Pbl Exam 4 Case 7

Front 1

1. What is transcription?

Back 1

Transcription is the transfer of the genetic message from DNA to RNA

Front 2

2. What is translation?

Back 2

Translation is the transfer of the genetic message form the nucleotide language of nucleic acids to the AA language of proteins.

Front 3

3. What makes ups the nucleic acid alphabet?

Back 3

There are only four characters, corresponding to the four nucleotide of mRNA (A, G, C, and U).

We have 20 amino acids. We need three bases to make up one amino acid, because 4^2=16 whereas 4^3=64 combinations. The 64 combinations or "codons" are more than required, but not overly excessive.

Front 4

4. What are tRNA molecules?

Back 4

Each tRNA molecule contains an anticodon and binds covalently a specific AA at its 3'-end.

Front 5

5. What are anticodons of tRNA?

Back 5

The anticodon of a tRNA molecule is a set of three nucleotides that can interact w/a codon on mRNA.

To interact, the codon and anticodon must be complimentary (i.e. they must be able to form base pairs in an antiparallel orientation.

Thus, the anticodon of a tRNA serves as the link between an mRNA codon and the AA that the codon specifies.

Front 6

6. What are the three codons that terminate protein synthesis and are known as "stop" codons?

Back 6

UGA, UAG, UAA

Front 7

7. Which two amino acids only have one codon?

Back 7

AUG = methionine

UGG = tryptophan

Front 8

8. What does it mean when the genetic code is described as degenerate?

Back 8

Degenerate means that an AA may have more than one codon.

However, each codon specifies only one amino acid, and the genetic code is thus unambiguous.

Front 9

9. What is the "wobble" hypothesis?

Back 9

Watson and Crick noted that the pairing between the 3' base of the codon and the 5' base of the anticodon does not always follow the strict base pairing rules that he and Watson has previously discovered.

At the third base of the codon (the 3'position of the codon and the 5' position of the anticodon), the base pairs can "wobble"; for example, G can pair with U, and A, C, or U can pair w/the unusual base hypoxanthine (I) found in tRNA.

B/c of "wobble" between the codon and anticodon, fewer than 61 tRNAs are required to translate the genetic code.

Front 10

10. How is the genetic code almost universal?

Back 10

ALl organissm studied so far sue the same genetic code, with some rare exceptions in human mitochondrial mRNA:

1. UGA codes for tryptophan instead of serving as a stop codon
2. AUA codes for methionine instead of isoleucine
3. CUA codes for threonine instead of leucine

Front 11

11. How is the the genetic code nonoverlapping and w/o punctuation?

Back 11

mRNA does not contain punctuation to separate one codon from the next, and the codons do not overlap. Each nucleotide is read only once.

Beginning with a start codon (AUG) near the 5' end of the mRNA, the codons are read sequentially, ending w/a stop codon (UGA, UAG, or UAA) near the 3' end of the mRNA.

Front 12

12. What is the relationship between mRNA and the protein product?

Back 12

The start codon (AUG) sets the reading frame -the order in which the sequence of bases in the mRNA is sorted into codons.

The order of the codons in the mRNA determines the sequence in which AAs are added to the growing polypeptide chain.

Thus the order of the codons in the mRNA determines the linear sequence of AAs in the protein.

Front 13

13. What are the mutations in genetic code?

Back 13

Mutations that result from damage to the nucleotides of DNA molecules or from unrepaired errors during replication can be transcribed into mRNA and therefore can result in the translation of a protein w/an abnormal AA sequence.

Front 14

14. What are the four different types of mutations?

Back 14

1. Point mutations
2. Insertions
3. Deletions
4. Frameshift

Front 15

15. What are point mutations?

What are the three types?

Back 15

Point mutations occur when only one base in DNA is altered, producing a change in a single base of an mRNA codon.

The three basic types of point mutations are:
1. Silent
-said to be silent when they do not effect the AA sequence of the protein.

2. Missense
-one AA in the protein is replaced by a different AA

3. Nonsense
-a codon change causes a codon to be replaced by a stop codon, so synthesis of the mutant protein terminates at this point.

Front 16

16. What are insertion and deletion mutations?

Back 16

An insertion occurs when one or more nucleotides are added to DNA. If the insertion does not generate a stop codon, a protein with more AAs than normal could be produced.

When one or more nucleotides are removed form the DNA, the mutation is known as a deletion. If the deletion does not affect the normal start and stop codons, a protein w/fewer than the normal number of AAs could be produced.

Front 17

17. What are frame-shift mutations?

Back 17

A frame-shift mutation occurs when the number of inserted or deleted nucleotides is not a multiple of three. The reading frame shifts at the point where the insertion or deletion begins. It usually leads to premature termination by new stop codons in the new reading frame.

Beyond that point, the AA sequence of the protein translated from the mRNA differs from the normal protein.

Front 18

18. What are splice site mutations?

Back 18

Splice site mutations-

May decrease splicing efficiency.
May alter splicing, inserting sequence from intron into mRNA or cause exon skipping, loss of one or more exons

Significant alterations in amount of protein made or production of substantially altered protein

Front 19

19. What are triplet repeat expansion?

Back 19

Triplet repeat expansion-

Proteins with long run of same codon, may increase number of repeats with time.

At some length, the repeat interferes with protein function and/or production

Front 20

20. What is an aminoacyl-tRNA?

Back 20

A tRNA that contains an AA attached covalently to its 3'-end is called an aminoacyl-tRNA and is said to be "charged."

Aminoacyl-tRNAs are named both for the AA and the tRNA that carries the AA.

Front 21

21. What do tRNAs recognize?

Back 21

A particular tRNA recognizes only the AUG start codon that initiates protein synthesis and not other AUG codons that specify insertion of mehtionine within the polypeptide chain.

Front 22

22. What attaches AAs to their tRNAs?

Back 22

Amino acids are attached to their tRNAs by highly specific enzymes known as aminoacyl-tRNA synthetases.

20 different synthetases exist, one for each AA. Each synthestase recognizes a particular AA and all of the tRNAs that carry that AA.

Front 23

23. How is the ester bond formed that links the AA to the tRNA by aminoacyl-tRNA synthetase?

Back 23

It is an energy-requiring process that occurs in two steps:

1. the AA is activated by ATP to form an enzyme/aminoacyl-AMP complex and pyrophosphate
2. the activated AA is transferred to the 2' or 3' hydroxyl group of the 3' terminal A residue of the tRNA, and AMP is released.

The energy in the aminoacyl-tRNA ester bond is subsequently used in the formation of a peptide bond during the process of protein synthesis.

Front 24

24. So, the insertion of the AA into a growing polypeptide chain depends on what?

Back 24

Depends solely on the bases of the anticodon, through complimentary base pairing w/the mRNA codon.

Front 25

25. What are the three steps of translation?

Back 25

1. Initiation
2. Elongation
3. Termination

Front 26

26. Translation steps summary

Back 26

It begins with the formation of the initiation complex.

Subsequently, synthesis of the polypeptide occurs be a series of elongation steps that are repeated as each AA is added to the growing chain.

Termination occurs where the mRNA contains an in-frame stop codon and the completed polypeptide chain is released.

Front 27

27. What occurs in the initiation of translation?

Back 27

1. In eukaryotes, translation begins w/formation of complex of met-tRNA , mRNA, and a ribosome.

2. Next, the mRNA must associate with a small ribosomal subunit (30S/40S)
-uses 5' cap and cap binding protein (CBP) in eukaryotes
- uses Shine-Dalgarno sequence in prokaryotes

3. The charged Met-tRNA binds to an initiation factor and large subunit (50S/60S)
-Met is formylated in prokaryotes ONLY

4. These components plus other initiation factors associate producing functional ribosomes
-requires ATP and GTP hydrolysis for energy.

Front 28

28. The functional ribosome is now complete and consists of what...?

During initiation, where does Met-tRNA bind?

Back 28

1. One small subunit
2. One large subunit
3. Two binding sites for tRNA
-P (peptidyl) site
-A (aminoacyl) site

During initiation, Met-tRNA binds to the ribosome at the P site.

Front 29

29. How does the initiation process differ for prokaryotes and eukaryotes?

Back 29

1. In bacteria, the initiating met-tRNA is formylated, producing a formyl-mehtionyl-tRNA that participates in formation of the initiation complex.

2. Only three initiation factors are required to generate this complex in prokaryotes, compared with the dozen or more required by eukaryotes.

3. The ribosomes also differ in size:
-Prokaryotes have 70S ribosomes, composed of 30S and 50S subunits
-Eukaryotes have 80S ribosomes, composed of 40S and 60S subunits.

4, Unlike eukaryotic mRNA, bacterial mRNA is not capped. It uses the Shine-Dalgarno sequence to identify the initiating AUG triplet.

Front 30

30. How is the initiation of translation regulated?

Give an example...

Back 30

Regulated at the level of initiation factors.

For example, insulin, an anabolic hormone, stimulates general protein synthesis by activating the initiation factor eIF4E.

Normally, eIF4E is bound to an inhibitor protein, designated 4E-binding protein (4E-BP). When insulin binds to its cell surface receptor, it initiates an intracellular sequence of events resulting in phosphorylation of 4E-BP.

Phosphorylated 4E-BP no longer binds to eIF4E, and eIF4E is now free to participate in the initiation of protein synthesis.

Front 31

31. How is eIF2 a regulator of the initiation step in protein synthesis?

Back 31

When eIF2 is phosphorylated, it is inactive, and protein synthesis cannot begin.

Conditions such as starvation, heat shock, and viral infection result in phosphorylation of eIF2 by a specific kinase.

Front 32

32. What does eIF2 have to do with globin synthesis?

Back 32

The regulation of globin synthesis by heme in reticulocytes illustrates the role of eIF2 in the regulation of translation.

Reticulocytes, which arethe precursors of RBCs, synthesize the oxygen carrying hemoglobin molecules from the globin polypeptide chains and Fe binding pigment, heme.

In the absence of heme, the rate of initiation of globin synthesis decreases. Heme acts by inhibiting the phosphorylation of the initiation factor eIF2. Thus, eIF2 is active in the presence of heme and globin synthesis is initiated.

Front 33

32. What does eIF2 and EF1 have in common?

Back 33

Both eukaryotic initiation factor 2 (eIF2) and elongation factor 1 (EF1) are types of heterotrimeric G proteins.

The dramatically change their conformation and actively form complexes when they bind GTP but become inactive and dissociate when they hydrolyze this GTP to GDP.

GTP can then displace the bound GDP to reactivate the initiation factor eIF2 or the elongation factor EF1.

Front 34

33. What is translation elongation?

Back 34

Elongation: amino acids are added to the carboxyl end of the growing polypeptide

After the initiation complex is formed, addition of each amino acid to the growing polypeptide chain involves binding of an aminoacyl-tRNA to the A site on the ribosome, formation of a peptide bond, and translocation of the peptidyl-tRNA to the P site.

The peptidyl-tRNA contains the growing polypeptide chain.

Front 35

34. How is the aminoacyl-tRNA bound to the A site?

Back 35

When Met-tRNA is bound to the P site, the mRNA codon in the A site determines which aminoacyl-tRNA will bind to that site.

An aminoacyl-tRNA binds when its anticodon is antiparallel and complimentary to the mRNA codon.

In eukaryotes, the incoming aminoacyl-tRNA first combines w/elongation factor EF1α containing bound GTP before binding to the mRNA-ribosome complex.

When the aminoacyl-tRNA-EF1α-GTP complex binds to the A site, GTP is hydrolyzed to GDP.

This prompts dissociation of EF1α-GDP from the aminoacyl-tRNA ribosomal complex, thereby allowing protein synthesis to continue.

Front 36

35. What happens to the free EF1α-GDP?

Back 36

The free EF1α-GDP reassociates w/the EF1βγ subunits, and GDP is released.

Subsequently, GTP binds and the βγ subunits dissociate.

Thus, EF1α-GDP is ready to bind another aminoacyl-tRNA molecule.

Front 37

36. How is the process of elongation different in prokaryotes?

Back 37

The process is very similar in prokaryotes, except that the corresponding factor for EF1α is named EF-Tu and the associating elongation factors are called EF-Ts instead of EF1βγ

Front 38

37. During elongation, how is the formation of a peptide bond accomplished?

Back 38

The amino acid on the tRNA in the A site forms a peptide bond with the methionine on the tRNA in the P site.

In subsequent rounds of elongation, the AA on the tRNA in the A site forms a peptide bond with the peptide on the tRNA in the P site.

The tRNA in the A site now contains the growing polypeptide chain, and the tRNA in the P site is uncharged.

Front 39

38. What catalyzes the formation of the peptide bonds?

Back 39

Peptidyltransferase, which is not a protein but the rRNA of the large ribosomal subunit, catalyzes the formation of the peptide bond.

Front 40

39. How is translocation accomplished?

Back 40

Translocation in eukaryotes involves another G-protein, elongation factor EF2 (EF-G in prokaryotes) that complexes w/GTP and binds to the ribosome, causing a conformational change that moves the mRNA and its base-paired tRNAs with respect to the ribosome.

The uncharged tRNA moves from the P site and is released from the ribosome.

The peptidyl-tRNA moves into the P site, and the next codon of the mRNA occupies the A site.

During translocation, GTP is hydrolyzed to GDP, which is released from the ribosome along w/the elongation factor.

Front 41

40. What terminates translation?

Back 41

The three elongation steps are repeated until the FIRST termination (stop) codon moves into the A site on the ribosome.

B/c no tRNAs w/anticodons that can pair w/stop codons normally exist in cells, release factors bind to the ribosome instead, causing peptidyltransferase to hydrolyze the bond between the peptide chains and tRNA,

The newly synthesized polypeptide is released from the ribosome, which dissociates into its individual subunits, releasing the mRNA.

Front 42

41. In sum, what are the four steps of translation?

Back 42

1. Polypeptide starts at amino terminus with methionine

2. Charged tRNAs aligned on mRNA by ribosome

3. Amino acids transferred from tRNA to growing polypeptide chain

4. Uncharged tRNA exits and can be attached to amino acid and be used again

Front 43

42. Energy requirements of protein synthesis

How many high-energy bonds are cleaved for each AA of a polypeptide?

