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426 Cards in this Set
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|
Specific tests to diagnose and assess rheumatic disease
|
Rheumatoid factor (RF)
Antinuclear antibodies (ANA) Antineutrophil cytoplasmic antibodies (ANCA) Complement Anticyclic citrullinated peptide (anti-CCP) |
|
Nonspecific tests to diagnose and assess rheumatic disease
|
Erythrocyte sedimentation rate (ESR)
C-reactive protein (CRP) Synovial fluid analysis |
|
Rheumatoid factor positive result
|
< 1:20 and > 20 IU/mL
|
|
When are RFs most commonly seen?
|
in rheumatoid arthritis
|
|
Are rheumatoid factors specific to rheumatoid arthritis?
|
No
|
|
Correlation between RF and RA
|
RF increases with worsening RA
|
|
Rheumatic diseases that may cause RFs
|
Rheumatoid arthritis (RA)
Systemic lupus erythematosus (SLE) Progressive systemic sclerosis (Scleroderma) Mixed connective-tissue disease (MCTD) Sjogren's syndrome |
|
Can patients be RF positive with no rheumatic disease present?
|
Yes
|
|
Nonrhumatic disease that may cause RFs
|
mononucleosis
hepatitis or chronic liver disease malaria TB syphilis bacterial endocarditis cancer |
|
What are ANAs?
|
Antinuclear antibodies
A heterogeneous group of autoantibodies directed against nucleic acids and nucleoproteins within the nuceus and cytoplasm |
|
What do ANAs target?
|
DNA
RNA nuclear histones acidic nuclear proteins complexes of these molecular elements |
|
What do ANAs help diagnose?
|
SLE
Drug-induced lupus MCTD (mixed conn. tissue disease) |
|
Are ANAs used to screen for rheumatic or nonrheumatic diseases?
|
No
Low specificity |
|
Anti-dsDNA
|
high specificity to SLE
|
|
Anti-ssDNA
|
high sensitivity to SLE
|
|
Normal ANA
|
Negative at 1:20 dilution
|
|
ANA titer >1:640
|
suspect autoimmune disorder
cannot be used to diagnose a condition |
|
ANA False positives
|
False positives are common
Associated with a low titer (<1:40) |
|
Correlation between ANA titer and disease activity
|
No correlation
|
|
What should be assessed if ANA titers are high?
|
Staining patterns of nucleus
|
|
What ANA characteristic may be useful to differentiate types of autoimmune diseases?
|
Pattern of immunofllourescent staining
|
|
Four most common staining patterns for ANA
|
homogenous
speckled nuclear rim nucleolar |
|
Diseases with ANA homogenous staining pattern
|
Common in SLE
drug-induced lupus RA vasculitis polymyositis |
|
Diseases with ANA speckled staining pattern
|
Common in SLE
MCTD Sjogren's syndrome Progressive systemic sclerosis Polymyositis RA |
|
Diseases with ANA nuclear rim staining pattern
|
Highly specific for any rheumatic disease
Mostly seen in SLE |
|
Diseases with ANA nucleolar staining pattern
|
Polymyositis
Progressive systemic sclerosis Vasculitis rare in SLE |
|
What are ANCAs?
|
Antineutrophil Cytoplasmic Antibodies
Antibodies directed against neutrophil cytoplasmic antigens |
|
What are ANCAs useful for?
|
Diagnosing and classifying various forms of vasculitis
Wegener's granulomatosis Microscopic polyangiitis Churg-Stauss syndrome |
|
When may ANCAs be positive?
|
Wegener's granulomatosis
Microscopic polyangiitis Churg-Stauss syndrome Conn. Tissue Disease (RA, SLE, myositis) Chronic infections (cystic fibrosis, endocarditis, HIV) GI disease (IBD, sclerosing cholangitis, autoimmune hepatitis) |
|
What drugs may cause an ANCA false positive?
|
hydralazine
propylthiouracil penicillamine minocycline |
|
What is Complement made of?
|
At least 17 different plasma proteins
|
|
What does Complement provide?
|
Defense mechanism against microbes by aiding in humoral immunity
|
|
Where does Complement deposit?
|
On pathologic targets which aids in the inflammatory process and phagocytosis
|
|
Do proteins circulate in active or inactive form?
|
inactive
|
|
What happens when a protein is activated in a Complement system?
|
activates the next protein in cascade
|
|
Complement pathways
|
Classical pathway
Alternative pathway Lectin pathway |
|
Classical complement pathway
|
Activated when IgM or IgG antibodies bind to antigens (viruses and bacteria)
|
|
Alternative complement pathway
|
Surveillance system that does not require the presence of specific antibodies
|
|
Lectin Pathway
|
Similar to classical pathway but mannose binding protein binds to sugar residues on the surface of pathogens instead of antibodies
|
|
Complement Lab Assessment
|
Serum complement levels reflect a balance between synthesis and catabolism
|
|
What is hypocomplementemia associated with?
|
Hypercatabolism due to activation of the immune system
|
|
Causes of hypocomplementemia
|
rheumatic disease (SLE, RA, systemic vasculitis)
Non-rheumatic disease |
|
Do complement response correlate with disease activity?
|
No
|
|
Aspects to consider when interpreting complement results
|
reference ranges are wide
normal results should be compared with previous results if available |
|
What is anti-CCP?
|
Anticyclic citrullinated peptide
antibody that binds to nonstandard amino acid citrulline that is formed from removal of amino groups from arginine |
|
When may proteins be transformed to citrulline? What will this cause?
