Pbl Exam 6 Case 6

Front 1

1. What are two factors that can severely reduce cardiac output?

Back 1

1. Cardiac abnormalities that decrease the ability of the heart to pump blood. These include MI, toxic states, severe heart valve dysfunction, arrhythmias, and other conditions.

2. Factors that decrease venous return also decrease CO b/c the heart cannot pump blood that does not flow into it.

Front 2

2. What are the most common causes of decreased venous return?

Back 2

Diminished blood volume is the most common.

Decreased vascular tone, and obstruction to blood flow at some point can also result in decreased venous return.

Front 3

3. What is cardiogenic shock?

Back 3

The circulatory shock that results from diminished CO is called cardiogenic shock.

Front 4

4. What are two situations in which circulatory shock occurs w/o diminished cardiac output?

Back 4

1. Excessive metabolism of the body, so that even a normal cardiac output is inadequate

2. Abnormal tissue perfusion patterns, so that most of the CO is passing thru blood vessels besides those that supply the local tissues w/nutrition.

Front 5

5. All of the important causes of shock eventually lead to...?

Back 5

Inadequate delivery of nutrients to critical tissues and critical organs and also cause inadequate removal of cellular waste products from the tissues.

Front 6

6. What happens to the arterial pressure in circulatory shock?

Back 6

The arterial pressure can often be misleading. At times, a person may be in severe shock and still have an almost normal arterial pressure b/c of nervous reflexes that keep the other pressure from falling.

At other times, the arterial pressure can fall to half of normal, but the person still has normal tissue perfusion and is not in shock.

*For the most part, in most types of shock, the arterial blood pressure decreases at the same time the CO decreases, although not as much.

Front 7

7. What is the vicious circle of shock?

Back 7

Once circulatory shock reaches a critical state of severity, the shock itself breeds more shock.

Thus, the inadequate blood flow causes the body tissues to begin deteriorating, including the heart and circulatory system itself. This causes an even greater decrease in CO, and the vicious circle ensues, with progressively increasing circulatory shock and less adequate tissue perfusion and so on...

Front 8

8. What are the three stages of shock?

Back 8

1. A nonprogressive stage (aka compensated stage), in which the normal reflexes can fully compensate and promote full recovery.
2. A progressive stage, in which w/o therapy, the shock becomes steadily worse until death
3. An irreversible stage, in which the shock has progressed to such an extend that all forms of therapy are inadequate to save the life.

Front 9

9. What is hypovolemia?

What is the most common cause?

Back 9

Hypovolemia means diminished blood volume. Hemorrhage is the most common cause of hypovolemic shock.

Hemorrhage decreases the filling pressure of the circulation and thus decreases venous return. As a result, CO falls and shock may ensue.

Front 10

10. What are the three important effects that are a result of the sympathetic reflexes in shock?

Back 10

1. The arterioles constrict in most parts of the systemic circulation, thereby increasing the total peripheral resistance.
2. The veins and venous reservoirs constrict, thereby helping to maintain adequate venous return.
3. Heart activity increases markedly, sometimes increasing the HR to as much as 160-180 bpm.

Front 11

11. How important are the sympathetic nervous reflexes?

Back 11

W/o the sympathetic reflexes, only 15-20% of the blood can be removed over a period of 30 min before a person dies.

W/the sympathetic reflexes, a personal can lose 30-40% of their blood in the same amount of time and still survive.

Front 12

12. What are the sympathetic reflexes gear towards helping more - maintaining arterial pressure or maintaining CO?

Back 12

The sympathetic reflexes are geared more for maintaining arterial pressure than for maintaining CO. They increase the arterial pressure mainly by increasing total peripheral resistance, which has little effect on CO.

However, the sympathetic constriction of the veins is important to keep venous return and CO from falling too much.

Front 13

13. What is a special value of the maintenance of normal arterial pressure in the presence of decreasing CO?

Back 13

A special value of the maintenance of normal arterial pressure even in the presence of decreasing CO is protection of blood flow through the coronary and cerebral circulatory systems.

The sympathetic stimulation does not cause significant constriction of either the cerebral or the cardiac vessels. Also in both these vascular beds, local blood flow autoregulation is excellent, which prevents moderate decreases in arterial pressure from reducing their blood flows.

Front 14

14. Can the circulatory system recover from hemorrhage?

Back 14

The circulatory system can recover as long as the degree of hemorrhage is no greater than a certain critical amt. Crossing this threshold by even a few mL of blood loss causes the shock to become more progressive and then leads to death.

Front 15

15. What are the six factors that are negative feedback control mechanisms that try to prevent the vicious circle of shock?

Back 15

1. Baroreceptor reflexes
2. CNS ischemic response (not activated until the arterial pressure drops below 50 mm Hg.
3. Reverse stress-relaxation of the circulatory system
4. Formation of angiotensin by the kidneys
5. Formation of ADH by the posterior pituitary
6. Compensatory mechanisms that return the blood volume back toward normal

Front 16

16. What is reverse stress-relaxation?

Back 16

This system causes the blood vessels to contract around the diminished blood volume, so that the blood volume that is available more adequately fills the circulation.

Front 17

17. How long does it take to maximally activate the sympathetic reflexes after hemorrhage?

Back 17

30 seconds to a minute after hemorrhage.

It takes the angiotensin and ADH mechanism as well as the reverse stress relaxation mechanisms about 10 min to 1 hour to respond completely.

Front 18

18. What is the compensatory mechanisms that return the blood volume back toward normal?

Back 18

This includes the absorption of large quantities of fluid from the intestinal tract, absorption of fluid into the blood capillaries form the interstitial spaces of the body, conservation of water and salt by the kidneys, and increased thirst and increased appetite for salt, which make the person drink water and eat salty foods if able.

This compensatory mechanism requires about 1-48 hours to become active, provided the shock doesn't become severe enough to enter the progressive stage.

Front 19

19. What causes progressive shock?

Back 19

Progressive shock is caused by a vicious circle of cardiovascular deterioration.

These include:
1. Cardiac depression
2. Vasomotor failure
3. Sludged blood
4. Increased capillary permeability
5. Release of toxins by ischemic tissue
6. Generalized cellular deterioration
7. Acidosis in shock

Front 20

20. When is the deterioration of the heart more important?

Back 20

In the early stages of shock, this plays little role b/c the deterioration of the heart is not severe at first, and also b/c the heart has tremendous reserve capability that normally allows it to pump 300-400% more blood than is required by the body for adequate tissue nutrition.

In the latest stages, however, deterioration of the heart is probably the most important factor in the final lethal progression of shock.

Front 21

21. What is vasomotor failure?

Back 21

In the early stages of shock, sympathetic reflexes help delay depression of the CO and especially arterial pressure.

However, there comes a point when diminished blood flow to the brain's vasomotor center depresses the center so much that it, too, becomes progressively less active and finally totally inactive.

Fortunately, the vasomotor center usually does not fail in the early stages of shock if the arterial pressure remains above 30 mm Hg.

Front 22

22. What is "sludged blood"?

Back 22

In time, blockage occurs in many of the very small blood vessels in the circulatory system, an this also causes the shock to progress.

The initiating cause of this blockage is sluggish blood flow in the microvessels. B/c tissue metabolism continues despite the low flow, large amts of lactic and carbonic acid continue to empty into the local blood vessels and make the blood acidic.

This acid, plus other deterioration products from the ischemic tissues, causes local blood agglutination, resulting in minute blood clots, leading to very small plugs in the small vessels.

Front 23

23. What causes increased capillary permeability?

Back 23

After many hours of capillary hypoxia and lack of nutrients, the permeability of the capillaries gradually increases, and large amts of fluid begin to transude into the tissues.

This decreases blood volume even more.

*Capillary hypoxia does not cause increased capillary permeability until the late stages of prolonged shock.

Front 24

24. What toxins are released by ischemic tissues?

Where is this toxin produced and absorbed?

Back 24

Quantitative studies have proved the significance of at least one toxin, endotoxin, in some types of shock.

Endotoxins are released from the bodies of dead gram-negative bacteria in the intestines. Diminished blood flow to the intestines often causes enhanced formation and absorption of this toxic substance.

This toxin then causes increased cellular metabolism despite inadequate nutrition of the cells; **this has a specific effect on the heart muscle, causing cardiac depression.

Front 25

25. What organ is especially susceptible to generalized cellular deterioration?

Back 25

The liver. This occurs mainly b/c of lack of enough nutrients to support the normally high rate of metabolism int eh liver cells, abut also partly b/c of the extreme exposure of the liver cells to any vascular toxin or other abnormal metabolic factor occurring in shock.

Front 26

26. What four damaging cellular effects that are known to occur in most body tissues during shock?

Back 26

1. Active transport of Na⁺ and K⁺ thru the cell membrane is diminished. As a result, Na⁺ and Cl⁻ accumulate in the cells, and K⁺ is lost from the cells. This causes the cells to swell.
2. Mitochondrial activity in the liver cells as well as in many other tissues becomes severely depressed?
3. Lysosomes in the cells in widespread tissue areas begin to break open, w/intracellular release of hydrolases that cause further intracellular deterioration.
4. Cellular metabolism of nutrients, such as glucose become depressed in the last stages of shock. The actions of some hormones, such as insulin, become 100% depressed.

Front 27

27. What are three specific effects shock has on the organs?

Back 27

1. The liver, w/depression of its many metabolic and detox functions
2. The lungs, w/eventual development of pulmonary edema and poor ability to oxygenate the blood
3. The heart, thereby further depressing its contractility.

Front 28

28. What is effect does tissue necrosis have on organs?

Back 28

Patchy areas of necrosis occur b/c of patchy blood flows in different organs. More nutritive deficiency and necrosis occurs around the venous ends of capillaries than elsewhere.

For instance, the portion of the lobule that is last to be exposed to the blood as it passes thru the liver sinusoids is the central portion of a liver lobule.

