the doctor determines that the meniscal cartilage has a high likelihood of healing on its own based on its location. Justify the doctor's decision based on the location of the meniscal injury, the vascular anatomy of this region, and the ability of cartilage to heal on its own.

1) The patient has acute gouty arthritis triggered by precipitation of monosodium urate (MSU) crystals into the joints. Macrophages phagocytose MSU crystals, which are recognized by the intracellular inflammasome. The inflammasome activates caspase-1 which promotes production of IL-1b and other biologically active cytokines. Proinflammatory IL-1b promotes accumulation of neutrophils and macrophages in the joint. These inflammatory cells release additional cytokines, free radicals, and proteases, which augment leukocyte recruitment into the synovium, causing tissue injury and inflammation. MSU crystals may also cause injury through activation of the complement cascade with release of neutrophil-derived lysosomal enzymes. 2) The enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT), via the salvage pathway, catalyzes the recycling of purine bases (such as hypoxanthine and guanine) as IMP and GMP, back to the cellular purine nucleotide pool for reuse. Deficiency in HGPRT would lead to excessive cellular accumulation of the afore-mentioned purine bases. The purines are subsequently metabolized (oxidation) via xanthine into uric acid by the enzyme xanthine oxidase leading to increased production of uric acid. This would cause an increase in plasma level of uric acid (hyperuricemia) and subsequent precipitation of urate crystals in the joints, causing pain and swelling, as seen in the patient. 3) Hypoxanthine is the first purine that is synthesized in the cell using amino acids, carbon dioxide, and the formyl groups, via the De novo pathway. Hypoxanthine is then converted into adenine and guanine, the standard purine bases that compose nucleotides (the building blocks of nucleic acids). Hypoxanthine and guanine accumulation in the cell (due to DNA wear and tear) can also be salvaged and reused for nucleotide biosynthesis. However, accumulation of the hypoxanthine and guanine in abnormally high concentrations may lead to the build-up of purine nucleotides (such as IMP, GMP, and AMP) which would then shut down the de novo purine biosynthesis pathways via product inhibition. Thus, to avoid accumulation of purines in high concentrations, cells oxidize excess hypoxanthine and guanine into uric acid via a 2-step pathway, catalyzed by xanthine oxidase. Uric acid is then eliminated via urine. 4) The patient has recurrent gouty arthropathy with hyperuricemia and an indication for treatment to reduce serum uric acid. Allopurinol is a purine analogue, xanthine oxidase inhibitor that competitively inhibits the oxidation of purine-derived hypoxanthine to xanthine and uric acid. Allopurinol decreases serum uric acid levels which may prevent the recurrent episodes of acute gouty arthropathy and may facilitate the resorption of gouty tophi.

A 57-year-old male is evaluated in the community clinic for repeated episodes of pain and swelling of the right first metatarsophalangeal joint over the past ten months. These episodes generally occur after consumption of alcohol, especially Guinness dry stout beer. Vital signs are normal except for BP 140/90 mmHg and BMI 30 kg/m2. Physical examination reveals marked tenderness with swelling and erythema of the right first metatarsophalangeal joint. Arthrocentesis is performed, and synovial fluid analysis reveals numerous neutrophils and needle-like crystals with negative birefringence on polarization microscopy. 1) Describe the pathogenesis of the patient's acute disease precipitated by the negatively birefringent, needle-like crystals in the synovial fluid. 2) Blood tests reveal hyperuricemia. Identify an enzyme involved in purine biosynthesis which leads to hyperuricemia when deficient. Discuss the biochemical mechanism that leads to excess uric acid production in the absence of this specific enzyme. 3) Correlate cellular purine biosynthesis with cellular uric acid production. 4) Justify the use of allopurinol in the management of this patient's disease.

