Pbl Exam 8 Case 6-2

Front 1

1. What are astrocytes?

Back 1

The astrocytes are found in the CNS and are star-shaped cells that provide physical and nutritional support for neurons. During development of the CNS, the astrocytes guide neuronal migration to their final adult position, and form a matrix that keeps them in place.

These cells phagocytose debris left behind by cells, provide lactate (from glucose metabolism) as a carbon source for the neurons), and control the brain EC ionic environment.

Astrocytes help to regulate the content of the ECF by taking up, processing, and metabolizing nutrients and waste products.

Front 2

2. What are oligodendrocytes?

Back 2

Oligodendrocytes provide the myelin sheath that surrounds the axon, acting as insulation for many neurons in the CNS.

Oligodendrocytes can form myelin sheaths around multiple neurons in the CNS by sending out processes that bind to the axons on target neurons. Along with astrocytes, they also form a supporting matrix for the neurons.

They have a limited capacity for mitosis, and if damaged, do not replicated. If this occurs, demyelination of the axons may occur.

Front 3

3. What are Schwann cells?

Back 3

Schwann cells are the supporting cells of the PNS. Like oligodendrocytes, they also form myelin sheaths around the axons, but they can only myelinate one axon.

Schwann cells also clean up cellular debris in the PNS. The Schwann cells also provide a means for peripheral axons to regenerate if damage. There is a synergistic interaction among the Schwann cells, secreted growth factors, and the axon that allows damaged axons to reconnect to the appropriate target axon.

Front 4

4. What are microglial cells?

Back 4

The microglial cells are the smallest glial cells in the nervous system. They serve as immunologically responsive cells that function similarly to the action of macrophages in the circulation.

Microglial cells destroy invading micro-organisms and phagocytose cellular debris.

Front 5

5. What are ependymal cells?

Back 5

The ependymal cells are ciliated cells that line the vacities (ventricles) of the CNS and the spinal cord.

In some areas of the brain, the ependymal cells are functionally specialized to elaborate and secrete CSF into the ventricular system. The beating of the ependymal cilia allow for efficient circulation of the CSF throughout the CNS.

Recent data has found that cells within the ependymal layer can act as neural stem cells which can regenerate neurons.

Front 6

6. What is the function of the CNS?

Back 6

The CSF acts as both a shock absorber protecting the CNS from mechanical trauma and as a system for the removal of metabolic wastes.

The CSF can be aspirated from the spinal canal and analyzed to determine whether disorder of CNS function, with their characteristic CSF changes, are present.

Front 7

7. What is the BBB?

Back 7

The BBB begins with the endothelial cells that form the inner lining of the vessels supplying blood to the CNS.

These cells are joined by tight junctions that do not permit the movement of polar molecules from the blood into the interstitial fluid bathing the neurons. They also lack mechanisms for transendothelial transport that are present in other capillaries of the body. These mechanisms include fenestrations or transpinocytosis.

Front 8

8. What are the five important components of the BBB?

Back 8

1. Tight junctions btwn endothelial cells
2. Narrow intercellular spaces
3. Lack of pinocytosis
4. Continuous basement membrane
5. Astrocyte extension

Front 9

9. What is the role of the endothelial cells in the BBB?

Back 9

These cells serve actively and passively to protect the brain. B/c they contain a variety of drug-metabolizing enzyme systems similar to those in the liver, the endothelial cells can metabolize neurotransmitters and toxic chemicals and thus form an enzymatic barrier to entry of these substances.

They actively pump hydrophobic molecules that diffuse into endothelial cells back into the blood (esp xenobiotics) with P-glycoproteins, which act as transmembranous, ATP-dependent efflux pumps).

Front 10

10. What molecules can passively diffuse across the BBB?

Back 10

Lipophilic substances, water, oxygen, and carbon dioxide can readily cross the BBB via passive diffusion.

Other molecules depend on specific transport systems. Differential transporters on the luminal and abluminal endothelial membranes can transport compounds into as well as out of the brain.

Front 11

11. What is the role of the basement membrane in the BBB?

Back 11

Further protection against the free entry of blood-borne compounds into the CNS is provided by a continuous collagen-containing basement membrane that completely surrounds the capillaries.

The BM appears to be surrounded by the foot processes of astrocytes.

Front 12

12. How is glucose transported to the brain?

Back 12

GLucose is transported thru both endothelial membranes by facilitated diffusion via the GLUT-1 transproter.

GLUT-3 transporters present on the neurons then allow the neurons to transport the glucose from the ECF.

Glial cells express GLUT-1 transporters.

Front 13

13. What happens to the energy metabolism of the brain when blood glucose levels fall?

Back 13

Normally the rate of glucose transport into the ECF normally exceeds the rate required for energy metabolism by the brain. However, glucose transport may become rate-limiting as blood glucose levels fall below the normal range.

Thus, people begin to experience hypoglycemic symptoms at approx 60 mg/dL, as the glucose levels are reduced to or below the Km of the GLUT-1 transporters in the endothelial cells of the BBB barrier.

Front 14

14. How are large neutral amino acids transported into the brain?

Back 14

Large neutral AAs, such as phenylalanine, leucine, tyrosine, isoleucine, valine, tryptophan, methionine, and histidine, enter the CSF rapidly via a single AA transporter (L-leucine-preferring system AA transporter).

B/c a single transporter is involved, these AAs compete with each other for transport into the brain.

Front 15

15. What about the entry of small neutral AAs?

Back 15

The entry of small neutral AAs, such as alanine, glycine, proline, and GABA, is marked restricted b/c their influx could dramatically change the content of neurotransmitters.

They are synthesized in the brain, and some are transported out of the CNS and into the blood via the A(alanine)-preferring system carrier.

Front 16

16. What is receptor mediated transcytosis?

Back 16

Certain proteins, such as insulin, transferrin, and insulinlike growth factors, cross the blood-brain barrier by receptor-mediated transcytosis.

Once the protein binds to its membrane receptor, the membrane containing the receptor-protein complex is endocytosed into the endothelial cell to form a vesicle. It is released on the other side of the endothelial cell.

Front 17

17. What are the two basic structural categories of molecules that serve as neurotransmitters?

Back 17

1. Small nitrogen-containing molecules
-glutamate, GABA, glycine, ACh, dopamine, norepinephrine, serotonin, and histamine, NO

2. Neuropeptides
-endorphins, GH, TSH

Front 18

18. What are the general features of neurotransmitter synthesis?

Back 18

Most of the transmitters are synthesized from AAs, intermediates of glycolysis and the TCA cycle, and O2 in the cytoplasm of the presynaptic terminal. The rate of synthesis is generally regulated to correspond to the rate of firing of the neuron.

Once synthesized, the transmitters are stored in storage vesicles by an ATP requiring pump linked with the proton gradient. Release from the vesicle is triggered by an action potential that depolarizes the membrane and causes an influx of calcium ions. This causes the fusion of the vesicle with the synaptic membrane and release of the neurotransmitter.

Front 19

19. What determines the action of the neurotransmitter?

Back 19

The action of the neurotransmitter is terminated thru reuptake into the presynaptic terminal, uptake into glial cells, diffusion away from the synapse, or enzymatic inactivation.

The enzymatic inactivation may occur in the postsynaptic terminal, the presynaptic terminal or an adjacent astrocyte microglial cell, or in endothelial cells in the brain capillaries.

Front 20

20. How is dopamine, norepinephrine, and epinephrine synthesized?

Back 20

These three neurotransmitters are synthesized in a common pathway from the AA L-tyrosine.

*The first and rate limiting step in the synthesis of these neurotransmitters from tyrosine is the hydroxylation of the tyrosine ring by tyrosine hydrolase. The product formed is called dopa.

The second step is the decarboxylation of dopa to form dopamine.

Most stop here, but to get to norepinephrine, dopamine is hydroxylated by dopamine beta hydroxylase.

Epinephrine synthesis is dependent on the presence of adequate levels of vitamin B12 and folate.

Front 21

21. Where does the synthesis of the catecholamines take place?

Back 21

Ordinarily, only low concentrations of catecholamines are free in the cytosol, whereas high concentrations are found within the storage vesicles.

Conversion of tyrosine to L-dopa and that of L-dopa to dopamine occurs in the cytosol. Dopamine is then taken up into the storage vesicles.

In norepinephrine containing neurons, the final beta-hydroxylation reaction occurs in the vesicles.

Front 22

22. Where does the storage and release of catecholamines occur?

Back 22

The catecholamines are transported into VMAT. The mechanism that concentrates the catecholamines in the storage vesciles is an ATP-dependent process linked to a proton pump. Protons are pumped into the vesicles via a vesicular ATPase (V-ATPase).

The protons then exchange for the positively charged catecholamine via the transporter VMAT2. The influx of the catecholamine is thus driven by the H+ gradient across the membrane.

In the vesicles, the catecholamines exist in a complex with ATP and acidic proteins known as chromogranins.

Front 23

23. What are the two roles of the vesicles?

Back 23

1. They maintain a steady supply of catecholamines at the nerve terminal that is available for immediate release

2. They mediate the process of release When an action potential reaches the nerve terminal, the calcium influx promotes the fusion of vesicles with the neuronal membrane. The vesicles then discharge their soluble contents, including the neurotransmitters, ATP, chromogranins, and DBH, into the extraneuronal space by the process of exocytosis.

Front 24

24. What are two of the major reactions in the process of inactivation and degradation of catecholamines?

Back 24

1. Monoamine oxidase
-present on the outer mitochondrial membrane of many cells

2. Catechol-O-methoyltransferase (COMT)
-also found in many cells, including RBCs

Front 25

25. What is MAO?

Back 25

MAO is present on the outer mitochondrial membrane of many cells and oxidizes the carbon containing amino group to an aldehyde, thereby releasing ammonium ion. In the presynaptic terminal MOA inactivates catecholamines that are not protected in storage vesicles. Thus, drugs that deplete storage vesicles indirectly increase catecholamine degradation.

There are two isoforms of MAO. MAO in the liver and other sites protects against the ingestion of dietary biogenic amines such as the tyramine found in many cheeses.

Front 26

26. What are the two isoforms of MAO?

Back 26

MAO-A preferentially deaminates norepinephrine and serotonin

MAO-B acts on a wide spectrum of phylethylamines (this refers to a -CH2- group linked to a phenyl ring).

Front 27

27. What is COMT?

Back 27

COMT works on a broad spectrum of extraneuronal catechols and those that have diffused away from the synapse. COMT transfers a methyl group from SAM to a hydroxyl group on the catecholamine or its degradation product.

B/c the inactivation reaction requires SAM, it is indirectly dependent on vitamin B12 and folate.

Front 28

28. In the CSF, what is an indicator of dopamine degradation?

Back 28

CSF homovanillylmandelic acid (HVA) is an indicator of dopamine degradation.

Its concentration is decreased in the brain of pts with Parkinson's disease.

Front 29

29. What regulates tyrosine hydroxylase?

Back 29

Tyrosine hydroxylase, the first committed step and rate-limiting enzyme in the pathway, is regulated by feedback inhibition that is coordinated with depolarization of the nerve terminal.

Tyrosine hydroxylase is inhibited by free cytosolic catecholamines that compete at the binding site on the enzyme for the pterin cofactor (tetrahydrobiopterin).

Depolarization of the nerve terminal activates tyrosine hydroxylase, along with other protein kinases, (PK-C and PK-A) can CAM kinases that phosphorylate tyrosine hydroxylase and cause it to bind BH4 more tightly.

Front 30

30.. What about the long-term regulation of tyrosine hydroxylase?

Back 30

A long-term process involves alterations in the amts of tyrosine hydroylase and dopamine beta-hydroxylase present in the nerve terminals.

When sympathetic neuronal activity is increased for a prolonged period, the amts of mRNA that code for tyrosine hydroxylase and dopamine-beta-hydroxylase are increased.

This increased gene transcription may be the result of phosphorylation of CREB by protein kinase A. CREB then binds to the CRE in the promoter region of the gene.