Also, patchy lesions also occur in the kidneys, especially in the epithelium of the kidney tubules, leading to kidney failure and occasionally uremic death.

Front 29

29. What is shock lung syndrome?

Back 29

Deterioration of the lungs also often leads to respiratory distress and death several days later - called shock lung syndrome.

Front 30

30. What happens to the high energy phosphate reserves in irreversible shock?

Back 30

The high energy phosphate reserves in the liver and heart are greatly diminished. Essentially all the creatine phosphate has been degraded, and almost all the ATP has been degraded to ADP, and eventually adenosine.

Then much of this adenosine diffuses out of the cells into the circulating blood and is converted into uric acid, a substance that cannot re-enter the cells to reconstitute ATP. New adenosine can only be synthesized about 2% of the normal amt an hour, meaning that once the high-energy phosphate stores of the cells are depleted, they are difficult to replenish.

Front 31

31. What two conditions cause severe plasma loss?

Back 31

1. Intestinal obstruction, which causes fluid to leak from the capillaries into the intestinal walls which is protein rich and reduces the total blood plasma protein and plasma volume.

2. In almost all patients who have severe burns or other conditions of the skin, so much plasma is lost thru the damaged skin areas that the plasma volume becomes markedly reduced.

Front 32

32. What is the difference between hypovolemic shock caused by hemorrhage vs. plasma loss?

Back 32

They are the same, except for one complicating factor in plasma loss shock: the blood viscosity increases greatly as a result of increased RBC concentration in the remaining blood, and this exacerbates the sluggishness of blood flow.

Front 33

33. What five things can cause dehydration shock?

Back 33

1. Excessive sweating
2. Fluid loos in severe diarrhea or vomiting
3. Excess loss of fluid by nephrotic kidneys
4. Inadequate intake of fluid and electrolytes
5. Destruction of the adrenal cortices, w/loss of aldosterone secretion and failure of the kidneys to reabsorb sodium, chloride, and water.

Front 34

34. Hypovolemic shock caused by trauma...

and GO!

Back 34

One of the most common causes of circulatory shock is trauma to the body. Often it results simply from hemorrhage caused by the trauma, but it also can occur w/o hemorrhage, b/c extensive contusion of the body can damage the capillaries sufficiently to allow excessive loss of plasma into the tissues.

Traumatic shock seems to result mainly from hypovolemia,although there might also be a neurogenic shock caused by loss of vasomotor tone.

Front 35

35. What is neurogenic shock?

Back 35

Shock sometimes results from a sudden increase in vascular capacity due to a sudden loss of vasomotor tone through the body.

An increase in vascular capacity or a decrease in blood volumes reduces the mean systemic filling pressure, which reduces venous return to the heart. Diminished venous return caused by vascular dilation is called venous pooling of blood.

Front 36

36. What are three causes of neurogenic shock?

Back 36

1. Deep general anesthesia often depresses the vasomotor center
2. Spinal anesthesia blocks the sympathetic nervous outflow
3. Brain damage - many patients w/damage in the basal regions of the brain develop profound neurogenic shock.

*Also, brain ischemia for long periods can cause total inactivation of the vasomotor neurons in the brain stem

Front 37

37. What are three effects of histamine in anaphylaxis?

Back 37

1. An increase in vascular capacity b/c of venous dilation, thus causing a marked decrease in venous return.
2. Dilation fo the arterioles, resulting in greatly reduced arterial pressure
3. Greatly increased capillary permeability, w/rapid loss of fluid and protein into the tissue spaces.

Front 38

38. What is the most frequent cause of shock related death in the modern hospital (besides cardiogenic shock)?

Back 38

Septic shock. Some features of septic shock include:
1. High fever
2. Marked vasodilation
3. High CO, high metabolic rate, high body temp
4. Sludging of the blood
5. DIC

Front 39

39. What are five typical causes of septic shock?

Back 39

1. Peritonitis causes by spread of infection from the uterus and fallopian tubes
2. Peritonitis resulting from rupture of the GI system
3. Generalized bodily infection resulting from spread of a skin infection such as streptococcal or staph infection
4. Generalized gangrenous infection resulting from gas gangrene bacilli
5. Infection spreading into the blood from the kidney or urinary tract, often caused by colon bacilli

Front 40

40. Can plasma substitute for blood in hypovolemic shock due to hemorrhage?

Back 40

Plasma can usually substitute if whole blood is not available. However, plasma cannot restore a normal HCT, but the human body can usually stand a decrease in HCT to about 1/2 of normal before serous consequences ensue.

Front 41

41. What is principal requirement of a truly effect plasma substitute?

Back 41

The it remain in the circulatory system, not filter thru the capillary pores into the tissue space. In addition, the solution must be non-toxic and must contain appropriate electrolytes to prevent derangement of the body ECF electrolytes on administration.

Thus, it needs to have a large enough molecular size to exert osmotic colloid pressure.

Front 42

42. What is a typical plasma substitute?

Back 42

If plasma is unavailable, dextran solution can substitute. Dextran is a large polysaccharide polymer of glucose. It is grown by bacteria and thus by varying the growth conditions the molecular weight can be controlled to the desired value.

Front 43

43. In what two types of shock have sympathomimetic drugs proved beneficial?

In which type is it not useful?

Back 43

1. Neurogenic shock
2. Anaphylatic shock

Not useful in hemorrhagic shock. The sympathetic nervous reflexes are almost always maximally active so adding more stimulating factors to them won't have any beneficial effects.

Front 44

44. What are three other treatments of shock?

Back 44

1. Treatment by the head-down therapy, especially in the hemorrhagic and neurogenic shock, which increases venous return, and thus CO.
2. Oxygen therapy
3. Treatment w/glucocorticoids (they increase the strength of the heart in late stages of shock, the stabilize lysosomal enzymes, and the might aid in the metabolism of glucose by the damaged cells).

Front 45

45. What is a condition closely allied to circulatory shock?

Back 45

Circulatory arrest, AKA cardiac arrest or Vfib.

Cardiac arrest often results from too little oxygen in the anesthetic gaseous mixture or from a depressent effect of the anesthesia itself.

Front 46

46. Does hypoxia cause brain damage during circulatory arrest?

Back 46

No. Experimetns have shown that if blood clots are prevented from occurring in the blood vessels of the brain, this will also prevent most of the early deterioration of the brain during circulatory arrest.

***Thus, it is likely that the severe brain damage that occurs from circulatory arrest is caused mainly by permanent blockage of many small blood vessels by blood clots, thus leading to prolonged ischemia and eventual death of the neurons.

Front 47

47. What are the properties of oxygen?

Back 47

The oxygen molecule is a biradical, which means it has two single electrons in different orbitals (triplet state).

It is relatively nonreactive by comparison w/most radicals b/c in order to oxidize a covalent bond, one of its electrons would have to flip its spin around to make new pairs. This is called spin restriction, and w/o it, organic life forms would not be forms b/c they would be spontaneously oxidized by oxygen.

Front 48

48. What is a free radical?

What is a ROS?

What is a RNOS?

Back 48

A free radical is any species capable of independent existence that contains one or more unpaired electrons.

ROS are reactive intermediate oxygen species which include both radicals and non-radicals (Hydroxyl radicals i the most potent)

RNOS are reactive intermediate species which contain both nitrogen and oxygen; it includes both radicals and nonradicals.

Front 49

49. How are ROS generated?

Back 49

Can be generated nonenzymatically as accidental byproducts or major products of reactions.

Superoxide may be generated nonenzymatically from CoQ, or from metal-containing enzymes (e.g. cytochrome P450, xanthine oxidase, and NADPH oxidase).

The highly toxic hydroxyl radical is formed nonenzymatically from superoxide (O₂⁻) in the presence of iron or copper by the Fenton reaction, and from hydrogen peroxide in the Haber-Weiss reaction.

Front 50

50. How do cells limit the occurrence of the Fenton reaction?

Back 50

Accessibility to transition metals, such as copper and iron, are highly restricted in cells, or in the body as a who. Thus, events that release iron from cellular storage sites, such as crushing injury, are associated w/increased free-radical injury.

Front 51

51. What are the three major sources of primary ROS in the cell?

Back 51

1. CoQ generates superoxide (O₂⁻)
2. Oxidases, oyxgenases, and peroxidases
3. Ionizing radiation

Front 52

51. How does CoQ generate superoxide (O₂⁻)?

Back 52

Coenzyme Q →
Mitochondrial electron transport chain →
Superoxide (O₂⁻)

Front 53

52. How do cytochrome P450 enzymes generate superoxide (O₂⁻)?

Back 53

P450 enzymes are a major source of free radicals leaked from reactions. These leaked radicals initiate chain reactions in the surrounding polyunsaturated lipids of the ER. Induction of P450 enzymes by EtOH, drugs, or chemical toxins leads to increased cellular injury.

Cytochrome P450s → endoplasmic reticulum → O₂⁻

Front 54

53. How are hydrogen peroxide and lipid peroxides generated?

Back 54

These are generated enzymatically as major reaction products by a number of oxidases present in peroxisomes, mitochondria, and the ER.

1. MOA generates H₂O₂ at the mitochondrial membrane of certain neurons when it degrades dopamine.
2. Peroxisomal fatty acid oxidase generates H₂O₂ rather than FAD(2H) during the oxidation of very-long-chain fatty acids.
3. Xanthine oxidase is an enzyme of purine degradation that can reduce O₂ to O₂⁻ or H₂O₂ in the cytosol, and is though to be a major contributor to ischemia-reperfusion injury, esp in the intestinal mucosal and endothelial cells.
4. Lipid peroxides are also formed enzymatically as intermediates in the pathways for synthesis of many eicosanoids, including leukotrienes and prostaglandins.