1) The patient's gait would be affected by decreased sensory feedback from his legs and the plantar surface of his foot (feet). He could adopt different mechanisms to compensate for the loss of sensation in his legs and feet. Individuals with diabetic peripheral neuropathy (DPN) often experience loss of proprioception of their legs and feet along with atrophy of the muscles in their legs and feet. Therefore, their balance and overall ability to push off with their plantar flexors effectively or eccentrically contract their dorsiflexors during heel strike are affected. Individuals with DPN walk more slowly than individuals of the same age, demonstrate a decreased stride length (swing phase: single support phase) and demonstrate an increased double support phase with a wider base of support. Decreased sensory input from the tibial nerve innervating the sole of the foot, gastrocnemius and soleus and decreased input from the common fibular nerve innervating the anterolateral compartments of the leg could be involved.

A 57-year-old male presents to his primary care doctor for evaluation of bilateral numbness and tingling in his legs and feet. He has been a contractor for a large commercial building company for the past 10 years. Several times a day he stops at 7-11 to pick up a Big Gulp Soda. When he takes his rigid work boots off, he has noticed that he has difficulty walking and occasionally trips over his toes. He was recently diagnosed with type II diabetes. 1) Describe how the neurological deficits in the patient's feet and legs affect his gait. Be specific with regards to which phase of the gait cycle is altered and identify the muscle groups affected by decreased sensory feedback.

1) The patient is experiencing symptoms from consuming botulism toxin produced by Clostridium botulinum. The C. botulinum toxin is complexed with nontoxic proteins that protect the neurotoxin during passage through the digestive tract. The botulinum heavy chain (B subunit) binds specific sialic acid receptors and glycoproteins on the surface of motor neurons and stimulates endocytosis of the toxin molecule. The botulinum toxin remains in the endosome at the neuromuscular junction. Acidification of the endosome stimulates heavy-chain-mediated release of the light chain (A subunit). The botulinum endopeptidase then inactivates the SNARE complex proteins (synaptobrevin/VAMP, syntaxin-1, and SNAP-25) that regulate release of acetylcholine, blocking neurotransmission at peripheral cholinergic synapses. Because acetylcholine is required for excitation of skeletal muscle, the resulting clinical presentation of botulism is a flaccid paralysis.

A 62-year-old female is admitted to the hospital with nausea, vomiting, severe abdominal cramps, and difficulty speaking. The patient's daughter, who brought her in, reports that she began complaining of blurred vision and difficulty swallowing when they were having lunch. Physical examination reveals drooping of the patient's eyelids and facial muscles on both sides of her face. Vital signs are T 98.3°F(36.8°C), BP 126/84 mmHg, P 82 bpm, and RR 10/min. Neurological testing shows deficits on both side of the body. Further questioning of the daughter reveals that the patient cans her own vegetables and has recently eaten from one of the jars. An hour later, the patient starts to develop paralysis in her upper extremities, and soon after, her breathing ceases. She is placed on a ventilator. CT scan is normal, showing no signs of stroke or hemorrhage. Laboratory analysis is positive for toxins. 1) Identify the toxin being produced, indicate the microorganism responsible for its production, and explain the toxin's mechanism of action.

1) 1. Lay out options: present different treatment options such as physical therapy, exercise, maintaining a healthy weight, and different classes of pharmacotherapy 2. Discuss the reasons to have the intervention: decreasing pain; increasing function; decreasing cardiovascular disease (CVD) risk, glucose control, BP control, lipid control with exercise and healthy weight 3. Discuss the reasons not to have the intervention: barriers to each of the treatment options such as cost and convenience; side effects of the different classes of pharmacotherapy: e.g., NSAIDS and GI bleed risk, nephropathy, and BP increase 4. Ask for patient input: have the patient discuss which of these options seem the best fit after considering the pros and cons of each option 2) The relative benefit is 24.3%. It is calculated in the following manner: (68.0%-54.7%)/54.7%=24.3%. The absolute benefit is 13.3% (or .133). It is calculated in the following manner: Absolute benefit= 68.0%-54.7%= 13.3% or .133 The NNT is 8. It is calculated in the following manner: NNT= 1/.133= 7.5=> 8

