USMLE RX SET 3
The remodeling phase of wound healing involves the replacement of type III collagen w/type I. What benefit does this offer?
' the tensile strength of the tissue
What is an inflammasome and what is its role in acute inflammation?
A protein complex that recognizes microbial dead cell components, microbial products and crystals; induces IL-1 activation and inflammation
A man w/severe CHF has a pleural effusion. What quantity of protein do you expect to find w/in the fluid?
A value < 2.5 g/dL (this is a transudative fluid)
Name some tissues where lipofuscin is commonly found on autopsy.
All tissues, but especially the heart, colon, liver, kidneys, and eyes
What are the roles of TGF-β in wound healing?
Angiogenesis, fibrosis
Name some infectious causes of granulomatous diseases.
Bacteria (eg, Bartonella, L monocytogenes, Mycobacteria, Treponema pallidum), fungi (eg, histoplasmosis), parasites (eg, schistosomiasis)
Why must you test for latent TB before starting an anti-TNF medication?
Because these Meds (via TNF inhibition) lead to the breakdown of granulomas and can unleash disseminated disease
Name the 5 main cytokines (released in response to bacterial products) that guide leukocytes to the site of injury or infection.
C5a, IL-8, LTB4, kallikrein, and platelet-activating factor
An immunocompromised pt undergoes a workup. Neutrophil studies show impaired tight binding. A defect in which subunit is to blame?
CD18 integrin subunit, important for tight binding and impaired in leukocyte adhesion deficiency type 1
What is the relation of the type of calcification shown in the image to the serum Ca2+ level?
Ca2+ level is abnormally high (this is metastatic calcification)
CXR of pt w/chronic cough shows hilar LAD & parenchymal infiltrates. Lung Bx reveals noncaseating granulomas. How may Ca2+ levels change?
Ca2+ levels '; granulomatous diseases are associated w/hypercalcemia due to calcitriol production (sarcoidosis)
Name some enzymes that degrade free radicals.
Catalase, glutathione peroxidase, and superoxide dismutase
A woman taking an ErbB1-inhibitor for cancer Tx sustains an injury. Reduced function of which signaling molecule will impede healing?
Cell growth will be impaired by a reduction in tyrosine kinase function (in this case, EGFR)
Tissue repair after injury occurs by which 2 processes?
Cell regeneration and scar formation
Describe the process of migration during leukocyte extravasation.
Cells travel to the site of infection or injury w/the guidance of chemotactic signals, including bacterial products and cytokines
Provide 2 examples of neoplastic transformation as a result of chronic inflammation.
Chronic HCV infection resulting in hepatocellular carcinoma; chronic H. pylori infection resulting in gastric adenocarcinoma
What are the hallmark features of chronic inflammation?
Chronic inflammation is characterized by persistent destruction and repair w/blood vessel proliferation and fibrosis
Name some disorders that lead to a high systemic burden of calcium-phosphate complexes and, therefore, metastatic calcification.
Chronic renal failure w/hyperparathyroidism, long-term dialysis, calciphylaxis, or multiple myeloma
What is the difference between the classical and alternative macrophage activation pathways?
Classical activation is proinflammatory; Alternative activation is anti-inflammatory and promotes repair
A pt sustained a cut on his arm 2 days ago. What are the characteristics of the current phase of healing of his wound?
Clot formation, ' vessel permeability, neutrophil migration (inflammatory phase)
Compare hypertrophic and keloid scars w/respect to collagen synthesis and chance of recurrence after resection.
Collagen synthesis is ' in keloids compared w/hypertrophic scars; unlike hypertrophic scars, keloids often recur after resection
What are the possible outcomes of an acute inflammatory episode?
Complete resolution, persistent acute inflammation, abscess formation, progression to chronic inflammation, scarring
A 36 yo pt w/hypercalcemia presents w/hypervitaminosis D. Where does one tend to see the deposits, and what is the mechanism of deposition?
Deposits usually occur in interstitial tissues of kidney, lungs, & gastric mucosa (tissues losing acid ' pH, favoring Ca2+ deposition)
A pt presents w/a scar (see image). What is the collagen organization of the scar?