|
RA patients
Leads to joint inflammation |
|
Anti-CCP is highly specific for what?
|
RA
|
|
What test is helpful in identifying the etiology of inflammatory arthritis in patients with negative RF titers?
|
anti-CCP
|
|
Normal anti-CCP
|
<20 EU/mL (Elisa units)
|
|
What tests are useful to monitor disease regression or progression, especially in SLE?
|
Complement Hemolytic 50%
C3 and C4 |
|
Complement Hemolytic 50% reference range
|
100-250 IU/mL
|
|
What does Complement Hemolytic 50% measure?
|
the ability of a patient's serum to lyse 50% of a standard suspension of sheep erythrocytes coated with rabbit antibody
|
|
What components of the classical pathway are required to produce a normal reaction in complement hemolytic 50%?
|
All 9
|
|
What test may be useful in guiding therapy in SLE and lupus nephritis?
|
Complement Hemolytic 50%
|
|
What test may be useful when a complement deficiency is suspected?
|
Complement Hemolytic 50%
|
|
C3 reference range
|
72-156 mg/dL
|
|
C4 reference range
|
20-50 mg/dL
|
|
C3 vs. C4
Most abundant? More sensitive? |
C3 is most abundant
C4 more sensitive to smaller changes in complement activation |
|
What test helps monitor progression of SLE?
|
Complement Hemolytic 50%
|
|
What do Complement Hemolytic 50% results help with?
|
Following patients who present with low levels and then under treatment (SLE)
|
|
What are acute phase reactants?
|
plasma proteins that increase in response to inflammatory stimuli (tissue injury/infection)
|
|
Acute phase reactants in rheumatic disease
|
Levle of increase in APR can aid inn determining disease stagin, progression, regression with proper therapy
Especially CRP and ESR |
|
Can CRP and/or ESR be used to confirm/exculde particular diagnoses?
|
Neither
|
|
ESR reference range
|
0-20 mm/hr
|
|
What test is mainly used to monitor patients on drug therapy?
|
ESR
|
|
What may cause ESR false positives?
|
obesity
age drugs |
|
CRP reference range
|
normal < 1mg/dL
moderate increase 1-10 mg/dL marked increase >10 mg/dL |
|
What is CRP?
|
C-reactive protein
plasma protein released in response to inflammation |
|
What is synovial fluid?
|
ultrafiltrate of plasma which lubricates and nourishes the avascular articular cartilage
|
|
Normal synovial fluid presentation
|
clear and acellular (<200 cells/mm3)
high viscosity due to hyaluronic acid |
|
Synovial fluid:
High viscosity |
Normal
Non-inflamed |
|
Synovial fluid:
Low viscosity |
Inflammatory
|
|
Synovial fluid:
Variable viscosity |
Septic
|
|
Synovial fluid:
Colorless |
Normal
|
|
Synovial fluid:
Straw/yellow color |
Non-inflamed
|
|
Synovial fluid:
Yellow color |
Inflammatory
|
|
Synovial fluid:
Variable color |
Septic
|
|
Synovial fluid:
Transparent |
Normal
Non-inflamed |
|
Synovial fluid:
Translucent/opaque |
Inflammatory
|
|
Synovial fluid:
Opaque |
Septic
|
|
Synovial fluid:
<200 WBCs |
Normal
|
|
Synovial fluid:
50-1000 WBCs |
Non-inflamed
|
|
Synovial fluid:
1000-75000 WBCs |
Inflammatory
|
|
Synovial fluid:
>100,000 WBCs |
Septic
|
|
Synovial fluid:
PMN < 25% |
Normal
Non-inflamed |
|
Synovial fluid:
PMN > 50% |
Inflammatory
|
|
Synovial fluid:
PMN > 85% |
Septic
|
|
Synovial fluid:
Negative culture |
Normal
Non-inflamed Inflammatory |
|
Synovial fluid:
Positive culture |
Septic
|
|
Synovial fluid:
glucose level same as BG |
Normal
Non-inflamed |
|
Synovial fluid:
Glucose 25-50 mg/dL |
Inflammatory
|
|
Synovial fluid:
Glucose >50 mg/dL (less than blood) |
Septic
|
|
Synovial fluid:
Protein 1-2 g/dL |
Normal
|
|
Synovial fluid:
Protein 1-3 g/dL |
Non-inflammed
|
|
Synovial fluid:
Protein 3-5 g/dL |
Inflammatroy
Septic |
|
Monosodium urate crystals:
Size Morphology Birefringence |
2-10 micrometers
needles, rods Negative bireg. |
|
Calcium pyrophosphate dihydrate (CPPD):
Size Morphology Birefringence |
2-10 micrometers
rhomboids, rods Weak positive biref. |
|
Calcium oxalate crystals:
Size Morphology Birefringence |
2-10 micrometers
polymorphic Positive biref. |
|
Cholesterol crystals:
Size Morphology Birefringence |
10-80 micrometers
Rectandular +/- biref. |
|
Depot corticosteroid crystals:
Size Morphology Birefringence |
4-15 micrometers
irregular rods +/- biref. |
|
Diseases associated with monosodium urate crystals?
|
Gout
|
|
Diseases associated with calcium pyrophosphate dihydrate (CPPD) crystals?
|
Pseudogout
Osteoarthritis |
|
Diseases associated with calcium oxalate crystals?
|
Renal failure
|
|
Diseases associated with cholesterol crystals?
|
Chronic orheumatoid or osteoarthritc effusions
|
|
Diseases associated with depot corticosteroids crystals?