Back 43

Formation of each aminoacyl-tRNA requires the equivalent of 2 high-energy phosphate bonds b/c ATP is converted to AMP and pyrophosphate, which is cleaved to form two inorganic phosphates.

As each AA is addded to the growing peptide chain, two GTPs are hydrolyzed, one at the step involving EF1 and the second at the translocation step.

Thus, 4 high-energy bonds are cleaved for each AA of the polypeptide.

Front 44

43. What are polysomes?

Back 44

As one ribosome moves along the mRNA, producing a polypeptide chain, a second ribosome can bind to the vacant 5' end of the mRNA.

Many ribosome can simultaneously translate a single mRNA, forming a complex known as a polysome.

Front 45

44. Ribosomes and polysomes

Back 45

A single ribosome covers approx 80 nucleotides of mRNA.

Therefore, ribosomes are positioned on mRNA at intervals of approx 100 nucleotides.

The growing polypeptide chains attached to the ribosomes become longer as each ribosome moves from the 5' end toward the 3' end of the mRNA.

Front 46

45. How are proteins processed?

Back 46

Nascent polypeptide chains (i.e. polypeptides that are in the process of being synthesized) are processed.

As they are produced, they travel through a tunnel in the ribosome, which can hold about 30 AA residues.

As polymerization of the chain progress, the AA residues at the N-terminal end begin to emerge from this protected region w/in the ribosome and to fold and refold into the 3-D conformation of the polypeptide.

Front 47

46. What mediates and helps the folding process?

What catalyzes disulfide bond formation?

Back 47

Proteins bind to the nascent polypeptide and mediate the folding process. These mediators are called chaperones b/c they prevent improper interactions from occurring.

Disulfide bond formation between cysteine residues is catalyzed by disulfide isomerases and may also be involved in producing the 3D structure of the polypeptide.

Front 48

47. What are the post-translational modification?

Back 48

The initial methionine is removed by specific proteases; methionine is not the N-terminal AA of all proteins.

Subsequently, other specific cleavages also may occur that convert proteins to more active forms.

In addition, AA residues w/in the peptide chain can be modified enzymatically to alter the activity or stability of the proteins, direct it to a subcellular compartment, or prepare it for secretion from the cell.

Front 49

48. . What are the 9 posttranslational modifications and what are the purpose of them?

Back 49

1. Carboxylation - (Glu) coagulation cascade
2. Hydroxylation (Pro, Lys) collagen stability
3. Phosphorylation (Ser, Thr, Tyr) enzyme activity
4. Glycosylation (Ser, Asn) secretion, membrane
5. Fatty acylation - membrane anchor
6. Prenylation - membrane anchor
7. ADP-ribosylation - enzyme activity
8. Methylation
9. Acetylation

Front 50

49. Targeting of proteins to subcellular and extracellular locations

Back 50

Proteins for secretion, membranes, organelles are often modified in ER and Golgi

Synthesized by ribosomes of rough ER:
-Signal peptide of nascent protein binds signal recognition particle (SRP)
-Docks with receptor on ER
-Protein enters ER lumen via pore, can be modified and enter secretion pathway

Front 51

50. What occurs in the Golgi and the ER?

Back 51

The Golgi complex serves to process the proteins it receives from the rER and to sort them so that they are delivered to their appropriate destinations.

Processing, which can be initiated in the ER, involves glycosylation, the addition of carbohydrate groups, and modification of existing carbohydrate chains.

Sorting signals permit delivery of proteins to their target locations.

Front 52

51. What is the KDEL sequence?

Back 52

Proteins containing the KDEL (lys-asp-glu-leu) sequence at their carboxyl terminal are returned to the ER from the Golgi.

Front 53

52. Mannose-6-phosphate

Back 53

Glycosylation fo enzymes destined to become lysosomal enzymes results in the presence of a mannose 6-phosphate residue on an oligosaccharide attached to the enzyme.

This residue is recognized by the mannose 6-phosphate receptor protein, which incorporates the enzyme into a clathrin-coated vesicle.

The vesicle travels to endosomes and is eventually incorporated into lysosome.

Front 54

53. Tay-sachs disease

Back 54

An insertion in exon 11 of the α-chain of the hexosaminidase A gene is the most common mutation found in Jews who have Tay-sachs disease.

Hexosaminidases are lysosomal enzymes that are necessary for the normal degradation of glycosphingolipids, such as the gangliosides.

Asa result, gangliosides are found in high concentrations in the nervous system, causing a wide array of neurologic disorders known as gangliosidoses. Eventually, symptoms include UMN and LMN deficits, visual difficulties, seizures, and increasing cognitive dysfunction.

Front 55

54. What is the cause of sickle cell anemia?

Back 55

Sickle cell anemia is caused by a missense mutation. In the sickle cell gene, GTG replaces the normal GAG.

Thus, in the mRNA, the codon GUG replaces GAG and a valine residue replaces a glutamate residue in the protein.

Front 56

55. Is it possible that people with thalassemia have either a nonsense mutation in codon 17 or a large deletion in the β-globin gene?

Back 56

A nonsense mutation at codon 17 would cuase a premature terminatino of translation.

A nonofunctional peptide containing only 16 AAs would result, producing a β⁰-thalassemia if the mutation occurred in both alleles.

A large deletion in the coding region of the gene could also produce a truncated protein.

Front 57

56. How do antibiotics work?

What about streptomycin?

Back 57

Many antibiotics are protein synthesis inhibitors.

These drugs take advantage of the differences between the mechanisms for proteins synthesis in prokaryotes and eukaryotes.

For example, streptomycin binds to the 16S rRNA of the 30S ribosomal subunit of prokaryotes. It interferes w/initiation of protein synthesis and causes misreading of mRNA.

Front 58

57. How does tetracycline work?

Back 58

Tetracycline binds to the 30S subunit of prokaryotes and inhibits binding of aminoacyl-tRNA to the A site of the ribosome.

Many bacteria are resistant.

Front 59

58. How do the macrolide antibiotics work?

Back 59

The macrolide antibiotics (e.g., erythromycin, clarithromycin) bind to the 50S subunit of bacteria and inhibit translocation.

Front 60

59. How does chloramphenicol work?

Back 60

Chloramphenicol is an antibiotic that interferes w/the peptidyltransferase activity of the 50S subunit of bacteria.

Can inhibit mitochondrial activity (this explains its toxicity)

Only used under SERIOUS conditions

Front 61

60. What is diphtheria?

Back 61

Diphtheria is a highly contagious disease caused by a toxin secreted by the bacterium Corynebacterium diphtheriae. Although the toxin is a protein, it is not produced by a bacterial gene, but by a gene brought into the bacterial cell by an infecting bacteriophage.

Front 62

61. What is the composition of the diphtheria toxin?

Back 62

The diphtheria toxin is composed of two protein subunits. The B subunit binds to a cell surface receptor, facilitating the entry of the A subunit into the cell. In the cell, the A subunit catalyzes a reaction in which the ADP ribose portion (ADPR) of NAD is transferred to EF2.

In this reaction, the ADPR is attached covalently to a posttranslationally modified histidine residue, known as diphthamide.

ADP-ribosylation of EF2 inhibits protein synthesis, leading to cell death.

Front 63

62. What is I-cell disease?

Back 63

I-cell disease (mucolipidosis II) is a disorder of protein targeting. Lysosomal proteins are not sorted properly form the Golgi to the lysososmes, and lysosomal enzymes end up being secreted from the cell.

This is b/c of a mutation in the enzyme N-acetylglucosamine phosphotransferase, which is a required first step for attaching the lysosomal targeting signal, mannose 6-phosphate, to lysosomal proteins.

Thus, lysosomal proteins cannot be targets to the lysosomes, and these organelles become clogged w/materials that cannot e digested, destroying overall lysosomal function.

This leads to a lysosomal storage disease of severe consequence.

Front 64

63. β-thalassemiass

Back 64

In β⁰-thalassemia, little or none of the Hgb β-chain is produced.

β-thalassemia intermedia is usually the result of two different mutations, or, less frequently, homozygosity for a mild mutation in the rate of synthesis, or a complex combo of mutations

Front 65

64. What are topoisomerases?

Back 65

These enzymes catalyze DNA replication and segregation by breaking, rotating, and religating DNA strands.

The enzymes that have been most successfully targeted by antibiotics are topoisomerases.

Front 66

65. What are the two types of topoisomerases?

Back 66

1. Type 1
-form and reseal single-stranded breaks in DNA to decrease positive supercoiling.

2. Type 2
-performs nuclease and ligase operations on both strands of DNA.

Front 67

66. What are the similarities/differences between types 1 and 2 topoisomerases?

Back 67

Both types of topoisomerases can remove excess DNA supercoils during DNA replication.

However, only type 2 topoisomerases can resolve intertwined copies of double-stranded DNA to permit segregation of the DNA to daughter cells.

Type 2 enzymes are both more complex and more versatile than type 1 topoisomerases, and the type 2 enzyme serves as a more frequent molecular target for chemotherapeutic agents.

Front 68

67. What is the MOA of a type 2 topoisomerase?

Back 68

1. The enzyme binds to a segment of DNA and forms covalent bonds w/phosphates form each strand, thereby nicking both strands.

2. The enzyme causes a second stretch of DNA from the same molecule to pass through the break, relieving supercoilding.

This passage of double-stranded DNA through a double stranded break is what permits separation of intertwined copies of DNA following replication, and thereby, segregation of DNA into progeny cells.

Front 69

68. What are the two main bacterial type 2 topoisomerases?

Back 69

1. DNA gyrase
2. Topoisomerase IV

DNA gyrase is particularly crucial for segregation in some bacteria, while topoisomerase IV is the critical enzyme in other bacteria.

Front 70

69. What enzyme catalyzes transcription?

How is this different in prokaryotes/eukaryotes?

Back 70

RNA polymerase.

In bacteria, one RNA polymerase synthesizes all the RNA in the cell. Furthermore, bacterial RNA polymerase is composed of only five subunits.

In contrast, eukaryotes express three different RNA polymerases, and each enzyme is considerably more complex in its subunit structure than the bacterial counterpart.

Front 71

70. What are inhibitors of toposiomerases called?

Back 71

Quinolones.

Quinolones are a major class of bactericidal antibiotics that act by inhibiting bacterial type II topoisomerases.

Front 72

71. MOA of quinolones

Back 72

Quinolones act by inhibiting one or both fo the two prokaryotic type 2 topoisomerases in sensitive bacteria, DNA gyrase and topoisomerase IV.

Quinolones primarily inhibit DNA gyrase in Gram-negative organisms, and they inhibit topoisomerase IV in Gram-positive organisms such as S. aureus.

Front 73

72. Quinolone activity at low vs. high concentrations

Back 73

At low concentrations, quinolones inhibit type II topoisomerases reversibly, and their action is bacteriostatic.

At higher concentrations, however, quinolone convert the topoisomerases into DNA-damaging agents by stimulating dissociation of the enzyme subunits form the broken DNA.

Doubly-nicked DNA cannot be replicated, and transcription cannot proceed through such breaks. Topoisomerase dissociation from the DNA and/or the bacterial response to the double stranded break lead ultimately to cell death.

Thus, at therapeutic doses, the quinolone antibiotics are bactericidal.

Front 74

73. What are the names of the quinolones?

Back 74

1. Ciprofloxacin
2. Gatifloxacin
3. Levofloxacin
4. Moxifloxacin
5. Norfloxacin
6. Ofloxacin

Front 75

74. What are the quinolones used to treat?

Back 75

They are widely used to treat common urogenital, respiratory, and GI infections caused by E. coli, Klebsiella pneumoniae, Campylobacter jejuni, Pseudomonas aeruginosa, Neisseria gonorrhoeae, and Enterobacter, Salmonella, and Shigella species.

Front 76

75. Ciprofloxacin

Back 76

MOA: Inhibits prokaryotic type 2 topoisomerases. At therapeutic doses, it has a bactericidal effect by causing double-stranded DNA breaks and cell death.

PURPOSE: Gram-negative infections

ADVERSE: Cartilage damage, tendon rupture, peripheral neuropathy, increased ICP, seizure, severe hypersensitivity reaction, rash, GI disturbance

CONTRA: Concomitant tizanidine administration and hypersensitivity to quinolones

NOTES: Avoid coadministration of thioridazine due to increased risk of cardiotoxicity.

Front 77

76. Gatofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin

Back 77

MOA: Inhibits prokaryotic type 2 topoisomerases. At therapeutic doses, it has a bactericidal effect by causing double-stranded DNA breaks and cell death.

PURPOSE: Gram-negative infections

ADVERSE: Cartilage damage, tendon rupture, peripheral neuropathy, increased ICP, seizure, severe hypersensitivity reaction, rash, GI disturbance

CONTRA: Hypersensitivity to quinolones

NOTES: Avoid coadministration of thioridazine due to increased risk of cardiotoxicity.

Front 78

77. How do bacterial evolve resistance to the quinolones?

Back 78

Bacteria evolve resistance through chromosomal mutations in the genes that encode type 2 topoisomerases, or through alterations in the expression of membrane porins and efflux pumps that determine drug levels inside the bacteria.

Front 79

78. What are the inhibitors of transcription called?

Back 79

Rifamycin derivatives, such as:

1. Rifabutin
2. Rifampin

These are semisynthetic derivatives of the naturally occurring antibiotic rifamycin B.

Front 80

79. Rifampin

Back 80

MOA: Form a stable complex w/bacterial DNA-dependent RNA polymerase, thereby inhibiting RNA synthesis. It targets the β-subunit of bacterial RNA polymerase.

PURPOSE: Prophylaxis of meningococcal disease and for mycobacterial infections, including tuberculosis

ADVERSE: Thrombocytopenia, hepatotoxicity, saliva, tear, sweat and urine discoloration, influenza like illness, elevated LFTs, GI disturbance

CONTRA: Active Neisseria meningitidis infection

Front 81

80. Rifampin NOTES

Back 81

NOTES: Particularly effective against phagosome-dwelling mycobaceria b/c it is bactericidal for intracellular as well as extracellular bacteria.