Front 55

54. How does ionizing radiation generate free radicals?

Back 55

Ionizing radiation has a high enough energy level that it can split water into hydroxyl and hydrogen radicals, thus leading to radiation damage to the skin, mutations, cancer, and cell death. It may also generate organic radicals thru direct collision w/organ cellular components.

Front 56

55. What are the properties of the superoxide anion (O₂⁻), hydrogen peroxide (H₂O₂), and the hydroxyl radical?

Back 56

O₂⁻
-highly reactive
-limited solubility
-cannot diffuse far

Hydroxyl radical
-most potent of the ROS
-reacts w/DNA, lipids, and proteins

H₂O₂
-weak oxidizing agent
-can generate the hydroxyl radical
-can diffuse thru membranes

Front 57

56. What are three ways in which ROS induce cellular injury?

Back 57

1. Membrane attack - formation of lipid and lipid peroxy radicals
2. Oxidative damage to proteins and peptides
3. Base alterations and strand breaks in DNA

Front 58

57. What is lipid peroxidation?

Back 58

Free radical induced chain reaction in which a hydroxyl radical begin the chain reaction. It extracts a hydrogen atom from the double bond of a polyunsaturated FA in a membrane lipid. The chain reaction is propagated when O₂ added to form lipid peroxyl radicals and lipid peroxides.

Eventually, lipid degradation occurs, which forms aldehydes which can cross link proteins. This results in the disruption of membrane integrity.

Front 59

58. How can one detect free radical damage via lipid peroxidation?

Back 59

Malondialdehyde is found in the blood and urine and is used as an indicator.

Also, ethane and pentane are detected in the breath.

Front 60

59. Which AA's are particularly susceptible to oxidative damage?

What are three ways in which proteins become oxidatively damaged by ROS?

Back 60

Amino acids such as proline, histidine, arginine, cysteine, and methionine are particularly susceptible to hydroxyl radical attack and oxidative damage.

These radicals oxidatively damage the proteins and cause:
1. Fragmentation
2. Increased susceptibility to degradation
3. Formation of cross-links and aggregates which prevents degradation

Also, oxidation of glutathione (GSH) increases oxidative damage in the cell.

Front 61

60. How does DNA become damaged via oxidation?

Back 61

The nonspecific binding of iron to DNA facilitates localized production of the hydroxyl radical, which can cause base alterations in the DNA.

It can also attack the deoxyribose backbone and cause strand breaks.

Front 62

61. What are nitric oxide and RNOS?

Back 62

NO, like O₂, is both essential to life and toxic. NO has a single electron and therefore binds to other compounds that contain single electrons, such as Fe3+.

At low concentrations, it functions physiologically as a neurotransmitter and as a hormone that causes vasodilation.

At high concentrations, however, it combines with O₂ or with superoxide to form additional reactive and toxic species that contain both nitrogen and oxygen (RNOS). RNOS are involved in neurodegenerative diseases, such as Parkinson's disease and in RA.

Front 63

62. What are the three different tissues specific isosoforms of NO synthase?

How are each regulated?

Back 63

1. Neuronal NO synthase (nNOS I)
2. Inducible NO synthase (iNOS II)
3. Endothelial NO synthase (eNOS III)

nNOS and eNOS are tightly regulated by calcium concentration to produce the small amts of NO required for its role as a neurotransmitter and a hormone.

In contrast, iNOS is present in many cells such as macrophages and brain astroglia. ***iNOS is regulated principally by induction of gene transcription, and NOT by changes in calcium concentrations. It produces high and very toxic levels of NO to assist in killing microbes.

Front 64

63. What are the two categories of NO toxicity?

Back 64

1. Direct toxic effects resulting from binding to Fe-containing proteins.
2. Indirect toxic effects mediated by compounds formed when NO combines with O₂ or with superoxide to form RNOS.

Front 65

64. Where are the direct toxic effects of NO?

Back 65

Major destrive sites of attack include Fe-S centers (e.g. electron transprot chain complexes I-III, aconitase) and FE-heme proteins (e.g. Hgb and electron transport chain cytochromes).

However, there is usually little damage b/c NO is present in low concentration and Fe-heme compounds are vast. *NO does cause damage, however, thru direct inhibition of respiration in cells already compromised thru oxidative phosphorylation diseases or ischemia.

Front 66

65. When NO is present in very high concentrations (e.g. inflammation), it does what?

Back 66

It combines nonenzymatically w/superoxide to form peroxynitrate or with O₂ to for N₂O₃.

Peroxynitrate is a strong oxidizing agent and can diffuse thru cell and lipid membranes to methionine side chain and -SH groups (e.g. Fe-S centers). It also breaks down to form addition RNOS. It can also react w/aromatic rings, forming compounds such as nitrotyrosine or nitroguanosine.

N₂O₃ is the agent of nitrosative stress and it nitrosylates sulfhydryl. Nitrosylation usually interferes w/the proper functioning of the protein or lipid hat has been modified.

Front 67

66. What are three categories of free radical generation during phagocytosis and inflammation?

Back 67

1. NADPH oxidase (oxidative burst)
2. Myeloperoxidase and HOCl
3. RNOS and inflammation

Front 68

67. How does NADPH oxidase generate free radicals?

Back 68

The respiratory burst results from the activity of NADPH oxidase, which catalyzes the transfer of an electron from NADPH to O₂ to form superoxide.

Superoxide is then release into the intramembranous space of the phagolysosome, where it is generally converted to H₂O₂ and other ROS that are effective against bacterial and fungal pathogens.

Front 69

68. How does myeloperoxidase and HOCl generate free radicals?

Back 69

The formation of HOCl from H₂O₂ is catalyzed by myeloperoxidase, a heme-containing enzyeme that is present only in phagocytic cells of the immune system (*predominantly neutrophils). The hypochlorous acid then rapidly dissociates and loses a protein.

Myeloperoxidase enzyme contains two Fe-hemelike centers, which gives it the green color seen in pus.

Front 70

69. What happens when neutrophils of the immune system are activated to produce NO?

Back 70

NADPH oxidase is also activated. NO reacts rapidly w/superoxide to generate peroxynitrate, which forms additional RNOS.

During stroke or MI, phagocytic cells that move into the ischemic area to remove dead cells may increase the area and extent of the damage.

In RA, as a result of free radical release, the IgG proteins present in the synovial fluid are partially oxidized, which improves their binding w/RA antibody. This binding, in turn, stimulates more free radical generation by neutrophils.

Front 71

70. What are the cellular defenses against oxygen toxicity?

Back 71

Antioxidant defense system (scavenging enzymes) include:
1. Superoxide dismutase (SOD)
2. Catalase
3. Glutathione peroxidase and glutathione reductase

Front 72

71. How does superoxide dismutase work?

Back 72

Conversion of superoxide anione to H₂O₂ and O₂ (dismutation) by SOD is often called the primary defense against oxidative damage.

SOD exists as three isoforms, in the cytosol, mitochondria, and extracellularly.

Its activity in the cytosol is increased by chemicals or conditions that increase the production of superoxide.

Front 73

72. What are the three isoforms of SOD?

What diseases or damage are mutations in each related to?

Back 73

1. Cytosolic SOD (Cu-Zn SOD)
-Encoded by the SOD1 gene
-Mutations in the SOD1 gene cause the development of familial amyotrophic lateral sclerosis (ALS)

2. Mitochondrial SOD (Mn SOD)
-Encoded by the SOD2 gene
-Age-dependent response to oxidative stress

3. Extracellular SOD (Cu-Zn SOD)
-Encoded by the SOD3 gene
-Major SOD isoenzyme in extracellular fluids such as plasma, lymph and synovial fluid

*All three forms of SOD are inducible!!!

Front 74

74. How does catalase work?

Back 74

H₂O₂, once formed, must be reduced to water to prevent it from forming the hydroxyl radical in the Fenton reaction or the Haber-Weiss reaction.

Catalase is found principally in peroxisomes and in the cytosol and microsomal fraction of the cell.

The highest activities are found in the kidney and liver. In cells of the immune system, catalase serves to protect the cell against its own respiratory burst.

Front 75

75. What is glutathione?

When it becomes oxidized, how is it reduced?

Back 75

Glutathione is the body's principal means of protecting against oxidative damage.

Glutathione peroxidases exists as a family of Se enzymes w/somewhat different properties and tissue locations. W/in cells, they are the major means for removing H₂O₂ produced outside of peroxisomes.

*A major source of NADPH for the reduction of oxidized glutathione is from the pentose phosphate pathway.

Front 76

76. How is vitamin E a free radical scavenger?

Back 76

Vitamin E (α-tocopherol - most potent antioxidant in our diet)

Most-widely distributed antioxidant in nature

Lipid soluble → inhibits lipid peroxidation; can donate a second electron to terminate the chain reactions b/c it is stabilized via resonance.

Front 77

77. How is ascorbic acid (vitamin C) a free radical scavenger?

Back 77

Vitamin C (ascorbic acid)

-Regenerates the active form of vitamin E by donating electrons in a redox cycle.
-Reacts with ROS and NO₂.
-Water soluble → circulates unbound in blood and extracellular fluid

Front 78

78. How are carotenoids free-radical scavengers?

Back 78

β-Carotene
-Carotenoids (have oxygen-containing substituents on their rings).
-Precursor of vitamin A (which is required for vision, and prevents age-related macular degeneration)
-Might slow the progression of cancer, atherosclerosis, and degenerative diseases by acting as chain breaking antioxidants.

Front 79

79. What are other dietary antioxidants?

Back 79

Flavoanoids:

MOA:
-Inhibition of O₂⁻ production (i.e., enzyme inhibition)
-Chelation of transition metal ions (e.g., Cu+, Fe2+)
-Free radical scavenging

Found in red wine, green tea, chocolate and other plant-derived foods. Has high pro-oxidant activity, but is poorly absorbed.