|
Iatrogenic postinjection flare
|
|
Rheumatoid arthritis in adults:
Rheumatoid factor |
Positive
Most titers >/= 1:320 RF higher in patient with RA |
|
Is RF usually used to assess a patient's current clinical status or disease progression?
|
No
|
|
Rheumatoid arthritis in adults:
ANA |
Usually negative in RA patients
|
|
Rheumatoid arthritis in adults:
Complement |
Normal or elevated (especially in acute flare)
Chronic RA can lead to hypocomplementemia |
|
Rheumatoid arthritis in adults:
Acute phase reactants (ESR/CRP) |
usually elevated
can be used to monitor disease activity |
|
SLE:
ANA |
Positive
Higher tiers more likely in SLE |
|
SLE:
Complement |
CH50 decreased
low levels lower levels = worse disease |
|
SLE:
Acute phase reactants (ESR/CRP) |
elevated (esp. ESR)
can be used to monitor disease preogression |
|
Serum uric acid reference range
|
2.4-7 mg/dL
|
|
What is serum uric acid?
|
Metabolic end-product of the purine base of DNA
|
|
How is serum uric acid excreted?
|
Renally
|
|
What may cause serum uric acid build-up?
|
overproducers of uric acid or underexcretors of uric acid
|
|
Risk of gout and serum uric acid
|
Risk for gout increases and serum uric acid increases
|
|
Urine uric acid reference range
|
250-750 mg/day
|
|
What do increased amounts of uric acid excretion increase risk of?
|
nephrolithiasis
|
|
Neurologic Exam Components
|
1. Higher cortical function (mental status)
2. Cranial Nerves 3. Motor Function 4. Reflexes 5. Sensory Function 6. Gait |
|
What does a MMSE measure?
|
Mini mental status exam
orientation, attention, recall, speech, fund of information, insight, judgment, abstract thought, calculations memory, language |
|
Maximum MMSE score
|
30 points
|
|
MMSE score indicating cognitive impairment
|
<23 points
|
|
CN I
|
Olfactory
|
|
CN II
|
Optic
|
|
CN III
|
Oculomotor
|
|
CN IV
|
Trochlear
|
|
CN V
|
Trigeminal
|
|
CN VI
|
Abducens
|
|
CN VII
|
Facial
|
|
CN VIII
|
Auditory
|
|
CN IX
|
Glossopharyngeal
|
|
CN X
|
Vagus
|
|
CN XI
|
Spinal accessory
|
|
CN XII
|
Hypoglossal
|
|
Function of Oculomotor CN
|
eye movements
|
|
Testing of Oculomotor CN
|
reaction to light and accommodation
|
|
Function of Trochlear CN
|
eye movements
|
|
Testing of Trochlear CN
|
reaction to light and accommodation
|
|
Function of Abducens CN
|
eye movements
|
|
Testing of Abducens CN
|
reaction to light and accommodation
|
|
Function and Testing of Trigeminal CN
|
Sensory - corneal reflex
Motor - jaw clench |
|
Function of Facial CN
|
Facial symmetry
|
|
Function and Testing of glossopharyngeal CN
|
Position and symmetry of palate and uvula
gag reflex, swallowing, coughing, phonation |
|
Function and Testing of Vagus CN
|
Position and symmetry of palate and uvula
gag reflex, swallowing, coughing, phonation |
|
Function and Testing of spinal accessory CN
|
Trapezius and sternomastoid muscles
Test shoulder shrug and head rotation against resistance |
|
Function of Hypoglossal CN
|
motor function of tongue
|
|
Normal motor function
|
5/5
|
|
Normal muscle stretch reflexes
|
2
(0 = slow, 4 = fast) |
|
Babinski sign
|
abnormal plantar reflex
great toe flexes toward top of food and other toes fan out after sole of foot stroked Indicates CNS damage |
|
Romberg test
|
Test patients balance with their eyes closed
|
|
Neurological disorders associated with abnormalities in mental status
|
dementias
stroke metabolic encephalopathies |
|
Neurological disorders associated with abnormalities in cranial nerves
|
myasthenia gravis
Parkinson's disease stroke ALS |
|
Neurological disorders associated with abnormalities in motor function
|
myasthenia gravis
Parkinson's disease stroke ALS |
|
Neurological disorders associated with abnormalities in reflexes
|
stroke
spinal cord lesions endocrine diseases |
|
Neurological disorders associated with abnormalities in sensory function
|
stroke
migraine aura peripheral neuropathy DM spinal cord lesions |
|
Neurological disorders associated with abnormalities in gait
|
stroke
Parkinson's disease spinal cord lesions |
|
Imaging techniques to see extracranial arteries
|
Ultrasound: duplex sonography, carotid Doppler, color-flow Doppler
MRA CTA intraarterial angiography |
|
Imaging techniques to see intracranial arteries
|
TCD
MRA CTA Intraarterial angiography |
|
Which X-ray produces thick slice images of the brain?
|
CT
|
|
Which is better? CT or MRI?
|
MRI - improved anatomic detail, no radiation
|
|
MRA
|
Magnetic resonance angiograpy
MRI for blood vessels |
|
PET
|
tests brain function
|
|
SPECT
|
better than PET
provides cross-sectional images of brain assesses cerebral blood flow |
|
EEG
|
records electrical activity of brain from scalp
|
|
EMG
|
Electromyography
assesses muscle dysfunction due to primary muscle disease or secondary dysfunction due to nerve injury |
|
NCV
|
Nerve Conduction Velocities
measured by stimulating the nerve and recording the speed of impulse conduction detects peripheral nerve injuries |
|
PSG
|
Polysomnography
Sleep Lab Involves EEG, EOG |
|
Meningitis
|
Inflammation of subarachnoid space or spinal fluid
|
|
Signs and symptoms of meningitis
|
fever, chills, V, photophobia, severe H/A, nucal rigidity, Brudzinski's sign, Kernig's sign
|
|
Kernig's sign
|
severe stiffness of hamstrings which causes an inability to straighten leg when hip is flexed at 90 degree angle
|
|
Where does CSF circulate?