A 62-year-old male presents to his internist for evaluation of two to three years of increasing pain in the knees. For the last six to eight weeks, he has noticed some mild swelling and increasing pain with activity in the left knee. The patient reports taking ibuprofen. Radiographs of the left knee one year ago showed femoral condylar osteophytosis and tricompartmental joint space narrowing. Vital signs include a BP of 140/90 mm Hg and BMI 30 kg/m2. Physical examination reveals small, cool effusions in both knees. The medial joint line of the left knee is tender. No limitation in range of motion is noted in either knee. 1) Discuss the four elements of shared decision-making in the management of the patient's osteoarthritis. 2) This patient asks his physician about tanezumab 2.5 mg as a medication to help ameliorate his pain. Tanezumab has been shown to decrease pain by 30% in 68.0% of osteoarthritic patients compared to a similar pain reduction in 54.7% of osteoarthritic patients treated with a placebo. Indicate the relative benefit of tanezumab 2.5 mg, the absolute benefit, and the number needed to treat (NNT) to decrease pain by 30%.

1) Upon injury, membrane phospholipids are converted to arachidonic acid (AA) via phospholipase (PLA2). Once liberated, AA is metabolized rapidly to oxygenated products by cytochrome p450s (CYP), lipoxygenases (LOX), and cyclooxygenases (COX). The major products of COX metabolism of AA include prostanoids such as prostaglandins, thromboxanes, and prostacyclins. Peripheral nociceptors express receptors (e.g. prostaglandin receptors) for many of these inflammatory mediators (e.g. prostaglandin) and contribute to the inflammatory pain response. Prostaglandins also increase the sensitivity of nociceptors in inflamed tissue by decreasing nociceptor threshold potentials. 2) Triamcinolone acetonide is a glucocorticoid that enters the cell as the free molecule. The intracellular glucocorticoid receptor is bound to stabilizing proteins and several other chaperone proteins. When the receptor complex binds a molecule of the synthetic glucocorticoid, the chaperone proteins disassociate and the steroid-receptors dimerize, enter the nucleus, bind to a glucocorticoid response element (GRE) on the regulatory region of the gene, and regulate transcription and associated transcription factors. The resulting mRNA is edited and exported to the cytoplasm to produce proteins that bring about the final hormone response including the increased expression of anti-inflammatory proteins and the decreased expression of proinflammatory proteins resulting in decreased inflammatory pain signaling. Additionally, glucocorticoids inhibit phospholipase 2 (PLA2)-mediated arachidonic acid (AA) synthesis; PLA2 inhibition of AA results in decreased prostaglandin and thromboxane -mediated inflammatory pain signals. 3) For patients with OA who have not responded satisfactorily to NSAIDs and physical therapy, duloxetine may provide analgesic effect via the modulation of endogenous pain inhibitory pathways through the selective inhibition of serotonin and norepinephrine reuptake. 4) The meniscus plays a role in shock absorption. The two attachments of the medial meniscus are the intercondylar area of the tibia and the inner surface of the tibial collateral ligament. 5) Supplements and/or botanicals with likely benefit for osteoarthritis include: - Glucosamine sulfate: cartilage (structural matrix) precursor - Chondroitin sulfate: cartilage (structural matrix) precursor - S-adenosylmethionine (SAMe): multiple postulated mechanisms, including simulation of cartilage synthesis, reduction of inflammation/oxidation, and/or DNA methylation maintenance - Methylsulfonylmethane (MSM): anti-inflammatory / analgesic - Capsaicin cream: analgesic / anti-inflammatory - Omega-3 fatty acids (fish oil): anti-inflammatory - Curcumin (turmeric): anti-inflammatory - Boswellia serrata (Indian frankincense): anti-inflammatory - Ginger: anti-inflammatory

A 63-year-old female presents to her family medicine physician for evaluation of bilateral knee pain. She reports the gradual onset of debilitating pain over the last six months. She nearly fell walking down a flight of stairs four days ago because her knee "gave way." She does not recall having injured her knee at any time. She reports a few minutes of morning stiffness and worsened pain with excessive walking, but she denies pain in other joints. Upon questioning, she confirms that her mother had been diagnosed with knee arthritis and was also overweight for most of her adult life. The patient has a BMI of 31 kg/m2. 1) Outline the arachidonic acid pathway including pertinent intermediates, enzymes, and products that contribute to the inflammatory pain response in this patient. 2) Describe the mechanism(s) of action of intra-articular triamcinolone acetonide for relief of the patient's left knee pain. 3) Symptoms persist despite four months of NSAID use and physical therapy. Justify the use of duloxetine in this patient with reference to the drug's class. 4) Upon further imaging, damage was observed to the medial meniscus. Describe the function(s) and two attachments of this articular disc. 5) Indicate the primary mechanism of action for four supplements and/or botanicals that could be helpful for this patient's arthritis.