Front 31

31. How is serotonin synthesized and degraded?

Back 31

The first enzyme of the pathway, tryptophan hydroxylase, uses an enzymic mechanism to hydroxylate the ring structure of tryptophan.

The second step of the pathway is a decarboxylation reaction catalyzed by the same enzyme that decarboxylates DOPA.

Serotonin, like the catecholamines, can be inactivated by MAO.

Front 32

32. How is melatonin produced?

Back 32

The neurotransmitter melatonin is also synthesized from tryoptophan.

Melatonin is produce din the pineal gland in response to the light-dark cycle, it level in the blood rising in a dark environment. It is probably thru melatonin that the pineal gland conveys info about light-dark cycles to the body. Melatonin also may be involved in regulating reproductive functions.

Front 33

33. What cells release histamine in the brain?

Back 33

Within the brain, histamine is produced both by mast cells and by certain neuronal fibers. Mast cells are a family of bone marrow-derived secretory cells that store and release high concentrations of histamine.

They are prevalent in the thalamus, hypothalamus, dura mater, leptomeninges, and choroid plexus.

Histaminergic neuronal cell bodies in the human are found in the tuberomamillary nucleus of the posterior basal hypothalamus. The fibers project into nearly all areas of the CNS, including the cerebral cortex, the brainstem, and the spinal cord.

Front 34

34. How is histamine synthesized?

Where is it stored?

Back 34

Histamine is synthesized form histidine in a single enzymatic step. The enzyme histidine decarboxylase requires pyridoxal phosphate, and its mechanism is very similar to that of dopa decarboxylase.

Histamine is stored in the nerve terminal vesicles. Depolarization of nerve terminals activates the exocytotic release of histamine by a voltage-dependent as well as a calcium dependent mechanism.

Front 35

35. Once released from neurons, what happens to histamine?

Back 35

Histamine is thought to activate both postsynaptic and presynaptic receptors.

Unlike other neurotransmitters, histamine does not appear to be recycled into the presynpatic terminal to any great extent.

However, astrocytes have a specific high-affinity uptake system for histamine and may be the major sites of the inactivation and degradation of this monoamine.

Front 36

36. How is histamine degraded?

Back 36

The first step in the inactivation of histamine in the brain is methylation. The enzyme histamine methyltransferase transfers a methyl group from SAM to a ring nitrogen of histamine to form methylhistamine.

The second step is oxidation by MAO-B, followed by an additional oxidation step.

In peripheral tissues, histamine undergoes deamination by diamine oxidase, followed by oxidation to a carboxylic acid.

Front 37

37. How is ACh synthesized?

Back 37

The synthesis of ACh from acetyl coenzyme A and choline is catalyzed by the enzyme choline acetyltransferase (ChAT). This synthetic step occurs in the presynaptic terminal. The compound is stored in vesicles and later released thru calcium-mediated exocytosis.

Choline is taken up by the presynaptic terminal from the blood via a low-affinity transport system and from the synaptic cleft via a high-affinity transport mechanism.

It is also derived from the hydrolysis of phosphatidylcholine in membrane lipids.

Front 38

38. How is choline made?

Back 38

Choline is a common component of the diet but also can be synthesized in the human as part of the pathway of the synthesis of phospholipids. The only route for choline synthesis is via the sequential addition of three methyl groups from SAM to the ethanolamine portion of phosphatidylethanolamine to form phosphatidylcholine.

Phosphatidylcholine is subsequently hydrolyzed to release choline or phosphocholine. This conversion is folate and vitamin B12 dependent.

Front 39

39. Where does the acetyl group used for ACh synthesis come from?

Back 39

The acetyl group is derived principally form glucose oxidation to pyruvate and decarboxylation fo pyruvate to form acetyl CoA via the pyruvate dehdyrogenase reaction.

This is b/c the neuronal tissues have only a limited capacity to oxidize fatty acids to acetyl CoA, so glucose oxidation is the major source of acetyl groups. Pyruvate dehydrogenase is found only in mitochondria.

Front 40

40. How is ACh inactivated?

Back 40

Via acetylcholinesterase, which is a serine esterase that forms a covalent bond with the acetyl group. The enzyme is inhibited by a wide range of compounds that form a covalent bond with this reactive serine group. This is how Sarin nerve gas works.

ACh is the major neurotransmitter at the neuromuscular junctions; inability to inactivate this molecule leads to constant activation of the nerve-muscle synapses, a condition that leads to varying degrees of paralysis.

Front 41

41. How is glutamate synthesized?

Back 41

Glutamate = excitatory neurotransmitter within the CNS. Within nerve terminals, glutamate is generally synthesized de novo from glucose rather than taken up from the blood, b/c its plasma concentration is low and it does not readily cross the BBB.

It is synthesized primarily from the TCA cycle intermediate alpha-ketoglutarate. via glutamate dehydrogenase or via transamination.

Front 42

42. What is GABA?

Back 42

GABA is the major inhibitory neurotransmitter in the CNS.

It is synthesized by the decarboxylation of glutamate via glutamic acid decarboxylase. GABA is recycled in the CNS by a series of reactions called the GABA shunt, which conserves glutamate and GABA.

Front 43

43. Much of the uptake of GABA occurs where?

Back 43

In glial cells. The GABA shunt in glial cells produces glutamate, which is converted to glutamine and transported out of the glial cells to neurons, where it is converted back to glutamate.

Glutamine thus serves as a transporter of glutamate between cells in the CNS.

Glial cells lack GAD and cannot synthesize GABA.

Front 44

44. What is aspartate?

Back 44

Aspartate, like glutamate, is an excitatory neurotransmitter, but it functions in far fewer pathways. It is synthesized from the TCA cycle intermediate oxaloacetate via transamination reactions.

Like glutamate syntehsis, aspartate synthesis uses oxaloacetate that must be replaced thru anaplerotic reactions.

Aspartate cannot pass thru the BBB.

Front 45

45. What is glycine?

Back 45

Glycine is the major inhibitory neurotransmitter in the spinal cord. Most of the glycine in neurons is synthesized de novo within the nerve terminals from serine by the enzyme serine hydroxymethyltransferase, which requires folic acid.

Serine in turn is synthesized from the intermediate 3-phosphoglycerate in the glycolytic pathway. The action of glycine is probably terminated via uptake by a high affinity transporter.

Front 46

46. What is the action of NO?

How is it made?

Back 46

NO is synthesized from arginine in a reaction catalyzed by NO synthase.

The synthesis of NO occurs in response to a stimulator binding to a receptor on some cells or to a nerve impulse in neurons. NO enters smooth muscle cells, stimulating guanylate cyclase to produce cGMP, which causes smooth muscle cell relaxation. When the smooth muscle cells relax, blood vessels dilate.

It can readily cross cell membranes b/c it is a gas.

Front 47

47. What is hypoglycemic encephalopathy?

Back 47

Hypoglycemia signs reflect the appearance of physiologic protective mechanisms initiated by hypothalamic sensory nuclei such as sweating, palpitations, anxiety, and hunger. If these symptoms are ignored, they proceed to a more serious CNS disorder, progressing thru confusion and lethargy to seizures and eventually coma.

Prolonged hypoglycemia can lead to irreversible brain damage.

Front 48

48. What occurs during hypoglycemic encephalopathy when the blood sugar falls to 2.5 - 2.0 mM?

Back 48

As blood glucose falls below 2.5 mM, the brain attempts to use internal substrates such as glutamate and TCA cycle intermediates as fuels. B/c the pool size of these substrates is quite small, they are quickly depleted. If blood glucose levels continue to fall below 1 mM, ATP levels become depleted.

As the blood glucose drops from 2.5 to 2.0 mM, the symptoms appear to arise from decreased synthesis of neurotransmitters in particular regions of the brain rather than a global energy deficit.

Front 49

49. What occurs during hypoglycemic encephalopathy when the blood sugar falls below 1 mM?

Back 49

The EEG becomes isoelectric, and neuronal cell death ensues.

Cell death is not global in distribution; rather, certain brain structures, in particular hippocampal and cortical structures, are selectively vulnerable to hypoglycemic insult.

Front 50

50. The pathophysiologic mechanisms responsible for neuronal cell death in hypoglycemia include...?

Back 50

Glutamate excitotoxicity. Glutamate excitotoxicity occurs when the cellular energy reserves are depleted.

The failure of the energy-dependent reuptake pumps results in a buildup of glutamate in the synaptic cleft and overstimulation of the postsynaptic glutamate receptors. The prolonged glutamate receptor activation leads to prolonged opening of the receptor ion channel and the influx of lethal amounts of calcium ion, which can activate cytotoxic intracellular pathways in the postsynaptic neuron.

Front 51

51. What is hypoxic encephalopathy?

Back 51

When mild to moderate hypoxia occurs, there is diminished cognitive function due to impaired neurotransmitter synthesis. In mild hypoxia, cerebral blood flow increases to maintain oxygen delivery to the brain.

In addition, anaerobic glycolysis is accelerated, resulting in maintenance of ATP levels. This occurs, however, at the expense of an increase of lactate production and a fall of pH. Acute hypoxia (PaO2 < 20 mmHg) generally results in a coma.

Front 52

52. What occurs during hypoxic encephalopathy?

Back 52

All forms of hypoxia result in diminished neurotransmitter synthesis.

Inhibition of pyruvate dehydrogenase diminished ACh synthesis, which is acutely sensitive to hypoxia.

Glutamate and GABA synthesis, which depend on a functioning TCA cycle, are decreased as result of elevated NADH levels, which inhibit TCA cycle enzymes. NADH levels are increased when oxygen is unavailable to accept electrons from the ETC.

Even the synthesis of catecholamine neurotransmitters may be decreased b/c the hydroxylase reactions require O2.

Front 53

53. What is the relationship between glutamate synthesis and the anaplerotic pathways of pyruvate carboxylase and methylmalonyl CoA mutase?

Back 53

Synthesis of glutamate removes alpha-ketoglutarate from the TCA cycle, thereby decreasing the regeneration of oxaloacetate in the TCA cycle. B/c oxaloacetate is necessary for the oxidation of acetyl CoA, oxaloacetate must be replaced by anaplerotic reactions.

There are two major types of anaplerotic reactions: (1) pyruvate carboxylase and (2) the degradative pathway of the branched chain AAs, valine and isoleucine, which contribute succinyl CoA to the TCA cycle. This pathway uses vitamin B12 but not folate in the reaction catalyzed by methylmalonyl CoA mutase.

Front 54

54. What types of fatty acids does the BBB restrict?

Back 54

The BBB restricts the entry of nonessential FAs, such as palmitate, that are released from adipose tissue or present in the diet. B/c the BBB significantly inhibits the entry of certain FAs and lipids into the CNS, virtually all lipids found there must be synthesized within the CNS.

Conversely, essential FAs are taken up by the brain (e.g., linoleic and linolenic acid).

Front 55

55. What is an important type fatty acid that is synthesized in the brain?

Back 55

Very long chain fatty acids are synthesized int he brain, where they play a major role in myelin formation.

As a result, peroxisomal fatty acid oxidation is important in the brain b/c the brain contains very long-chain fatty acids and phytanic acid, both of which are oxidized in the peroxisomes by alpha oxidation.

Front 56

56. What is Refsum disease?

Back 56

Disorders that affect peroxisome biogenesis (such as Refsum) severely affect brain cells b/c of the inability to metabolize both branched chain and very long chain FAs.

Front 57

57. What is the predominant cerebroside?

Back 57

Galactosylcerebroside, which has a single sugar attached to the hydroxyl group of the sphingosine.

Galactocerebrosides pack more tightly together than phosphatidylcholine; the sugar, although polar, carries no positively charged AA or negatively charged phosphate. The high cholesterol content of the membrane also contributes to the tight packing.

Front 58

58. What are the two major myelin structural proteins in the CNS?

Back 58

1. Proteolipid protein (PLP)
2. Myelin basic proteins (MBPs)

Front 59

59. What is PLP?

Back 59

The PLP is a very hydrophobic protein that forms large aggregates in aqueous solution and is relatively resistant to proteolysis.