|
into the third and fourth ventricle and passes to the subarachnoid space
|
|
Total CSF in adults
|
150 mL
|
|
How much CSF is produced daily?
|
500 mL
|
|
CSF Color:
Clear |
Normal
|
|
CSF Color:
Yellow |
blood breakdown products
hyperbilirubinemia CSF protein > 150 mg/dL >100,000 RBCs/mm3 traumatic LP |
|
CSF Color:
Orange |
blood breakdown products
high carotenoid ingestion traumatic LP |
|
CSF Color:
Pink |
blood breakdown products
traumatic LP |
|
CSF Color:
Green |
hyperbilirubinemia
purulent CSF |
|
CSF Color:
Brown |
meningeal melanomatosis
|
|
CSF Opening pressure:
<180 mmH20 |
Normal
|
|
CSF Opening pressure:
Elevated (<180) |
Bacterial infection
Viral infection Fungal infection TB |
|
CSF Appearance:
Clear |
Normal
|
|
CSF Appearance:
Turbid |
Bacterial infection
Viral infection (clear or turbid) Fungal infection (slightly turbid) TB (clear or turbid) |
|
CSF WBCs:
0-5 |
Normal
|
|
CSF WBCs:
400-2000 (avg. 800) |
Bacterial infection
|
|
CSF WBCs:
5-2000 |
Viral infection (avg. 80)
TB (avg 200) |
|
CSF WBCs:
20-2000 (avg. 100) |
Fungal infection
|
|
CSF differential:
No predominance |
Normal
|
|
CSF differential:
>80 PMNs |
Bacterial infection
TB |
|
CSF differential:
>50 lymphs; <20 PMNs |
Viral infection
|
|
CSF differential:
>50 lymphs |
Fungal infection
|
|
CSF Protein:
<100 |
Normal
|
|
CSF Protein:
>100 |
Bacterial infection
|
|
CSF Protein:
30-150 |
Viral infection
Fungal infection |
|
CSF Protein:
>50 |
TB
|
|
CSF Glucose:
45-100 (2/3 serum) |
Normal
|
|
CSF Glucose:
<45 (<1/2 serum) |
Bacterial infection
|
|
CSF Glucose:
45-70 |
Viral infection
|
|
CSF Glucose:
30-70 |
Fungal infection
|
|
CSF Glucose:
<40 |
TB
|
|
Gold standard for diagnosing viral, fungal, and bacterial meningitis
|
CSF gram stain and culture
|
|
What type of staining should be done to CSF if TB is suspected?
|
acid-fast staining
|
|
Latex agglutination (LA)
|
allows rapid detection of bacterial antigens in CSF
Sensitivity varies between bacteria Useful in partially treated meningitis cases Not routinely used |
|
Polymerase Chain Reaction (PCA)
|
Allows for fast diagnosis of variety of CNS infections
Can be used in diagnosis of TB meningitis |
|
What is the preferred method for diagnosing viral meningitis?
|
PCA
|
|
BinaxNOW
|
Aids in diagnosis of bacterial meningitis due to Strep pneumo
Results w/in 15 minutes |
|
Which meningitis test is not affected by previous antibiotic use?
|
BinaxNOW
|
|
In vivo drug interference
|
interference happens inside the body
change in analyte conc./activity prior to collection |
|
Can a drug produce a change in the lab result based on its pharmacologic effects?
|
Yes
Ex. thiazide/loop diuretics effects on serum potassium levels |
|
Can a drug produce a change in lab results based on it's toxicological effects?
|
Yes
Ex. statins effect on liver |
|
In vitro drug interference
|
interference happens outside the body
drug in person's body fulid/tissue that directly interferes with lab test during in vitro analytical process |
|
T/F
In vitro drug interference depends on lab test assay used. |
True
Ex. Heparin test tubes used to measure aPTT |
|
Can drugs simultaneously illicit in vivo and in vitro effects?
|
Yes, very rare
Ex. PCN with AGs |
|
Should a drug interference be suspected if test results don't correlate with patient's signs, symptoms, or PMH?
|
Yes
|
|
Should a drug interference be suspected if results of a different test assessing the same organ conflicts with the test?
|
Yes
|
|
Should a drug interference be suspected if there is a large variation of the test within a short period of time?
|
Yes
|
|
Should a drug interference be suspected if results for a series of the same test change in a counterintuitive direction?
|
Yes
|
|
Key tertiary literature resources for Drug Interference with Lab tests
|
Package inserts (PDR)
AHRS Drug Info Meyler's Side Effects of Drugs Effects of Drugs on Clin. Lab Tests eFacts, Lexi, MicroMedex |
|
Key secondary literature resources for Drug Interference with Lab tests
|
PubMed
CINHAL |
|
Key primary literature resources for Drug Interference with Lab tests
|
Journal articles on drug interference
|
|
Specimen of choice for drug screens
|
Urine
|
|
What do drug screens determine?
|
Presence of a specific substance or group of substances
|
|
What are drug screens also referred to as?
|
toxicology screen
tox screen |
|
T/F.
