Translational Physiology Block 1 Flashcards Preview

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Flashcards in Translational Physiology Block 1 Deck (69):
1

What is Paroxysmal Nocturnal Hematuria?

Hemoglobin appearing in the urine at night

2

What is the complement cascade?

Complement is a complex collection of proteins that circulate in the blood plasma. The complement system recognizes antibodies that are bound to the surface of a bacterium or polysaccharides in the bacterial membrane. This recognition initiates a cascade of enzymatic cleavages that results in the assembly of a subset of complement proteins to form the membrane attack complex, which inserts itself into the membrane of the target organism and forms a large pore that allows water to rush in (osmotic lysis)

3

Is the complement cascade very selective? (Give an example and what condition it causes; why does this happen)

No; hemolysis of erythrocytes or paroxysmal nocturnal hematuria; a spontaneous mutation occurs in the PIG-A gene (f(x)s in anchoring of GPI-linked proteins) which prevents two proteins (DAF and CD59) from being expressed on the membrane to prevent lysis by the complement cascade

4

What is an inclusion cell or I cell? What is the pathophysiology are result of?

Characterized by lysosomes lacking hydrolases (overstuffed lysosomes); phosphosugar transferase, which creates mannose-6-phosphate signal, is mutated (hydrolases are exocytosed from cell)

5

What is the pathophysiology of Tay-Sachs disease?

Hex A mutation preventing degradation of certain sugar linkages in lysosomes

6

How does cholera toxin cause diarrhea?

The cholera toxin has multiple subunits; following proteolytic cleavage, one of the subunits transfers the ADP ribosylation moiety of NAD+ to Gs (prevented it from being inactivated by ADP) causing increasing in cAMP and loss of chloride from the cell (water follows it)

7

How does whooping cough increase cAMP production?

Pertussin bacteria adds ADP ribosylation moiety to Gi (inactivating the GTPase) preventing the suppression of adenylyl cyclase and production of cAMP

8

What is the difference between COX1 and COX2? (What drugs acts on them and what is their side effects?)

COX1: thrombosis and prostacyclins in GI (aspirin blocks clotting at the expense of GI bleeding); COX2: inflammation (aspirin at high doses is weak inhibitor; NSAIDs block inflammation but are not suggested for cardiac patients)

9

What are the important molecules associated with anaphylaxis in the lungs? (what other diseases are they present in)

Leukotrienes (bronchoconstriction); psoriasis, Crohn's, RA, and bowel syndromes

10

What is an important characteristic of oncogenes?

Aberrant (constitutive) signaling of key signaling pathways (i.e. Ras and RTKs)

11

What are β-Thalassemias?

Anemic disorders caused by deficiency in production of B-chain of hemoglobin (deletion of the LCR)

12

What is aberrant in patients with acute premyelocytic leukemia?

Fusion of PML and RARalpha repressing differentiation by constitutively binding to N-Cor repressor for differentiated genes

13

What is a result of extremely high extracellular osmolality from dehydration? Why is this difficult to solve clinically?

Shrinkage of brain cells and possible intracerebral hemorrhage; returning the fluid levels back to normal too quickly may result in brain edema and possible tentorial herniation

14

What is the pathophysiology of Charcot-Marie Tooth disease?

neuropathy (peripheral nerves); mutations in connexins important for communication between different Schwann cells (demylelination syndrome)

15

What is hyperkalemic periodic paralysis?

mutations in membrane-spanning segment S5 of domain II and S6 of domain IV in sodium channels (abnormal kinetics) results in increased extracellular potassium

16

What is paramyotonia congenita?

mutation in the linker region of sodium channels (important for sodium inactivation); disease phenotype presents by exposure to cold temperature

17

What is long QT syndrome?

cardiac arrhythmia caused by mutation in linker region of sodium channel; or by mutation in potassium channels (defective repolarization can lead to premature heartbeats or asynchronous ventricular contraction)

18

What is Lambert-Eaton syndrome? How is different from myasthenia gravis?