*It is highly conserved in sequence among species. Its role is thought to be one of promoting the formation and stabilization of the multilayered myelin structure.

Front 60

60. What are the MBPs?

Back 60

The MBPs are a family of proteins. Unlike PLP, MBPs are easily extracted from the membrane and are soluble in aqueous solution. The major MBP has no tertiary structure; it is located on the cytoplasmic face of myelin membranes.

***Antibodies directed against MBPs elicit experimental allergic encephalomyelitis.

Front 61

61. What is the major myelin structural protein in the PNS?

Back 61

Po, a glycoprotein that accounts for > 50% of the PNS myelin protein content. Po is thought to play a similar structural role in maintaining myelin structure as PLP does in the CNS.

MBPs are also found in the PNS. The major PNS-specific MBP is P2.

Front 62

62. Most of the signs and symptoms of catecholamine excess can be masked by...?

Back 62

Phenoxybenzamine, a long acting α1- and α2-receptor antagonist, combined with a β1- and β2-receptor blocker such as propranolol.

This therapy alone is reserved for pts with inoperable pheochromocytomas.

Front 63

63. What is the primary injury to the CNS in MS?

Back 63

The primary injury to the CNS in MS is the loss of myelin in the white matter, which interferes w/nerve conduction along the demyelinated area.

The CNS compensates by stimulating oligodendrocytes to remyelinate the damaged axon, and when this occurs, remission is achieved.

Front 64

64. What is a consequence of the remyelination in MS?

Back 64

Often remyelination leads to a slowing in conduction velocity b/c of a reduced myelin thickness (speed is proportional to myelin thickness) or a shortening of the internodal distances (the action potential has to be propagated more times).

Eventually, when it becomes too difficult to remyelinate large areas of the CNS, the neuron adapts by upregulating and redistributing along its membrane ion pumps, to allow nerve conductance along demyelinated axons. Eventually this adaptation also fails, and the disease progresses.

Front 65

65. Treatment of MS is based on...?

Back 65

Treatment of MS is now based on blocking the action of the immune system. B/c antibodies directed against cellular components appear to be responsible for the progression of the disease, agents that interfere with immune responses have had various levels of success in keeping pts in remission for extended periods.

Front 66

66. What mutation leads to Charcot-Marie-Tooth polyneuropathy syndrome?

Back 66

Inherited mutations in Po (the major PNS myelin protein) leads to a version of Charcot-Marie-Tooth polyneuropathy syndrome.

The inheritance pattern for this disease is autosomal dominant, indicating that the expression of one mutated allele leads to the expression of the disease.

Front 67

67. What mutation leads to Pelizaeus-Merzbacher disease and X-linked spastic paraplegia type 2 disease?

Back 67

Mutations in PLP (the major myelin protein in the CNS) lead to Pelizaeus-Merzbacher disease and X-linked spastic paraplegia type 2 disease.

These diseases display a wide range of phenotypes, from a lack of motor development and early death (most severe) to mild gait disturbances. The phenotype displayed depends on the precise location of the mutation within the protein.

An altered function of either Po or PLP leads to demyelination and its subsequent clinical manifestations.

Front 68

68. What is facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome?

Back 68

In this disorder, GLUT1 transporters are impaired, which results in a low glucose concentration in the CSF (called hypoglycorrhachia).

A diagnostic indication of this disorder is that in the presence of normal blood glucose levels, the ratio of CSF glucose to blood glucose levels is < 0.4.

Clinical features are variable but include seizures, developmental delay, and a complex motor disorder. These symptoms are the result of inadequate glucose levels in the brain. The disorder can be treated by prescribing a ketogenic diet. This will force the pt to produce ketone bodies, which can spare the brain's requirement for glucose as an energy source.

Front 69

69. The mental retardation in untreated PKU and maple syrup urine disease may be attributable to...?

Back 69

High levels of either phenylalanine or branched-chain amino acids in the blood.

These high levels overwhelm the large, neutral AA carrier, so excessive levels of the damaging AA enter the CNS.

In support of this theory is the finding that treatment of PKU pts with large doses of LNAAs that lack phenylalanine resulted in a decrease of phenylalanine levels in the CSF and brain, with an improvement in the pts cognitive functions as well.

Front 70

70. What is reserpine?

How did it help the understanding of depression?

Back 70

Reserpine blocks catecholamine uptake into vesicles and had been used as an antihypertensive and antiepileptic drug for many years, however, it was noted that a small percentage of pts on the drug become depressed and even suicidal.

Thus, a link was forged between monoamine release and depression in humans.

Front 71

71. Why are chromogranins necessary?

Back 71

Chromogranins are required for the biogenesis of the secretory vesicles. When chromogranins are released from the vesicles, they can be proteolytically clipped to form bioactive peptides.

*Elevated levels of chromogranins in the circulation may be found in pts who have neuroendocrine tumors, such as pheochromocytomas.

Front 72

72. In albinism, what enzymes may be defective?

Back 72

In albinism, either the copper-dependent tyrosine hydroxylase of melanocytes (which is distinct from the tyrosine hydroxylase found in the adrenal medulla) or other enzymes that convert tyrosine to melanins may me defective.

Front 73

73. What is tyramine?

Back 73

Tyramine is a degradation product of tyrosine that can lead to headaches, palpitations, nausea and vomiting, and elevated blood pressure if it is present in large quantities.

Tyramine mimics norepinephrine and binds to norepinephrine receptors, stimulating them.

Tyramine is inactivated by MAO-A, but if a person is taking and MAOI, foods containing tyramine should be avoided.

Front 74

74. What are the first generation of MAOIs?

Back 74

The first generation of MAOIs, exemplified by iproniazid, which was originally used as an antituberculosis drug and was found to induce mood swings in pts) were irreversible inhibitors of both the A and B forms of MAO.

Although they did reduce the severity of depression (by maintaining higher levels of serotonin), these drugs suffered from the cheese effect.

Cheese and other foods contain tyramine. Usually tyramine is inactivated by MAO-A, but if an individual is taking an MAOI, tyramine levels increase.

Front 75

75. What about the next generation of MAOIs?

Back 75

When it was realized that MAO existed in two forms, selective irreversible inhibitors were developed; exampled include clorgyline for MAO-A, and deprenyl for MAO-B.

Front 76

76. What is the role of deprenyl?

Back 76

Deprenyl - MAO-B inhibitor; has been used to treat Parkinson's disease. Deprenyl, however, is not an antidepressant.

Front 77

77. What is the role of clorgyline?

Back 77

Clorgyline (MAO-A inhibitor) is an antidepressant but suffers from the cheese effect.

Front 78

78. What is moclobemide?

Back 78

This is a third generation MAOI. Moclobemide is a specific, reversible inhibitor of MAO-A and is effective as an antidepressant.

More important, b/c of the reversible nature of the drug, the cheese effect is not observed, b/c as tyramine levels increase, they displace the drug from MAO, and the tyramine is safely inactivated.

Front 79

79. What is Redux?

Back 79

Redux increases the secretion of serotonin. Drugs that can increase serotonin levels may be able to control appetite and depression.

Redux was a second generation drug developed from fenfluramine, a known appetite suppressant. Redux acts as an SSRI but also increase the secretion of serotonin, leading to elevated levels of this compound in the synapse.

Front 80

80. Why was fenfluramine ineffective?

Back 80

When it was first used, it could not be resolved between two distinct optical isomers. The l-isomer induced sleepiness, so to counteract this effect, fenfluramine was often given with phentermine, which elevated epinephrine levels to counteract the drowsiness (known as fen/phen).

Once the two optical isomers of fenfluramine could be resolved, Redux, dexfenfluramine, was developed.

Front 81

81. What is the result of histamine secretion?

Back 81

Histamine is the major mediator of the allergic response. It leads to vasodilation and an increase in the permeability of blood vessel walls. When it is released in the lungs, the airways constrict in an attempt to reduce the intake of the allergic material. The ultimate result of this, however, is bronchospasm, which can lead to difficult in breathing.

Front 82

82. Is histamine excitatory or inhibitory in the brain?

Back 82

In the brain, histamine is an excitatory neurotransmitter. This is why antihistamines cause drowsiness.

Front 83

83. What causes the neurologic symptoms in vitamin B12 deficiency?

Back 83

It is believed that the vitamin B12 requirement for choline synthesis contributes to the neurolgic symptoms.

The methyl groups for choline synthesis are donated by SAM, which is converted to S-adenosyl homocytsteine in the reaction.

The formation of SAM thru recycling of homocysteine requires both tetrahydrofolate and vitamin B12 (unless extra amounts of methionine are available to bypass the B12-dependent methionine synthase step).

Front 84

84. What can be supplemented in the diet to increase choline synthesis?

Back 84

Supplementation of the diet with lecithin (phosphatidylcholine) has been sued to increased brain ACh in pts suffering from tardive dyskinesia (often persistent involuntary movements of the facial muscles and tongue).

The neonate has a very high demand for choline. High levels of phosphatidylcholine in maternal milk and a high activity of a high affinity transport system thru the BBB for choline in the neonate help to maintain brain choline requirements.

Front 85

85. How does the fetus obtain choline?

Back 85

There is a high affinity transport system for choline across the placenta. The choline is derived from maternal stores, maternal diet, and synthesis primarily in the maternal liver.

B/c choline synthesis is dependent on folate and B12, the high fetal demand may contribute to the increased maternal requirement for both vitamins during pregnancy.

Front 86

86. What are the results of an inherited pyruvate dehydrogenase deficiency, a thiamine deficiency, or hypoxia?

Back 86

In all these conditions, the brain is deprived of a source of acetyl CoA for ACh synthesis, as well as a source of acetyl CoA for ATP generation from the TCA cycle.

Front 87

87. What is tiagabine?

Back 87

Tiagabine is a drug that inhibits the reuptake of GABA from the synapse, and it has been used to treat epilepsy as well as other convulsant disorders.

B/c GABA is an inhibitory neurotransmitter in the brain, its prolonged presence can block neurotransmission by other agents, thereby reducing the frequency of convulsions.

Front 88

88. What is the normal rate of cerebral blood flow?

Back 88

The normal blood flow thru the brain of the adult person averages 50-65 mL per 100 g of brain tissue per minute.

For the entire brain, this amts to 750-900 ml/min, or 15% of the resting cardiac output.

Front 89

89. What three metabolic factors have potent effects in controlling cerebral blood flow?

Back 89

1. Carbon dioxide concentration
2. Hydrogen ion concentration
3. Oxygen concentration

Front 90

90. How does carbon dioxide concentration in the arterial blood perfusing the brain effect cerebral blood flow?

Back 90

An increase in carbon dioxide concentration greatly increases the cerebral blood flow.

Carbon dioxide is believed to increase cerebral blood flow by combining first with water in the body fluids to form carbonic acid, with subsequent dissociation of this acid to form hydrogen ions.

The hydrogen ions then cause vasodilation of the cerebral vessels - the dilation being almost directly proportional to the increase in hydrogen ion concentration up to a blood flow limit of about 2x normal.

Front 91

91. How does the acidity of the brain tissue (hydrogen ion concentration) affect cerebral blood flow?

Back 91

Any other substance that increases the acidity of the brain tissues will likewise increase cerebral blood flow.

Such substances include lactic acid, pyruvic acid, and any other acidic material formed during the course of tissue metabolism.

Front 92

92. What is the importance of cerebral blood flow control by carbon dioxide and hydrogen ions?

Back 92

Increased hydrogen ion concentration greatly depresses neuronal activity. Therefore, an increase in hydrogen ion concentration causes an increase in blood flow, which in turn carries hydrogen ions, carbon dioxide and other acid forming substances away from the brain tissues.

Thus, this mechanism helps maintain a constant hydrogen ion concentration in the cerebral fluids and thereby helps to maintain a normal, constant level of neuronal activity.

Front 93

93. Oxygen deficiency in the brain causes does...?

Back 93

If blood flow to the brain ever becomes insufficient to supply the needed amt of oxygen, the oxygen deficiency mechanism for causing vasodilation immediately causes vasodilation, returning the brain blood flow and transport of oxygen to the cerebral tissues to near normal.

