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Pathobiology > First Pass Miss Exam 1 > Flashcards

First Pass Miss Exam 1 Flashcards

1
Q

How does RAS work?

A

It sits attached to the membrane, with a GTP binding domain.

Normally, its inactive form has GDP bound. Once activated by tyrosine kinase phosphorylation with a bridging protein, it has GTP bound.

GTP-bound Ras can activate RAF / MAPK and mTOR cascades to signal cell proliferation

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2
Q

How does the cell progress from G1 to S phase? When is the restriction point?

A
  1. Growth factors lead to accumulation of cyclin D via MYC.
  2. Cyclin D activates CDK which start phosphorylating Rb, allowing E2F to begin producing cyclin E (think E for E2F).
  3. G1 restriction point -> point of no return where cyclin E has accumulated enough that the cell cycle will move forward without more growth factor / cyclin D
  4. Hyperphosphorylated Rb has now completely lost control of E2F, which stimulates cyclin A from E2F-targeted genes
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3
Q

What actually initiates mitosis?

A

Phosphorylation of the cyclin B / CDK complex and accumulation of these complexes in the nucleus. These processes can be inhibited by G2/M checkpoint mechanisms.

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4
Q

G1 - cyclins D -> E
S - cyclin A
G2 - cyclin B
M - cyclin B

DEAB

A

What major cyclins are present at each phase of the cell cycle?

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5
Q

What is the function of the p53 protein at the G1/S checkpoint?

A

Upregulates DNA repair and also induces p21, a CDK inhibitor protein to arrest a cell cycle
-> will suicide if DNA repair is successful, otherwise upregulates BAX, and suppresses cyclins / Bcl-2

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6
Q

How does a growth factor like PDGF induce cyclin D formation?

A

PDGF -> dimerize than autophosphorylate RTK’s, activate Ras via bridging proteins, which can activate mTOR and MAPK pathways. MAPK / mTOR induce expression of MYC. MYC-MAX induces transcription of cyclin D.

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7
Q

What are the two types of physiologic hyperplasia and give examples of each?

A
  1. Hormonal induced
    - > proliferation of breast epithelium in puberty / pregnancy
    - > smooth muscle of uterus in pregnancy
  2. Compensatory
    - > regeneration of liver after hepatectomy
    - > enlargement of contralateral kidney after unilateral nephrectomy
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8
Q

What is the example of connective tissue metaplasia?

A

Skeletal muscle -> bone after trauma, calsed myositis ossificans

Since they are both derived from mesoderm

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9
Q

What causes cardiac hypertrophy and what are its basic mechanisms?

A

Increased workload due to valvular stenosis or hypertension

Mechanisms:
Mechanical / trophic signals lead to transcription of normal as well as re-expression of fetal / neonatal genes which are more efficient and increase cardiac capacity / reduce workload

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10
Q

What is the most common reason for autophagy?

A

Macroautophagy - for survival in low nutrient conditions (during atrophy)

-> vs heterophagy, which is done to foreign materials by professional phagocytes like PMNs / MACs

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11
Q

What happens to the intermediate filaments in alcohol hepatitis?

A

Tend to form aggregates with breakdown of cytoskeletons

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12
Q

What are the pathways which typically cause accumulation of endogenous and exogenous substances in cells?

A

Endogenous:
Cellular reaction rate imbalances (excess production or decreased removal)
Defects in cellular reactions (abnormal synthesis, metabolism, or transport)

Exogenous:
Lack of metabolic / secretory pathways for removal

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13
Q

How does bilirubin appear as a pigment under the microscope? How to distinguish from lipofuscin?

A

A green to golden-brown pigment. Although it can be brown and near the nucleus at times, typically it is found in the bile ducts / bile canaliculi, and is much more globular in appearance (lipofuscin is very granular)

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14
Q

How does glycogen appear on H&E and how can it be definitively told apart from cholesterol / TAGs?

A

Small, clear, cytoplasmic vacuoles

  • > can be told apart by periodic acid schiff stain for carbohydrates
  • > accumulates in GSDs like Pompe’s and diabetes mellitus
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15
Q

What is transferrin saturation? What is the normal amount?

A

Serum iron levels (variable) divided by iron binding capacity (level of transferrin)

Normally, about 1/3 of transferrin iron-binding sites are filled

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16
Q

What are some things that can cause intrahepatic / extrahepatic cholestasis?

A

Intrahepatic - metastases of the liver, destruction of bile ducts, cirrhosis, etc

Extrahepatic - Gall stones stuck in bile duct (choledocholithiasis), malignancies pushing on bile duct (i.e. pancreatic cancer), etc

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17
Q

What are the deleterious cell reactions which can occur with a depletion of ATP?

A
  1. Increased H20 / Na in cell -> Decreased function of Na/K ATPase
  2. Drop in cellular pH leading to chromatin clumping -> glycolysis / fermentation
  3. Influx of Ca+2 -> failure of Ca+2 ATPase
  4. Abnormal protein synthesis -> loss of RER integrity (mostly due to swelling because of the above effects)
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18
Q

What is the mechanism of carbon tetrachloride toxicity (CCl4)?

A

CCl4 is metabolized by CYP450s in the liver to make CCl3 radical, which starts the lipid peroxidation of membranes in the cell.

  • > decreases RER protein synthesis in liver, leading to apoprotein deficiency and fatty change of liver
  • > also damages mitochondria / cellular membranes leading to cellular death longterm
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19
Q

How does the appearance of the cytoplasm change in necrosis and why?

A
  1. Increased eosinophilia
    - > RNA degraded by lysosomal enzymes
    - > Decreased pH due to lactic acidosis
    - > denatured proteins accumulate
  2. Dense, clumped, irregular appearance
    - > decreased glycogen which normally gives cell a granular appearance
    - > disrupted cytoskeleton from enzymatic activation
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20
Q

What are the causes of liquefactive necrosis? What is the exception?

A
  1. Pyogenic bacterial infections with acute inflammatory infiltrate, and release of WBC lysosomal enzymes which enzymatically digest tissue.
  2. Exception - caused by hypoxia / ischemia in CNS due to high lipid content and a small amount of PMNs
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21
Q

What is fat necrosis and where does it typically occur?

A

Necrosis from inappropriate release and activation of pancreatic lipases, leading to breakdown of membranes / intracellular TAGs to free fatty acids + MAGs.
-> leads to saponification (soap formation) of calcium bound to free fatty acids

-> typically occurs in pancreas (acute pancreatitis)

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22
Q

What are the first steps in induction of the intrinsic pathway?

A

Sensor proteins are activated due to stressors like DNA damage or excessive misfolded proteins.

Pro-apoptotic proteins like BAX and BAK replace anti-apoptosis protein BCL-2 in mitochondrial membrane
-> increasing mitochondrial membrane permeability

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23
Q

What is the gross and microscopic appearance of fat necrosis?

A

Gross - white, chalky patches of fatty on pancreas usually

Microscopic - hazy, basophilic outlines of adipocytes with acute inflammation associated.
-> looks like coagulative necrosis + basophilic hue from the calcium

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24
Q

What is the main mechanism of the extrinsic apoptosis pathway?

A

FasL on T-cells binds Fas receptor on cell to die.

  1. Binding of FasL
  2. Fas receptors cross-link
  3. Binding of Fas-associated death domain (FADD) adaptor protein
  4. Activation of Caspase 8 and executioner caspases
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25
Q

What do caspases do in the execution phase?