Rifampin increases the in vitro activity of isoniazid

Displays high selectivity for bacteria, so it is generally well tolerated, and the incidence of adverse effects is low.

Rifampin is not used as a single angent b/c of rapid development of resistance

May reduce cyclosporine concentration and efficacy

Front 82

81. Rifabutin

Back 82

MOA: Form a stable complex w/bacterial DNA-dependent RNA polymerase, thereby inhibiting RNA synthesis. It targets the β-subunit of bacterial RNA polymerase.

PURPOSE: Mycobacterial infections, including tuberculosis

ADVERSE: Thrombocytopenia, hepatotoxicity, saliva, tear, sweat and urine discoloration, influenza like illness, elevated LFTs, GI disturbance

CONTRA: Active Neisseria meningitidis infection

NOTES: Avoid concurrent administration of clarithromycin w/rifabutin, b/c clarithromycin increases plasma concentration of rigabutin and rifabutin reduces plasma concentration of clarithromycin

Front 83

82. What are three general consideration that apply to inhibitors of bacterial translation?

Back 83

1. Translation inhibitors target either the 30S or 50S subunit of the bacterial ribosome.

2. In addition to their inhibitor effects on bacterial ribosomes, protein synthesis inhibitors can affect mammalian mitochondrial ribosomes, cytosolic ribosomes, or both.

3. Complete inhibition of protein synthesis is not sufficient to kill a bacterium.

Front 84

83. What is the most common mechanism by which inhibitors of translation cause adverse effects?

Back 84

Through inhibition of host ribosomes.

Front 85

84. What are the three categories of drugs that target the 30S ribosomal subunit?

Back 85

1. Aminoglycosides
2. Spectinomycin
3. Tetracyclines

Front 86

85. What are aminoglycosides?

What are the names of the aminoglycosides?

Back 86

Aminoglycosides are used mainly to treat infections caused by Gram-negative bacteria. These agents are charged molecules that are not orally bioavailable so they must be administered parenterally.

They include:
1. Streptomycin
2. Amikacin
3. Gentamicin
4. Kanamycin
5. Neomycin
6. Netilmicin
7. Paromomycin
8. Tobramycin

Front 87

86. Aminoglycosides

Back 87

MOA: Bind to 16S rRNA of the 30S subunit and elicit concentration-dependent effects on protein synthesis. Aminoglycosides are bactericidal due to induction of mRNA misreading; misread mRNA causes synthesis of aberrant proteins that insert into membrane, forming pores that eventually lead to cell death.

PURPOSE: Serious Gram-negative infections

ADVERSE: Ototoxicity, acute renal failure, neuromuscular blockage, respiratory paralysis

CONTRA: Hypersensitivity to aminoglycosides

NOTES: Act synergistically w/β-lactam antibiotics

Front 88

87. What are the three mechanisms by which bacteria can become resistant to aminoglycosides?

Back 88

1. Plasmid-encoded production of a transferase enzyme or enzymes that inactivate aminoglycosides.

2. Impaired drug entry, possibly by alteration or elimination of porins or other proteins involved in drug transport.

3. Mutation of the drug target on the 30S ribosomal subunit.

Front 89

88. What is the David model?

Back 89

The David model frames the story of cell death in terms of the concentration dependent effects of aminoglycosides.

When drug first enters the cell, it is poorly transported across bacterial membranes. At these initial low concentrations, misreading occurs, leading to synthesis of aberrant proteins. Some of these proteins insert into membranes and cause the formation of membrane pores, which allow aminoglycosides to flood the cell and halt protein synthesis completely.

As a result, the damage to the membrane cannot be repaired, and leakage of ions and, later, larger molecules leads to cell death.

Front 90

89. What is the single most important factor restricting aminoglycoside use?

Back 90

Ototoxicity (manifesting as either auditory or vestibular damage).

The aminoglycosides are known to accumulate in the perilymph and endolymph of the inner ear and at high concentrations, to damage highly sensitive hair cells.

Aminoglycosides can also cause acute renal failure, apparently as a result of drug accumulation in proximal tubular cells.

Front 91

90. Spectinomycin

Back 91

MOA: Structural relative of the aminoglycosides that also binds to the 16S rRNA of the 30S ribosomal subunit. Spectinomycin permits formation of the 70S complex but inhibits translocation. It is not bactericidal but is bacteriostatic.

PURPOSE: Alternative therapy for gonorrheal infections

ADVERSE: Injection site pain, nausea, dizziness, insomnia

CONTRA: Hypersensitivity to spectinomycin

Front 92

91. What are tetracyclines and what are their names?

Back 92

Tetracyclines are broad-spectrum, bacteriostatic antibiotics that are used widely.

They are:
1. Chlortetracycline
2. Demeclocycline
3. Doxycycline
4. Methacycline
5. Minocycline
6. Oxytetracycline
7. Tetracycline

Front 93

92. MOA of tetracyclines

Back 93

Tetracyclines bind reversibly to the 16S rRNA of the 30S subunit and inhibit protein synthesis by blocking the binding of aminoacyl tRNA to the A site on the mRNA ribosome complex.

This action prevents the addition of further AAs to the nascent peptide.

Front 94

93. What is the reason for the high selectivity of tetracyclines in bacteria?

Back 94

The high selectivity derives from active accumulation of these drugs in bacteria but not in mammalian cells.

Tetracyclines enter Gram-negative bacteria by passive diffusion through porin protein in the outer membrane, followed by active transport across the inner cytoplasmic membrane.

In contrast, mammalian cells lack the active transport system found in susceptible bacteria.

Front 95

94. Tetracyclines

Back 95

MOA: Bind reversibly to the 16S rRNA of the 30S subunit and inhibit protein synthesis by blocking the binding of aminoacyl tRNA to the A site on the mRNA ribosome complex.

PURPOSE: Used to treat a variety fo infections, including Corynebacterium acnes, Haemophilus influenze, Vibrio cholerae, spirochetes, Mycoplasma pneumoniae, Chlamydia species, and rickettsial species. Also used for malaria prophylaxis (doxycycline).

ADVERSE: Bulging fontanelle, discoloration and hypoplasia of teeth and temporary stunting of growth, hepatotoxicity, pseudotumor cerebri, photosensitivity, rash, GI disturbance, vestibular disturbance (minocycline), candidal infection.

CONTRA: Last half of pregnancy, infancy, < 8 y/o; patients with sever renal impairment should not be treated w/any tetracyclines except for doxycycline.

Front 96

95. How does tetracycline resistance occur?

Back 96

Tetracycline resistance occurs by plasmid-encoded efflux pumps, production of proteins that interfere w/binding of tetracyclines to the ribosome, or enzymatic inactivation of tetracyclines.

Front 97

96. Important pharmacokinetic feature of tetracyclines

What do tetracyclines have to do with acitretin?

Back 97

Interaction of these drugs w/foods high in calcium.

B/c these products and medicines impair the absorption of tetracyclines, the tetracyclines are generally taken on an empty stomach.

Once they are in the circulation, however, the same interaction w/cations, can cause sequestration of the drugs in bone and teeth.

*Also, avoid coadministration with acitretin due to increased risk of elevated ICP

Front 98

97. What are the two most problematic adverse effects of the tetracyclines?

Back 98

Kideny toxicity and GI distress.

Nausea and vomiting are the most common reasons for premature discontinuation of a course of tetracycline.

Front 99

98. What's so special about doxycycline?

Back 99

Compared w/other tetracyclines, a lower fraction of doxycycline is eliminated via the kidney, making this drug safer for use in patients w/renal failure.

Also, doxycycline is excreted in the feces largely in an inactive form, so this agent has the added advantage of minimally altering intestinal flora.

Hence, doxycline use is associated w/a lower incidence of nausea, vomiting, and superinfection w/pathogenic organisms than the other tetracyclines, especially in an immunocompromised patient.

Front 100

99. What are the glycylcyclines?

Back 100

They are a new class of antibiotics.

It includes Tigecycline, which has a broad spectrum of activity and has been approved for IV administration in the treatment of serious skin and abdominal infections.

Front 101

100. Tigecycline

Back 101

MOA: Resembles that of the tetracyclines; Bind reversibly to the 16S rRNA of the 30S subunit and inhibit protein synthesis by blocking the binding of aminoacyl tRNA to the A site on the mRNA ribosome complex. It is bacteriostatic.

PURPOSE: Skin or subcutaneous infection, complicated abdominal infection

ADVERSE: GI disturbance

CONTRA: Hypersensitivity to tigecycine

Front 102

101. What are the five categories of antibiotics that target the 50S ribosomal subunit?

Back 102

1. Macrolides and ketolides
2. Chloramphenicol
3. Lincosamides
4. Streptogramins
5. Oxazolidinones

Front 103

102. What are macrolides?

What is their MOA?

Back 103

Macrolides are named for their large lactone rings. They are especially important in the treatment of pulmonary infections, including Legionnaire's disease.

They are bacteriostatic antibiotics that block the translocation step of protein synthesis by targeting the 23S rRNA of the 50S subunit. Macrolides bind to a specific segment of 23S rRNA and block the exit tunnel form which nascent peptides emerge.

Front 104

103. What are the names of the macrolides and ketolides?

Back 104

1. Azithromycin
2. Clarithromycin
3. Erythromycin
4. Telithromycin

Front 105

104. What is erythromycin used to treat?

Back 105

Erythromycin is used to treat a variety fo infections, notably those due to Corynebacterium acnes, Legionella pneumophila, Treponema pallidum (syphilis), Mycoplasma pneumoniae, and Chlamydia species

Front 106

105. What is clarithromycin used to treat?

Back 106

Clarithromycin has increased activity against H.. influenzae.

Front 107

106. What is azithromycin used to treat?

Back 107

Azithromycin has increased activity against H. influenzae and Moraxella catarrhalis.

Front 108

107. Adverse effects and contraindications of macrolides and ketolides

Back 108

ADVERSE: Acute cholestatic hepatitis, ototoxicity, fulminant hepatic necrosis (rare, telithromycin), and GI disturbance

CONTRA: Hepatic dysfunction

Front 109

108. How is resistance accomplished by bacteria against macrolides?

Back 109

Resistance can be onferred by chromosomal mutations leading to alteration of the 50S ribosomal binding site, production of methylases that alter the 50S binding site, or production of esterases that degrade macrolides.

Front 110

109. What is the most frequent reason for discontinuing erythromycin?

Back 110

GI intolerance, as the drug can directly stimulate gut motility and cause nausea, vomiting, diarrhea, and sometimes anorexia.

Azithromycin and clarithromycin are generally well tolerated, although these drugs can also cause liver impairment.

Front 111

110. What are the pharmacological interactions with macrolide use?

Back 111

Macrolides and ketolides inhibit hepatic metabolism of cyclosporine, carbamazepine, warfarin, and theophylline, and can lead to toxic levels of these drugs.

Macrolides eliminate certain species of intestinal flora that inactivate digoxin, thereby leading to greater oral absorption of digoxin in some patients.

Front 112

111. Telithromycin

Back 112

This is the ketolide that has a MOA similar to that of the macrolides, but w/a higher affinity for the 50S ribosomal subunit due to its ability to bind an additional site on 23S rRNA.

This higher affinity allows the use of telithromycin in treating infections due to certain bacterial strains that are resistant to macrolides.

Front 113

112. Chloramphenicol

Back 113

MOA: Binds to 23S rRNA and inhibits peptide bond formation, apparently by occupying a site that interferes w/proper positioning of the aminoacyl moiety of tRNA in the A site.

PURPOSE: Bacteriostatic broad-spectrum antibiotic that is effective against Gram+ and Gram- bacteria (especially anaerobes), and rickettsiae.

ADVERSE: Hemolytic anemia in patients with low levels of G6PD, aplastic anemia, gray baby syndrome

CONTRA: Hypersensitivity to chloramphenicol

NOTES: Most adverse effects are due to inhibition of mitochondrial function.

Front 114

113. What are the organisms most highly susceptible to chloramphenicol treatment?

Back 114

1. Haemophilus influenzae
2. Neisseria meningitidis
3. Some strains of Bacteriodes

This drug is still used occasionally in the treatment of typhoid fever, bacterial meningitis, and rickettsial diseases, but only when safer alternatives are not available.

Front 115

114. How have microbes developed resistance to chloramphenicol?

Which two mechanisms are at work here...?

Back 115

1. Low level resistance has emerged by the selection of mutants w/decreased permeability to the drug.

2. More clinically significant is the type of resistance that has arisen from the spread of specific plasmid-encoded acetyltransferases that inactivate the drug.

Front 116

115. What is the gray baby syndrome?

Back 116

Occurs when chloramphenicol is administered at high doses to newborn infants.

B/c newborns lack an effective glucuronic acid conjugation mechanism for the degradation and detox of chloramphenicol, the drug can accumulate to toxic levels and cause vomiting, hypothermia, gray color, respiratory distress, and metabolic acidosis.

Front 117

116. What are the pharmacologic interactions with chloramphenicol?

Back 117

Cloramphenicol antagonizes the bactericidal effects of penicillins and aminoglycosides

Like the macrolides, it also inhibits hepatic metabolism of warfarin, phenytoin, tolbutamide, and chlorpropamide, and thereby potentiates their effects.

Front 118

117. Lincosamides: clindamycin

Back 118

MOA: Clindamycin blocks peptide bond formation, apparently through interactions with both the A site (like chloramphenicol) and the P site.

PURPOSE: Bacterial infections due to anaerobic organisms

ADVERSE: Psuedomembranous colitis, increased liver function tests, jaundice, GI disturbance, rash

CONTRA: Hypersensitivity to clindamycin

*NOTES: Clindamycin is associated w/overgrowth of C. difficile, which can result in pseudomembranous colitis.

Front 119

118. What are the drugs that are mixed in streoptogramins?

Back 119

1. Dalfopristin, a group A steptogramin

2. Quinupristin, a group B streptogramin

Front 120

119. Streptogramins

Back 120

MOA: Inhibit protein synthesis by binding to the peptidyl transferase center of bacterial 23S rRNA.

