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disease of progressive bone loss caused by an imbalance in the activity of osteoclasts (bone resorption) and osteoblasts (bone forming cells) causing an overall decrease in bone mass and strength, and an increased risk of fracture
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Osteoporosis
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risks for osteoporosis
- age 65 +,
- post-menopausal women, and people with small body frame.
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Lifestyle Factors that could cause osteoporosis
- low dietary calcium intake, vitamin D deficiency, insufficient physical
- activity, smoking, and alcohol abuse
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Genetic factors that could cause osteoporosis
- cystic fibrosis, osteogenesis imperfecta, fam hx of osteoporosis or hip
- fractures
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Medical diseases that can cause osteoporosis
hyperparathyroidism, hyperthyroidism, hypogonadal syndromes, anorexia nervosa, diabetes mellitus, Cushing’s disease, Celiac disease, gastric bypass, Crohn's disease, malabsorptive disorders, cirrhosis, leukemia, lymphoma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Parkinson’s, HIV, COPD, heart failure, and chronic kidney disease
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Medications that can cause osteoporosis
long-term use of: anticoagulants, hormone therapy, glucocorticosteroids, lithium, and proton pump inhibitors
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Osteoporsis caused by aging and hormone changes
Primary
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Osteoporosis caused by meds, lifestyle, and other diseases
secondary
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What determines person's peak bone mass
genetics
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What determines the amount of bone a person will retain until they die
Peak bone mass
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what percent of peak bone mass is genetically determined
60-80%
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What can cause bone to accumulate microdamage or little tears/splinters between osteocytes which could lead to fractures
repeated inc of activity over time
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What helps bone adapt to usage by communicating with each other to sense changes or damages in the bone and initiate signaling pathways for repair and modeling
osteocytes
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WHat happens when bone is damaged
apoptosis initiates > RANKL pathway brings cytokines to bone > signals osteoclasts to remove damaged cells and osteoblasts to repair bone
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What hormone deficiency plays large role in osteoporosis
estrogen
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what estrogen receptor is primary mediator for estrogen interactions with skeleton and effects on osteoclast precursors, mature osteoclasts, and lymphocytes
receptor alpha
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deficiency of estrogen causes (during and following menopause)
- an increased production in inflammatory cytokines and promotes the activation of T-cells; the activation of T-cells produces more cytokines which stimulate osteoclastic activity and inhibit
- osteoblasts.
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What two mediators are known to inhibit osteoclast spoptosis when there is a deficiency in estrogen
TNF and IL-1
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Progression of osteoporosis
- Osteomalacia
- Osteopenia
- Osteoporosis
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softening of bones typically due to vit d deficiency
osteomalacia
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lower than normal bone density or bone mass
osteopenia
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What does osteopenia and osteoporosis depend on
T score
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When is T score calculated
women and men >50
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What does Dexa scan measure
how much xray travels through bone
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What is T score based off of
number of standard deviations that the bone mineral density is above or below a normal healthy bone mineral density
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T score = -1--2.5
Ostopenia
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T score <-2.5
Osteoporosis
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T score <-2.5 with fractures
severe osteoporosis
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s/s of osteoporosis
none until fracture occurs
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recommended BMD testing
- women >65 and men >70, or postmenopausal women 50-69 years
- >50 with fracture
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Tx of osteoporosis
- biphosphonates
- calcitonin
- estrogens and estrogen agonist
- RANKL inhibitor
- PTH
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What kind of exercises is good for osteoporosis
- weight bearing (walk, dance, jog)
- yoga, pilates muscle strengthen
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Break in thoracic vertebre can cause
restrictcive lung disease
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break in lumbar vertebre can cause
abdominal pain and constipation
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hip fractures mortality rate
8-36%
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What conducts and sends signals from the brain to the entire body
axons on nerves
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What type of axons are fast and efficient
myelinated
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What is the most common cause of Peripheral nerve disease
Diabetes
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what percent of DM overall have peripheral neuropathy
50%
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What percent of DM that have had it for 15 years have peripheral neuropathy
80%
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Name two primary patho mechanisms of peripheral nerve disease