A

They are proteases which rapidly, sequentially activative other caspases

  1. Degradation of cytoskeleton and matrix
  2. Endonuclease activation - specific internucleosome DNA cleavage sites (can be seen as a ladder on gel electrophoresis)
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26
Q

What is the mechanism by which cytotoxic T cells induce apoptosis?

A

If they detect foreign antigen on MHC Class 1:

  1. Instrinic pathway: Use perforins to open up the cell, which mediates entry of granzymes.

Granzymes activate caspases and also Bid protein, which stimulates cytochrome C release from mitochondria

  1. Extrinsic pathway: Use FasL to bind Fas on target cell
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27
Q

How are cell membranes modified in apoptosis and what is the purpose of this?

A

Phosphatidylserine becomes expressed on the outside rather than interior of cells

  • > enhanced macrophage recruitment and phagocytosis
  • > efficient removal of apoptotic cell without inflammation
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28
Q

Why does the necroptosis pathway exist?

A

Programmed necrosis:

If the caspase-8 pathway is inhibited (i.e. by a pathogen evasion mechanism or a tumor mutation), apoptosis will still occur via necrosis

-> necrosome causes metabolic alterations (via mitochondrial changes) that decrease ATP production and increase ROS production -> necrotic cell death

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29
Q

How does pyroptosis work and what cytokines are involved?

A

Microbial infections / certain autoimmnue processes results in activation of inflammosome within macrophages and dendritic cells, leading to release of IL-1 and IL-18 via Caspase-1 mediated pathway as well as necrotic cell death. This leads to massive immune recruitment.

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30
Q

How can apoptosis be seen on morphology?

A

Cells are often hard to find and coexist with necrosis

  • > rounded, condensed, hypereosinophilic cell which is reduced in size, with peripherally compacted nuclear chromatin
  • > will form dense, membrane-bound apoptotic bodies
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31
Q

What factors contribute to cumulative nonlethal cellular injury?

A
  • > repetitive damage by oxygen derived free radicals from Ox-Phos
  • > Repeated damage and decreased repair of DNA
  • > Decreased normal folding of proteins / accumulation of misfolded proteins
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32
Q

What is the pathogenesis of dystrophic calcification?

A

In cell injury / necrosis, there is increased membrane permeability leading to accumulation of calcium within cells, as well as membrane dysfunction leading to formation of extracellular vesicles which also hold calcium.

  • > phosphate binds intracellular and extracellular calcium
  • > development of calcium phosphate crystals in and around necrotic tissue (i.e. bicuspid aortic valve)
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33
Q

What tissues are more susceptible to metastatic calcification?

A

Normal organs with alkaline interstitium (calcium precipitates in basic conditions)

  • > places which secrete acids
  • > stomach, kidneys, lungs
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34
Q

What are calcifications often confused with grossly?

A

Fat necrosis, or even caseous necrosis

Calcifications are much harder

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35
Q

What are two unique variants of dystrophic calcification?

A
  1. Psammoma bodies - circular, onion-like concretions with concentric layering
  2. Ectopic bone - i.e. myositis ossificans, a typical of connective tissue metaplasia
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36
Q

What are the four mechanisms of how vascular permeability is increased in acute inflammation, and which is most common?

A

Adaptation-related:

  1. Formation of gaps between endothelial cells of venules - most common
  2. Endothelial transcytosis

Injury-related:

  1. Injury to endothelium of microcirculation
  2. Secondary to angiogenesis - forming blood vessels are immature / leaky
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37
Q

What two mediators cause hyperemia?

A

Histamine, NO

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38
Q

What are the two mechanisms behind forming gaps between endothelial cells? What mediates this?

A
  1. Immediate response -> endothelial cell contraction mediated by histamine, bradykinin, and leukotrienes
  2. Delayed, longer-lasting response -> retraction of endothelium due cytoskeletal changes mediated by cytokines (IL-1, TNF, and IFN-y)
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39
Q

How does rolling occur? What upregulates this

A

Leukocytes transiently attach to E-selectins on endothelium in a low affinity interaction to slow them down via their sialylated carbohydrate ligands (sialyl-Lewis) receptors.

P selectins are upregulated via histamine, and secreted by Weibel-Palate bodies

E selectins are upregulated via TNF, and IL-1

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40
Q

What mediates adhesion?

A

Firm attachment, high affinity interaction between VCAM-1 and ICAM-1 (integrin ligands) of endothelial cells and integrins on leukocytes. These are upregulated via IL-1 and TNF.

ICAM = integrin cell adhesion molecule

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41
Q

How do chemokines influence leukocyte trafficking?

A

They are secreted in the interstitium, are transcytosed and expressed on the vessel interior via the endothelium. These are presented by endothelium and act as coreceptors for leukocytes. Furthermore, they bind GPCRs as chemotaxic agents which induces actin polymerization and movement of immune cells

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42
Q

What acute inflammatory substances are the “early responders” present in preformed stores, and what releases them? What do they do generally?

A

Vasoactive amines - cause vasodilation and increased vascular permeability

  1. Histamine - mast cells
  2. Serotonin - activated platelets
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43
Q

What are the pathways by which complement is activated?

A
  1. Classical - Binding of C1 to IgG or IgM - General Motor Classic cars
  2. Lectin - C1 binds the lectin which binds mannose (MBL) on the pathogen
  3. Alternative - C3b directly binds to the pathogen and is stabilized by factor B and properdin to C3 convertase for further opsonization, and also make C3bBb3b = C5 convertase
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44
Q

What are the anaphylatoxins of the complement pathway and how do they exert their effects?

A

C3a and C5a -> cause vasodilation and increased vascular permeability by directly stimulating mast cell release of histamine

C5a is also a neutrophil chemoattractant

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45
Q

What is the kinin system and how is it activated?

A

A system of plasma proteins which are activated in inflammation (much like complement)

Activated when Hageman factor (Factor 12) contacts collagen, which facilitates its conversion to 12a. Hageman factor will form kallikrein from prekallikrein, as well as 11a from 11

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46
Q

What are the four functions of kallikrein?

A

Kallikrein - 4 functions

  1. Chemotactic agent like C5a or IL-8
  2. Converts HMW kininogen to bradykinin
  3. Converts plasminogen to plasmin (as does tPA)
  4. Increases conversion of 12 (Hageman factor) to 12a (with HMWK as cofactor) -> positive feedback loop
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47
Q

How does thrombin contribute to inflammation?

A

In addition to converting fibrinogen to fibrin, Thrombin (2a) binds to receptors on many cell types, increasing the inflammatory response by causing expression of adhesion molecules, production of cytokines, and generation of prostaglandins.

Also, further upregulates the intrinsic coagulation pathway.

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48
Q

What are the general functions of the prostaglandins? What induces them?

A

Bradykinin-like -> vasodilation, increased vascular permeability, pain

inhibit platelet aggregation

PGE2 - FEvEr

Induced by cytokines like IL-1, TNF, and thrombin which lead to increased cytosolic Ca+2 -> PLA2 activation, giving substrates for COX1/COX2 (inducible)

TXA2 = vasconstriction and platelet aggregation

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49
Q

What leukotriene is a chemoattractant for neutrophils and where is it produced?