1) Lidocaine is a local anesthetic. During neuronal excitation, voltage gated sodium channels open, and a fast, inward sodium current quickly depolarizes the membrane toward the sodium equilibrium potential (+40 mV). Local anesthetics block voltage-gated sodium channels located on peripheral nociceptors to inhibit increases in intracellular sodium concentrations and subsequent nociceptor/pain sensing neuron depolarization. Local sodium channel blockade prevents pain signal transduction from the peripheral site of the noxious stimulus (e.g. biopsy incision) to the central nervous system to inhibit pain perception. 2) The structure identified by the arrows is a crust overlying the central portion of the tumor. The crust develops as the malignant tumor invades into the epidermis, causing erosion (focal loss of the epidermis) and seepage of serous fluid. The crust consists of dried serous fluid. 3) Partial Thickness: Curettage and Shave Biopsy Curettage: Good for keratotic lesions such as warts, molluscum contagiosum, seborrheic keratoses. The book says this is OK for Basal Cell Carcinoma, but this is not commonly done in practice. Shave Biopsy/Excision: Good for raised lesions that don't require a full-thickness evaluation such as skin tags, nevi, keratoses, basal cell carcinomas. Full Thickness: Punch Biopsy and Excision Punch Biopsy: Removal of small lesions and representative sampling of large lesions. Recommended for suspected melanoma. Excision: Removes entire lesion, and margins can be well-assessed. Good for tumors where margin assessment is required. 4) The skin lesion is a solitary pink nodule with central crusting and ulceration on the right arm.

A 72-year-old male presents to his primary care physician with concern of several skin lesions (as shown in the image) that have developed over the past few months. 1) Subcutaneous lidocaine is administered prior to obtaining a skin biopsy to minimize the patient's pain during the procedure. Relate the mechanism of action of lidocaine to its anesthetic effect. Include the drug class in your response. 2) On physical examination, a small nodule is seen on his upper arm (as seen in the image). Overall, his skin shows marked sun damage. A punch biopsy confirms a malignant skin tumor. Explain how the structure overlying the tumor (identified by the arrows) most likely developed. Describe its components. 3) Name two partial thickness and two full thickness techniques of skin sampling and describe a type of skin lesion appropriately sampled with each technique. 4) A skin exam is performed on the patient and the above skin lesion is seen on his right arm. Describe the morphology of the lesion using accurate medico-anatomical terminology.

1) The proposed cell of origin of sarcomas is an undifferentiated pluripotential mesenchymal stem cell that acquires driver mutations. As a general rule, younger patients tend to more often be afflicted by malignancies exhibiting simple karyotypes with mutations characteristic of the specific tumor. Such tumors (such as Ewing's Sarcoma or synovial sarcoma) tend to be monomorphic in appearance. Older patients tend more often to be afflicted by tumors with complex and unpredictable karyotypes. Such tumors tend to be more pleomorphic in appearance. 2) CDKs acquire the ability to phosphorylate protein substrates (i.e., kinase activity) by forming complexes with the relevant cyclins. Transiently increased synthesis of a particular cyclin leads to increased kinase activity of the appropriate CDK binding partner; as the CDK completes its round of phosphorylation, the associated cyclin is degraded and the CDK activity abates. Thus, as cyclin levels rise and fall, the activity of associated CDKs likewise wax and wane. Enforcing the cell cycle checkpoints is the job of CDK inhibitors (CDKIs); they accomplish this by modulating CDK-cyclin complex activity.

A 72-year-old male presents with pain and swelling of his right thigh. Physical examination reveals a palpable mass deep in the biceps femoris muscle. A core biopsy is performed, and the pathology report indicates a malignant soft tissue tumor. Additional tissue is requested to further characterize the lesion. 1) Identify the proposed cell of origin for this patient's mass. Discuss the general relationship between age, tumor karyotype, and tumor differentiation of malignant soft tissue neoplasms. 2) Based on normal cell proliferation, describe the roles and interactions of the cyclins (as a class of proteins), cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CDKIs) in the normal cell cycle.