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What patho mechanism of peripheral vascular disease occurs when the axon of the neuron is damaged
axonal neuropathy
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what patho mechanism of peripheral vascular disease occurs when schwann cells that produce myelin is damaged
demyelination neuropathy
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WHAT DAMAGES THE AXON IN AXONAL NEUROPATHY
transection of the neuron through trauma, inflammation, or ischemia
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What happens to the neuron after it is damaged in axonal neuropathy
the distal portion of the axon and myelin sheath begin to disintegrate
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What is disintegrated axons and myelin sheaths called
myelin ovoids
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After macrophages are recruited and clean up nonfunctional debris during axonal neuropathy, how fast does axons regenerate
one millimeter per day
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what guides the regenerating axon and prunes it as it makes its way to the distal transected end
schwann cells
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What happens if the axon cannot regenerate enough to reach the distal transected end
it forms a pseudotumor called a traumatic neuroma
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What does a traumatic neuroma consist of
painful nodule of proliferated axonal and schwann cells
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What happens when damage of neurons occurs more rapidly than production in Axonal neuropathy
progressive loss of neurons
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WHat is the myelin like that is regenerated following demyelination neuropathy
not as thick and slower nerve impulses
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What neuropathy occurs when schwann cell with its myelin sheath is destroyed but the axon is preserved
demyelinating neuropathy
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What pattern is most often associated with diabetic peripheral neuropathy
ascending distal symmetric sensorimotor polyneuropathy
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In what direction does neuron damage occur in peripheral neuropathy
- distal extremities first
- feet to legs to hands (stocking and glove)
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What theory of diabetes prevalance is supported by many
metabolic and vascular involvement
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What 2 things does hyperglycemia cause damage to in DM
- production of AGEs which activate and recruit inflammatory mediators
- NADPH is depleted increasing damaging free radicals
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What causes vascular damage in DM patients
HLD that causes dec blood flow and ischemia to peripheral nerves
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Most common morphologic finding in DM neuropathy
nerve biopsies show dec axon amount and axons that are there have degenerated myelin sheaths
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S/S of peripheral nerve disease
- Sensory deficit (numb, loss of pain/sensation)
- Paresthesias (pain by damaged nerves)
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Where does paresthesias usually occur in DM neuropathy and when does it get worse and how does it improve
- toes or feet
- worse with rest and improves with walking
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WHat percent of pts with DM experience autonomic nervous system dysfunction
30%
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S/s of autonomic nervous system dysfunction in pts with DM
- incomplete emptying of bladder
- postural hypotension
- erectile dysfunction
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How can lack of sensation and decreased circulation be an issue for pts with DM w/ peripheral neuropathy
- foot and ankle injuries
- chronic skin ulcers
- delayed healing
- microvascular disease resulting in amputation
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Name 3 ways DM neuropathy is treated
- foot care
- tight control of BG levels
- Neuropathy-related pain management
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What is considered more effective than opioids in treating DM neuropathy related pain
- antidepressants (amitrptyline)
- anticonvulsants
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Name 4 things AGEs cause in DM neuropathy
- proinflammatory effects
- procoagulant activity
- inc vascular permeability
- adhesion molecule expression and monocyte recruitment
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What does Inc BG metabolism in the cell cause an accumulation of
sorbitol
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How does sorbitol s/c to inc BG metabolism cause damage
causes metabolic dysfunction leading to damage from ROS
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What is the main issue with vascular damage s/c to DM neuropathy
ischemia to distal extremities hindering nourishment of sensory nerves leading to damage and disintegration
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What meds used to treat pain s/c to DM neuropathy are thought to act on central perception of pain
- Amitryptiline and desipramine (TCA)
- Seratonin and duloxetine
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What anticonvulsant med uses to tx DM neuropathy is thought to be a presynaptic inhibitor of glutamate, substance P, and calcitonin gene-related peptide
Gabapentin
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Have you found any specific disease states or meds that may be linked to development of peripheral nerve disease
- Autoimmune disorders including:
- Sjogren's syndrome
- Lupus
- RA
- ESRD
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How does autoimmune diseases lead to peripheral nerve disease
inflammation caused by there diseases spread directly into surrounding nerve fibers causing nerve compression and entrapment leading to nerve injuries
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How does ESRD lead to peripheral nerve disease
Toxins usually filtered out by kidneys can accumulate and can cause nerve tissue damage