A

LTB4 - produced by neutrophils only as a chemoattractant for other neutrophils

  • > made by lipoxygenases
  • > all other leukotrienes are made by neutrophil / platelet interaction
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50
Q

What are the leukotriene / lipoxin functions?

A

Leukotrienes - smooth muscle contraction -> cause vasoconstriction, increased vascular permeability, and bronchospasm

Lipoxins - made via lipoxygenase pathway as well, anti-inflammatory

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51
Q

How is PAF made and what does it do?

A

Platelet activating factor (PAF)

Made from phospholipids (not A2) in many cell types

  1. Stimulates platelet AND leukocyte activation
  2. Has leukotriene-like effects -> bronchoconstriction, increased vascular permeability
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52
Q

What are the important inflammatory cytokines mediating local effects and what do they do?

A

TNF and IL-1, produced primarily by macrophages

  1. Endothelial cell activation (E-selectin, ICAM/VCAM)
  2. Leukocyte stimulation (increased cytokine secretion / response)
  3. Stimulation of fibroblasts transition into repair phase
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53
Q

What are the acute vs chronic effects of cytokines TNF, IL-1, and IL-6?

A

Acute - fever (IL-1), anorexia, fatigue, production of APPs (IL-6), (systemic inflammatory response syndrome - SIRS, including leukocytosis)

Chronic - cachexia - due to increased lipid / protein mobilization from chronic inflammation - mostly mediated via TNF.

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54
Q

Is nitric oxide considered proinflammatory or anti-inflammatory, and how does it work?

A

Mixture, although production is increased during inflammation by macrophages / endothelial cells

Proinflammatory properties:

  1. Vasodilation
  2. Antimicrobial activity - substrate for production of peroxynitrite free radicals

Anti-inflammatory:
Reduction of platelet and leukocyte adhesion

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55
Q

What is substance P?

A

A pro-inflammatory neuropeptide, increases pain response in CNS / PNS

Substance P(AIN)

(along with bradykinin and prostaglandins)

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56
Q

What substance is thought to mediate the invasion of the immune system into hypoxic tissue?

A

Hypoxia-induced factor 1alpha

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57
Q

What is suppurative inflammation and what causes it?

A

Also called purulent inflammation, often caused by pyogenic bacteria

It is a dense collection of inflammatory cells with exudative edema and cell debris (does not always destroy tissue structure to cause necrosis)

  • > extended period = liquefactive necrosis
  • > fibrin capsule around liquefactive necrosis = abscess
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58
Q

What are the two broad categories of macrophages? How are they activated and what is their function?

A

M1 - classically activated - via TH1 cells and IFN-y, function in inflammation and microbial killing

M2 - alternatively activated - via TH2 cells, release anti-inflammatory factors like IL-10 and TGF-beta, and stimulate fibrosis / tissue repair via growth factors

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59
Q

Give two general causes of granulomatous inflammation, as well as the underlying pathogenesis.

A

Hallmark of granulomatous inflammation is activated M1 macrophages - epitheloid histiocytes. May be accompanied by lymphocytes and giant cell aggregates.
T cells will secrete IL-2 for further T cell response, and IFN-y to keep macrophages active. Macrophages release IL-12 to activate more Th1 cells.

  1. Organisms resistant to killing which will cause a Type 4 hypersensitivity: i.e. TB, histoplasmosis
    - > causes caseating necrosis
  2. Particulate material which cannot be degraded -> nonabsorbable sutures, uric acid crystals
    - > causes non-caseating necrosis
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60
Q

What is fibrinous inflammation? How does it appear histologically?

A

Acute inflammatory process where extravascular fibrin deposition predominates -> often on tissue surfaces in body cavities

Appears similar to serous inflammation as it is sparsely cellular, but very eosinophilic due to fibrin buildup extravascularly. It results from increased vascular permeability more than serous, allowing clotting factors to seep out and form fibrin.

May ultimately result in the formation of granulation tissue with subsequent fibrosis

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61
Q

How is uric acid proinflammatory?

A

Indication of necrosis / cell death, can lead to production of the IL-1 after activation of the inflammasome

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62
Q

What is a leukemoid reaction?

A

Reactive neutrophilia (left shift with band forms) which is so strong it looks like leukemia -> often in severe infection, will appear with Dohle bodies and toxic granulation

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63
Q

What are the functions of haptoglobin, ferritin, and hepcidin and are they positive or negative APPs?

A

Haptoglobin - binds free hemoglobin
Hepcidin - decreases iron absorption and transport (kills da iron)
Ferritin - binds free iron, need more so you can store more, with assistance via ceruloplasmin (copper carrier enzyme which oxidizes it to Fe+3, mobile form)

  • > decreases microbes ability to take up free iron
  • > positive APPs
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64
Q

What is the erythrocyte sedimentation rate? Does this increase or decrease in inflammation and why?

A

Distance that RBCs settle in a vertical column of anticoagulated blood in one hour

Decreases in inflammation because of elevated fibrinogen levels (+APP), leading to increased thombosis risk

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65
Q

Why are transthyretin and cortisol-binding globulin negative APPs?

A

Decreased levels reduce hormone binding capacity -> temporary increase in action of free hormone (T4 and cortisol)

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66
Q

Why are albumin, transferrin, and retinol-binding proteins negative APPs?

A

Mostly to delegate more amino acids towards +APP synthesis

-> transferrin also needs to be decreased to reduce circulating iron levels for microbes

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67
Q

What are the two types of stem cell pools and which one is utilized most commonly for tissue expansion? What is their primary difference?

A
  1. Tissue stem cells -> most common
    - Restricted differentiation capacity, i.e. basal cells of epithelium, base of intestinal crypts
  2. Multipotent adult progenitor cells
    - broad differentiation capacity
    - identified in many tissues, including bone marrow
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68
Q

What two factors are needed for angiogenesis as well as tissue regeneration and healing?

A

Vascular endothelial growth factor (VEGF)

Fibroblast growth factor (FGF)

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69
Q

What three growth factors are used for the stimulation of proliferation of mesenchymal cells? What cell types would these be?

A

Platelet-derived growth factor (PDGF) (healing near wound site)
Fibroblast growth factor (FGF)
Transforming growth factor beta (TGF-beta)

Includes fibroblasts, smooth muscle, and endotheliums

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70
Q

What is the function of TGF-beta?

A

Transforming growth factor beta

  • > strong stimulus for fibrosis (induces fibroblast motility, proliferation, and ECM production)
  • > terminates the inflammatory response, solidifies formation of scar
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71
Q

What is the primary determining factor of whether tissue regeneration can occur?

A

After the insult, is the ECM framework intact? If so, tissue regeneration can occur. Otherwise the cells will grow back by mass, but not the same way they were before (compensatory hyperplasia)

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72
Q

What type of insult would produce an injury that requires healing with fibrosis?

A
  1. Severe injury - damage to ECM or deep structures where stem cell pool is destroyed
  2. Chronic inflammation
  3. Involvement of permanent cell types
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73
Q

What typically causes reactive lymphocytosis and what types of lymphocytes are present (one of these is abnormal and common)

A

Most common in viral infections

  • > polyclonal lymphocytes with unique surface antigen receptors
  • > atypical lymphocytes - activated CD8 cells which are large and amorphous
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74
Q

How does angiogenesis in granulation tissue commence, and how does this relate to fibroblast proliferation?