Thus, this local blood flow regulatory mechanism is almost exactly the same in the brain as in coronary vessels, in skeletal muscle, and in most other ares of the body.

Front 94

94. A decrease in cerebral tissue PO2 below ____ begins to increase cerebral blood flow?

Back 94

Below about 30 mm Hg (normal value is 35 to 40 mm Hg).

This is important b/c brain function becomes deranged at not much lower values of PO2, esp so at PO2 levels below 20 mm Hg. Even coma can result at these low levels.

Front 95

95. How does the blood flow in the brain change in response to neuronal activity?

Back 95

It has become clear that blood flow in each segment of the brain changes as much as 100-150% within seconds in response to changes in local neuronal activity.

Front 96

96. How is the cerebral blood flow regulated when the arterial pressure changes?

Back 96

Cerebral blood flow is autoregulated extremely well between arterial pressure limits of 60-140 mm Hg. That is the mean arterial pressure can be between these values without significant changes in cerebral blood flow.

But, if the arterial pressure falls below 60 mm Hg, the cerebral blood flow then does becomes severely depressed.

Front 97

97. What is the sympathetic innervation to the brain?

Back 97

The cerebral circulatory system has strong sympathetic innervation that passes upward from the superior cervical ganglia in the neck and then into the brain along with the cerebral arteries. This innervation supplies both the large brain arteries and the arteries that penetrate into the substance of the brain.

However, transection of the sympathetic nerves or mild to moderate stimulation of them usually causes very little change in cerebral blood flow b/c the blood flow autoregulation mechanism can override the nervous effects.

Front 98

98. What is the role of the sympathetic nervous system in controlling cerebral blood flow?

Back 98

When mean arterial pressure rises acutely to an exceptionally high level, such as during strenuous exercise, the sympathetic nervous system normally constricts the large- and intermediate-sized brain arteries enough to prevent the high pressure from reaching the smaller brain blood vessels.

*This is important in preventing vascular hemorrhages in the brain (cerebral stroke).

Front 99

99. What is the cerebral microcirculation?

Back 99

The number of blood capillaries in the brain is greatest where the metabolic needs are greatest.

The overall metabolic rate of the brain gray matter where the neuronal cell bodies lie is about 4x as great as that of white matter; correspondingly, the number of capillaries and rate of blood flow are also about 4x as great in the gray matter.

Front 100

100. What is an important structural characteristic of the brain capillaries?

Back 100

They are much less "leaky" than the blood capillaries in almost any other tissue of the body.

A reason for this is that the capillaries are supported on all sides by glial feet, which are small projections from the surrounding glial cells that abut against all surfaces of the capillaries and provide physical support to prevent overstretching of the capillaries in case of high capillary blood pressure.

Front 101

101. What happens to the walls of the small arterioles leading to the brain capillaries in people with HTN?

Back 101

The walls of the small arterioles leading to the brain capillaries become greatly thickened in ppl with HTN. These arterioles remain significantly constricted all the time to prevent transmission of the high pressure to the capillaries.

Front 102

102. What causes most strokes?

Back 102

Cerebral strokes occur when cerebral blood vessels are blocked.

Most strokes are caused by arteriosclerotic plaques that occur in one or more of the feeder arteries to the brain. The plaques can activate the clotting mechanism of the blood, causing a blood clot to occur and block blood flow in the artery, thereby leading to acute loss of brain function in the localized area.

Front 103

103. One of the most common types of stroke is blockage of what artery?

Back 103

The middle cerebral artery that supplies the midportion of one brain hemisphere. For instance, if the MCA is blocked on the left side of the brain, the person is likely to become almost totally demented b/c of lost function in Wernicke's speech comprehension areas in teh left cerebral hemisphere, and he or she also becomes unable to speak words b/c of loss of Broca's motor area for word formation. In addition, loss of function of neural motor control areas of the left hemisphere can create spastic paralysis of most muscle son the opposite side of the body.

Front 104

104. What about blockage of the PCA?

Back 104

Blockage of a PCA will cause infarction of the occipital pole of the hemisphere on the same side as the blockage, which causes loss of vision in both eyes in the half of the retina on the same side as the stroke lesion.

Front 105

105. Why are strokes involving the midbrain especially devastating?

Back 105

This can block nerve conduction in major pathways between the brain and spinal cord, causing both sensory and motor abnormalities.

Front 106

106. What is the capacity of the cerebral cavity? How much of it is taken up by the CSF?

Back 106

Capacity of entire cerebral cavity = 1600-1700 mL

About 150 mL of this is occupied by the CSF and the remainder by the brain and cord.

The CSF is present in the ventricles of the brain, in the cisterns around the outside of the brain, and in the subarachnoid space around both the brain and the spinal cord.

Front 107

107. What is a major function of the CSF?

Back 107

To cushion the brain within its solid vault. The brain simply floats in the CSF.

Front 108

108. What is a contrecoup injury?

Back 108

When a blow to the head is extremely severe it may not damage the brain on the side of the head where the low is struck but on the opposite side.

If on same side as impact injury = coup injury

Front 109

109. What parts of the brain are often the sites of injury and contusions after a severe blow to the head?

Back 109

The poles and the inferior surfaces of the frontal and temporal lobes, where the brain comes into contact with bony protuberances in the base of the skull.

Front 110

110. What is the rate of formation fo teh CSF?

Back 110

The CSF is formed at a rate of about 500 mL each day, which is 3-4x as much as the total volume of fluid in the CSF system.

About 2/3's or more of this fluid originates as secretion from the chorioid plexuses in the four ventricles, *mainly in the two lateral ventricles.

Front 111

111. After the CSF flows into the two lateral foramina of Luschka and a midline foramen of Magendie, where does it go?

Back 111

It enters the cisterna magna, a fluid spaces that lies behind the medulla and beneath the cerebellum.

The cisterna magna is continuous with the subarachnoid space that surrounds the entire brain and spinal cord. Almost all the CSF then flows upward from the cisterna magna thru the subarachnoid spaces surrounding the cerebrum. From here, the fluid flows into and thru multiple arachnoidal villi that project into the large sinuses.

Front 112

112. The choroid plexus projects into what four areas?

Back 112

1. Temporal horn of right lateral ventricle
2. Temporal horn of left lateral ventricle
3. Posterior portion of the third ventricle
4. Roof of the fourth ventricle

Front 113

113. Secretion of fluid into the ventricles by the choroid plexus depends mainly on...?

Back 113

Active transport of sodium ions thru the epithelial cells lining the outside of the plexus.

The sodium ions in turn pull along large amts of chloride ions as well b/c the positive charge of the sodium ions attracts the chloride ion's negative charge.

The two of these together increase the quantity of osmotically active sodium chloride in the CSF, which then causes almost immediate osmosis of water thru the membrane, thus providing the fluid of the secretion.

Front 114

114. What are the characteristics of the composition of CSF in comparison to the plasma?

Back 114

Osmotic pressure, approx equal to that of plasma

Sodium ion concentration; also approx equal to that of plasma

Chloride ion, about 15% greater than in plasma

Potassium ion: approx 40% less

Glucose: about 30% less

Front 115

115. Absorption of CSF occurs through...?

Back 115

The arachnoidal villi are microscopic fingerlike inward projections of the arachnoidal membrane thru the walls and into the venous sinuses.

Conglomerates of these villi form macroscopic structures called arachnoidal granulations that can be seen protruding into the sinuses.

Front 116

116. What three things are allowed relatively free flow in the arachnoidal villi?

Back 116

1. CSF
2. Dissolved protein molecules
3. Particles as large as red and white blood cells into the venous blood

Front 117

117. What is the pia mater and the perivascular space?

Back 117

The large arteries and veins of the brain lie on the surface of the brain but their ends penetrate inward, carrying with them a layer of pia mater, the membrane that covers the brain.

The pia is only loosely adherent to the vessels, so that a space, the perivascular space, exists between it and each vessel.

Therefore, perivascular spaces follow both the arteries and the veins into the brain as far as the arterioles and venules go.

Front 118

118. What is the lymphatic function of the vascular space?

Back 118

A small amt of protein leaks out of the brain capillaries into the interstitial spaces of the brain. B/c no true lymphatics are present in brain tissue, excess protein in the brain tissue leaves the tissue flowing with fluid thru the perivascular spaces into the subarachnoid spaces. On reaching the subarachnoid spaces, the protein then flows with the CSF and is absorbed thru the arachnoidal villi into the large cerebral veins.

Therefore, perivascular spaces are a specialized lymphatic system for the brain.

Front 119

119. What is the normal CSF pressure when one is lying in a horizontal position?

Back 119

Avgs 130 mm of water (100 mm Hg), although is may be as low as 65 mm or as high as 195 even in the normal healthy person.

Front 120

120. What regulates the CSF pressure?

Back 120

The arachnoidal villi. They function like valves that allow CSF and its contents to flow readily into the blood of the venous sinuses while not allowing blood to flow backward in the opposite direction.

Normally, this valve action allows CSF to flow into the blood when CSF pressure is about 1.5 mm Hg greater than the pressure of blood in the venous sinuses. Then, if the pressure still rises, the valves open more widely.

Front 121

121. What can block the villi?

Back 121

In some disease state, the villi sometimes become blocked by large particulate matter, by fibrosis, or by excesses of blood cells that have leaked into the CSF in brain disease. Such blockage can cause high CSF pressure.

Front 122

122. What can increase the CSF pressure?

Back 122

1. Large brain tumors
2. Hemorrhage or infarction due to large numbers of RBCs and WBCs
3. Some babies are born with hydrocephalus due to an abnormally high resistance to fluid reabsorption thru the arachnoidal villi.

Front 123

123. How does one measure the CSF pressure?

Back 123

The person lies horizontal so the pressure in the spinal canal is equal to that in the cranial vault.

A spinal needle is then inserted into the lumbar spinal canal and the needle is connected to a vertical glass tube that is open to the air at its top. The spinal fluid is allowed to rise in the tube as high as it will.

Whatever level it rises to above the level of the needle, is indicative of the actual pressure.

Front 124

124. High CSF pressure causes...?

Back 124

Papilledema. When the pressure in the CSF rises, ti also rises inside the optic nerve sheath. The retinal artery and vein pierce this sheath a few mm behind the eye and then pass along with the optic nerve fibers into the eye itself.

Front 125

125. What are three things that cause papilledema due to high CSF pressure?

Back 125

1. High CSF pressure pushes fluid first into the optic nerve sheath and then along the spaces between the optic nerve fibers to the interior of the eyeball.
2. The high pressure decreases outward fluid flow in the optic nerves, causing accumulation of excess fluid in the optic disc
3. The pressure in the sheath also impeded flow of blood in the retinal vein, thereby increasing the retinal capillary pressure throughout the eye, which results in still more retinal edema.

Front 126

126. What is noncommunicating hydrocephalus?

Back 126

Usually the noncommunicating type is caused by a block in the aqueduct of Sylvius, resulting from atresia before birth in many babies or from blockage by a brain tumor at any age.

As fluid is formed in the 2 lateral and third ventricles, the volumes of these three ventricles increase greatly. This flattens the brain into a thin shell against the skull.

Front 127

127. What is the communicating type of hydrocephalus?

Back 127

The communicating type is usually caused by blockage of fluid flow in the subarachnoid spaces around the basal regions of the brain or by blockage of the arachnoidal villi where the fluid is normally absorbed into the venous sinuses.

Fluid therefore collects both on the outside of the brain and to a lesser extent inside the ventricles.

Front 128

128. BBBs exist at the choroid plexus and at the tissue capillary membranes in essentially all areas of the brain parenchyma except...?

Back 128

Except in some areas of the hypothalamus, pineal gland, and area postrema, where substances diffuse with greater ease into the tissue spaces.

The ease of diffusion in these areas is important b/c they have sensory receptors that respond to specific changes in the body fluids such as changes in osmolality and in glucose concentration, as well as receptors for peptide hormones that regulate thirst, such as angiotensin II. It also has specific carrier molecules that facilitate transport of hormones, such as leptin, to control appetite.