PURPOSE: Vancomycin-resistant enterococcus (VRE) infection, skin and subcutaneous infection caused by staphylococcal or streptococcal species.

ADVERSE: Injection site inflammation, GI disturbance, hyperbilirubinemia, arthralgia, myalgia, headache

NOTES: Should not be coadministered w/SSRIs, due to risk of serotonin syndrome. Coadministration with pimozide should be avoided due to increased risk fo cardiotoxicity

Front 121

120. How are streptogramins unusual among the 50S antibiotics?

Back 121

They are bactericidal against many, but not all, susceptible bacterial species.

Current hypothesis is that, unlike other 50S antibiotics, the streptogramins induce a conformational change in the ribosome that is reversible only after subunit dissociation.

Front 122

121. Oxazolidinones: Linezolid

Back 122

MOA: Linezolid appears to act at the 50S ribosomal subunit b/c mutations in 23S rRNA can confer drug resistance.

PURPOSE: Gram+ bacterial infections, especially VRE, MRSA, S. agalactiae, S. pneumoniae (including multi-drug resistant strains) and S. pyogenes, nosocomial pneumonia, complicated diabetic foot infections

ADVERSE: Myelosuppression, peripheral neuropathy, optic neuropathy

CONTRA: Hypersensitivity to linezolid

NOTES: Available in both oral and IV formulation; precise mechanism of action remains uncertain.

Front 123

122. Cystic fibrosis (CF)

Back 123

Most common lethal genetic disease affecting whites.

It affects epithelial ion transport resulting in abnormal fluid secretion in exocrine glands and in respiratory, GI and reproductive mucosa.

Front 124

123. Gene responsible for CF and consequences of mutations in this gene

Back 124

The gene responsible for CF encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein.

CFTR regulates the movement of multiple ions as well as affecting other cellular processes; however, CFTR is primarily a chloride channel, and mutations in the CFTR gene disrupt epithelial chloride transport.

Thus, normal sweat ducts require CFTR for resorption of chloride; inability to resorb chloride causes increased sweat chloride concentration

Front 125

124. What is the primary defect in cystic fibrosis?

Back 125

The primary defect in cystic fibrosis results from abnormal function of an epithelial chloride channel protein encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome ban 7q31.2.

Front 126

125. CFTR

Back 126

Has two transmembrane domains, two nucleotide binding domains, and a regulatory domain that contains protein kinase phosphorylation sites.

Various mutations in the CF gene affect different regions of CFTR, resulting in distinct functional consequences and differing severity of clinical sequelae.

Front 127

126. Activation of the CFTR channel is mediated by what...?

Back 127

Activation of the CFTR channel is mediated by agonist induced increases in cAMP, followed by activation of a protein kinase A.

Front 128

127. What does CFTR regulate?

Back 128

CFTR regulates multiple additional ion channels and cellular processes.

It not only regulates chloride-conductance channels, but it also regulates, the potassium channels, the epithelial sodium channels (ENaC), gap junction channels, and cellular processes involved in ATP transport and mucus secretion.

Front 129

128. Of all the ion channels CFTR regulates, which one has possibly the most pathophysiolgic relevance in cystic fibrosis?

Back 129

The interaction of CFTR with ENaC.

The ENaC is situated on the apical surface of exocrine epithelial cells, and is responsible for intracytoplasmic sodium transport from the luminal fluid, rendering it (the luminal fluid) hypotonic.

The ENaC is inhibited by normally functioning CFTR; hence in cystic fibrosis, ENaC activity increases, markedly augmenting sodium transport across the apical membrane.

Front 130

129. What is the exception to this increased in sodium transport across the apical membrane in CF?

Back 130

In human sweat ducts, where ENaC activity decreases as a result of CFTR mutations; therefore, a hypertonic luminal fluid containing both high sweat chloride and high sodium content is formed.

Front 131

130. What is CFTR's role in the respiratory and intestinal epithelium?

Back 131

CFTR forms one of the most important avenues for active luminal secretion of chloride. At these sites, CFTR mutations result in loss or reduction of chloride secretion into the lumen.

Active luminal sodium absorption is also increased (due to loss of inhibition of ENaC activity)

Front 132

131. So, a decreased chloride secretion and increased sodium absorption at the luminal membrane leads to what...?

Back 132

Both of these ion changes increase passive water reabsorption from the lumen, lowering the water content of the surface fluid layer coating mucosal cells.

Front 133

132. So what causes the pathogenesis of respiratory and intestinal complications in CF?

Back 133

These problems appear to stem from an isotonic but low-volume surface fluid layer.

In the lungs, this dehydration leads to defective mucociliary action and the accumulation of hyperconcentrated, viscid secretions that obstruct the air passages and predispose to recurrent pulmonary infections.

Front 134

133. What does CFTR have to do with bicarbonate ions?

Back 134

CFTR can also transport bicarbonate ions, and in some CFTR mutant variants, chloride transport is completely or substantially preserved, while bicarbonate transport is markedly abnormal.

This leads to a decrease luminal pH which can cause adverse effects such as increased mucin precipitation and plugging of ducts, and increased binding of bacteria to plugged mucins.

Pancreatic insufficiency, a feature of classic CF, is virtually always present when there are CFTR mutations with abnormal bicarbonate conductance.

Front 135

134. What are the six classes of CFTR mutations?

Back 135

Class 1. Defective protein synthesis
Class 2. Abnormal protein folding, processing, and trafficking
Class 3. Defective regulation
Class 4. Decreased conductance
Class 5. Reduced abundance
Class 6. Altered regulation of separate ion channels

Front 136

135. What is the most common mutation in CF?

Back 136

A class 2 mutation that leads to a three-nucleotide deletion coding for phenylalanine at position F508;

This results in defective intracellular CFTR processing w/degradation before it reaches the cell surface.

Patients homozygous for the F508 mutation have virtual absence of CFTR function; they present w/severe disease.

This mutation can be found in approx 70% of CF patients.

Front 137

136. Which classes are usually associated with a milder phenotype of CF?

Back 137

Classes 4 and 5

These classes have mutations on one or both alleles that results in a less sever phenotype.

Front 138

137. Which classes are usually associated with a more severe phenotype of CF?

Back 138

Classes 1, 2, and 3 mutations produce virtual absence of membrane CFTR and are associated with the classic CF phenotype (pancreatic insufficiency, sinopulmonary infections, and GI symptoms).

Front 139

138. Individuals that present with what unrelated clinical phenotypes may also harbor CFTR mutations?

Back 139

1. Idiopathic chronic pancreatitis
2. Late-onset chronic pulmonary disease
3. Idiopathic branchiectasis
4. Obstructive azoospermia caused by BAVD

These patients my not demonstrate other features of CF, yet they harbor bi-allelic CFTR mutations. These subsets are classified as non-classic or atypical CF.

Front 140

139. What other genes play a role in modifying the frequency and severity of organ-specific manifestations?

Back 140

A cystic fibrosis modifier locus (CFM1) which influences the incidence and severity of meconium ileus has been recently mapped to chromosome 19q13.

Another candidate genetic modifier is mannose-binding lectin, a key effector of innate immunity involved in opsonization and phagocytosis of microorganisms. Functional polymorphisms in one or both mannose-binding lectin alleles associated with lower circulating levels of the protein confer a 3x higher risk of end-stage lung disease and reduced survival following chronic bacterial infection in the setting of CF.

Front 141

140. What environmental modifiers might also cause significant phenotypic differences in the CFTR genotype?

Back 141

In pulmonary disease, concurrent viral infection predispose to colonization of pseudomonas aeruginosa species.

The static mucus creates a hypoxic microenvironment in the airway surface fluid, which in turn favors the production of alginate, a mucoid polysaccharide capsule.

Alginate production protects bacteria from antibodies or antibiotics, allowing them to evade host defenses and cause chronic destructive lung disease.

Front 142

141. CF and pancreas

Back 142

Abnormalities occur in 85-90% of patients; they range from mucus accumulation in small ducts w/mild dilation to total atrophy of the exocrine pancreas, leaving only islets within fibrofatty stroma.

Absence of pancreatic exocrine secretions impairs fat absorption; resulting deficiency of vitamin A occurs

Front 143

142. CF and intestines

Back 143

Thick viscous plugs of mucus (meconium ileus) may cause small intestinal obstruction

Front 144

143. CF and liver

Back 144

Plugging of bile canaliculi by mucinous material results in diffuse hepatic cirrhosis.

Hepatic steatosis is not an uncommon finding in liver biopsies.

Front 145

144. CF and salivary glands

Back 145

Commonly involved w/progressive duct dilation, ductal squamous metaplasia, and glandular atrophy followed by fibrosis.

Front 146

145. CF and lungs

Back 146

Involved in most cases and such changes are the most serious complication of CF.

Mucus secreting cells hyperplasia and viscous secretions block and dilate bronchioles.

Superimposed infections and pulmonary abscesses are common, and these give rise to chronic bronchitis and bronchiectasis. In many instances lung abscesses develop.

Front 147

146. What are the three most common organisms responsible for lung infections in CF?

Back 147

1. Staphylococcus aureus
2. Hemophilus influenzae
3. Pseudomonas aeruginosa

Front 148

147. CF and male genital tract

Back 148

Azoospermia and infertility occur in 95% of males surviving to adulthood, frequently w/congenital bilateral absence of the vas deferens (CBAVD).

Front 149

148. Clinical course of CF

Back 149

1. Pancreatic exocrine insufficiency
2. Malabsorption of fats
3. Steatorrhea
4. Fat soluble vitamin deficiencies
5. Cardiorespiratory complications
-chronic cough
-lung infections
-COPD
-cor pulmonale

Front 150

149. Pancreas insufficient phenotype in CF

Back 150

Pancreatic exocrine insufficiency occur in the majority of patients w/CF and is associated w/severe CFTR mutations on both alleles (F508/F508).

Front 151

150. Pancreas sufficient phenotype in CF

Back 151

Those with one severe and one mild CFTR mutation (F508/R117H), or two mild CFTR mutations retain enough pancreatic exocrine function so as not to require enzyme supplementation.

The pancreas sufficient phenotype is usually not associated w/other GI complications and in general these individuals demonstrate excellent growth and development.

Front 152

151. What is the single most common cause of death (~80%) in CF patients?

Back 152

Cardiorespiratory complications, such as persistent lung infections, obstructive pulmonary disease, and cor pulmonale.

Front 153

152. After cardiorespiratory complications, what is the next most common cause of death in CF patients?

Back 153

Liver disease.

Most studies suggest that symptomatic or biochemical liver disease in CF has its onset at or around puberty, w/a prevalence of 13-17%.

Front 154

153. Dx of CF

Back 154

Sequencing of the CFTR gene is the gold standard.

The Dx can be based on elevated sweat electrolyte concentrations > 60 mM/L.

Measurement of nasal transepithelial potential difference in vivo can also be useful, as individuals w/CF demonstrate significantly more negative baseline nasal potential difference than controls.

Front 155

154. What are common causes of laryngitis and tracheitis?

Back 155

Usually, the cause is a parainfluenza virus, but sometimes it is RSV, influenza virus, or an adenovirus. Diphtheria may involve the larynx or trachea.

Front 156

155. What are less common causes of laryngitis and tracheitis?

Back 156

Bacteria such as group A streoptocci, H. influenzae, and S. aureus are less common causes of laryngitis and tracheitis.

Front 157

156. Symptoms of laryngitis and tracheitis

Back 157

Laryngeal infection and tracheitis cause hoarseness and a burning retorsternal pain.

The larynx and trachea have non-expandable rings of cartilage in the wall, and are easily obstructe din children b/c of their narrowness.

Swelling of the mucous membrane may lead to a dry cough and inspiratory stridor known as croup.

Difficulty w/respiration may lead to hospitalization.

Front 158

157. What is diphtheria?

Back 158

Diphtheria is caused by toxin-producing strains of Corynebacterium diphtheriae and can cause life threatening respiratory obstruction.

Non-toxigenic strains occur in the normal pharynx, but bacteria producing the extracellular toxin must be present to cause the disease. They can colonize the pharynx, the larynx, the nose and occasionally the genital tract and the skin.

Front 159

158. What is the false membrane in diphtheria?

Back 159

The bacteria multiply locally w/o invading deeper tissues or spreading throughout the body.

The toxin destroys epithelial cells and polymorphs, and an ulcer forms, which is covered w/a necrotic exudate forming a false membrane.

This soon becomes dark and malodorous, and bleeding occur on attempt to remove it.

Front 160

159. What is the most severe form of diphtheria?

Back 160

Nasopharyngeal diphtheria is the most severe form of the disease.

When the larynx is involved, ti can result in life-threatening respiratory obstruction.

Anterior nasal diphtheria is a mild form of the disease if it occurs on its own.

Front 161

160. What are the effects of the diphtheria toxin?

Back 161

1. Constitutional upset, w/fever, pallor, exhaustion

2. Myocarditis, usually w/in the first 2 weeks. ECG changes are common and cardiac failure can occur. If this is not lethal, complete recover is usual.

3. Polyneuritis, which may occur after the onset of illness, due to demyelineation. Can affect CN IX.

Front 162

161. How is diphtheria treated?

Back 162

As soon as the Dx is suspected, the patient is isolated, and the treatment is begun w/antitoxin. The antitoxin is produced in horses.

Penicillin or erythromycin is given as an adjunct. Laryngeal diphtheria may require a tracheotomy to assist w/respiration.

Front 163

162. Diphtheria toxin composition

Back 163

Has two parts:
1. Fragment B (binding) at the carboxyl end which attaches the toxin to the host cells

2. Fragment A (active) at the amino end, which is the toxic fragment.

Front 164

163. What forms the Fragment A in the diphtheria toxin?

Back 164

Fragment A is only formed by protease cleavage and reduction of disulfide bonds after cellular uptake of the toxin.

Fragment A inactivates EF-2 by ADP ribosylation and thereby inhibits protein synthesis.

Prokaryotic and mitochondrial protein synthesis are not affected b/c a different EF is involved.

For some reason, myocardial and peripheral nerve cell are particularly susceptible.

Front 165

164. What is the whooping cough?

Back 165

Whooping cough is caused by the bacterium Bordetella pertussis.