A

VEGF and FGF cause migration and proliferation of endothelial cell precursors from bone marrow, as well as sprouting off of existing blood vessels (most common).

Since primitive vessels are leaky prior to maturation -> exudative edema occurs. The edema serves as a good matrix for fibroblasts to migrate in develop connective tissue.

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75
Q

What secretes all these growth factors? How are they secreted?

A

All these growth factors are secreted in a paracrine fashion by fibroblasts, macrophages, and endothelial cells

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76
Q

What are the hallmarks of scar formation (vs granulation tissue)

A
  1. Decreased number of proliferating endothelial cells and fibroblasts
  2. Increased deposition and development of ECM, especially fibrillar collagens (will be much more blue than granulation tissue on trichrome)
  3. Connective tissue remodeling (Type 3 collagen -> Type 1 collagen, higher tensile strength, less pliability)
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77
Q

What factors might be in play to impede wound healing?

A
  1. Most common -> persistent infection, local or systemic (i.e. S. aureus)
  2. Inadequate circulating or drainage
  3. Decreased immune response due to immunosuppressive drugs or immundeficiency
  4. Malnutrition (protein or vitamin C deficiency (needed for collagen))
  5. Wound disruption - i.e. mechanical stress or foreign bodies present
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78
Q

What is “proud flesh”?

A

A form of excessive wound repair in which “overabundant granulation tissue” extends far above the skin surface, preventing the skin from being re-epithelialized

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79
Q

What stain is used to visualize amyloid, and what two types of microscopy? How does the stain work?

A

Congo-red stain -> dye intercalates between the beta-pleated sheet structure of the amyloid fibrils, which are each composed of sets of beta pleated sheets forming filaments, which are crossed at 90 degrees

Light microscopy -> stain will appear red-orange

Polarization microscopy -> appears green or yellow (if you turn it perpendicularly 90 degrees it will change to the other color, since the beta sheets are crossed and 90 degrees offset)

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80
Q

What component is conserved in all amyloid proteins?

A

Serum amyloid P component -> stabilizes the protein

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81
Q

How is AE formed?

A

Endocrine amyloid -> formed from proteins like calcitonin, islet amyloid polypeptide, and atrial natriuretic factor (ANF)

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82
Q

What are the three major biochemical types of amyloid?

A

AL - amyloid light chain

AA - amyloid-associated

Abeta - Beta-amyloid

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83
Q

What are the four types of systemic amyloidosis? Which is most common?

A
  1. Primary amyloidosis - most common -AL amyloid
  2. Secondary or reactive amyloidosis - AA amyloid due to chronic inflammation (IBD, rheumatoid arthritis) or infection (TB, osteomyelitis)
  3. Hemodialysis-associated amyloidosis - Abeta2 amyloid (causes carpal tunnel due to small joint / tendon sheath accumulation)
  4. Senile amyloidosis (ATTR amyloid, cardiac amyloidosis
84
Q

What are the two main types of localized amyloidosis?

A
  1. Cerebral amyloidosis
    - > Abeta amyloid
  2. Endocrine amyloidosis
    - > AE amyloid, due to T2DM pre-beta-cell failure (islet polypeptide), ANF (heart failure), or calcitonin (medullary thyroid carcinoma - C / parafollicular cancer)
85
Q

What are the 4 minor biochemical types of amyloid?

A
  1. Abeta2 - hemodialysis-associated
  2. ATTR - senile amyloidosis, familal amyloidic neuropathies
  3. AE - endocrine amyloidosis (focal)
  4. PrP - prion protein amyloid
86
Q

What are the two types of hereditary / familial amyloidosis? What is the inheritance pattern of each?

A
  1. Familial Mediterranean fever - AA amyloid. Pyrin defect leads to excess IL-1 -> constant SAA acute phase protein.
    - Autosomal recessive
  2. Familial amyloidotic neuropathies - ATTR amyloid -> caused by transthyretin mutation, amyloid tends to deposit in peripheral / autonomic nerves, even heart.
    - Autosomal dominant
87
Q

What happens to blood vessels in interstitial and intravascular amyloid accumulation?

A

They become brittle and prone to hemorrhage

-> organs will be enlarged, firm, and pale

88
Q

Where will amyloid accumulate in the liver and what happens if this occurs?

A

In the space of Disse (between the sinusoids and hepatocytes)

The hepatocytes around the accumulation will undergo pressure atrophy, but liver will not fail until late because there are a great excess of hepatocytes

89
Q

Why is amyloidosis in the spleen so diagnostic?

A

You will have splenomegaly but no thrombocytopenia (typical of splenomegaly)
-> amyloid protein will accumulate and not leave a place for platelets to stay

  • > sago spleen = accumulation of amyloid in white pulp
  • > Lardaceous spleen = accumulation of amyloid in red pulp
90
Q

What is one example of amyloidosis causing skeletal muscle atrophy?

A

Atrophy of tongue muscles in macroglossia

-> can even cause speech and swallowing impairment

91
Q

Where does amyloid tend to collect in the skin?

A

Under the eyelids

92
Q

What is the final type of edema other than exudative and transudative and give two causes.

A

Edema due to lymphatic obstruction

  1. Infection blocking lymph drainage -> i.e. filariasis
  2. Malignancy physically blocking lymph drainage
93
Q

What cells are definitive for chronic congestion in the lungs?

A

Heart failure cells - hemosiderin-laden macrophages in the alveoli
-> eating up RBCs which sometimes leak out of capillaries from microhemorrhages due to congestion

94
Q

What happens to the alveolar septae in chronic lung congestion?

A

Alveolar septal fibrosis

due to fibroblasts losing contact with ECM when they are exposed to so much edema chronically

95
Q

What are the acute vs chronic effects of liver congestion? What areas of the liver are susceptible?

A

Acute: centrilobular sinusoids expand (central vein is the drain)

Chronic:
Centrilobular necrosis or atrophy, with accumulation of fibrosis and hemosiderin-laden macrophages
Periportal - normal or fatty change

96
Q

What are purpura and what causes them?

A

Slightly larger hemorrhages than petechiae, typically due to vascular pathology (i.e. vasculitis)

Petechiae are typically caused by a platelet problem, or asphyxiation

97
Q

What is the microscopic progression of lung edema and when does this lead to dyspnea? What does this lead to on radiograph?

A
  1. First spills out of capillaries into alveolar septae
    - > leads to Kerley B lines on X-ray
  2. Pneumocyte occluding junctions burst due to increased pressure -> fluid accumulates in alveolar airspace
    - > this leads to dyspnea and interstitial fluid on X-ray
98
Q

How are you likely to tell the difference between hyperemia and congestion in the lung?

A

Both will have pulmonary capillaries filled up with RBCs

Congestion: More likely in the setting of transudative edema and few immune cells
(passive process)

Hyperemia: More likely in the setting of acute inflammation, as inflammatory cells are actively inducing the increased RBCs
(active process)

99
Q

What are the three phases of formation of the primary hemostatic plug?

A

3 A’s

  1. Adhesion - 1b receptor to vWF
  2. Activation (Secretion)
  3. Aggregation
100
Q

How do thrombomodulin and tissue factor pathway inhibitor (TFPI) work?

A

Thrombomodulin -> binds thrombin, activates protein C and protein S -> degrades factors 5 and 8 which are needed for thrombin formation

TFPI - inhibits interaction between TF-7a complex and X

101
Q

How does fibrinogen increase platelet aggregation?