Front 80

80. What are two endogenous antioxidants?

Back 80

1. Melatonin
-Free radical scavenger
-Donation of electron (as hydrogen)
-Direct reaction with ROS and RNOS to form addition products
-Neurohormone - regulates circadian rhythm, light-dark signal transduction and sleep cycle
-Hydrophilic/lipophilic → passes through membranes and the blood-brain barrier

2. Uric acid
-Major free radical scavenger in plasma (e.g., HO•, ROO•)
-Formed from the degradation of purines
-Released into extracellular fluids (e.g., blood, saliva, lung lining fluid)
-Particularly important in the upper airways, where there are few other antioxidants

Front 81

81. What are the roles of the basal ganglia, neostriatum, and substantia nigra?

Back 81

The basal ganglia are part of a neuronal feedback loop that modulates and integrates the flow of information from the cerebral cortex to the motor neurons of the spinal cord.

The neostriatum is the major input structure from the cerebral cortex.

The substantia nigra pars compacta consists of neurons that provide integrative input to the neostriatum thru pigmented neurons that use dopamine (nigrastriatal pathway).

Integrated information feeds back to the basal ganglia and to the cerebral cortex to control voluntary movement. *In Parkinsons disease, a decrease in the dopamine reaching the basal ganglia results in the movement disorder.

Front 82

82. What is ischemia-reperfusion injury?

Back 82

After reperfusing a previously ischemic area with freshly oxygenated blood, injury occurs. This is caused by cytotoxic ROS derived from oxygen in the blood that reperfuses previously hypoxic cells.

It may also occur when tissue oxygenation is interrupted during surgery or transplantation.

Front 83

83. What happens during ischemia of the heart of ATP levels?

Back 83

The heart mitochondria are unable to maintain cellular ATP levels, resulting in high intracellular sodium and calcium levels.

The reduced state of the electron carriers in the absence of oxygen and loss of mitochondrial ion gradients or membrane integrity, leads to increased superoxide production once oxygen becomes available during reperfusion.

The damage can be self-perpetuating, especially if iron bound to components of the electron transport chain becomes available for the Fenton reaction, or the mitochondrial permeability transition is activated.

Front 84

84. What is a MOA B inhibitor?

Back 84

MOA B inhibitors are administered to inhibit dopamine degradation and decrease the production of H₂O₂ in neurons in those with Parkinson's disease.

It also decreases the free radical formation within the cells of the basal ganglia.

The dopaminergic neurons involved are particularly susceptible to the cytotoxic effects of ROS and RNOS that may arise from H₂O₂.

Front 85

85. What happens to production of ROS by xanthine oxidase in endothelial cells during ischemia reperfusion?

Back 85

The production of ROS by xanthine oxidase increases. When O₂ levels decrease, phosphorylation of ADP to ATP decreases, and degradation of ADP and adenine thru xanthine oxidase increases. In the process, xanthine dehdyrogenase is converted to an oxidase. As long as O₂ levels are below the Km of the enzyme for O₂, little damage is done.

However, during reperfusion, when O₂ levels return to normal, xanthine oxidase generates H₂O₂ and O₂⁻ at the site of injury.

Front 86

86. What are lipofuscin granules?

Back 86

The appearance of lipofuscin granules are related to lipid peroxidation products, such as malondialdehyde. These dark pigments appear in the skin as liver spots and are a traditional hallmark of aging.

In patients w/Parkinsons, lipofuscin appears as Lewy bodies in degenerating neurons.

Front 87

87. In patients w/chronic granulatomous disease, phagocytes have genetic defects in ....?

Back 87

In patients w/chronic granulatomous disease, phagocytes have genetic defects in NAPH oxidase.

NADPH oxidase has six different subunits, and the genetic defect may be in any of the four genes that encode these subunits.

The β-subunit is affected most often in X-linked chronic granulatomous disease, whereas the α-subunit is affected in a rare autosomal recessive form.

The cytosolic subunits p47 and p67 are affected most often in patients w/autosomal recessive forms of granulatomous disease.

Front 88

88. How is CoQ and other single electron components affected during ischemia and reperfusion injury?

Back 88

CoQ and other single electron components of the ETC become saturated w/electrons.

When oxygen is reintroduced, electron donation to O₂ to form superoxide is increased.

Macrophages in the area clean up cell debris from ischemic injury and produce NO, which may generate RNOS, and thus increase the infarct size.

Front 89

89. What mutations are related to ALS?

Back 89

The intracellular form of Cu+-Zn2+ SOD encoded by the SOD1 gene is mutated in ALS. 58 mutations in this gene have been discovered in those affected by familial ALS.

Only 5-10% of the total cases of ALS are caused by the familial form.

Front 90

90. Why does the cell need a high concentration of SOD in mitochondria?

Back 90

Mitochondria are major sites for generation of superoxide from the interaction of CoQ and O₂.

Mitochondria also have a high content of glutathione and glutathione peroxidase and thus can prevent lipid peroxidation.

Front 91

91. What is selenium?

Back 91

Selenium is present in human proteins principally as selenocysteine which functions in catalysis and has been found in four enzymes of the glutathione peroxidas family.

Se in the diet can be converted to selenophosphate, which reacts w/tRNA-containing bound serine to form a selenocysteine-tRNA, which incorporates the selenocysteine into the appropriate protein as it is being synthesis.

Se homeostasis in the body is controlled principally thru regulation of its secretion as methylated Se.

Front 92

92. What are the relative cancer benefits and risks of Vitamins E, C, and β-Carotene?

Back 92

Higher intakes of foods containing Vitamins E, C, and β-Carotene have a lower risk of cancer and certain ofther ROS related diseases. However, this is not significant if one has sufficient intake of these vitamins.

In fact, well nourished populations only, vitamin E has been found to be beneficial.

On the other hand, β-Carotene (Vitamin A and β-Carotene was associated w/a higher incidence of lung cancer among smokers. In one study, vitamin E was associated w/higher incidences of hemorrhagic stroke (possibly b/c of vitamin K mimicry).

Front 93

93. What is age-related macular degeneration?

Back 93

AMD is the leading cause of blindness in the US among persons older than 50. It is related to oxidative damage to the retinal pigment epithelium. Lipofuscin granules accumulate and initiate damage by absorbing blue light and generating singlet oxygen that forms other radicals.

Dark sunglasses are protective, and intake of lutein and zeanthin in dark green leafy vegetables are protective.

Front 94

94. What are the most important mechanisms of ozone-induced injury?

Back 94

Polyunsaturated FAs represent the primary target for ozone, and peroxidation of membrane lipids is the most important mechanism of ozone induced injury.

Front 95

95. What are the two phases of lung lining fluid?

Back 95

1. Gel phase that traps microorganisms and large particles
2. Soluble phase containing a variety of ROS defense mechanisms.

Front 96

96. Which is the primary antioxidant in the nasal cavity? In the proximal and distal regions of the respiratory tract? Last resort defense?

Back 96

Uric acid is present in the fluid lining the nasal cavity.

In the proximal and distal regions of the respiratory tract, glutathione and ascorbic acid, and uric acid.

Ozone that escapes this antioxidant screen may be exposed to vitamin E and glutathione peroxidase and extracellular SOD.

Front 97

97. What are the five paradigms that characterize the mechanisms of drug toxicity?

Back 97

1. "On-target" adverse effects, which are the result of a drug binding to its intended receptor, but at an inappropriate concentration, w/suboptimal kinetics, or in the incorrect tissue.
2. "Off-target" adverse effects, which are caused by the drug binding to a target or receptor for which it was not intended, or in the incorrect tissue.
3. Production of toxic metabolites.
4. Production of harmful immune responses.
5. Idiosyncratic responses.

Front 98

98. What are on-target effects in drug toxicity?

Back 98

"On-target" adverse effects are the result of a drug binding to its intended receptor, but at an inappropriate concentration, w/suboptimal kinetics, or in the incorrect tissue.

All such changes can lead to an increase in the effective concentration of the drug and thus to an increased biological response.

Front 99

99. What is a rare adverse effect of statin therapy?

Back 99

Muscle toxicity, including rhabdomylolysis and myositis; this side effect is due to the physiologic role of HMG CoA reductase in regulating the posttranslational modification of several muscle proteins thru a lipidation process called gerany-geranylation.

Front 100

100. What are off-target effects in drug toxicity?

What is an example of this effect?

Back 100

"Off-target" adverse effects are caused by the drug binding to a target or receptor for which it was not intended, or in the incorrect tissue.

Few drugs are so selective that they interact w/only one molecular target.

Enatiomers fo a drug cause off-target effects. This occurred w/the administration of racemic thalidomide; while the R-enantiomer was and effective sedative, the S-enantiomer was a potent teratogen.

Another common off-target effect is the unintended activation of different receptor subtypes. This occurs in beta-blockers, in which non specific beta blockers also inadvertently cause airway constricting by antagonizing beta 2 receptors.

Front 101

101. What is the metabolism of acetaminophen in normal doses?

Back 101

In its therapeutic dose range, acetaminophen is metabolized predominantly by glucuronidation and sulfation, and these conjugated products account for approximately 95% of these total excreted metabolites. P450 enzymes oxidize a small % of acetaminophen to a reactive intermediate, N-acetyl-benzoquinoneimine, which is immediately conjugated to glutathione.

Front 102

102. What is the metabolism of acetaminophen in toxic doses?

Back 102

However, when the level of acetaminophen exceeds the therapeutic range, the glucuronidation and sulfation pathways become saturated and the stores of glutathione in the liver become depleted. This results in excessive accumulation of N-acetyl-benzoquinoneimine, an electrophile that reacts w/nucleophilic groups on proteins to produce covalent protein derivatives.

Front 103

103. What drug exhibits a type I hypersensitivity response?

Back 103

Remember, IgE production causes this.

Penicillin fragments formed either in vivo or in the administered drug formulation can act as haptens and are responsible for such hypersensitivity reaction.