Disorganized (this is a keloid scar)
Which collagen type(s) is(are) predominantly seen w/keloid formation?
Disorganized type I and type III collagen
Differentiate between dystrophic and metastatic calcification.
Dystrophic: Ca2+ deposition in abnormal tissue w/injury or necrosis; metastatic: deposition in normal tissue in setting of hypercalcemia
What type of tissue mediator is known to stimulate cell growth via the tyrosine kinases? Name an example of such a tyrosine kinase.
EGF; an example is EGFR, as expressed by ErbB1
Name 4 pathways for free radical degradation.
Enzymes (catalase, glutathione peroxidase), spontaneous decay, antioxidants (vitamins A, C, E), metal carriers (transferrin, ceruloplasmin)
List the cellular components of a granuloma.
Epithelioid cells (macrophages w/pink cytoplasm) surrounded by multinucleate giant cells and lymphocytes.
Which ethnicities are at ' risk for keloid scar formation after a wound?
Ethnicities w/darker skin (not solely African Americans)
Where does leukocyte extravasation typically occurâ€"arterioles or postcapillary venules?
Extravasation takes place at the postcapillary venules
A pt has a pleural effusion LDH of 500. Normal serum LDH is 100â€"250 IU/L. Is this a transudate or an exudate?
Exudate (Pleural effusion LDH>2/3 of the upper limit of normal serum LDH, which is one of the Light criteria for exudative pleural effusion)
A pt has a pleural effusion protein/serum protein ratio of 0.7. Is this a transudate or an exudate?
Exudate (for transudate, the ratio has to be < 0.5)
Compare exudates and transudates w/respect to cellularity and protein content.
Exudates: cellular, protein rich; Transudates: hypocellular, protein poor
All aspects of angiogenesis during wound healing are stimulated by which tissue mediator(s)?
FGF, TGF-β, and VEGF
Free radical damage by carbon tetrachloride causes what pathologic change in the human body?
Fatty change in the liver (CCl4 is converted into CCl3 free radical by cytochrome P-450, leading to " apolipoprotein synthesis)
Which cells are most important in mediating the remodeling process of wound healing?
Fibroblasts
Which 2 metal storage diseases can result in free radical injury?
Hemochromatosis (iron) and Wilson disease (copper)
A pt overdoses on acetaminophen. What pathologic changes may be seen in his liver?
Hepatotoxicity
Name 2 growth factors/cytokines that help in resolution and healing following acute inflammation.
IL-10 and TGF-β
Which cytokine is ' in persistent acute inflammation?
IL-8
There are 3 phases of wound healing. What are they, and how long do they generally last?
Inflammatory (up to 3 days), proliferative (3 days to weeks), remodeling (1 week to 6+ months)
Which phase of wound healing is characterized by infiltration of platelets, neutrophils, and macrophages at the site of injury?
Inflammatory phase
Which type of scar extends beyond the borders of the original wound?
Keloid scar (w/claw-like projections, typically on earlobes, face, and upper extremities)
How do leukocytes reach the site of acute inflammation?
Leukocytes extravasate from postcapillary venules (via margination, adhesion, diapedesis, migration) and accumulate at the area of injury
Describe the process of diapedesis during leukocyte extravasation.
Leukocytes use PECAM-1 (CD31) to migrate between endothelial cells to exit the blood vessel
Which diagnostic criteria compare serum and pleural fluid protein and LDH levels?
Light criteria
List non-infectious causes of dystrophic calcification.
Liquefactive/fat necrosis, infarcts, atherosclerotic plaques, thrombi, psammoma bodies, CREST
Name 3 pathologic processes that lead to the formation of exudates.
Lymphatic obstruction, malignancy, and inflammation/infection
What are the dominate cell types in chronic inflammation?
Macrophages
A 36 yo pt has had a red, inflamed leg for 3 weeks. Through what mechanism does acute inflammation transition into chronic inflammation?