A

Cross-links platelets via their GpIIb/IIIa receptors which are exposed during platelet activation (blocked by abciximab)

102
Q

How does the extrinsic pathway work and is this the vitamin K dependent pathway or no? Include cofactors as applicable

A

Tissue factor released by injured endothelium converts 7 to 7a an forms a complex

TF-7a complex activates factors IX and X to activate downstream pathways

-> note that activation of factor 9 is a bit of an overlap with the instrinsic pathway for activation of 10

YES - 2, 7, 9, and 10 are extrinsic pathway, depend on vitamin K

103
Q

Normal endothelial cells do not want clotting to occur around them. When antiplatelet factors do they constantly release?

A
  1. Prostacyclin (PGI2) - vasodilator and inhibitor of aggregation
  2. NO - vasodilator
  3. ADPase - interferes with ADP for platelet aggregation
104
Q

What exactly does thromin promote to get the instrinsic pathway going? What are the other amplification functions?

A

Amplifies conversion of 11 to 11a, is the only thing which can convert 8 to 8a

Also:
Amplifies 5 to 5a (for factor 10) and
Activates 13 to 13a (for cross-linking of fibrin)

105
Q

What is the sequence of the intrinsic pathway?

A

Hageman factor (12) is converted to 12a upon contacting collagen, converts prekallikrein to kallikrein and 11 to 11a

11a converts 9 to 9a with thrombin (2a) as an amplifier. (9 also activated by TF-7a)

Once 8 is activated to 8a via thrombin, 9a + 8a can convert 10 to 10a, feeding into the pathway.

Sequence is 12->11->9->10(conversion requires 8)

106
Q

What is the overall role of thrombin in inflammation?

A
  1. Coagulation cascade -> amplifies multiple steps, makes fibrin and facilitates its crosslinking via 13a, also 8 to 8a
  2. Platelets -> enhances activation and aggregation
  3. Endothelial cells -> binds receptors to stimulate leukocyte adhesion, has procoagulant and anticoagulant functions via thrombomodulin / heparin-like molecule
107
Q

What is the purple collection tube for? Give the additive. What is it used for?

A

Whole blood (anticoagulated formed blood elements + plasma)

  • > EDTA is a strong irreversible sequesterer of calcium to prevent clotting
  • > used for CBCs and peripheral blood smears
108
Q

What do alpha and delta granules contain?

A

Alpha - factors 5 and 8, fibrinogen, fibronectin, vWF, platelet factor 4 (inactivates heparin-like molecules)

Delta - ADP and calcium

Platelets also upregulate phospholipids on their surfaces + synthesize TXA2

109
Q

What is the blue collection tube? Give the additive. What is it used for?

A

Plasma (supernatant of spun anticoagulated / whole blood)

  • > Contains clotting factors + serum (no platelets)
  • > additive is sodium citrate (reversibly binds calcium, enough calcium can be added to induce clotting)
  • > Used for coagulation tests like PT and aPTT
110
Q

What is the red collection tube for? How is it made? what is it used for?

A

Serum (plasma minus clotting factors)
Made by drawing out the liquid after the blood is clotted
-> Made in a glass tube without clotting activator (silica will spontaneously cause clotting)
or
-> plastic tube with clotting activator added

Used for serology (antibody tests) / routine chemistry

111
Q

What is added to perform a prothrombin time (PT)? What are we measuring

A

Citrated plasma + few platelets, tissue factor, phospholipid surface, and excess Ca+2 to overcome citrate
-> measure time it takes to form fibrin clot (in seconds)

-> only difference for aPTT is addition of silica contact activator instead of tissue factor

112
Q

What two things can cause an elevated thrombin time?

A
  1. Deficiencies / defects in fibrinogen

2. Inhibitors of thrombin (i.e. heparin use, stops thrombin greatly in intrinsic pathway as well)

113
Q

Give examples of procoagulant and anticoagulant clotting factors which can be mutated to cause primary hypercoagulability.

A 
Procoagulant: 
Factor 5 (Leiden) mutation -> cannot be lysed by protein C, no negative feedback via thrombomodulin

Anticoagulant:
AT3, protein C/S deficiences

114
Q

What type of disorder is heparin-induced thrombocytopenia and its pathogenesis?

A

Secondary hypercoagulability

Immune complexes form to platelet-factor 4 / heparin complexes (PF4 normally inactivates heparin-like molecules on endothelium).

These immune complexes bind platelets and increase activation, leading to a thrombocytopenia (more clots, more splenic clearance via opsonins) but overall increased clotting risk

115
Q

What is Virchow’s triad?

A

The triad of interrelated factors leading to thrombosis, including

  1. Endothelial injury
  2. Abnormal blood flow
  3. Hypercoagulability
116
Q

Do anticardiolipin antibodies elevate aPTT and PT?

A

Yes -> they are antiphospholipid and interfere with this surface needed to form a clot (typically present on activated platelet)

  • > however, this is just in the lab. In vivo, anticardiolipin antibody syndrome actually causes hypercoagulation by unknown mechanisms
  • > seen in with repeated pregnancy complications
117
Q

How does estrogen cause increased clotting risk?

A

also estrogen predisposes you to clotting due to increased fibrinogen synthesis

118
Q

What is the most common source of systemic thromboemboli?

A

Mural thrombi

-> walls of heart or aorta

119
Q

What determines whether a patient will have pulmonary hemorrhage, pulmonary infarction, or sudden death from a pulmonary thromboembolus?

A

Pulmonary hemorrhage - patient with good bronchial circulation to cover blood flow, but increased blood from systemic pressure -> destruction of alveolar septae (happens more in young people)

Pulmonary infarction - smaller embolus but poor bronchial circulation -> not enough blood to save tissue (happens more in elderly)

Sudden death -> very large or saddle embolus blocking multiple airways, or many small emboli simultaneously
-> decreased blood to LV and drop in cardiac output leads to sudden death

120
Q

What is the most severe complication of a fat embolus? What is the classic presentation?

A

Fat embolism syndrome
-clinical triad: hypoxemia (respiratory difficulty due to pulmonary involvement), neurologic abnormalities, and petechial rash (due to thrombocytopenia from coated platelets)

121
Q

What are the acute manifestations of decompression sickness?

A
  1. Bends - pain from air emboli within skeletal muscle and large joints
  2. Chokes - respiratory difficulty due to pulmonary injury
    - > chronic = caisson disease with long bone necrosis due to blockade of blood flow
122
Q

How do amniotic fluid emboli arise and what do they typically cause?

A

Arise when amniotic fluid enters uterine veins, gets in lungs, and causes diffuse alveolar damage + DIC (from endothelial cells of baby seeding coagulation)
-> same presentation of fat embolism syndrome, just need to lung sample

123
Q

What is the primary cause of hemorrhagic infarct, and what organs are most likely to develop this?

A

Venous obstruction -> leads to blood buildup in capillaries and hemorrhage into tissues

Common in tissues with dual blood supply / anastomoses: i.e. liver, lung, small bowel

124
Q

What is the gross and microscopic appearance of hemorrhagic infarct?

A

Gross - pyramidal shaped region most often, with rust-brown appearance

Microscopic - Coagulative necrosis with hemorrhage, along side numerous hemosiderin-laden macrophages from RBCs

125
Q

What do cerebral and septic infarcts cause? Include what causes septic infarct

A

Cerebral infarct - liquefactive necrosis

Septic infarct - abscess
-> caused by embolus with bacteria in it lodging somewhere

126
Q

What is the direct effect of the immune cells in causing organ failure in septic shock?