Subsequent exposure to the antigen causes mast cells to degranulate, releasing inflammatory mediators such as histamine and leukotrienes that promote bronchoconstriction, vasodilation, and inflammation.

Manifested in the skin, a type I hypersensitivity response results in a wheal-and-flare reaction.

Front 104

104. What drug exhibits a type II hypersensitivity response?

Back 104

Remember, antibody dependent cytotoxic hypersensitivity results when a drug binds to cells, usually RBCs, and is recognized by antibodies, usually IgG.

Type II responses are rare adverse responses to several drugs, including penicillin and quinidine.

Front 105

105. What drug exhibits a type III hypersensitivity response?

Back 105

Type III responses occur when antibodies, usually IgG or IgM are formed against soluble antigens. The antigen-antibody complexes are deposited in tissues and cause damage by initiated an inflammatory response called serum sickness.

Antivenins, buproprion and ceflacor are examples of drugs that have type III responses.

Front 106

106. What drug exhibits a type IV hypersensitivity response?

Back 106

A type IV response is a delayed type hypersensitivity that results from the activation of TH1 and cytotoxic T cells.

It most commonly presents as contact determatitis.

Ciprofloxacin, poison ivy, and latex allergies exhibit this type of response.

Front 107

107. Why type of autoimmune reactions does methyldopa have?

What drugs can produce a SLE like syndrome?

Back 107

Methyldopa can cause hemolytic anemia by eliciting an autoimmune reaction against the Rhesus antigens (Rh factors).

Hydralazine, isoniazid, and procainamide can cause a lupus like syndrome by inducing antibodies to myeloperoxidaze (hydralazine and isoniazid) or DNA (procainamide).

Front 108

108. What are idiosyncratic drug reactions?

Back 108

Idiosyncratic drug reactions are rare adverse effects for which no obvious mechanism is apparent. These reactions are due to individual genetic differences in the way drugs are metabolized.

Front 109

109. What are pharmacokinetic drug-drug interactions?

Back 109

Pharmacokinetic drug-drug interactions arise if one drug changes the absorption, distribution, metabolism, or excretion of another drug, thereby altering the concentration of active drug in the body.

Front 110

110. How does P450 induction and inhibition work?

Back 110

If two drugs are metabolized by the same P450 enzyme, the competitive or irreversible inhibition of that P450 enzyme by one drug can lead to an increase in the plasma concentration of the second drug.

On the other hand, the induction of a specific P450 enzyme by one drug can lead to a decrease in the plasma concentrations of other drugs that are metabolized by the same enzyme.

Front 111

111. What is penicillin often given with?

What is imipenem given with?

Back 111

Penicillin is cleared via tubular secretion in the kidney and the elimination half life of this drug can be increased if the drug is given concomitantly w/probenecid, an inhibitor of renal tubular transport.

A second example is provided by the combination of imipenem, a broad-spectrum antibiotic, and cilastatin, a selective inhibitor of a renal brush border dipeptidase. B/c imipenem is rapidly inactivated by dehydropeptidase I, coadministration of imipenem w/cilastatin is required to achieve therapeutic plasma concentrations of the antibiotic.

Front 112

112. What are pharmacodynamic drug-drug interactions?

Back 112

Pharmacodynamic drug-drug interactions arise when one drug changes the resposne of target or nontarget tissues to another drug.

Toxic pharmacodynamic interactions can occur when two drugs activate complementary pathways, leading to an exaggerated biological effect.

Front 113

113. What is an example of pharmacodynamic drug-drug interactions?

Back 113

The coadministration of sildenafil (for ED) and nitroglycerin (for angina). Sildenafil inhibits PDE5 and thus prolongs the action of cyclic GMP, and nitroglycerin stimulates guanylyl cyclase to increase cGMP levels in vascular smooth muscle.

Co-exposure to the two drugs increases cGMP to an even greater degree, increasing the risk of severe hypotension.

Front 114

114. Simultaneous use of ginkgo biloba and NSAIDs leads to...?

Echinacea in combo w/acetaminophen leads to...

SSRIs w/St Johns wort may cause...

Back 114

Ginkgo w/NSAIDs may increase the risk of bleeding due to platelet inhibition.

Echinacea in combo w/acetaminophen depletes glutathione stores and increases the risk of acetaminophen toxicity.

SSRIs with St. Johns wort may cause a mild serotonergic syndrome.

Front 115

115. What is the main difference in how the body responds to apotosis vs. necrosis?

Back 115

While apoptotic cells undergo cell death w/minimal inflammation and disruption of adjacent tissue, necrotic cells attract inflammatory cells and can damage nearby healthy cells.

Front 116

116. Emphysemal changes in the lungs are due to...?

Fibrotic changes in the lungs are due to...?

Back 116

Emphysematous changes are caused by the destruction of pulmonary elastin by neutrophil-derived elastase. Agents that elicit an inflammatory resposne can lead to emphysema.

Pulmonary fibrosis, on the other hand, is caused by excessive and abnormal collagen deposition in the alveolar interstitium. Amiodarone and bleomycin are known to cause pulmonary fibrosis.

Front 117

117. How does retinoic acid cause teratogenicity?

When is organogenesis most susceptible to terratogens?

Back 117

Vitamin A (retinoic acid) possesses significant on-target teratogenic toxicity. Retinoic acid activates nuclear retinoid receptors (RAR) and retinoid X receptors (RXRs) that regulate a number of key transcriptional events during development.

Organogenesis is most susceptible to terratogens before the 3rd week and in between weeks 3-8.

Front 118

118. How does carbon monoxide cause poisoning?

Which way does the Hgb O₂ curve shift?

Back 118

CO causes tissue hypoxia by binding more strongly to the heme iron in Hgb than does O₂, thereby reducing the transport of oxygen in the blood. In addition, carboxyhemoglobin shifts the dissociation cure for oxyhemoglobin to the left, impeding the dissociation of O₂.

Front 119

119. What is the difference between hydrofluoric acid and hydrochloric acid?

Back 119

HF causes milder skin burns than an equivalent amt of HCl. However, once HF reaches deeper tissue, it destroys the calcified matrix of bone. In addition to the direct effects of the acid, the release of calcium stored in bone can cause life-threatening cardiac arrhythmias. For this reason, HF can be more dangerous than an equivalent amt of HCL.

Front 120

120. What are three characteristics that determine the extent of tissue damage?

Back 120

1. The compounds identity
2. Its concentration/strength
3. Its buffering capacity, or ability to resist change in pH or redox potential

Front 121

121. How are organophosphate insecticides poisonous?

Back 121

Insecticides derived from phosphoric or thiophosphoric acid include parathion, malathion, diazinon, fenthion, and chlorpyrifos.

These compounds are AChE inhibitors due to their ability to phosphorylate AChE at its esteratic active site.

Inhibition of AChE, and consequent accumulation of ACh at cholinergic junctions in nerve tissue and effector organs, produces acute muscarinic, nicotinic, and CNS effects such as bronchconstriction, increased bronchial secretions, salivation, lacrimation, sweating, nausea, vomiting, diarrhea, and miosis, as well as twitching, fasciculations, muscle weakness, cyanosis, and elevated BP.

Symptoms usually occur w/in minute or hours of exposure and resole w/in a few days in nonlethal poisonings.

Front 122

122. What are the pyrethroid insecticides and how are they poisonous?

Back 122

Pyrethroid insecticides, such as permethrin, deltamethrin, cypermethrin, and cyfluthrin, are semisynthetic chemicals that are structurally related to the naturally occurring pyrethrins found in chrysanthemum flowers.

The pyrethroids have very high affinity for plasma membrane sodium channels, and, while they do not alter activation of sodium currents by membrane depolarization, they significantly delay terminal of the action potential.

Front 123

123. What are the two classes of pyrethroids?

Back 123

1. Type I pyrethroids do not contain a cyano group, produce shorter duration sodium tail currents and repetitive discharges, and cause a tremor (T) syndrome in mammals that can include fine tremor, increased response to stimuli, and hyperthermia.

2. Type II pyrethroids usually contain a cyano group, produce a longerduration sodium tail current and stimulus dependent nerve depolarization and block, and cause a choreoathetosis-with-salivation syndrome that may include sinuous writhing and salivation, coarse tremor, clonic seizures, and hypothermia.

Front 124

124. How is the Amanita phalloides toxic to humans?

Back 124

The amatoxins bind strongly to RNA polymerase II, greatly slowing RNA and protein synthesis and leading to hepatocyte necrosis.

COnsumpation of Amanita species can thus cause severe liver dysfunction, even hepatic and renal failure and death. Initial symptoms of poisoning such as abdominal pain, nausea, severe vomiting and diarrhea, fever and tachycardia may occur 6-24 hours after consumption of the mushrooms. There is no antidote.

Front 125

125. How is jimson weed toxic?

Back 125

All parts of the plant are toxic, but the seeds and leaves in particular contain atropine, scopolamine, and hyoscyamine. These compounds are rapidly absorbed and produce anticholinergic symptoms such as mydriasis, dry flushed skin, agitation, tachycardia, hyperthermia, and hallucinations.

Front 126

126. What is the mnemonic for anticholinergic effects?

Back 126

"Blinds as a bat; dry as a bone; red as a beet, mad as a hatter, and hot as a hare"

Front 127

127. What are psoralen isomers (furocoumarins)?

Back 127

These substances come from pants such as parsley, hogweed, figs,, etc... Psoralen isomers can be absorbed into the skin after contact. Subsequent exposure to UV-A radiation can excite furocoumarins, which then form DNA-damaging adducts in epidermal tissue.

W/in 2 days, burning, redness and blistering are observed in areas of contact w/the plant and light; after healing, hyperpigmentation may persist.