Macrophages and other APCs present Ags that result in activation of CD4+ Th cells; secrete cytokines that result in chronic inflammation
Describe the mechanism of activation of proinflammatory cytokines in chronic inflammation.
Macrophages interact w/T cells ' Th1 cells secrete INF-γ ' macrophages undergo classical activation
Describe the mechanism of activation of anti-inflammatory cytokines in chronic inflammation.
Macrophages interact w/T cells ' Th2 cells to secrete IL-4, IL-13 ' macrophage alternative activation
A particular cell type peaks at 2-3 days after the onset of acute inflammation. What is its role in acute inflammation?
Macrophages; they influence the outcomes of acute inflammation by secreting various cytokines
Name the 4 steps involved in leukocyte extravasation.
Margination and rolling, adhesion, diapedesis, and migration
Free radicals damage cells by which 3 main mechanisms?
Membrane lipid peroxidation, protein modification, and DNA breakage
A kidney Bx of a 64 yo man w/nephrogenic diabetes insipidus shows Ca deposits in collecting ducts. What is the mechanism of calcification?
Metastatic calcification (due to abnormal serum Ca levels)
Which immune cells mediate chronic inflammation?
Mononuclear cells (macrophages, lymphocytes, plasma cells) and fibroblasts
A 72 yo pt w/multiple past abdominal surgeries has scar formation on his anterior abdomen. What is the tensile strength of this scar tissue?
Most likely 70-80% very little strength is regained after 3 months of a severely acute or chronic injury
2 wks after sustaining a skin injury in a motor vehicle accident, a pt sees wound contraction. What cell type is responsible for this?
Myofibroblasts
A 12 yo pt injured his foot in a sport an hour ago. You aspirate the fluid and do microscopic analysis. What cells are shown in the image?
Neutrophils
Chronic inflammation is always preceded by acute inflammation. Is this statement true?
No, chronic inflammation may or may not be preceded by acute inflammation
How is scar tissue formed after severe acute or chronic injury?
Nonregenerated cells are replaced by connective tissue, resulting in scar formation
A 46 yo African immigrant w/TB undergoes a biopsy (see image). Will the serum Ca2+ level be normal or abnormal?
Normal; the biopsy specimen shows dystrophic calcification, probably a result of injury/necrosis caused by caseating granulomas in TB
Which tissue mediator in wound healing induces vascular remodeling and smooth muscle cell migration?
PDGF
Which tissue mediator is secreted by platelets and macrophages and stimulates fibroblast growth for collagen synthesis during wound healing?
PDGF
A pt presents w/a scar (see image) after sustaining a 1-cm wound. What is the collagen organization of the scar?
Parallel (this is a hypertrophic scar)
Name types of stimuli that can result in chronic inflammation.
Persistent infections, autoimmune diseases, foreign bodies, prolonged exposure to toxic agents, (eg, silica)
Name some disorders that lead to hypercalcemia and, therefore, metastatic calcification.
Primary hyperparathyroidism, sarcoidosis, and hypervitaminosis D
Which phase of wound healing has infiltration of fibroblasts, myofibroblasts, endothelial cells, and keratinocytes at the site of injury?
Proliferative phase
Which wound healing phase has collagen deposition, angiogenesis, clot dissolution, epithelial cell proliferation, and wound contraction?
Proliferative phase
A pt has her wound studied by a medical student. Biopsy of the wound shows type III collagen. Which phase of healing is the wound in?
Proliferative phase; type III collagen is formed alongside granulation tissue
Free radical injury can be induced by exposure to what substances and processes?
Radiation, metabolism of drugs (phase I), transition metals, redox reactions, nitric oxide, and leukocyte oxidative burst
A pt undergoes thrombolysis for acute limb ischemia. What type of free radical injury is of greatest concern?
Reperfusion injury (eg, from superoxide formation)
An infant born at 22 wks' gestation is given O2 therapy. He goes blind, and respiratory distress develops. Why?
Retinopathy of prematurity (eyes) and bronchopulmonary dysplasia (lungs) due to O2-mediated free radical formation
Name some noninfectious causes of granulomatous diseases.