Patients afflicted with this condition produce antibodies against presynaptic Ca 2+ channels; attacks limb muscles; repetitive stimulation of a particular muscle leads to enhanced amplitude of the postsynaptic action potential, whereas in patients with myasthenia, repetitive stimulation leads to progressive lessening of the action potential. Thus, repeated muscle stimulation leads to increasing contractile strength in patients with Lambert-Eaton syndrome and to decreasing strength in patients with myasthenia.

19

What type of channel is altered by hypokalemic periodic paralysis?

Skeletal DHP receptors

20

What is the definition of myasthenia?

weakness in the absence of primary muscle disease, neuropathy, or CNS disorder

21

What is a characteristic of young people who are affected by myasthenia gravis? older people? why is is this gland so important?

woman who have hyperplasia in the thymus; cancer of the thymus gland; The cells of the thymus possess nicotinic AChRs, and the disease arises as a result of antibodies directed against these receptors.

22

What are the symptoms of myasthenia gravis?

general fatigue and weakness of skeletal muscles (one subtype only affects the extraocular muscles); symptoms fluctuate (greatest weakness at the end of the day or following exertion)

23

Why does prolonged activation of acetylcholine receptors result in acute paralysis?

overstimulation of the postsynaptic receptors, prolonged depolarization of the postsynaptic membrane, inactivation of neighboring Na + channels, and thus synaptic blockade.

24

What are treatment options for myasthenia gravis?

Immunosuppression: corticosteroids (prednisone) and IV IgGs or plasmapheresis; removal of thymoma; AchE inhibitors (pyridostigmine)

25

What kind of mutation was clearly described in the textbook to demonstrate congenital myasthenic syndrome?

The burst duration of AChR openings was greatly prolonged in comparison with that of normal human AChR channels; The molecular defect is a point mutation of Thr to Pro at position 264 in the adult ɛ subunit of the AChR. This amino acid residue corresponds to an evolutionarily conserved position in the M2 membrane-spanning segment, which is involved in formation of the channel pore. Thus, a human mutation in the pore region of the AChR protein results in failure of the channel to close normally

26

What is effect of botulism toxins?

Patients begin to complain of symptoms attributable to inhibition of synaptic vesicle release in the autonomic nervous system, such as dry mouth, double vision, and difficulty in swallowing and speaking, and later begin to experience gastrointestinal complications, including vomiting, pain, and diarrhea. Symptoms attributable to inhibition of synaptic vesicle release at the neuromuscular junction, such as weakness and paralysis of the limbs, may soon follow; ultimately, paralysis of the respiratory muscles can be fatal.

27

What is the effect of tetanus toxin?

The organism gains entry to its host through a cut or puncture wound. The toxin then travels along the peripheral nerves to the spinal cord, the major site of its attack. There, the toxin inhibits synaptic vesicle release by interneurons that normally inhibit firing of the motor neurons that, in turn, activate skeletal muscle. Thus, because the toxin suppresses inhibition of the normal reflex arc, muscle contraction leads to profound spasms, most characteristically of the jaw muscles but potentially affecting any muscle in the body.

28

What causes malignant hyperthermia?

Affected individuals are at risk for a potentially life-threatening syndrome on exposure to any of the various inhalation anesthetic agents, particularly halothane (and sometimes succinylcholine)

29

Describe malignant hyperthermia.

uncontrolled muscle contraction—somehow triggered by the administration of halothane and succinylcholine—causes excessive ATP hydrolysis to provide energy for contraction. The increased rate of ATP hydrolysis leads to an increased metabolic rate as muscle tries to replenish and to sustain its ATP stores. Hyperthermia develops because of the heat liberated by the hydrolysis of ATP (CICR; increases probability that the ryanodine is open at a given time)

30

What are signs that indicated malignant hyperthermia?

development of tachypnea (rapid breathing), low plasma [O 2], high plasma [CO 2], tachycardia (rapid heart rate), and hyperthermia (rising body temperature) as well as by rigidity, sweating, and dramatic swings in blood pressure.

31

What is the treatment regimen for malignant hyperthermia?

Dantrolene is an effective therapeutic agent because it blocks EC coupling between T tubules and the SR; Therapy also includes intravenous hydration and the judicious use of diuretics to keep the urine flowing; this lessens damage to the kidneys from the release of breakdown products, such as myoglobin from the damaged muscles. Sodium bicarbonate is given to counter the lactic acidosis, and patients may be mechanically hyperventilated to blow off the excess CO 2.