Drug screens provide an exact determination of how much of the substance is present in urine. |
False
|
|
T/F.
Negative urine drug screen means drug was not present or taken. |
False
Only means it was not detected in screening |
|
What 5 categories are required by the SAMHSA to be routinely included in tox screens?
|
Amphetamines
Cocaine metabolites Marijuana metabolites Opiate metabolites Phencyclidine |
|
What opiods are not detected in urine tox screens?
|
meperidine
propoxyphene pentazocine fentanyl |
|
How long can amphetamines be detected by UDTs?
|
2-5 days
up to 2 weeks with prolonged use |
|
How long can cocaine metabolites (benzoylecgonine) be detected by UDTs?
|
12-72 hrs
Up to 1-3 weeks with prolonged/heavy use |
|
How long can Marijuana metabolites be detected by UDTs?
|
7-10 days
Up to 1-2 months with prolonged or heavy use |
|
How long can Opiods be detected by UDTs?
|
2-3 days
Up to 6 days with SR formulations Up to 1 week with prolonged or heavy use |
|
How long can Phencyclidine be detected by UDTs?
|
2-10 days
1 month or more with prolonged or heavy use |
|
What agents may cause a UDT false-positive for cocaine?
|
Cross-reactivity with cocaethylene varies with assay
False positives from -caine anesthetics and other drugs unlikely |
|
What agents may cause a UDT false positive for marijuana?
|
Ibuprofen
Naproxen Efavirenz Hemp seed/oil |
|
What agents may cause a UDT false positive for opiods?
|
Rifampin
Some FQs poppy seed quinine in tonic water varying cross-reactivity for codeine, oxycodone, hydrocodone, semisynthetic opiods |
|
What agents may cause a UDT false positive for Phencyclidine?
|
Ketamine
Dextromethorphan Diphenhydramine Sertraline |
|
What agents may cause a UDT false positive for amphetamines?
|
Ephedrine
pseudoephedrine ephedra phenylephrine desoxyephedrine selegiline chlorpromazine trazodone bupropion desipramine, amantadine ranitidine, phenylpopanolamine brompheniramine, methylenedioxymethampehtaimine propylhexedrine, isomethaptene labetolol, fenfluramine phentermine, isoxsuprine |
|
Are serum drug levels used for screening tests?
|
No
|
|
What do serum drug levels measure?
|
concentration of toxin within serum
Based on consideration that conc. correlates with effect no standard panel |
|
What levels are used to guide treatment of poisoning/overdose?
|
serum drug levels
|
|
Ethanol breath test measurement vs lab serum measurement
|
breath test = 0;08%
lab conc. = 0.08% = 80 mg/dL |
|
How long before signs/symptoms of APAP toxicities are seen?
|
1-3 days
|
|
How long must you wait after acute ingestion or regular release APAP to get levels to assess risk of APAP hepatotoxicity?
|
at least 4 hours
|
|
What types of products correlate with Rumak-Matthew APAP nomogram?
|
Tylenol ER
Tylenol arthritis cannot use SR products |
|
Equation to determine X vials of immune fragment antibody for digoxin overdose
|
#vials of IFA = (serum conc of dig x weight)/100
|
|
What is used to quickly revers the toxic effects of digoxin?
|
Immune fragment antibody
|
|
How is the dose of antibody for digoxin determined?
|
empirically based on amount ingested (overdose situation) or serum steady state concentration
|
|
T/F
Digoxin serum concentration will increase after antibody is given. |
True
No correlation to degree of toxicity due to bound digoxin to antibody |
|
Therapeutic Drug Monitoring (TDM)
|
use of drug concentrations to optimize drug therapy for an individual patient
|
|
What is the primary goal of drug therapy?
|
maximize benefit of a drug in shortest possible time with minimal risk of toxicity
|
|
When should TDM be completed?
|
Only if result will affect some future action or decision
|
|
Indications for TDM
|
therapeutic confirmation
dosage optimization confirm toxicity avoid inefficacy or toxicity distinguish noncompliance |
|
What info is needed for planning and evaluating drug concentrations?
|
patient ID, dempographics and characteristics
specimen info drug info drug conc. history purpose of assay and urgency of request |
|
Therapeutic range
|
range of drug conc. within which the probability of the desire clinical response is relatively high and the probability of unacceptable toxicity is relatively low
|
|
Sample timing
|
most requent source of error when TDM results do not agree with clinical picture
|
|
When should you obtain a sample for steady state?
|
wait at least 3 half lives unless suspect early toxicity during therapy
|
|
When do you usually draw a trough for TDM?
|
if intermittent dosing is used
|
|
T1/2 of SR drugs vs. prompt release
|
SR drugs have long T1/2
Prompt release with short T1/2 |
|
What is cancer?
|
mutant cell that beins to replicate in uncontrolled manner
|
|
Where are tumor markers found?
|
Found in blood or other body fluids or measured directly in tumor masses or lymph nodes
|
|
Types of tumor markers
|
tumor-specific proteins
non-specific proteins overexpressed normal proteins |
|
Potential clinical uses of tumor markers
|
screening/detection
diagnosis staging/prognosis monitoring or treatment (recurrence or progression) |
|
PSA
|
Prostate speciic antigen
Protein produced by both normal and malignant prostate tissue |
|
T/F
PSA is produced by normal and malignant prostate tissue. |
True
|
|
What may cause an increase in PSA concentration?
|
Age
Prostate size (BPH) Prostate manipulation Ejaculation |
|
What may cause a decrease in PSA concentration?
