Clinical Correlations Flashcards
What are muscular dystrophies?
Genetic conditions that cause progressive weakness and atrophy of skeletal muscles, starting in childhood
What is the most common muscular dystrophy and what are its characteristics?
Duchenne muscular dystrophy (DMD)
X-linked recessive mutation of gene encoding dystrophin
Dysfunctional dystrophin leads to uneven transfer of force through sarcolemma to external lamina and endomysium during contraction.
Leads to weaker contractions and damage to sarcolemma and external lamina
Damage to EL also damages satellite cells - tissue less able to repair and regenerate, death of muscle fibers and satellite cells
What happens within a few days after minor damage to skeletal muscle repair?
Satellite cells activate, proliferate, and differentiate into myoblasts
Myoblasts align and fuse end to end to form myotubes and myotubes fuse side to side to form muscle fibers
What occurs with satellite cells with age or injury?
Number of satellite cells decreases with age - slower healing as age increases
Muscle injury damages external lamina usually damages/kills satellite cells - intact EL is important for muscle cell repair
If damage to skeletal muscle fibers is extensive, what occurs?
Fibers not repaired and eventually replaced with scar tissue and fat
Why does cardiac muscle tissue not regenerate after cell damage?
No satellite cells
Dead cells replaced with collagenous CT scar tissue
What occurs with the tau protein in patients with Alzheimer’s Disease?
Hyperphosphorylation of tau protein causes it to aggregate in an insoluble form
Makes tau protein unable to bind to microtubules - they become unstable and start disintegrating
Unbound tau forms clumps, neurofibrillary tangles, that disrupt cell function and can lead to neuronal death
What causes dendritic spines to decrease in number?
Dendritic spines decrease with age and with poor nutrition
Patients with trisomy 21 or trisomy 13 also have fewer dendritic spines
What do some viruses use to travel from neuron to neuron in CNS?
Viruses like HSV and rabies use retrograde transport
Also method that toxins are transported from body periphery to CNS
What are most primary brain tumors in adults derived from?
Fibrous astrocytes
How often does the process of PNS axon regeneration occur?
3-4 mm/day
Are tracts in the CNS able to regenerate?
No
What is hyperuricemia?
Elevated uric acid
Deposition of sodium urate crystals
Caused by:
Decreased renal clearance of urate - renal insufficiency and metabolic acidosis
Increased urate production - hemolytic disease and chemotherapy
What is gout?
Recurrent attack of inflammatory arthritis
Deposition of sodium urate crystals in the joints of the extremities
Triggers an inflammatory response with pain and join swelling
Can progress to acute gouty arthritis
What are kidney stones?
Common in patients who suffer gout
Deposition of uric acid stones in the kidney - uric acid urolithiasis
What is allopurinol?
Analog of hypoxanthine converted to oxypurinol by xanthine oxidase
Inhibit xanthine oxidase and conversion of hypoxanthine and xanthine to uric acid
Hypoxanthine and xanthine more soluble than uric acid - eliminated in urine
Reduces uric acid formation
What is the rare hereditary condition that presents with high levels of orotic acid in the urine and hypochromic megaloblastic anemia?
Orotic aciduria
High levels of orotic acid in urine causes crystalluria
Hypochromic megaloblastic anemia - unresponsive to B12 and folic acid
Growth retardation
Neurologic abnormalities
What is severe combine immunodeficiency syndrome (SCID)?
Group of immune disorders impacting both B cell and T cell function
15% of cases due to mutation in adenosine deaminase
Adenine metabolites build up
Accumulation of dATP inhibits ribonucleotide reductase
Conversion of NDPs to corresponding dNDPs blocked
Lack of purine and pyrimidine deoxyribonucleotides block DNA replication
Inability to replicate DNA prevent cell proliferation events required for effective immune response
Alternatively, adenine metabolites directly toxic to lymphocytes
What occurs with inhibition of thymidylate synthase?