Front 128

128. What are three mechanisms of alcoholic hepatotoxicity?

Back 128

1. Associated w/a nutritional deficiency, which leads to a hypermetabolic state and increased oxygen demand on the liver.
2. The metabolism of alcohol generates NADH and NADPH, which shift the redox potential of the hepatocyte. The altered redox potential leads to the increased production of lactic acid and uric acid and to hypoglycemia.
3. Ethanol metabolism produces harmful ROS, including acetaldehyde, and hydroxyl radicals, superoxide anions, and hydrogen peroxide (produced by the action of the enzyme P450 2E1).

Front 129

129. How is lead toxic?

Back 129

Lead causes a disruption of the blood-brain barrier, allowing both lead and other potential neurotoxins to reach the CNS. There, lead can block voltage-dependent calcium channels, interfere w/neurotransmitter function, and most importantly interfere w/cell-cell interactions in the brain.

Overt lead encephalopathy can occur, which results in lethargy, vomiting, irritability, dizziness, and progresses to coma and death if untreated.

Front 130

130. How is lead toxic to Hgb?

Back 130

Lead interferes w/the synthesis of hemoglobin at multiple steps, causing a microcytic, hypochromic anemia. Specifically, lead inhibits the action of delta-aminolevulinic acid dehydratase (ALA-D), which catalyzes the synthesis of porphobilinogen, a heme precursor. Lead also inhibits the incorporation of iron into the porphyrin ring.

Front 131

131. What is cadmium?

Back 131

Cadmium dusts and fumes may be encountered in various occupations. It has a particular toxicity to the kidney following inhalation exposure.

Abnormal renal function, consisting of proteinuria and decreased GFR occurs. The proteinuria consists of LMW proteins that are normally filtered but in this case they are not. Cadmium exposed workers also have a higher rate of kidney stone formation, perhaps due to disruption of calcium metabolism as a consequence of renal damage.

Front 132

132. What is metallothionein, and how is it involved w/cadmium?

Back 132

Metallothionein may be involved in cadmium related kidney damage; this cadmium-binding protein, which is synthesized in the liver and kidney, appears both to facilitate transport of cadmium to the kidney and to promote retention of cadmium in the kidney.

Front 133

133. What are the 3 strategies used alter the toxicokinetics of a poison so as to minimize exposure?

Back 133

1. Decrease the absorption
2. Preventing toxication of a benign compound
3. Increasing the metabolism or elimination of the toxin

Front 134

134. What is the antidote to beta-adrenergic antagonist overdose?

How does it work?

Back 134

Glucagon; this is used to increase HR and BP and parenteral fluids to treat hypotension.

Glucagon increases cAMP in cardiac cells by stimulating glucagon receptor-mediated activation of adenylyl cyclase. Glucagon is also locally metabolized to a mini-glucagon fragment that increases intracellular calcium by stimulating phospholipase A2.

Front 135

135. What is used to treat salicylate poisoning?

Back 135

Sodium bicarb is administered both to maintain a normal serum pH and to alkalinize the urine. Alkalinizing the urine promotes the renal excretion of salicylate.

Front 136

136. What is the most common method of inducing emesis?

How does it work?

Back 136

Ipecac syrup. Locally, it irritate the GI tract, while centrally, it activates the chemoreceptor trigger zone in the area postrema of the brain.

Front 137

137. What is the antidote to antifreeze poisoning?

Back 137

B/c ethanol is also metabolized by alcohol dehydrogenase, it can function as a competitive inhibitor for both methanol and ethylene glycol.

More recently, fomepizole has been employed instead of ethanol b/c it is not itself metabolized by alcohol dehydrogenase and does not cause symptoms of inebriation.

Front 138

138. What is used to treat cyanide poisoning?

Back 138

Treated w/a kit containing amyl nitrite or sodium nitrite and sodium thiosulfate.

The nitrates act by oxidizing Hgb to methemoglobin to provide a substrate that can compete w/cytochrome c oxidase for cyanide molcules. The methemoglobin-bound cyanide is then oxidize to the relatively nontoxic thiocyanate by the enzyme rhodanese.

The addition of thiosulfate provides a ready source of sulfur for the detox reaction and enhances cyanide metabolism.

Front 139

139. What is ion trapping?

Back 139

Ion trapping involves alkalinization of the urine to enhance renal clearance of a weakly acidic toxin.

In ion trapping, the neutral form of the toxin is filtered thru the glomerulus, and this form becomes deprotonated in the alkalinzed urine. The ionized form of the toxin is not reabsorbed and is therefore excreted in the urine.

Clinically, ion trapping is accomplished by administering bicarb to the patient and titrating to a urine pH of 7.5-8.5. This technique is especially useful in the elimination of salicylates and phenobarbital.

Front 140

140. What is hemodialyssi used for?

Back 140

Hemodialysis is generally useful for small molecules that have a small volume of distribution, are relatively water soluble, and are not highly bound to plasma proteins (which cannot cross the dialysis membrane).

Front 141

141. What is hemofiltration used for?

Back 141

B/c the plasma is exposed to a filter rather than a semipermeable membrane, larger molecules can be clears w/hemofiltration than w/hemodialysis

Front 142

142. What is hemoperfusion?

Back 142

Blood is passed thru a cartridge where ti comes in contact w/an ion-exchange resin or activated charcoal that can adsorb the toxin.

B/c of the direct contact between blood and the adsorbent material, hemoperfusion poses a risk of thrombosis and it could deplete plasma of calcium and magnesium.

Front 143

143. What is a chelator?

What are the requirements for chelators?

Back 143

A chelator is a multidentate structure w/multiple binding sites. Binding the metal at multiple sites shifts the equilibrium constant in favor of metal ligation. High-affinity metal-ligand binding is critical b/c the chelatory must compete w/tissue macromolecules for binding.

In addition, the chelator should be nontoxic and water soluble and readily cleared.

Finally, an ideal chelator should have a low binding affinity for endogenous ions such as calcium.

Front 144

144. What are the most important heavy metal chelators?

Back 144

EDTA, which can be used to bind lead;

Dimercaprol, which binds gold, arsenic, lead, and mercury to its two thiol groups

Succimer which as supplanted dimercaprol for the removal of lead, cadmium, mercury, and arsenic.

Deferoxamine is used for the removal of toxic levels of iron.

Removal of copper, typically in patients w/Wilson's disease, is accomplished w/penicillamine, or for patients who do not tolerate penicillamine, tientine.

Front 145

145. What is the treatment for digoxin overdose?

Back 145

Digoxin immune Fab. It is an antibody that includes on the Fab fragment of the immunoglobulin.

This treatment is used in cases where the patient is experiencing signs or symptoms due to toxic plasma levels of the drug.

Front 146

146. What is an inherent danger in the use of antibodies as inactivators?

Back 146

One inherent danger in the use of antibodies as inactivators is the risk of developing serum sickness, a type III hypersensitivty reaction. Both antivenins and digoxin immune Fab can cause serum sickness.

Front 147

147. What is the treatment for opioid overdose?

Back 147

An opioid overdose can be treated w/naloxone, a pharmacologic antagonist of the opioid receptor. Naloxone has a rapid onset of action is is highly potent.

Front 148

148. What is the treatment for benzodiazepine overdose?

Back 148

Flumazenil is a pharmacologic antagonist at the GABA receptor an dis used to treat benzodiazepine overdose and zolpidem overdoses.

Front 149

149. What is the treatment for AChE inhibition?

Back 149

Atropine. By antagonizing the muscarinic ACh receptor, atropine restores cholinergic balance and prevents bronchocontriction, the most common cause of death in patients with exposure to AChE inhibitors.

Front 150

150. What is the treatment for jimson weed poisoning (AChE excess)?

Back 150

Treatment involves the administration of physostigmine which blocks AChE to increase cholinergic tone.

*It should be noted that atropine, an anticholinergic agent, is the DOC for organophosphate poisoning of AChE, whereas an AChE inhibitor is the DOC for poisoning w/an anticholinergic toxin.

Front 151

151. What is the treatment for CO and cyanide poisoning?

Back 151

Treatment invovles displacing the small molecule from its heme target. For CO poisoning, high concentrations of oxygen are administered. For severe poisonings, a pt may be placed in a hyperbaric oxygen chamber.

Cyanide cannot be displaced from oxygen. However, by oxidizing Hgb to its ferric state with amyl nitrite or sodium nitrite, a competitor for cyanide is generated. Afterwards, methylene blue can reduce the ferric iron to its ferrous state.

Front 152

152. What is the treatment of acute organophosphate poisoning?

Back 152

Acute treatment for organophosphate poisoning involves restoration of the active site of the enzyme. While the administration of atropine can block the excess ACh at muscarinic receptors, it cannot restore the enzymatic function of AChE.

However, pralidoxime can enhance the hydrolysis of the serine-phosphate bond between the organophosphate and AChE.

Front 153

153. What are candida species?

Back 153

Candida, including C. albicans and Candida tropicalis, are part of the normal flora of the skin, mouth, and GI tract; they can cause superficial infections in healthy individuals and disseminated visceral infections in neutropenic patients.

Front 154

154. What are the virulence factors of Candida?

Back 154

Candida virulence factors include adhesins that mediate binding to host cells, enzymes that contribute to invasiveness, and catalases that aid intracellular survivial by resisting phagocyte oxidative killing.

Front 155

155. Where do Candida infections occur?

Back 155

Candida grows best on warm, moist surfaces; it freq causes vaginitis (particularly during pregnancy), diaper rash, and oral thrush.

Candida infections of the mouth and vagina produce superficial curdy white patches; these are easily detached to reveal a reddened, irritated mucosa.

Front 156

156. What is the morphology of Candida infections?

Back 156

In tissue sections, C. albicans can appear as yeastllike forms (blastoconidia), pseudohyphae, and less, commonly true hyphae, defined by the presence of septae.

Pseudohyphae are an important diagnostic clue for C. albicans and represent budding yeast cells joined end to end at constrictions, thus simulating true fungal hyphae.