|
5-alpha reductase inhibitors (finasteride, dutasteride)
|
|
Does PSA degree of elevation correlate with a worse pathological grading and prognosis?
|
Yes
|
|
Uses of PSA
|
screening
staging/prognosis monitoring of treatment |
|
Cons of PSA screening
|
expensive
overagressive - many reasons it could be elevated not much evidence it makes a difference |
|
CEA
|
Carcinoembryonic Antigen
protein found in intestines, pancreas, and liver of fetal tissue |
|
Is CEA higher is smokers or nonsmokers?
|
smokers
|
|
What may cause an increase in CEA concentration?
|
malignancy
GIT diseases Oxaliplatin may cause spurious increase |
|
Can CEA be used as a screening tool?
|
Not in asymptomatic patients
Not sensitive or specific enough |
|
What is CEA used for?
|
Obtain baseline level once patient diagnosed with colon cancer
Prognosis Monitoring of Treatment (recurrence or progression) Possible use for monitoring breast cancer treatment |
|
CA 19-9
|
Cancer antigen 19-9
Tumor-associated antien expressed by several gastric cancers |
|
What may increase CA 19-9?
|
pancreatitis
ulcerative colitis other GI related tumors, etc |
|
What phenotype may not be able to synthesize CA 19-9?
|
Le a-b-
|
|
Can CA 19-9 be used as a screening tool?
|
Not recommended
|
|
What is CA 19-9 used for?
|
Monitoring of pancreatic cancer (recurrence or progression)
|
|
CA-125
|
Cancer Antigen 125
Protein found on cells lining pelvic organs and peritoneum |
|
What may increase CA-125 concentrations?
|
endometriosis
pregnancy menstruation peritonitis |
|
What may decrease CA-125 concentrations?
|
oral contraceptive use
menopause |
|
Can CA 125 be used as a screening tool?
|
Not recommended
|
|
What is CA-125 used for?
|
Obtain baseline level if suspicion of ovarian cancer
Monitoring of ovarian cancer |
|
What blood test correlates with CA 125 levels?
|
OVA-1
|
|
Is OVA1 a screening or diagnostic tool?
|
Neither!
|
|
HCG
|
Human Chorionic Gonadotropin
Protein normally produced by placenta during pregnancy Also produced by tumors of germ cell origin |
|
What may increase HCG concentrations?
|
pregnancy
|
|
Can HCG be used as a screening tool?
|
Not recommended
|
|
What is HCG used for?
|
Germ cell tumors (testes, less common ovarian cancers, etc)
Monitoring of Treatment |
|
AFP
|
Alpha Fetoprotein
Protein made in liver, GIT, and fetal yolk sac |
|
When is AFP found in high concentrations?
|
During fetal development
|
|
What may cause elevations in AFP?
|
hepatocellular carcinoma (HCC)
testicular germ cell cancer pregnancy hepatitis cirrhosis |
|
What is AFP used for?
|
Screeing = diagnostic aid for HCC
Monitoring of disease progression or recurrence |
|
Estrogen and Progesterone Receptor Assays
|
Hormone status determined from tumor biopsy
|
|
What are estrogen and progesterone receptor assays used for?
|
As part of work-up to predict prognosis and treatment option in breast cancer
Therapy recommendations |
|
What estrogen and progesterone receptor assays correlate with response to hormonal therapies?
|
Positive ER
Positive PR |
|
HER-2
|
c-neu or HER-2/neu
Transmembrane receptor which functions in the growth and control of many normal cells and malignant cells |
|
20-40% of breast cancers exhibit overexpression of this receptor
|
HER-2
|
|
What is HER-2 used for?
|
Part of invasive breast cancer work-up
|
|
Trastuzumab and HER-2
|
Trastuzumab is an antibody that binds selectively to the HER2 protein. When it binds to defective HER2 proteins, the HER2 protein no longer causes cells in the breast to reproduce uncontrollably.
|
|
Ph
|
Philadelphia Chromosome
|
|
What may Ph be diagnostic for?
|
Chronic myelogenous leukemia (CML)
|
|
BCR-ABL fused gene leads to...
|
altered Tyrosine Kinase activity
|
|
Tyrosine kinase inhibitors
|
imatinib
nilotinib dasatinib |
|
Testing methods for BCR-ABL and Ph
|
Direct chromosomal analysis (cytogenetic monitoring)
Cell counts with RT-PCR (molecular monitoring) |
|
Complete response to direct chromosomal analysis
|
No cells with Philadelphia chromosome
|
|
Partial response to direct chromosomal analysis
|
1-35% of cells with Philadelphia chromosome
|
|
Minor response to direct chromosomal analysis
|
>35% of cells with Philadelphia chromosome
|
|
Complete response to cell counts with RT-PCR
|
undetectable BCR-ABL mRNA
|
|
What are BCR-ABL and Ph used for?
|
Diagnosis of CML
Monitoring treatment |
|
CA 15-3 and CA 27.29
|
Additional Breast Cancer Markers
Both test for circulating MUC-1 mucin glycoprotein (breast cancer-associated antigen) |
|
When is CA 15-3 elevated?
|
Metastatic breast cancer
Other cancers, cirrhosis, hepatitis |
|
Do CA 15-3 and CA 27.29 demonstrate a clinical impact (overall survival, QOL, etc.)
|
No
|
|
What are CA 15-3 and CA 27.29 used for?
|
Monitoring of treatment of breast cancer
|
|
CTC Assay
|
Circulating Tumor Cell Assay
Contraversial Use |
|
What are CTCs?