1) Chondrosarcoma tends to present in older individuals and preferentially involves the axial skeleton as seen in this patient. The presence of a highly pleomorphic area not associated with matrix production indicates that this represents a dedifferentiated chondrosarcoma. The presence of lung nodules on imaging strongly suggests metastatic (stage IV) disease, which portends a grave prognosis. 2) EPO binds the EPO receptor expressed by erythrocyte progenitors in the bone marrow. Ligand binding alters the conformation of the receptor such that it has high affinity for intracellular JAK proteins, which then bind the receptor and phosphorylate it. These sites have high affinity for the STAT protein, which bind them. JAK then phosphorylates STAT. This decreases the affinity of STAT for the receptor site, so the phosphorylated STAT proteins re-enter the cytoplasm and dimerize with similar STAT proteins. These dimers of phosphorylated STAT proteins are transcription factors, and they enter the nucleus and bind to specific sites on the DNA, initiating transcription of proteins critical to starting the process of erythropoiesis. 3) The attending must inform the medical power of attorney of: 1. The nature of the referral. 2. The benefits, risks, and consequences of hospice care; and 3. The alternatives to hospice along with their benefits, risks, and consequences. 4. In addition, the medical power of attorney's decision, based on this information, must be voluntary.

A 72-year-old man with advanced Alzheimer's Disease is noted by his caretaker to have an impaired gait which has resulted in several falls. Imaging demonstrates a destructive lesion involving the pelvis which extends into the soft tissue around the hip. Additional imaging demonstrates multiple small bilateral lung nodules. Biopsy demonstrates malignant cells associated with chondroid matrix, with focal areas showing highly pleomorphic cells not associated with cartilage. 1) Correlate this clinical presentation, these histologic findings, and these imaging findings with the disease process (including subtype) and this particular patient's prognosis. 2) As the patient's clinical condition rapidly declines, he is noted to have anemia with a hemoglobin of 8.5 g/dL (reference 12-16 g/dL) and a compensatory rise in serum erythropoietin (EPO). Describe the canonical JAK/STAT signaling pathway which is used by the EPO receptor (an enzyme-associated receptor), from ligand binding of the receptor to the first steps of transcriptional activation in the nucleus. 3) Based on the patient's poor prognosis and co-morbidities, the attending physician recommends referral to hospice care. The patient's wife, who is his medical power of attorney, expresses concern about giving up on her husband, but ultimately agrees to the referral. Identify the elements that must be present for her agreement to constitute informed consent to the referral.

