Clinical Applications Week 1 Flashcards
Listeriosis
serious food poisoning
listeria monocytogenes
mechanism:
ActA → hijacks Arp2 /3 → actin rapidly propels bacteria → protrudes to adjacent cell to infect
Symptoms:
- fever
- muscle aches
- nausea
- diarrhea
Alzheimer Disease
Tau: MAP, multiple microtubule binding domains to form bundles
TAU → phosphorylated and dissociates from microtubule in neuron → aggregates to form neurofibrillary tangles → neuronal degeneration
TAU → phosphorylated and dissociates from microtubules → promotes microtubule disassembly
Retrograde transport of toxins
use DYNEIN to transport toxins to neuronal body
- clostridium tetani
- herpes simplex
- poliovirus
- rabies virus
Asthenozoospermia
causes infertility
bent sperm flagella → poor motility
9 + 2 arrangement is disrupted in microtubules
- mutations in inner and outer dynein protein
Primary Ciliary Dyskinesia
Symptoms:
- chronic respiratory tract infections
- infertility/ectopic pregnancy
- hearing loss
- abnormally positioned organs (Kartagener syndrome- mirror image reversal of organs)
Kartagener Syndrome
mirror image reversal of organs
caused by primary ciliary dyskinesia
Epidermolysis Bullosa Simplex
- mutations in keratin
- cell-to-cell contacts are weakened
epithelial tissue → blistering and trauma from mechanical forces
Hutchinson Gilford Progeria Syndrome
mutation in LMNA
causes premature aging in infants
Emery-Dreifuss Muscular Dystrophy
mutation in lamin binding protein or LMNA
Symptoms:
- normal intelligence
- atrophy of muscles
- stiff joints
- absent tendon reflexes
- toe walking (shortened achilles)
- abnormal cardiac rhythms
Dunnigan Lidodystrophy
mutation in lamin binding protein or LMNA
- variable loss of fat from extremities/trunk
- excess subq fat in chin/supraclavicular region
- begins at puberty
Multiple Sclerosis
chronic autoimmune demyelinating of the CNS
- peak age 20-40
- Myelin sheath prevents current leakage and improves signal propagation; important to maintain speed
Symptoms:
- sensory loss/paresthesia
- optic neuritis (inflammation of optic nerve causing eye pain/blurred vision)
- weakness, diploplia, ataxia
- Lhermitte sign (electrical sensation down spine when neck is flexed)
- Bladder disfunction
- Cognitive disfunction
Guillain-Barre Syndrome
Autoimmune disorder
- Molecular mimicry related demyelination in PNS
Symptoms:
- Proximal muscle weakness (rising from chair, combing hair, stairs)
- Rapidly evolving ascending paralysis
- Afebrile (not feverish)
- Antecedent infection (enteritis or upper respiratory/viral infection)
- Absence of reflexes
illness script
epidemiology- age/risk factors
pathophysiology- why
key clinical features- time course, signs, symptoms
diagnostic data
treatment
homocystinuria cause
cystathionine beta-synthase deficiency
- autosomal recessive
- can also be acquired- diet lacking B12, B6, foliate
homocystinuria epidemiology
both males and females, but occurs more often in males
identified on state newborn screening labs
1/100,000-300,000
Homocystinuria progression
- unaffected at birth with disease progression if untreated
homocystinuria key clinical features- musculoskeletal
- marfanoid body habitus
- not necessarily tall
- hypotonia
- baby not meeting milestones
- osteoporosis
- especially increased risk after menopause
- pectus carinatum/excavatum
homocystinuria key clinical features- CNS
- developmental delay
- intellectual disability
- psychiatric/behavioral disorders
- seizures
homocystinuria key clinical features- opthalmologic
- INFERIOR lens dislocation
- myopia
homocystinuria key clinical features- cardiovascular
- thromboembolic disease
- prone to DVT and PE
- extensive atheromas at young age
- cerebrovascular disease
- myocardial infarction
homocystinuria key clinical features- dermatologic
- fair complexion with sparse blonde hair
- hyperpigmentation/vitiligo if POC
- livedo reticularis- lacy skin pattern, not raised
Homocystinuria basic science
autosomal recessive
cystathionine beta synthase mutation → cystathionine beta synthase enzyme deficiency → increased levels of homocysteine
- homocysteine binds to endothelial cells
- proinflammatory cytokines
- inflammation
- ischemia
- blood cloths
- homocysteine replaces cysteine
- in eye- zonular fibrosis → downward dislocation
Homocystinuria diagnosis
increased levels of homocysteine in urine and serum
increased levels of methionine in serum
homocystinuria differential dx
marfan syndrome
homocystinuria treatment
- low protein (methionine) diet
- B6, B12, foliate, betaine supplementation
- IV cysteine supplementation to infants
- genetic counselling
- multidisciplinary team approach
Marfan’s Syndrome Epidemiology
both males and females
phenotype becomes more apparent with age
2-3/10,000
Marfan’s syndrome key clinical features- cutaneous