Blocks de novo dTMP synthesis
Reduced dTTP available for DNA synthesis and blocks cell proliferation
What is 5-fluorouracil?
Analog of uracil
Cancer treatment for colon carcinoma
For dermatology uses - topical for actinic keratosis
What is methotrexate?
Folate analog
Used in treatment of various cancers, severe psoriasis, and sever rheumatoid arthritis
Inhibits dihydrofolate reductase
Lack of N5N10-methylene THF inhibits thymidylate synthase
Lack of pyrimidine synthesis blocks cell proliferation
What is Lesch-Nyhan syndrome?
Hereditary syndrome
Severe or complete deficiency of HGPRTase activity
Results in hyperuricemia - causes tiny, orange crystals of sodium urate in infant’s diapers
Also results in uric acid stones, intellectual disability, and self-injurious behavior (biting fingers)
What drug can help with fungal infections by fungi like Cryptococcus neoformans? Caused headache, nausea, fatigue, and altered mental state
Flucytosine
Systemic fungal infection prevalent in those with compromised immune systems (AIDS, patients on immunosuppressants)
Flucytosine (5-fluorocytosine) is an analog of cystine. Fungi express cytosine deaminase (humans do not). This enzyme converts cytosine/5-fluorocytosine to 5-fluorouracil which is then converted to FUMP. 5-fluorocytosine is toxic to fungi and relatively non toxic to humans
Chronic Granulomatosis Disease
Deficiency in NADPH oxidase in phagocytes
Leads to recurrent infections because NADPH oxidase is activated in response to bacterial infection
Where is iron found in the body?
Iron found in tetrapyrroles (heme, cytochromes)
Bound to ferritin (cell storage)
Bound to transferrin (blood transport)
What are diseases leading to iron overload?
Hereditary hemochromatosis
Thalassemia (alpha and beta)
Sickle cell anemia
Frequent blood transfusions
What is hereditary hemochromatosis?
Mutation in HFE gene
Causes excessive iron accumulation in tissues and organs
Leads to organ destruction
How does thalassemia (alpha and beta) and sickle cell anemia lead to iron overload?
Leads to excessive destruction of red blood cells causing iron overload
What is amyotrophic lateral sclerosis (ALS)?
Deficiency in Cu/Zn-superoxide dismutase (SOD1) or misfolded Cu/Zn-SOD1 (sporadic)
Progressive degeneration of motor neurons
Leads to muscle weakness, paralysis, death within 3-5 years of diagnosis (adult onset)
Where is adipose CT present in a fatty heart?
Present along other parts of the heart’s surface other than in sulci/grooves or surrounding coronary vessels
What is thickness of epicardial fat on heart surface positively correlated with?
Obesity
Diabetes 2
Pro-inflammatory cytokine level
Vascular aging
Subclinical atherosclerosis
What occurs to contractile cardiomyocytes after a myocardial infarction?
During and following a MI, contractile cells in the affected part of the myocardium undergo necrosis
Rupture of membranes releases cardiac-specific troponin T and troponin I into surrounding ECM, which goes to tissue fluid, lymph vessels, and then blood
Serum troponin T levels are elevated about 2-3 hours following chest pain onset and peak 12-48 hours
What can cause an arrhythmia?
Abnormalities in the spatial distribution of gap junction in intercalated discs
What is ANP?
Atrial Natriuretic Peptide
What is BNP?
B-type natriuretic peptide
what are the serum levels of ANP and BNP during congestive heart failure?
Both are elevated
Heart still is beating, but is weak and cannot pump enough blood to meet oxygen demands
ANP and BNP increase kidney filtration rate by natriuresis (increased sodium excretion) and diuresis (increased fluid excretion)
Both ANP and BNP are vasodilators
What is BNP a more sensitive biomarker of?
Heart failure
Especially left ventricular dysfunction because levels of BNP increase as failure worsens
Used to track treatment progress
What is SARS-CoV-2 infection associated with?