Microscopically, lesions contain yeast, hyphae, and pseudohyphae w/acute and chronic inflammation, and sometimes granulomas.

Front 157

157. What is chronic mucocutaneous candidiasis?

Back 157

Chronic mucocutaneous candidiasis occurs in persons w/AIDS, w/defective T cell immunity, or w/polyendocrine deficiencies (hypoparathyroidism, hypoadrenalism, and hypothyroidism. Disseminated candidiasis is rare in this disease.

Front 158

158. What is severe, invasive candidiasis?

What is the most common type of fungal endocarditis?

Back 158

Severe, invasive candidiasis occurs via blood-borne dissemination in neutropenic persons.

Typically, microabscesses w/fungi in the center are surrounded by areas of tissue necrosis. Common areas include renal abscesses, heart abscesses, brain involvement (most commonly meningitis), endophthalmitis, hepatic abscesses and candida pneumonia.

Candida endocarditis is the most common fungal endocarditis, usually occurring in the setting of prosthetic heart valves or in IV drug abusers.

Front 159

159. What is Cryptococcosis?

In what population does it occur?

Back 159

Cryptococcus neoformans causes meningoencephalitis in patients w/AIDS, leukemia or lymphoid malignancies, lupus sarcoidosis, or organ transplants, or those receiving high-dose corticosteroids.

Front 160

160. What are the virulence factors of C. neoformans?

Back 160

Virulence is associated w/the capsular polysaccharide; in tissues, the capsule stains bright red w/mucicarmine, and in CSF, it is negatively stained w/India ink.

Also includes id melanin production which protects the fungi from the epinephrine oxidative system present in the host nervous system.

Front 161

161. What is the clinical course of cryptococcosis?

Back 161

In healthy individuals, C. neoformans can form a solitary pulmonary granuloma.

In immunosuppressed pts, it produces small cysts ("soap bubble lesions") w/in the gray matter of the brain (Virchow-Robin perivascular space), occasionally w/no inflammatory response.

Front 162

162. What is Aspergillosis?

Back 162

Aspergillus fumigatus is a ubiquitous mold causing allergies and colonization in otherwise healthy persons; in neutropenic persons it can cause severe sinusitis, pneumonia, and disseminated disease.

Front 163

163. What is the pathogenesis of aspergillus fumigatus?

Back 163

Aspergillus occurs in people with corticosteroids and neutropenia. Aspergillus fumigatus grows on peanuts can secrete the carcinogen aflatoxin, a major cause of liver cancer.

Allergic bronchopulmonary aspergillosis is a hypersensitivity reaction associated w/asthma.

Preexisting pulmonary lesions caused by tuberculosis, bronchiectasis, old infarcts, or abscesses may develop local Aspergillus colonies (aspergillomas) w/o tissue invasion.

Front 164

164. What are the four virulence factors of Aspergillus fumigatus?

Back 164

1. Adhesins (binds to fibrinogen, laminin, complement, fibronectin, collagen, and surfactant)

2. Antioxidants (melanin pigment, mannitol, catalases, and superoxide dismutases)

3. Enzymes (pshopholipases, proteases)

4. Toxins (aflatoin, restrictocin and mitogillin - (ribotoxins)).

Front 165

165. What is the morphology of invasive aspergillosis?

Back 165

Invasive aspergillosis is an opportunistic infection of immunosuppressed hosts. Primary lesions manifest as necrotizing pneumonia w/sharply delineated, rounded gray foci w/in hemorrhagic borders (***called target lesions).

Histologically, aspergillus forms septate hyphae with acute-angle branching, and sometimes fruiting bodies.

Front 166

166. What happens when Aspergillus fumigatus invades blood vessels?

Back 166

Aspergillus fumigatus invade blood vessels w/resulting thrombosis, consequently, areas of hemorrhage and infarction are superimposed on necrotizing inflammation.

Patients with aspergillomas usually have recurrent hemoptysis.

Front 167

167. What is zygomycosis (murcormysosis)?

Back 167

Murcormysosis is an opportunistic infection caused by bread mold fungi (Mucor, Absidia, Rhizopus, and Cunninghamella). It occurs most commonly in neutropenic pts and ketoacidotic diabetics.

The primary site (nasal sinuses, lungs, or GI tract) depends on whether the spores are inhaled or digested.

***In diabetics, the fungus may spread from nasal sinuses to the orbit or brain, giving rise to rhinocerebral murcormycosis.

Front 168

168. What is the morphology of murcormysosis?

Back 168

Zygomycetes form nonseptate, irregularly wide fungal hyphae w/frequent right-angle branching.

Front 169

169. What are the symptoms of malaria?

Back 169

P. vivax, P. ovale, and P. malariae cause low parasitemia, mild anemia, and in rare instances, splenic rupture and nephrotic syndrome.

P. falciparum causes high levels of parasitemia, severe anemia, cerebral symptoms, renal failure, pulmonary edema, and death.

Front 170

170. What is the morphology of P. falciparum infection?

Back 170

P. falciparum infection initially causes congestion and enlargement of the spleen. Parasites are present w/in RBCs and there is increased phagocytic activity of macrophages in the spleen.

W/progression of malaria, the liver becomes progressively enlarged and pigmented. Kupffer cells are heavily laden w/malarial pigment, parasites and cellular debris, while some pigment is also present in the parenchyma cells.

Front 171

171. What is malignant cerebral malaria?

Back 171

Caused by P. falciparum, brain vessels are plugged w/parasitized RBCs w/surrounding hemorrhage and ischemia. About the vessels, there are ring hemorrhages that are probably related to local hypoxia incident to the vascular stasis and small focal inflammatory reactions (called malarial or Durck granulomas).

***This is caused by endothelial adhesion, and is this main cause of malarial death in children.

Front 172

172. What are the genetic resistances to malaria?

Back 172

Sickle cell trait (HbS) and hemoglobin C (HbC) lessen malria severity by reducing parasite proliferation.

Many Africans are not susceptible to P. vivax infection b/c they lack the erythrocyte Duffy blood group antigen that permits parasite binding.

P. falciparum evades the immune response by antigenic variation of PfEMP1; repeated infection freq produce an immune response repertoire capable of minimizing disease severity.

Front 173

173. Individuals w/which HLA allele are resistant to P. faciparum?

Back 173

Individuals w/the HLA allele B53 are resistant to P. falciparum, perhaps b/c HLA-B53 presents liver stage specific malaria antigens to cytotoxic T lymphocytes, which then kill malaria-infected hepatocytes.

Front 174

174. What is babesiosis?

Back 174

Baesia microti is a malaria-like protozoan transmitted from white-footed mice to humans by Ixodes ticks, or rarely, contracted thru blood transfusion.

Babesiae cause fever and thru RBC parasitization, cause hemolytic anemia that is particularly severe in debilitated or splenectomized pts.

Front 175

175. What is the morphology of babesiosis?

Back 175

*Babesia form characteristic tetrads (Maltese cross) ,which are diagnostic if found.

They resemble P. falciparum schizont stages, although they lack hemozoin pigment and are more pleomorphic.

Front 176

176. What is Leishmaniasis?

Back 176

Leishmaniasis is a chronic inflammatory disease of the skin, mucous membranes, or viscera caused by obligate intracellular, kinteoplastic protozoan parasites thransmitted thru the bite of infected sandflies.

It occurs in four different lesions in humans: (1) visceral, (2), cutaneous, (3) mucocutaneous, and (4) diffuse cutaneous

Front 177

177. What is the morphology of visceral leishmaniasis?

Back 177

Visceral disease is caused by L. donovani and L. chagasi; parasites invade macrophage and cause severe systemic disease marked by hepatosplenomegaly, lymphadenopathy, pancytopenia, fever, and weight loss.

Often there is hyperpigmentation of the skin in the extremities, which is why the disease is called "black fever" in Hindi.

Front 178

178. What is the morphology of cutaneous leishmaniasis?

Back 178

Cutaneous is caused by L. major and L. aethiopica and L. mexican and L. baziliensis.

It is a relatively mild, localized disease consisting of a single ulcer on teh exposed skin. The lesion (often called a tropical sore), begins as an itching papule that changes into a shallow and slowly expanding ulcer w/irregular borders.

Front 179

179. What is the morphology of mucocutaneous leishmaniasis?

Back 179

Mucocutaneous leishmaniasis is caused by L. major and L. baziliensis.

Moist, ulcerating or nonulcerating lesions, which may be disfiguring, develop in the larynx and at the mucocutaneous junctions of the nasal septum, anus, or vulva.

On microscopic exam, there is a mixed inflammatory infiltrate w/lymphocytes and plasma cells.

Front 180

180. What is the morphology of diffuse cutaneous leishmaniasis?

Back 180

Diffuse cutaneous leishmaniasis is a rare form of dermal infection that begins as a single skin nodule, which continues spreading until the entire body is covered by bizarre nodular lesions. These lesions resemble keloids or large verrucae, and are freq confused w/leprosy.

The lesions do not ulcerate but contain vast aggregates of foamy macrophages stuffed w/leishmania.

Front 181

181. What are the virulence factors for leishmaniasis?

What is necessary for adequate host defense?

Back 181

Promastigotes produce two glycoconjugates teh enhance virulence:

Lipophosphoglycan forms a glycocalyx that activates complement but also inhibits complement action by preventing MAC assembly.

gp63 cleaves complement and lysosomal antimicrobial enzymes, and also binds fibronectin to promote mastigote adhesion to macrophages.

*Activation fo macrophages by IFN is probably necessary for adequate host defense; activated macrophages kill parasites thru toxic metabolites of oxygen and NO.

Front 182

182. What is African trypanosomiasis?

Back 182

African trypanosoma are extracellular parasites transmitted by tsettse flies.

Trapanosoma brucei rhodesiense (East Africa) is acute and virulent, and Trypanosoma brucei gambiense (W. Africa) is chronic.