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What is the most common cause of dementia in the elderly
Alzheimers disease (AD)
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What disease is characterized by severe memory loss, behavior disorders, motor difficulties, language defecits, problems with visuospatial orientation, personality, and paranoia
AD
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How many people in US are currently dx with AD
5 million
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How much is AD expected to grow in the US by 2050
115 million
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How many years does AD double when it is measured from age 60
5 years
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What age and percent of population is AD prevalent
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Over how long does AD progress (worsen)
5-10 years
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Two forms of AD
- early onset (familial)
- Late onset
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Which form of AD is most common (95% of all cases)
Late onset
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What mutation directly leads to EOAD
APP, PSEN1 and PSEN2 via Mendellin way
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WHat gene is found to be a clear risk for LOAD
e4 allele at ApoE locus on chromosome 19
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What two protein buildups characterize AD
- neuritic plaques
- neurofibrillary tangles
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What are plaques made up of in AD
B-amyloid peptide (AB) deposits
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WHat is considered a KEY COMPONENT OF DEGENERATION of neurons IN AD
B amyloid peptide (AB deposits)
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WHat are tangles made up of in AD
modified Tau protein
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WHat happens to Tau protein in AD
loses its ability to bind with microtubules, shifts to somatic-dendritic distribution, and becomes hyperphosphorylated
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What correlates with the degree of dementia found in pts with AD
number of tangles
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What is the initiating event of AD
AB generation
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Why is AB more linked with AD than other neurodegenerative diseases even more so than tau
no AB deposits are found in other disease states, only presence of Tau
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What mutation causes various alterations of AB which lead to FAMILIAL form of AD
APP (amyloid precursor protein)
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mutation of the gene that forms tau leads to what
frontotemporal lobar degeneration, NOT AD
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What chromosome does APP gene coding lie on
21, same as DS
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What happens when APP is cleaved by B-amyloid converting enzyme (BACE) and y-secretase
forms harmful AB peptides leading to tangles and plaques in AD
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What biomarkers are associated with AD can be found years before any symptoms occur
- hyperphospholated tau
- reduced AB in CSF
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Morpho changes in AD
- cortical atrophy
- widening cerebral sulci in frontal, temporal, parietal lobes
- compensatory ventricular enlargement (hydrocephalus)
- MAIN: PLAQUES & TANGLES
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What are focal groups of dystrophic neurites around amyloid cores composed mainly of AB peptides
Plaques
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What size do plaques range from in AD
20-200 um in diameter
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WHere can diffuse plaques be found in AD
- hippocampus
- amygdala
- neocortex
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Difference between neuritic and diffuse plaques in AD
neuritic still have amyloid core but no dystrophic neurites surround it
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Where can neuritic plaques be found in AD
- cerebral cortex
- basal ganglia
- cerebellar cortex
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What are neurofibrillary tangles made up of
Tau
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Where is Tau normally found in AD
- Cortical neurons (entorhinal cortex)
- pyramidal cells of hippocampus, amygdala, basal forebrain, raphe nuclei
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The insoluble tangles of AD remain for how long
even after neuronal death
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What is another disease in which tangles are found that is not AD
cerebral amyloid angiopathy
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Where are amyloid deposits found in cerebral amyloid angiopathy
walls of blood vessels in the brain
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HALLMARK of AD s/s
progressive memory loss
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2 Early signs of AD and 2 signs that follow initial symptoms
- forgetfulness
- memory disturbances
- visual spatial impairment
- language disorders
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ATypical s/s of AD
cognitive impairment rather than memory
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Later s/s of AD
- incontinence
- deficit of learned motor skills
- inability to walk or talk
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What hypothesis is thought to dictate patho of AD
amyloid cascade
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What clinical trial is being studied for AD treatment
anti-inflammatory immunotherapy directed against amyloid B1-42to reduce brain amyloid
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What is the deadliest form of brain tumor
Glioblastoma (GBM)
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What is the survival rate of GBM
2 year survival rate of 3-5%
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What accounts for 80% of primary brain tumors in adults
infiltrating astrocytomas
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When and how do astrocytomas typically present