Front 129

129. The BBBs are highly permeable/impermeable to...?

Back 129

Permeable to water, carbon dioxide, oxygen, and most lipid soluble substances such as alcohol and anesthetics.

It has slight permeability to electrolytes such as sodium, chloride, and potassium.

It is totally impermeable to plasma proteins and most non-lipid-soluble large organic molecules.

Front 130

130. What is the cause of the low permeability of the BBB?

Back 130

The endothelial cells are joined together by tight junctions.

Front 131

131. What is the usual cause of brain edema?

Back 131

The usual cause is either greatly increased capillary pressure or damage to the capillary wall that makes the wall leaky to fluid.

A very common cause is a serious blow to the head, leading to brain concussion, in which the brain tissues and capillaries are traumatized so that capillary fluid leaks into the traumatized tissues.

Front 132

132. What are the two vicious circles of brain edema once it begins?

Back 132

1. Edema compresses the vasculature, which causes brain ischemia. The ischemia in turn causes dilation with sill further increase in capillary pressure. The increased capillary pressure then causes more edema fluid.

2. The decreased cerebral blood flow also decreases oxygen delivery. This increases the permeability of the capillaries, allowing still more fluid leakage. It also turns off the sodium pumps of the neuronal tissue cells, thus allowing these cells to swell in addition.

*Concentrated mannitol solution can be used to stop this.

Front 133

133. What is the brain metabolic rate under resting but awake conditions?

Back 133

The resting brain accounts for 15% of the total metabolism in the body. Therefore, even under resting conditions, brain metabolism per unit mass of tissue is about 7.5x the avg metabolism in non-nervous system tissues.

*Most of this excess metabolism of the brain occurs in the neurons not in the glial supportive tissues.

Front 134

134. What is the major need for metabolism in the neurons?

Back 134

Mainly to pump ions through their membranes; transport sodium and calcium ions to the outside of the neuronal membrane and potassium ions to the interior.

Front 135

135. Is the brain capable of anaerobic metabolism?

Back 135

The brain is not capable of much anaerobic metabolism. One of the reasons for this is the high metabolic rate of the neurons, so that most neuronal activity depends on second-by-second delivery of oxygen from the blood.

Front 136

136. Is glucose delivery to the neurons dependent on insulin?

Back 136

No. Therefore, there is no loss of mental function in diabetic pts.

However, when a diabetic pt is overtreated with insulin, the blood glucose levels fall so low that not enough glucose is left in the blood to supply the neurons properly and mental function does then become seriously deranged, sometimes leading to coma.

Front 137

137. What do Neisseria look like?

Back 137

Neisseria are Gram-negative diplococci that are flattened on the adjoining sides, giving the pair the shape of a coffee bean.

These aerobic bacteria have stringent nutritional requirements and grow best on enriched media such as lysed sheep's blood agar (chocolate agar).

The two clinically significant Neisseria are N. meningitidis and N. gonorrhoeae.

Front 138

138. What is N. meningitidis?

Back 138

N. meningitidis is a significant cause of bacterial meningitis, particularly among people ages 5-19. The organism is a common colonizer of the oropharynx and is spread by the respiratory route.

There are at least 13 serotypes of N. meningitidis. Invasive disease mainly occurs when people living in crowded quarters encounter new strains to which they are not immune..

Front 139

139. Do all people get meningitis in the absence of an immune response to N. meningitidis?

Back 139

Even in the absence of an immune response, only a small fraction of those infected get meningitis. The bacteria must invade respiratory epithelial cells and travel to the basolateral side of the cells to enter the blood.

Once in the blood, the capsule of the bacteria reduces opsonization and destruction of the bacteria by complement proteins. Regardless, the efficacy of complement against N. meningitidis is very good. Perople without MAC (C5-C9) have high rates of disease.

Front 140

140. What is N. gonorrhoeae?

Back 140

N. gonorrhoeae is an important cause of STD,. It is second only to Chlamydia as a causative agent of STD.

Infection in men causes urethritis. In women, infection is often asymptomatic and so might go untreated. Untreated infection can lead to pelvic inflammatory disease, which can cause infertility or ectopic pregnancy.

Front 141

141. How does N. gonorrhoeae usually manifest?

Back 141

As a local infection in the genital or cervical mucosa, pharynx, or anorectum, however, disseminated infections may occur. In ppl with deficient MAC, disseminated infection is highly likely.

Disseminated infection of adults and adolescents usually causes septic arthritis accompanied by a rash of hemorrhagic papules and pustules. Neonatal N. gonorrhoeae infection causes blindness, and rarely sepsis.

Front 142

142. What are the virulence factors for Neisseria?

Back 142

Neisseria organisms use antigenic variation to evade immune responses. Neisseria adhere to and invade non-ciliated epithelial cells at the site of entry. Bacterial persistence or invasion depends on escape from immune defenses.

The antigenic variation arises by expression of alternative genes for adhesive pili (which bind to CD46) and OPA proteins. OPA proteins increase binding of Neisseria to epithelial cells and promote entry of bacteria.

Front 143

143. What is whooping cough?

Back 143

Whooping cough is caused by the Gram-negative coccobacillus Bordetella pertussis, and is an acute, highly communicable illness characterized by paroxysms of violent coughing followed by a loud inspiratory "whoop".

Front 144

144. What is the pathogenesis of whooping cough?

Back 144

B. pertussis colonizes the brush border of the bronchial epithelium and also invades macrophages. *Coordinated expression of virulence factors is regulated by the Bordetella virulence gene locus (bvg). BVGS is a transmembrane protein that sense signals that induce expression of virulence factors.

Pertussis toxin ADP ribosylates and inactivates guanine nucleotide-binding proteins. As a result, G-proteins cannot transduce plasma membrane receptor signals. The toxins produced by B. pertussis paralyze the cilia, thus impairing an important pulmonary defense.

Front 145

145. What is the morphology of whooping cough?

Back 145

Bordetella bacteria cause a laryngotracheobronchitis that in severe cases features bronchial mucosal erosion, hyperemia, and copious mucopurulent exudate. Unless superinfected, the lung alveoli remain open and intact.

In parallel with a striking peripheral lymphocytosis, there is hypercellularity and enlargement of the mucosal lymph follicles and peribronchial lymph nodes.

Front 146

146. What is pseudomonas infection?

Back 146

Pseudomonas aeruginosa is an opportunistic aerobic Gram-negative bacillus that is a frequent, deadly pathogen of pts with CF, severe burns, or neutropenia. P. aeruginosa is a common cause of hospital acquired infections.

P. aeruginosa also causes a corneal kertatitis in wearers of contact lenses, endocarditis and osteomyelitis in IV drug abusers, external otitis in healthy individuals, and severe external otitis in diabetics.

Front 147

147. What is the pathogenesis of pseudomonas infection?

Back 147

P. aeruginosa has pili and adherence proteins that bind to eptihelial cells and lung mucin, as well as an endotoxin that causes the symptoms of gram-negative sepsis.

In the lungs of pts with CF, these bacteria secrete a mucoid exopolysaccharide called alginate, forming a slimy biofilm in which bacteria are protected from antibodies, complement, phagocytes, and antibiotics.

The organisms also secrete exotoxin A, which inhibits protein synthesis by ADP-ribosylating EF-2.

Front 148

148. What else does pseudomonas secrete?

Back 148

P. aeruginosa also releases exoenzyme S, which may interfere with host cell growth.

They also secrete phospholipase C that lyses RBCs and degrades pulmonary sufactant, and an elastase that degrades IgGs and ECM proteins. These enzymes may be important in tissue invasion and destruction of the cornea in keratitis.

Front 149

149. What is the morphology of Pseudomonas pneumonia?

Back 149

Pseudomona pneumonia is the prototype of necrotizing inflammation, distributing thru the terminal airways in a fleur-de-lis pattern, w/striking whitish necrotic centers and red, hemorrhagic peripheral areas. On microscopic exam, masses of organisms cloud the tissue w/a blush haze, concentrating in the wall of blood vessels.

This picture of Gram-negative vasculititis accompanied by thrombosis and hemorrhage is highly suggestive of P. aeruginosa infection.

Front 150

150. What is the morphology CF pts with pseudomonas?

Back 150

Bronchial obstruction caused by mucous plugging and subsequent P. aeruginosa infection are frequent complications of CF. Despite antibiotic treatment, chronic P. aeruginosa infection may result in bronchiectasis and pulmonary fibrosis.

Front 151

151. What is the morphology of P. aeruginosa in skin burns?

Back 151

In skin burns, P. aeruginosa proliferates widely, penetrating deeply into the veins and spreading to cause massive bacteremias.

Well demarcated and necrotic and hemorrhagic skin lesions of oval shape often arise during these bacteremias, called ecthyma gangrenosum. DIC is a frequent complication of bacteremia.

Front 152

152. What is the plague?

Back 152

Yersinia pestis is a gram-negative facultative intracellular bacterium that is transmitted by fleabites or aerosols and causes a highly invasive, frequently fatal systemic infection called plague.

Front 153

153. How does the Yersinia infect?

Back 153

The pathogenic Yersinia proliferate w/in lymphoid tissue.

These organisms have a complex of genes, called the Yop virulon, which enable the bacteria to kill host phagocytes, weakening the immune system. The Yop virulon includes a type III secretion system, which is a hollow syringe-like structure that injects bacterial toxins, called Yops into the cell.

The toxins block phagocytosis and cytokine production.

Front 154

154. What is the morphology of Y. pestis infection?

What are 4 distinctive histologic feature?

Back 154

Y. pestis causes lymph node enlargement (buboes), pneumonia, or sepsis, all with a striking neutrophilia.

The distinctive histologic features are:
1. Massive proliferation of the organisms
2. Early appearance of protein rich and polysaccharide-rich effusions with few inflammatory cells but with marked tissue swelling
3. Necrosis of tissues and blood vessels with hemorrhage and thrombosis
4. Neutrophilic infiltrates that accumulate adjacent to necrotic areas as healing begins.

Front 155

155. What is the morphology of bubonic plague?

Pneumonic and septicemic plague?

Back 155

In bubonic plague, the infected fleabite is usually on the legs and is marked by a small pustule or ulceration. The draining lymph nodes enlarge dramatically within a few days and become soft, pulpy, and plum colored and may infarct or rupture thru the skin.

In pneumonic plaque, there is a severe, confluent, hemorrhagic, and necrotizing bronchopenumonia, often with fibrinous pleuritis.

In septicemic plague, lymph nodes throughout the body as well as organs rich in mononuclear phagocytes develop foci of necrosis. Fulminant bacteremias also induce DIC with widespread hemorrhages and thrombi.

Front 156

156. What is a chancroid?

Back 156

Chancroid is an acute, sexually transmitted, ulcerative infection caused by Hemophilus ducreyi. This disease is most common in tropical and subtropical areas and is more prevalent in lower socioeconomic groups and among men who have regular contact with prostitutes.

*Chancroid is one of the most common causes of genital ulcers in Africa and Southeast Asia, which it probably serves as an important cofactor in the transmission of HIV-1 infection.

Front 157

157. What is the development of a chancroid like?

Back 157

4-7 days after inoculation, the pt develops a tender, erythematous papule involving the external genitalia. In males, the primary lesion is usually on the penis; in females, most lesions occur in the vagina or the periurethral area.

Over the course of several days, the surface of the primary lesion erodes to produce an irregular ulcer, which is more apt to be PAINFUL in males than in females.

Front 158

158. What is the morphology of a chancroid?

Back 158

In contrast to the primary chancre of syphilis, the ulcer of chancroid is not indurated, and multiple lesions may be present. The base of the ulcer is covered by shaggy, yellow-gray exudate. The regional lymph nodes in the inguinal region become enlarged and tender and can progress to erode or ulcerate and drain.

Front 159

159. What are the microscopic features of a chancroid ulcer?

Back 159

Microscopically, the ulcer contains a superficial zone of neutrophilic debris and fibrin, w/an underlying zone of granulation tissue containing areas of necrosis and thrombosed vessels.