African trypanosomes have a variant surface glycoprotein (VSG) that undergoes antigen variation to evade the host response.

Front 183

183. What is the morphology of African trypanosomiasis?

Back 183

A large, red, rubbery chancre forms at the site of the insect bite, where large numbers of parasites are surrounded by a dense, largely mononuclear, inflammatory infiltrate.

Trypanosomes concentrate in capillary loops, such as the choroid plexus and glomeruli.

Plasma cells containing glycoprotein globules are frequent and are referred to as flame cells or Mott cells.

Front 184

184. What is the clinical course of African trypanosomiasis?

Back 184

Trypanosomes proliferate in the blood, causing intermittent fevers, lymphadenopathy, splenomegaly, brain dysfunction (sleeping sickness), cachexia, and death.

Lymph nodes and spleen enlarge as a result of hyperplasia and infiltration by lymphocytes, plasma cells, and parasite laden macrophages.

Front 185

185. What is Chagas disease?

Back 185

Chagas disease occurs in S. America and is caused by Trypanosoma cruzi, an intracellular protozoan.

T. cruzi is transmitted between animal (cats, dogs, rodents), and humans by "kissing bugs" (triatomids) that pas parasites in their feces as they bite.

Front 186

186. What is the pathogenesis of Chagas disease?

Back 186

T. cruzi has on its surface a homologue of the human complement regulatory protein decay accelerating factor (DAF), which inhibits C3 convertase formation and alternative pathway complement activation.

*T. cruzi require exposure to acidic phagolysosome to stimulate amastigote development.

Front 187

187. What is the clinical course of Chagas disease?

Back 187

Acute Chagas disease may be mild or severe (high aprasitemia, fever, or progressive cardiac dilation and failure).

In 20% of patients, chronic Chagas disease occurs years later and may manifest as myocardial inflammation (four chamber cardiac dilation, infiltration of lymphocytes , plasma cells, and monocytes seen heaviest in the right bundle branch of the cardiac conduction system) and damage to the myenteric plexus causing colon and esophageal dilation.

Front 188

188. What is the morphology of Strongyloidiasis?

Back 188

In mild strongyloidiasis, larvae are present in the duodenal crypts w/an underlying eosinophil-rich infiltrate.

In immunocompromised hosts, larvae hatched i the gut can invade colonic mucosa and reinitate infection; such hyperinfection results in larval invasion of the colonic submucosa, lymphatics, blood vessels, and other organs.

Front 189

189. What is the morphology of Taenia solium infection?

Back 189

T. solium can be transmitted to humans in 2 ways w/distinct outcomes:

1. Larval cysts (cysticerci) ingested in port attach to the intestinal wall where they mature and produce egg-laden proglottids (segments) that are passed in the stool.

2. Intermediate hosts (pigs or humans) can ingest eggs in feces-contaminated food or water; when larvae hatch, they penetrate the gut wall, and disseminate to encyst in many organs, including the brain (causing severe neurologic manifestations).

Front 190

190. What is T. saginata (beef tapeworm) and Diphyllobothrium latum (fish tapeworm) infection?

Back 190

T. saginata (beef) and Diphyllobothrium latum (fish) are acquired by eating undercooked meat. In humans , these parasites live only in the gut, and do not form cysticerci.

Front 191

191. What is E. granulosus and E. multilocularis?

Back 191

Humans are accidental hosts for E. granulosus and E. multilocularis.

These are normally passed only between the definitive (dog or fox) and intermediate (sheep and rodents) hosts.

Front 192

192. What is hydatid disease?

Back 192

Hydatid disease is caused by ingestion of echinoccal eggs in food contaminated w/dog or fox feces. The eggs hatch in the duodenum and invade the liver, lungs, or bones, where they form cysts.

Front 193

193. Where are cysticerci usually found?

Back 193

Cysticerci may be found in any organ, but the more common locations include the brain, muscles, skin and heart.

Cerebral symptoms depend on the location of the cysts, which include the meninges, gray and white matter, sylvian aqueduct, and ventricular foramina.

The cysts are ovoid and white to opalescent, rarely exceeding 1.5 cm, and contain an invaginated scolex with hooklets that are bathed in a clear cyst fluid.

Front 194

194. What is Trichinosis?

Back 194

Trichinella spiralis is acquired by ingestion of larvae in undercooked meat from pigs that have themselves been infected by eating infected rats or pork!.

In the gut, larvae deelop into adults that release new larva that disseminate and penetrate muscle cells causing fever, myalgias, eosinophilia, and periorbital edema.

Front 195

195. What is the pathogenesis of T. spiralis?

Back 195

T. spiralis stimulates TH2 responses, with production of IL-4, IL5, IL-10, and IL-13. These cells activate eosinophils and mast cells and increase gut contractility to expel worms.

Front 196

196. What is the morphology of trichinosis?

Back 196

In the heart, there is a patchy interstitial myocarditis characterized by many eosinophils and scattered giant cells.

In the lungs, trapped larvae cause focal edema and hemorrhages, sometimes w/an allergic eosinophlic infiltrate.

T. spiralis preferentially encysts in striated skeletal muscle w/the most blood supply. *Coiled larvae are approx 1 mm long and are surrounded by membrane bound vacuoles w/in nurse cells.

Front 197

197. What is schistosomiasis?

Back 197

Schistosomiasis is caused by Schistosoma mansoni, S. haematobium, and S. japonicum or S. mekongi. It is transmitted from freshwater snails.

Larvae penetrate human skin, migrate thru the vasculature and settle in the pelvic or portal venous systems, where females produce eggs that are released in urine or stool.

Front 198

198. What is the pathogenesis of schistosomiasis?

Back 198

The immune resposne to S. mansoni and S. jamponicum eggs in the liver causes the severe pathology of schistosomiasis. While the immune response does provide some protection in animal models, the price of this response is granuloma formation and hepatic fibrosis.

Chronic schistosomiasis is associated w/a dominant TH2 response; acute is associated w/a TH1 response.

Front 199

199. What is the morphology of mild S. mansoni or S. japonicum infections?

Back 199

White, pinhead size granulomas are scattered thru the gut and liver. At the center of the granuloma is the shistosome egg, which contains a miracidium. It is usually surrounded by macrophages and eosinophils.

Front 200

200. What is the morphology of severe S. mansoni or S. japonicum infections?

Back 200

In severe S. mansoni or S. japonicum infections, inflammatory patches or pseudopolyps may form in the colon. The surface of the liver is bumpy, whereas cut surfaces reveal granulomas and a widespread fibrous portal enlargement. B/c these fibrous triads resemble the stem of a clay pipe, the lesion is named pip-stem fibrosis.

Front 201

201. What is the morphology of S. haematobium infection?

What is the most freq complication of this infection?

Back 201

In S. haematobium infection, bladder inflammatory patches due to massive egg deposition and granulomas appear early, and when they erode, they cause hematuria.

Later, the granulomas calcify and develop a sandy appearance.

*The most freq complication of this infection is inflammation and fibrosis of the ureteral walls, leading to obstruction, hydronephrosis, and chronic pyelonephritis.

Front 202

202. What is lymphatic filariasis?

Back 202

Lymphatic filariasis is caused by two nematodes, Wuchereria bancrofti (90% of cases) and Brugia malayi.

Larvae are contracted from mosquitoes and develop into adults in lymphatic channels, where they mate and release microfilariae that enter the bloodstream.

Filariasis can manifest as asymptomatic microfilaremia, chronic lymphadenitis w/swelling of the dependent limb or scrotum (elephantitis), or tropical pulmonary eosinophilia.

Front 203

203. What is the pathogenesis of tropical pulmonary eosinophilia?

Back 203

There is an IgE-mediated hypersensitivity to microfilariae in tropical pulmonary eosinophilia. IgE and eosinophils may be stimulated by IL-4 and IL-5, respectively, secreted by filaria-specific TH2 helper T cells.

Front 204

204. What is the morphology of tropical pulmonary eosinophilia?

Back 204

TPE results in restictive lung disease. It is marked by eosinophilia caused by TH2 responses and cytokine production or by dead microfilariae surrounded by stellate, hyaline, eosinophilic precipitates embedded in small, epithelioid granulomas (Meyers-Kouvenaar bodies).

Front 205

205. What are four ways in which Brugia malayi evades/inhibits immune defenses?

Back 205

Brugia malayi produces numerous molecules to evade or inhibit immune defenses:

1. Antioxidant glycoproteins protect from oxygen radical injury
2. Homologues of cystatins, cysteine protease inhibitors, impair antigen presentation
3. Serpins (serine protease inhibitors) inhibit neutrophil proteases
4. Homologues of TGF-β bind to host TGF-β receptors, and down-regulate inflammatory responses

Front 206

206. What is onchocerciasis?

Back 206

Onchocerca volvulus is a filarial nematode transmitted by black flies; it affects more than 17 million people in Africa, South America, and Yemen.

Nematodes mate in the host dermis, surrounded by host inflammatory cells that produce a subcutaneous nodule (onchocercoma).

Female worms release large numbers of microfilariae that accumulate in the skin and eye chambers, causing pruritic dermatitis and blindness.

Treatment includes doxycycline to kill the symbiotic Wolbachia bacteria that live inside O. volvulus and are required for worm fertility.

Front 207

207. What is the morphology of onchocerciasis?

Back 207

O. volvulus causes chronic, itchy dermatitis w/focal darkening or loss of pigment and scaling, referred to as leopard, lizard, or elephant skin. Foci of epidermal atrophy and elastic fiber breakdown may alternate w/areas of hyperkeratosis, hyperpigmentation w/pigment incontinence, dermal atrophy, and fibrosis.

The progressive eye lesions begin w/punctate keratitis along w/small, fluffy opacities of the cornea cause by degenerating microfilariae, which evoke and eosinophilic infiltrate.