Can trigger myocarditis (inflammation of the myocardium)
Estimates of incidence vary greatly, but it occurs even in asymptomatic of mildly symptomatic patients (including children and athletes) and can occur following COVID-19 vaccination
Also associated with:
Fibrin clots and microclots (platelet clots) in myocardium capillaries
Recruitment of megakaryocytes to myocardium
Clotting of myocardium capillaries can cause localized tissue damage (ischemia)
What does pacemaker cells and heart rate have to do with each other?
Number of SA nodal cells (pacemaker cells) determines maximum HR
What does SA nodal cell do with age?
SA nodal cell number decreases with age - progressive slowing of conduction velocity and voltage loss
Highest number of SA nodal cells in fetuses - this is why fetal HR is so high
Reduction in SA nodal cell number drives the decrease in max (and target HR) that occurs with age
This is a reduction in intrinsic heart rate - it happens whether sedentary or active, even in elite athletes
What are Purkinje fibers vulnerable to?
Vulnerable during infection of the endocardium (ex. infective endocarditis (microbial infection of the endocardium))
Subendocardium is very close to the chamber lumen and Purkinje fibers are critical for heart function
What does having extra glycogen make Purkinje fibers more resistant to?
Resistant to hypoxia vs contractile cardiac cells
Valvular Degeneration
Valves with comprised structure have compromised function
Valvular diseases often result in inefficient blood flow - patent valve (too much flow when shut), stenosis (too little flow when open), and valvular regurgitation (backflow)
Consequence of valvular degeneration - cardiac muscle tissue is often weakened from the extra strain caused by inefficient blood flow through the heart
What is important about pericytes and how they can differentiate into fibroblasts, smooth muscle cells, and endothelial cells?
Important role during blood vessel formation and repair - these are the cells you would need to synthesize a new endothelium, tunica media (smooth muscle), and tunica externa (CT)
What are continuous capillaries necessary for given their solid walls?
Necessary for proper function of the blood-brain barrier and blood-gas barrier (alveolar wall in lungs)
What are varicose veins?
Weakened or incompetent valves allow blood to pool or backflow in veins
Valves stays partially open
Instead of being pushed toward the hear, blood backflows (gravity)
Blood settles in valve leaflets, pools, and causes bulging
What is often used as a coronary artery bypass graft?
Great saphenous vein
Because it has thick and muscular walls and is of similar size to coronary arteries
How does edema relate to lymphatic drainage?
Tissue edema occurs when the capacity for lymphatic drainage is exceeded:
Hydrostatic pressure is too high
Oncotic pressure is too low
Lymph capillaries are damaged or blocked (lymph flow impeded)
What occurs with patients with low levels or malformed von Willebrand factor?
Have bleeding problems
Clots either take longer to form or form incorrectly
Leads to easy bruising, heavy menses, and bleeding gums
What is von Willebrand disease?
Most common hereditary blood clotting disorder
Affects 1% of the population worldwide, affects men and women equally
Severity of bleeding varies by subtype
What are the effects of aging on the aorta?
The number of elastic lamellae in the tunica media increases from birth to adult age
What are the effects of aging on all elastic arteries?
Moderate intimal fibrosis - thickening of tunica intima by addition of collagen I fibers
Minor fragmentation of elastic lamellae (media) - elastin protein starts to break down and wear out
Acute tonsillitis
Infectious mononucleosis (mono)
Caused by Epstein Barr virus and spread via saliva
Fatigue and fever
Severe pharyngitis (inflammation of pharynx) usually with tonsillitis (inflammation of tonsils)
Lymph nodes also usually swollen and splenomegaly
DiGeorge Syndrome
Patients are born with cleft palate and have other distinct facial features
Leads to absence/hypoplasia of the parathyroid glands and the thymus
Lack of thymus causes severe T cell deficiency or complete absence of T cells. Patients lack a cell mediated immune response, resulting in frequent and recurring infections
Allergic and autoimmune manifestations
Higher risk of some autoimmune conditions
Absence of parathyroid glands cause issues regulating calcium (too low) and phosphorus (too high)