Sarcoidosis, Crohn disease, 1° biliary cholangitis, subacute thyroiditis, Wegener, Churg-Strauss, giant cell arteritis, Takayasu arteritis
A pt is diagnosed w/leukocyte adhesion deficiency type 2. Which leukocyte receptor is deficient or mutated?
Sialyl-LewisX receptor
In which step of leukocyte extravasation do E-selectin, P-selectin, GlyCAM-1, and CD34 play a role?
Step 1, margination and rolling
In which step of leukocyte extravasation do ICAM-1 (CD54) and VCAM-1 (CD106) play a role?
Step 2, tight binding (or adhesion)
In which step of extravasation does " CD18 integrin subunits on leukocytes lead to a defect?
Step 2, tight binding, as a result of inability to attach to ICAM-1 (CD54)
In which step of leukocyte extravasation does PECAM-1 (CD31) play a role?
Step 3, diapedesis
In which step of leukocyte extravasation do bacterial products, C5a, IL-8, LTB4, kallikrein, and platelet-activating factor play a role?
Step 4, migration
A Mexican immigrant not up to date on vaccines has caseating granulomas on a liver biopsy and a 3-mo h/o cough. What is the cause?
TB (miliary type); remember, TB involves caseating granulomas
What is the histologic difference between granulomas seen in TB and those seen in sarcoidosis?
TB involves caseating granulomas; in sarcoidosis, granulomas are noncaseating
List infectious causes of dystrophic calcification.
TB, schistosomiasis, congenital CMV/toxoplasmosis/rubella
Which inflammatory markers are chiefly responsible for E-selectin upregulation?
TNF and IL-1
The biopsy of a lung lesion is shown in the image. How does this lesion form?
Th1 cells secrete IFN-γ, activating macrophages, which secrete TNF-α, inducing & maintaining granuloma formation (sarcoidosis)
A pt has a crescendo-decrescendo murmur. ECHO reveals calcific aortic stenosis. What is the likely serum Ca2+ abnormality in this pt?
There is none (In fact, pts usually have normal Ca2+ levels.); dystrophic calcification of the valve is responsible for the murmur
What causes the yellow-brown color of the macrophages seen on autopsy of an elderly woman (see image)?
They are formed by oxidation and polymerization of organellar membranes that have undergone autophagocytosis (this is lipofuscin)
What is the role of the tissue mediator metalloproteinase?
Tissue remodeling
A pt has a pleural effusion LDH/serum LDH of 0.5. Is this a transudate or an exudate?
Transudate (for exudate, the ratio has to exceed 0.6)
A pathologist analyzes a sample w/acute inflammation. What stimuli can cause this phenomenon?
Trauma, infection, foreign bodies, necrosis
What collagen type(s) is(are) predominantly seen w/hypertrophic scar formation?
Type III collagen
A 70 yo man has persistent infections over many years. What hypersensitivity reaction is occurring?
Type IV hypersensitivity due to chronic inflammation
4 mo after a skin laceration, a pt asks if his skin can be expected to gain further tensile strength after scarring. What is your reply?
Unlikely; after about 3 months, the skin has regained 70-80% of its tensile strength and is unlikely to regain any additional strength
What is the role of vasodilation in acute inflammation?
Vasodilation and ' endothelial permeability deliver cells and proteins to the site of infection/injury
An 82 yo F pt experiences delayed wound healing 5 days after taking a fall. What vitamin and mineral deficiencies can cause this?
Vitamin C and copper deficiencies can cause delayed wound healing during the proliferative phase
Name the 3 vitamins w/antioxidant properties involved in degrading free radicals.
Vitamins A, C, and E
P-selectin is released primarily from which endothelium-derived structure?
Weibel-Palade bodies
An elderly M pt experiences delayed wound healing 2 wks after a large laceration. What mineral deficiency can cause this?
Zinc deficiency can cause delayed wound healing during the remodeling phase (collagenases require zinc to break down type III collagen)