Bordetella pertussis is confined to humans and is spread form person to person by air-borne droplets.

Bordetella pertussis infection is associated w/the production of a variety of toxic factors

Front 166

165. What are the four toxic factors produced by a Bordetella pertussis infection?

Back 166

1. Pertussis toxin, which resembles diphtheria and other toxins with a A and B subunit.

2. Adenylate cyclase toxin, which is a single peptide that can enter host cells and cause them to increase their cAMP to supraphysiologic levels. The result is inhibition of chemotaxis, phagocytosis, and bactericidal killing.

3. Tracheal cytotoxin, which is a cell wall component derived from the peptidoglycan of Bordetella pertussis that specifically kills tracheal epithelial cells

4. Endotoxin, which differs from the classic endotoxin of other Gram- rods, but has functional similarities and may play a role in the pathogenesis of infection.

Front 167

166. What are the symptoms of whooping cough?

Back 167

Bordetella pertussis infection is characterized by paroxysms of coughs followed by a whoop. After an incubation period of 1-3 weeks, B. pertussis infection is manifest first as a catarrhal illness w/little to distinguish it from other URI.

This is followed up to 1 week later by a dry non-productive cough, which becomes paroxysmal.

A paroxysm is characterized by series of short coughs producing copious mucus, followed by a whoop.

Front 168

167. What are some complications of Bordetella pertussis infections?

Back 168

Complications include CNS anoxia, exhaustion and secondary pneumonia due to invasion of the damaged respiratory tract by other pathogens.

Front 169

168. What is the treatment for whooping cough?

Back 169

Supportive care is of prime importance.

Erythromycin is the drug of choice.

Erythromycin prophylaxis of close contacts of active cases is helpful in controlling the spread of infection.

Front 170

169. What vaccines are currently used to prevent Bordetella pertussis?

Back 170

Accelular pertussis vaccines have replaced the whole cell vaccine as they provide the same or better protection.

The acellular vaccines contain pertussis toxoid and other bacterial components; they cause fewer side effects as they are highly purified w/much reduced levels of endotoxin compared w/whole cell vaccines.

Front 171

170. What is acute bronchitis?

What are the causes?

Back 171

Acute bronchitis is an inflammatory condition of the tracheobronchial tree, usually due to infection.

Causative agents include rhinoviruses and coronaviruses, which as also found infecting the upper respiratory tract, and lower tract pathogens such as influenza virus, adenoviruses, and Mycoplasma pneumoniae.

Front 172

171. What are the secondary bacterial infections that may play a role in forming acute bronchitis?

Back 172

1. Streptococcus pneumoniae
2. Haemophilus influenzae

Front 173

172. What if the influenza virus causes the acute bronchitis?

Back 173

W/influenza virus infection, it may be extensive and leave the host prone to secondary bacterial invasion.

Front 174

173. What if Mycoplasma pneumoniae infection causes the acute bronchitis?

Back 174

Specific attachment of the organism to receptors on the bronchial mucosal epithelium and the release of toxic substances by the organism results in sloughing of affected cells.

A dry cough is the most prominent presentation, and treatment is largely symptomatic.

Treatment involves antibiotics such as tetracyclines or macrolides.

Front 175

174. What things lead to an acute exacerbation of chronic bronchitis?

Back 175

Chronic bronchitis is a condition characterized by cough and excessive mucus secretion.

Infection appear to be only one component of the syndrome, the others being cigarette smoking and inhalation of dust or fumes from the workplace.

Front 176

175. What organisms are most freq implicated in acute exacerbation of chronic bronchitis?

Back 176

1. S. pneumoniae
2. Haemophilus influenzae

Front 177

176. What is bronchiolitis?

Back 177

Bronchiolitis is a disease restricted to childhood, and usually to children under 2 years of age.

The bronchioles become swollen by inflammation and the passage of air is restricted.

Infection results in necrosis of the epithelial cells lining the bronchioles and leads to peribronchial infiltration, which may spread into the lung fields to give and interstitial pneumonia.

Front 178

177. What causes most of the bronchiolitis infections?

Back 178

As many as 75% of these infection are caused by RSV and most of the remaining 25% are also of viral etiology, although Mycoplasma pneumoniae is implicated occasionally.

Front 179

178. What is RSV?

Back 179

RSV is a typical paramyxovirus; it uses a viral envelope to enter the cell membrane and also fuses host cells to form syncytia.

RSV infection is transmitted by droplets and to some extent by hands.

It can be particularly severe in young infants, and lead to cough, rapid respiratory rate, and cyanosis.

Front 180

179. What does the RSV infection appear to have an immunopathologic basis?

Back 180

Maternal antibodies react w/virus antigens, pehaps w/the liberation of histamine and other mediators from the host's cells.

In early trials, a killed vaccine was used, and during subsequent RSV infection, the vaccinees had more frequent and severe lower respiratory tract disease compared w/unimmunized children, supporting an immune-mediated pathogenesis.

Front 181

180. What type of antigens are detectable in RSV?

Back 181

RSV specific antigens are detectable in smears of exfoliated cells.

Front 182

181. What is the treatment for RSV?

Back 182

Treatment is supportive, involving hydration, bronchodilators, and if needed, oxygen.

The antiviral agent ribavirin has been sued successfully in a number of settings.

A monoclonal antibody, palivizumab, can be used as prophylaxis to prevent RSV infection in children under 2 y/o.

Front 183

182. What is the hantavirus cardiopulmonary syndrome (HCPS)?

How is it transmitted?

Back 183

The reservoir host for Sin Nombre virus, a new world hantavirus, is the deer mouse found commonly in north America.

It leads to flu-like symptoms as viral invasion of the pulmonary capillary endothelium led to fluid pouring into the lungs due to increased vascular permeability, and death results secondary to pulmonary edema, hypotension, and cardiogenic shock.

The route of transmission is by inhaling Sin Nombre virus infected rodent feces, saliva, or urine.

Front 184

183. How do microorganisms reach the lungs in pneumonia?

Back 184

Via inhalation, aspiration, or via the blood.

Front 185

184. What is an important cause of pneumonia in individuals w/AIDS?

Back 185

Pneumocystis jiroveci

Front 186

185. Lobar pnemonia

Back 186

Refers to the involvement of distinct region of the lung. The polymorph exudate formed in response to infection clots in the alveoli and renders them solid. Infection may spread to adjacent alveoli until constrained by anatomic barriers between segments or lobes of the lung.

Thus, one lobe may show complete consolidation.

Front 187

186. Bronchopneumonia

Back 187

Bronchopneumonia refers to a more diffuse patchy consolidation which may spread throughout the lung as a result of the original pathologic process in the small airways.

Front 188

187. Interstitial pneumonia

Back 188

Involves invasion of the lung interstitum and is particularly characteristic of viral infections of the lungs.

Front 189

188. Lung abscess

Back 189

Sometimes called necrotizing pneumonia, it is a condition in which there is cavitation and destruction of the lung parenchyma.

Front 190

189. What types of pneumonia are more common in children and neonates?

Back 190

Most childhood pneumonia is viral (e.g. RSV, parainfluenza) or bacterial secondary to viral respiratory infection (e.g. after measles)

Neonates may develop interstitial pneumonitis caused by Chlamydia trachomatis acquired from the mother at birth.

Front 191

190. What types of pneumonia are more common in adults?

Back 191

Bacterial causes are more common than viral

Front 192

191. What types of pneumonia are more common in patients with CF?

Back 192

Children and young adults w/CF are very prone to infections caused by:
1. S. Aureus
2. H. Influenzae
3. Pseudomonas aeruginosa.

Front 193

192. What is the classic bacterial cause of acute community acquired pneumonia?

Back 193

Streptococcus pneumoniae is the classic bacterial cause of acute community acquired pneumonia

Front 194

193. What are the five causes of atypical pneumonia?

Back 194

1. Mycoplasma pneumoniae
2. Chlamydophila psittaci
3. Chlamydophila pneumoniae*
4. Legionella pneumophila
5. Coxiella burnetii

*Common cause

Front 195

194. Moraxella catarrhalis

Back 195

Moraxella catarrhalis is recognized increasingly as a cause of pneumonia, particular in patients w/carcinoma of the lung or other underlying lung disease.

Front 196

195. What are the signs and symptoms of a chest infection?

Back 196

1. Chest pain, which may be pleuritic in nature (pain on inspiration)
2. A cough, which may produce sputum
3. Shortness of breath
4. Chest exam may reveal abnormal crackling, called rales, and evidence of consolidation, even before change become evident on radiography.

Front 197

196. Chest radiographs reveal what in patients w/pneumonia?

Back 197

Patients w/pneumonia usually have shadows in one or more areas of the lung.

Front 198

197. What is the most common cause of death in the elderly?

Back 198

Pneumonia, duh.

Front 199

198. When should sputum sample be collected?

Back 199

Sputum is best collect in the morning and before breakfast

Front 200

199. Gram stain of pneumonia patient sputum

Back 200

Exam of the Gram-stained sputum gives a Dx within minutes if the film reveals a host response in the form of abundant polymorphs and the putative pathogen, e.g. Gram+ diplococci characteristic of S. pneumonia.

However, remember that Legionella pneumophilia will not be seen in Gram stained smears.

Front 201

200. How is microbiologic Dx of atypical pneumonia confirmed?

Back 201

By serology.

In some infections, IgM, antigen or genome detection are being used to make the Dx at an early stage.

The classic techniques involve detection of a single high titer of specific antibodies, or demonstration of a rising titer between the acute and convalescent phase of the disease, but the Dx is often made retrospectively.

Front 202

201. What is the first DOC in treatment of community acquired pneumonia?

Back 202

Ampicillin + erythromycin

Front 203

202. Viral pneumonia and interstitial pneumonitis

Back 203

Sometimes the virus fails to spread significantly to air spaces, but remains in interstitial tissues to cause interstitial pneumonitis.

An example is cytomegalovirus (CMV) pneumonitis in immunodeficient patients, particularly bone marrow transplant recipients.

Front 204

203. Parainfluenza virus infection

Back 204

As w/RSV, parainfluenza viruses are most likely to cause lower respiratory tract disease, croup and pneumonia, in children.

Front 205

204. Four types of parainfluenza viruses

Back 205

The surface spikes of parainfluenza viruses are composed of hemagglutinin plus neuraminindase on one type of spike and fusion proteins on another.

The four types have different antigens.

Front 206

205. Parainfluenza viruses 1-4

Treatment?

Back 206

Parainfluenza viruses 1-3 cause pharyngitis, croup, otitis media, bronchiolitis, and pneumonia.

Croup is seen in children under 5 years of age, and consists of acute laryngotracheobronchitis w/a harsh cough and hoarseness.

Parainfluenza virus 4 is less common and generally causes a common cold type illness.

Ribavirin may be given in severe infections or in immunosuppressed individuals but there is no vaccine.

Front 207

206. Adenovirus infection

Back 207

Adenoviruses cause about 5% of acute respiratory tract illness overall.

There are 41 antigenic types of adenovirus, some of which cause URI such as pharyngoconjunctival fever and sore throat and lower respiratory tract infections.

Adensovirus respiratory tract infection generally cause non-specific symptoms in children under 5 years of age. As maternal antibody wanes, these lower respiratory tract infections become more frequent, especially w/adenovirus 7.

Front 208

207. Human metapneumovirus (hMPV)

Back 208

hMPV is a respiratory pathogen closely related to RSV, peaks in the winter months and accounts for up to 15% of respiratory tact infections.

It is associated w/a spectrum of illness from mild infection to bronchiolitis and pneumonia.

Symptoms may include a fever, runny nose, cough, sore throat, and wheeze.

Infection occurs in infants and young children w/some reports that by 5 years of age most children have had and hMPV infection.

Front 209

208. Human Bocavirus

Back 209

Human Bocavirus is a member of the parvoviridae subfamily.

Can be the cause in children that are negative for other respiratory viruses but have lower respiratory tract symptoms.

Front 210

209. What is Influenza A virus known for?

Back 210

Influenza A viruses cause epidemics and occasionally pandemics, and there is an animal reservoir, notably in birds.

Front 211

210. What is Influenza B virus known for?

Back 211

Influenza B viruses only cause epidemics and do not involve animal hosts

Front 212

211. What is the Influenza C virus known for?

Back 212

Influenza C viruses do not cause epidemics and give rise to only minor respiratory illnesses.

Front 213

212. What antigenic changes do influenza viruses undergo as they spread through the host species?

Back 213

1. Antigenic drift
-small mutations affecting the H and N antigens occur constantly. When changes in these antigens enable the virus to multiply significantly in individuals w/immunity to preceding strains, the new subtype can reinfect the community. This type of drift is seen w/all types of influenza.

2. Antigenic shift
-Less commonly, and only w/influenza A, there is a sudden major change referred to as shift, in the antigenicity of the H or N antigens.

Front 214

213. How do the antigenic shifts occur in influenza A?

Back 214

This shift is based on recombination between different virus strains when they infect the same cell. The major change in H or N means that the new strain can spread through populations immune to pre-existing strains and the stage is set for a new pandemic.

Associated w/the change in H and N are other genetic changes, which may or may not confer increased pathogenicity or change the ability to spread rapidly from person to person.

Front 215

214. What is the avian influenza virus H7N7?

Back 215

H7N7 is highly pathogenic in birds and may be more transmissible between humans.

Symptoms are conjunctivitis and or flu-like symptoms and can lead to pneumonia and acut erespiratory distress.

Front 216

215. How are novel strains of influenza viruses formed?

Back 216

Reassortment between H5N1 or H7N7 and human H1N1 or H3N2 influenza viruses may result in efficient transmissibility together w/retention of viral pathogenicity.

An influenza pandemic could then evolve.

Front 217

216. How do epidemics or pandemics come about?

Back 217

Epidemics and pandemics are due to the appearance of new strains of viruses so that a given individual is regularly re-infected w/different strains.

This is in contrast to viruses that undergo minimal antigenic variation, such as measles or mumps, for which on infection confers life-long immunity.

Front 218

217. What is the transmission of influenza?

Back 218

Via droplet inhalation.