thin, highly distensible skin
linear striae
Marfan’s syndrome key clinical features- ocular
myopia
UPWARD AND MEDIAL lens dislocation
Marfan’s syndrome key clinical features- cardiovascular
- Mitral valve prolapse
- may hear a click between systole and diastole
- aortic root dilation
Marfan’s syndrome key clinical features- musculoskeletal
- long, narrow extremities
- tall stature
- longer wingspan than height
- chest wall asymmetries
- acachnodactyly (long, slender fingers)
- thumb sign
- wrist sign
- joint hyper-extensibility
Marfan’s syndrome key clinical features- respiratory
blebs, bullae- predisposed to spontaneous pneumothroax
Marfan’s syndrome basic science
autosomal dominant
FBN1 mutation resulting in DEFECTIVE FIBRILIN-1
fibrillin loss → increased TBFbeta → decreased vascular muscle, extracellular matrix → compromised strength, elasticity
Marfan’s Syndrome diagnosis
Skeletal abnormalities
personal/family history of aortic aneurism
Differential dx: homocystinuria, ehlers-danlos
Marfan’s syndrome diagnostic tests
echocardiogram, x-ray, MRI
Marfan’s syndrome treatment
genetic testing
multidisciplinary team approach
monitor aorta/valvular abnormalities
counsel to limit participation in contact sports/competitive athletics/heavy lifting
Ehlers-Danlos Syndrome epidemiology
both males and females
broad range of presentations
1/5-20,000
Ehlers-Danlos key clinical features
6 subtypes
- type 3
- hyper-mobility
- joint instability
- classical (type 1 and 2)
- joint instability and hyper-extensible skin
- vascular (type 4)
- easy bruising
- muscles and organs prone to rupture
- mitral valve prolapse
- flat feet, kyphosis, scoliosis
- tendon sprains, joint dislocations/subluxations
- impaired would healing
EDS Basic Science
- inheritance: varies by subtype
- Classical (types 1 and 2)
- autosomal dominant (50% de novo)
- COL5A1/COL5A2 mutation → type V collagen mutation
- type V collagen interacts with type I collagen
EDS diagosis
clinical exam
beighton score
genetic counseling (not available for type 3)
differential dx:
- marfan’s syndrome
- OI
- Larsen syndrome
- include craniofacial abnormalities
EDS treatment
treat/manage pain with NSAIDs
physical therapy
orthotics/casting
education/counseling
Osteogenesis imperfecta epidemiology
both males and females
symptoms apparent from childhood
range from fatal neonatally to mild
1/ 20,000
OI key clinical features
- multiple fractures +/- bone deformities
- short stature
- blue sclera
- dental imperfections
- hearing loss
Type I
- mild bone fragility
- minimal fractures before walking
- normal stature
- higher risk of hearing loss/osteoporosis as adults
Type III-IX
- Type III is most severe that is compatible with life
- moderate to severe rate of fracture
- short stature
- hearing loss/osteoporosis later in life
Type II
- LETHAL
- fractures in utero
OI basic science
autosomal dominant
COL1A1/COL1A2 mutation
→ triple helix defect → decreased synthesis of Type I collagen
OI diagnosis
- clinical signs
- family history
- x-ray skeletal survey
- dermal fibroblast culture
- may be less of normal collagen or abundant abnormal collagen
- differential dx
- CHILD ABUSE
- ricketts
- osteomalacia
OI treatment
Biphosphate treatment
surgical repair
physical therapy
Alpha-1 Antitrypsin deficiency epidemiology
both males and females
child with cholestasis and poor growth
young adult with emphysema +/- cirrhosis
AAT clinical features
- infant/child with cholestasis/poo growth
- younger adult patient with emphysema in a non-smoker
- more pronounced at base of lungs
- earlier/more severe if a smoker
- adult with cirrhosis
- portal hypertension/esophageal varices
- jaundice
- hepatocellular carcinoma
- decreased synthesis of coagulation factors
- panniculitis
- inflammation of subq fat
AAT basic science
autosomal dominant
SERPINA1 mutation → decreased or absent AAT → increased activity of proteases → increased breakdown of elastic → decreased elasticity of alveoli → COPD
misfolded ZAAT in liver → polymerization of ZAAT → iclusion bodies in hepatocyte ER → cirrhosis
AAT diagnosis
serum AAT level
gene sequency
liver biopsy
differential dx
- COPD
- cystic fibrosis
- interstitial pneumonia
AAT treatment
Monitoring:
- pulmonary functioning testing
- routine liver functioning testing
- liver ultrasound
therapy:
- avoid active/passive smoke exposure
- follow COPD guidelines for therapy
- pulmonary rehab
- nutritional support
- IV A1AT
- May require liver/lung transplant
Saxitonin poisoning
- Saxitonin: produced by algae and found in shellfish
- voltage-gated sodium channel blocker
- blocks action potentials in neurons/muscle cells
Symptoms:
- inactivation of sympathetic nerves: hypotension
- paralysis of diaphragm → death
- dyspnea
- headache
- nausea/vomiting/diarrhea
- generalized weakness
- hyporeflexia