A

Endothelial injury / activation

  • > Endothelium becomes prothrombotic and causes DIC (injury due to oxygen free radicals)
  • > vasodilation and increased vascular permeability also increases procoagulant effects (sludge in blood vessels) (from histamine / complement activation)
127
Q

What happens in the progressive phase of shock? Why? Think of skeletal muscle, kidney, and brain.

A

Widespread tissue hypoperfusion / hypoxia for a number of reasons

  1. Lactic acid builds and causes vasodilation
  2. Endothelium becomes injured -> DIC causing microthrombi, petechiae, hemorrhagic diathesis
  3. Renal hypoperfusion -> electrolyte abnormalities
  4. Cerebral hypoxia -> confusion
128
Q

What does it look like microscopically in brain with ischemia / hypoxia? Heart? Kidneys? Adrenal glands?

A

Brain - red, dead neurons which die before glial cells
Heart - Contraction band necrosis from catecholamine overstimulation
Kidneys - Acute tubular necrosis (proximal tubules die first)
Adrenal glands - stress reaction, increased glucocorticoid first, followed by dropoff when fat stores are depleted

129
Q

What is seen in the lungs during septic shock?

A

Diffuse alveolar damage due to inflammation in the capillaries

130
Q

What is the definition of shock?

A

Systemic hypoperfusion leading to widespread tissue hypoxia

131
Q

What are the metabolic derangements of septic shock?

A
  1. Acute phase responses like fever, left-shift, and APP
  2. Increased gluconeogenesis and decreased insulin to cause hyperglycemia
  3. Increased glucocorticoid production until fatty stores decrease and it drops (adrenal stress reaction)
132
Q

What are the three phases of shock which characterizes cardiogenic and hypovolemic shock?

A
  1. Nonprogressive phase
    - > due to hormonal (i.e. RAA/ADH) and neuronal (sympathetic) compensated
  2. Progressive phase
  3. Irreversible phase
    - > with manifestations of ischemic damage
133
Q

What does vitamin A squamous metaplasia cause in other tissues?

A

Follicular hyperkeratosis

-> secretory epithelium dysfunction, i.e. upper airway, urinary tract, adnexal ducts

134
Q

What are the normal ways in which vitamin A exerts its effect, and what tissues are highly dependent in light of this?

A
  1. It binds nuclear hormone DNA-binding receptors (RAR / RXR heterodimers) to influence gene expression
    - > most critical for differentiation of mucus-secreting epithelium
  2. Also is a component of Rhodopsin which is needed for seeing in low light
  3. Immune system -> increased susceptibility to infection
135
Q

What is another one of the bone deformities in rickets (earliest sign of rickets)?

A

Rachitic rosary - rib cage popping out on the sides where the cartilage is growing

136
Q

What can vitamin K deficiency in neonates cause and why does this happen?

A

Hemorrhagic disease of newborn

-> due to absence of gut flora (makes vitamin K) and poor placental transportation of vitamin

137
Q

What eye epithelium changes can occur due to vitamin A deficiency?

A

Keratomalacia - Corneal ulceration

Xerophthalmia - dry eye due to squamous metaplasia of secretory epithelium

138
Q

What are the two forms of B1 deficiency that is not WK syndrome and what causes each of them?

A

Dry beriberi - due to impaired glucose metabolism -> peripheral polyneuropathy with myelin degeneration and symmetrical numbness / muscle wasting

Wet beriberi - abnormal ATP synthesis affects cardiac function -> peripheral vasodilation and high output myocardial failure (dilated cardiomyopathy) causing peripheral edema

139
Q

What is Wernicke vs Korsakoff syndrome / classic triad and what causes that?

A

Wernicke encephalopathy - triad of ACO: ataxia, confusion, and ophthalmoplegia

Korsakoff psychosis - irreversible, retrograde / anterograde amnesia due to damage to mammillary bodies, thalamus, and periventricular gray matter

140
Q

What are the features of riboflavin deficiency?

A

2 C’s of B2
1. Cheilosis - cracking at side of mouth
2. Corneal vascularization
+
3. Glossitis - cyanotic color of tongue (cannot turn over the keratinized epithelium of tongue fast enough, causes hyperemia / inflammation)
4. Dermatitis - greasy, scaling skin of face / genitalia

141
Q

What does B6 deficiency cause?

A

Neuropathy / hyperirritability / convulsions due to loss of neurotransmitters / function in energy storage

Anemias due to impaired hemoglobin synthesis, with buildup of iron (B6 is used in heme synthesis)

Also same symptoms as B2 deficiency: Dermatitis, cheilosis, glossitis

142
Q

What are the functions of vitamin C?

A

Antioxidant / free radical scavenger

Immune function (along with vitamin A)

Procollagen / collagen cross-linking (lysine / proline hydroxylation)

Biosynthesis of carnitine and neurotransmitters like NE

143
Q

What does vitamin C deficiency cause?

A

Scurvy -> bleeding tendency (especially perifollicular),

slow / inadequate wound healing (due to weak collagen in granulation tissue),

dermatologic changes (i.e. gums / periodontal disease),

and skeletal changes in children (similar to Rickets, but in this case, production of osteoid is insufficient, bone does not mineralize but tends to overgrow cartilage)

144
Q

What causes pernicious anemia? What pathologic changes will this cause?

A

Autoimmune destruction of stomach mucosa / parietal cells

Autoantibodies will be against -> intrinsic factor or parietal cells themselves

-> Antibodies will cause T-cell mediated destruction of parietal cells, with B12 deficiency, achlorhydria (HCl secretion deficiency) and intestinal metaplasia

145
Q

What drugs can inhibit folate absorption / metabolism?

A

Oral contraceptives, alcohol, phenytoin (sketchy salad dropping), sulfonamides (interferes with biosynthesis), methotrexate (inhibits dihydrofolate reductase)

146
Q

Other than RBCs, what other blood cells are abnormal in B12/B9 deficiency?

A

Neutrophils -> hypersegmented

Megakaryocytes -> abnormal

147
Q

What is the name of the neurological condition that develops in B12 but NOT B9 deficiency? Is it reversible?

A

Subacute combined degeneration (SCD)
-> myelin degeneration in the dorsal column, lateral corticospinal tract, and spinocerebellar tract (same as vitamin E there)

Not reversible

148
Q

What disease is characterized by the triad of atrophic glossitis, esophageal webs, and anemia?

A

Plummer-Vinson syndrome

think of iron pipes!

149
Q

What does vitamin A toxicity cause? How can it mimic a brain tumor in children?

A

Teratogenic -> due to retinoic acid derivative

Hepatic dysfunction (polar bear liver)

In children -> causes increased ICP (pseudotumor cerebri)

150
Q

What is the adult form of iodine deficiency characterized by?

A

Myxedema - diffuse dermal mucinous edema with slowing of mental / physical functions, including heart function

-> mucinous edema, slowed mental / physical (heart) functions

151
Q

How does kwashiorkor occur / what are the physical manifestations?