The infection is almost entirely restricted to the coldest months of the year b/c people spend more time inside building w/limited air space.

Avian influenza viruses are spread by movement of poultry and poultry products, live poultry markets and unhygienic practices; and backyard flocks that are not controlled.

Front 219

218. What are the symptoms and course of influenza?

Back 219

These initial symptoms are due to direct viral damage and associated inflammatory responses.

The virus enters the respiratory tract in droplets and attaches to sialic acid receptors on epithelial cells via the H glycoprotein of the virus envelope.

About 1-3 days after infection, the cytokines liberated from damaged cells cause symptoms such as chills, malaise, fever, and muscular aches.

Runny nose and cough are common. Most people feel better w/in 1 week.

Front 220

219. How does secondary bacterial infection form with influenza?

Back 220

Influenzal damage to the respiratory epithelium predisposes to secondary bacterial infection.

These invaders are:
1. Staphylococci
2. Pneumococci
3. H. Influenzae

Front 221

220. What causes life-threatening influenza?

Back 221

Life-threatening influenza is often due to secondary bacterial infect, especially w/S. aureus, the viral infection being brought under control by antibody and cell-mediated immune responses to the infecting virus.

Front 222

221. What are the CNS complications of influenza?

Back 222

They are rare, but include encephalomyelitis and polyneuritis.

These appear to be indirect immunopathologic complications rather than due to CNS invasion.

Guillain Barre syndrome occurred as a sequel to the widespread vaccination of citizens in the USA with inactivated H3N2 virus in 1976.

Front 223

222. What are the types of influenza virus vaccines in use?

What types of strains are included in the vaccines?

Back 223

1. Those consisting of egg-grown virus, which are then purified, formalin inactivated and extracted w/ether

2. The less reactogenic purified H and N antigens prepared from virus that has been disrupted b lipid solvents.

Influenza A (H3N2 and H1N1 strains) and influenza B are included in the vaccine.

Front 224

223. What is severe acute respiratory syndrome (SARS)

Back 224

The SARS-associated coronavirus is a new member of the coronavirus family. Main symptoms are high fever, cough, shortness of breath or difficulty in breathing.

Chest x-rays consistent w/pneumonia are often seen.

Front 225

224. How did the SARS virus spread?

Back 225

Although the natural reservoir has not been discovered, a number of SARS like viruses have been detected in various wildlife species including Himalyan masked palm civet cats, Chinese ferret badgers, raccoon dogs, and horseshoe bats.

Can spread mainly by respiratory droplets, feces, or infected animals. The virus was shown to be stable at room temp and survives up to 2 days on surfaces and up to 4 days in feces.

Front 226

225. What is the SARS receptor on host cells that binds the viral spike protein?

Back 226

Angiotensin-converting enzyme 2 (ACE2).

Front 227

226. What is used to treat SARS?

Back 227

No specific antiviral treatment was available, although ribavirin was used to treat some individuals.

Corticosteroids damped down the effect of virally induced cytokine response that could damage lung tissue.

Also, interferons were reported to inhibit the virus.

Front 228

227. What does measles have to do w/pneumonia?

Back 228

Secondary bacterial pneumonia is a frequent complication of measles in developing counties.

The virus replicates in the epithelium of the nasopharynx, middle ear and lung, intefering w/host defenses and enabling bacteria such as pneumococci, staphylococci, and meningococci to establish infection.

It can also cause giant cell pneumonia in those w/impaired immune systems, and is a rare and usually fatal manifestation.

Front 229

228. What are the symptoms of measles?

Back 229

After and incubation period of 10-14 days, symptoms include fever, runny nose, conjunctivitis, and cough.

Koplik's spots and then the characteristic rash appear 1-2 days later.

Front 230

229. What is the treatment for measles?

Back 230

Antibiotics are needed for secondary bacterial complications of measles, bu the disease can be prevented by immunization.

If severe, ribavirin treatment is available.

Also, children w/severe measles generally have very low levels of serum retinol; recovery is hastened and death is less likely when they are given 400 000 IU vitamin A.

Front 231

230. What is CMV?

Back 231

Cytomegalovirus infection can cause an interstitial pneumonitis in immunocompromised patients, in particular bone marrow transplant recipients.

Front 232

231. What is tuberculosis?

Back 232

Caused by Mycobacterium tuberculosis.

Other species of mycobacteria-so-called atypical mycobacteria, mycobacteria other than tuberculosis (MOTT) or non-tuberculous mycobacteria (NTM)-also cause infection in the lungs.

Front 233

232. How is tuberculosis acquired?

Back 233

Infection is acquired by inhalation of M. tuberculosis in aerosols and dust.

Airborne transmission of tuberculosis is efficient because infected people cough up enormous numbers of mycobacteria, projecting them into the environment, where their waxy outer coat allows them to withstand drying and therefore survive for long periods of time in air and house dust.

Front 234

233. That pathogenesis of tuberculosis depends on what...?

Back 234

Depends upon the history of previous exposure to the organism.

In primary infection (i.e. infection in individuals encountering M. tuberculosis for the first time), the organisms are engulfed by the alveolar macrophages in which they can both survive and multiply. Non-resident macrophages are attracted to the site, ingest the mycobacteria and carry them via the lymphatics to the local hilar lymph nodes. In the lymph nodes the immune response, predominantly a CMI response, is stimulated.

Front 235

234. How does the CMI response help spread the mycobacterium tuberculosis?

Back 235

Some M. tuberculosis organisms may have already escaped to set up foci of infection in other body sites.

Sensitized T cells release lymphokines that activate macrophages and increase their ability to destroy the mycobacteria.

The body reacts to contain the organisms within 'tubercles', which are small granulomas consisting of epithelioid cells and giant cells. The lung lesion plus the enlarged lymph nodes is often called the Ghon or primary complex. After a time the material within the granulomas becomes necrotic and caseous or cheesy in appearance.

Front 236

235. What is the course of the tubercles?

Back 236

The tubercles may heal spontaneously, become fibrotic or calcified, and persist as such for a lifetime in people who are otherwise healthy.

They will show up on a chest radiograph as radio-opaque nodules.

However, in a small percentage of people with primary infection, and particularly in the immunocompromised, the mycobacteria are not contained within the tubercles, but invade the bloodstream and cause disseminated disease ('miliary' tuberculosis).

Front 237

236. What causes secondary tuberculosis?

Back 237

Secondary tuberculosis is due to reactivation of dormant mycobacteria, and is usually a consequence of impaired immune function resulting from some other cause such as malnutrition, infection (e.g. AIDS), chemotherapy for treatment of malignancy, or corticosteroids for the treatment of inflammatory diseases.

Front 238

237. How does tuberculosis illustrate the dual role of the immune response in infectious disease?

Back 238

On the one hand, the CMI response controls the infection and, when it is inadequate, the infection disseminates or reactivates.

On the other hand, nearly all the pathology and disease is a consequence of this CMI response, as M. tuberculosis causes little or no direct or toxin-mediated damage.

Front 239

238. Where does reactivation of the mycobacteria occur?

Why?

Back 239

Reactivation occurs most commonly in the apex of the lungs.

This site is more highly oxygenated than elsewhere, allowing the mycobacteria to multiply more rapidly to produce caseous necrotic lesions, which spill over into other sites in the lung, and from where organisms spread to more distant sites in the body.

Front 240

239. What are the symptoms in primary tuberculosis?

Back 240

Patients are often asymptomatic. The onset of tuberculosis is insidious, the infection proceeding for some time before the patient becomes sufficiently ill to seek medical attention.

Primary tuberculosis is usually mild and asymptomatic and in 90% of cases does not proceed further. However, clinical disease develops in the remaining 10%.

Front 241

240. What are the clinical manifestations of tuberculosis?

Back 241

The clinical manifestations are variable: fatigue, weight loss, weakness and fever are all associated with tuberculosis.

Infection in the lungs characteristically causes a chronic productive cough, and the sputum may be blood-stained as a result of tissue destruction.

Necrosis may erode blood vessels, which can rupture and cause death through hemorrhage.

Front 242

241. Where does the mycobacterium spread?

Back 242

The organism may disseminate via the lymphatics and bloodstream to other parts of the body.

This usually occurs at the time of primary infection, and in this way chronic foci are established, which may proceed to necrosis and destruction in, for example, the kidney.

Alternatively, spread may be by extension to a neighboring part of the lung, for instance when a tubercle erodes into a bronchus and discharges its contents, or into the pleural cavity, resulting in a pleural effusion.

Front 243

242. How is tuberculosis diagnosed?

Back 243

A diagnosis of tuberculosis is suggested by the clinical signs and symptoms referred to above, supported by characteristic changes on chest radiography and positive skin test reactivity in the tuberculin (Mantoux) test.

Front 244

243. How is the Dx of tuberculosis confirmed?

Back 244

The Ziehl-Neelsen stain of sputum can provide a diagnosis of tuberculosis within 1 hour, whereas culture can take 6 weeks.

Microscopic examination of a smear of sputum stained by Ziehl-Neelsen's method often reveals acid-fast rods.

This result can be obtained within 1 hour of receipt of the specimen in the laboratory.

Front 245

244. What is the combination treatment for tuberculosis?

Back 245

Isoniazid, rifampicin, ethambutol to prevent emergence of resistance

Front 246

245. How long is the prolonged therapy for tuberculosis?

Back 246

Minimum 6 months period which is necessary to eradicate these slow growing intracellular organisms.

Front 247

246. How is tuberculosis prevented?

Back 247

Prevented b improved social conditions, immunization, and chemoprophylaxis.

Immunization w/a live attenuated BCG (bacile Calmette-Guerin) vaccine, does not prevent infection, but it allows the body to react quickly to limit proliferation of the organisms.

Prophylaxis w/isoniazid for 1 year is recommended for people who have had close contact w/a case of tuberculosis.

Front 248

247. What are the four most common pathogens that cause lower respiratory tract infections in patients with CF?

Back 248

1. Staph aureus, which causes respiratory distress and lung damage, but can be well controlled by specific antistaphylococcal chemotherapy
2. Psuedomonas aeruginosa
3. P. cepacia, another member of the genus Pseudomonas, which has become increasingly problematic
4. H. influenza, typically non-encapsulated strains, contributes to respiratory exacerbations.

Front 249

248. In what age does P. aeruginosa infections develop in patients w/CF?

Back 249

P. aeruginosa infection is uncommon in those under 5 years of age, but colonizes the lungs of almost all patients aged 15-20 years, often encouraged by its intrinsic resistance to antistaphylococcal agents

P. aeruginosa rarely invades beyond the lung even in the most severely infected individuals.

Front 250

249. What is the treatment of lower respiratory tracts in patients w/CF?

Back 250

Although specific antibacterial chemotherapy can reduce the symptoms of infection and improve the quality of life, infections, particularly with P. aeruginosa and P. cepacia, are impossible to eradicate and are frequently a cause of death.

Heart-lung transplantation is a successful alternative treatment for some patients.

Front 251

250. What are lung abscesses?

Back 251

Lung abscesses usually contain a mixture of bacteria including anaerobes.

This is a suppurative infection of the lung, sometimes referred to as 'necrotizing pneumonia'

Front 252

251. What is the most common predisposing cause of lung abscesses?

Back 252

The most common predisposing cause is aspiration of respiratory or gastric secretions as a result of altered consciousness.

The infection is therefore endogenous in origin and cultures often reveal a mixture of bacteria, with anaerobes such as Bacteroides and Fusobacterium playing an important role.

Front 253

252. What are the symptoms of lung abscesses?

Back 253

Patients with lung abscesses may be ill for at least 2 weeks before presentation and usually produce large amounts of sputum, which, if foul smelling, gives a strong hint of the presence of anaerobes and often suggests the diagnosis.

Most diagnoses are made from chest radiographs and the cause confirmed by microbiologic investigation.

Front 254

253. Treatment for lung abscesses

Back 254

Treatment of lung abscess should include an anti-anaerobic drug and last 2-4 months.

Because of the likely presence of anaerobes, a suitable anti-anaerobic agent such as metronidazole should be part of the treatment regimen, and treatment may be needed for 2-4 months to prevent relapse.

If diagnosis and treatment are delayed, infection may spread to the pleural space, giving rise to empyema

Front 255

254. What do pleural effusion and empyema have to do with pneumonia?

Back 255

Up to 50% of patients w/pneumonia have a pleural effusion. Sometimes the organisms infecting the lung spread to the pleural space and give rise to a purulent exudate or 'empyema'.

Pleural effusions can be demonstrated radiologically, but detection of empyema can be difficult, particularly in a patient with extensive pneumonia.

Aspiration of pleural fluid provides material for microbiologic examination, and Staph. aureus, Gram-negative rods and anaerobes are commonly involved.

Treatment should be directed at drainage of pus, eradication of infection and expansion of the lung.

Front 256

255. In what type of patient are fungal infections most commonly seen?

Which two species are most important in these infections?

Back 256

Patients w/defective immunity, either as a consequence of immune suppressive treatment or of concomitant disease.

The two are of particular importance: Aspergillus fumigatus and Pneumocystis jiroveci.

Front 257

256. Aspergillus fumigatus

Back 257

Aspergillus fumigatus can cause allergic bronchopulmonary aspergillosis, aspergilloma, or disseminated aspergillosis.

Treatment of invasive aspergillosis is very difficult due to the limited number and toxic nature of antifungal agents active against Aspergillus and the lack of functional host defenses.

Front 258

257. Pneumoncystis jiroveci

Back 258

This is an important opportunistic infection in patients with AIDS. P. jiroveci is an atypical fungus, commonly found in normal humans and in rodents.

Infection spreads by droplet transmission. Disease occurs in debilitated and immune-deficient individuals.

Before the advent of highly active antiretroviral therapy (HAART), a high proportion of AIDS patients develop pneumocystis pneumonia, and this can be fatal.

Front 259

258. Clinical course of P. jiroveci infections

Back 259

Pneumocystis occurs as a trophic form, up to 5 μm diameter, as sporocysts and spore cases. Spores are released when these cases rupture.

Disease is associated with an interstitial pneumonitis, with plasma cell infiltration. Infections of sites other than the lung have also been reported.