A dense, lymphoplasmacytic inflammatory infiltrate is present beneath the layer of granulation tissue.

Front 160

160. What is a granuloma inguinale?

Back 160

Granuloma inguinale, or donovanosis, is a chronic inflammatory disease caused by Calymmatobacterium donovani, a minute, encapsulated, coccobacillus that is related to the Klebsiella genus. The organism is sexually transmitted.

Untreated cases are characterized by the development of extensive scarring, often associated with lymphatic obstruction and lymphedema (elephantitis).

Front 161

161. What is the morphology of granuloma inguinale?

Back 161

Granuloma inguinale begins as a raised, papular lesion involving the moist, stratified squamous epithelium of the genitalia, or the extragenital sites include the oral mucosa or pharynx. The lesion eventually undergoes ulceration, accompanied by the development of abundant granulation tissue, which is manifested grossly as a protuberant, soft, painless mass.

Front 162

162. What are the microscopic features of C. donovani infection?

Back 162

Microscopic exam of active lesions reveals marked epithelial hyperplasia at the borders of the ulcer, sometimes mimicking CA (pseudoepithleiiomatous hyperplasia).

A mixture of neutrophils and mononuclear inflammatory cells is present at the base of the ulcer beneath the surrounding epithelium. The organisms are demonstrable in Giemsa stained smears of the exudate as minute, encapsulated coccobacilli (Donovan bodies) in macrophages.

Front 163

163. What are mycobacteria?

Back 163

Bacteria in the genus Mycobacterium are slender, aerobic rods that grow in straight or branching chains. Mycobacterium have a waxy cell wall composed of mycolic acid, meaning they are acid fast and will retain stains even on treatment with a mixture of acid and alcohol. Mycobacteria stain weakly positive with Gram stain.

Front 164

164. In what areas/populations is tuberculosis more common?

Back 164

Tuberculosis flourishes wherever there is poverty, crowding and chronic debilitating illness. In the US, tuberculosis is mainly a disease of the elderly, the urban poor and people with AIDS.

*Certain disease states also increase the risk: DM, Hodgkin's lymphoma, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition, alcoholism, and immunosuppression.

Front 165

165. What is the difference between tuberculosis infection and disease?

Back 165

Infection is the presence of organisms, which may or may not cause clinically significant disease. Most infections are acquired by person-to-person transmission of airborne droplets of organisms from an active case to a susceptible host. In most people, primary tuberculosis is asymptomatic, although it may cause fever and pleural effusion.

Generally, the only evidence of infection, if any remains, is a tiny, fibrocalcific nodule at the site of the infection. Viable organisms may remain dormant in such lesions for decades. When the person's immune defenses are lowered, the infection may reactivate to produce communicable and potentially life-threatening disease.

Front 166

166. How is tuberculosis infection detected?

Back 166

Infection w/M. tuberculosis typically leads to the development of delayed hypersensitivity to M. tuberculosis antigens, which can be detected by the tuberculin (Mantoux) test. About 2-4 weeks after infection, intracutaneous injection of purified protein derivative (PPD) of M. tuberculosis induces a visible and palpable induration that peaks in 48-72 hours.

A positive tuberculin test result signifies cell-mediated hypersensitivity to tubercular antigens. It does not, however, differentiate between infection and disease.

Front 167

167. What is the pathogenesis of tuberculosis?

Back 167

The pathoglogical manifestations of tuberculosis, such as caseating granulomas and cavitation, are the result of the hypersensitivity that is part and parcel of the host immune response. B/c the effector cells that mediate immunity also mediate hypersensitivity and tissue destruction, the appearance of hypersensitivity also signals the acquisition of immunity to the organism.

*Macrophages are the primary cells infected by M. tuberculosis. Early in infection, tuberculosis bacilli replicate essentially unchecked, while later in infection, the T-helper response stimulates macrophages to contain the proliferation of the bacteria.

Front 168

168. How does M. tuberulosis enter macrophages?

Back 168

Via endocytosis mediated by several macrophage receptors: mannose receptors bind liparabinomannan, and complement receptors bind opsonized mycobacteria.

Front 169

169. Once in the macrophage, what does the mycobacteria do?

Back 169

Within macrophages, M. tuberculosis blocks phagosome-lysosome fusion, allowing unchecked bacterial proliferation in the phagosome.

Thus the earliest stage of primary tuberculosis (<3 weeks) in the nonsensitized individual is characterized by the proliferation of bacteria in the pulmonary alveolar macrophages and air-spaces, with resulting bacteremia and seeding of multiple sites. Despite the bacteremia, most pts at this stage are asymptomatic or have a mild flulike illness.

Front 170

170. People with a polymorphism in what gene may allow disease development without an effective immune response?

Back 170

Polymorphisms in the NRAMP1 gene. NRAMP1 protein is a transmembrane protein found in endosomes and lysosomes that pumps divalent cations into the lysosome. This may have a role in generation of anti-microbial oxygen radicals.

Front 171

171. What happens about 2 weeks after infection with tuberculosis?

Back 171

A TH1 response against M. tuberculosis is mounted that activates macrophages to become bactericidal. TH1 cells are stimulated by mycobacterial antigens drained to the lymph node, which are presented with MHC II proteins by APCs.

Differentiation of TH1 cells depends on the presence of IL-12, which is produced by APCs that have encountered the mycobacteria.

Front 172

172. What is the critical mediator which drives the macrophages to become competent to contain the M. tuberculosis infection?

Back 172

IFN-γ, produced by mature TH1 cells.

IFN-γ stimulates formation of the phagolysosomes in infected macrophages, exposing the bacteria to an acidic environment. IFN-γ also induces the expression of iNOS, which produces NO to help destroy the mycobacteria.

Front 173

173. In addition to stimulates macrophages to kill mycobacteria, what else does the TH1 response do?

Back 173

The TH1 response orchestrates the formation of granulomas and caseous necrosis.

Activated macrophages, stimualted by IFN-γ, produce TNF, which recruits monocytes. These monocytes differentiate into the "epithelioid histiocytes" that characterize the granulomatous response.

Front 174

174. Pts with RA who are treated with a TNF antagonist have an increased/decreased risk of tuberculosis reactivation?

Back 174

Pts with RA who are treated with a TNF antagonist have an increased risk of tuberculosis reactivation.

Front 175

175. Defects in any of the steps in generating a TH1 response results in...?

Back 175

Results in absence of resistance, and disease progression.

Front 176

176. What are the features of reactivation of the infection or re-exposure?

Back 176

Results in rapid mobilization of a defensive reaction but also increased tissue necrosis.

Front 177

177. What is primary tuberculosis?

Back 177

Primary tuberculosis is the form of disease that develops in a previously unexposed, and therefore unsensitized person.

95% of people have asymptomatic infections with a persistent, latent lung infection focus.

5% have symptomatic infections with lobar consolidation, hilar adenopathy, and pleural effusion (progressive primary tuberculosis).

Front 178

178. What is the difference between primary tuberculosis and progressive primary tuberculosis?

Back 178

Progressive primary tuberculosis more often resembles an acute bacterial pneumonia, with lower and middle lobe consolidation, hilar adenopathy, and pleural effusion.

*Cavitation is rare, especially in pts with severe immunosuppresison.

Front 179

179. What causes tuberculous meningitis and miliary tuberculosis?

Back 179

Lymphohematogenous dissemination is a dreaded complication and may result in the development of tuberculos meningitis and miliary tuberculosis.

Front 180

180. What is secondary tuberculosis?

Back 180

Secondary tuberculosis is the pattern of disease that arises in a previously sensitized host.

Infectious usually occurs from reactivation of latent infection when immune resistance is weakened.

Typically, infection causes cavitation in apex of upper lung lobes, with associated low-grade fever, night sweats, and weight loss.

Front 181

181. Secondary pulmonary tuberculosis is classically localized to what part of the lungs...?

Back 181

The apex of the upper lobes or one or both lungs. This may be b/c the high oxygen tension in the apices promotes growth of the bacteria. As a result of this localization, the regional lymph nodes are less prominently involved early in the secondary disease that they are in primary tuberculosis.

On the other hand, cavitation occurs readily in the secondary form, resulting in dissemination of mycobacteria along the airways.

Front 182

182. HIV pts with CD4+ T cell counts greater than 300 cells/mm present with...?

Back 182

Usual secondary tuberculosis (apical disease w/cavitation)

Front 183

183. HIV pts with CD4+ T cell counts less than 200 cells/mm present with...?

Back 183

A clinical picture that resembles progressive primary tuberculosis (lower and middle lobe consolidation, hilar lymphadenopathy, and non-cavitary disease).

The extent of immunodeficiency also increases the freq of extrapulmonary involvement,.

*However, there is alack of characteristic granulomas in tissues, particularly in the late stages of HIV.

Front 184

184. What is the morphology of primary tuberculosis?

Back 184

As sensitization develops to an inhaled bacilli in the lung, a 1 to 1.5 cm area of gray-white inflammatory consolidation emerges, known as the Ghon focus.

In most cases, the center of this focus undergoes caseous necrosis. Tubbercule bacilli drain to the regional lymph nodes, which also often caseate.

*This combination of parenchymal lung lesion and nodal involvement is referred to as the Ghon complex.

The Ghon complex undergoes progressive fibrosis, often followed by radiologically detectable calcification (Ranke complex).

Front 185

185. What are the histological characteristics of primary tuberculosis?

Back 185

The sites of active involvement are marked by a characteristic granulomatous inflammatory reaction that forms both caseating and non-caseating tubercules.

Individual tubercles are microscopic; it is only when they coalesce into granulomas that they become macroscopically visible.

Front 186

186. What is the morphology of secondary tuberculosis?

Back 186

The initial lesion is usually a small focus of consolidation, less than 2 cm in diameter, within 1-2 cm of the apical pleura. Such foci are sharply circumscribed, firm, gray-white to yellow areas that have a variable amt of central caseation and peripheral fibrosis.

Histologically, the active lesions show characteristic coalescent tubercles with central caseation.

Localized apical, secondary pulmonary tuberculosis may head with fibrosis either spontaneously or after therapy, or the disease may progress and extend along several different pathways.

Front 187

187. What is the morphology of progressive pulmonary tuberculosis?

Back 187

Progressive pulmonary tuberculosis may ensue in the elderly and immunosuppressed. The apical lesion enlarges w/expansion of the area of caseation. Erosion into a bronchus evacuates the caseous center, creating a ragged, irregular cavity lined by caseous material that is poorly walled off by fibrous tissue.

Erosion of blood vessels results in hemoptysis.

***The pleural cavity is invariably involved, and serous pleural effusions, tuberculous empyema, or obliterative fibrous pleuritis may develop.

Front 188

188. What is miliary pulmonary disease?

Back 188

Miliary pulmonary disease occurs when organisms drain thru lymphatics into the lymphatic ducts, which empty into the venous return to the right side of the heart and thence into the pulmonary arteries.

Individual lesions are either microscopic or small, visible (2 mm) foci of yellow-white consolidation scattered thru the lung parenchyma.

Miliary lesions may expand and coalesce to yield almost total consolidation of large regions or even whole lobes of the lung.

Front 189

189. What is endobronchial, endotracheal, and laryngeal tuberculosis?

Back 189

These may develop when infective material is spread either thru lymphatic channels or from expectorated infectious material.

The mucosal lining may be studded with minute granulomatous lesions, sometimes apparent only on microscopic exam.

Front 190

190. What is systemic miliary tuberculosis?

Back 190

Systemic miliary tuberculosis ensues when infective foci in the lungs seed the pulmonary venous return to the heart; the organisms subsequently disseminate thru the systemic arterial system. Almost every organ in the body can be seeded.

Lesions resemble those in the lung. Miliary tuberculosis is most prominent in the liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes, and epididymis.

Front 191

191. What is isolated organ tuberculosis?

Back 191

Isolated organ tuberculosis may appear in any of the organs or tissues seeded hematogenously and may be the presenting manifestation of tuberculosis.