1) Onset of fever: Inflammatory mediators and cytokines act within the hypothalamus to increase Ts. To match the Ts, Tc increases by thermogenic mechanisms such as shivering and reduced skin blood flow. When fever breaks: The effect of the inflammatory agents in the hypothalamus is reduced so that Ts returns to normal body temperature. Tc falls to match Ts by mechanisms that promote heat loss such as sweating and increased skin blood flow. 2) The causative infectious agent responsible for this patient's infection is the measles virus (Morbillivirus/Rubeola). The measles virus vaccine is a live, attenuated vaccine given in combination with mumps and rubella (MMR). Live vaccines are prepared with microbes that are limited in their ability to cause disease (also known as attenuated) and will elicit a T-cell-mediated immune response following infection. Immunity to live vaccines is long-lived (so fewer doses may be required) and mimics a normal immune response to an infectious agent. Live vaccines may be dangerous to immunosuppressed or pregnant women because they are unable to fight a weakened viral infection and the vaccine may cause mild symptoms of the infection. 3) Measles may lead to pneumonia with or without superimposed bacterial superinfection and subsequently death. Another complication of measles includes encephalitis, which can be a result of the direct infection of neurons, an immune-mediated post-infectious encephalitis, or subacute sclerosis panencephalitis (SSPE) due to defective measles variant that persists in the brain. In addition to measles, the other four classic childhood viral exanthems include rubella, roseola, fifth disease (parvovirus B19), and varicella zoster virus (VZV). Therefore, any two of the following would be considered acceptable responses: • Rubella can lead to congenital rubella syndrome when a mother is infected during pregnancy because the virus can replicate in the placenta and most tissue of the fetus causing alterations in the growth and structure of the fetal cells. This syndrome consists of cataracts, deafness, heart defects, microcephaly, growth abnormalities, and intellectual disability. • Roseola is a common cause of febrile seizures in children due to the high fever associated with the infection and may be reactivated in transplant patients leading to failure of the graft. • Parvovirus B19 can induce aplastic crisis in patients with chronic hemolytic anemia, such as sickle cell disease, because B19 targets and is cytolytic to erythroid precursor cells. Additionally, by the same mechanism, parvovirus B19 can cause hydrops fetalis, which includes anemia, edema, and congestive heart failure in a fetus of a seronegative mother infected with B19. • VZV can cause interstitial pneumonia due to an exaggerated immune response in adults leading to increased inflammation at the site of primary infection in the lungs. VZV can also lead to postherpetic neuralgia, which is a chronic pain syndrome, due to reactivation of latent varicella in the dorsal root ganglia after the primary infection. 4) The lumbar puncture samples cerebrospinal fluid, which is found in the subarachnoid space. A lumbar puncture should be performed below the L3-L4 intervertebral to avoid injuring the conus medullaris (end of the spinal cord). In a child at one year of age the conus medullaris is found at about the level of L3. The tissues and spaces pierced by the needle from superficial to deep include the following: 1. Skin 2. Subcutaneous tissue and fat 3. Supraspinous ligament 4. Interspinous ligament 5. Ligamentum flavum 6. Epidural space 7. Dura mater 8. Subdural space 9. Arachnoid mater 10. Subarachnoid space

A one-year-old previously healthy male presents to the emergency department with fever of 104ºF (40 ºC), cough, rhinorrhea, and congestion for three days. Parents also noticed spots in his mouth yesterday and a rash developing on his forehead this morning. Physical exam is significant for an ill-appearing, febrile boy with bilateral conjunctivitis, gray-white vesicles with red halos on his buccal mucosa, and an erythematous maculopapular rash on his face and upper trunk. He attended an amusement park 10 days ago in the United States and has not yet been to his one-year-old well child check. 1) The patient has had a fever for 3 days. Identify the temporal changes in core temperature (Tc) and setpoint temperature (Ts) that occur at the onset of the fever and when the fever "breaks" and explain the major physiological mechanisms that mediate these changes. 2) Identify the causative infectious agent responsible for this patient's infection. Describe the type of vaccine used to prevent this infection, the immune response it elicits, and its contraindications. 3) Identify the potential complications of this patient's infection. Briefly describe the potential complications of two other classic childhood viral exanthems and explain why these occur. 4) On day seven of illness, the boy develops worsening fever, vomiting, and lethargy, which prompts you to suspect encephalitis, a known complication of this viral infection. Due to the change in his clinical course, you perform a lumbar puncture to confirm this diagnosis. Identify at what vertebral level you would perform a lumbar puncture and justify this location in terms of anatomy of the spinal cord. Next, identify all the tissue layers and spaces that will be punctured by the needle, as it progresses from superficial to the appropriate space for sampling the cerebrospinal fluid.

1) Osteochondromas are characterized by a sessile or pedunculated bony excrescence with a cartilage cap. The growth of these benign lesions is characterized by endochondral ossification of the cartilage cap, which histologically resembles a disorganized growth plate. The underlying genetic abnormalities tend to be loss of function mutations involving the EXT1 or EXT2 genes in both familial and sporadic tumors. These lesions tend to cease growing at the time of closure of the growth plate. 2) RB is a key negative regulator of the G1/S cell cycle transition. It exists in an active hypophosphorylated state in quiescent cells, in which it binds E2F transcription factors. It must be put into an inactive hyperphosphorylated state, in which E2F is released, for cells to pass through the G1 /S cell cycle transition. The phosphorylation is accomplished by activated cyclin-CDK complexes. These CDKs can be inhibited by CDKI proteins, which can thus prevent progression through the cell cycle. One of the major ways these CDKIs are activated is by the tumor suppressor protein p53, which can, for example, upregulate expression of the CDKI p21, which maintains RB in an active, hypophosphorylated state and blocks the progression of cells from G1 phase to S phase.