A

Adequate caloric intake with deficient protein intake -> visceral compartment wasting

Physical - loss of endogenous protein synthesis results in:
Edema - loss of albumin
Hepatomegaly - fatty change due to apolipoprotein synthesis decrease

152
Q

What nutrients do phenobarbital, nitrous oxide, and alcohol cause the depletion of?

A

Phenobarbital - Induces liver enzymes to metabolism Vitamin D (steroid hormone)

Nitrous oxide - increases degradation of B12 (causes neuropathy)

Alcohol - B1, B2, and B9 (decreased nutrition status)

153
Q

What other symptoms are present in kwashiorkor? How does this present in hospitalized patients?

A

Loss of appetite (patient feels ill), hair / skin changes are present (due to oxidative damage) including dermatosis, and mental changes

-> impaired wound healing in hospitalized patients is common

154
Q

What are the characteristic features of a fatty streak and what cell types are present?

A

Earliest stage of atherosclerotic lesion, even found in children / adolescents.

Flat or slightly elevated lesion which is made of lipid rich foam cells which does not interfere with flow. Foam cells are from intracellular inclusions in:

  1. Macrophages / monocytes
  2. Smooth muscle cells

No fibrosis / necrosis

155
Q

What happens in hemorrhage into the plaque?

A

Can cause acute expansion or rupture of the plaque (leading to ulceration (with embolization of contents) or thrombosis)
-> bleeding into the intimal layer

156
Q

What cell types are primarily present in atheromatous plaques? What produces the extracellular matrix?

A
  1. Smooth muscle cells - proliferate and produce the extracellular matrix (collagen / elastic fibers)
  2. Monocytes / macrophages
  3. T lymphocytes (fatty streak will not have this)

-> the “5” includes platelets and endothelial cells

157
Q

What happens to cause aneurysmal dilatation of the vessel?

A

Plaque erodes into the tunica media, causing loss of elastic tissue and smooth muscle cells due to pressure from plaque, ischemic atrophy, or inflammatory damage
-> vessel ultimately balloons out

158
Q

What are modifiable major risk factors for atherosclerosis?

A
  1. Hyperlipidemia
  2. Diabetes mellitus
  3. Hypertension
  4. Cigarette smoking
159
Q

What three labs are considered minor risk factors for AS?

A
  1. Increased homocysteine level
  2. Increases blood lipoprotein Lp(a) level
  3. Increased C-reactive protein level (stroke)
160
Q

How are free radicals thought to play a part in atherosclerosis pathogenesis?

A

By initiating the process of lipid peroxidation, oxidized LDL becomes chemotactic to blood monocytes and holds immune cells within the plaque. Furthermore, oxidized lipids are toxic to endothelial and smooth muscle cells, and further facilitate the development of foam cells and expansion of plaques.

161
Q

What growth factors are thought to underlie the proliferation of SMCs into the intima?

A
  1. PDGF - platelet-derived growth factor
  2. FGF - fibroblast growth factor
  3. Heparin-like compounds (inhibitory growth factor, concentrations are decreased)
162
Q

What is the role of T cells in atherosclerotic plaques?

A

Cross-talk with macrophages, leading to both cellular and humoral immune activation
-> promote inflammation which is associated with AS

163
Q

What are the five outcomes / types of complicated lesions (advanced atherosclerotic plaques)

A
  1. Calcification (dystrophic)
  2. Ulceration / focal rupture
  3. Thrombosis
  4. Hemorrhage into the plaque
  5. Aneurysmal dilatation of vessel wall
164
Q

What electrolyte imbalance happens in burns and why?

A

Hyperkalemia, due to cellular lysis from heat (high K+ in cells is released into interstitium)

Hyponatremia -> loss of plasma into interstitium, subsequent dilution of sodium

165
Q

What are the signs and symptoms of heat cramps, and what causes them?

A

Involuntary, painful muscle spasms during or after strenuous exercise

Caused by electrolyte abnormalities like hyponatremia (due to only replenishing water but not electrolytes)

166
Q

What are the signs and symptoms of heat exhaustion? How will the skin feel?

A

Sudden dizziness, nausea, headache, profuse sweating, fatigue associated with hypotension, tachycardia, and a low-grade fever

Skin feels pale, cool, and moist -> vasoconstriction due to hypovolemia with sweating

167
Q

What GI side effect is a result of the acute, extreme physiological distress of burns?

A

Curling ulcers (think “Curling irons can burn”) -> gastric ulcers in the setting of a burn

168
Q

What are the signs and symptoms of heat stroke?

A

High core body temp (>104F/40C)
Hot, dry, flushed skin (peripheral vasodilation for convection)
Tachycardia, neurologic symptoms, difficulty breathing

Severest form: Looks like septic shock due to heat shock protein activation
-> Multiorgan failure and rhabdomyolysis

169
Q

What is the first manifestation of focal tissue injury in hypothermia, what does this look like, and what can it progress to? Pathogenesis?

A

Frostbite -> appears like blisters due to edema in the injured area, which becomes discolored and eventually turns black / loses sensation.

Progresses to gangrene, particularly in areas with poor collateral circulation which will be most affected by vasoconstriction

  • > interstitial fluid crystallizes, proteins denature, and vascular permeability increases due to endothelial cell injury by these crystals.
  • > hypercoagulant prothrombotic state results
170
Q

How can radiation cause dental caries?

A

Fibrosis of salivary gland -> dry mouth (no saliva production) -> dental caries

Note: radiation induces double-stranded breaks in DNA

171
Q

What is radiation dermatitis?

A

Induction of skin ULCERATION due to tissue atrophy and necrosis, often associated with pallor and telangectasia

172
Q

What are the late vascular and interstitial manifestations of radiation exposure?

A

Vascular and interstitial fibrosis, with associated tissue atrophy

-> telangectasia and pallor are very common
Lungs - most commonly fibrosed organ
Cataracts - most common eye manifestation
Can lead to atherosclerosis and MI due to endothelial damage

173
Q

What are the early complications of radiation exposure?

A
  1. Parenchymal cell injury (Reversible or irreversible in susceptible tissues). Susceptible tissues are highly vascular (easy to fibrose), with a good oxygen supply and quick replication time
  2. Endothelial damage -> leads to hyperemia, increased vascular permeability, hemorrhage, and thrombosis (blood vessels very susceptible)
174
Q

What is the mode of inheritance of Hutchinson-Guilford syndrome, what is it also called, and what is the nature of the defect?

A

Infantile progeria syndrome -> defect in lamin A gene, a nuclear membrane protein.

Autosomal recessive

Average life expectancy is about 12 years

175
Q

What is the general vs specific view of aging?

A

General view: aging is the sum of all structural / functional changes occurring over time

Specific view: post-maturational period of decline in health (senesence), ultimately resulting in death

176
Q

What are sirtuins and what are a few of their functions?

A

NAD-dependent protein deacetylases

Function in DNA repair, gene expression, apoptosis, and aging
-> have a protect effect against DNA damage via deacetylation of proteins which are active to cause DNA dysfunction

177
Q

What do genomic mechanisms of aging suggest?

A

Specific aging genes, including genes which control cell doubling (telomerase), apoptosis, and gene regulation sirtuins, control the ultimate senescence of the organism.

178
Q

What is the somatic mutations theory?

A

A wear and tear mechanism of aging (umbrella term), which suggests that cumulative DNA damage from processes such as radiation or chronic insult leads to impairment of cell / organism survival.

179
Q

What are the two regulatory system mechanisms of aging?