Organs that are typically involved include the meninges, kidneys, adrenals, bones, and fallopian tubes.

*When the vertebrae are affected, the disease is referred to as Pott's disease. Paraspinal "cold" abscesses in these pts may track along the tissue planes to present as an abdominal or pelvic mass.

Front 192

192. What id the most frequent form of extrapulmonary tuberculosis?

Back 192

Lymphadenitis is the most frequent form of extrapulmonary tuberculosis, usually occurring in the cervical region ("scrofula").

In HIV negative individuals, lymphadenopathy tends to be unifocal, and most pts do not have evidence of extranodal disease.

HIV positive pts, on the other hand, almost always demonstrate multifocal disease, systemic symptoms, and either pulmonary or other organ involvement by active tuberculosis.

Front 193

193. What is mycobacterium avium-intracellulare complex?

Back 193

Mycobacterium avium (which includes three subspecies), and Mycobacterium intracellulare are separate species, but the infection they cause are very similar, and are called MAC>

MAC is common in soil, water, dust, adn domestic animals. Clinically significant infection w/MAC is uncommon except among people with AIDS and low levels of CD4+ lymphocytes (< 60 cells/mm)

Front 194

194. What are the symptoms of MAC in AIDS pts?

Back 194

In AIDS pts, MAC causes widely disseminated infections, and organisms proliferate abundantly in many organs, commonly including the lungs and GI system.

Unchecked by the immune response, the organissm reach very high levels. Pts are feverish, with drenching night sweats and weight loss.

In the rare cases of MAC in a pt w/o HIV, the organisms primarily infect the lung, causing a productive cough and sometimes fever and weight loss.

Front 195

195. What is the morphological hallmark of MAC infections in pts with HIV?

Back 195

*Abundant acid-fast bacilli within macrophages.

MAC infections are usually widely disseminated throughout the mononuclear systems, causing enlargement of the involved lymph nodes, liver, and spleen. There may be a yellowish pigmentation to these organs secondary to the large number of organisms present in swollen macrophages.

Granulomas, lymphocytes, and tissue destruction are rare.

Front 196

196. What is leprosy?

Back 196

Leprosy, or Hansen disease, is a slowly progressive infection caused by Mycobacterium leprae, affecting the skin and peripheral nerves and resulting in disabling deformities.

M. leprae is, for the most part, contained w/in the skin, but leprosy is likely to be transmitted from person-to-person thru aerosols from lesions in the upper respiratory tract.

Inhaled M. leprae, like M. tuberculosis, is taken up by alveolar macrophages and disseminates thru the blood, but grows only in relatively cool tissues of the skin and extremities.

Front 197

197. What are the important characteristics of M. leprae?

Back 197

M. leprae is an acid-fast obligate intracellular organism that grows very poorly in culture but can be grown in the armadillo. It grows more slowly than other mycobacteria and grows best at 32-34 degrees C, the temp of the human skin and the core temp of armadillos.

Like M. tuberculosis, M. leprae secretes no toxins,and its virulence is based on properties of its cell wall.

Cell mediated immunity is reflected by delayed type hypersensitivity reactions to dermal injections of a bacterial extract called lepromin.

Front 198

198. What are the two different patterns of leprosy?

Back 198

Tuberculous (less severe)

and

Lepromatous (more severe)

Front 199

199. What is tuberculous leprosy?

Back 199

Pts with this form have dry scaly skin lesions that lack sensation. They often have large, asymmetric peripheral nerve involvement.

*This form is caused by a TH1 response, with production of IFN-γ and IL-2. Also, IL-12 is produced by APCs and is important to the generation of TH1 cells.

Front 200

200. What is lepromatous leprosy?

Back 200

The more sever form of leprosy includes symmetric skin thickening and nodules. This is also called anergic leprosy, b/c of the unresponsiveness of the host immune system.

Cooler areas of skin, including the earlobes and feet, are more severely affected than warmer areas. Damage to the nervous system comes from widespread invasion of the mycobacteria into Schwann cells and into endoneural and perineural macrophages.

*This form is caused by a TH2 response, with production of IL-4, IL-5, and IL-10, which may suppress macrophage activation in response to M. leprae.

Front 201

201. What is the morphology of tuberculoid leprosy?

Back 201

Tuberculoid leprosy begins w/localized skin lesions that are first flat and red but enlarge and develop irregular shapes w/indurated, elevated, hyperpigmented margins and depressed pale centers (central healing). Neuronal involvement dominates tuberculoid leprosy. Nerves become enclosed within granulomatous inflammatory reactions, and if small enough, are destroyed.

Nerve degeneration causes skin anesthesias and skin and muscle atrophy, with the development of indolent skin ulcers.

*On microscopic exam, all sites of involvement disclose granulomatous lesions closely resembling those found in tuberculosis, and bacilli are almost never found.* The presence of granulomas and absence of bacteria reflect strong T-cell immunity.

Front 202

202. What is the morphology of lepromatous leprosy?

Back 202

Lepromatous leprosy involves the skin, peripheral nerves, anterior chamber of the eye, upper airways (down to the larynx), testes, hands and feet. The vital organs and CNS are rarely affected (b/c the core temp is too high). Peripheral nerves are symmetrically invaded.

***Lepromatous lesions contain large aggregates of lipid-lade macrophages (lepra cells), often filled w/masses of acid-fast bacilli (globi).***

The failure to contain the infection and to form granulomas reflects failure of the TH1 response. With progression, nodular lesions coalesce to form distinctive leonine facies. Lymph nodes show aggregation of foamy macrophages in the paracortical (t-cell) areas.

Front 203

203. What are spirochetes?

Back 203

Spirochetes are Gram-negative, slender corkscrew-shaped bacteria w/axial periplasmic flagella wound around a helical protoplasm.

The bacteria are covered in a membrane called an outer sheath, which may mask bacterial antigens from the host immune response.

Front 204

204. What is the causative organism of syphilis?

What are the three stages of syphilis?

Back 204

Treponema pallidum.

1. Primary syphilis
2. Secondary syphilis
3. Tertiary syphilis

Front 205

205. What is primary syphilis?

Back 205

The primary stage occurs 3 weeks after contact, features a single firm, *nontender*, raised, red lesion (chancre) located at the site of treponemal invasion on the penis, cervix, vaginal wall, or anus. The chancre heals in 3-6 weeks with or w/o therapy.

*Spirochetes are plentiful w/in the chancre and can be seen by dark-field microscopy or immunofluorescent stains of serous exudate. Treponemes spread throughout the body by hematologic and lymphatic dissemination even before he appearance of the chancre.

Front 206

206. What is secondary syphilis?

Back 206

Secondary syphilis occurs 2-10 weeks later in 75% of untreated pts, with spread and proliferation of spirochetes within the skin and mucocutaneous tissues.

*The skin lesions, which frequently occur on the palms or soles of the feet, may be maculopapular, scaly, or pustular*. Moist areas of the skin may have condylomata lata.

All these painless superficial lesions contain spirochetes and are infectious.

Lymphadenopathy, mild fever, malaise, and weight loss are also common. The symptoms of secondary syphilis last several weeks, after which the pt enter the latent phase of the disease.

Front 207

207. What is tertiary syphilis?

Back 207

Tertiary syphilis is rare but occurs in 1/3 of untreated pts, usually after a latent period of 5 years or more. There are three main manifestations: (1) cardiovascular syphilis, (2), neurosyphilis, and (3) benign tertiary syphilis.

Front 208

208. What is cardiovascular syphilis?

Back 208

Cardiovascular syphilis, in the form of syphilitic aortitis, accounts for more than 80% of tertiary disease.

*The aortitis leads to slowly progressive dilation of the aortic root and arch, which causes aortic valve insufficiency and aneurysms of the proximal aorta.

Front 209

209. What is neurosyphilis?

Back 209

May be symptomatic or asymptomatic. Symptomatic disease manifests in either chronic meningovascular disease, tabes dorsalis, and a generalized brain parenchymal disease called general paresis.

Front 210

210. How is asymptomatic neurosyphilis detected?

Back 210

It is detected when a pts CSF exhibits abnormalities such as pleocytosis, elevated protein levels, or decreased glucose.

Antibodies stimulated by the spirochetes can also be detected in CSF, this is the most specific test for neurosyphilis.

Front 211

211. What is benign tertiary syphilis?

Back 211

Benign tertiary syphilis is characterized by the formation of gummas in various sites. These are nodular lesions probably related to the development of delayed type hypersensitivity to the bacteria.

Gummas occur most commonly in bone, skin, and the mucous membranes of the upper airway and mouth.

Front 212

212. What is congenital syphilis?

Back 212

Congenital syphilis usually occurs with maternal primary or secondary syphilis. Intrauterine and perinatal death each occur in 25% of cases.

Early congenital syphilis includes nasal discharge, skin sloughing, hepatomegaly, and skeletal abnormalities.

Late (tardive) syphilis manifests as notched central incisors, deafness, and interstitial keratitis with blindness (Hutchinson triad).

Front 213

213. What is the morphology of primary syphilis?

Back 213

The chancre occurs on the penis or scrotum in 70% of men and on the vulva or cervix of 50% of women.

The chancre is a slightly elevated, firm, reddened papule up to several cm in diameter, that erodes to create a clean based shallow ulcer. The contiguous induration creates a buttonlike mass directly adjacent to the eroded skin.

On histologic exam, treponemes are visible at the surface of the ulcer with silver stains (e.g., Warthin-Starry stain).

The regional lymph nodes are usually enlarged and may show a nonspecific acute or chronic lymphadenitis.

Front 214

214. What is the morphology of secondary syphilis?

Back 214

Widespread mucocutaneous lesions involve the oral cavity, palms of hands, and soles of feet. The rash is frequently macular, w/discrete red-brown spots less than 5 mm in diameter, but it may be follicular, pustular, annular, or scaling.

Histologically, the lesions show the same plasma cell infiltrate and obliterative endarteritis as the primary chancre, although the inflammation is often less intense.

Front 215

215. What is the morphology of the aortitis in tertiary syphilis?

Back 215

The aortitis is caused by endarteritis of the vasa vasorum of the proximal aorta. Occlusion of the vasa vasorum results in scarring of the media of the proximal aortic wall, causing a loss of elasticity.

There may be narrowing of the coronary artery ostia caused by subintimal scarring w/resulting myocardial ischemia.

Front 216

216. What is the morphology of neurosyphilis?

Back 216

Syphilitic gummas are white-gray and rubbery, occur singly or multiply, and vary in size from microscopic defects resembling tubercles to large tumorlike masses.

They occur in most organs but particularly in skin, subcutaneous tissue, bone and joints.

*In the liver, scarring as a result of gummas may cause a distinctive hepatic lesion known as hepar lobatum*.

On histologic exam, the gummas contain a center of coagulated, necrotic material and margins composed of plump or palisaded macrophages and fibroblasts surrounded by large numbers of mononuclear leukocytes, chiefly plasma cells.

Front 217

217. What are the skeletal deformities in early congenital syphilis?

Back 217

Syphilitic osteochondritis and periostitis affect all bones, although lesions of the nose and lower legs are most distinctive. Destruction of the vomer causes collapse of the bridge of the nose and later on, the characteristic saddle nose deformity.

Periostitis of the tibia leads to excessive new bone growth on the anterior surfaces and anterior bowing, or saber shin. There is also widespread disturbance in endochrondral bone formation.

Front 218

218. What are the lung deformities in congenital syphilis?

Back 218

The lungs may be affected by a diffuse interstitial fibrosis. In the syphilitic stillborn, the lungs appear as pale, airless organs (pneumonia alba).

Front 219

219. What is the triad of late occurring congenital syphilis?

Back 219

The triad consists of:

1. Interstitial keratitis
2. Hutchinson teeth
3. CN 8 nerve deafeness

Front 220

220. What is the pathogenesis of T. pallidum infection?

Back 220

The immune response to T. pallidum reduces the burden of bacteria, but it may also have a central role in the pathogenesis of the disease.