A ten-year-old boy presents to his pediatrician with a bony lump in the distal metaphysis of the right radius. Subsequent radiographs show a benign-appearing exostosis. 1) Describe the histologic appearance, genetics, growth process, and biologic behavior of osteochondroma. Include the natural event that results in cessation of growth. 2) The lump consists of cells which are proliferating inappropriately. Describe how RB normally regulates the progression of a cell through the cell cycle and by what mechanism p53 can normally regulate RB.

1) The most appropriate and effective pharmacotherapy is denosumab, which is a monoclonal antibody that binds to and prevents the action of RANKL to inhibit osteoclast formation and activity. Denosumab is equally efficacious as bisphosphonates for the management of osteoporosis, but unlike bisphosphonates, denosumab is not cleared by the kidney, so can be used in patients with advanced renal disease. 2) The following lifestyle modifications should be discussed (via motivational interviewing) with the patient: • An anti-inflammatory diet that emphasizes omega-3 fats, plant-based protein, whole soy foods, and anti-inflammatory herbs, teas, and spices (in addition to the standard components of the Mediterranean diet) • Adequate calcium and vitamin K intake (via diet and/or supplementation) • Adequate vitamin D (serum 25-OH vitamin D concentration ≥ 40 ng/mL) • Physical activity for 30 to 45 minutes most days of the week that includes weight-bearing, aerobic, and weight-lifting exercise • Daily mind-body practice (meditation, self-hypnosis, guided imagery, biofeedback, and breath work) • Avoidance of smoking and excess alcohol intake • Reduction of fall risks

An 82-year-old white female presents at the emergency department after she slipped and fell in her bathroom. She complains of pain in her left hip and needs assistance to walk. She has a history of fracture, having fractured her wrist seven years ago. Her previous DEXA scan indicated a -2.4 T-score. She reports a 40-year history of smoking, hypertension, and acute renal insufficiency. 1) Identify the most appropriate and effective pharmacotherapy to manage the patient's underlying condition and explain your rationale. 2) List appropriate lifestyle approaches to reduce this patient's risk of a bone fracture.

1) Stinchfield (straight leg raise against resistance), FABER (Flexion, abduction and external rotation- passively), FADIR (flexion, adduction and internal rotation- passively) and Thomas test (hip extension), palpation of the iliopsoas (and scour test). Positive Thomas test and palpation of the iliopsoas would suggest iliopsoas strain/sprain. Positive FABER would be more suggestive of SI joint pathology, and if pain is replicated in the anterior groin, helpful for intra-articular pathology. Stinchfield and FADIR are positive in intra-articular hip pathology. Stinchfield, in addition, could be positive for iliopsoas pathology. 2) Thomas test: patient supine and positioned with affected extremity hanging off the edge of the plinth with the uninjured lower extremity (LE) flexed at hip and knee and held to chest. The clinician observes contralateral (symptomatic) LE for tightness based on the height of the symptomatic LE above the plinth. The iliopsoas and rectus femoris muscles are tested. The clinician can apply pressure to the thigh or increase flexion of the knee to ascertain amount of involvement of the iliopsoas vs. rectus femoris muscle.

Eliana Brown, a 35-year-old female, presents to her primary care physician with right-sided groin pain. Two days ago, she participated in the 2018 cystic fibrosis San Antonio Tower Climb. After climbing 70 floors of the 75-floor climb, she noticed anterior groin pain without radiation of symptoms. In addition, there was locking of the hip in internal rotation and slight flexion. She had to quit and take the elevator down. On exam, the patient is noted to have a partially flexed right hip and cannot stand up straight without pain. A Thomas test is positive on the right side. 1) Explain the exam maneuvers/special tests that would help differentiate the origin of pain/differential diagnosis and justify your answer. 2) Outline the steps involved in performing the Thomas test and indicate the muscles being assessed.