32

What is type II diabetes? what does it mean to be insulin resistant?

beta cells can secrete insulin but not enough for good control of blood glucose; Increased insulin resistance = decreased insulin sensitivity

33

How does the relationship between insulin receptor occupancy and biological response to insulin change in type II diabetes?

In a normal individual, the maximum response in glucose transport to insulin is reached when only 5% of the receptors are bound to insulin; in type II diabetes, the maximum response is reached at much higher levels of receptors bound to ligand

34

In progression to type II diabetes, how does the B-cell's phenotype change?

In healthy B cells, insulin resistance is combated by increasing secretion of insulin (hyperinsulemia); in abnormal B cells, insulin production cannot compensate resulting in hyperglycemia

35

What are the physiological mechanism dysregulated in type II diabetes? (which cell types)

Muscle: decreased glucose uptake (glycogen; most important) and utilization; adipose tissue: increased lipolysis; liver: increased glucose production (all result in increased expression of FFAs, hyperglycemia, and dylipidemia)

36

Accumulation of PIP3 – the product of the PI3-kinase enzyme – causes increased glucose influx into adipocytes because ...

PIP3 activates a protein kinase cascade that regulates exocytosis of membrane vesicles with glucose transporters

37

Accumulation of cAMP in response to b-adrenergic receptors rapidly increases lipolysis in adipocytes because ...

PKA-mediated phosphorylation of triglyceride-hydrolyzing lipases acts as a stimulatory molecular switch for those lipases (perilipins)

38

Activation of the TNFa receptor induces decreased function of the insulin receptor because ...

JNK-MAP kinase-mediated serine phosphorylation of the insulin receptor acts as an inhibitory molecular switch for insulin receptor

39

Increases in intracellular lipid metabolites, such as fatty acyl-CoA and diacylglycerol, activate PKC, which does what?

Phosphorylates and inhibits IRS signaling

40

MCP-1 is chemo-attract (chemokine-like) that activates which receptors in macrophages? what is the result?

G-protein coupled receptors; increased TNFalpha

41

Insulin promotes the synthesis of LPL in the adipocyte; what happens next?

The adipocyte then exports this enzyme to the endothelial cell, where it breaks down the triglycerides contained in chylomicrons and VLDL, thus yielding fatty acids. These fatty acids then enter the adipocyte for esterification and storage in fat droplets as triglycerides.

42

What are clinical features of hypovolemia? what symptoms are ambiguous at first?

Poor skin turgor, weight loss, tachycardia (lower intravascular volume results in increased pulse (CO = SV x HR)); sunken eyes, dry mouth, and not complaining of thirst may be clinical features of elderly patients (not necessarily hypovolemic)

43

What are abnormal labs for a hypovolemic patient?

elevated sodium in serum (elevated chloride); sodium in urine is low as a result of the kidney trying to reabsorb fluid

44

Why is a hypovolemic patient lethargic and confused? (AMS); What is the treatment for this patient? What can go wrong?

Shrinkage of neuronal cells (high plasma osmolality (hypernatremia) cause water to flow out of cells) (may result in cerebral hemorrhage); 5% glucose + water to expand both ICF and ECF without hemolysis; infusing water too quickly can cause cerebral edema and potentially tentorial hernaition

45

What are the primary symptoms of generic myopathy?

myalgia, cramps, dyspnea (trouble breathing), dysphagia (swallowing), and fatigue. Mostly affect proximal muscles

46

Describe Duchenne's muscular dystrophy. How does it compare to Beckers?

Duchenne: frameshift mutation in X-linked gene (onset in early childhood; patients have large calves, waddling gait, stand on tip-toes later results in achilles tendon damage, scoliosis, and hyperlordosis; Gower sign; increased creatine kinase in serum; wheelchair by 13 and ventilation by 18. Beckers: later onset; result of large in frame mutation

47

What are palliative treatments for Duchenne's muscular dystrophy?

Surgery for various symptoms (achilles, spine); ventilation, brace, physical therapy, and prednisone; gene therapy to convert to BMD has been attempted (must either inject in every muscle of body or potentially inject near aorta)

48

What are symptoms associated with Guillem-Barre syndrome?