The T-helper cells that infiltrate the chancre are TH1 cells, suggesting that activation of macrophages to kill bacteria may cause resolution of the local infection. However, the antibody response does not eliminate the infection. *The outer membrane of T. pallidum appears to protect the bacteria from antibody binding.

Front 221

221. What is relapsing fever?

Back 221

Relapsing fever is an insect-transmitted disease characterized by recurrent fevers with spirochetemia.

Epidemic relapsing fever is caused by body louse-transmitted Borrelia recurrentis, which only infects humans.

Endemic relapsing fever is caused by several Borrelia species, which are transmitted from small animals to humans by Ornithodorus (soft-bodied) ticks.

Front 222

222. What are the clinical features of relapsing fever?

Back 222

In both louse-and tick-transmitted borreliosis, there is a 1- to 2-week incubation period after the bite as the spirochetes multiply in the blood.

Clinical infection is heralded by shaking chills, fever, headache, and fatigue, followed by DIC and multiorgan failure.

Front 223

223. What is the pathogenesis of relapsing fever?

Back 223

Spirochetes are temporarily cleared from teh body by anti-Borrelia antibodies, which target a single major surface protein called the variable major protein.

After a few days, bacteria bearing a different surface antigen emerge and reach high densities in the blood, and symptoms return until a second set of host antibodies clears these organisms.

Front 224

224. What is the Jarish-Herxheimer reaction?

Back 224

Antibiotic treatment of Borrelia infections may cause a massive release of endotoxin, resulting in the production of cytokines that cause fevers with rigors, fall in blood pressure, and leukopenia.

Front 225

225. What is the morphology of relapsing fever?

Back 225

Dx can be made by identification of spirochetes in blood smears obtained during febrile periods. In fatal louse-borne disease, the spleen is moderately enlarged and contains focal necrosis and miliary collections of leukocytes, including neutrophils, and numerous borreliae. There is congestion and hypercellularity of the red pulp.

The liver may also be enlarged and congested with prominent Kupffer cells and septic foci.

Scattered hemorrhages resulting from DIC may be found in serosal and mucosal surfaces, skin, and viscera. Pulmonary bacterial superinfection is a frequent complication.

Front 226

226. What is Lyme disease?

Back 226

Lyme disease is caused by the spirochete Borrelia burdorferi, transmitted from rodents to people by Ixodes deer ticks.

Front 227

227. What is the first stage of Lyme disease?

Back 227

Spirochetes multiply at the site of the tick bite, causing an expanding area of redness, often with a pale center (erythema chronicum migrans), fever, and lymphadenopathy.

Front 228

228. What is the second stage of Lyme disease?

Back 228

Spirochetes spread hematogenously, causing secondary skin lesions, lymphadenopathy, migratory joint and muscle pain, cardiac arrhythmias, and meningitis.

Front 229

229. What is the third stage of Lyme disease?

Back 229

A few years later after the initial bite, Lyme borreliae cause a chronic arthritis sometimes with severe damage to large joints and an encephalitis that varies from mild to debilitating.

Front 230

230. What is the pathogenesis of B. burdorferi infection?

Back 230

The initial immune response is stimulated by binding of bacterial lipoproteins to TLR-2 expressed by macrophages. In response, these cells release IL-6 and TNF and generate bactericidal NO, reducing but not eliminating the infection.

***B. burgdorferi escapes the antibody response through antigenic variation.

Front 231

231. What is the morphology of B. burgdorferi infection?

Back 231

Skin lesions are characterized by edema and a lymphocytic plasma cell infiltrate. In early Lyme arthritis, the synovium resembles that of early RA.

*A distinctive feature of Lyme arthritis is an arteritis, with onionskin-like lesions resembling those seen in lupus.*

In late Lyme disease, there may be extensive erosion of the cartilage in large joints.

Front 232

232. What are the usual causes of abscesses?

Back 232

Commensal bacteria from adjacent sites (oropharynx, intestine, and female genital tract) are the usual cause of abscesses, so the species found in the abscess reflect the species found in the normal flora.

Front 233

233. What causes head and neck abscesses?

Back 233

Oral flora: (Prevotella and Porphromonas, mixed with S. auereus and S. pyogenes).

Front 234

234. What causes abdominal abscesses?

Back 234

1. Bacteroides fragilis
2. Peptostreptococcus
3. Clostridium spp.
4. E. coli

Front 235

235. What causes genital tract abscesses?

Back 235

Caused by anaerobic gram negative bacilli, including Prevotella spp, often mixed with E. coli or S. agalactiae.

Front 236

236. What is Lemierre syndrome?

Back 236

Lemierre syndrome is characterized by infection of the lateral pharyngeal space and spetic jugular vein thrombosis.

*It is caused by Fusobacterium necrophorum, an oral commensal.

Front 237

237. What is the morphology of abscesses?

Back 237

The pus of the abscesses is discolored and foul smelling owing to the presence of anaerobes, especially in lung abscesses, and the suppuration is often poorly walled off.

Front 238

238. What does C. perfringens infection cause?

Back 238

C. perfringens causes cellulitis and myonecrosis of traumatic and surgical wounds (gas gangrene), uterine myonecrosis often associated with illegal abortions, mild food poisoning and infection o f the small bowel of ischemic or neutropenic pts often leading to severe sepsis.

Front 239

239. What does C. tetani cause?

Back 239

C. tetani proliferates in puncture wounds and in the umbilical stump of newborn infants in developing countries and releases a potent neutrotoxin, called tetanospasmin, that causes convulsive contractions of skeletal muscles (lockjaw).

Front 240

240. What is the major virulence factor in clostridial infections?

Back 240

Their most powerful virulence facotrs are the many toxins they produce.

*C. perfringens secretes 14 toxins, the most important of which is α-toxin. This toxin is a phospholipase C, a phingomyelinase, and it releases IP3, prostaglandins and thromboxanes.

Front 241

241. How does tetanus toxin cause violent spastic paralysis?

Back 241

It blocks the release of the neurotransmitter GABA from motor neurons.

Front 242

242. C. difficle produces what toxins?

Back 242

Produces toxin A that stimulates chemokine production and thus attracts leukocytes.

It also secretes toxin B, which causes distinctive cytopathic effects in cultures cells.

Both toxins are glucosyl transferases.

Front 243

243. What is associated with dusk-colored, wedge-shaped infarcts in the small bowel, particularly in neutropenic pts?

Back 243

C. perfringens.

Front 244

244. What is the morphology of chlamydia infection?

Back 244

The morphologic features of C. trachomatis urethritis are virtually identical to those of gonorrhea. The primary infection is characterized by a mucopurlent discharge containing a predominance of neutrophils. Organisms are not visible in Gram-stained smears or sections.

Front 245

245. What causes chlamydial infection?

Back 245

Chlamydiae trachomatis serotypes D-K cause sexually transmitted genital infections.

The chlamydiae are very small bacteria that are obligate intracellular parasites. They have a more complicated life cycle than free living bacteria b/c they can exist in different forms.

Front 246

246. What are the two forms of chlamydiae?

Back 246

1. The elementary body (EB) is adapted for extracellular survival and for initiation of infection

2. The reticulate body (RB) is adapted for intracellular multiplication

Front 247

247. What are the three groups of serotypes of Chlamydia trachomatis?

Back 247

1. Serotypes A, B, and C are the causes of the serious eye infection trachoma.
2. Serotypes D-K are the cause of genital infections and associated ocular and respiratory infections.
3. Serotypes L1, L2, and L3 cause the systemic disease lymphogranuloma venereum (LFV).

Front 248

248. How do chlamydiae enter the host?

Back 248

Chlamydiae enter the host thru minute abrasions in the mucosal surface. They bind to specific receptors on the host cells and enter the cells via parasite-induced endocytosis.

Once in the cell, fusion of the chlamydia-containing vesicle w/lysosomes is inhibited and the EB begins its developmental cycle.

Within 9-10 hr or cell invasion, the EBs differentiate into metabolically active RBs, which divide via binary fission and produce fresh Eb progeny. These are then released into the EC environment.

Front 249

249. What is lyphogranuloma venereum (LGV)?

Back 249

LGV is caused by C. trachomatis serotypes L1, L2, and L3.

LGV is a serious disease especially common in Africa, Asia, and South America.

LGV is a systemic infection involving lymphoid tissue and is treated with doxycline or erythromycin.

Front 250

250. What does LGV infection look like?

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The primary lesion is an ulcerating papule at the site of inoculation and may be accompanied by fever, headache, and myalgia. The lesion heals rapidly, but the chlamydiae proceed to infect the draining lymph nodes, causing characteristic inguinal buboes which gradually enlarge, and can coalesce and rupture.

The infection may disseminate from the lymph nodes to cause proctitis, or rectal strictures.

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251. What is the morphology of lympogranuloma venereum?

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The lesions of lympogranuloma venereum contain a mixed granulomatous and neutrophilic inflammatory response. Regional lymphadenopathy is common.

***Lymph node involvement is characterized by a granulomatous inflammatory reaction associated with irregularly shaped foci of necrosis and neutrophilic infiltration (stellate abscesses).***

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252. What are the three main Rickettsial infections?

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1. Epidemic typhus (R. prowazekii
2. Scrub typhus (Orienta tsutsugamushi)
3. Spotted fevers (R. rickettsii)

These organisms have the structure of Gram-negative, rod shaped bacteria, although they stain poorly with Gram stain.

Front 253

253. What is epidemic typhus?

Back 253

Epidemic typhus, which is transmitted from by body lice, is associated with wars and human suffering.

In mild cases, the gross changes are limited to a rash and small hemorrhages due to the vascular lesions. In more severe cases, there may be areas of necrosis of the skin with gangrene of the tips of the fingers, nose, earlobes, scrotum, penis and vulva.

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254. What are the most prominent microscopic changes in typhus fever?

Back 254

The small vessel lesions that underlie the rash and the focal areas of hemorrhage and inflammation in the various organs and tissues affected.

Endothelial swelling in the capillaries, arterioles, and venules may narrow the lumina of these vessels. A cuff of mononuclear inflammatory cells usually surrounds the affected vessels. Necrosis of the vessel wall is unusual in typhus compared to RMSF.

Front 255

255. What is scrub typhus?

Back 255

Scrub typhus, transmitted by chiggers, was a major problem for US. solders in WWII.

It is a mite-borne infection, and is usually a milder form of typhus fever. The rash is usually transitory or might not appear.

Vascular thrombosis is rare, but there may be a prominent inflammatory lymphadenopathy.

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256. What is ehrlichiosis?

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*Human ehrlichiosis is an acute, febrile illness, fever, headache, and malaise, which may progress to respiratory insufficiency, renal failure, and shock.

It is caused by infection in macrophages by Ehrlichia chaffeensis, or infection of neutrophils by Anaplasma phagocytophilum.*

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257. What are the characteristic Dx features of ehrlichiosis?

Back 257

Characteristic cytoplasmic inclusions (morulae), occasionally shaped like mulberries and composed of masses of bacteria, can be seen in the appropriate leukocytes in ehrlichiosis.

Rash occurs in approx 40% of pts with E. chaffeensis infection.

Front 258

258. What is RMSF?

Back 258

The causative organism, Rickettsia rickettsii, is transmitted from dogs or small wild animals to ticks and then to humans. Infection occurs primarily during warmer months, the period of greatest tick activity.

The fulminant onset of severe frontal headache, chills, fever, myalgias, and conjunctivitis occur after 2-14 days; cough and SOB develop in 25% of patients.

*Typically occurs in the southeastern US.

Front 259

259. What does the rash look like in RMSF?

Back 259

The hemorrhagic rash characteristically begins on day 3-5 of illness as 1-4 mm erythematous macules on the hands, wrists, feet and ankles. Palms and soles may also be involved. The rash may be transient, but it usually spreads to the trunk and may become petechial.

Dx is via specific complement fixation test which shows a rise in titers and allows retrospective confirmation of Dx.

Front 260

260. What is the major cause of death with RMSF?

Back 260

A noncardiogenic pulmonary edema causing adult respiratory distress syndrome is the major cause of death with RMSF.