Front 260

259. Nematodes such as Ascaris and the hookworms

Back 260

These parasites migrate through the lungs as they move to the small intestine, breaking out of the capillaries around the alveoli to enter the bronchioles.

The damage caused by this process, and the development of inflammatory responses, can lead to a transient pneumonitis.

Front 261

260. Schistosome larvae

Back 261

Schistosome larvae may cause mild respiratory symptoms as they migrate through the lungs .

Front 262

261. Microfilariae of filarial nematodes such as Wuchereria or Brugia

Back 262

The microfilariae of filarial nematodes such as Wuchereria or Brugia produce larvae that become sequestered in the capillaries of the lung.

Under certain conditions the presence of the larvae triggers a condition known as 'tropical pulmonary eosinophilia' (TPE or Weingarten's syndrome).

This is characterized by cough, respiratory distress and marked eosinophilia; microfilariae are usually absent from the blood.

Front 263

262. Ascaris and Strongyloides infections

Back 263

Ascaris and Strongyloides infections may also trigger a pulmonary eosinophilia, although the condition is distinct from TPE.

Front 264

263. Echinococcus granulosus infection

Back 264

Echinococcus granulosus infection, which leads to the development of hydatid cysts in a proportion (20-30%) of cases due to localization of the larvae of the tapeworm in the lungs.

These cysts may reach a considerable size, causing respiratory distress, largely as a consequence of the mechanical pressure exerted on lung tissue.

Front 265

264. Entamoeba histolytica infection

Back 265

Entamoeba histolytica infection, which may rarely involve the lung.

Front 266

265. Paragonimus westermani

Back 266

Paragonimus westermani, the oriental lung fluke, is the most important example of the very few adult parasites that live in the lung.

Infection is acquired by eating crustaceans containing the infective metacercariae. These migrate from the intestine across the body cavity and penetrate into the lungs.

The adults develop within fibrous cysts, which connect with the bronchi to provide an exit for the eggs.

Infections cause chest pain and difficulty in breathing, and can cause bronchopneumonia when large numbers of parasites are present.

Praziquantel is an efficient anthelmintic for this infection.

Front 267

266. Fundamental tests of pulmonary performance

Back 267

1. Blood PO2
2. CO2
3. pH

Front 268

267. Determination of blood pH

Back 268

Measured using a glass pH electrode; the voltage generated by the glass electrode is a measure of pH and is read by a voltmeter

Front 269

268. Determination of blood CO2

Back 269

Glass electrode pH meter can be used to determine CO2

When a weak solution of HCO3- is exposed to CO2 the CO2 dissolves in the solution until an equilibrium state is established

In this equilibrium state, the pH of the solution is a Fx of the CO2 and the HCO3- ion concentrations in accordance w/Henderson Hasselbach

Front 270

269. Determination of blood PO2

Back 270

Measured by polarography

Electric current is made to flow btwn small negatie electrode and the solution

If the voltage of the electrode is more than -.6 V different from the voltage of the solution, O2 will deposit on the electrode.

Rate of current flow thru electrode will be directly proportional to concentration of O2

Front 271

270. Maximum expiratory flow

Back 271

When a person expires w/great force, the expiratory airflow reaches a maximum flow beyond which the flow cannot be increased, even with greatly increased additional force

Front 272

271. Constricted lungs

Back 272

Have both total lung capacity and reduced residual volume

b/c lung cannot expand to the normal max volume even w/the greatest respiratory effort, the maximal expiratory flow cannot rise to that of normal

Front 273

272. Constricted lung diseases (two categories)

Back 273

1. Fibrotic diseases of lung itself
-tuberculosis
-silicosis

2. Diseases that constrict the chest cage such as
-kyphosis
-scoliosis
-fibrotic pleural disease

Front 274

273. Diseases w/airway obstruction

Back 274

Usually much more difficult to expire than to inspire b/c the closing tendency of the airways is greatly increased w/extra positive pressure required in the chest to cause expiration

By contrast, the neg extra pleural pressure that occurs during inspiration actually pulls the airways open at the same time it expands the alveoli allowing air to enter easily and become trapped in lungs

Front 275

274. Forced expiratory vital capacity

Back 275

Pt inspires maximally to the total lung capacity

Exhales into spirometer w/maximum expiratory effort as rapidly and completely as possible

Total volume changes are not greatly different btwn normal lungs and partial airway obstruction; major difference is in the amt of air the person can expire each second

Front 276

275. Pulmonary emphysema

Back 276

Literally means excess air in lungs

Usually used to describe complex obstructive and destructive processes of the lungs caused by many years of smoking

Front 277

276. Three pathophysiologic changes associated w/emphysema

Back 277

1. Chronic infection
-due to smoking; causes excessively thick mucus blocking it from moving out

2. Chronic obstruction of smaller airways

3. Entrapment of air in the alveoli and overstretching of them
-leads to destruction of as much as 50-80% of the alveolar walls

Front 278

277. Physiologic changes associated w/emphysema

Back 278

Depends on severity of disease and relative degree of bronchiolar obstruction vs lung parenchymal destruction

1. Increased airway resistance which causes increased work of breathing
2. Decreased diffusing capacity of lungs b/c of loss of alveolar walls
3. Extremely abnormal ventilation/perfusion ratios resulting in poor aeration of the blood
-poor aeration in blood can vary btwn people b/c of differing abnormalities in ventilation/perfusion ratios
4. Pulmonary hypertension which eventually causes right sided heart failure

Net result of all these effects is severe prolonged devastating air hunger that can last for years until hypoxia and hypercapnia cause death

Front 279

278. Pneumonia

Back 279

Any inflammatory condition in the lung in which some or all of the alveoli are filled w/fluid or blood cells.

Common type is bacterial pneumonia caused by pneumococci

Begins w/infection in the alveoli; then the pulmonary membrane becomes inflamed and highly porous so that fluid and blood cells leak out of the blood and into the alveoli.

Infection spreads by extension of bacteria or virus from alveolus to alveolus

Front 280

279. Pneumonia and gas exchange functions

Back 280

Changes in different stages of disease

Early disease process may be localized to only one lung w/alveolar ventilation reduced while blood flow thru lung continues normally.

This results in:
1. Reduction of the total available surface area of the membrane
2. Decreased ventilation perfusion ratio

Front 281

280. Ventilation/perfusion ratio (or V/Q ratio)

Back 281

In respiratory physiology, the ventilation/perfusion ratio (or V/Q ratio) is a measurement used to assess the efficiency and adequacy of the matching of two variables

"V" - ventilation - the air which reaches the lungs
"Q" - perfusion - the blood which reaches the lungs

Front 282

281. Atelectasis

Back 282

Means collapse of alveoli

Can occur in localized areas or in the entire lung

Most common causes are total obstruction of airway or lack of surfactant

Front 283

282. Atelectatic lung

Back 283

When an entire lung becomes collapsed; a condition called massive collapse of the lung

Effects are:
1. Collapse of lung tissue not only occludes the alveoli but almost always increases the resistance to blood flow thru pulmonary vessels in the collapsed lung
2. Hypoxia in the collapse alveoli cause additional vasoconstriction
3. Vasoconstriction causes blood flow to become slight, however the V/Q ratio is only moderately compromised b/c most of the blood is routed thru the ventilated lung

Front 284

283. Surfactant disorder

Back 284

Called hyaline membrane disease AKA respiratory distress syndrome

Quantity of surfactant secreted by the alveoli is so low that the surface tension causes the lungs to collapse

Front 285

284. Asthma and IgE antibodies

What four things do the mast cells release in response to the IgE?

Back 285

Allergic persons have a tendency to form abnormally large amts of IgE

These antibodies react w/specific antigens and then become attached to mast cells and then the mast release:
1. Histamine
2. Slow reacting substance of anaphylaxis
3. Eosinophilic chemotactic factor
4. Bradykinin

Front 286

285. Effects of factors released by mast cells in asthma

Back 286

1. Localized edema in the walls of small bronchioles as well as secretion of thick mucus into the bronchiolar lumens

2. Spasm of bronchiolar smooth muscle

Front 287

286. Three clinical measurements of asthmatic person

Back 287

1. Greatly reduced max expiratory rate

2. Reduced timed expiratory volume

3. Functional residual capacity and residual volume of the lung become increased during the acute attack b/c of the difficulty in expiring the air.
Results in dyspnea

Front 288

287. Tuberculosis

Back 288

Tubercle bacilli cause tissue reaction in the lungs :

1. Invasion of the infected tissue by macrophages
2. Walling off of the lesion by fibrous tissue to form the so called tubercle
-helps to limit further transmission of the bacilli in the lungs but can cause significant destruction of lung tissue w/formation of large abscess cavities

Front 289

288. Three effects of tuberculosis

Back 289

1. Increased work on the part of respiratory muscles to cause pulmonary ventilation and reduced vital capacity and breathing capacity
2. Reduced total respiratory membrane surface area and increased thickness of surface membrane causing diminished diffusing capacity
3. Abnormal ventilation perfusion ratio in the lungs, further reducing overall pulmonary diffusion of O2 and CO2

Front 290

289. Five causes of hypoxia

Back 290

1. Inadequate oxygenation of blood due to extrinsic reasons (i.e. atmosphere)
2. Pulmonary disease
3. Venous to arterial shunts (right to left cardiac shunts)
4. Inadequate O2 transport to the tissues by blood
5. Inadequate tissue capability of using O2

Front 291

290. Inadequate tissue capability of using O2

Back 291

Caused by cyanide poisoning in which action of cytochrome oxidase is blocked by cyanide

The disease beriberi, in which several important steps in tissue utilization of O2 due to vitamin B12 deficiency

* Inadequate tissue capability of using O2 cannot be corrected by O2 therapy

Front 292

291. Effects of hypoxia on the body

Back 292

1. Depressed mental activity sometimes culminating in coma

2. Reduced work capacity of muscles

Front 293

292. Cyanosis

Back 293

Means blueness of the skin and is caused by excessive amts of deoxygenated Hb in the skin and blood vessels, esp in the capillaries

Generally appears when arterial blood contains more than 5g of deoxygenated Hb per 100 mL blood

Not usually w/anemia but does occur w/polycythemia vera

Front 294

293. Hypercapnia

Back 294

Means excessive CO2 in body fluids which occurs w/hypoxia only when it is caused by hypoventilation or circulatory deficiency

At higher levels of Pco2, excess CO2 actually begins to depress respiration rather than stimulate it; causing more CO2 to accumulate and cause further depression of respiration and results in respiratory death

Front 295

294. Dyspnea

Back 295

Means mental anguish associated w/the inability to ventilate enough to satisfy the demand for air

AKA air hunger

Three factors:
1. Abnormality of respiratory gases in the body fluids, esp hypercapnia
2. Amt of work that must be performed by respiratory muscles to provide adequate ventilation
3. State of mind (called neurogenic dyspnea or emotional dyspnea)
-hyperventilation due to anxiety

Front 296

295. Artificial respiration

Back 296

1. Resuscitator

2. Tank respirator (AKA iron lung)

*Both can reduce the cardiac output b/c of inadequate venous return b/c the pressure inside the lungs become greater than everywhere else

Front 297

296. What are the five ways in which the lung clearing mechanisms can be interfered?

Back 297

1. Loss or suppression of the cough reflex, as a result of coma, anesthesia, neuromuscular disorders, drugs, or chest pain.
2. Injury to the mucociliary apparatus, by either impairment of ciliary function or destruction of ciliated epithelium
3. Interference w/the phagocytic or bactericidal action of alveolar macrophages by alcohol, tobacco smoke, anoxia, or oxygen intoxication
4. Pulmonary congestion and edema
5. Accumulation of secretions in conditions such as cystic fibrosis and bronchial obstruction.

Front 298

297. Defects in innate immunity and humoral immunodeficiency lead to an increase in infections with...?

Back 298

Pyogenic bacteria

Front 299

298. Cell-mediated immune defects lead to increased infections with...?

Back 299

Intracellular microbes such as mycobacteria and herpesviruses as well as with microorganisms of very low virulence, such as Pneumocystis carinii.

Front 300

299. What are three important points to remember about pneumonia?

Back 300

1. One type of pneumonia sometimes predisposes to another, especially in debilitated patients

2. Hematogenous spread from one organ to other organs can occur

3. Many patients w/chronic diseases acquire terminal pneumonias while hospitalized.

Front 301

300. Streptococcus pneumonia

Back 301

This is the most common casuse of community acquired acute pneumonia.

The presence of gram-positive, lancet shaped diplococci within neutrophils is indicative of diagnosis, but it must be remembers that this organisms is part of the endogenous flora in 20% of adults.

Front 302

301. Haemophilus influenzae

Back 302

H. influenzae are pleomorphic, gram-negative, encapsulated (six serotypes - 5%) or unencapsulated (untypable - 95%) bacterial.

They cause life-threatening lower respiratory tract infections and meningitis in children and are a common cause of pneumonia in adults, especially those with COPD.

Front 303

302. Which type of H. influenzae is the most frequent cause of severe invasive disease?

Back 303

Used to be type B, but not the most frequent cause is from infections with nonencapsulated forms.

Front 304

303. What mediates the adherence and survival of the H. influenzae?

Back 304

Pili on the surface of H. influenzae mediate adherence to the respiratory epithelium.

Survival of this organism in the blood stream correlates w/the presence of the capsule, which, like that of pneumococcus, prevents opsonization by complement and phagocytosis by host cells.

Front 305

304. Moraxella catarrhalis

Back 305

Causes bacterial pneumonia, especially in the elderly.

It is the second most common bacterial cause of acute exacerbation of COPD.

It is also a common cause of otitis media in children.

Front 306

305. S. aureus

Back 306

S. aureus is an important cause of secondary bacterial pneumonia in children and healthy adults following viral respiratory illness.

Staphylococcal pneumonia is associated w/a high incidence of complications such as lung abscess and empyema.

IV drug abusers are at high risk of developing staphylococcal pneumonia in association w/endocarditis.

Front 307

306. Klebsiella pneumoniae

Back 307

K. pneumoniae is the most common cause of gran-negative pneumonia.

It afflicts debilitated individuals, especially chronic alcoholics.