Waddling gait, less of reflexes, tingling sensation (sensation may be normal when tested); acute paralysis; afflicted with a bacterial or viral disease in the weeks prior to admission

49

What are clinical features of Guillem-Barre syndrome?

muscle weakness lower extremity traveling upward; areflexia or hyporeflexia; high protein in CSF without increase in cells. Physician must first rule out myelopathy, poliomyelitis, and myasthenia!!!!

50

What are the subtype of Guillem-Barre syndrome?
Which one is the most favorable? worst?

AIDP (demyelinating; most favorable); AMAN (axonal damage): AMSAN (axonal damage in both motor and sensory; worst)

51

What are the causes of Guillem Barre syndrome?

Bacteria has molecular mimicry to ligands with ligand-gated channels on nerve cell membranes (immune system attacks these cells)

52

What are treatments for Guillem Barre syndrome?

Plasma exchange (plasmapheresis); IV IgG

53

What is the effect of insulin secretion?

increased GLUT4 activity; glycogenesis (production of glycogen); fatty acid synthesis; inhibition of triglyceride breakdown; glucose utilization in liver, muscle, and adipocytes

54

What are two intracellular signaling pathways activated upon insulin dimerization?

PI3K binds to phosphorylated IRS and becomes activated. PI3K phosphorylates a membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP 2) to form PIP 3 (downstream AKT and transport of GLUT transporters to membrane); both phosphorylated SHC and activated GRB2 trigger the Ras signaling pathway, leading through MEK and MAP kinases to increased gene expression

55

What is the insulin binding site on insulin receptors?

amino terminus; extracellular domain cysteine rich

56

How many phosphates are attached to PIP3? PIP2? PIP?; phosphotydalinositol? Cleavage of PIP2 results in what?

4; 3; 2; 1; IP3

57

Activation of the insulin receptor tyrosine kinase rapidly decreases lipolysis in adipocytes because ...

Akt/PKB-mediated phosphorylation of cAMP-hydrolyzing phosphodiesterases acts a stimulatory molecular switch for those phosphodiesterases (counteracts catecholamines)

58

What is the definition of dehydration? how is this different from hypovolemia?

pure water loss; hypovolemia = ECF volume loss

59

What is the effect of diarrhea on fluid balance?

diarrhea = isotonic fluid loss (decrease ECF, no change in ICF)

60

What is the trend in the age at which epilepsy presents?

Early childhood (co-associated with cerebral palsy and other cerebral disorders); after 70 (associated with brain tumors)

61

What are structural causes of epilepsy? metabolic?

Infection, inflammation, neoplasia, trauma, dysplasia, and congential malformations; hypoglycemia, hyponatremia, liver failure (there is a genetic component)

62

What are the tests to diagnose epilepsy?

MRI and EEG

63

Can epilepsy be characterized as a monogenic phenotype?

No

64

Why do seizures happen infrequently (relatively) in epilepsy patients?

A lot of feedback loops in the neuronal network

65

What occurs in a tonic/clonic seziure?

Whole body becomes rigid followed by body jerking

66

What is a paroxysmal depolarization shift?

A PDS is characterized by an initial rapid and prolonged depolarization of the membrane potential, followed by a burst of repetitive action potentials lasting several hundred milliseconds. The initial depolarization is mediated by AMPA receptors, while the sustained depolarization is a consequence of NMDA receptor activation. The PDS terminates with a prolonged hyperpolarization phase that is mediated primarily by inhibitory potassium and chloride conductances, carried by voltage-gated potassium channels and GABA receptors, respectively.

67

After a patient has had hyperkalemia for more than an half-hour he/she experiences muscle weakness. Which of the following best describes the pathophysiology of this patient’s muscle weakness?

Sodium channels are closed because the cell is depolarized (cells are refractory to stimulation)

68

What type of drugs are anti-epileptics?

sodium channel blockers, gaba agonists, NMDA receptor antagonists (20% of patients do not respond)

69

What happens if epilepsy is left untreated?

Worsening (more seizures), injuries, and potentially death from symptoms of specific ictal events