- tingling/numbness
- around mouth/neck/face
Tetrodotoxin Poisoning
- Voltage gated sodium channel blocker
- affects nerve, skeletal, cardiac muscle
- comes from newts, shellfish, PUFFERFISH
- mild intoxication: euphoria, paresthesia around lips
Symptoms:
- nausea
- vomiting
- diffuse extremity weakness
- loss of reflexes
- bilateral ptosis
- bifacial weakness
- death from respiratory failure/cardiac arrhythmia
Hypokalemic Periodic Paralysis
- painless total body muscle weakness
- usually due to potassium shift intracellularly
- autosomal dominant
- mutation in L-type VGCC in muscle
- leads to activation of Na+-K+-ATPase
- potassium pumped into cell → less in serum
- membrane HYPERPOLARIZES (becomes more negative)
- muscle cells become less reactive to stimuli
- leads to activation of Na+-K+-ATPase
- Clinical presentation:
- onset: adolescence
- transient generalized weakness sin arms/legs after exercise or carbohydrate intake
- treatment: PO potassium
Symptomatic hyperkalemia
older age due to chronic kidney disease, DM, CFD, medications
Hyperkalemic Periodic Paralysis
- Mutation in SCN4A (voltage gated sodium channel at neuromuscular junction)
- resting membrane potential gets MORE POSITIVE (depolarizes)
- when it gets above threshold potential, a muscle that has depolarized and contracted won’t be able to repolarize to allow another contraction
- Clinical presentation:
- muscle weakness
- flaccid paralysis
- dyspnea
- nausea/vomiting
- paresthesia
- peaked T-waves on ECG
- cardiac arrest
- Treatment:
- IV calcium gluconate
- calcium raises threshold and reduces firing
- albuterol
- insulin
- albuterol and insulin activate Na-K-ATPase and put potassium back into cells
- Glucose/Carbohydrate PO
- IV calcium gluconate
dermatophagoides pteronyssinus
common dust mite
- inhaled fecal pellets contain serine and cysteine peptidases
- cleave occludins and ZO-1
- compromise TIGHT JUNCTIONS of respiratory epithelium
- Clinical presentation:
- wheezing
- SOB/chest tightness
- non productive cough
- cleave occludins and ZO-1
Clostridium perfringens
pathological agent found in meats
disrupts TIGHT JUNCTIONS
- enterotoxin binds claudins to prevent incorporation into tight junction in the epithelia of the intestines
- causes diarrhea
hypomagnesemia renal disease
progressive renal disease with characteristic magnesium wasting, progressive renal failure, hypercalciuria and nephrocalcinosis associated with severe ocular abnormalities
mutation in CLDN19
Ovarian cancer
beta catenin: transcription factor to activate genes promoting cell growth and proliferation
- migrates to the nucleus → mutations can promote its role as a transcription factor
- clinical presentation:
- bloating
- constipation
- increased urination
- early satiety
- family history
- often misdiagnosed as IBS
pemphigus vulgaris/foliaceus
autoimmune disease affecting DESMOSOMES
intraepidermal blistering due to acanthyolysis (adjacent epithelial cells pull apart)
- pemphigus vulgaris
- antibodies against desmoglein 3
- MUCOUS MEMBRANES AND EPIDERMIS
- antibodies against desmoglein 3
- pemphigus foliaceus
- antibodies against desmoglein 1
- expressed in desmosomes of SCALP AND FACE
- antibodies against desmoglein 1
bullous pemphigoid
subepidermal blistering
antibodies agaisnt: dystonin or type XVII colalgen
- blisters usually do not rupture
- unblistered skin peels and wrinkles when pressure is applied
dystrophic epidermolysis bullosa
mutation in type VII collagen
basement membrane separates from underlying tissue
- lifting off as a sheet is less severe than cells themselves separating
Cholera toxin
vibrio cholera
Mechanism: inhibits GalphaS GTP-ase activity (causing it to stay on, because hydrolysis of GTP turns off) → increased levels of cAMP
GalphaS stimulates Cl- and water secretion
Symptoms: severe diarrhea
Pertussis toxin
mechanism: inactivates GalphaI such that it cannot inhibit adenylyl cyclase → activity of cAMP increases
→whooping cough
Transfusion-Related Acute Lung Injury (TRALI)
characterized by sudden, acute respiratory distress during or within six hours or a blood component/product being administered
- dyspnea and tachypnea, SpO2<90%
- bilateral pulmonary edema unassociated with heart failure
- recipient neutrophils are activated by donor-derived antibodies targeting human leukocyte antigens or human neutrophil antigens
Organophosphate poisoning
caused by acetylcholinesterase inhibition
acetylcholine increases at cholinergic neuroeffector junction
causes: drugs, insecticides
Symptoms: SLUDGEM
- salivation
- lacrimation
- urination
- defecation
- gastrointestinal upset
- emesis (vomiting)
- miosis (unable to focus/fixed close vision; ciliary muscles contracted)
- bradycardia/wheezing (smooth muscle contracted in lungs)
Fentanyl toxicity
pinpoint pupils
Respiratory distress