late adulthood (4-6 decade) as a primary lesion
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GBM progression from low-grade gliomas is common in which population
younger
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How do gliomas form
arise from progenitor cell that preferentially differientiates one of the cellular lineages
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Name 3 lineages of gliomas
- astrocytoma
- oligodendroglioma
- ependymomas
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Where does GBM most often occur
cerebral hemispheres
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Where else can GBM occur
- brainstem
- cerebellum
- spinal cord
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4 molecular types of malignant gliomas
- classic
- proneural
- neural
- mesenchymal
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What is the classic subtype mostly made up of
primary glioblastoma
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What is classic subtype glioma attributed to
- mutation of PTEN suppressor gene
- deletion of C10
- Amplification of EGFR oncogene
- deletion of CDKN2A TSG
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What do the other glioma subtypes attributed to
RB and P53 inactivation
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What feature is present in 80-90% of primary glioblastomas
RB and P53 inactivation causing uncontrolled cell growth
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What is associated with proneuronal subtype of secondary glioblastoma
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What is associated with neural subtype of glioblastoma
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What is associated with mesenchymal subtype of glioblastoma
NF1 on C17 causing DEC NF1 protein
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Two MAJOR hallmarks of cancer (glioblastoma)
- sustained proliferative signaling
- evasion of growth suppressor
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What mutations drive cells from G1 to S phase without proper checkpoint assessment in glioblastoma
PDGFRA and EGFR amplification resulting in INC receptor kinase signaling
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WHat is the only molecular characteristic that provides ay prognostic significance
IDH1 mutation (better outcome than wild type mutation)
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Morpho Hallmark of GBM
soft, partially necrotic mass
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S/s of well-differientiated astrocytomas
asymptomatic, stable or slowly grow over the years
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s/s of glioblastoma as a result of RAPID growing tumor with high histologic grade
- HA and SZ (50%)
- Memory loss
- weakness
- visual sx
- language issues
- sognitive/personality changes
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What can cause papilledema in glioblastoma
swelling of optic nerve due to INC pressure in brain
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What do CT/MRI scans show of GBM
bright, ring shaped lesion (halo)
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What causes halo sign of glioblastoma on CT/MRI
abnormally leaky vessels permeable BBB
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WHen can pathological dx of GBM be made
after surgical resection of tissue
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Current standard of care for GBM
- surgical resection
- combo of radiation/chemo
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For subtotal or unresectable GBM what is tx option
external beam radiation and gamma knife therapy
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What is oral chemo of choice for glioblastoma
temozolomide
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How does temozolomide act when used for glioblastoma tx
targets infiltrative component of tumor to slow progression
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What has been proposed to tx glioblastoma normally difficult due to BBB
nanocarriers
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WHat has been linked with dec risk of glioblastoma
- hx of NSAID use
- asthma
- allergies/high IgE levels
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WHat med has inc risk of developing glioblastoma
antihistamine
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IF BBB is infiltrated with immune cells, why don't they attack the abnormal glioblastoma, and what do they do instead
- GBM is highly immunosuppressive
- Since BBB is breached, glioma can metastizes
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What has further research focused on to defeat GBM
inhibit immunosuppressive qualities of GBM so the proinflammatory state can allow immune system to eliminate the GBM
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I was interested in the treatment of the traumatic neuromas that can
form when nerve regeneration cannot fully complete, as I had never heard
of them before. Are these the primary cause of the pain patients
experience in neuropathy, and is that pain to be managed medically with
the antidepressants/anticonvulsants as you mentioned, or are they large
enough to be removed surgically or otherwise?
- The traumatic neuromas that occur with the nerve regeneration would not necessarily be considered malignant. If the tumor is causing pain, bleeding, increased neurologic deficit, disfigurement, or suspicion for malignancy would all be indications for surgical removal. It is important to remember that surgery can increase neurological deficits so if the tumor is not causing undesirable symptoms nor has a suspicion for malignancy the best course of action might be observation. Any tumor
- that has a clinical change should be considered for suspected malignancy. These tumors are not necessarily the cause for the pain
- experienced by these patients. The pain is from the degenerated nerve being unable to innervate the distal extremity as it should.
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wondering if there is a way to differentiate between familial AD and sporadic AD?
Familial AD is associated with the genes APP, PSEN1, and PSEN2. However, the gene responsible for sporadic AD is APOE.
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