A
  1. Immune function - declining immune function results in higher incidence of autoimmune disease / neoplasia
  2. Neuroendocrine - HPA axis governs length of life based on “biological clock”
180
Q

What are some age-related and age-dependent diseases?

A

Age-related: Atherosclerosis / CVD, septicemia, pneumonia, Alzheimer’s / Parkinsons, cancers

Age-dependent: Osteoporosis, temporal arteritis, cataracts, BPH, osteoarthritis

181
Q

What cardiovascular changes are likely in chronic alcoholism?

A

Atherosclerosis, hypertension, and dilated cardiomyopathy

182
Q

What two conditions of cardiovascular disease does smoking predispose you to and why?

A
  1. Atherosclerosis - toxins injure the endothelium
  2. Myocardial infarction - oxygen supply decreased by atherosclerosis + increased oxygen demand from catecholamine stimulation (nicotine = stimulant)
183
Q

Alcohol causes fatty change in the liver acutely, kk? What is one upper GI manifestation which can occur acutely and why?

A

Mallory-Weiss tears in lower esophagus
Think of mallory mager marrying a troll
-> due to vomiting from alcohol intoxication

184
Q

What types of carcinoma does cigarette smoking predispose you to?

A

Lung, upper digestive tract (lip, mouth, pharynx/larynx), esophagus (all easy)

Harder:
Pancreas
Urinary bladder and kidney -> excretion of products
Uterine cervix -> helps support fullblown cancer in precancer cells

185
Q

What two primary enzymes are inhibited by lead? By what mechanism? What buildups does this cause in urine?

A
  1. ALA dehydratase - aminolevulinic acid accumulates
  2. Ferrochelatase - protoporphyrin 9 builds up in urine (final step to put iron in heme)

Disrupts the sulfhydryl groups of enzymes

186
Q

What GI tract manifestations does chronic alcoholism produce?

A

Gastritis, acute and chronic pancreatitis, peptic ulcer disease, and esophageal varices (can cause severe GI bleed)

187
Q

How do RBCs appear in the bone marrow as a result of lead toxicity? Peripheral blood?

A

Ringed sideroblasts

  • > iron cannot be put into heme (ferrochelatase inhibition)
  • > erythrocyte precursors with ironladen mitochondria on prussian-blue stain.

Peripheral blood:
Microcytic, hypochromic anemia with basophilic stippling (aggregates of ribosomal RNA caused by 5’ nucleotidase inhibition, RNA stays in the cell)

188
Q

What part of the nervous system is most prominently affected in children by lead poisoning? Mechanism and manifestations?

A

Central nervous system (poorer BBB)

  • > mechanism: substitution for calcium channels during nerve conduction
  • > learning disability, ADD, behavior problems / coordination problems, decreased IQ / hearing
  • > neuronal necrosis and demyelination

In adults, it’s wrist drop peripheral neuropathy

189
Q

What is the primary system affected by mercury poisoning and what does this cause?

A

Central nervous system
-> impaired hearing / vision, seizures, sensory / motor nerve dysfunction, fine tremor / ataxia, and personality changes

“mad as a hatter”

190
Q

What is the most common toxicity of Cadmium, and its indirect consequence?

A

Renal tubular dysfunction (kidney damage)

-> leads to osteomalacia from failure to make vitamin D, and resultant osteoporosis

191
Q

What are the acute and chronic effects of benzene?

A

Acute - CNS effect, mostly sedating / confusing but can lead to LOC and death

Chronic - Increased risk of acute myeloid leukemia**** (AML)

192
Q

What is vinyl chloride associated with increased risk of?

A

Hepatic angiosarcoma (cancer of the liver sinusoid endothelial cells)

Very rare malignancy, only happened in PVC factories

-> oral contraceptives increase risk of liver cell adenoma (benign tumor of parenchyma), especially in smokers

193
Q

What do oral contraceptives reduce your risk of in pre-menopausal women?

A

Endometrial and ovarian carcinoma

note: increased risk of endometrial cancer in POST-menopausal women

194
Q

What are the acid-base disturbances of aspirin toxicity, from early to late?

A

Early - respiratory alkalosis due to direct stimulation of respiratory center, with compensatory loss of bicarbonate in kidney

Late - metabolic acidosis due to uncoupling of OxPhos leading to lactate buildup, and lack of buffering of acid due to renal excretion of bicarbonate

195
Q

What does chronic arsenic poisoning cause?

A

Increased risk of skin and lung cancer

Raindrop pigmentation on skin and Mees lines in nails, as well as hyperkeratosis of palms and soles

196
Q

What does aspirin overdose do to your core body temp?

A

Increases it due to uncoupling of OxPhos, can lead to dehydration

(counterintuitive, since you would think it would decrease prostaglandin E2 synthesis in the hypothalamus)

197
Q

What are the hearing and CNS effects of aspirin overdose?

A

Ototoxicity, tinnitus, lethargy, seizures, excitability, coma

198
Q

What are the respiratory tract manifestations of cadmium inhalation, acutely and chronically?

A

Acutely - chemical pneumonitis - potentially lethal

Chronic - anosmia with obstructive changes, and lung cancer

199
Q

What will typically be present on an entrance wound but not an exit wound?

A
  1. bevelling of bone on the inside

2. abrasion from rubbing the edges of the bullet through the skin

200
Q

When does rigor mortis occur / peak? When does it decline? What is one component of rigor mortis relating to hair you might not think about?

A

Starts shortly after death, peaks after 8-12 hours, and slowly passes after 24 hours. Goosebumps after death -> arrectores pilorum

Body which is greater than 1 day old will have no rigor mortis but livor mortis.

201
Q

What will happen to the muscles of a burnt body?

A

Pugilistic appearance - contraction of arms and legs, with heat-related fractures common, including skull

202
Q

What are the low vs high voltage mechanisms of death? Which is associated with a burn?

A

Low voltage - ventricular fibrillation due to current in heart

High voltage - Thermal injury from current (burn), or respiratory arrest due to brainstem damage
-> only high voltage associated with burn

203
Q

How is diagnosis of cocaine overdose made?

A

Cocaine in blood, or benzoylecgonine in blood due to 4-5 hour halflife (can still break down after death without liver function due to plasma esterases)

204
Q

What is considered “near-contact” range and what will be found there?

A

2-3 inches. Soot and gunpowder stippling over low distribution, with muzzle flame possibly burning skin edges

vs close-range which is within 8 inches

205
Q

What is a very common finding of rotational brain injuries in young children?

A

Retinal hemorrhages -> especially in non-accidental trauma, but still can be seen in accidents

206
Q

What is the general cause of epidural vs subdural hematoma? Why are adults more likely to get both?

A

Epidural - temporal bone fracture with tear of middle meningeal artery, (typically less likely in children due to firm adherence of dura to skull in children, vs adults where the dural attachment is loser)

Subdural - venous bleeding due to tearing of a bridging vein, most often due to tension of bridging veins in brain atrophy (alcoholics and older adults)

207
Q

Why are children’s brains more susceptible to rotational forces? Do these forces commonly cause head injury?

A

They are large (vs adult brain proportions), have higher water content, are soft, and have a flat, short, and narrow skull base allowing for increased movement. Often, fontanelles are not yet closed.

Yes-> translational forces are infrequently the cause of diffuse brain injury in children

Pathobiology (20 decks)

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