|
cells present in blood that possess genetic characteristics of a specific tumor type
|
|
CellSearch Assay
|
Uses labeled monoclonal antibodies specific for leukocytes (CD-45) and cytokeratins 8, 18, 19
Contraversial use |
|
Multiparameter gene expression analysis
|
Assessing multiple genes in a tumor sample may predict tumor behavior
|
|
When is Multiparameter gene expression analysis used?
|
Earlier stages of breast cancer
Helps decide if patient needs chemotherapy or not |
|
OncotypeDX
|
Includes 21 genes associated with proliferation, estrogen, invasion, HER2, etc. and control genes
16 cancer-related genes 5 control genes |
|
Process of OncotypeDX test
|
tumor tissue sent to reference lab
Result given as a recurrence score - helps decide if chemo necessary |
|
What does the OncotypeDX test help with?
|
Deciding if chemo is necessary
|
|
OncotypeDX Result:
Low risk |
RS < 18
|
|
OncotypeDX Result:
Intermediate risk |
RS >/= 18 and < 31
|
|
OncotypeDX Result:
High risk |
RS >/= 31
|
|
What is the OncotypeDX risk used for?
|
To help predict likelihood of breast cancer recurrence, in specific situations
|
|
MammaPrint assay
|
Includes 70-gene RNA expression profile that correlated with short time to metastasis
Genes associated with proliferation, invasion, metastasis, stromal integrity, angiogenesis |
|
Process of MammaPrint assay
|
Tumor tissue sent to reference lab
|
|
Result of MammaPrint assay
|
Low vs. High risk
|
|
Use of MammaPrint assay
|
Report level of risk of breast cancer metastasis, in specific situations
|
|
PFS
|
Progression Free Survival
|
|
Ruzzo Study
|
Patient treated with FOLFOX-4 (oxaliplatin, folinic acid, FU)
Some studies polymorphisms (TS, XPD-751, ERCC1, GSTPI) |
|
Ruzzo study results
|
reduced progression-free survival with unfavorable genotypes
Increased drug toxicity with unfavorable genotypes |
|
TS or TYMS
|
thymidylate synthase
|
|
XPD-751
|
Xeroderma pigmentosum group D
|
|
ERCC1
|
Excision repair cross complementing group 1
|
|
GSTPI
|
Glutatione S-transferase
|
|
What is PFS and the Ruzzo study associated with?
|
Colorectal cancer pharmacogenetic profiling
|
|
What is TS involved with?
|
DNA synthesis
|
|
What inhibits TS?
|
fluorouracil
|
|
What is overexpression of TS associated with?
|
Drug resistance
|
|
How do GSPs help eliminate toxic compounds?
|
GSPs attach reduced glutathione to electrophilic groups resulting in elimination of toxic compounds
|
|
What do GSP polymorphisms help predict?
|
Resistance or toxicity to oxaliplatin
|
|
What is used to predict resistance or toxicity to oxaliplatin?
|
GSP polymorphisms
|
|
DPD or DPYD
|
Dihydropyrimidine dehydrogenase
|
|
What is DPD responsible for?
|
degrading pyrimidines
|
|
What does DPD deficiency result in?
|
flurouracil or capectiabine toxicity
|
|
What may cause flurouracil or capectiabine toxicity?
|
DPD deficiency
|
|
UGT1A1
|
Codes for UDP-glucuronosyltransferase
Part of a series of drug metabolism enzymes |
|
What drug metabolism is UGT1A1 associated with?
|
bilirubin
estrogens thyroid hormone chemo agents (etoposide, irinotecan) |
|
How is irinotecan metabolized?
|
UGT1A1
Irinotecan --> SN-38 --> SN-38G |
|
What UGT1A1 variants result in drug toxicity?
|
*28 or *6
|
|
EGFR
|
Epidermal Growth Factor Receptor protein
Receptor tyrosine kinase encoded by c-erb-B (HER-1) proto-oncogene |
|
Where is EGFR expressed?
|
tumors (including colon, head/neck, and lung cancer)
Normal tissue (including skin and hair follicles) |
|
Examples of agents that target EGFTR
|
cetuximab
Panitunumab |
|
Efforts to identify a molecular marker
|
EGFR mutation
EGFR gene copy number % of cells expressing EGFR intensity |
|
Cetuximab and panitunumab indications
|
EGFR-mutation expressing colorectal cancer
|
|
Is EGFR mutation status required for head and neck cancer?
|
No
|
|
KRAS
|
human homolog of the Kirsten rat sarcoma-2 virus oncogene
a signal transducer in response to stimulation of EGFR receptor |
|
Where are KRAS mutations mostly seen?
|
colorectal cancer tumors
|
|
ALK gene
|
Anaplastic lymphoma kinase gene
Fusion product between ALK and echinoderm microtubule-associated protein-like 4 (EML4) found in some lung cancers |
|
Where is the ALK gene seen?
|
Some lung cancers
|
|
Is ALK testing necessary for patient treatment selection?
|
Yes
|
|
"Left shift"
|
increase in immature neutrophils (bands)
|
|
Increase in ESR or CRP
|
sign of infection
|
|
coccus
|
round organism
|
|
bacillus
|
rod organism
|
|
Do gram stains provide an exact ID of the organism?
|
no
|
|
Sterile body sites
|
blood
CSF pericardial fluid pleural fluid peritoneal fluid synovial fluid bone urine |
|
Why are antimicrobial susceptibility tests performed?