Thick and gelatinous sputum is characteristic b/c the organism produces an abundant viscid capsular polysaccharide, which the patient may have difficulty coughing up.

Front 308

307. Pseudomonas aeruginosa

Back 308

Pseudomonas aeruginosa is common in cystic fibrosis patients.

Front 309

308. Legionella pneumophila

Back 309

L. pneumophila spreads through aerosolization; infection causes severe pneumonia in the immunocompromised patient, such as those individuals with cardiac, renal, or hematologic disease.

It is common in artificial aquatic environments.

Front 310

309. Pontiac fever

Back 310

Pontiac fever is a related self-limited upper respiratory tract infection caused by L. pneumophila, without pneumonic symptoms.

Front 311

310. What is the morphology of bacterial pneumonia?

Back 311

There are two gross patterns of anatomic distribution:

1. Bronchopneumonia
2. Lobar pneumonia

Most important from the clinical standpoint are identification of the causative agent and determination of the extent of the disease.

Front 312

311. What is the morphology of bronchopneumonia?

Back 312

Bronchopneumonia is marked by patchy exudative consolidation of lung parenchyma; staphyloccci, pneumococci, H. influenzae, P. aeruginosa, and coliform bacteria are the most common agents.

Grossly, the lungs show dispersed, elevated, focal areas of palpable consolidation and suppuration.

Histologically, there is acute (neutrophilic) suppurative exudation filling airways and air spaces, usually around bronchi and bronchioles.

Resolution spaces of the exudate usually restores normal lung structure, but organization w/fibrous scarring can occur, or aggressive disease can produce abscesses.

Front 313

312. What is the morphology of lobar pneumonia?

Back 313

Lobar pneumonia involves a large portion of or an entire lobe of lung.

Most lobar pneumonias are caused by pneumococci entering the lungs via the airway.

Occasionally, they are caused by other organisms (K. pneumoniae, staphylococci, streptococci, H. influenzae).

Front 314

313. What are the four stages of lobar pneumonia?

Back 314

1. Congestion
-characterized by vascular engorgement, intra-alveolar fluid w/few neutrophils, and often the presence of numerous bacteria.

2. Red hepatization
-characterized by massive confluent exudation w/red cells (congestion), neutrophils, and fibrin filling the alveolar spaces.

3. Gray hepatization
-characterized by progressive disintegration of red cells and the persistence of a fibrinosuppurative exudate.

4. Resolution
-the consolidated exudate within the alveolar spaces undergoes progressive enzymatic digestion to produce a granular, semifluid, debris that is resorbed, ingested by macrophages, coughed up, or organized by fibroblasts growing into it.

Front 315

314. What are four complication of lobar pneumonia or bronchopneumonia?

Back 315

1. Abscess formation
2. Empyema (spread of infection to pleural cavity)
3. Organization of exudate into fibrotic scar tissue
4. Bacteremia and sepsis, with infection of other organs

Front 316

315. What are the community acquired atypical (viral and mycoplasmal) pneumonias?

Back 316

Infections by viruses or Mycoplasma pneumoniae range from relatively mild URI to severe lower respiratory tract disease.

The term atypical means a moderate amount of sputum, no physical findings of consolidation, only moderate elevation of WBCs and lack of alveolar exudate.

The pneumonitis is most commonly caused by Mycoplasma pneumoniae.

Front 317

316. What is the common pathogenetic mechanism of the atypical pneumonias?

Back 317

The common pathogenetic mechanism is attachment of the organisms to the upper respiratory tract epithelium followed by necrosis of the cells and an inflammatory response.

Damage to and denudation of the respiratory epithelium inhibit mucociliary clearance and predispose to secondary bacterial infections.

Front 318

317. What is the morphology of atypical pneumonias?

Back 318

Patchy or lobar areas of congestion are seen without the consolidation of bacterial pneumonias. Other findings are:

1. Predominant interstitial pneumonitis w/widened, edematous alveolar walls containing mononuclear inflammatory cell infiltrates may be seen.
2. Hyaline membranes reflect diffuse alveolar damage
4. Frequent, superimposed bacterial infection is seen
5. Certain viruses cause necrosis in sever infections (herpes simplex, adenovirus, varicella); in some, characteristic cytopathic changes occur (e.g. cytomegaly and nuclear inclusions in CMV).

Front 319

318. Influenza infections

Back 319

Type A influenzaviruses infect humans and are the major cause of influenza epidemics through viral mutations.

Types B and C do not mutate; consequently, childhood infections result in largely life-long antibody-mediated protection against future disease.

Front 320

319. What are the two mechanisms that account for the clearance of primary influenza virus infection?

Back 320

1. Cytotoxic T cells
2. Intracellular anti-influenza protein (called Mx1) is induced in macrophages by the cytokines interferon alpha and beta.

Front 321

320. What is the morphology of influenza infections?

Back 321

Viral URIs are marked by mucosal hyperemia and swelling witha predominantly lymphomonocytic and plasmacytic infiltration of the submucosa accompanied by overproduction of mucus secretions.

The swollen mucosa and viscid exudate may plug the nasal channels, sinuses, or the eustachian tubes and lead to secondary bacterial infection.

Virus-induced tonsillitis w/enlargement of the lymphoid tissue within Waldeyer ring is frequent in children.

Front 322

321. What is the morphology of laryngotracheobronchitis and bronchiolitis?

Back 322

There are vocal cord swelling and abundant mucous exduation.

Impairment of bronchociliary function invites bacterial superinfection w/more marked suppuration. Plugging of small airways may give rise to focal lung atelectasis.

Can result in obliterative bronchiolitis and permanent lung damage.

Front 323

322. What is SARS?

Back 323

SARS first appear in China in 2002.

One third of patients recover; the remainder progress to severe respiratory disease and nearly 10% die.

It is caused by a previously unknown coronavirus, spread mainly through infected respiratory secretions.

The lungs show diffuse alveolar damage and multinucleated giant cells.

Front 324

323. What is nosocomial pneumonia?

Back 324

Nosocomial pneumonia is defined as infection acqruired during hospitalization.

These pneumonias occur in patients with severe underlying disease or invasive access devices, and are serious life-threatening complications.

Front 325

324. What are the most common isolates in nosocomial pneumonia?

Back 325

Gram negative rods (enterobacteriaceae and Pseudomonas species) and Staphylococcus aureus are the most common isolates.

Front 326

325. What is aspiration pneumonia?

Back 326

Aspiration pneumonia occurs in markedly debilitated or unconscious patients; it results in partly chemical (gastric acid) and partly bacterial (mixed oral flora) pneumonia.

Aerobes are more commonly found than anaerobes.

Front 327

326. What are lung abscesses?

Back 327

Lung abscess describes a local suppurative process within the lung, characterized by necrosis of lung tissue.

Commonly involved are staphylococci, stretococci, numerous gram-negative species, and anaerobes.

Mixed infections are frequent, reflecting aspiration of oral contents as a common etiology.

Front 328

326. How are the causative organisms of lung abscesses introduced? Five ways...

Back 328

1. Aspiration of infective material
2. Antecedent primary bacterial infection (S. aureus, Klebsiella pneumonia, and the type 3 pneumococcus)
3. Septic embolism
4. Neoplasia
5. Miscellaneous

Front 329

327. What is the morphology of abscesses?

Back 329

They contain variable mixtures of pus and air, depending on avaiable drainage through airways.

Pulmonary abscesses due to aspiration are more common on the right, and are most often single.

Continued infection leads to large, fetid, green-black, multilocular cavities with poor demarcation of their margins, designated gangrene of the lung. CONTINUED

Front 330

328. What is the cardinal histologic change in all lung abscesses?

Back 330

Suppurative destruction of the lung parenchyma within the central area of cavitation.

In chronic cases, considerable fibroblastic proliferation produces a fibrous wall.

Front 331

329. What are the clinical manifestations of lung abscesses?

Back 331

Cough, fever, copious amount of foul-smelling purulent or sanguineous sputum.

Fever, chest pain, and weight loss are common. Clubbing of the fingers and toes may appear within a few weeks after the onset of an abscess.

Front 332

330. What is chronic pneumonia?

Back 332

Chronic pneumonia is typically a localized granulomatous inflammation in immunocompetent patients, with or without regional lymph node involvement.

In the immunocompromised, the infection may become disseminated.

Can be caused by bacteria or fungi.

Front 333

331. What is histoplasmosis?

Back 333

Histoplasmosis capsulatum infection is acquired by inhalation; it is endemic along the Ohio and Mississippi rivers and in the Caribbean.

Heat shock protein expressed by the fungus binds to the surface of macrophages, which stimulates interferon and TNF which kills the fungus.


Lacking cellular immunity, patients with AIDS are susceptible to disseminated infections with Histoplasma, which is a major opportunistic pathogen in this disease.

Front 334

332. Morphology of histoplasmosis

Back 334

Infection produces granulomas with coagulative necrosis and coalesce to produce large areas of consildation but may also liquefy to form cavities.

With sponaneous or drug control of the infection, these lesions subsequently undergo fibrosis and concentric calcification *tree bark appearance).

Silver stain identifies the 3-5 um thin walled cyst of the fungus, which can persist for years.

Front 335

333. Chronic histoplasmosis

Back 335

Gray-white granulomas are usually present in the apices of the lungs with retraction and thickening of the pleura and in the hilar nodes.

Further progression involves more and more of the lung parenchyma, with cavity formation less frequent than in tuberculosis.

Front 336

334. Fulminant disseminated histoplasmosis

Back 336

Occurs in immunosuppressed individuals. Epithelioid cell granulomas are not formed; instead, there are focal accumulations of mononuclear phagocytes filled w/fungal yeasts throughout the tissues and organs of the body.

The presence of macrophages stuffed with organisms resembles that found in severe cases of visceral leishmaniasis.

Front 337

335. What are the clinical presentations of histoplasmosis?

Four items...

Back 337

1. A self-limited and often latent primary pulmonary involvement, which may result in coin lesions on chest radiography
2. Chronic, progressive, secondary lung disease, which is localized to the lung apices and causes cough, fever, and night sweats.
3. Localized lesions in extrapulmonary sites, including mediastinum, adrenal, liver, or meninges
4. A widely disseminated involvement, particularly in immunosuppressed patients.

Front 338

336. What is blastomycosis?

What are the three clinical forms?

Back 338

Blastomyces dermatidis is a soil-inhabiting, dimorphic fungus that is difficult to isolate.

It occurs in the central and southeastern US, Canada, Mexico, the Middle east, Africa, and India.

Three clinical forms:
1. Pulmonary blastomycosis
2. Disseminated blastomycosis
3. Rare primary cutaneous form that results from direct inoculation of organisms into the skin

Front 339

337. What is the clinical presentation of blastomycosis?

Back 339

Pulmonary bastomycosis most often presents as an abrupt illness w/productive cough, headache, chest pain, weight loss, fever, abdominal pain, night sweats, chills, and anorexia.

Chest radiographs reveal lobar consolidation, multilobar infiltrates, perihilar infiltrates, multiple nodules, or miliary infiltrates.

The upper lobes are most frequently involved.

Front 340

338. What is the morphology of bastomycosis?

Back 340

In the normal host, the lung lesions of blastomycosis are suppurative granulomas.

Macrophages have a limited ability to ingest and kill B. dermatidis, and the persistence of the yeast cells leads to continued recruitment of neutrophils.

In tissue, B. dermatidis is a round, 5- to 15um yeast cell that divides by broad-based budding. It has a thick, double-contoured cell wall and multiple nuclei.

When in cutaneous form, it can be mistaken for squamous cell CA.

Front 341

339. What is coccidioidomycosis?

Back 341

Coccidioidomycosis is endemic to areas of the Southwest and western US and Mexico.

Coccidioides immitis causes lesions varying from pyogenic to granulomatous; silver stains demonstrate a 20-60 um thick walled spherule containing small endospores.

Front 342

340. What are the common causes of pneumonia in the immunocompromised host?

Back 342

1. Bacteria (Pseudomonas aeruginosa, Mycobacterium species, Leionella pneumophilia, and Listeria monocytogenes)

2. Viruses (CMV and herpes virus)

3. Fungi (Pneumocystic carinii, Candida species, Aspergillus species, the Phycomycetes, and Cryptococcus neoformans)

Front 343

341. What are the pulmonary diseases associated in patients with AIDS?

Back 343

In theses patients pulmonary disease may be due to more than one cause and symptoms may be atypical.

The CD4+ T-cell count can define the risk of infection w/specific organisms.

In addition to opportunistic infections, the usual bacterial pathogens cause severe disease

Malignancies (Kaposi sarcoma, lymphoma, lung CA) also cause pulmonary disease

Front 344

342. CD4+ T cell count rules of thumb

Back 344

1. Bacterial and tubercular infections are more likely at higher CD4+ counts (> 200 cells/mm^3)

2. Pneumocystic pneumonia usually strikes at CD4+ counts below 200 cells/mm^3

3. CMV and Mycobacterium avium complex infections are uncommon until the very late stages of immunosuppression (<50cells/mm^3)

Front 345

343. Pulmonary infections in lung transplantations

Back 345

They are esentially those of any immunocompromised host.

They include bacterial and viral (especially CMV), penumonias, Pneumocystic carinii, and fungal infections.

In the early posttransplant period, bacterial infections are most common.

Front 346

345. When do most pulmonary infections in lung transplantations occur?

Back 346

Most cases occur in the months 3-12 after transplant.

Front 347

346. Morphology of acute rejection of transplanted lung

Back 347

The morphologic features of acute rejection are those of inflammatory infiltrates (lymphocytes, plasma cells, and few neutrophils and eosinophils), either around small vessels, in the submucosa of airways, or both.

Front 348

347. Chronic rejection of transplanted lung

What is the major morphological correlate of chronic rejection?

Back 348

Chronic region is a significant problem in at least half of all lung transplant patients by 3-5 years.

The major morphological correlate of chronic rejection is bronchiolitis obliterans, the partial or complete occlusion of small airways by fibrosis, with or w/o active inflammation.

Bronchiolitis obliterans is patchy and therefore difficult to Dx via transbronchial biopsy.