|
to help direct and streamline antibiotic therapy
|
|
Dilution susceptibility tests
|
broth microdilution
|
|
Gold standard for determining bacterial susceptibility
|
Broth microdilution
|
|
What indicates MIC in broth microdilution?
|
First tube that is clear = complete inhibition of bacterial growth
|
|
MIC
|
minimum inhibitory concentration
|
|
Who developed disk diffusion?
|
Kirby Bauer
|
|
Disc Diffusion
|
greater diameter of "zone of clearance" more active antibiotic is
|
|
E-test
|
Epsilometer test
antibiotic concentration gradient method |
|
MIC on E-test
|
where ellipse intercepts strip impregnated with antibiotic
|
|
Antibiogram
|
hospital susceptibility report
help select most appropriate empiric therapy |
|
Methods of obtaining specimens from the urinary tract
|
clean catch midstream urine specimen
catheterized specimen suprapubic bladder aspiration |
|
UTI diagnostic tests
|
Rapid screening reagent strips
Urinalysis Urine culture |
|
What test detects the presence of leukocyte esterases in urine?
|
Rapid screening reagent strips
|
|
Leukocyte esterases
|
enzyme produced by neutrophils (pyuria) mobilized in the host's response to infection
|
|
Urinalysis
|
microscopic exam for color, clarity, specific gravity, presence of protein, glucose, RBCs, WBCs, bacteria, epithelial cells
|
|
Urinalysis:
cloudy and presence of pyuria |
suggestive of infection
|
|
Urinalysis:
presence of epithelial cells |
suggestive of contamination
|
|
Contaminated urinalysis
|
>2-5 epithelial cells
|
|
Hallmark for diagnosis of UTIs
|
urine culture
|
|
Which 5 organisms cause a UTI?
|
E. Coli
Proteus mirabilis Klebsiella sp. Enterococcus Staphylococcus saprophyticus |
|
What is the most likely cause of a UTI?
|
E. coli
|
|
Diagnostic tests for URTIs
|
Throat culture
Rapid antigen detection test |
|
Rapid antigen detection test
|
expedite and confirm diagnosis of group A strep pharyngitis (strep throat)
|
|
Common pathogens of URTIs
|
strep pyogenes
strep viridens strep pneumo (most common) H. influenzae M. catarrhalis |
|
Diagnostic tests for LRTIs
|
Expectorated sputum
Induced sputum Tracheal aspirate Bronchostomy |
|
Ratio of WBCs: epithelial cells <1
|
contaminated sample
|
|
Useful expectorated sputum sample
|
>25 WBCs (PMNs)
< 10 epithelial cells ratio WBCs:ECs >1 |
|
Common pathogens of community acquired LRTIs
|
S. pneumo
H. influenzae M. catarrhalis Legionella pneumophilia Chlamydia pneumoniae Mycoplasma pneumoniae |
|
Common pathogens of hospital acquired LRTIs
|
S. aureus (including strep)
Pseudomonas Klebsiella pneumoniae Enterobacter Citrobacter Serratia macescens Acinetobacter |
|
Common pathogens of SSTIs
|
staph. aureus
strep. pyogenes strep. viridens staph. epi |
|
Common pathogens for meningitis:
< 1 month old |
Group B strep (S. agalactate)
E. coli Listeria monocytogenes Klebsiella |
|
Common pathogens for meningitis:
1-23 months |
S. pneumo
N. meningitides S. agalactiae E. coli H. influenzae (rare) |
|
Common pathogens for meningitis:
2-50 years old |
S. pneumo
N. meningitides |
|
Common pathogens for meningitis:
>50 years old |
S. pneumo
N. meningitides Listeria monocytogenes H. influenzae (rare) |
|
How well will an antibiotic penetrate site of infection of UTI?
|
good penetration
|
|
How well will an antibiotic penetrate site of infection of abscesses?
|
poor penetration - drain abscess
|
|
How well will an antibiotic penetrate site of infection of lungs?
|
intermediate penetration
|
|
How well will an antibiotic penetrate site of infection of bone?
|
poor penetration
|
|
How well will an antibiotic penetrate site of infection of CNS?
|
poor penetration
|
|
Diagnosis tests for HIV
|
HIV antibody assays
ELISA Western Blot |
|
When can HIV antibodies be detected?
|
in blood: 4-12 weeks after exposure
|
|
ELISA
|
Enzyme linked immunosorbent assay
Initial screening test to detect HIV antibodies |
|
Initial screening test to detect HIV antibodies
|
ELISA
|
|
Why should an ELISA test never be used alone?
|
Occurrence of false results
|
|
Western-Blot
|
confirms ELISA test results
detects HIV-specific antibodies |
|
Tests for monitoring progression of HIV
|
Plasma HIV-RNA (viral load)
CD+T lymphocyte count (CD4 count) |
|
Plasma HIV-RNA (viral load)
|
information about the patient's virologic status
HIV copies/mL or log base 10 values |
|
What is the current lowest limit of detection of viral load?
|
20 copies/mL
|
|
When is a patient's viral load undetectable?
|
<20 copies/mL
|
|
Helper-induced T cells
|
CD4 T lymphocytes
|
|
cytotoxic suppressor T cells
|
CD8 T lymphocytes
|
|
Does HIV infection cause an increase or decrease in the total number of lymphocytes?
|
decrease (particularly the CD 4 cells)
|
|
Normal CD4 count
|
800-1100 cells/mm3
|
|
What values are indicative of severe immunosuppression (AIDS)?
|
CD4 < 200 or <14% of the total lymphocyte count
|
